Liver Cancers

From Mechanisms to
Management
Tim Cross
Daniel H. Palmer
Editors

123
Liver Cancers
Tim Cross • Daniel H. Palmer
Editors

Liver Cancers
From Mechanisms to Management
Editors
Tim Cross Daniel H. Palmer
Royal Liverpool University Hospital University of Liverpool
Liverpool Liverpool Early Drug Development Unit
Merseyside Liverpool
UK UK

ISBN 978-3-319-92215-7    ISBN 978-3-319-92216-4 (eBook)

https://doi.org/10.1007/978-3-319-92216-4

Library of Congress Control Number: 2018957857

© Springer Nature Switzerland AG 2019

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broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
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Dedicated to the Memory of Dr. CG ‘Harry’
Antoniades (1974–2018).
Foreword

There has been stunning progress in treating viral hepatitis over the last decade.
Despite that, the number of patients across the world with liver disease is increasing
annually, and in the United Kingdom, this has had a disproportionate and adverse
effect on younger patients, such that chronic liver disease in England is now the
second and fourth most common cause of years lost in women and men, respec-
tively. Almost all of the increase over the past two decades can be attributed directly
to the epidemic of obesity in first-world countries, although in many parts of the
world alcohol continues to play an important aetiological role. There is also a strong,
disproportionate effect of socio-economic deprivation on the prevalence of liver
disease.
So it was inevitable that the numbers of patients presenting with hepatocellular
carcinoma (HCC) would rise in parallel with those developing chronic liver disease.
The increased numbers presenting to liver specialists with primary liver cancer have
been almost overwhelming, while the change in the demographics underlying these
tumours has been striking. No more of the young male immigrant born in the
African or Asian continents with Hepatitis B virus acquired perinatally driving cir-
rhosis as we were taught. Now it is the elderly, slightly overweight, male diabetic in
the clinic who has never consumed alcohol to excess and who may not even have
cirrhosis.
These remarkable lifestyle-driven increases in cases presenting with hepatocel-
lular carcinoma have made clinicians and more recently basic scientists look more
closely at every aspect of the disease from the molecular pathways that precede
disease or modify the clinical course, through screening (still contentious) or early
detection to curative or palliative treatment and end-of-life care.
The proportion of patients that can be offered curative therapy is small but
increasing. Recent data suggest that this proportion is greater in those centres with
greater experience and turnover. The options for curative therapy are limited and by
no means novel but earlier diagnosis, better case selection, and more experience
mean that these older approaches (surgery or liver transplantation or both) are being
used more appropriately with improved outcomes. The many options for therapy
intended to halt or slow the disease for patients with more advanced disease have

vii
viii Foreword

also been used with increasing frequency and efficacy. But it is not clear which of
these approaches is best for which patients nor is it clear if these approaches have
additive benefit. Most centres report better survival now with non-curative therapy
than a decade ago, reflecting greater availability of these approaches and again bet-
ter selection based on growing experience. International meetings and the literature
now report on potential pathways for novel approaches to primary liver cancer.
Those who deal with primary liver cancers will often be the same clinicians that
are faced with benign tumours of the liver or with secondary malignancies.
HCC-UK was established 4 years ago to bring all of those interested in liver
cancer. The faculty for this volume: Liver Cancers: From Mechanisms to
Management are integral to HCC-UK and represent the best of UK specialist care
in the field, so that every aspect of our current knowledge and clinical practice is
covered.

Graeme Alexander
The Sheila Sherlock Liver Centre
The Royal Free Hospital
London, UK
Preface

There has been a well-documented rise in the prevalence of advanced liver disease
over the last few decades. The culmination of this has been an increase in patients
with cirrhosis and its complications. One of the most feared of these was hepatocel-
lular carcinoma (HCC). At one time, this diagnosis heralded a universally grim
prognosis, and the treatment options, particularly cure, in the absence of surgical
resection, was rarely achieved. But the development of new technologies and the
availabilities of new treatments, in particular, liver transplantation, have revolution-
ized treatment for these patients. Yet, the majority of patients still remain undiag-
nosed until the disease is at an incurable stage. For these patients, provided that their
liver function and performance status permits, there are treatments that can extend
life, and novel treatments appear tantalizingly close, in particular immune therapies.
In addition, forms of targeted radiotherapies are appearing on the horizon (e.g.,
stereotactic body radiotherapy – SBRT) and could provide further treatment options
for clinicians. So as the horizons for HCC are broadening so are treatment options
for cholangiocarcinoma and other forms of malignancy that involve the liver. The
contribution to be made by different specialities in a multidisciplinary team involv-
ing surgery, transplantation surgery, hepatology, medical oncology, clinical oncol-
ogy, and palliative care is vital to ensure the best possible outcome for these patients
and cannot be overemphasized.
This book is aimed at the hospital specialist in training in the medical or surgical
specialities, nurse specialists, and consultants and researchers who just want an
approachable and usable management guide. The chapters have been written by
experts in their fields and focuses primarily on hepatocellular carcinoma whilst hav-
ing comprehensive sections on cholangiocarcinoma, neuroendocrine tumours, and
colorectal cancer liver metastases. Many authors are members of HCC-UK which is
a UK group of clinicians and researchers with an interest in HCC who wish to
improve the care and outcome for these patients. Professor Graeme Alexander must
be thanked for having the vision to set up this group, and the intention is to work
together to deliver management changing high-impact publications in the future.
There was some constraint on what could be included and so detailed chapters on
endoscopic therapies and radiotherapy will have to wait for further editions.

ix
x Preface

I am grateful to all the contributors for the time and effort they put into producing
their chapters and also to the production team at Springer in particular Maha and
Evgenia. Finally, this book is dedicated to the memory of Dr. CG ‘Harry’ Antoniades
who died suddenly this year. He was reader in medicine at Imperial College London,
St Mary’s Hospital. He was an exceptional clinician and researcher, as well as a
great friend and colleague. He will be deeply missed by all those who knew him. He
leaves behind his wife Rebecca (herself an oncologist) and two wonderful children
Amelie and Theo. Our thoughts and prayers are with them, and this book is a small
token to show the respect and esteem in which he was held.

Liverpool, UK Tim Cross

April, 2018
Contents

Part I Hepatocellular Carcinoma

1 The Epidemiology of Hepatocellular Carcinoma������������������������������������   3
Philip Johnson
2 Surveillance for Hepatocellular Carcinoma�������������������������������������������� 13
Eleanor J. Taylor and Ian A. Rowe
3 Roles of the Immune System in the Development
and Progression of Hepatocellular Carcinoma �������������������������������������� 23
João Maurício, Helen Reeves, and Caroline L. Wilson
4 Mechanisms of Disease: The Damaged Genome in HCC���������������������� 39
Matthew Hoare
5 The Role of Histology in Hepatocellular and Cholangiocarcinoma������ 59
Alberto Quaglia
6 Diagnosis and Staging of Hepatocellular Carcinoma (HCC)���������������� 67
Vinay Kumar Balachandrakumar, Nadya Fatima Jabbar,
David White, and Nicholas Stern
7 The Role of Liver Resection for the Treatment
of Hepatocellular Carcinoma�������������������������������������������������������������������� 83
Mikael H. Sodergren and Dinesh Sharma
8 Liver Transplantation for the Treatment
of Hepatocellular Carcinoma�������������������������������������������������������������������� 99
Aileen Marshall
9 The Role of Interventional Radiology and Image-Guided
Ablation in Primary Liver Cancer ���������������������������������������������������������� 109
Jen-Jou Wong and Nabil Kibriya
10 Transarterial Embolization Therapies in Hepatocellular
Carcinoma: Principles of Management �������������������������������������������������� 123
Tim Cross and Jonathan C. Evans
xi
xii Contents

11 Radioembolisation in Hepatocellular Carcinoma:

Principles of Management������������������������������������������������������������������������ 139
Bruno Sangro and Andrea Casadei Gardini
12 Oncotherapies for HCC���������������������������������������������������������������������������� 153
Alexa Childs and Tim Meyer

Part II Cholangiocarcinoma
13 Mixed Hepatocellular/Cholangiocarcinomas:
Current Perspectives and Management�������������������������������������������������� 169
Ray Tan, Alberto Quaglia, and Paul J. Ross
14 Epidemiology and Pathogenesis of Cholangiocarcinoma���������������������� 179
Stephen McClements and Shahid A. Khan
15 Diagnosis and Staging of Cholangiocarcinoma�������������������������������������� 187
Jessica R. Hale and Olusola O. Faluyi
16 Cholangiocarcinoma: From Mechanisms to Management�������������������� 199
Leonard M. Quinn, Nicholas Bird, Robert Jones, David Vass,
and Hassan Malik
17 Oncotherapies for Cholangiocarcinoma�������������������������������������������������� 213
Oliver Pickles and Yuk Ting Ma

Part III Neueoendocrine Tumours

18 Novel Treatments for Advanced Cholangiocarcinoma �������������������������� 227
Jenny Cotton, Angela Lamarca, Mairéad G. McNamara,
and Juan W. Valle
19 Making the Diagnosis of Neuroendocrine Tumour Disease ������������������ 245
Vandana M. Sagar, Mona Elshafie, and Tahir Shah
20 Treatment of Neuroendocrine Tumour Disease�������������������������������������� 259
Andrew R. Moore and Vincent S. Yip

Part IV Colo-Rectal Metastases and Benign Liver Tumours

21 Colorectal Liver Metastasis���������������������������������������������������������������������� 277
Rafael Diaz-Nieto and Graeme J. Poston
22 Benign Liver Tumours ������������������������������������������������������������������������������ 295
James Pape and Charles Imber

Appendix ������������������������������������������������������������������������������������������������������������ 309

Contributors

Nicholas Bird, MBBS, MRCS Hepatobiliary Surgery, Digestive Diseases unit,

Aintree University Hospital, Liverpool, UK
Alexa Childs Department of Oncology, UCL Medical School, London, UK
Jenny Cotton Department of Medical Oncology, The Christie NHS Foundation
Trust, Manchester, UK
Department of Medical Oncology, The Clatterbridge Cancer Centre, Wirral, UK
Tim Cross, BMedSci (hons), MBBS, FRCP, MD The Royal Liverpool Hospital,
Liverpool, UK
Department of Molecular and Clinical Cancer Medicine, University of Liverpool,
Liverpool, UK
Rafael Diaz-Nieto, MD, PhD Hepatobiliary Surgery, Digestive Diseases Unit,
Aintree University Hospital, Liverpool, UK
Mona Elshafie, MBChB, MSc, MD Birmingham Neuroendocrine Tumour
Centre, Queen Elizabeth Hospital, Birmingham, UK
Jonathan C. Evans, MRCP, FRCR The Royal Liverpool Hospital, Liverpool,
UK
Olusola O. Faluyi, MBChB (Hons), PhD, MRCP Clatterbridge Cancer Centre,
Wirral, UK
Andrea Casadei Gardini Department of Medical Oncology, Istituto Scientifico
Romagnolo per Lo Studio e Cura Dei Tumori (IRST) IRCCS, Meldola, Italy
Jessica C. Hale, MRCP Clatterbridge Cancer Centre, Wirral, UK
Matthew Hoare, MAMB, MRCP (UK), PhD Cancer Research UK Cambridge
Centre, University of Cambridge, Cambridge, UK
Department of Medicine, Addenbrooke’s Hospital, University of Cambridge,
Cambridge, UK

xiii
xiv Contributors

Charles Imber, MD, FRCS, Mb, BCHir, BSc, Hons Centre For HPB Surgery
and Liver Transplantation, Royal Free Hospital, London, UK
Nadya Fatima Jabbar, FRCR Aintree University Hospital, Liverpool, UK
Philip Johnson, MD, FRCP Department of Molecular and Clinical Cancer
Medicine, University of Liverpool, Liverpool, UK
Robert Jones, BSc, MB, ChB, PhD Department of Liver surgery, Aintree
University Hospital NHS Foundation Trust, Liverpool, UK
Shahid A. Khan, BSc (Hons), MBBS, PhD, FRCP St Mary’s Hospital (Imperial
College), London, UK
Nabil Kibriya, MBBS, FRCR Kings College Hospital, London, UK
Vinay Kumar Balachandrakumar, MBBS, MRCP (UK) University of Liverpool,
Liverpool, UK
Angela Lamarca Department of Medical Oncology, The Christie NHS Foundation
Trust, Manchester, UK
Yuk Ting Ma, PhD, FRCP Department of Medical Oncology, Queen Elizabeth
Hospital, Birmingham, UK
Hassan Malik, MB, ChB, FRCS, MD Department of Liver surgery, Aintree
University Hospital NHS Foundation Trust, Liverpool, UK
Aileen Marshall The Sheila Sherlock Centre for hepatology and liver transplanta-
tion, The Royal Free Hospital, London, UK
João Maurício Northern Institute for Cancer Research, Newcastle University,
Newcastle upon Tyne, UK
Stephen McClements St Mary’s Hospital (Imperial College), London, UK
Mairéad G. McNamara, MB, ChB, BMedSci, BSc, PhD Department of Medical
Oncology, The Christie NHS Foundation Trust, Manchester, UK
Division of Cancer Sciences, University of Manchester, Manchester, UK
Tim Meyer, BSc, FRCP, PhD UCL Cancer Institute, University College London,
London, UK
Andrew R. Moore, MB, ChB, PhD, MRCP Liverpool Regional Neuroendocrine
Tumour Service, Royal Liverpool University Hospital, Liverpool, UK
James Pape, MB, ChB, MRCS Centre For HPB Surgery and Liver Transplantation,
Royal Free Hospital, London, UK
Oliver Pickles Department of Medical Oncology, Queen Elizabeth Hospital,
Birmingham, UK
Contributors xv

Graeme J. Poston, DSc Hepatobiliary Surgery, Digestive Diseases unit, Aintree

University Hospital, Liverpool, UK
Alberto Quaglia, MD, PhD, FRCPath The Institute of Liver Studies, King’s
College Hospital, London, UK
Leonard M. Quinn, MB, ChB (hons), MRCS Hepatobiliary Surgery, Digestive
Diseases unit, Aintree University Hospital, Liverpool, UK
Helen Reeves, BMedSci, MBBS, PhD, FRCP Northern Institute for Cancer
Research, Newcastle University, Newcastle upon Tyne, UK
Paul J. Ross, MBBS, PhD, FRCP Department of Medical Oncology, Guy’s
Cancer, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Department of Oncology, King’s College Hospital NHS Foundation Trust, London,
UK
Ian A. Rowe, MRCP, PhD Liver Unit, St. James’s University Hospital, Leeds, UK
Leeds Institute for Data Analytics, University of Leeds, Leeds, UK
Vandana M. Sagar Birmingham Neuroendocrine Tumour Centre, Queen Elizabeth
Hospital, Birmingham, UK
Bruno Sangro, MD, PhD Liver Unit and HPB Oncology Area, Clinica Universidad
de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
Tahir Shah, MBBS, FRCP, MD Birmingham Neuroendocrine Tumour Centre,
Queen Elizabeth Hospital, Birmingham, UK
Dinesh Sharma, MBBS, MS, FRCS (Ed) The Sheila Sherlock Centre for hepa-
tology and liver transplantation, The Royal Free Hospital, London, UK
Mikael H. Sodergren Department of Surgery and Cancer, Imperial College
London, London, UK
Nicholas Stern, MB, ChB, MD, FRCP Aintree University Hospital, Liverpool, UK
Ray S. Tan, MBBS, MRCP Department of Medical Oncology, Guy’s Cancer,
Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Eleanor J. Taylor Liver Unit, St. James’s University Hospital, Leeds, UK
Juan W. Valle Department of Medical Oncology, The Christie NHS Foundation
Trust, Manchester, UK
Division of Cancer Sciences, University of Manchester, Manchester, UK
David Vass Hepatobiliary Surgery, Digestive Diseases unit, Aintree University
Hospital, Liverpool, UK
David White, FRCR Aintree University Hospital, Liverpool, UK
xvi Contributors

Caroline L. Wilson, BSc (hons), PhD Faculty of Medical Sciences, Institute of

Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
Jen-Jou Wong Department of Radiology, The Royal Lilverpool Hospital,
Liverpool, UK
Vincent S. Yip, MB, ChB, MD, FRCS Department of Hepatobiliary and
Pancreatic Surgery, Royal Liverpool & Broadgreen University Hospital, Liverpool,
UK
 Part I
Hepatocellular Carcinoma
Chapter 1
The Epidemiology of Hepatocellular
Carcinoma

Philip Johnson

Key Learning Points

1. Hepatocellular carcinoma (HCC), the most common form of primary liver
cancer, is predominantly a male disease, associated with increasing age
and many types of chronic liver disease.
2. It is most prevalent in China and the Far East, Japan and sub-Saharan
Africa.
3. This geographic variation is accounted for by the distribution of aetiologi-
cal factors which include chronic hepatitis B virus infection (HBV),
chronic hepatitis C virus (HCV) infection, alcoholic cirrhosis and obesity/
metabolic syndrome—related to non-alcoholic fatty liver disease.
4. Vaccination against HBV and antiviral therapy for HCV will decrease the
incidence of HCC in many populations and change the epidemiology.
5. In the West mortality from HCC is rising mainly due to fatty liver disease,
consequent upon the increasing prevalence of obesity.

Areas of Controversy and Uncertainty

1. The long-term impact of obesity on the incidence of hepatocellular
­carcinoma in the West. The relationship between obesity-related HCC and
cirrhosis is a major area of uncertainty.

P. Johnson ()
Department of Molecular and Clinical Cancer Medicine, University of Liverpool,
Liverpool, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 3

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_1
4 P. Johnson

2. The long-term impact of antiviral treatment on the incidence of HCC both

in the West (specifically hepatitis C) and the East (specifically hepatitis B).
3. The risk of HCC development after clearance of the hepatitis C virus by
the action of direct-acting antiviral agents and the optimal strategy for sur-
veillance amongst those who clear the virus.

Introduction and Magnitude of the Problem

In an increasingly globalised world, understanding the epidemiology of HCC has

important implications for the clinical management of HCC.
Worldwide, primary liver cancer or hepatocellular carcinoma (HCC) is the sixth
most commonly occurring cancer and the second largest contributor to cancer-­
related mortality. Due to the aggressive nature of the tumour, the associated under-
lying liver disease, late presentation and the limited range of therapeutic options,
incidence and mortality rates are very close. It is the commonest of the two main
primary malignancies of the liver, the other major hepatic cancer being cholangio-
carcinoma (CC) which accounts for between 5 and 10% of malignant primary liver
tumours, although it is increasingly recognised that there can be overlap of the
­features of HCC and CC.

Demography

The incidence of HCC can be broadly classified according to geographical region as

high-, medium- and low-incidence areas (Fig. 1.1). The high-incidence areas include
China, Southeast Asia, Japan and sub-Saharan Africa, with an incidence rate of over
20/100,000. Intermediate areas (incidence 5–20/100,000) include Southern Europe,
and low-incidence areas include the USA, Scandinavia and Northern Europe [1].
In most areas of the world, the disease occurs predominantly in men over the age
of 60 years, but the age at onset is significantly lower in sub-Saharan Africa. The
reason for the male preponderance is unknown, but the regional variation in ­incidence
is clearly accounted for by the geographic distribution of the major risk factors.

Risk Factors

The most striking feature of the epidemiology of HCC is the wide geographical
variation in incidence (Fig. 1.2) which largely reflects the global distribution of the
major aetiological factors, as described below. However, the relative importance and
thereby the geographical distribution are changing rapidly with the development of
new therapies and public health initiatives.
1 The Epidemiology of Hepatocellular Carcinoma 5

Male:Female
Norway 2,2:1
Brazil, Sao Paulo 2,9:1
Israel: Jews 2,2:1
UK, England, Thames 2,5:1
Colombia, Cali 1,3:1
Canada, Ontario 3,1:1
New Zealand 2,7:1
India, Mumbai (Bombay) 2,2:1
Australia, New South Wales 2,8:1
Costa Rica 1,6:1
USA SEER (9 Registries) White 3,1:1
Germany, Saarland 2,6:1
USA SEER (9 Registries): Black 3,7:1
Italy, Varese Province 3,4:1
Switzerland, Geneva 4,4:1
France, Bas-Rhin 5,4:1
Zimbabwe, Harare: African 1,2:1
China, Shanghai 3,1:1
Egypt, Gharbiah 4,0:1
Japan, Osaka Prefecture 2,9:1
China, Hong Kong 3,9:1
Republic of Korea, Seoul 3,4:1
40 30 20 10 0 10 20
Male, Age-Standardized Incidence Rate Female, Age-Standardized Incidence Rate

Fig. 1.1 Age-adjusted incidences per 100,000 of liver cancer among men and women by region,
2003–2007. Age-adjusted to world standard (Available at http://ci5.iarc.fr)

Incidence ASR
Both sexes

Liver cancer
9.2+
5.4-9.2
4.2-5.4
3.0-4.2
<3.0
No Data

Fig. 1.2 Geographic variation in liver cancer incidence (age-standardised) (Available from http://
globocan.iarc.fr)

The Hepatitis B Virus

The classic study of the natural history of hepatitis B virus infection and its relation-
ship with HCC was reported from Taiwan [2]. This study followed up 22,707 HBV
carriers for 5 years (Fig. 1.3). The annual incidence rate among those developing
HCC was about 100-fold risk of the control group, thereby conclusively demon-
strating the aetiological relevance of the HBV virus to HCC development and laying
the basis for mass prevention strategies.
6 P. Johnson

Fig. 1.3 The Taiwan

prospective study of HCC Prospective study of HCC development
development in patients in HBsAg seropositive male chinese
with chronic hepatitis B
virus infection. From HCC development
Beasley et al. [2] 19,223 (HBsAg -ve) 9

22,707 Mean follow-up = 8.9 years

Male Chinese

3,454 (HBsAg +ve) 152

Relative risk = 98.4 (50.2-193)

The natural history and global distribution of chronic HBV infection are now
well documented [3, 4]. HBV is transmitted from mother to newborn at, or around,
the time of birth, and this observation, combined with the Beasley study, led to a
programme of mass vaccination against HBV, initiated in Taiwan in 1984 and
supplemented by HBIG (hepatitis B immunoglobulin). The vaccine is extremely
safe and effective, but, for a variety of reasons, vaccine-induced immunity cover-
age is much less than 100%, even in countries where universal vaccination is
advocated.
The subsequent progress of this initiative in Taiwan and other countries and
regions has been well documented. The latest analysis clearly shows that the preva-
lence of HBsAg seropositivity has fallen from around 10% to less than 2% among
those born in the immunisation period, and there has been a dramatic decrease in the
incidence of HCC although the full impact will not be realised for another 30 years,
when the first vaccines reach their sixth decade [5]. In the West most HBV-related
disease arises from intravenous drug abuse or is sexually transmitted. First-­
generation immigrant populations coming from high HBV incidence areas to the
West also tend to be over-represented with respect to HCC.
Obviously immunisation will have no impact on those who are already HBV car-
riers, but current evidence suggests that antiviral therapy significantly reduces the
incidence of HCC [6]. Nonetheless, and in marked contradistinction to the current
situation in HCV, sustained virus control is difficult and expensive to achieve. Thus,
the combination of immunisation and antiviral therapy is likely to alter the epidemi-
ology of HCC dramatically over the coming decades, although the gap between
what is medically possible and what is, in financial and political terms, deliverable
remains wide.
All therapeutic interventions are small when compared to the impact of immuni-
sation and other methods by which the hepatitis B virus can be eliminated or
controlled.
1 The Epidemiology of Hepatocellular Carcinoma 7

 epatitis C Virus and the Changing Epidemiology

H
of HCC in the West

Initially classified as ‘non-A/non-B‘virus infection, HCV was identified in 1989,

and although such rigorous epidemiological studies as described above for HBV
were never undertaken, case-control studies left little doubt that the virus was
strongly associated with HCC. In the West HCV was acquired mainly though intra-
venous substance abuse or by blood transfusion. In Japan there was a major epi-
demic which led to around 35,000 cases developing per year for the 50 years
following the end of the Second World War, after which there had been extensive
use of infected blood [7].
In the last few years, effective therapy for HCV has been developed to the extent
that complete “cure” can be obtained within a few months of treatment, and in sev-
eral countries, the complete eradication of HCV is envisaged. After achievement of
sustained virological remission, the risk of HCC decreases dramatically, further
supporting the aetiological role of the virus [8].

Alcohol

Alcoholic cirrhosis has long been considered a major risk factor for HCC account-
ing for a high proportion of cases in the West. However, it now seems likely that,
whilst there is a significant increase in HCC among patients with a history of high
alcohol intake, some of this is related to associated factors such as coexisting HBV
and HCV infection, which were not recognised in earlier studies, and the increasing
recognition that alcohol likely acts in a synergistic manner to encourage HCC in
patients with other underlying causes [9, 10, 11–13].

Aflatoxin

Aflatoxin B1 is a potent carcinogen derived from the mould Aspergillus flavus

(hence aflatoxin) that grows in humid conditions on stored grain and ground nuts. It
is a very likely contributor to the high incidence of HCC in sub-Saharan Africa and
coastal regions of Southeast Asia and China [14]. Exposure to AFB1 is associated
with a specific DNA mutation in the p53 gene (a 249ser mutation) [15]. It has a
synergistic association with HBV in increasing the risk of HCC. The population
attributable risk of AFB1 in sub-Saharan Africa is between 10 and 20%.
In general, in areas of the world where AFB1 exposure is high, chronic HBV
infection is highly prevalent. As little can be done to alter the HBV chronic infection
8 P. Johnson

state, once established, eradicating AFB1 from the food supply is an important strat-
egy to reduce HCC incidence. In parts of Africa and China where AFB1 eradication
programmes have been implemented, significant reductions in HCC rates have been
documented [16].

Other Rarer Forms of Chronic Liver Disease

HCC is a recognised complication of all types of cirrhosis and chronic liver disease
including primary biliary cirrhosis, Wilson’s disease and alpha-1 antitrypsin
­deficiency. HCC is a major cause of mortality in haemochromatosis but can be
prevented by venesection therapy if instituted before cirrhosis develops. This justi-
fies careful screening of families with a history of haemochromatosis so as to
achieve early diagnosis and to initiate appropriate therapy at a presymptomatic,
pre-cirrhotic stage.

Obesity/Metabolic Syndrome and NAFLD

There remain between 10 and 30% of cases in which no aetiological factors can be
identified. Such cases were previously referred to as “cryptogenic”. Over the past
two decades, however, it has become apparent that in such cases there is a high
incidence of obesity [17, 18] and diabetes. The associated liver disease is called
non-­alcoholic fatty liver disease (NAFLD) [19]. In a subgroup of this population,
there is a fat-related inflammatory response that is likely to progress to serious liver
disease—so-called non-alcoholic steatohepatitis (NASH). However, HCC may
arise in NAFLD, without any associated chronic liver disease or cirrhosis [20].
Tobacco consumption probably imposes a risk, comparable to that of obesity.

Implications of Epidemiology for Prevention

Epidemiological investigations have identified the relevant risk factors such that the
major ones act as a target for preventative strategies. There is another and quite
distinct epidemiological approach that may result in further preventative measures,
and this relates to the analysis of large datasets that have been collected for pur-
poses other than direct investigation of the prevention of HCC. This approach falls
under the heading of “repurposing” of drugs. Thus, large-scale datasets reporting
the incidence of HCCs in populations treated with various agents for purposes unre-
lated to their potential anticancer are an area of extensive research. Aspirin and
non-­steroidal anti-inflammatory drugs have well-documented activity in reducing
the incidence of most gastrointestinal cancers, including HCC [21], and the
1 The Epidemiology of Hepatocellular Carcinoma 9

evidence that statins have an equivalent effect is now substantial [22]. Antidiabetic
drugs such as metformin have also been proposed, but the most recent meta-­
analyses are less convincing [23].

The Changing Face of HCC Epidemiology

As suggested throughout this chapter, HCC is a preventable disease, and, over the
last decade, evidence has emerged that preventative strategies are starting to have an
impact on incidence. Chronic HBV infection rates, as a result of immunisation and
antiviral treatment, are falling with resulting stabilisation or decrease in HCC rates
across China and the Far East. In Japan and Southern Europe, the peak incidence of
the post-war HCV epidemic is passing, and the later drug abuse-related epidemic in
the West may be eradicated by direct-acting antiviral agents. Against these encour-
aging trends, it is sobering to note that HCC is now the most rapidly rising cause of
cancer-related mortality at a time when the incidence of other cancers is falling by
around 1–2% per annum (Fig. 1.4). The reason is clear. The major current aetiologi-
cal factors are all related to the great addictions of Western societies, namely, alco-
hol, tobacco and, particularly, food. There is little prospect that this situation will
change over the foreseeable future.

Trends in US cancer mortality rates

All other cancers

(Average) Corpus & Uterus, NOS

Testis

Lung & Bronchus (Female)

Esophagus

Thyroid
Liver

-2 -1.5 -1 -0.5 0 0.5 1 1.5 2

Annual percent change (1994-2003*)

*Represents the annual percent change over the time interval

National Cancer Institute Website.
Available at: http://seer.cancer.gov/csr/1975 2003/sections.html. Accessed September 21, 2006.

Fig. 1.4 Change in cancer mortality rate in the USA. Note that “liver” is the most rapidly rising
cause of cancer-related mortality at a time when the mortality from most cancers is decreasing
10 P. Johnson

References

1. Ferlay J, Parkin DM, Curado MP, et al. Cancer incidence in five continents, volumes I to X:
IARC CANCERBase No. 10. 2014. [Internet]. Available at: http://ci5.iarc.fr. Accessed 25 Nov
2014.
2. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A
prospective study of 22 707 men in Taiwan. Lancet. 1981;2(8256):1129–33.
3. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49(5
Suppl):S45–55. [PubMed: 19399792]
4. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus
infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine.
2012;30(12):2212–9. PubMed: 22273662
5. Chiang CJ, Yang YW, You SL, Lai MS, Chen CJ. Thirty-year outcomes of the national hepatitis
B immunization program in Taiwan. JAMA. 2013;310(9):974–6. PubMed: 24002285
6. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K,
Keene ON, Dixon JS, Gray DF, Sabbat J, Cirrhosis Asian Lamivudine Multicentre Study
Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J
Med. 2004;351(15):1521–31.
7. Umemura T, Ichijo T, Yoshizawa K, Tanaka E, Kiyosawa K. Epidemiology of hepatocellular
carcinoma in Japan. J Gastroenterol. 2009;44(Suppl 19):102–7.
8. El-Serag HB, Kanwal F, Richardson P, Kramer J. Risk of hepatocellular carcinoma after
sustained virological response in Veterans with hepatitis C virus infection. Hepatology.
2016;64(1):130–7. https://doi.org/10.1002/hep.28535. Epub 2016 Apr 19
9. Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P, Patt YZ. Risk
factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes
mellitus. Hepatology. 2002;36:1206–13.
10. Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Risk for hepatocellular carcinoma
in patients with alcoholic cirrhosis: a danish nationwide cohort study. Ann Intern Med.
2012;156:841–7.
11. Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, Decarli A, Trevisi P, Ribero
ML, Martelli C, Porru S, Nardi G. Alcohol and hepatocellular carcinoma: the effect of lifetime
intake and hepatitis virus infections in men and women. Am J Epidemiol. 2002;155:323–31.
12. La Vecchia C. Alcohol and liver cancer. Eur J Cancer Prev. 2007;16:495–7. 52.
13. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology.
2004;127:S87–96.
14. Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment.
Environ Health Perspect. 2010;118(6):818–24. PubMed: 20172840
15. Hsia CC, Kleiner DE Jr, Axiotis CA, Di Bisceglie A, Nomura AM, Stemmermann GN, Tabor
E. Mutations of p53 gene in hepatocellular carcinoma: roles of hepatitis B virus and aflatoxin
contamination in the diet. J Natl Cancer Inst. 1992;84:1638–41.
16. Chen JG, Egner PA, Ng D, et al. Reduced aflatoxin exposure presages decline in liver cancer
mortality in an endemic region of China. Cancer Prev Res (Phila). 2013;6(10):1038–45.
17. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality
from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–38.
18. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular
carcinoma: a weighty connection. Hepatology. 2010;51:1820–32. 47.
19. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease
and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol.
2012;10:1342–59.
20. Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis,
to prevention and treatment. Liver Int. 2016;36:317–24.
1 The Epidemiology of Hepatocellular Carcinoma 11

21. Sahasrabuddhe VV, Gunja MZ, Graubard BI, et al. Nonsteroidal anti-inflammatory drug use,
chronic liver disease, and hepatocellular carcinoma. J Natl Cancer Inst. 2012;104(23):1808–14.
22. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced
risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology.
2012;144(2):323–32.
23. Hagberg KW, McGlynn KA, Sahasrabuddhe VV, Jick S. Anti-diabetic medications and risk of
primary liver cancer in persons with type II diabetes. Br J Cancer. 2014;111(9):1710–7.
Chapter 2
Surveillance for Hepatocellular Carcinoma

Eleanor J. Taylor and Ian A. Rowe

Key Learning Points

1. Surveillance for the development of HCC in patients at risk, particularly
those with cirrhosis, is logical with the aim to reduce overall mortality.
2. Six-monthly ultrasound scans (with or without AFP testing) is the current
standard of care defined by professional societies.
3. The overall benefits of surveillance are small in populations of patients
with cirrhosis, accounting for a reduction in overall mortality over 5 years
of surveillance of approximately 1–2%.
4. The effectiveness of surveillance is reduced by eligible patients not enter-
ing surveillance programmes and by patients ineligible for curative treat-
ments entering such programmes.
5. There are harms associated with surveillance that need to be communi-
cated to the patient, together with the benefits that might be achieved.

Areas of Controversy and Uncertainty

1. The magnitude of the benefit of surveillance in patients with cirrhosis is
uncertain and is subject to confounding.

E. J. Taylor
Liver Unit, St. James’s University Hospital, Leeds, UK
I. A. Rowe (*)
Liver Unit, St. James’s University Hospital, Leeds, UK
Leeds Institute for Data Analytics, University of Leeds, Leeds, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 13

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_2
14 E. J. Taylor and I. A. Rowe

2. Models that predict benefits of surveillance are based on confounded

­retrospective estimates.
3. The significance of the harms of surveillance is uncertain.
4. There is a rationale for developing a randomised controlled trial of surveil-
lance to address this uncertainty, but this is not be supported by the expert
consensus.

The majority of hepatocellular carcinoma (HCC) globally is associated with chronic

viral hepatitis, and it occurs most frequently in individuals with cirrhosis [1]. In the
developed world, HCC associated with cirrhosis is the predominant form of the
disease, accounting for at least 80% of cases [2]. Outcomes after diagnosis of HCC
remain poor, particularly when HCC is diagnosed at late stage. It is for these reasons
that surveillance for HCC, using regular 6-monthly ultrasound scans, is proposed as
a method to improve outcomes for patients with cirrhosis. The aim of that surveil-
lance is to improve overall survival of patients with cirrhosis.
In this chapter we will discuss the rationale for surveillance and the evidence that
supports it, rates and barriers to the uptake of surveillance at the population level,
and the expected outcomes of surveillance given current diagnostic and treatment
methods.

The Rationale for Surveillance

Patients with chronic liver diseases, including viral hepatitis, alcohol-related liver
disease and non-alcoholic fatty liver disease, as well as those with rarer metabolic
diseases such as genetic haemochromatosis and autoimmune liver diseases, are at
risk of developing cirrhosis. Treatment of the underlying cause of liver disease will
usually prevent progression to cirrhosis and abrogate the risk of later developing
complications of liver disease, including HCC. Those individuals who are not diag-
nosed with liver disease or those where treatment is for whatever reason unavailable
or ineffective are at risk of disease progression through accumulation of liver fibro-
sis to cirrhosis. Once cirrhosis has developed, there is a risk of developing liver
failure and also a risk of developing HCC. Since HCC is a major cause of mortality
in this group, it is logical to consider surveillance to diagnose HCC early so that
potentially curative treatments can be used to improve the overall survival of both
the patient and the population with cirrhosis.
Typically surveillance is done using 6-monthly ultrasound scans and that is the
method that is endorsed by the European Association for the Study of the Liver
(EASL) as well as the United Kingdom National Institute for Health and Care
Excellence (NICE) [3, 4]. There are however proponents for the addition of blood-­
based biomarkers of HCC development, most notably alpha-fetoprotein, to ultra-
sound to maximise early diagnosis. The additional benefits of AFP are frequently
2 Surveillance for Hepatocellular Carcinoma 15

discussed and it is listed as optional in some guidelines [5]. Whilst there is a small
increase in the sensitivity of surveillance in general for early HCC by incorporating
AFP, this comes at the cost of increasing the numbers of false-positive surveillance
assessments [6]. This will also inevitably increase the rates of surveillance-­
associated harms that are discussed later.

The Target Population

Patients at risk of developing HCC are characterised as those with cirrhosis (from
any cause) as well as those with advanced fibrosis from hepatitis C virus infection
and those with hepatitis B virus (HBV) infection and associated risk factors includ-
ing age, family history of HCC and active hepatitis. These groups are selected,
largely on the basis of cost-effectiveness studies, as those with the most to gain from
early diagnosis of HCC where the incidence is sufficient to warrant that intervention
[3]. It is apparent that the annual incidence of HCC in each of the groups is differ-
ent, ranging from 3% in those with hepatitis C cirrhosis to approximately 0.2% for
those with HBV infection and associated risk factors. Given the low incidence in the
non-­cirrhotic HBV group, a number of investigators have tried to identify scores
that will allow patients at high risk of HCC to be identified so that the whole group
need not be entered into surveillance [7]. This is an attractive approach, but unless
these scores can reliably identify groups with a zero risk of HCC development, it is
challenging to implement given strong recommendations from the major profes-
sional associations [3, 5] for ongoing surveillance in this group.

Evidence of the Benefits of Surveillance

There have been two randomised controlled trials of surveillance done in China.
These studies are not applicable to current practice, either because they did not use
current methods of surveillance (i.e., 6-monthly ultrasound examinations) or
because they included patients without cirrhosis. There are also a number of meth-
odological concerns regarding these studies [8]. Consequently, they cannot be used
to justify surveillance in Western patients with cirrhosis today.
There are a large number of retrospective studies from Europe, the United States
and the Far East that suggest benefits of surveillance. These have been systemati-
cally reviewed by two groups, one of whom pooled the data that were extracted in a
meta-analysis. The conclusions of the two reviews were similar in that they each
concluded that it was probable that surveillance allows earlier diagnosis of HCC but
diverged on the impact on mortality. One review concluded that the quality of the
published evidence was very low, and there was uncertainty as to whether surveil-
lance improved survival in patients with cirrhosis [9]. The second review concluded
that surveillance improved survival in patients with cirrhosis based on the outcomes
16 E. J. Taylor and I. A. Rowe

of their meta-analysis [10], and this study has been used to support subsequent rec-
ommendations for surveillance in the American Association for the Study of Liver
Diseases guideline for patients with HCC [5].
To understand the apparently contradictory findings of these reviews, it is critical
to explore the evidence base further. The studies included in these reviews were all
case control studies where the outcomes of patients with HCC were stratified by
whether they had received surveillance or not. This design can therefore only assess
whether surveillance improves outcomes in patients who have developed HCC and
not those who have cirrhosis as a whole. Furthermore this design is subject to over-
estimation of the impact of surveillance since there will be confounding by a num-
ber of factors. These include confounding by the indication for surveillance where
patients who are better suited to treatment for HCC are selected for surveillance,
apparently improved survival as a consequence of lead time bias, as well as by
length bias, each of which are well recognised in studies of other screening and
surveillance programmes (Fig. 2.1). These factors are difficult to adjust for, and
when adjustments for lead time bias in particular are made, there is a substantial
reduction in the magnitude of the benefit that is apparent in those studies where this
is done. Several studies have been published recently that aim to quantify the ben-
efits of surveillance using a case control design with adjustments for lead time bias,
and in those the absolute risk reduction in mortality at 3–5 years after the diagnosis
of HCC is in the region of 10% [11, 12]. That is less than half of that reported in the
meta-analysis and still subject to residual confounding from other sources.
It remains unclear from observational data therefore that surveillance using
­ultrasound will improve survival in patients with cirrhosis. Supportive evidence
comes from both cost-effectiveness analyses and modelling studies of surveillance.

a b Screening test

Symptoms
Cancer
development Death

Rapidly
Unscreened progressive
survival HCC

Screening test Symptoms

Survival with screening Slowly

progressive
HCC

Time

Fig. 2.1 Lead time and length bias in cancer screening. Lead time bias (a) defines an apparent
improvement in survival as a consequence of early diagnosis of cancer due to screening or surveil-
lance in the case of HCC although there is no change in the natural history of that cancer through
treatment. Length bias (b) identifies the likelihood that more indolent cancers are diagnosed by
screening or surveillance before symptoms present. Each of these biases serves to overestimate the
efficacy of screening or surveillance interventions
2 Surveillance for Hepatocellular Carcinoma 17

These use published data to provide estimates of the likelihood of events in popula-
tions with cirrhosis and draw from the published literature estimates of treatment effi-
cacy and are therefore subject to the same biases as the original observational studies.

Uptake of Surveillance at the Population Level

Despite low-quality evidence, surveillance is strongly recommended by all profes-

sional associations that represent physicians caring for patients with cirrhosis. Other
expert bodies, including the US National Cancer Institute, do not recommend sur-
veillance, but it is expected that most physicians would follow guidance issued by
their professional societies. However, international studies, particularly from the
United States and from the United Kingdom, suggest that only a minority of patients
with cirrhosis receive surveillance. In the best characterised population, including
individuals with cirrhosis due to HCV infection, rates of routine surveillance were
calculated to be 42% in the first year after diagnosis and declined thereafter to 12%
for individuals with at least 2 years of follow-up [13].
In the United Kingdom, a questionnaire study identified important deficits in
surveillance for patients with cirrhosis. Whilst the majority of respondents reported
that there was a surveillance programme in their hospital, there was often no mecha-
nism to routinely recall the patient for follow-up imaging, and patients were not
reliably informed of the reasons that surveillance was suggested [14].

Barriers to Effective Surveillance

Clinical effectiveness of an intervention, such as surveillance for HCC, defines how

well that intervention performs in the real world. Even for an intervention that is
100% efficacious, factors that limit its use mean that the clinical effectiveness is
often much less than 100%. Where there are questions about the efficacy of surveil-
lance when it is done, any factors that reduce its use or that impair its performance
will inevitably further reduce its clinical effectiveness (Fig. 2.2). Barriers to patients
entering surveillance, patients entering surveillance where there are contraindica-
tions to anticancer treatment such as advanced liver or non-liver co-morbidities, and

Population with 50% Enter surveillance 40% Suitable for curative 80% Survive during 90% Surveillance
cirrhosis for HCC treatment surveillance diagnosis of HCC

Fig. 2.2 Factors affecting the clinical effectiveness of surveillance for HCC. Multiple steps before
a diagnosis of HCC in surveillance diminish the overall benefit of surveillance in the population.
In this illustration estimated over 5 years, only 14% (=100×0.5×0.4×0.8×0.9) of the population
with cirrhosis are eligible to benefit from surveillance. If 10% of those eligible to benefit from
surveillance develop HCC and there is a 10% absolute risk reduction in mortality from a diagnosis
of HCC in surveillance, then the anticipated survival benefit at the population level is 0.14%
(=14×0.1×0.1)
18 E. J. Taylor and I. A. Rowe

competing causes of mortality each reduce the clinical effectiveness of surveillance

in this context.
Overall, the greatest barrier to a patient entering surveillance is not knowing that
the patient has cirrhosis. Many patients with well-compensated cirrhosis are not
diagnosed until complications (either liver failure or HCC) develop, and without
that diagnosis, surveillance cannot be implemented. The principal factor that
reduces the clinical effectiveness of surveillance for patients known to have cirrho-
sis, other than its efficacy, is patients not entering a surveillance programme. In the
example shown in Fig. 2.2, the barriers to surveillance substantially reduce the num-
ber of individuals with cirrhosis who are eligible to benefit from that intervention.
Since HCC only develops in a minority and surveillance has limited efficacy, the
impact of surveillance at the level of the population with cirrhosis is minimal.
Several studies have evaluated physician’s perspectives of surveillance and a
number of themes have emerged [14, 15]. These largely relate to concerns about the
lack of efficacy of surveillance and costs and availability of specialist ultrasonogra-
phy. It is striking that these issues would be best addressed by the generation of high-
quality prospective data that assess the effectiveness of surveillance. It is also striking
that since fewer than half of patients with cirrhosis receive effective surveillance,
making a cogent argument for a randomised controlled trial that compared surveil-
lance with no surveillance. Such a trial would both increase the number of patients
receiving high-quality surveillance and would provide a clear answer as to the (cost-)
effectiveness of surveillance. In many ways it is therefore puzzling that this approach
is not supported by many of the experts in the field (Controversies box).

Expected Outcomes of Surveillance

Benefits

For patients considering surveillance today, it is important that they receive bal-
anced information about both the possible benefits and harms of that intervention so
that they can make an informed decision to participate (or not). The possible bene-
fits in patients who have developed HCC have been discussed above, but this tells
only part of the story since the majority of patients with cirrhosis will never develop
HCC and will undergo surveillance without any chance of benefit. For those patients
there are only the risks of surveillance.
To derive a clearer perspective of the benefits of surveillance in the population
with cirrhosis, one needs to consider the natural history of patients with compen-
sated cirrhosis more closely. It is apparent that in viral hepatitis, where there are the
best data, diagnosis of HCC is the most common early liver event in patients with
compensated cirrhosis. It is also clear that these individuals remain at risk of death
from other causes, including cardiovascular disease and extrahepatic malignancy.
Critically, the balance of these competing risks is different, for instance, in patients
2 Surveillance for Hepatocellular Carcinoma 19

with alcohol-related liver disease (ArLD) where the incidence of HCC is lower than
in viral hepatitis with implications for the outcomes with surveillance.
Two groups, including ours, have developed models to identify the benefits of
surveillance in the population with cirrhosis in the absence of a relevant and appli-
cable randomised controlled trial [16, 17]. The approach to modelling is different,
but the short-term outcomes are similar, showing a small, 1–2% decrease in overall
mortality at 5 years after the onset of surveillance and assuming that surveillance is
complete. This decrease is much smaller than is anticipated by the case control stud-
ies simply because the modelling studies take into account the majority of patients
that do not develop HCC in the follow-up period. Critically, these estimates are
made for patients with an incidence of HCC of 2.5% per annum and low rates of
competing mortality from both liver and non-liver causes. If the models were refined
to consider a population with a lower incidence of HCC and a higher rate of compet-
ing mortality (as would be expected in an ArLD population), the estimated mortality
reduction would be smaller still.

Harms

Considering the small benefit that surveillance offers at the population level, a
patient considering entering surveillance will need information on the possible
harms. Until recently there has been little attention focussed on this topic, and in a
decision aid that aimed to assess feasibility of a randomised controlled trial, they
were summarised as the possibility of a false alarm following a surveillance ultra-
sound [15]. It is now recognised that this is an oversimplification of the situation. In
general, in the cancer screening literature, there are a number of potential harms
recognised. These harms relate to physical and psychosocial harms from the test
itself, harms resulting from false-positive screening tests and subsequent down-
stream testing as well as harms that result from false-negative testing.
Whilst a surveillance ultrasound scan is itself a safe intervention in the wider
context, there are predictable harms that are likely to result. In prospective studies
of surveillance [18], the false-positive rate for each ultrasound was in the region of
2%, meaning that approximately 1 in 50 individuals attending for ultrasound
required additional testing with the attendant concerns that liver cancer had devel-
oped when it had not. In the United States, it has been reported that a quarter of
patients in surveillance (over a short follow-up period of 2 years on average)
required additional scans because of either a false-positive or indeterminate ultra-
sound scan [18]. This high rate of false-positive testing has further implications if
the European Association for the Study of the Liver (EASL) recall policy [3] is
applied. This policy mandates biopsy of 1–2 cm indeterminate lesions on cross-­
sectional imaging to determine the impact of this on patients in surveillance, and
one of the modelling studies done to assess the benefits of surveillance also
addressed this area. The study concluded that the harms of surveillance were more
20 E. J. Taylor and I. A. Rowe

frequent than the benefits: 15% of individuals required additional testing, including
4% who (according to the EASL recall policy) underwent ‘unnecessary’ liver
biopsy since that biopsy did not diagnose HCC [16].
False-negative testing, that is ‘missing’ cancer that is present, is also an issue in
surveillance since only small HCC can be treated with curative intent. In the same
prospective studies that required an ultrasound at baseline that did not identify
HCC, 20% of those patients subsequently diagnosed with HCC had disease that had
progressed beyond traditional curative criteria [19]. This is a substantial minority,
and this partially explains why the efficacy of surveillance is not high.
Finally, there are clearly predictable harms that relate to concerns regarding the
possible diagnosis of HCC in patients with cirrhosis. Patients with cirrhosis are (or
should be) familiar with the possible complications of that disease. Six-monthly
ultrasound scans will serve, in some patients at least, to emphasise the possibility
that cancer might develop. Reports of quality of life in cirrhosis show significant
impairments in many domains, and this might partially be explained by concerns
regarding progression of liver disease and/or the development of HCC. For instance,
in a report of patients undergoing surveillance in Texas, two thirds of patients were
concerned they would develop HCC, and almost half were worried that they would
die from HCC. This was despite half of patients already having advanced liver dis-
ease marked by the presence of ascites [20]. The majority of these patients will not
develop HCC, and for those with ascites, there is no known survival benefit from
surveillance, and the focus on HCC in this context is unwarranted and unhelpful.

Improving Surveillance for the Future

Surveillance for HCC in patients with cirrhosis is logical but the evidence that supports
it is of low quality. Surveillance is associated with frequent and sometimes significant
physical harms and probably also psychosocial harms that are not well quantified. It is
critical that we, as physicians caring for patients with liver disease, work together to
improve surveillance and thereby improve outcomes of patients with cirrhosis. This
might be achieved in a number of ways. First, there is a clear need to collect high-
quality information regarding the current effectiveness of surveillance, including data
on each of the parameters included in Fig. 2.2. That will allow specific targeted inter-
ventions with the greatest predicted benefit on outcomes. Second, there is a need to
improve the efficacy of the surveillance intervention. Ideally, this would increase the
sensitivity of the test and decrease the rate of false-positive testing. Currently, achiev-
ing this aim seems distant since although the addition of biomarkers to 6-monthly
ultrasound might increase the sensitivity of the test, it is almost certain that this will
also increase the false-positive rate and increase harm that accrues through surveil-
lance. Finally, there is a need to better characterise the psychosocial harms of surveil-
lance so that the process of information giving and consent can be optimised and the
risk of HCC development put into context for patients with cirrhosis.
2 Surveillance for Hepatocellular Carcinoma 21

References

1. Global Burden of Disease Mortality, Causes of Death Collaboration. Global, regional, and
national age-sex specific all-cause and cause-specific mortality for 240 causes of death,
1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet.
2015;385(9963):117–71.
2. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–27.
3. European Association for the Study of the Liver, European Organisation for Research and
Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocel-
lular carcinoma. J Hepatol. 2012;56(4):908–43.
4. NICE. Clinical Guideline 50: Cirrhosis in over 16s: Assessment and management. 2016;
https://www.nice.org.uk/guidance/ng50/evidence/full-guideline-2546537581. Accessed 12 Jul
2016.
5. Heimbach JK, Kulik LM, Finn R, et al. AASLD guidelines for the treatment of hepatocellular
carcinoma. Hepatology. 2017;67(1):358–80.
6. Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients
with hepatocellular carcinoma. Gastroenterology. 2016;150(4):835–53.
7. Wong VW, Janssen HL. Can we use HCC risk scores to individualize surveillance in chronic
hepatitis B infection? J Hepatol. 2015;63(3):722–32.
8. Lederle FA, Pocha C. Screening for liver cancer: the rush to judgment. Ann Intern Med.
2012;156(5):387–9.
9. Kansagara D, Papak J, Pasha AS, et al. Screening for hepatocellular carcinoma in chronic liver
disease: a systematic review. Ann Intern Med. 2014;161(4):261–9.
10. Singal AG, Pillai A, Tiro J. Early detection, curative treatment, and survival rates for hepa-
tocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med.
2014;11(4):e1001624.
11. Mittal S, Kanwal F, Ying J, et al. Effectiveness of surveillance for hepatocellular carcinoma in
clinical practice: A United States cohort. J Hepatol. 2016;65(6):1148–54.
12. Cucchetti A, Trevisani F, Pecorelli A, et al. Estimation of lead-time bias and its impact on
the outcome of surveillance for the early diagnosis of hepatocellular carcinoma. J Hepatol.
2014;61(2):333–41.
13. Davila JA, Henderson L, Kramer JR, et al. Utilization of surveillance for hepatocellular
carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med.
2011;154(2):85–93.
14. Cross TJ, Villanueva A, Shetty S, et al. A national survey of the provision of ultrasound surveil-
lance for the detection of hepatocellular carcinoma. Frontline Gastroenterol. 2016;7:82–9.
15. Poustchi H, Farrell GC, Strasser SI, Lee AU, McCaughan GW, George J. Feasibility of con-
ducting a randomized control trial for liver cancer screening: is a randomized controlled trial
for liver cancer screening feasible or still needed? Hepatology. 2011;54(6):1998–2004.
16. Taylor EJ, Jones RL, Guthrie JA, Rowe IA. Modeling the benefits and harms of surveil-
lance for hepatocellular carcinoma: Information to support informed choices. Hepatology.
2017;66(5):1546–55.
17. Yang JD, Mannalithara A, Piscitello AJ, et al. Impact of surveillance for hepatocellular carci-
noma on survival in patients with compensated cirrhosis. Hepatology. 2017;68(1):78–88.
18. Atiq O, Tiro J, Yopp AC, et al. An assessment of benefits and harms of hepatocellular carci-
noma surveillance in patients with cirrhosis. Hepatology. 2016;65(4):1196–205.
19. Trinchet JC, Chaffaut C, Bourcier V, et al. Ultrasonographic surveillance of hepatocellular car-
cinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology.
2011;54(6):1987–97.
20. Farvardin S, Patel J, Khambaty M, et al. Patient-reported barriers are associated with
lower hepatocellular carcinoma surveillance rates in patients with cirrhosis. Hepatology.
2016;65(3):875–84.
Chapter 3
Roles of the Immune System
in the Development and Progression
of Hepatocellular Carcinoma

João Maurício, Helen Reeves, and Caroline L. Wilson

Key Learning Points

1. The liver is constantly exposed to antigens and pathogen-derived mole-
cules from the gut and has intrinsic tolerogenic mechanisms to ensure that
chronic and systemic immune responses do not occur.
2. Hepatocellular carcinoma (HCC) is known to develop on a background of
chronic liver disease and inflammation.
3. Despite evidence of immune responses against tumour-associated antigens
(TAA), the HCC microenvironment fosters an immunosuppressive niche
that escapes immune surveillance.
4. The inflammatory niche created in HCC is a critical target for immuno-
therapy, including vaccines, oncolytic immunotherapy, cell-based therapy,
cytokines/cytokine inhibitors and immune checkpoint inhibitors.

Areas of Controversy and Uncertainty

1. There has been a steady increase in patients presenting with HCC arising
in the absence of significant liver disease or underlying inflammation—the
cause of which is uncertain.

J. Maurício · H. Reeves (*)

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
e-mail: [email protected]; [email protected]
C. L. Wilson
Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University,
Newcastle upon Tyne, UK

© Springer Nature Switzerland AG 2019 23

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_3
24 J. Maurício et al.

2. Cancers arising in the absence of chronic liver disease tend to be associ-

ated with the metabolic syndrome. Obesity and type 2 diabetes may also
affect immune responses, although these are less well studied.
3. Understanding how to activate a suppressed antitumour immune response
safely and effectively is challenging.
4. The cancer immunotherapy era is an exciting one, but likely to be hindered
by the present lack of biomarkers to guide selection of mono or combina-
tion therapies and monitor response.
5. The use of therapies activating aspects of the antitumour immune response
in immunosuppressed patients will require careful consideration.

Introduction

Hepatocellular carcinoma (HCC) accounts for 70–85% of the total primary liver
cancer burden. It usually arises in a background of chronic liver disease consequent
to hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, alcoholic-related liver
disease (ARLD) or non-alcoholic fatty liver disease (NAFLD), which is tightly
linked to the metabolic syndrome and obesity [1]. While HCC is the fifth most com-
mon cancer in men and the ninth most common one in women, it is the second most
common cause of cancer-related death worldwide [2], reflecting late-stage presenta-
tion and limited therapeutic options. Surgery, liver transplantation and local ablative
therapies can be curative in early disease, but most patients are offered palliative
treatments or supportive care. Currently, the only first-line FDA-approved treatment
for advanced-stage HCC is sorafenib, a multikinase inhibitor, which offers a median
overall survival (OS) benefit of just 10 weeks. Hence, there is a clear and urgent
need for new therapies—with a recent focus in the oncology field on immune check-
point inhibitors.
The liver is continually exposed to a multitude of antigens, gut-derived patho-
gens, toxins and environmental and bacterial products—entering the liver from the
gastrointestinal tract via the portal vein. The liver has therefore developed constitu-
tive tolerogenic mechanisms to prevent persistent gut-associated immune stimula-
tion and systemic and chronic inflammation. A common feature underpinning HCC
development, however, is chronic inflammation—consequent to the persistent hepa-
tocyte injury associated with the aetiologies described above, which occurs in
approximately 90% of the cases. The combination of chronic inflammation and the
intrinsic tolerogenic properties of the liver creates an environment that facilitates
cancer development, with progression promoted by additional immunosuppressive
manipulation by the tumour itself.
In this chapter we will discuss some of the knowledge we have to date on how
immune tolerance is evaded during liver disease and what we know about its
3 The Immunosuppresive Hepatic Niche and HCC 25

c­ ontribution to HCC development and progression. We will also highlight some of

the current therapeutic approaches designed to harness the immune system as a
therapy for HCC.

Pathobiology of HCC-Related Aetiologies

ARLD and NAFLD

ARLD is the most common aetiology of HCC in industrialised countries, being

responsible for 32–45% of cases [3]. However, in the last decades, the incidence of
NAFLD-related HCC has been increasing worldwide, possibly because of the obe-
sity and type 2 diabetes epidemic [4]. The mechanisms leading to HCC in either
ARLD or NAFLD are similar, and several reviews have focused on these [1, 3–5].
A key aspect is the chronic damage and hence chronic stimulation of the immune
system that overrides liver tolerance. Increased exposure to gut pathogens and per-
sistent hepatotoxicity result in the production of regulatory miRNAs, pro-­
inflammatory mediators and damage-associated molecular patterns (DAMPs) that
activate the immune response. Alcohol increases levels of miR-212 in gut epithelial
cells, leading to decreased expression of ZO-1, a tight junction protein, disrupting
gut integrity and allowing for translocation of bacterial endotoxins to the liver.
There, the endotoxins impact Kupffer cells (liver-resident macrophages), hepato-
cytes and endothelial cells; Kupffer cells are activated, upregulate miR-155 and
release pro-inflammatory mediators including tumour necrosis factor (TNF), con-
tributing to hepatic inflammation. Additionally, alcohol induces oxidative stress: in
hepatocytes, levels of miR-34a and miR-217 increase, resulting in hepatic steatosis
via SIRT1 and, in endothelial cells, levels of miR-199a decrease, leading to endo-
thelin-­1 and hypoxia-inducible factor α (HIF-1 α) release, all contributing to the
amplification of inflammation [3, 5].
In NAFLD, high-fat and carbohydrate (mainly fructose) intake can exacerbate
cytokine production and increase hepatic de novo lipogenesis (via SREBP and
ChREBP transcription factors), thus promoting lipid peroxidation and DNA dam-
age. The underlying dysfunctional adipose tissue releases additional factors: TNFα
and interleukin (IL)-6 enhance c-Jun N-terminal kinase (JNK)/nuclear factor kappa
B (NF-κB) and Janus kinase (JAK)/signal transducer and activator of transcription
(STAT)3 pathways, while leptin activates Akt/mTOR, leading to expression of
genes involved in cell proliferation, migration and survival. Low levels of adiponec-
tin hinder its anti-inflammatory activity and antagonising effect on leptin. In obe-
sity, fatty liver may also be susceptible to carcinogens as a result of impaired ATP
production, defective autophagy mechanisms, deregulation of energy and hormonal
balance, hypoxia and systemic inflammation. Increased susceptibility of the s­ teatotic
26 J. Maurício et al.

liver to carcinogenic insults can be due to several local and systemic pathological
changes that occur including metabolic imbalances and the “metabolic syndrome”,
hyperinsulinemia and the presence of insulin-like growth factor receptors in HCC,
the systemic effects of dysregulated cytokines and adipokines, immune dysregula-
tion and alteration in gut microbiota [1, 4].

HBV and HCV

Viral hepatitis plays a significant role in up to 80% of all HCC globally, with HBV
being responsible for two-thirds of all cases; HCV is responsible for 25% of
HCC-­related deaths. HCV is the primary cause of end-stage liver disease world-
wide, and, unlike HBV-related acute hepatitis, it only resolves in about 10–40%
of cases [6].
Histological changes are similar between both HBV and HCV infections,
namely, hepatocyte death, inflammation, steatosis and progressive fibrosis, lead-
ing to cirrhosis and HCC. Specific mechanisms causing disease progression
include expression of viral hepatitis B surface antigen (HBsAg) on the surface of
hepatocytes, resulting in stimulation of the host’s immune system, chronic inflam-
mation, increased production of reactive oxygen species (ROS) and oxidative
DNA damage. Integration of the viral DNA into the host genome can also result
in genomic instability, chromosomal loss and abnormal gene activation. These
effects are compounded by the ability of viral proteins to interfere with the regula-
tion of cell cycle proteins and promote apoptotic escape. Moreover, persistent
chemokines, cytokines, proteases and ROS produced by the inflammatory cell
infiltrate promote the carcinogenic process further by inducing cell survival and
proliferation [6].

 hronic Inflammation, Immune Suppression

C
and HCC Progression

In tumour-bearing hosts, cancer progression is driven by mechanisms promoting

immune tolerance to tumour-associated antigens (TAA), including a failure to rec-
ognise malignant cells and suppression of the immune cells responsible for the
death and clearance of the tumour. Despite a lack of knowledge concerning these
pathways, available data thus far highlights the multiple immune responses impli-
cated in HCC progression and allows for identification of promising new targets for
future therapy [7, 8]. These cancer-related changes in the immune response com-
prise of changes in the number and/or function of immune cells, changes in cytokine
levels and immune receptor/ligand expression, some of which will be reviewed here
(Fig. 3.1).
3 The Immunosuppresive Hepatic Niche and HCC 27

Antibodies
TAA

IFNg TRAIL

Vaccines TNF IL-1

NK TIL Elimination of
suppressor cells
CD80/86 Treg TAM
Cytokines
Neutrophils
Tumour elimination
Blockade of
MDSC IL-10 IL-4 immunosuppressive
cytokines
PD-1/PD-L1

TIM-3 CTLA-4 Checkpoint blockade

Tumour progression

Fig. 3.1 Crosstalk between multiple immune mechanisms determines the outcome of tumour cell
death or growth. The different immunotherapy approaches are summarised and aim to promote
tumour elimination or suppress tumour progression. Key: TAA tumour-associated antigen, TIL
tumour-infiltrating lymphocytes, NK natural killer cell, CD80/86 B7 costimulatory molecules
expressed on the surface of antigen-presenting cells, TRAIL TNF-related apoptosis-inducing
ligand, IL-1 interleukin-1, TNF tumour necrosis factor, IFNγ interferon γ, Treg T regulatory cells,
MDSC myeloid-derived suppressor cells, TAM tumour-associated macrophage, CTLA-4 cytotoxic
T-lymphocyte-associated protein 4, PD-1 programmed death 1, PD-L1 programmed death ligand
1, TIM3 T-cell immunoglobulin and mucin domain-containing protein 3, IL-4 interleukin-4, IL-10
interleukin-10

 enescence and the Senescence-Associated Secretory

S
Phenotype (SASP)

Cellular senescence is a stress-response mechanism aimed at inducing proliferative

arrest in a cell at risk of malignant transformation. In the liver, such process can be
triggered by chronic inflammation, leading to recurring events of hepatocyte death,
compensatory regeneration of hepatocytes and either replicative senescence or
oncogene-driven senescence. A recent study by Eggert et al. [9] was designed to
further address the implications of hepatocyte senescence in HCC development and
progression. The SASP, which comprises of cytokines and chemokines secreted by
senescent cells, is designed to recruit and activate myeloid cells and clear senescent
hepatocytes, thus preventing tumorigenesis. However, this is dependent upon the
context—SASP of senescent hepatocytes may also promote the growth of estab-
lished HCC via recruitment of immunosuppressive immature myeloid cells which
in turn inhibit NK-cell antitumour function, can dampen antitumour T cell responses
28 J. Maurício et al.

and even promote tumour growth by production of growth factors, proteases and
cytokines [9]. Hence, peritumoral tissue senescence contributes to accelerated
tumour growth in mice and to decreased overall and recurrence-free survival in
humans.

Immune Cells Involved in the Immunosuppressive HCC Niche

T Cells

The role of T cells in HCC is complex in that the outcome and prognosis differ
depending on the type of T cell present and its ability to contribute to antitumour
immunity. CD8+ T cells recognise antigens presented on major histocompatibility
(MHC) complex I and kill tumour cells by secretion of cytolytic granules. CD4+
Th1 cells are able to kill tumour cells via the TNF-related apoptosis-inducing ligand
(TRAIL) pathway. They secrete the cytokine interferon gamma (IFN-γ) which acti-
vates antigen-presenting cells (APC) and promotes CD8+ and NK-cell activation.
CD4+ Th2 cells on the other hand are thought to be more immunosuppressive, pro-
ducing the cytokines IL-4, IL-5, IL-10 and IL-13 involved in eosinophil recruitment
and B-cell proliferation. CD4+ regulatory T cells (Treg) promote self-tolerance and
prevention of autoimmunity, and these cells are often increased in patients’ tumours
and blood. Induced by transforming growth factor (TGF)-β, Treg cells can supress
CD8+ and NK cytotoxic killing.
Significant changes in gene expression occur in the liver microenvironment,
which influence HCC progression. A unique gene signature comprising 17 immune-­
related genes was shown to strongly predict the development of venous metastases
and relapse in HCC patients [10]. Here, a global shift from a Th1 to a Th2 cytokine
setting was observed, most likely compounded by the elevated expression of mac-
rophage colony-stimulating factor (CSF1). In this immunosuppressive environment
of the metastatic HCC, pro-inflammatory cytokines such as IL-1, TNF and IFN-γ
were significantly downregulated, whereas the anti-inflammatory cytokines such as
IL-4, IL-5, IL-8, and IL-10 were strongly upregulated. These results centred on
HBV-positive metastatic HCC. However, changes in the proportions of T-cell sub-
types and function associated with HCC are well established in many mouse models
of HCC and in human samples.
A recent study by Ma et al. [11] elucidated a role for CD4+ T cells in NAFLD-­
associated HCC. Here authors showed, in both mouse models and human samples,
that dysregulation of lipid metabolism typical of NAFLD originates a selective loss
of intrahepatic CD4+ but not CD8+ T cells, leading to accelerated hepatocarcino-
genesis. CD4+ T cells had a greater mitochondrial mass than CD8+ T cells and
produced higher levels of mitochondrial-derived ROS, which ultimately caused
their death. Linoleic acid, a fatty acid accumulated in NAFLD, was found to be
largely responsible for this mitochondrial dysfunction. The in vivo use of antioxi-
dants reversed NAFLD-induced HCC. This novel link between obesity-associated
3 The Immunosuppresive Hepatic Niche and HCC 29

lipid accumulation and selective CD4+ T-cell loss suggests a crucial role for CD4+
T cells in the disease progression from NAFLD to HCC.
In the chronically inflamed liver (particularly due to chronic viral infection) and
HCC, it is common to find lymphocytic immune cell aggregates consisting pre-
dominantly of T and B cells, which form distinct structures known as ectopic lym-
phoid structures (ELS). The pro-tumorigenic role of ELS in HCC was recently
reported, demonstrating that these lymphocyte structures—driven by NF-κB activa-
tion—provide a cellular and cytokine microniche that supports the growth and
egress of malignant hepatocyte progenitor cells [12]. The authors identified HCC
with similar chromosomal alterations, pointing towards a common source of malig-
nant progenitor cells originating in ELS [12].
In HBV or HCV hepatitis-associated HCC, T- and B-cell production of the pro-­
inflammatory cytokines lymphotoxin (LT) α and β is markedly upregulated (along-
side their receptor, LTβR) [13]. LTαβ acts mainly on hepatocytes expressing the
LTβR, leading to elevated LT signalling, increased NF-κB activation and the release
of chemokine C-C motif ligand (CCL)2, CCL7, chemokine C-X-C motif ligand
(CXCL)1 and CXCL10 chemokines. The resulting increase in inflammatory cell
recruitment leads to hepatocyte secretion of cytotoxic cytokines (IL-6, IL-1β,
LTαβ), tissue damage, hepatocyte proliferation and death. In this scenario, hepato-
cytes are increasingly more predisposed to genomic instability leading to
HCC. Furthermore, the authors also showed that LTβR inhibition in LTαβ-transgenic
mice with hepatitis suppresses HCC formation [13].

Neutrophils

Neutrophils are often thought to be innocent bystanders in cancer development and

progression. However, controversial roles have emerged in recent years [14–16].
Friedlander and colleagues (2009) identified N1 antitumour neutrophils as being
those that “fight infection and cancer”, while N2 pro-tumour neutrophils—which
display increased arginase and a loss of oxidative burst and phagocytic capacity—
are present in the cancer microenvironment and promote tumour progression [17].
Subsequently, a study led by Wilson et al. [18] further highlighted the pro-tumour
role of neutrophils using a diethylnitrosamine (DEN)-induced model of HCC. A
tumour suppressor function for hepatocellular nfkb1 that controls hepatocyte pro-
duction of neutrophil chemokines was also described. The chemokine network
comprising of S100A9, CXCL1 and CXCL2 was responsible for neutrophil recruit-
ment to the liver, where neutrophils induced ROS-mediated telomere damage in
hepatocytes and increased the development of HCC. In nfkb1 knockout mice, sev-
eral features were exacerbated—namely, steatosis, neutrophil recruitment, fibrosis,
hepatocyte telomere damage and ultimately HCC. By antibody-mediated depletion
of neutrophils or disruption of the chemokine network, these effects were abrogated
and HCC development attenuated.
In another recent neutrophil study, researchers aimed at evaluating the role of
tumour-associated neutrophils (TAN) in the progression of HCC and sorafenib
30 J. Maurício et al.

resistance [19]. Here, they showed that CCL2 and CCL17 were highly expressed by
TAN and peripheral blood neutrophils (PBN) when exposed to conditioned media
from HCC cell lines. The number of CCL2+ or CCL17+ TANs correlated with
tumour size, microvascular invasion, tumour encapsulation, tumour differentiation
and stage. Also, patients whose tumours presented lower levels of CCL2+ or
CCL17+ TAN had longer survival times than those with higher numbers of these
cells. CCL2 enhanced the recruitment of macrophages, whereas CCL17 induced the
recruitment of Treg cells (but not CD4+ CD25– or CD8+ lymphocytes).
Mechanistically, the authors identified the PI3K/Akt and p38/MAPK signalling
pathways as crucial mediators of the transformation of PBN into TAN in
HCC. Regarding the neutrophil impact in sorafenib treatment, it was demonstrated
that sorafenib-induced hypoxia activated NF-κB signalling, thus enhancing CXCL5
secretion by HCC cells, which initiated TAN recruitment. Depletion of TAN resulted
in a reduction in tumour volume and enhancement of the effects of sorafenib [19].

Myeloid-Derived Suppressor Cells (MDSC)

MDSC are a heterogeneous group of immature myeloid cells known for their immu-
nosuppressive and pro-tumoural functions—they can induce tumour angiogenesis
by vascular endothelial growth factor (VEGF) secretion, and they are able to disrupt
both innate and adaptive antitumour activity [8, 20]. For example, Li et al. have
shown that MDSC abrogate natural killer (NK)-cell cytotoxicity, NKG2D expres-
sion and IFN-γ production via membrane-bound TGF-β. Moreover, the authors
demonstrated that depletion of MDSC restored NK function [21].

Macrophages

Macrophages are known to exist in a continuous spectrum of phenotypes, although

they are usually referred to by the simplified nomenclature of M1 (classically acti-
vated, antitumour) and M2 (alternatively activated, pro-tumour) macrophages [22].
The transition between pro- and antitumour phenotypes is fluid and dependent upon
signals from the local microenvironment but can have a profound effect on tumoural
immunity via production of pro/anti-inflammatory mediators and expression of inhibi-
tory molecules against T cells and NK cells such as PD-L1. In a mouse model of HCC,
TGF-β has been shown to skew macrophages towards an M2 pro-tumour phenotype,
inducing the expression of IL-6, and T-cell immunoglobulin and mucin domain-­
containing protein 3 (TIM-3), which is an inhibitory receptor for T cells. TIM-3 expres-
sion by tumour-associated macrophages (TAM) also correlated with tumour grade and
poor survival in HCC patients [23]. It appears that HCC cells can halt the maturation
of infiltrating monocytes into macrophages by secreting cytokines that promote immu-
nosuppressive TAM function, promoting evasion of antitumour immunity.
3 The Immunosuppresive Hepatic Niche and HCC 31

I mmunotherapy Approaches: Harness the Immune System

to Modulate HCC Progression

Natural occurring adaptive immune responses towards HCC have been previously
described and recently reviewed by Makarova-Rusher et al. [7]. Most patients
develop adaptive immune responses against TAA, such as α-fetoprotein (AFP),
telomerase reverse transcriptase (TERT), melanoma antigen gene-A (MAGE-A)
and foetal oncoprotein glypican-3 (GPC3). However, the interactions between the
HCC cells and the immune system mainly foster an immunosuppressive microenvi-
ronment that prevents antigen-mediated clearance of tumour cells via some of the
mechanisms discussed above. A number of clinical trials have evaluated approaches
aimed at enhancing the immune response against TAA or dampening the suppres-
sive signals, as summarised in Table 3.1.

Table 3.1 Immunotherapy clinical trials in HCC (https://clinicaltrials.gov/)

Target/approach Study features Outcome
Vaccines
4 AFP peptides Single arm [24] (2003) AFP-specific
T-cell responses
detected
DC + auto-tumour lysate Single arm, 2 schedules [25] (2005) PR (4) 12.9%,
SD (17) 54.8%, 1-year
OS 40.1 months
Oncolytic viruses
JX-594 oncolytic virus-carrying Dose-finding study (low vs high (2013) ORR 15%,
human GM-CSF genes dose) [26] intrahepatic disease
control rate 46%
Adoptive cell transfer (ACT)
Activated T cells + DC vaccine Non-randomised [27] (2014) RFS 24.5 vs
12.6 months
(p = 0.01), OS 97.7 vs
41.0 months, p = 0.029
CAR-T cell to GPC3 NCT02723942. Randomised, Completed
phase I/II, 60 patients (2017)—NDA
PIK-PD-1 cells NCT02632006. Randomised, Completed
phase I/II, 40 patients, advanced (2017)—NDA
HCC
GPC3 redirected autologous T cells NCT02715362. Single arm, phase Ongoing
I/II, 30 patients, advanced HCC
CIK NCT02568748. Non-­randomised, Ongoing
phase III, 20 patients, advanced
HCC
(continued)
32 J. Maurício et al.

Table 3.1 (continued)

Target/approach Study features Outcome
Cytokines
LY2157299 (small molecule Randomised to 2 doses [29] (2014) OS 36 weeks
inhibitor if TGF-β receptor I)
Immune checkpoint inhibitors
Tremelimumab (anti-CTLA-4) Single arm (HCV patients), PR 17.6%, SD 58.8%,
21 patients [30] OS 8.2 months, TTP
6.48 months
Nivolumab (anti-PD-1) Single arm [32] NDA
Nivolumab (anti-PD-1) vs sorafenib NCT02576509. Randomised, Ongoing
phase III, 726 patients, advanced
HCC
Combination therapies
JX-594 oncolytic virus + anti-PD-1 NCT03071094. Single arm, phase Ongoing
antibody nivolumab as first-line I/II, 30 patients
treatment
Microwave ablation + T NCT02851784. Non-­randomised, Ongoing
lymphocyte phase II/III, 50 patients
JX-594 oncolytic virus + sorafenib NCT02562755. Randomised, Ongoing
vs Sorafenib alone phase III, 600 patients
Precision T cells specific to NCT02638857. Randomised, Completed
multiple common TAA + TACE phase I/II, 60 patients, advanced (2017)—NDA
HCC
Irreversible electroporation + NK NCT03008343. Randomised, Ongoing
cells phase I/II, 20 patients, recurrent
HCC
RFA + CTL vs RFA alone NCT02678013. Randomised, Ongoing
phase III, 210 patients, recurrent
HCC
Radical surgery followed by NCT02632188. Randomised, Completed
DC-PMAT phase I/II, 60 patients (2017)—NDA
Nivolumab or nivolumab in NCT01658878. Non-­randomised, Ongoing
combination with other agents phase I/II, 620 patients, advanced
HCC
Resection + CTL vs resection alone NCT02709070. Randomised, Ongoing
phase III, 210 patients
Carbon-ion radiotherapy + NCT02946138. Single arm, phase Ongoing
GM-CSF II, 44 patients
Durvalumab (anti-­ NCT02519348. Randomised, Ongoing
PD-­L1) + tremelimumab (anti-­ phase II, 440 patients,
CTLA-­4) vs durvalumab or unresectable HCC
tremelimumab alone
Neoadjuvant cabozantinib + NCT03299946. Single arm, phase Ongoing
nivolumab (anti-PD-1) I, 15 patients
3 The Immunosuppresive Hepatic Niche and HCC 33

Table 3.1 (continued)

Target/approach Study features Outcome
LY2157299 (TGF-β receptor I NCT01246986. Non-­randomised, Ongoing
inhibitor) as monotherapy and in phase II, 235 patients
combination with sorafenib or
ramucirumab (anti-VEGFR2)
Ramucirumab (anti-­ NCT02572687. Non-­randomised, Ongoing
VEGFR2) + durvalumab phase I, 114 patients, locally
(anti-PD-L1) advanced and unresectable or
metastatic disease
AFP alpha fetoprotein; CIK cytokine-induced killer cells; CTL cytotoxic T lymphocytes; CTLA-4
cytotoxic T lymphocyte antigen 4; DC dendritic cells; DC-PMAT dendritic cell-precision multiple
antigen T cells; GM-CSF granulocyte-macrophage colony-stimulating factor; GPC3 glypican-3;
NDA no data available; NK natural killer cells; ORR objective response rate; OS overall survival;
PD-1 programmed cell death receptor 1; PD-L1 programmed death ligand 1; PIK-PD-1 pluripo-
tent killer T cells expressing antibodies for programmed death 1; PR partial response; RFA radio-
frequency ablation; RFS recurrence-free survival; SD stable disease; TAA tumour-associated
antigens; TACE transarterial chemoembolisation; TTP time to progression; VEGFR2 vascular
endothelial growth factor receptor 2

Vaccines

AFP was the first TAA to be targeted in the clinic for HCC treatment, in 2003. The
clinical trial reported measurable (albeit transient) CD8+ T-cell responses following
patient immunisation with a vaccine to four HLA-restricted AFP peptides [24].
Improvement in clinical outcomes in vaccine trials can be achieved by co-­
administering dendritic cells (DC)—which are professional antigen-presenting
cells—pulsed with autologous tumour lysates [25].

Adoptive Cell Transfer

Adoptive cell transfer (ACT) is an autologous infusion of ex vivo-selected, ex vivo-­

activated and ex vivo-expanded tumour-infiltrating lymphocytes (TIL), which are
obtained from a patient’s tumour or peripheral blood. Cytokine-induced killer cells
(CIK) and genetically modified T cells can also be used, including TAA-specific T
cells, e.g., GPC3 (Table 3.1). In a clinical trial developed by Shimizu K et al. [27],
patients were treated with an autologous tumour lysate-pulsed DC vaccine and acti-
vated T-cell transfer, after curative resection. Preliminary data support remarkable
differences in OS between patients submitted to surgery alone (41.0 months) and to
combination treatment (97.7 months).
34 J. Maurício et al.

Oncolytic Viruses

The use of oncolytic viruses as vectors for the delivery of transgenes is a relatively
recent approach in the treatment of different types of cancer, including HCC. The
JX-594 (Pexa-Vec) is an oncolytic poxvirus engineered to carry the human gene for
granulocyte-macrophage colony-stimulating factor (GM-CSF) and has been used to
stimulate antitumour responses. This particular virus selectively replicates in cancer
cells due to a disruption of the viral thymidine kinase gene. Infected cells lyse and
release TAA, which can be taken up by antigen-presenting cells, with the additional
expression of GM-CSF heightening the antitumour immune responses. In liver can-
cer, a study in which patients were randomised to one of two doses of vaccinia
demonstrated encouraging results, particularly for the higher dose. Notably, both
doses produced equivalent response rates between injected and distant non-injected
tumours, supporting the establishment of a systemic immune response [26]. An
ongoing trial (NCT03071094) is set to evaluate the safety and efficacy of combining
this oncolytic vaccinia with an immune checkpoint inhibitor (anti-PD-1) as a first-­
line treatment for advanced HCC.

Cytokines

Inflammatory changes associated with liver disease and HCC often display a clear
dysregulation in the balance between immunosuppressive (e.g., IL-10, IL-4, IL-5)
and immune-activating (e.g., TNF, IFN-γ, IL-1) cytokines, promoting Treg expan-
sion and a reduction in DC function. Trials with the immune modulator IFNα
showed early promise which was not realised in a larger trial [28]. Treatments with
cytokine inhibitors for the treatment of HCC are ongoing, with mixed results
reported thus far. TGF-β is known for regulating cell differentiation, proliferation
and death, as well as for its immunosuppressive functions towards T cells, NK cells
and neutrophils [8, 17]. In an ongoing phase II non-randomised clinical trial with a
novel small molecule inhibitor of TGF-β receptor I, LY2157299, preliminary results
suggest AFP expression may influence response [29]. This molecule is currently
being studied in a phase II, non-randomised trial as a single agent and in combina-
tion with sorafenib or ramucirumab, an anti-vascular endothelial growth factor
receptor (VEGFR) 2 monoclonal antibody (NCT01246986).

Immune Checkpoint Inhibitors

T cells and NK cells require organised activation and recognition signals before
they are able to mediate tumour cell killing. However, essential inhibitory signalling
also exists to prevent unwanted T- and NK-cell responses and “self-harm”.
3 The Immunosuppresive Hepatic Niche and HCC 35

Unfortunately, tumour cells can hijack this inhibitory pathway in order to evade
immune cell destruction.
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory check-
point receptor expressed on T cells, upregulated in patients with viral hepatitis.
Upon contact with the activation molecules B7-1 and B7-2 expressed on antigen-­
presenting cells, CTLA-4 transmits co-inhibitory signals to the T cell, impairing its
activity and preventing T-cell immunity [7, 8]. A CTLA-4-targeted antibody therapy
has been clinically evaluated in a phase II, noncontrolled, multicentre clinical trial
for patients with advanced HCC and chronic HCV infection. As a single agent, the
trial reported a partial response rate of 17.6%, stable disease rate of 76.4% and
median OS of 8.2 months, with evidence also of antiviral activity [30].
Another immune checkpoint pathway is that regulated by programmed cell death
1 receptor (PD-1). PD-1 is upregulated in T cells in HCC and its ligands—pro-
grammed death ligand 1 or 2 (PD-L1/PD-L2)—are involved in immune suppression
of T cells by inducing their apoptosis or dysfunction [7, 8]. Monoclonal antibodies
that target this pathway have been approved by the FDA as treatments for other
cancer types, with encouraging results in patients with HCC [31, 32]. In September
2017, the Food and Drug Administration (FDA) granted accelerated second-line
approval for nivolumab, for the treatment of HCC in patients who have progressed
on sorafenib. Approval was based on a 154-patient subgroup of the CHECKMATE-040
(NCT01658878) trial. As a condition of accelerated approval, further trials will be
required to verify the clinical benefit of the antibody for this indication. Ongoing
clinical trials with immune checkpoint inhibitors in combination with other thera-
pies are summarised in Table 3.1, e.g., phase I trial for ramucirumab and durvalumab
(anti-PD-L1) in the setting of locally advanced and unresectable or metastatic gas-
trointestinal or thoracic malignancies, including HCC (NCT02572687) [8].
In addition to CTLA-4 and PD-1, there are other immune checkpoint inhibitors
expressed on activated T cells and NK cells including KIR, TIM-3 and LAG-3 [8]
and further highlight the promise of dual or triple therapy in patients with high
expression of these receptors.

Conclusions and Future Perspectives

As we begin to understand how the chronic inflammatory responses associated

with chronic liver disease, associated with HCC-induced immune tolerance, we
are entering an exciting era of immunotherapy—with perhaps tangible hope for
the first time that effective anti-HCC therapies delivering long-term survival are
on the horizon. How we will select and monitor these therapies and use them
safely in different groups of patients is not yet clear, as the field is hampered by
the lack of either tissue are circulating biomarkers to guide clinical decision
making. Progress in these fields is also set to have a substantial impact on the
future for patients with HCC.
36 J. Maurício et al.

References

1. Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cir-
rhosis. Annu Rev Med. 2016;67:103–17.
2. Knudsen ES, Gopal P, Singal AG. The changing landscape of hepatocellular carcinoma: etiol-
ogy, genetics, and therapy. Am J Pathol. 2014;184(3):574–83.
3. Stickel F. Alcoholic cirrhosis and hepatocellular carcinoma. Adv Exp Med Biol.
2015;815:113–30.
4. Reeves HL, Zaki MY, Day CP. Hepatocellular carcinoma in obesity, type 2 diabetes, and
NAFLD. Dig Dis Sci. 2016;61(5):1234–45.
5. Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol.
2013;10(9):542–52.
6. Alison MR, Nicholson LJ, Lin WR. Chronic inflammation and hepatocellular carcinoma.
Recent Results Cancer Res. 2011;185:135–48.
7. Makarova-Rusher OV, Medina-Echeverz J, Duffy AG, Greten TF. The yin and yang of evasion
and immune activation in HCC. J Hepatol. 2015;62(6):1420–9.
8. Obeid JM, Kunk PR, Zaydfudim VM, Bullock TN, Slingluff CL Jr, Rahma OE. Immunotherapy
for hepatocellular carcinoma patients: is it ready for prime time? Cancer Immunol Immunother.
2017;67(2):161–74.
9. Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, et al. Distinct functions of senescence-­
associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell.
2016;30(4):533–47.
10. Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, et al. Prediction of venous metastases,
recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response
signature of the liver microenvironment. Cancer Cell. 2006;10(2):99–111.
11. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD
causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature.
2016;531(7593):253–7.
12. Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, et al. Ectopic lymphoid structures
function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol.
2015;16(12):1235–44.
13. Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, et al. A lymphotoxin-driven
pathway to hepatocellular carcinoma. Cancer Cell. 2009;16(4):295–308.
14. Sagiv JY, Michaeli J, Assi S, Mishalian I, Kisos H, Levy L, et al. Phenotypic diversity and
plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 2015;10(4):562–73.
15. Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev
Cancer. 2016;16(7):431–46.
16. Powell DR, Huttenlocher A. Neutrophils in the tumor microenvironment. Trends Immunol.
2016;37(1):41–52.
17. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated
neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009;16(3):183–94.
18. Wilson CL, Jurk D, Fullard N, Banks P, Page A, Luli S, et al. NFkappaB1 is a suppressor of
neutrophil-driven hepatocellular carcinoma. Nat Commun. 2015;6:6818.
19. Zhou SL, Zhou ZJ, Hu ZQ, Huang XW, Wang Z, Chen EB, et al. Tumor-associated neutrophils
recruit macrophages and T-regulatory cells to promote progression of hepatocellular carci-
noma and resistance to sorafenib. Gastroenterology. 2016;150(7):1646–58 e17.
20. Medina-Echeverz J, Eggert T, Han M, Greten TF. Hepatic myeloid-derived suppressor cells in
cancer. Cancer Immunol Immunother. 2015;64(8):931–40.
21. Li HQ, Han YM, Guo QL, Zhang MG, Cao XT. Cancer-expanded myeloid-derived sup-
pressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol.
2009;182(1):240–9.
22. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity.
2014;41(1):49–61.
3 The Immunosuppresive Hepatic Niche and HCC 37

23. Yan W, Liu X, Ma H, Zhang H, Song X, Gao L, et al. Tim-3 fosters HCC development by enhanc-
ing TGF-beta-mediated alternative activation of macrophages. Gut. 2015;64(10):1593–604.
24. Butterfield LH, Ribas A, Meng WS, Dissette VB, Amarnani S, Vu HT, et al. T-cell responses
to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with
hepatocellular cancer. Clin Cancer Res. 2003;9(16 Pt 1):5902–8.
25. Lee WC, Wang HC, Hung CF, Huang PF, Lia CR, Chen MF. Vaccination of advanced hepa-
tocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J
Immunother. 2005;28(5):496–504.
26. Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, et al. Randomized dose-­finding
clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med.
2013;19(3):329–36.
27. Shimizu K, Kotera Y, Aruga A, Takeshita N, Katagiri S, Ariizumi SI, et al. Postoperative den-
dritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive
hepatocellular carcinoma. Hum Vaccin Immunother. 2014;10(4):970–6.
28. Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, et al. Long-term results of a random-
ized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular
carcinoma after curative resection. Ann Surg. 2012;255(1):8–17.
29. Faivre SJ, Santoro A, Kelley RK, Merle P, Gane E, Douillard J-Y, et al. A phase 2 study
of a novel transforming growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299
monohydrate (LY), in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol.
2014;32(suppl 3):abstract LBA173.
30. Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, et al. A
clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carci-
noma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8.
31. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients
with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative,
phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502.
32. Sangro B, Crocenzi TS, Welling TH, Iñarrairaegui M, Prieto J, Fuertes C, et al. Phase I dose
escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO- 4538) in patients (pts) with
advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis. J Clin
Oncol. 2013;31(suppl):abstr TPS3111.
Chapter 4
Mechanisms of Disease: The Damaged
Genome in HCC

Matthew Hoare

Abbreviations

AFP Alpha-fetoprotein
CNV Copy number variation
DEN Diethylnitrosamine
EGF Epidermal growth factor
HCC Hepatocellular carcinoma
HH Hereditary haemochromatosis
HSC Hepatic stellate cell
LINEs and SINEs Long and short interspersed nuclear elements
NAFLD Non-alcoholic fatty liver disease
NGS Next-generation sequencing
SNP Single nucleotide polymorphism
SNVs Single nucleotide variants

Introduction

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-­

related death worldwide, with a rising incidence across Europe and the United
States [1, 2]. This relates, in part, to the epidemic of non-alcoholic fatty liver disease
(NAFLD) as a consequence of increasing obesity and prevalence of the metabolic
syndrome. The global annual death toll from HCC remains at similar levels to its

M. Hoare ()
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
Department of Medicine, University of Cambridge, Cambridge, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 39

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_4
40 M. Hoare

incidence [3], which speaks of our lack of ability to cure most patients who present
with this cancer.
Worldwide, the dominant risk factor for the development of HCC is chronic hep-
atitis B virus (HBV) infection, and more than 80% of new cases of HCC occur in
Africa and East Asia where seropositivity rates for HBV are considerably higher
than in Europe and the United States [4]. In Europe and the United States, the pre-
dominant risk factors include NAFLD, alcohol-related liver disease and hepatitis C
virus (HCV) infection.
In recent years there has been an explosion of knowledge about the molecular
mechanisms underpinning the development and progression of HCC [5]. Amongst
these, our knowledge about the structure and function of the hepatocyte genome and
how it changes from chronic liver disease (CLD) to cancer has revealed multiple
potential avenues for future therapeutic exploration in a cancer that currently has
few effective therapies. In this review we discuss the current state of knowledge
about HCC-associated genomic changes, as well as changes in DNA methylation
and their potential role in prognostication or therapy.

Genetic Predisposition to HCC

As the majority of HCCs develop in patients with CLD, hereditary genetic syn-
dromes driving the development of CLD are also associated with the subsequent
development of HCC. Hereditary haemochromatosis (HH), an autosomal recessive
disorder caused mostly by mutations of the HFE gene, results in the excessive tissue
accumulation of iron, particularly in the liver [6]. CLD due to HH is associated with
one of the highest attributable risks for HCC development with around 4%
per annum developing a tumour [7]. A meta-analysis of studies of European patients
found that the C282Y variant of HFE increased risk of HCC development in HH,
but heterozygosity also increased the risk of development of HCC in patients with
alcohol-related liver disease [7]. Other inherited genetic liver diseases such as
Wilson’s disease, porphyria or the glycogen storage disorders are less frequently
associated with the development of HCC [8].
Non-disease-associated genetic variation can also predispose to, or predict, the
subsequent development of HCC. Epidermal growth factor (EGF) signalling has
been implicated in the pathogenesis of HCC [9]. Analysis of the EGF61*G genetic
polymorphism, associated with an increased half-life, secretion and serum concen-
tration of EGF, has shown that a G/G genotype is associated with a fourfold
increased risk of HCC in cirrhotics, compared to the non-risk A/A genotype [10,
11]. This suggests that modulation of EGF signalling could represent a plausible
therapeutic target to prevent HCC development in CLD. Candidate gene or pathway
studies have highlighted numerous single nucleotide polymorphisms (SNPs) in oxi-
dative stress, DNA repair and inflammatory pathways that are associated with the
development of HCC [12]. Subsequent unbiased genome-wide association studies
of an HBV-infected Chinese population identified a susceptibility locus on 1p36
4 Mechanisms of Disease: The Damaged Genome in HCC 41

[13], and a Japanese HCV-infected cohort identified a polymorphism at the MHC

class 1-associated MICA locus [14] as predictive of HCC development. However,
certain SNPs seem to lead to disease-specific risk effects: the PNPLA3 SNP found
in alcoholic and NAFLD-related liver disease can predict the development of HCC
in these conditions [15, 16], but not in patients with HCV [17].
Clearly the use of non-disease-associated genetic features in clinical practice as
either predictors or potential therapeutic targets for the prevention of HCC develop-
ment in cirrhotic patients remains some way away, but could represent a cheap
method of stratifying patients based on levels of risk of developing HCC.

Mechanisms of Genomic Damage in Chronic Liver Disease

Whilst germline genetic variation contributes to the risk of developing HCC, the
bulk of variation is derived from new somatic mutations arising during
CLD. Approximately 70–90% of patients with HCC have a background of long-­
term, usually inflammatory, CLD leading to cirrhosis.
Understanding of the major drivers of acquired genetic changes can be obtained
through exome or whole-genome sequencing analysis of cancer genomes. Population
analyses of sequencing data allow us to understand particular mutagenic signatures
that point to different mechanisms of genome injury [18]. A study of 27 HCCs from
patients with viral hepatitis found T>C/A>G transitions, commonly seen in other
cancers, but also identified C>A/G>T transversions and C>T/G>A transitions, spe-
cific for liver cancer and associated with chronic alcohol abuse [19]. A pan-cancer
analysis of mutational signatures found six individual signatures in HCC, more than
were seen with other cancers. This suggests that multiple and sometimes concurrent
processes contribute to genomic damage in HCC [20]. However, population effects
may predominate: Totoki el al. demonstrated that even in the context of common
CLD aetiology, the most important associate of mutational signature was the genetic
background of the patient [21], suggesting that genomes may become damaged in
different ways even in the face of a common injurious agent.

Chronic Inflammation and Genome Instability

Until recently it remained unclear how chronic liver inflammation drives carcinogen-
esis. However, recent discoveries suggest that inflammatory cytokines, and IL-6 in
particular, may drive genomic instability leading to cancer-associated mutations.
In CLD the primary source of hepatic fibrosis is the activated hepatic stellate cell
(HSC). Normally quiescent, in response to liver injury, they activate to become
secretory myofibroblasts in an adaptive response to restore tissue homeostasis [22].
After activation, they undergo a secretome switch to an inflammatory state, secret-
ing interleukins and chemokines [23] driving an immune-mediated response
42 M. Hoare

c­ learing the HSCs from the microenvironment. In CLD their chronic persistence
becomes maladaptive and drives HCC development; in a mouse model of NAFLD,
inflammatory, senescent HSCs led to the development of HCC. Abrogation of cyto-
kine secretion, through genetic or antibody-mediated inhibition from persistent
HSC, prevents HCC development [24].
Amongst the inflammatory cytokines, IL-6 has been implicated in the develop-
ment of genomic damage. Mdr2−/− mice develop chronic cholestatic liver injury and
subsequently HCC; transplantation of IL-6−/− bone marrow into these mice, leading
to immune-specific loss of IL-6, delays HCC development compared to control ani-
mals [25]. The regenerative response to hemi-hepatectomy in Mdr2−/− mice is asso-
ciated with the subsequent development of HCC. Depletion of IL-6 after
hemi-hepatectomy reduces hepatocyte proliferation and prevents the development
of HCC [26]. Importantly, blockade of IL-6 is also associated with reduced micro-
nuclei formation and therefore may prevent genomic instability in hepatocytes.
Consistently, blockade of IL-6 also reduces murine tumour formation after injection
of the carcinogen diethylnitrosamine (DEN). Mechanistically, IL-6 reduces
p53-dependent apoptosis and promotes β-catenin signalling through canonical
IL-6 signalling, but also promotes angiogenesis through non-canonical IL-6 signal-
ling to adjacent endothelial cells [27].
In a mouse model of impaired TGF-β signalling, treatment with IL-6 led CD133+
hepatic stem cells to undergo the epithelial-mesenchymal transition and become
highly aggressive cancer stem cells, suggesting that not only can IL-6 drive genome
instability, but also plasticity in the preneoplastic context [28]. These findings are
consistent with studies in other tissues of the additive effect of IL-6 and tissue dam-
age upon cellular reprogramming. Chronic tissue damage drives IL-6 secretion, cru-
cial for cellular reprogramming in response to expression of the Yamanaka factors
[29]. Inhibition of IL-6 signalling or prevention of damage-induced senescence, the
source of endogenous IL-6, prevented cellular reprogramming. Therefore, chronic
inflammation, and IL-6 in particular, within CLD is associated with extensive non-
autonomous effects driving genetic instability and promoting cellular plasticity,
potentially underpinning the development of HCC.
Interestingly, IL-6 signalling may underpin the tumorigenesis from other
genomic mutations. As we shall see later, amplification of fibroblast growth factor
19 (FGF19) is a frequent occurrence in human HCC. HCCs with this lesion develop
increased signalling through IL-6/STAT3 and become addicted to this pathway [30].
Pharmacological or genetic inhibition of IL-6 or downstream mediator Jak1 can pre-
vent HCC development in the context of Fgf19 amplification.
As a potential biomarker, IL-6 is significantly elevated in the serum of subjects
with HCC, compared to matched cirrhotic controls [31, 32]. In a case-control study,
Ohishi et al. found that retrospective analysis of serum IL-6 levels predicted the
subsequent development of HCC in atomic bomb survivors [33].
Therefore, IL-6 represents a potentially interesting target as both a biomarker of
HCC development and drug target to prevent development or progression of HCC
in the context of chronic liver diseases.
4 Mechanisms of Disease: The Damaged Genome in HCC 43

Integration of Hepatitis B and Genomic Damage

Whilst originally thought to reside as and episomal covalently closed circular DNA
(cccDNA) within hepatocyte nuclei, there is now abundant evidence that HBV inte-
grates into the human genome [34–36]. This preferentially occurs at dsDNA breaks
[37] or at microsatellites, prone to genomic instability [38]. Integration can disrupt
coding sequences, lead to viral-promoter-driven endogenous gene expression and
chimeric viral-human transcripts and can induce copy number variation (CNV)
[34]. Hepatocytes with integrated HBV genomes undergo clonal expansion [35],
implying a positive selection pressure. Sung et al. studied 81 HBV-infected tumour-­
background liver pairs and identified clustering of integration sites at the TERT
promoter as well as MLL4 (encoding the lysine-methyltransferase KMT2B) and
CCNE1 genes (encoding the cell cycle mediator cyclin E1, regulated by the p53–
p21 pathway) [34]. HBV integration into the TERT promoter has been confirmed in
whole-genome sequencing studies [19, 21] and bait-capture studies [39], where
integration was associated with upregulation of TERT expression.
Therefore, HBV infection leads to genomic damage through integration at sites
that, as we shall see, can drive the development of HCC.

Chronic Inflammation and Endogenous Retrotransposons

More than half of the human genome is comprised of mobile genetic sequences
called transposable elements [40]. Although the majority are epigenetically silenced
and no longer transpose, a small number retain the ability to transpose and induce
genetic damage within somatic cells. One major class of these elements is the ret-
rotransposons that include the long and short interspersed nuclear elements (LINEs
and SINEs). LINE-1-mediated retrotransposition has been demonstrated to lead to
insertional mutagenesis in human cancer: one of the first descriptions was of a
LINE-1 insertion within the MYC gene in breast cancer [41].
More recently it has become clear that retrotransposons can drive mutagenesis in
HCC. 20% of HCCs were found to have a LINE-1 insertion in the MCC gene, asso-
ciated with downregulation and subsequent de-repression of β-catenin signalling
[42]. Whilst LINE-1 insertions in established cancer have been demonstrated,
whether retrotransposition can occur in pre-neoplasia, as a driver of genetic instabil-
ity, is unknown. Interestingly, chronic inflammation, and IL-6 in particular, leads to
a downregulation of DNA methylation of LINE-1 sequences that would normally
repress transposition [43]. Whether chronic inflammation within the liver and sub-
sequent LINE-1-mediated mutagenesis occurs, as an initiating event in HCC, is not
known. Therapeutically, transposition can be inhibited with reverse transcriptase
inhibitors such as lamivudine [44] suggesting a potential mechanism to reduce
genome damage in CLD patients.
44 M. Hoare

Somatic Mutations and Copy Number Variation in HCC

The rapid development in next-generation sequencing (NGS) technologies has led

to a significant advancement in our understanding of the genetic landscape of
HCC. There are now multiple studies utilising either exome or whole-genome
sequencing that have defined multiple somatic mutations (Table 4.1) and CNVs in
various different disease backgrounds [19, 21, 45–52]. Importantly, these studies
analysed specimens derived from hepatic resection and therefore will be biased to
early stage, localised disease. A further caveat of sequencing studies derived from
limited analysis of tumour samples is the problem of tumour heterogeneity (Fig. 4.1).
Divergent evolution of different tumour clones, driven by distinct genetic changes,
has been recognised in a variety of tumours [54], but more recently in the context of
HCC [53, 55], where the problem of synchronous, genetically distinct primary
tumours further complicates the picture. Genetic analysis, for precision or targeted
therapy, would be pointless without analysis of each and every clone within the
overall tumour burden. This problem could be overcome through analysis of circu-
lating tumour cells or DNA (ctDNA) allowing a global picture of tumour-derived
genetic changes. Analysis of ctDNA in patients with HCC can demonstrate CNVs
such as the common loss of 8p [56] and single nucleotide variants (SNVs) [57] and
therefore in the future may represent the best method of identifying tumour
genotypes.
From the current published studies (Table 4.1), there are three dominant genetic
lesions in HCC: mutations of the core promoter of the TERT gene, encoding telom-
erase; mutations of TP53, encoding the p53 tumour suppressor; and mutations of
CTNNB1, encoding β-catenin.

TERT-Promoter Mutations

Telomerase is a highly conserved DNA polymerase responsible for maintenance

and elongation of telomere sequences. Telomeres are hexameric repeat sequences
protecting the end of each chromosome [58]. With each cell division DNA is repli-
cated, but DNA polymerase is unable to transcribe to the chromosomal ends.
Therefore, with each mitosis some telomeric length is lost; critically short telomeres
are detected as DNA double-strand breaks leading to cell cycle arrest [59]. This
proliferative arrest is the molecular correlate of replicative senescence and must be
overcome for tumours to develop. Telomerase, which can prevent replicative senes-
cence, is therefore tightly controlled outside of the stem cell compartment. The
telomerase complex consists of the TERT-encoded enzyme and an RNA template,
TERC, that is copied into new telomeric DNA sequence [60].
Telomerase is not expressed within adult hepatocytes, but patients with germline
inactivating mutations of telomerase develop both pulmonary fibrosis and cirrhosis
[61–63]. Interestingly, in mouse models of telomerase deficiency, cirrhosis and
 4

Table 4.1 A summary of recurrently mutated genes in HCC from next-generation sequencing studies. A summary table of the reported mutation frequency of
a selected group of recurrently mutated genes from studies using either whole-exome sequencing (WES) or whole-genome sequencing of HCC samples. Li
et al. performed WES in 10 patients and then validated their findings using targeted re-sequencing in a further 110 patients
First author n Year of publication TERT TP53 CTNNB1 ARID1A ALB AXIN1 ARID2 KEAP1 PIK3CA
TCGA 363 2017 44% 31% 27% 7% 13% 8% 5% 5% 4%
Schulze 243 2015 60% 24% 37% 13% 13% 11% 7% 4% 2%
Jhunjhunwala 42 2014 36% 17% 14%
Totoki 488 2014 68% 68% 31% 25% 21% 12% 13% 1%
Kan 88 2013 35% 16% 2% 5% 3%
Cleary 87 2013 18% 10% 2% 1% 8%
Fujimoto 27 2012 52% 11% 26% 11% 11%
Mechanisms of Disease: The Damaged Genome in HCC

Guichard 24 2012 21% 33% 17% 15% 6%

Huang 10+110 2012 28% 13% 4%
Li 10 2011 12% 24% 6%
Mean 57% 32% 23% 13% 12% 12% 6% 8% 2%
Frequency of mutation of common genes in HCC sequencing studies
45
46 M. Hoare

a Potential genetic heterogeneity in primary HCC

Single primary with Multiple synchronous

intrahepatic metastases primary HCC

Nodule within a nodule Multiple separate

tumour clones
b Potential for heterogeneous recurrence after resection

Recurrence
of primary tumour

Metachronous
HCC for resection new primary

Fig. 4.1 Genetic heterogeneity in HCC. (a) HCC develops on a background of chronic liver disease
in the majority of cases, where the liver has undergone a cancerisation field effect. Therefore, in a
multifocal tumour, it is currently radiologically impossible to distinguish between a single primary
lesion with intrahepatic metastases and multiple synchronous, genetically-distinct primaries.
Similarly, divergent clones with private genetic changes can arise within tumours, the so-­called
‘nodule within a nodule’ or a large primary containing multiple separate, genetically-distinct clones
resulting that genetic analysis of a single biopsy specimen will be insufficient to understand the
complete genomic landscape of the tumour. (b) After hepatic resection for HCC, a new tumour
deposit within the remnant liver cannot be assumed to be genetically identical to the original tumour,
as it may represent a metachronous, genetically-distinct primary tumour. Adapted from Lu et al. [53]

p­ rogressive liver failure develop that can be rescued through re-expression of telom-
erase [64]. These findings suggest that the liver is susceptible to replicative senes-
cence and subsequent declining function. This is potentially important if
telomerase-­modulating therapy is to be considered: telomerase inhibition to treat
telomerase-­expressing HCC may be complicated by declining function in the non-
tumourous background liver.
Sequencing studies have found that acquired mutations in the core promoter
sequences of TERT, leading to increased expression of telomerase [21, 65], are the
most common somatic changes seen in HCC. Totoki et al. found that 68% of cases
of HCC, from a variety of disease backgrounds, had SNVs or focal amplifications
of the TERT promoter [21]. Similarly, Nault et al. found 59% of HCCs, but also a
significant minority of preneoplastic hepatic adenomas [65] and dysplastic nodules
4 Mechanisms of Disease: The Damaged Genome in HCC 47

[66] had similar TERT promoter mutations, suggesting that these are amongst the
earliest genetic lesions in the dysplasia to carcinoma sequence in the liver. Similarly
to cancer-associated indels, HBV integration at the TERT promoter and subsequent
activation have been demonstrated [21, 67], suggesting that telomerase activation is
such an important event in HCC development that selection pressure drives multiple
mechanisms of TERT re-expression in human HCC.

Mutation or Loss of p53

p53 is one of the mostly commonly mutated or deleted genes in human cancer, sug-
gesting that it is amongst the most important tumour suppressor proteins [68]. It
controls the response to cellular stress or damage and underpins both apoptosis and
senescence. Mutations of p53 have long been associated with HCC as aflatoxin B1,
produced by food-contaminating Aspergillus sp., is associated with between 5 and
28% of the global burden of HCC cases [69]; aflatoxin exposure is associated with
a highly specific R249S mutation of the TP53 gene [70]. Subsequent sequencing
studies of non-aflatoxin-associated cases have found a range of SNVs of TP53 or
larger indels on 17p [19, 21, 45, 46, 48–50], with the recent TCGA dataset suggest-
ing that 33% of HCCs have mutated or lost p53 [48] (see Table 4.1). There is no
clustering of mutations across the coding region to suggest specific domains are
more important [71], but a spread of missense and truncating mutations that reduce
expression and likely impair its function or chromatin-binding (Fig. 4.2a).
The canonical p53 pathway involves constitutive repression of p53 by MDM2
that is relieved by cellular stress driving proteasomal degradation of MDM2; release
and subsequent chromatin-binding of p53 drive a highly conserved transcriptional
programme, including the tumour suppressor and cell cycle regulator p21.
Interestingly, whilst MDM2 and CDKN1A (the gene encoding p21) are frequently
mutated in other cancer types, they are rarely mutated in HCC. Similarly, the TP53
family members, TP63 and TP73, are also infrequently mutated stressing the impor-
tance of p53 loss in the pathogenesis of HCC (Fig. 4.2). Importantly, loss or mutation
of TP53 has a significant negative impact on prognosis after hepatic resection, with
p53-null tumours significantly more likely to recur (TCGA data, Fig. 4.2c), have a
higher alpha-fetoprotein (AFP) level and poorer differentiation grade [74, 75].
Mutations in TP53 are not currently targetable, but there is significant interest
in the potential of molecular chaperones designed to refold mutated p53 into a
wild-­type conformational structure and restore some level of p53 function [76].
Other potential therapeutic options include the use of hepatotropic adenoviral vec-
tors to deliver and re-express wild-type p53 in liver tumours; one study has utilised
trans-­arterial embolisation to deliver these directly to tumour tissue with some
success [77].
48 M. Hoare

a TP53 mutations in HCC R249S

11
# Mutations

0
P53.. P53 P53_tetr..

0 100 200 300 393 aa

b p53 family oncoprint in HCC
M unc tion
io g

at e
Tr ele

at in

ut ns
ut at

ion
n
D

M sse
e p

i
M
De

TP53 33%
TP63 2.7%
TP73 3%
CDKN1A 4%
MDM2 2.2%
Amplification
c Somatic TP53 indels and survival in HCC after resection
100%

90%

80%

70%
Overall survival (%)

60%

50%

40%

30%

20% Cases with indels of TP53

Cases with wild-type TP53
10% Logrank Test P = 0.0256
0%
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Months

Fig. 4.2 Mutations of TP53 and their prognosis in HCC. (a) Distribution of somatic SNVs across
the TP53 gene, from samples in the TCGA dataset. p53 trans-activation domain in green, DNA-­
binding domain in red and tetramerisation domain shown in purple. There is a small cluster at
amino acid 249 in the DNA-binding domain associated with exposure to aflatoxin B1. (b)
Oncoprint of indels and larger-scale deletions of TP53, the TP53 family members TP63 and TP73,
the p53-regulator MDM2 and the canonical p53 transcriptional target p21 (CDKN1A) demonstrat-
ing alterations at significant frequency only occur in TP53 itself. (c) Loss or indels of TP53 in HCC
are associated with a significantly worse prognosis after hepatic resection. Comparison by log rank
test. Data and visualisation from the TCGA dataset [48] and cBioPortal (http://www.cbioportal.
org) [72, 73]
4 Mechanisms of Disease: The Damaged Genome in HCC 49

Mutations in the Wnt/β-Catenin Pathway

The association between mutations in CTNNB1, the gene encoding β-catenin and
HCC was identified in the late 1990s when several groups found N-terminally
clustered missense mutations in 30–40% of HCC cases from both Europe and
Asia [78, 79]. These mutations were associated with increased nuclear localisa-
tion of β-catenin in tumour specimens [78, 80], reduced rates of large calibre
vascular invasion and improved prognosis compared to HCC with wild-type
CTNNB1 [75, 81].
β-Catenin is normally held in the cytoplasm by a multimolecular complex
containing APC, AXIN1 and GSK-3β. Upon binding of one of the Wnt family of
extracellular proteins to the membrane-bound Frizzled receptor, GSK-3β is dis-
placed from the complex releasing β-catenin to traverse to the nucleus, bind to
LEF/TCF transcription factors and recruit transcriptional co-activators to Wnt
target genes [82]. The stability of the β-catenin protein is controlled by phos-
phorylation at the N-terminus; mutations at this site are associated with greatly
increased stability of the protein; thus mutations of CTNNB1 are clustered at this
site [82].
Recent NGS studies have confirmed the earlier findings, with between 30 and
40% of HCCs found to have indels or deletions of CTNNB1 (Table 4.1), but also
a significant burden of genetic lesions in other members of the Wnt/β-catenin
pathway, particularly AXIN1 [21, 46, 48–50, 52]. Interestingly, nearly all studies
have demonstrated a near mutual exclusivity between mutations of TP53 and
CTNNB1.
Therapeutic targeting of the Wnt/β-catenin pathway is not currently possible,
with few agents progressing beyond phase 1 trials [83], but mouse models of
β-catenin-driven colon cancer suggest that restoration of normal β-catenin function
is associated with complete tumour regression in that context [84], raising hope that
if therapeutic vulnerabilities could be established, effective treatments could be
developed for this subtype of liver cancer.

Other High-Frequency Mutations in HCC

All of the NGS studies have suggested that HCC contains frequent mutations of
genes involved in regulation of chromatin structure and maintenance of the epig-
enome. Members of the SWI/SNF complex, responsible for nucleosome position-
ing, have been found to be recurrently mutated in a variety of human cancers and
notably mutated at much higher frequency than components of other chromatin-­
modifying pathways [85]. Therefore, this pathway likely represents a conserved
tumour suppressor mechanism. In HCC ARID1A and ARID2 are mutated at
50 M. Hoare

frequencies of up to 26% and 11%, respectively [19, 21, 46, 48, 49, 52]. Subsequent
functional genomic studies have found that ARID1B is crucial for oncogene-
induced senescence and suppression of RAS-induced HCC development in a mouse
model [86].
Members of the mixed-lineage leukaemia (MLL) family of histone methyltrans-
ferases are responsible for trimethylation of H3K4, associated with active transcrip-
tion. MLL is also involved with signalling through the HGF-cMET pathway [87].
Sequencing studies have demonstrated that various members of the MLL family are
mutated in HCC [19, 46, 48, 50].

Copy Number Variation in HCC

In addition to small-scale genomic damage, multiple studies have demonstrated

larger-scale chromosomal rearrangements, amplifications and deep deletions in
HCC. Utilising array-based comparative genomic hybridisation in HCC, many
groups have found amplifications and losses at key loci encoding putative onco-
genes and tumour suppressor genes [18]. One of the first studies utilised a targeted
oncogene panel array to demonstrate recurrent amplifications of CCND1, the gene
encoding cyclin D1 required for G1 to S-phase transition, at 11q13 (the locus that
also encodes FGF19), TERC, encoding the RNA component of telomerase and
MYC, nearly ubiquitously dysregulated in human cancers [88]. Subsequent studies
have confirmed these findings and demonstrated recurrent widespread CNV with
gains at 1q, 8q and 20q and losses at 1p, 4q, 8p, 13q, 16q and 17p in HCC specimens
from patients with different CLDs. In particular, loss of 8p and subsequent tran-
scriptomic changes in HCC from a range of background diseases is associated with
poor prognosis after resection [89].
The recently reported TCGA dataset has again confirmed many of the previously
reported CNVs, but also given us much greater insight into the relative frequency of
these changes in HCC (Table 4.2) [48]. Integrative analysis of indels and CNVs in
HCC has shown how two key tumour suppressor pathways are inactivated by dis-
tinct mechanisms. As discussed earlier TP53 is frequently mutated in HCC, pre-
dominantly through missense indels, whereas a second complementary pathway,
the p16-Rb pathway, is inactivated through larger-scale deletions of either CDKN2A
[90, 91] or RB1 [92]. Therefore, it is likely that different mechanisms of genome
injury are responsible for inactivation of these two tumour suppressor pathways.
P16, encoded by CDKN2A at the INK4A/ARF locus on 9p, is responsible for
repression of CDK4 and CDK6, which in combination with cyclin D1 in turn
repress Rb (see Fig. 4.3). Therapeutically novel agents such as palbociclib [93], a
p16-mimetic that represses CDK4 and 6, show promise in HCC. However, it will be
important to understand the pattern of loss of these different tumour suppressors in
patients with HCC. CDK4/CDK6 inhibition will effectively repress cell cycle pro-
gression in the context of TP53 mutations and loss of p16 through deep deletions of
the INK4A/ARF locus or epigenetic repression of CDKN2A, but would be inactive
in the context of deletions of RB1.
4 Mechanisms of Disease: The Damaged Genome in HCC 51

Table 4.2 Recurrent copy number alterations in HCC from the TCGA dataset (n = 442). GISTIC-­
based copy number variation (CNV) analysis of HCCs in the TCGA dataset demonstrating
common, recurrent chromosomal amplifications or deletions ranked by q-value. Data derived from
cBioPortal (http://www.cbioportal.org/) showing the number of genes affected and selected proto-­
oncogenes or tumour suppressor genes at these cytobands
Amp/ Number of genes Selected genes
Del Chr Cytoband at this locus at this locus Q-Value
Del 13 13q14.2 2 RB1 2.30E-­37
Del 1 1p36.31 114 TNFRSF4, TP73 1.20E-­33
Amp 11 11q13.3 2 CCND1, FGF19 3.40E-­29
Amp 1 1q21.3 3 2.10E-­24
Del 4 4q35.1 5 1.80E-­23
Del 9 9p21.3 2 CDKN2A CDKN2B 3.10E-­22
Amp 8 8q24.21 111 MYC 1.20E-­21
Del 1 1p36.11 267 HDAC1, LCK, ARID1A 1.70E-­20
Del 8 8p23.2 1 2.10E-­19
Del 6 6q27 4 3.40E-­15
Amp 17 17q25.3 7 1.30E-­14
Amp 3 3q26.31 1 6.70E-­11
Amp 5 5p15.33 6 TERT 1.10E-­10
Amp 13 13q33.3 148 ATP4B, FGF14 2.20E-­10
Del 17 17p13.1 252 4.00E-­10
Amp 13 13q32.3 45 6.80E-­10
Del 10 10q23.31 3 PTEN 2.10E-­09

Damage to the Epigenome in HCC

In addition to extensive genomic damage in HCC, there is abundant evidence that

epigenomic damage also occurs. As already discussed, DNA-sequencing studies
have identified multiple changes to chromatin-regulator genes of the SWI/SNF
complex and the MLL family, responsible for histone methylation.
The epigenome serves to regulate chromatin architecture and gene expression
through (1) chemical modification of DNA, particularly methylation, (2) chemical
modification of histones which define chromatin states and regulate transcription
and (3) expression of non-coding RNAs such as long non-coding RNA and micro-­
RNAs that regulate gene expression post-transcriptionally. The epigenetics of HCC
has been extensively reviewed elsewhere [94, 95]; therefore, only the role of DNA
methylation in HCC will be discussed.

DNA-Methylation Changes in HCC

Methylation of cytosine residues at CpG dinucleotides is stably transmitted to

daughter cells at mitosis by methyltransferases of the DNMT family. Clusters of
CpG sequences, termed CpG islands, are found adjacent to gene promoter sequences
52 M. Hoare

p53

p21 p16

CDK2 CDK4/6 CDK4/6

Cyclin E Cyclin D1 Inhibitors

Rb

Cell cycle

Fig. 4.3 p53 and p16 signalling pathways. The p53-p21 and p16-Rb tumour suppressor pathways
co-operatively regulate cell cycle progression. Both pathways are inactivated in HCC by distinct
mechanisms. Novel therapies, such as the CDK4/CDK6 inhibitors will only work in the context of
functional Rb

[96]. CpG island methylation is associated with transcriptional repression through

sterically inhibiting the transcriptional machinery from accessing the chromatin, but
also through recruitment of specific transcriptional inhibitors.
Global hypomethylation of CpG elements tends to occur as an early event in
many human cancers [97], and this pattern may also be seen in HCC [98], where it
seems to be associated with chromosomal instability. Several groups have defined
locus-specific methylation patterns and found site-specific increases in DNA meth-
ylation with associated transcriptional repression in HCC [98–101]. Promoter meth-
ylation increases from normal liver to cirrhosis, dysplasia and then HCC [102].
Importantly, genome-wide studies have demonstrated a significant increase in DNA
methylation at the INK4A/ARF locus [99, 100], consistent with previous candidate
gene approaches demonstrating p16-promoter hypermethylation [90, 91]. Therefore,
not only is p16 lost through deletion but also inactivated through epigenetic repres-
sion. Analysis of the prognostic implications of promoter DNA methylation shows
that epigenetic repression of a small group of genes, including both CDKN2A and
APC (a negative regulator of β-catenin), is associated with impaired prognosis com-
pared to HCCs without promoter methylation at these loci [103]. Genome-wide
4 Mechanisms of Disease: The Damaged Genome in HCC 53

analysis has identified a 36-gene methylation signature, including at APC, predic-

tive of poor prognosis after hepatic resection [104]. Site-specific methylation also
depends upon the β-catenin and p53 status of the HCC studied, implying distinct
mechanisms of epigenetic change occur in tumours of different genotypes [105].
Whilst therapeutic targeting of the epigenome, and DNA methylation in particu-
lar, remains some distance away, in vitro reversal of HCC-associated DNA-­
methylation changes has identified novel tumour suppressor genes that had not
previously been identified as their coding sequences were intact, eluding NGS stud-
ies [106].
Several groups have demonstrated the feasibility of analysing tumoral DNA-­
methylation changes from ctDNA [99, 107]. The ability to detect CDKN2A-specific
or whole-genome DNA-methylation profiles suggests that in the future stratification
by DNA and methyl-DNA sequencing will be possible to obtain information about
mutations, as well as epigenetically regulated expression changes in HCC.

Conclusions

CLD leads to extensive damage to the coding and non-coding DNA sequences of
the hepatocyte genome, but also damage to the epigenome that regulates gene
expression. Whilst tumour heterogeneity presents a significant problem for sequenc-
ing of single biopsies, the analysis of circulating tumour cells or ctDNA holds the
promise of seeing the global mutational burden within tumours. We have only begun
to understand the complex genomic architecture of HCCs and understand even less
of the driver changes that underpin the initiation of this disease. However, with
integration of this knowledge, we can start to target these genes and pathways to
finally improve the prognosis of patients with HCC.

Acknowledgements MH is supported by a CRUK Clinician Scientist Fellowship (C52489/

A19924).

References

1. Konfortion J, Coupland VH, Kocher HM, Allum W, Grocock MJ, Jack RH. Time and depri-
vation trends in incidence of primary liver cancer subtypes in England. J Eval Clin Pract.
2014;20(4):498–504.
2. El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States:
where are we? Where do we go? Hepatology. 2014;60(5):1767–75.
3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA
Cancer J Clin. 2011;61(2):69–90.
4. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology.
2012;142(6):1264–1273.e1.
5. Zucman-Rossi J, Villanueva A, Nault J-C, Llovet JM. Genetic landscape and biomarkers of
hepatocellular carcinoma. Gastroenterology. 2015;149(5):1226–1239.e4.
54 M. Hoare

6. Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment.

Gastroenterology. 2010;139(2):393–408. –408.e1–2
7. Jin F, Qu LS, Shen XZ. Association between C282Y and H63D mutations of the HFE gene
with hepatocellular carcinoma in European populations: a meta-analysis. J Exp Clin Cancer
Res. 2010;29(1):18.
8. Villanueva A, Newell P, Hoshida Y. Inherited hepatocellular carcinoma. Best Pract Res Clin
Gastroenterol. 2010;24(5):725–34.
9. Motoo Y, Sawabu N, Nakanuma Y. Expression of epidermal growth factor and fibroblast
growth factor in human hepatocellular carcinoma: an immunohistochemical study. Liver.
1991;11(5):272–7.
10. Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, Chung RT, et al. Epidermal
growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in
patients with cirrhosis. JAMA. 2008;299(1):53–60.
11. Abu Dayyeh BK, Yang M, Fuchs BC, Karl DL, Yamada S, Sninsky JJ, et al. A functional
polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular
carcinoma. Gastroenterology. 2011;141(1):141–9.
12. Nahon P, Zucman-Rossi J. Single nucleotide polymorphisms and risk of hepatocellular carci-
noma in cirrhosis. J Hepatol. 2012;57(3):663–74.
13. Zhang H, Zhai Y, Hu Z, Wu C, Qian J, Jia W, et al. Genome-wide association study identifies
1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B
virus carriers. Nat Genet. 2010;42(9):755–8.
14. Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, et al. Genome-wide asso-
ciation study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat
Genet. 2011;43(5):455–8.
15. Liu YL, Patman GL, Leathart JBS, Piguet AC, Burt AD, Dufour JF, et al. Carriage of the
PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver
disease associated hepatocellular carcinoma. J Hepatol. 2014;61(1):75–81.
16. Trépo E, Nahon P, Bontempi G, Valenti L, Falleti E, Nischalke H-D, et al. Association
between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from
a meta-analysis of individual participant data. Hepatology. 2014;59(6):2170–7.
17. Guyot E, Sutton A, Rufat P, Laguillier C, Mansouri A, Moreau R, et al. PNPLA3 rs738409,
hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis. J
Hepatol. 2013;58(2):312–8.
18. Shibata T, Aburatani H. Exploration of liver cancer genomes. Nat Rev Gastroenterol Hepatol.
2014;11(6):340–9.
19. Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome
sequencing of liver cancers identifies etiological influences on mutation patterns and recur-
rent mutations in chromatin regulators. Nat Genet. 2012;44(7):760–4.
20. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Biankin AV, et al.
Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.
21. Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, et al. Trans-ancestry
mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46(12):1267–73.
22. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.
Physiol Rev. 2008;88(1):125–72.
23. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, et al. Senescence of
activated stellate cells limits liver fibrosis. Cell. 2008;134(4):657–67.
24. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced
gut microbial metabolite promotes liver cancer through senescence secretome. Nature.
2013;499(7456):97–101.
25. Kong L, Zhou Y, Bu H, Lv T, Shi Y, Yang J. Deletion of interleukin-6 in monocytes/macro-
phages suppresses the initiation of hepatocellular carcinoma in mice. J Exp Clin Cancer Res.
2016;35(1):131.
26. Lanton T, Shriki A, Nechemia-Arbely Y, Abramovitch R, Levkovitch O, Adar R, et al.
Interleukin 6-dependent genomic instability heralds accelerated carcinogenesis following
4 Mechanisms of Disease: The Damaged Genome in HCC 55

liver regeneration on a background of chronic hepatitis. Hepatology. 2017;65(5):1600–11.

Available from:. https://doi.org/10.1002/hep.29004.
27. Bergmann J, Müller M, Baumann N, Reichert M, Heneweer C, Bolik J, et al. IL-6 trans-­
signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology.
2017;65(1):89–103.
28. Mitra A, Yan J, Xia X, Zhou S, Chen J, Mishra L, et al. IL6-mediated inflammatory loop
reprograms normal to epithelial-mesenchymal transition(+) metastatic cancer stem cells
in preneoplastic liver of transforming growth factor beta-deficient β2-spectrin(+/−) mice.
Hepatology. 2017;65(4):1222–36.
29. Mosteiro L, Pantoja C, Alcazar N, Marión RM, Chondronasiou D, Rovira M, et al. Tissue
damage and senescence provide critical signals for cellular reprogramming in vivo. Science.
2016;354:6315.
30. Zhou M, Yang H, Learned RM, Tian H, Ling L. Non-cell-autonomous activation of IL-6/
STAT3 signaling mediates FGF19-driven hepatocarcinogenesis. Nat Commun. 2017;8:15433.
31. Porta C, De Amici M, Quaglini S, Paglino C, Tagliani F, Boncimino A, et al. Circulating
interleukin-6 as a tumor marker for hepatocellular carcinoma. Ann Oncol. 2008;19(2):353–8.
32. Giannitrapani L, Cervello M, Soresi M, Notarbartolo M, La Rosa M, Virruso L, et al.
Circulating IL-6 and sIL-6R in patients with hepatocellular carcinoma. Ann N Y Acad Sci.
2002;963:46–52.
33. Ohishi W, Cologne JB, Fujiwara S, Suzuki G, Hayashi T, Niwa Y, et al. Serum interleukin-
­6 associated with hepatocellular carcinoma risk: a nested case-control study. Int J Cancer.
2014;134(1):154–63.
34. Sung W-K, Zheng H, Li S, Chen R, Liu X, Li Y, et al. Genome-wide survey of recurrent HBV
integration in hepatocellular carcinoma. Nat Genet. 2012;44(7):765–9.
35. Jiang Z, Jhunjhunwala S, Liu J, Haverty PM, Kennemer MI, Guan Y, et al. The effects of
hepatitis B virus integration into the genomes of hepatocellular carcinoma patients. Genome
Res. 2012;22(4):593–601.
36. Brechot C, Pourcel C, Louise A, Rain B, Tiollais P. Presence of integrated hepati-
tis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature.
1980;286(5772):533–5.
37. Bill CA, Summers J. Genomic DNA double-strand breaks are targets for hepadnaviral DNA
integration. Proc Natl Acad Sci U S A. 2004;101(30):11135–40.
38. Feitelson MA, Lee J. Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis.
Cancer Lett. 2007;252(2):157–70.
39. Toh ST, Jin Y, Liu L, Wang J, Babrzadeh F, Gharizadeh B, et al. Deep sequencing of the
hepatitis B virus in hepatocellular carcinoma patients reveals enriched integration events,
structural alterations and sequence variations. Carcinogenesis. 2013;34(4):787–98.
40. Kazazian HH, Moran JV. Mobile DNA in health and disease. N Engl J Med.
2017;377(4):361–70.
41. Morse B, Rotherg PG, South VJ, Spandorfer JM, Astrin SM. Insertional mutagenesis of the
myc locus by a LINE-1 sequence in a human breast carcinoma. Nature. 1988;333(6168):87–90.
42. Shukla R, Upton KR, Muñoz-Lopez M, Gerhardt DJ, Fisher ME, Nguyen T, et al.
Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma.
Cell. 2013;153(1):101–11.
43. Gasche JA, Hoffmann J, Boland CR, Goel A. Interleukin-6 promotes tumorigenesis by alter-
ing DNA methylation in oral cancer cells. Int J Cancer. 2011;129(5):1053–63.
44. Jones RB, Garrison KE, Wong JC, Duan EH, Nixon DF, Ostrowski MA. Nucleoside analogue
reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition. PLoS
One. 2008;3(2):e1547.
45. Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, et al. Whole-genome sequencing identifies
recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23(9):1422–33.
46. Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome
sequencing of hepatocellular carcinomas identifies new mutational signatures and potential
therapeutic targets. Nat Genet. 2015;47(5):505–11.
56 M. Hoare

47. Huang J, Deng Q, Wang Q, Li K-Y, Dai J-H, Li N, et al. Exome sequencing of hepatitis B
virus-associated hepatocellular carcinoma. Nat Genet. 2012;44(10):1117–21.
48. Cancer Genome Atlas Research Network. Electronic address: [email protected], Cancer
genome atlas research network. Comprehensive and integrative genomic characterization of
hepatocellular carcinoma. Cell. 2017;169(7):1327–1341.e23.
49. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analy-
sis of somatic mutations and focal copy-number changes identifies key genes and pathways
in hepatocellular carcinoma. Nat Genet. 2012;44(6):694–8.
50. Cleary SP, Jeck WR, Zhao X, Chen K, Selitsky SR, Savich GL, et al. Identification of driver
genes in hepatocellular carcinoma by exome sequencing. Hepatology. 2013;58(5):1693–702.
51. Jhunjhunwala S, Jiang Z, Stawiski EW, Gnad F, Liu J, Mayba O, et al. Diverse modes of
genomic alteration in hepatocellular carcinoma. Genome Biol. 2014;15(8):436.
52. Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, et al. Inactivating muta-
tions of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet.
2011;43(9):828–9.
53. Lu L-C, Hsu C-H, Hsu C, Cheng A-L. Tumor heterogeneity in hepatocellular carcinoma:
facing the challenges. Liver Cancer. 2016;5(2):128–38.
54. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor
heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med.
2012;366(10):883–92.
55. Zhai W, Lim TK-H, Zhang T, Phang S-T, Tiang Z, Guan P, et al. The spatial organization
of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular
carcinoma. Nat Commun. 2017;8:4565.
56. Jiang P, Chan CWM, Chan KCA, Cheng SH, Wong J, Wong VW-S, et al. Lengthening
and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci.
2015;112(11):E1317–25.
57. Ono A, Fujimoto A, Yamamoto Y, Akamatsu S, Hiraga N, Imamura M, et al. Circulating tumor
DNA analysis for liver cancers and its usefulness as a liquid biopsy. Cell Mol Gastroenterol
Hepatol. 2015;1(5):516–34.
58. Blackburn EH. Switching and signaling at the telomere. Cell. 2001;106(6):661–73.
59. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, von Zglinicki T,
et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature.
2003;426(6963):194–8.
60. Artandi SE, DePinho RA. Telomeres and telomerase in cancer. Carcinogenesis.
2010;31(1):9–18.
61. Calado RT, Brudno J, Mehta P, Kovacs JJ, Wu C, Zago MA, et al. Constitutional telomerase
mutations are genetic risk factors for cirrhosis. Hepatology. 2011;53(5):1600–7.
62. Calado RT, Young NS. Telomere Diseases. N Engl J Med. 2009;361(24):2353–65.
63. Hartmann D, Srivastava U, Thaler M, Kleinhans KN, N'Kontchou G, Scheffold A,
et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology.
2011;53(5):1608–17.
64. Rudolph KL, Chang S, Millard M, Schreiber-Agus N, DePinho RA. Inhibition of experimen-
tal liver cirrhosis in mice by telomerase gene delivery. Science. 2000;287(5456):1253–8.
65. Nault J-C, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, et al. High frequency
of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma
and preneoplastic lesions. Nat Commun. 2013;4:2218.
66. Nault J-C, Calderaro J, Di Tommaso L, Balabaud C, Zafrani ES, Bioulac-Sage P, et al.
Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration
in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis.
Hepatology. 2014;60(6):1983–92.
67. Paterlini-Bréchot P, Saigo K, Murakami Y, Chami M, Gozuacik D, Mugnier C, et al. Hepatitis
B virus-related insertional mutagenesis occurs frequently in human liver cancers and recur-
rently targets human telomerase gene. Oncogene. 2003;22(25):3911–6.
4 Mechanisms of Disease: The Damaged Genome in HCC 57

68. Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour sup-
pression. Nat Rev Cancer. 2014;14(5):359–70.
69. Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment.
Environ Health Perspect. 2010;118(6):818–24.
70. Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocel-
lular carcinoma from southern Africa. Nature. 1991;350(6317):429–31.
71. Qi L-N, Bai T, Chen Z-S, Wu F-X, Chen Y-Y, De Xiang B, et al. The p53 mutation spectrum
in hepatocellular carcinoma from Guangxi, China : role of chronic hepatitis B virus infection
and aflatoxin B1 exposure. Liver Int. 2015;35(3):999–1009.
72. Cerami E, et al. The cBio cancer genomics portal: an open platform for exploring multidi-
mensional cancer genomics data. Cancer Discov. 2012;2(5):401–4. PMID: 22588877
73. Gao J, et al. Integrative analysis of complex cancer genomics and clinical profiles using the
cBioPortal. Sci Signal. 2013;6(269):23550210.
74. Hayashi H, Sugio K, Matsumata T, Adachi E, Takenaka K, Sugimachi K. The clinical sig-
nificance of p53 gene mutation in hepatocellular carcinomas from Japan. Hepatology.
1995;22(6):1702–7.
75. Calderaro J, Couchy G, Imbeaud S, Amaddeo G, Letouzé E, Blanc JF, et al. Histological
subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour
classification. J Hepatol. 2017;67(4):727–38.
76. Bykov VJN, Wiman KG. Mutant p53 reactivation by small molecules makes its way to the
clinic. FEBS Lett. 2014;588(16):2622–7.
77. Liu Y, Zhang Y, Bautista D, Tang S, Zhou J, Li C, et al. Trans-arterial p53-gene-embolization
with gelatin sponge microparticles for hepatocellular carcinoma with BCLC stage B: single-­
center experience. Cell Biochem Biophys. 2015;71(1):99–104.
78. La Coste DA, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, et al. Somatic
mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas.
Proc Natl Acad Sci U S A. 1998;95(15):8847–51.
79. Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, et al. Activation of the beta-­
catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3.
Cancer Res. 1998;58(12):2524–7.
80. Van Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA. Nuclear accumula-
tion of mutated β-catenin in hepatocellular carcinoma is associated with increased cell prolif-
eration. Am J Pathol. 1999;155(3):703–10.
81. Mao TL, Chu JS, Jeng YM, Lai PL, Hsu HC. Expression of mutant nuclear beta-catenin cor-
relates with non-invasive hepatocellular carcinoma, absence of portal vein spread, and good
prognosis. J Pathol. 2001;193(1):95–101.
82. Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14(15):1837–51.
83. Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/β-catenin pathway in hepatocellular
carcinoma treatment. World J Gastroenterol. 2016;22(2):823–32.
84. Dow LE, O’Rourke KP, Simon J, Tschaharganeh DF, van Es JH, Clevers H, et al. Apc res-
toration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal
cancer. Cell. 2015;161(7):1539–52.
85. Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, et al. Proteomic and bioin-
formatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human
malignancy. Nat Genet. 2013;45(6):592–601.
86. Tordella L, Khan S, Hohmeyer A, Banito A, Klotz S, Raguz S, et al. SWI/SNF regulates
a transcriptional program that induces senescence to prevent liver cancer. Genes Dev.
2016;30(19):2187–98.
87. Takeda S, Liu H, Sasagawa S, Dong Y, Trainor PA, Cheng EH, et al. HGF-MET signals via
the MLL-ETS2 complex in hepatocellular carcinoma. J Clin Investig. 2013;123(7):3154–65.
88. Takeo S, Arai H, Kusano N, Harada T, Furuya T, Kawauchi S, et al. Examination of oncogene
amplification by genomic DNA microarray in hepatocellular carcinomas: comparison with
comparative genomic hybridization analysis. Cancer Genet Cytogenet. 2001;130(2):127–32.
58 M. Hoare

89. Roessler S, Long EL, Budhu A, Chen Y, Zhao X, Ji J, et al. Integrative genomic identification
of genes on 8p associated with hepatocellular carcinoma progression and patient survival.
Gastroenterology. 2012;142(4):957–966.e12.
90. Liew CT, Li HM, Lo KW, Leow CK, Chan JYH, Hin LY, et al. High frequency of p16(INK4A)
gene alterations in hepatocellular carcinoma. Oncogene. 1999;18(3):789–95.
91. Tannapfel A, Busse C, Weinans L, Benicke M, Katalinic A, Geissler F, et al. INK4a-ARF
alterations and p53 mutations in hepatocellular carcinomas. Oncogene. 2001;20(48):7104–9.
92. Murakami Y, Hayashi K, Hirohashi S, Sekiya T. Aberrations of the tumor suppressor p53 and
retinoblastoma genes in human hepatocellular carcinomas. Cancer Res. 1991;51(20):5520–5.
93. Bollard J, Miguela V, Ruiz de Galarreta M, Venkatesh A, Bian CB, Roberto MP, et al.
Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclini-
cal models of hepatocellular carcinoma. Gut. 2017;66(7):1286–96.
94. Ma L, Chua M-S, Andrisani O, So S. Epigenetics in hepatocellular carcinoma: an update and
future therapy perspectives. World J Gastroenterol. 2014;20(2):333–45.
95. Wahid B, Ali A, Rafique S, Idrees M. New insights into the epigenetics of hepatocellular
carcinoma. Biomed Res Int. 2017;2017:1609575.
96. Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet.
2013;14(3):204–20.
97. Feinberg AP, Koldobskiy MA, Göndör A. Epigenetic modulators, modifiers and mediators in
cancer aetiology and progression. Nat Rev Genet. 2016;17(5):284–99.
98. Nishida N, Kudo M, Nishimura T, Arizumi T, Takita M, Kitai S, et al. Unique association
between global DNA hypomethylation and chromosomal alterations in human hepatocellular
carcinoma. PLoS One. 2013;8(9):e72312.
99. Shen J, Wang S, Zhang Y-J, Kappil M, Wu H-C, Kibriyya MG, et al. Genome-wide DNA
methylation profiles in hepatocellular carcinoma. Hepatology. 2012;55(6):1799–808.
100. Song M-A, Tiirikainen M, Kwee S, Okimoto G, Yu H, Wong LL. Elucidating the landscape
of aberrant DNA methylation in hepatocellular carcinoma. PLoS One. 2013;8(2):e55761.
101. Hernandez-Vargas H, Lambert M-P, Le Calvez-Kelm F, Gouysse G, McKay-Chopin S,
Tavtigian SV, et al. Hepatocellular Carcinoma Displays Distinct DNA Methylation Signatures
with Potential as Clinical Predictors. PLoS One. 2010;5(3):e9749.
102. Lee S, Lee HJ, Kim J-H, Lee H-S, Jang JJ, Kang GH. Aberrant CpG island hypermethylation
along multistep hepatocarcinogenesis. Am J Pathol. 2003;163(4):1371–8.
103. Nishida N, Kudo M, Nagasaka T, Ikai I, Goel A. Characteristic patterns of altered
DNA methylation predict emergence of human hepatocellular carcinoma. Hepatology.
2012;56(3):994–1003.
104. Villanueva A, Portela A, Sayols S, Battiston C, Hoshida Y, Méndez-González J, et al. DNA
methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology.
2015;61(6):1945–56.
105. Nishida N, Nishimura T, Nagasaka T, Ikai I, Goel A, Ajay G, et al. Extensive methylation is
associated with beta-catenin mutations in hepatocellular carcinoma: evidence for two distinct
pathways of human hepatocarcinogenesis. Cancer Res. 2007;67(10):4586–94.
106. Revill K, Wang T, Lachenmayer A, Kojima K, Harrington A, Li J, et al. Genome-wide meth-
ylation analysis and epigenetic unmasking identify tumor suppressor genes in hepatocellular
carcinoma. Gastroenterology. 2013;145(6):1424–35.e1–25.
107. Wong IH, Lo YM, Zhang J, Liew CT, Ng MH, Wong N, et al. Detection of aberrant p16
methylation in the plasma and serum of liver cancer patients. Cancer Res. 1999;59(1):71–3.
Chapter 5
The Role of Histology in Hepatocellular
and Cholangiocarcinoma

Alberto Quaglia

Key Learning Points

1. Liver biopsy has a critical role in the histological diagnosis of hepatocel-
lular adenoma and hepatocellular carcinoma arising in patients with early
stage chronic liver disease or normal/near-normal liver.
2. A biopsy sample of tumour should always be accompanied by a separate
sample of background liver, taken well away from the lesion, and ideally
submitted in a separate container.
3. Histological examination of surgically resected specimens is essential to
confirm diagnosis and for prognosis in both hepatocellular and cholangio-
cellular tumours.
4. Intraoperative histological examination is critical to guide surgical inter-
vention and attempt completeness of resection particularly for hilar
cholangiocarcinoma.
5. Liver biopsy is the gold standard for the diagnosis of intrahepatic cholan-
giocarcinoma. Biliary brushing is increasingly used in the diagnosis of
hilar and distal cholangiocarcinoma.

Areas of Controversy and Uncertainty

1. Liver biopsy may regain a role in the diagnosis and management of early
hepatocellular carcinoma arising in patients with advanced stage chronic
liver disease, by bringing together histological and molecular techniques.

A. Quaglia ()
The Institute of Liver Studies, King’s College Hospital, London, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 59

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_5
60 A. Quaglia

2. The differential diagnosis between hepatocellular adenoma and well-­

differentiated hepatocellular carcinoma can be difficult, particularly when
based on liver biopsy specimens. The use of the term “hepatocellular neo-
plasm of uncertain malignant potential” has been advocated in such
instances.
3. The differential diagnosis between intrahepatic cholangiocarcinoma and
metastatic adenocarcinoma should not rely exclusively on immunohisto-
chemistry but needs to be based on clinico-pathological correlation.

Histopathologists retain a crucial role in the diagnosis of tumours, as eloquently

expressed by Dr. Fletcher [1]: “... Molecular genetic techniques are meaningful if
put into context and matched by morphology… proper professional interactions
between histopathologists and molecular biologists are critical… claims that new
modalities can replace histological interpretation need to be seen with suspicion....”
Histology remains the gold standard for the classification and diagnosis of primary
liver cancer. This chapter discusses the role of histology in hepatocellular carci-
noma (HCC) and cholangiocarcinoma (ChC), with reference to biopsy and surgi-
cally resected specimens for each tumour type. The role of histology in the context
of tumours with mixed hepatocellular and cholangiocellular differentiation is
reviewed in Chap. 13. Paediatric liver tumours and in particular hepatoblastoma are
outside the scope of this chapter.

Hepatocellular Carcinoma

Advanced stage chronic liver disease [2] is the main risk factor for HCC, but HCC
can occur in patients with chronic liver disease at an early stage and in patients with
normal or near-normal livers. Liver biopsy for the diagnosis of early HCC in patients
with advanced stage chronic liver disease is carried out rarely. This is the result
essentially of five factors which came together in the early 2000s: (1) the gener-
alised acceptance that cross-sectional imaging criteria based on arterial hypervascu-
larity and venous or delayed phase washout were sufficient for the diagnosis of
early HCC; (2) the limitations of histological interpretation based purely on
­morphological criteria in differentiating between large regenerative nodules and
low-­grade dysplastic nodules and between high-grade dysplastic nodules and well-
differentiated HCC; (3) lack of high-throughput molecular data; (4) the perception
that the morbidity, mortality and seeding risk related to the biopsy procedure out-
weighed the low diagnostic histological yield; and (5) the widespread application of
local ablative therapies as a bridge to liver transplantation.
Times have changed, and although cross-sectional imaging retains its diagnostic
role, its accuracy is now questioned and needs to be verified [3]; recommendation
for bridging therapy is conditional due to the available limited evidence of its
5 The Role of Histology in Hepatocellular and Cholangiocarcinoma 61

­benefits [4]; histopathologists have additional immunohistochemical and molecular

tools to place small hepatocellular lesions within a spectrum of malignant transfor-
mation and identify tumour subtypes including mixed variants; HCC molecular sig-
natures are now available [5]; the value of molecular and histological data may
offset the risk related to the biopsy procedure [3, 6]. A return to liver biopsy is
therefore advocated based on the benefits of integrating histological and molecular
data, as part of personalised medicine and clinical trial allocation [6].
Liver biopsy has a critical role in the diagnosis of HCC occurring in patients with
chronic liver disease at an early stage or with normal or near-normal liver. HCC in
this context has a bimodal distribution in terms of age of presentation, peaking at the
second and seventh decades [7]. These tumours remain asymptomatic for a long
time and tend to manifest when they reach a large size, because patients do not pres-
ent earlier with symptoms of advanced stage chronic liver disease and do not often
have high levels of serum alpha-fetoprotein. Common aetiological factors include
hepatitis B virus infection, non-alcoholic steatohepatitis, genetic haemochromatosis
and other metabolic disorders including glycogen storage disease, alpha-1-­
antitrypsin deficiency and porphyria, sex hormones and in particular anabolic ste-
roids, vascular disorders such as Budd-Chiari and portosystemic shunts and toxins
(e.g. aflatoxin B1). Fibrolamellar carcinoma is a subtype of HCC typically observed
in young patients with no evidence of underlying liver disease. It has been shown to
be associated with the DNAJB1-PRKACA fusion transcript.
The role of liver biopsy in these patients is diagnostic and usually to (1) establish
whether the tumour is primary or secondary; (2) differentiate between HCC and
ChC, except for tumours with a mixed hepatocellular and cholangiocellular pheno-
type; (3) confirm the clinical suspicion of fibrolamellar carcinoma; and (4) differen-
tiate between hepatocellular adenoma and HCC. The histological differential
diagnosis between HCC and hepatocellular adenoma may be difficult particularly
with biopsy specimens, which may not be representative of the whole lesion. The
use of the term “well-differentiated hepatocellular neoplasm of uncertain malignant
potential” has been advocated, in selected circumstances [8, 9].
Knowledge of the state of the background liver and presence of an underlying
disorder is critical to the histological interpretation of liver tumours. As a general
rule, a biopsy sample of non-lesional liver should always be taken in adjunct to the
lesional biopsy sample and should be submitted to the laboratory ideally in a sepa-
rate container.
Histological examination of resection specimens remains a critical step in the
management of patients with HCC. In the context of liver transplantation, a careful
macroscopic analysis of the explanted liver is critical to identify histological fea-
tures of prognostic value. Vascular invasion has been consistently shown to be
­associated with poor prognosis. Standardisation of the histological criteria for the
identification of vascular invasion is necessary to ensure reproducibility. The term
“cirrhotomimetic” refers to a rare variant of HCC characterised by minute tumour
nodules of similar size of, and intermixed with, the parenchymal nodules of the
background diseased liver. Except for those cases in which this pattern occurs in
addition to one or more larger dominant tumours, cirrhotomimetic HCC cannot be
62 A. Quaglia

identified on pre-transplantation imaging and is diagnosed exclusively by histology.

A proportion of cirrhotomimetic HCC have a very poor prognosis [10]. Examination
of the explanted liver reveals the effects of bridging local ablation therapy.
Cholangiocellular differentiation is frequently identified in tumours treated with
transarterial chemo-embolisation and may be associated with poor prognosis [11].
A careful examination of the explanted liver is necessary to confirm the tumour
staging at the time of listing or detect interval tumour progression. It may also iden-
tify small lesions, undetected by pre-transplantation imaging, or large lesions
resembling focal nodular hyperplasia or hepatocellular adenoma and mimicking
HCC [12, 13]. More studies correlating the histological findings in explanted liver
with antecedent imaging are needed to verify the accuracy of imaging techniques
[3]. Correlation of histology with molecular data remains a powerful tool in the
understanding of the pathogenesis and behaviour of HCC.
Histological examination of specimens removed at surgical resection of HCC is
necessary for diagnostic and prognostic purposes. Extensive sampling may be nec-
essary to confirm a diagnosis of HCC, particularly in the instance of well-­
differentiated hepatocellular lesions in which imaging and liver biopsy are not
conclusive. Identification of vascular invasion, evaluation of the resection margin
for completeness of rejection and the identification of additional small foci in the
vicinity of a dominant lesion implying either intrahepatic tumour spread or multifo-
cal disease may anticipate tumour recurrence in the liver remnant and/or extrahe-
patic spread. A recent study [14] on surgically resected HCC has shown the benefit
of correlating histology with molecular profiling and clinical data. In that study,
surgically resected HCC could be divided into two major groups based on their
histological phenotype and molecular profile. One consisted of large well-­
differentiated cholestatic CTNNB1-mutated tumours arranged in a microtrabecular
and pseudoglandular pattern. The other one consisted of TP53-mutated poorly dif-
ferentiated tumours in a compact growth pattern and with frequent vascular inva-
sion. In the same study, the scirrhous and steatohepatitic variants correlated with
specific mutations and molecular pathways, and a novel subtype designated
“macrotrabecular-­massive” was characterised by vascular invasion, high alpha-­
fetoprotein levels, TP53 mutation, FGF19 amplification and poor survival.

Cholangiocarcinoma

ChCs are adenocarcinomas composed of cells with a biliary phenotype and are
generally classified according to their presumed site of origin in intrahepatic, hilar
and distal ChC. The right and left hepatic duct confluence marks the point of separa-
tion between intrahepatic and hilar ChC. The biliary epithelial cells lining the bile
ducts are considered to be the origin of hilar and distal ChC. Biliary intraepithelial
neoplasia and intraductal papillary (biliary) neoplasms are the two well-­characterised
precursor lesions of ChC. Nakanuma et al. [15] have proposed that the similarities
between biliary and pancreatic neoplasms, and in particular between ductal-type
5 The Role of Histology in Hepatocellular and Cholangiocarcinoma 63

adenocarcinoma, mucinous cystic and intraductal papillary neoplasms, could be

due to the common embryological origin shared by the extrahepatic biliary tree and
the pancreas. Hilar ChC displays often an intestinal phenotype [16]. The pathogen-
esis of intrahepatic ChC is more complex. Cholangiocytes, progenitor/stem cells
possibly residing in the canals of Hering and hepatocytes are now regarded as the
possible cells of origin [17]. The term “cholangiolocellular carcinoma” refers to a
type of intrahepatic ChC composed of tubulo-glandular structures with an appear-
ance and immunohistochemical phenotype resembling cholangioles.
Intrahepatic ChC forms usually parenchymal nodular masses (mass-forming) in
patients with normal or near-normal liver, and more rarely in the context of advanced
stage chronic liver disease, not necessarily related to a chronic cholangiopathy.
Histological identification of incidental small intrahepatic ChC in the livers removed
at transplantation from patients with advanced stage chronic liver disease has shown
that very early tumours of 2 cm or less on diameter are associated with a good prog-
nosis and should not be a contraindication to liver transplantation [18]. Intrahepatic
ChC can grow to a relatively large size before becoming symptomatic. In contrast,
hilar and distal ChC become symptomatic earlier, due to biliary obstruction and
jaundice. Intrahepatic ChC can be diagnosed exclusively by histology, on biopsy or
surgical resection specimens. Intrahepatic ChC needs to be differentiated from
HCC, particularly in patients with a normal or near normal liver, with metastatic
adenocarcinoma and with benign biliary proliferations. The cells composing intra-
hepatic ChC can show an appearance very similar to that of hepatocytes and can
mimic HCC quite closely. Immunohistochemical markers in support of hepatocel-
lular differentiation include Hep Par 1, arginase 1, the identification of canaliculi
expressing specific antigens such as the bile salt export pump (BSEP) and the iden-
tification of albumin by in situ hybridisation. Markers in support of cholangiocel-
lular differentiation include CA19–9 and cytokeratin 19. None of these markers,
however, is entirely specific. This is particularly true when trying to differentiate
between ChC and metastatic adenocarcinoma, because there are no markers, to
date, sufficiently specific of cholangiocellular differentiation. The role of liver
biopsy in these instances is to confirm the presence of adenocarcinoma. Depending
on the clinical context, immunohistochemistry may be used to investigate a possible
site of origin but can be potentially misleading and needs to be interpreted in con-
junction with a full clinical history, imaging and endoscopic findings when
­applicable. Subcapsular lesions identified during oncological abdominal surgery or
staging laparoscopy are often sampled and submitted for intra-operatory diagnosis.
Differentiation between metastatic adenocarcinoma and a primary benign biliary
proliferation such as a microhamartoma or a biliary adenoma is straightforward in
some cases. In patients with obstructive jaundice and ascending cholangitis, reac-
tive biliary atypia and florid inflammation make it difficult to differentiate from
ChC, and it may be preferable to defer the diagnosis to paraffin-embedded sections.
Histological criteria in favour of intrahepatic ChC over benign biliary lesions such
as bile duct adenoma include the presence of infiltrative features, an angulated pro-
file of the tubule-glandular structures, the presence of mitoses, a high percentage of
lesional nuclei staining for Ki67 and a nuclear atypia. Tubulin-beta 3 has been
64 A. Quaglia

p­ roposed as an immunohistochemical marker of biliary malignancy but needs fur-

ther validation [19].
The diagnosis and grading of cystic mucinous neoplasms are purely histological.
Liver biopsy is not advocated in this context, and the diagnosis is usually carried out
on surgically resected specimens. Surgeons often request intraoperative histological
diagnosis on frozen sections obtained from samples of cyst wall removed during
cyst fenestration. False negatives are possible with this approach, because the histo-
logical changes necessary for the diagnosis of mucinous cystic neoplasm (e.g., the
lining epithelium and the ovarian-like stroma) can be patchy, particularly in lesions
with degenerative changes. Extensive sampling of the whole cystic lesion and
examination of paraffin-embedded sections are necessary for a reliable diagnosis,
proper grading of epithelial dysplasia and identification of foci of invasive ChC.
Liver biopsy has lesser of a role for the diagnosis of hilar and distal ChC. These
lesions may be difficult to target, as they tend to be of relatively small size, may be
difficult to delineate and targeted on imaging and have often a hard stromal compo-
nent, which cannot be pierced easily by the biopsy needle. In contrast, biliary tract
brushing carried out during endoscopic retrograde cholangiopancreatography
(ERCP) is gaining role in the diagnosis of malignant biliary strictures. The proce-
dure has high specificity but relatively low sensitivity. Its performance can be
improved by the use of fluorescent in situ hybridisation (FISH) and digital image
analysis (DIA) to identify chromosomal abnormalities and aneuploidy [20].
Histological examination of surgically resected specimen remains critical to con-
firm the diagnosis of intrahepatic, hilar and distal ChC and for prognosis.
Involvements of surgical margins, lymphovascular and perineural invasion, satellite
nodules, lymph node metastasis and poor differentiation are associated with poor
prognosis. Intraoperative histological examination is particularly important during
resection of hilar ChC in the attempt to achieve a complete resection.

References

1. Fletcher CDM. Diagnostic histopathology of tumors. 4th ed. Edinburgh: Churchill Livingstone;
2013.
2. Hytiroglou P, Snover DC, Alves V, Balabaud C, Bhathal PS, Bioulac-Sage P, et al. Beyond
"cirrhosis": a proposal from the International Liver Pathology Study Group. Am J Clin Pathol.
2012;137(1):5–9.
3. Mullhaupt B, Durand F, Roskams T, Dutkowski P, Heim M. Is tumor biopsy necessary? Liver
Transpl. 2011;17(Suppl 2):S14–25.
4. Heimbach JK, Kulik LM, Finn R, Sirlin CB, Abecassis M, Roberts LR, et al. AASLD guide-
lines for the treatment of hepatocellular carcinoma. Hepatology. 2017;67(1):358–80.
5. Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and
effects on patient prognosis. Gastroenterology. 2017;152(4):745–61.
6. Torbenson M, Schirmacher P. Liver cancer biopsy–back to the future?! Hepatology.
2015;61(2):431–3.
7. Trevisani F, Frigerio M, Santi V, Grignaschi A, Bernardi M. Hepatocellular carcinoma in non-­
cirrhotic liver: a reappraisal. Dig Liver Dis. 2010;42(5):341–7.
5 The Role of Histology in Hepatocellular and Cholangiocarcinoma 65

8. Balabaud C, Bioulac-Sage P, Ferrell L, Kakar S, Paradis V, Quaglia A, et al. Well-differentiated

hepatocellular neoplasm of uncertain malignant potential. Hum Pathol. 2015;46(4):634–5.
9. Bedossa P, Burt AD, Brunt EM, Callea F, Clouston AD, Dienes HP, et al. Well-differentiated
hepatocellular neoplasm of uncertain malignant potential: proposal for a new diagnostic cat-
egory. Hum Pathol. 2014;45(3):658–60.
10. Clayton EF, Malik S, Bonnel A, Mu Y, Olthoff K, Shaked A, et al. Liver transplantation
and cirrhotomimetic hepatocellular carcinoma: classification and outcomes. Liver Transpl.
2014;20(7):765–74.
11. Zen C, Zen Y, Mitry RR, Corbeil D, Karbanova J, O'Grady J, et al. Mixed phenotype hepa-
tocellular carcinoma after transarterial chemoembolization and liver transplantation. Liver
Transpl. 2011;17(8):943–54.
12. Calderaro J, Nault JC, Balabaud C, Couchy G, Saint-Paul MC, Azoulay D, et al. Inflammatory
hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis. Mod
Pathol. 2016;29(1):43–50.
13. Quaglia A, Tibballs J, Grasso A, Prasad N, Nozza P, Davies SE, et al. Focal nodular hyperplasia-­
like areas in cirrhosis. Histopathology. 2003;42(1):14–21.
14. Calderaro J, Couchy G, Imbeaud S, Amaddeo G, Letouze E, Blanc JF, et al. Histological
subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour
classification. J Hepatol. 2017;67(4):727–38.
15. Nakanuma Y, Sudo Y. Biliary tumors with pancreatic counterparts. Semin Diagn Pathol.
2017;34(2):167–75.
16. Zen Y, Quaglia A, Heaton N, Rela M, Portmann B. Two distinct pathways of carcinogenesis in
primary sclerosing cholangitis. Histopathology. 2011;59(6):1100–10.
17. Komuta M, Govaere O, Vandecaveye V, Akiba J, Van Steenbergen W, Verslype C, et al.
Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phe-
notypes. Hepatology. 2012;55(6):1876–88.
18. Sapisochin G, Facciuto M, Rubbia-Brandt L, Marti J, Mehta N, Yao FY, et al. Liver trans-
plantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study
supporting a prospective assessment. Hepatology. 2016;64(4):1178–88.
19. Zen Y, Britton D, Mitra V, Pike I, Sarker D, Itoh T, et al. Tubulin beta-III: a novel immu-
nohistochemical marker for intrahepatic peripheral cholangiocarcinoma. Histopathology.
2014;65(6):784–92.
20. Moreno Luna LE, Kipp B, Halling KC, Sebo TJ, Kremers WK, Roberts LR, et al. Advanced cyto-
logic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology.
2006;131(4):1064–72.
Chapter 6
Diagnosis and Staging of Hepatocellular
Carcinoma (HCC)

Vinay Kumar Balachandrakumar, Nadya Fatima Jabbar, David White,

and Nicholas Stern

Key Learning Points

1. Patient outcomes in HCC is determined by stage of disease, tumour ­factors,
patient factors and interventions available.
2. The patient’s performance status should be calculated using the Eastern
Cooperative Oncology Group (ECOG) system.
3. The possible poor impact of outcomes due to risk of liver failure needs to
be highlighted as it may be greater than the risk of dying from cancer.
4. Treatment allocation should be made after initial assessment of the patient
and multidisciplinary team (MDT) meeting decisions must be based on
this assessment.

Areas of Controversy and Uncertainty

1. Limitations of staging system based on tumour location.
2. Incorporation of novel biomarkers within staging systems to better under-
stand tumour biology, mechanisms of disease and treatment targets.
3. Role of routine use of liver biopsy in disease staging.

V. K. Balachandrakumar (*)
University of Liverpool, Liverpool, UK
N. F. Jabbar · D. White · N. Stern
Aintree University Hospital, Liverpool, UK

© Springer Nature Switzerland AG 2019 67

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_6
68 V. K. Balachandrakumar et al.

Background

Liver cancer is the fifth most common cancer worldwide, second most common
cause of cancer related deaths and accounts for 7% of all cancers. The incidence of
HCC is growing worldwide and increases progressively with advancing age in all
populations, with a peak age of 70 years. HCC has a strong male predominance with
a male to female ratio of 2–2.5:1. The pattern of HCC has a strong geographical
distribution, highest in East Asia and sub-Saharan Africa where around 85% of
cases occur, and is very much linked to the prevalence of viral hepatitis (B and C).
Obesity, diabetes and fatty liver disease have also been recognised to cause HCC
throughout the world [1].

Diagnosis

Improved imaging techniques have enabled earlier HCC diagnosis improving the
chance to offer potentially curative treatment. This trend is expected to grow with
the wider implementation of surveillance policies in developed countries. However,
detection of nodules of <2 cm poses a challenge as they are difficult to characterise
by radiological or pathological examination.
Defining nodules as pre-neoplastic lesions or early HCC has important implica-
tions. Dysplastic lesions should be followed up by regular imaging studies as one-­
third of them develop a malignant phenotype. Early tumours should be treated with
curative intent: procedures such as resection, transplantation and percutaneous
ablation.
HCC can be diagnosed radiologically in the presence of a cirrhotic liver with
criteria as detailed below. In those cases which are equivocal or the background
liver is non-cirrhotic, a histological diagnosis is needed.

Radiological Criteria

Imaging holds a central role in the diagnosis of HCC, and to date, it is the only solid
tumour for which non-invasive diagnosis is accepted [2]. Several imaging modali-
ties including ultrasonography (US), computed tomography (CT) and magnetic
resonance imaging (MRI) can be used in evaluating patients with chronic liver dis-
ease and suspected HCC. Dual phase contrast-enhanced CT or dynamic phase MRI
are the current recommended modalities of choice for imaging diagnosis of HCC as
per EASL and AASLD guidelines. These have the added benefit of providing
6 Diagnosis and Staging of Hepatocellular Carcinoma (HCC) 69

information about the background liver, the hepatic vasculature as well as extrahe-
patic disease. MRI affords better characterisation of HCCs as the signal character-
istics on several sequences aid the diagnosis, especially with equivocal cases.
Additionally, MRI spares the patient repeated exposures to ionising radiation and
iodinated contrast material. CT and MRI do have a significantly greater cost attached
to them, whereas US is a cheap and relatively easily accessible modality for
diagnosis.
The role of contrast-enhanced ultrasound (CEUS) in the diagnosis of HCC how-
ever is controversial and is not recommended in Western guidelines due to low
specificity even though it has a high sensitivity but can be utilised when CT and
MRI are inconclusive or contraindicated. Other limiting factors include inter-­
operator variability, inability to image the entire liver during one contrast injection
and limited views in obese patients [3–7].

Diagnostic Hallmark of HCC

In order to understand the imaging characteristics of HCC and to be able to differ-

entiate it from other nodules in the setting of the cirrhotic liver, it is important to
understand the changes in the vascular supply and neovascularisation that occur
through this dedifferentiation spectrum.
Regenerating nodules are supplied by the portal vein, and dysplastic nodules
have primarily a portal venous supply but have an increasing amount of supply
from the hepatic artery. HCCs are supplied by unpaired hepatic arteries, and thus
they enhance in the arterial phase when the bulk of the contrast lies within the
hepatic arteries. During the portal venous phase, as the contrast circulates through
the portal venous system, the background liver parenchyma enhances, and as the
HCC has no supply from the portal venous system, there is a “washout” of contrast.
This arterial phase enhancement and washout during the portal venous phase are
the hallmark of HCC.
Due to the difficulty in characterising small liver lesions (<1 cm), the radiologi-
cal criteria for diagnosis apply to those nodules of at least 1 cm in diameter. Small
HCCs, early HCCs and poorly differentiated HCCs may not show these typical
features, and in such cases, the role of delayed phase imaging on MR with
­hepatobiliary contrast agents is central in aiding diagnosis. The differentiation
between hepatobiliary and non-hepatobiliary agents is beyond the scope of this
chapter but suffice to say that HCCs do not take up hepatobiliary contrast as they do
not have functioning hepatocytes and are thus of low signal intensity on the delayed
phase sequences. The caveat to this rule is that well-differentiated HCCs may take
up the hepatobiliary contrast; in the latter cases, other ancillary features help in
making the diagnosis (Figs. 6.1, 6.2, 6.3, 6.4 and Table 6.1).
70 V. K. Balachandrakumar et al.

a b

c d

Fig. 6.1 (a) Axial T1-weighted sequence showing an iso-hypointense well-defined lesion with a
capsule and a central low signal area. (b) Axial T2-weighted sequence shows the internal hetero-
geneity of the lesion which has areas of low to intermediate signal intensity. (c and d) Diffusion-
weighted and corresponding ADC map showing a high signal on the diffusion-weighted sequence
with a corresponding low signal on the ADC map indicative of restricted diffusion within the lesion
and characteristics in keeping with a HCC

Morphological and Other Features

Presence of a capsule
Heterogeneity
Focus of calcification
Intralesional fat
Portal vein thrombus
Direct vascular invasion
Multifocality

CEUS

Hypo-echoeic pre-contrast
Arterial enhancement and washout
6 Diagnosis and Staging of Hepatocellular Carcinoma (HCC) 71

a b

c d

Fig. 6.2 (a–d) Dynamic sequences through the liver showing arterial enhancement of the lesion
with a gradual washout on the portal venous and delayed images in keeping with features of HCC.
Note the capsular rim

a b

Fig. 6.3 (a) Arterial phase CT showing a heterogeneous lesion with a necrotic centre. The periph-
ery of the lesion enhances on the arterial phase. (b) Portal venous phase CT at the same level shows
a washout of contrast in keeping with features of HCC
72 V. K. Balachandrakumar et al.

a b c

Fig. 6.4 (a) Ultrasound image showing a 5 cm lesion within the right lobe of the liver. Contrast-­
enhanced ultrasound after administration of IV contrast showing (b) early and heterogeneous
enhancement of the lesion at 13 s and (c) a rapid washout. The absence of uniform or continuous
peripheral enhancement is highly suspicious of a malignant lesion. The early arterial enhancement
and rapid wash out is characteristic of a HCC

CT

Low attenuation on unenhanced CT

Arterial enhancement and portal venous phase washout
Foci of calcification
Capsule
Internal mosaic pattern
Vascular invasion

MR

T1-Hypointense
Maybe hyperintense if they contain fat, copper, glycogen or iron
T2-hyperintense but less than benign lesions such as cysts and haemangiomas
May be isointense
In- and out-of-phase sequences: loss of signal depicting intralesional fat
Dynamic sequences: hyperintense on the arterial phase and hypointense during
the portal venous phase
Hypointense during the hepatobiliary phase
Diffusion-weighted sequences: increased signal intensity as they restrict
diffusion
 6

Table 6.1 Differential diagnosis and imaging characteristics [8–10]

Arterial phase sequences Portal venous sequences Delayed phase 20 min post Gd-EOB-­
Lesions T1 weighted T2 weighted CT and MR CT and MR MR DTPA MR
Haemangioma Iso- or Hyperintense Hyperintense Hyperintense Hyperintense Hypointense
hypointense
FNH Hypointense Iso- or Hyperintense Isointense Isointense Hyperintense
hyperintense
Adenoma Isointense Iso- or Hyperintense Isointense Isointense Hypointense
hyperintense
Hyper vascular Hypointense Hyperintense or Hyperintense Iso- or hypointense Hypointense Hypointense
metastasis variable
Regenerating nodules Iso- or Isointense Isointense Isointense Isointense Isointense
hyperintense
Dysplastic nodules Isointense Iso- or Hyperintense Isointense Isointense Isointense
Diagnosis and Staging of Hepatocellular Carcinoma (HCC)

hyperintense
Cholangiocarcinoma Hypointense Iso- or Iso- or hyperintense Iso- or hyperintense Hyperintense Hypointense
hyperintense
HCC Variable Hyperintense or Hyperintense Hypointense Hypointense Hypointense
variable
73
74 V. K. Balachandrakumar et al.

Histological Diagnosis

A histopathological diagnosis of HCC is based on the World Health Organization

(WHO) classification and International Consensus Group for Hepatocellular
Neoplasia. Sensitivity of liver biopsy depends on the location, size of tumour and
expertise. It can be difficult to determine the diagnosis of HCC on morphological
criteria alone between HCC and high-grade dysplasia. Pathologists cannot always
determine the pathological appearance of HCC or whether stromal invasion is pres-
ent. A positive biopsy is useful to make a diagnosis of HCC, but a negative biopsy
may not exclude the diagnosis. The risk of tumour seeding after liver biopsy is 2.7%
with a median time interval between biopsy and seeding of 17 months [11]. This can
clearly pose problems for patients potentially undergoing treatment with curative
intent.
Immunohistochemistry can aid the histopathological diagnosis. Combinations of
three different immunomarkers (glypican 3, HSP70 and glutamate synthetase) have
demonstrated a sensitivity and specificity of 72% and 100%, respectively [1, 12].
Both the WHO and International Consensus Group of Hepatocellular Neoplasia
have adopted this three-marker panel.

Use of Alpha-Fetoprotein (AFP)

Alpha-fetoprotein has been used for the diagnosis of HCC and as part of surveil-
lance algorithms. AFP is now felt to be insufficiently sensitive or specific to use as
a surveillance assay. AFP can be elevated in intrahepatic cholangiocarcinoma (ICC)
and in some metastases from colon cancer. Therefore, a mass in the liver with an
elevated AFP does not indicate HCC. ICC is also more common in cirrhotics than
in non-cirrhotics. Incidence of ICC is much lower than HCC, and given both are
common in cirrhosis, they should be distinguished due to differences in treatment
and outcomes [13].

Surveillance Strategy for Indeterminate or Dysplastic Nodules

Most nodules smaller than 1 cm that can be detected in a cirrhotic liver are not
HCCs. Therefore, a closer follow-up is recommended in these cases. An accepted
rule is to consider any nodule >1 cm as an abnormal screening result warranting
further investigation. These new nodules should prompt recall strategy for diag-
nosis with non-invasive or invasive (biopsy) criteria, as described above. If a
diagnosis cannot be reached with non-invasive criteria due to atypical radiologi-
cal appearance, then biopsy is recommended. If biopsy provides inconclusive
results, then a closer follow-up every 3–4 months is recommended [1]. A second
6 Diagnosis and Staging of Hepatocellular Carcinoma (HCC) 75

Mass/nodule at imaging

<1 cm >1 cm

Repeat US at 4 mo Multiphasic contrast-enhanced CT, or

multiphasic contrast-enhanced MRI*, or
gadoxetic-enhanced MRI**
Growing/changing
Stable****
pattern 1 positive technique:
HCC imaging hallmarks

No Yes
*****

Biopsy unclear: Use the other modality multiphasic

Consider re-biopsy contrast-enhanced CT, or
multiphasic contrast-enhanced MRI*, or
gadoxetic-enhanced MRI**, or
contrast-enhanced ultrasound***

1 positive technique:
HCC imaging hallmarks

No Yes

- Non-HCC malignancy Biopsy HCC

- Benign

Fig. 6.5 Diagnostic algorithm and recall policy in cirrhotic liver. *Using extracellular MR con-
trast agents or gadobenate dimeglumine. **Using the following diagnostic criteria: arterial phase
hyperenhancement (APHE) and washout on the portal venous phase. ***Using the following diag-
nostic criteria: arterial phase hyperenhancement (APHE) and mild washout after 60 s. ****Lesion
<1 cm stable for 12 months (three controls after 4 months) can be shifted back to regular six-month
surveillance.****Optional for centre-based programmes

biopsy may be considered in case of growth or change in the enhancement pattern

(Fig. 6.5).

Staging

Staging of Liver Function, Performance Status and Tumour

There are differing opinions on how best to stage and characterise HCC due to its
characteristic clinical and biological variations. Despite recommendations produced
by hepatologists, oncologists, surgeons and radiologists with multidisciplinary col-
laboration, there is still no single system used for classifying HCC.
As with any cancer, the aim of tumour staging in HCC is to estimate a patient’s
prognosis, which allows for appropriate therapy to be selected. The variations of
HCC are not only because of various aetiological factors for cancer but also of the
extent of impaired liver function. The contributions of cancer and hepatic dysfunc-
tion to overall prognosis were recognised with the first modern-era liver cancer
staging system proposed at the Hepatocellular Carcinoma International Symposium
in Kampala, Uganda, in 1971.
76 V. K. Balachandrakumar et al.

Assessment of Liver Function

Child-Turcotte-Pugh (CTP)

Initially, Child-Turcotte staging comprised clinical assessments of encephalopathy,

ascites and nutritional status with laboratory measurements of serum bilirubin and
albumin as a prognostic tool to predict mortality following variceal haemorrhage.
This was reformed by Pugh with the replacement of nutritional status by prothrom-
bin time. This simple and widely used system assesses liver function as a preopera-
tive benchmark. However, the drawbacks are many, including laboratory variations,
fluctuations in the key measurements and the subjective nature of the clinical grad-
ing of encephalopathy and ascites. It has been incorporated into many current scor-
ing systems including the Barcelona Clinic Liver Cancer (BCLC) and Cancer of the
Liver Italian Program (CLIP).

Model for End-Stage Liver Disease (MELD)

The MELD score, initially developed to determine prognosis following a transjugu-

lar intrahepatic portosystemic shunt (TIPSS), is now widely used in the liver trans-
plant arena to list donor liver allocation [14]. It is a logarithmic score that is
comprised of international normalised ratio (INR), serum creatinine, total serum
bilirubin and sodium. The advantage of the MELD score is its prediction of short-­
term mortality and is therefore able to identify the “sickest” patients for graft alloca-
tion. However, it fails to correctly classify a portion of patients with advanced
cirrhosis. Patients with HCC need to have an adjusted MELD score.

 nited Kingdom Model for End-Stage

U
Liver Disease (UKELD)

The UKELD score is a scoring system used to predict the prognosis in patients with
chronic liver disease. It is calculated using patients’ international normalised ratio
(INR), serum creatinine, serum bilirubin and serum sodium. This was developed in
2008 to aid clinicians in selecting patients for liver transplantation [15].

Overview of Current Staging Systems

Barcelona Clinic for Liver Cancer (BCLC) Staging Algorithm

The BCLC classification first published in 1999 was modified in 2018 and is con-
sidered the standard HCC system by the American Association for the Study of
Liver Disease (AASLD) [13] and European Association for the Study of the Liver
6 Diagnosis and Staging of Hepatocellular Carcinoma (HCC) 77

HCC in cirrhotic liver

Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal stage (D)
Single <2 cm Single or 2-3 nodules <3 cm Multinodular, Portal invasion/ Not transplantable HCC
Prognostic 1 1
Preserved liver function , Preserved liver function , PS 0 unresectable extrahepatic spread End-stage liver function
stage 1 1
PS 0 Preserved liver function , Preserved liver function , PS 3-4
2
PS 0 PS 1 -2

2-3 nodules
Solitary
≤3 cm

Optimal surgical
3
candidate

Transplant
Yes No candidate

Yes No

4 5
Treatment Ablation Resection Transplant Ablation Chemoembolization Systemic therapy BSC

Survival >5 years >2.5 years ≥10 months 3 months

Fig. 6.6 Modified BCLC staging system and treatment strategy. ¹“Preserved liver function” refers
to Child-Pugh A without any ascites, considered conditions to obtain optimal outcomes. This pre-
requisite applies to all treatment options apart from transplantation, that is instead addressed pri-
marily to patients with decompensated or end-stage liver function. ²PS 1 refers to tumour-induced
(as per physician opinion) modification of performance capacity. ³Optimal surgical candidacy is
based on a multiparametric evaluation including compensated Child-Pugh class A liver function
with MELD score <10, to be matched with grade of portal hypertension, acceptable amount of
remaining parenchyma and possibility to adopt a laparoscopic/minimally invasive approach.4 The
stage migration strategy is a therapeutic choice by which a treatment theoretically recommended
for a different stage is selected as best first-line treatment option. 5As of 2017 Sorafenib has been
shown to be effective in first line, while Regorafenib is effective in second line in case of radiologi-
cal progression under Sorafenib

(EASL) [1]. BCLC takes into account the size and extent of the primary tumour,
underlying liver function and physiological factors including performance status
(PST). There is a treatment algorithm for each stage ranging from curative therapies
such as resection or transplant for early-stage patients to best supportive care. BCLC
had the best prognostic stratification when compared to six other used staging
­systems [16].
This system lacks discrimination within the intermediate-stage (BCLC-B)
patients which forms a large proportion of the HCC population. The burden of liver
disease which falls under BCLC stage B can differ greatly, from four small tumours
to near-complete replacement of the liver by tumour, provided liver function is pre-
served and there is no vascular invasion, extrahepatic spread or compromised per-
formance status, which would upstage to BCLC stage C or D. Therefore, in practice,
some BCLB-B patients may no longer be eligible for liver-directed therapies and
are generally treated following BCLC-C algorithms. The performance status (PST)
is incorporated in the BCLC algorithm. The importance of patient fitness is under-
appreciated by clinicians and not accurately calculated using the ECOG system. A
subdivision of BCLC stage B has been suggested which may help to stratify this
heterogeneous group. In addition, scoring systems to predict the response to TACE
or further TACE have been developed to help tailor treatment algorithms (HAP and
ART scores) [17, 18] (Fig. 6.6).
78 V. K. Balachandrakumar et al.

TNM Staging

The criteria are developed by the American Joint Committee on Cancer (AJCC) and
the Union for International Cancer Control (UICC) and have been updated since the
first edition in 1977; the seventh edition took effect in 2010. The TNM system eval-
uates primary tumour features (T), the presence or absence of nodal involvement
(N) and distant metastasis (M). Additional information like the histologic grade (G)
and fibrosis score (F) may be included based on Ishak classification but do not affect
staging. The TNM system is based on histopathology and is appropriate in predict-
ing survival for the minority of patients who have undergone curative surgery.

Okuda Score

The Okuda system is a prognostic score which includes tumour features and degree
of underlying cirrhosis which was introduced in 1985. The staging system is based
on four factors which include tumour occupying greater or less than 50% of the
liver, the presence or absence of ascites, serum albumin and bilirubin levels. The
system’s limitation is its rather crude classification of early-stage patients, and sub-
sequent systems have refined Okuda stage I patients. It has a lower predictive capac-
ity compared to the modern systems.

Cancer of the Liver Italian Program (CLIP) Score

The CLIP score was proposed in 1998 and by combining Child-Pugh stage, tumour
morphology, AFP level and the presence or absence of portal vein thrombosis, it
includes both liver function and tumour characteristics. The CLIP score was first
validated by the original investigators on a prospective cohort of HCC patients. The
CLIP score is limited as it does not select the appropriate therapy for each patient.

Japanese Integrated System (JIS)

In 2003, the Liver Cancer Study Group of Japan (LCSGJ) proposed the JIS score.
The JIS score was developed from a cohort of Japanese patients and appeared supe-
rior at predicting survival compared to CLIP, particularly in patients with early-­
stage disease. The JIS system incorporates the Liver Cancer Study Group of Japan’s
modification of TNM system and the Child-Pugh score. Whilst it has been validated
in Japan and in other Asian populations, the JIS has not been prospectively validated
6 Diagnosis and Staging of Hepatocellular Carcinoma (HCC) 79

in a Western population. It is worth noting that the majority of patients with HCC in
Japan have a background of hepatitis C cirrhosis.

Chinese University Prognostic Index (CUPI)

The CUPI was developed at a single centre in Hong Kong based on a retrospective
analysis of ethnic Chinese patients with high proportion of hepatitis B-related cir-
rhosis. The model included TNM staging, presentation with asymptomatic disease,
AFP level, total bilirubin, serum alkaline phosphatase and clinical detection of asci-
tes as significant prognostic factors. The CUPI is well-designed and easy to use. But
it has not performed well in comparative studies in Western populations.

 roupe d’Etude et de Traitement du Carcinome

G
Hépatocellulaire (GRETCH)

The French scoring system, proposed by GRETCH in 1999, uses objective mea-
sures and an estimate of performance status to predict survival. This included per-
formance status by Karnofsky score, serum bilirubin, serum alkaline phosphatase,
AFP and presence or absence of portal obstruction by ultrasonography. The strength
of the French classification is that its variables are available at the time of initial
diagnosis and do not require imaging. Given the increasing use of imaging tech-
niques for the diagnosis of HCC, this may impact the prognostic value of the staging
system.

Limitations of Current Staging Systems

The variation of HCC has made it hard to implement a generally accepted staging
system. Although the staging systems consider the importance of underlying liver
function and tumour characteristics, none of the systems consider the location and
relation of the tumour to major vessels. Also, the worsening of the underlying liver
disease is also difficult to calculate as patients can be clinically stable for a long time
before having decompensated liver failure. The underlying liver disease and aetiol-
ogy as well as the complex tumour biology of HCC are not accounted for by any of
these systems. Many studies describe differences in cancer outcomes based on the
aetiology of cirrhosis. This highlights challenges in distinguishing the prognostic
impact of the extent and aetiology of underlying liver disease from that of tumour
factors such as stage and tumour biology [19] (Table 6.2).
80 V. K. Balachandrakumar et al.

Table 6.2 Comparison of current staging systems for HCC

Comparison of HCC staging system
System Hepatic function AFP PS Tumour staging
Europe-USA
BCLC CTP No Yes Tumour size, number of
nodules and PVT
TNM No No No Number of nodules, tumour
size, presence of PVT and
presence of metastasis
CLIP CTP <400 or No Number of nodules,
≥400 ng/mL tumour > or <50% area of liver
and PVT
GRETCH Bilirubin, ALP <35 or Yes PVT
≥35 μg/L
Asia
Okuda Ascites, albumin, No No Tumour > or < 50% area of
bilirubin liver
CUPI Bilirubin, ascites, <500 or Symptoms TNM
ALP ≥500 ng/mL
JIS CTP No No TNM
AFP alpha-fetoprotein; PS performance status; CTP Child-Turcotte-Pugh; PVT portal vein throm-
bosis; ALP alkaline phosphatase

Novel Staging Systems

With evolving understanding of HCC genomics, it is now apparent that common

molecular subclasses exist which are related with prognosis, which may be enriched
in certain subsets according to aetiology of liver disease and could impact response
to targeted therapies. Several recently proposed staging systems, which incorporate
molecular biomarkers, of both tumour and cirrhosis, are discussed below.

Genomic Signatures

Molecular signatures have been proposed to predict recurrence and cancer out-
comes in surgically resected HCC:
• Molecular signatures
–– G3 signature
–– Poor survival signature
• Five-gene score
These are at a very early stage and require further research to determine their
place in routine clinical practice [20].
6 Diagnosis and Staging of Hepatocellular Carcinoma (HCC) 81

Likewise, insulin-like growth factor-1 and vascular endothelial growth factor are
being looked at as initial studies have suggested correlation with survival in patient
with HCC [19].

Conclusion

There is no consensus as to which staging system is the best in predicting the sur-
vival of patients with HCC. Attempts to better describe and classify this disease
remain a challenge, particularly if we are able to identify patients who will have
substantial benefit from interventions.
Because of its widespread presence in current HCC research, and recommenda-
tion in several international guidelines for the management of HCC, BCLC is used
by many practitioners to guide clinical decision-making. This lays the framework
for investigators and treating physicians alike to make best use of current data in
treating a difficult cancer; however it should not be taken as evidence that BCLC is
the most accurate system.
There is likely to be modifications in the staging systems of HCC given our
growing understanding in tumour biology, advanced imaging techniques and better
management of underlying liver diseases. As a complement to clinical staging, it is
to be hoped that these evolving systems will allow us to advance our prognostic
ability and deliver better care to patients diagnosed with HCC.
Whilst there are significant advantages to the patients of the diagnostic criteria
which don’t involve tissue acquisition (not needing a liver biopsy), we need to men-
tion that this will lead to a small number of incorrect diagnoses. In addition this
practice limits the HCC tissue available to further develop the area of development
of biomarkers that may help us to predict the variability in the response of this
tumour to treatment.

References

1. EASL Clinical Practice Guidelines. Management of hepatocellular carcinoma. J Hepatol.

2018; https://doi.org/10.1016/j.jhep.2018.03.019.
2. Bota S, Piscaglia F, Marinelli S, Pecorelli A, Terzi E, Bolondi L. Comparison of inter-
national guidelines for noninvasive diagnosis of hepatocellular carcinoma. Liver Cancer.
2012;1(3–4):190–200.
3. Rimola J, Forner A, Reig M, Vilana R, de Lope CR, Ayuso C, et al. Cholangiocarcinoma in cir-
rhosis: absence of contrast washout in delayed phases by magnetic resonance imaging avoids
misdiagnosis of hepatocellular carcinoma. Hepatology. 2009;50(3):791–8.
4. Jang HJ, Kim TK, Burns PN, Wilson SR. Enhancement patterns of hepatocellular carci-
noma at contrast-enhanced US: comparison with histologic differentiation. Radiology.
2007;244(3):898–906.
5. Lencioni R, Mascalchi M, Caramella D, Bartolozzi C. Small hepatocellular carcinoma: dif-
ferentiation from adenomatous hyperplasia with color Doppler US and dynamic Gd-DTPA-­
enhanced MR imaging. Abdom Imaging. 1996;21(1):41–8.
82 V. K. Balachandrakumar et al.

6. Lencioni R, Pinto F, Armillotta N, Bartolozzi C. Assessment of tumor vascularity in hepa-

tocellular carcinoma: comparison of power Doppler US and color Doppler US. Radiology.
1996;201(2):353–8.
7. Lee JM, Trevisani F, Vilgrain V, Wald C. Imaging diagnosis and staging of hepatocellular car-
cinoma. Liver Transpl. 2011;17(Suppl 2):S34–43.
8. Choi JY, Lee JM, Sirlin CB. CT and MR imaging diagnosis and staging of hepatocellular
carcinoma: part I. Development, growth, and spread: key pathologic and imaging aspects.
Radiology. 2014;272(3):635–54.
9. Silva AC, Evans JM, McCullough AE, Jatoi MA, Vargas HE, Hara AK. MR imaging of hyper-
vascular liver masses: a review of current techniques. Radiographics. 2009;29(2):385–402.
10. Khosa F, Khan AN, Eisenberg RL. Hypervascular liver lesions on MRI. AJR Am J Roentgenol.
2011;197(2):W204–20.
11. Silva MA, Hegab B, Hyde C, Guo B, Buckels JA, Mirza DF. Needle track seeding following
biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-­
analysis. Gut. 2008;57(11):1592–6.
12. Di Tommaso L, Franchi G, Park YN, Fiamengo B, Destro A, Morenghi E, et al. Diagnostic
value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis.
Hepatology. 2007;45(3):725–34.
13. Bruix J, Sherman M. Management of hepatocellular carcinoma: An update. Hepatology.
2011;53(3):1020–2.
14. Botta F, Giannini E, Romagnoli P, Fasoli A, Malfatti F, Chiarbonello B, et al. MELD scoring
system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with
residual liver function: a European study. Gut. 2003;52(1):134–9.
15. Neuberger J, Gimson A, Davies M, Akyol M, O'Grady J, Burroughs A, et al. Selection of patients
for liver transplantation and allocation of donated livers in the UK. Gut. 2008;57(2):252–7.
16. Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram HS, Su GL, et al. Prognosis of hepa-
tocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology.
2005;41(4):707–16.
17. Kadalayil L, Benini R, Pallan L, O'Beirne J, Marelli L, Yu D, et al. A simple prognostic scoring
system for patients receiving transarterial embolisation for hepatocellular cancer. Ann Oncol.
2013;24(10):2565–70.
18. Sieghart W, Hucke F, Pinter M, Graziadei I, Vogel W, Muller C, et al. The ART of decision
making: retreatment with transarterial chemoembolization in patients with hepatocellular car-
cinoma. Hepatology. 2013;57(6):2261–73.
19. Subramaniam S, Kelley RK, Venook AP. A review of hepatocellular carcinoma (HCC) staging
systems. Chin Clin Oncol. 2013;2(4):33.
20. Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, et al. Combining clini-
cal, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma.
Gastroenterology. 2011;140(5):1501–12.e2.
Chapter 7
The Role of Liver Resection
for the Treatment of Hepatocellular
Carcinoma

Mikael H. Sodergren and Dinesh Sharma

Key Learning Points

1. Liver resection provides optimal outcomes for HCC in patients of good
performance status with limited liver disease in the absence of portal
hypertension.
2. Patient selection is crucial and should take place in a multidisciplinary care
setting.
3. EASL/AASLD guidelines can guide clinicians regarding management
decisions; however it is found too restrictive by clinicians, even in Western
subgroups.
4. Where local expertise exists, the laparoscopic approach may lead to
improved perioperative outcomes.
5. Recurrent disease should be treated aggressively, if possible, to optimise
outcomes.

Areas of Controversy and Uncertainty

1. Liver resection for patients outside of the BCLC algorithm and criteria has
been reported to improve oncological outcomes in select patient groups at
specialist centres but should be approached with caution.

M. H. Sodergren
Department of Surgery and Cancer, Imperial College London, London, UK
e-mail: [email protected]
D. Sharma (*)
The Sheila Sherlock Centre for Hepatology and Liver Transplantation, The Royal Free
Hospital, London, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 83

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_7
84 M. H. Sodergren and D. Sharma

2. The objective evaluation of portal hypertension to stratify risk for surgery

varies between groups, and novel dynamic imaging methods offer poten-
tially promising solutions.
3. The role of robotics surgery is not clearly defined, and this approach
requires further evaluation in the context of surgery for HCC.
4. ALPPS in patients with HCC is associated with high mortality, and further
assessment is required prior to routine application outside clinical trials or
registries.

Introduction

The incidence of HCC is increasing in the UK and many other countries. Surgery in
the form of liver resection or transplantation remains the mainstay of curative treat-
ment for HCC, even though selected patients with small tumours may also be cured
with ablation. Liver resection and transplantation are not necessarily two binary
choices in most patients and, despite all the debates, are often complementary treat-
ment modalities ideally suited to different patient groups. Thus characterisation of
patient and tumour characteristics to guide decision making is vital to achieve the
best outcome for patients, and these aspects will be discussed as pertaining to selec-
tion for liver resection in this chapter.
Even as recently as 20–30 years ago, long-term survival following liver resection
for HCC was rare. Significant advances have been made in early diagnosis, patient
selection and preoperative investigations to exclude those with underlying liver dys-
function and likely poor outcomes. Operative techniques and anaesthetic/critical
care management have been refined resulting in a <10% need for perioperative blood
transfusion and a treatment-related mortality of 1–3%, even in cirrhotic patients. The
5-year survival following surgical resection for HCC can today exceed 50%.
On these bases, all patients diagnosed with HCC should be referred to a multi-
disciplinary centre with access to hepatologists, pathologists, surgeons, interven-
tional radiologists, palliative care specialists and oncologists. Although
transplantation is discussed in other chapters, it is important to acknowledge the
role of liver resection as a bridge to transplantation in selected patients, particularly
in the context of long waiting lists for grafts.

Preoperative Assessment

The selection of patients for surgical resection should be made on a patient-by-­

patient basis in a tertiary centre multidisciplinary team setting and involves consid-
eration of the following three factors in the context of current guidelines and
available evidence:
7 The Role of Liver Resection for the Treatment of Hepatocellular Carcinoma 85

Tumour Staging

Assessment of size, number and extent of tumour nodules with relationship to vas-
cular structures, along with exclusion of extrahepatic disease, is the aim of a thor-
ough tumour staging. Staging and surgical planning should be completed by
evaluation of dynamic multiphase computed tomography (CT) or magnetic reso-
nance imaging (MRI) scans. Intraoperative ultrasound may further aid in detecting
smaller nodules and should be routinely be used for this purpose and to aid anatomi-
cal resection. Further tumour classification can be performed using the American
Joint Committee on Cancer (AJCC) tumour/node/metastasis (TNM) system, fibro-
sis score and histological grade.

 iver Function and Portal Hypertension:

L
Assessing Liver Remnant

The Child-Pugh score is the conventional measure used in BCLC guidelines. The
score divides patients into three groups (A, B and C) based on serum albumin, bili-
rubin and prothrombin time/INR, and presence and severity of ascites and encepha-
lopathy, correlating with severity of chronic liver disease as illustrated in Table 7.1.
Platelet count (<100,000/mm3) is a further useful parameter, particularly in combi-
nation with splenomegaly, to indicate clinically significant portal hypertension.
Further radiological indicators of portal hypertension and decompensated liver dis-
ease include morphological liver changes and the presence of varices/collaterals
and/or ascites. In Western countries the hepatic vein pressure gradient is used to
evaluate portal hypertension via hepatic vein catheterisation. A gradient of

Table 7.1 Child-pugh score and interpretation

Classification 1 2 3
Serum bilirubin <34 34–51 >51
(μmol/L)
Serum albumin (g/L) >35 28–35 <28
Presence of ascites Absent Controllable Refractory
Encephalopathy Absent Minimal Severe
INR <1.7 1.7–2.3 >2.3
Interpretation
Points Class Life expectancy Perioperative mortality
5–6 A 15–50 years 10%
7–9 B Candidate for 30%
transplant
10–15 C 1–3 months 82%
Score 5–6 (Child’s A), 7–9 (Child’s B), 10–15 (Child’s C)
86 M. H. Sodergren and D. Sharma

<10 mmHg in combination with a normal bilirubin is an excellent indicator for low
risk of post-hepatectomy liver failure [1]. The indocyanine green retention rate at
15 min (ICGR15) is more commonly used in Eastern practice. ICG is an inert, water-­
soluble, fluorescent tricarbocyanine, with a protein binding close to 95%, which in
healthy individuals shows a high hepatic extraction rate (>70%). There are now
commercially available transcutaneous non-invasive pulse dye densitometry sys-
tems that can be used at the bedside. Generally most liver resection in cirrhotic
patients are deemed safe with ICGR15 < 15% in the context of an adequate FLR [2].
The use of the model for end-stage liver disease (MELD) score is controversial in
the context of liver resection for HCC. However the prognostic value in surgery for
HCC is not well established, and there are concerns regarding the narrow range (9–14)
in which the score is applied. Emerging methods of preoperative assessment of liver
function include transient elastography, 99mTc-labeled GSA scintigraphy and func-
tional MRI using Gd-EOP-DTPA contrast enhancement. Although further data are
required prior to routine clinical implementation, liver stiffness on transient elastog-
raphy has been found to correlate with postoperative liver failure after hepatectomy
for HCC. Novel imaging such as 99mTc-GSA allows not only for measurement of
total liver function but also enables quantitative segmental assessment of liver func-
tion, which may be valuable in high-risk patient groups.
In addition to function, an assessment of liver remnant volume is essential prior
to surgery. In the context of cirrhosis, it is recommended that the future liver rem-
nant (FLR) should be at least 40%; however this should be considered on an indi-
vidual basis taking account other patient factors. There is no benefit for the use of
preoperative chemo-embolisation or portal vein embolisation in patients who meet
criteria for surgical resection. However portal vein embolisation may render unre-
sectable patients operable due to an increase in FLR and allows for evaluation of
regenerative capacity. When the liver does not regenerate after PVE, most agree that
major hepatectomy should be contraindicated to avoid severe postoperative liver
failure. Should trans-arterial embolisation be appropriate, it is desirable that this is
performed prior to portal vein embolisation [3].

Patient Fitness

Prior to being offered liver resection for HCC patients should undergo a thorough
clinical assessment with identification of any significant cardiac, pulmonary or renal
co-morbidities. Any suggestion in the history of underlying co-morbidities should be
extensively investigated. ASA score has been found to accurately predict mortality of
patients with liver cirrhosis undergoing abdominal surgery and should be accurately
documented. Even in patients of good performance status, pre-­existing co-morbidi-
ties may contraindicate surgical resection. In the authors’ institution, cardiopulmo-
nary exercise testing is sometimes used as an adjunct to other conventional assessments
of fitness such as the stairs test in determining suitability for surgery in borderline
cases.
7 The Role of Liver Resection for the Treatment of Hepatocellular Carcinoma 87

BCLC guidelines suggest that surgery should only be offered to patients with
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0; how-
ever many studies have shown PS to be least respected BCLC criteria. Age in itself
should not be a contraindication to surgery. Limited evidence suggests that there
may be a higher incidence of serious complications in this group; however disease-­
free survival and mortality appear similar to younger cohorts [4]; therefore careful
patient selection is essential, and particular caution should be applied for patients
outside BCLC guideline criteria.

Patient Selection

Guidelines/Criteria for Resection

The Barcelona Clinic Liver Cancer (BCLC) staging system utilises tumour stage,
physical status, liver function and cancer-related symptoms to recommend treat-
ment allocations. It has been externally validated and used in many clinical trials of
HCC treatment and therefore has also been used in the current European Association
for Study of the Liver (EASL) and American Association for the Study of Liver
Diseases (AASLD) guidelines for the treatment of HCC [5, 6], which are illustrated
in Fig. 7.1. Using these guidelines resection is recommended as the primary treat-
ment in patients with a single tumour (previously in smaller tumours though the

HCC

Stage 0 Stage A-C Stage D

PST 0, Child-Pugh A PST 0-2, Child-Pugh A-B PST >2, Child-Pugh C*

Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal stage (D)
Single <2 cm, Single or ≤3 nodules ≤3 cm, Multinodular, Portal invasion,
Carcinoma in situ PS 0 PS 0 N1, M1, PS 1-2

Single 3 nodules ≤3 cm

Portal pressure/bilirubin

Increased Associated diseases

Normal No Yes

Liver transplantation Best supprtive

Resection RF/PEI TACE Sorafenib
(CLT/LDLT) care

Curative treatment (30-40%) Target: 20% Target: 40% Target: 10%

Median OS >60 mo; 5-yr survival: 40-70% OS: 20 mo (14-45) OS: 11 mo (6-14) OS: <3 mo

Fig. 7.1 AASLD-EASL-EORTC treatment algorithm for HCC

88 M. H. Sodergren and D. Sharma

HCC

Extrahepatic No Yes
Spread

Liver Function Child-Pugh A/B Child-Pugh C Child-Pugh B/C Child-Pugh A

Vascular
invasion No Yes No Yes
a, b

Number Single 1-3 4 or more 9

With in Milan Exceeding Milan
Hypovascular criteria and criteria
Early HCCc Age≤ 65 or Age >65
Size ≤3 cm >3 cm

Treatment • Resection • TACE e • HAIC(Vp1-4) h • Transplantation

• Intensive • Resection • TACE • HAIC e • Sorafenib(Vp1-3)
h • TACE/Ablation
follow-up • Ablation
• TACE + • Resection f • TACE(Vp1-2) for Child-Pugh C Palliative care Sorafenib
Ablation d
• Ablation • Ablation f • Resection(Vp1-2)
i patients

Sorafenib e
(TACE refractory, Child-Pugh A)

Fig. 7.2 JSH Liver Cancer Study Group of Japan consensus-based treatment algorithm Kudo [7]

later versions have removed this restriction), Child-Pugh Class A liver function with
normal bilirubin, no evidence of portal hypertension (hepatic vein pressure gradient
<10 mmHg or platelet count >100,000) and good performance status. It is worth
noting that Eastern guidelines differ from those used in Western countries and on the
whole adopts a more aggressive treatment approach. Regarding the role of resection,
the Liver Cancer Study Group of Japan published guidelines [7], illustrated in
Fig. 7.2, and recommended potentially curable therapy with resection and ablation
to be attempted even in the presence of four or more nodules. Furthermore they
recommend TACE or resection in the case of minor vascular invasion (Vp1 or Vp2)
for which sorafenib would be the recommended treatment under Western guide-
lines. However, it is worth noting that in the East, the incidence of HCC in non-cir-
rhotic patients (40%) and HBV is much greater than that in Western countries (5%).

Extended Criteria Resections

It is well known that clinical practice sometimes deviates from the BCLC recom-
mendations, often found to be too restrictive at the authors’ institution especially for
intermediate or advanced disease, and there is a growing body of evidence that sug-
gests liver resection to be safe in selected patients with portal hypertension and
well-­compensated liver function, thereby including these patients on a curative
treatment pathway. Criteria have been extended to patients with macrovascular
invasion as well as multiple or large HCCs, in addition to portal hypertension, with
superior reported outcomes to palliative therapies in selected patients [8]. There are
however no randomised data to guide patient selection for these controversial
7 The Role of Liver Resection for the Treatment of Hepatocellular Carcinoma 89

indications, and a meta-analysis of patients with clinically significant portal hyper-

tension undergoing resection for HCC has shown a significant increase in 3- (OR
2.09, 95% CI: 1.52–2.88) and 5-year (OR 2.07, 95% CI 1.51–2.84) mortality and of
clinical decompensation (OR 3.04, 95% CI 2.02–4.59) after surgery [9]. An analysis
from ten high-volume centres of 2046 patients showed that only 50% of patients
were operated within BCLC recommendations with 36% and 14% of patients in
BCLC stage B or C undergoing surgery. The reported 5-year overall survival after
resection in BCLC groups A, B and C was 61%, 57% and 38%, respectively, with
5-year disease-free survival of 21%, 27% and 18% [10]. These survival curves are
illustrated in Fig. 7.3.

A Pragmatic Approach to HCC Resections

We would consider liver resection first in all standard risk resection patients, i.e.,
those with Child-Pugh A cirrhosis with a hepatic wedge pressure gradient of
10 mmHg or less and a good ICG clearance with a PDR15 of >15 with an R15 of <15,
with adequate liver remnant ideally >40%—especially for major resections. Despite
ongoing debate we feel a liver transplant for these patients does not necessarily
guarantee the best outcome and potentially deprives others in the UK setting.
Patients who are not within the standard risk category for resection will be con-
sidered for liver transplantation if appropriate (if they are within existing criteria
and fit).
Radiofrequency ablation will be considered as a possible curative treatment
modality if neither resection nor transplantation is feasible or appropriate with stan-
dard risk.
In patients for whom a low or standard risk resection, liver transplantation or
radiofrequency ablation (in that order of consideration) is not feasible or appropri-
ate, then a higher risk resection (for instance with multiple nodules or with some
portal hypertension or poor liver function or macrovascular invasion, as in Fig. 7.4)
may be considered as long as the size of resection is thought to be compatible with
the impairment of liver synthetic function or portal hypertension. This would be
discussed on a case-by-case basis by the multidisciplinary team. The approach
would of course vary in a different geocultural environment.

Anaesthetic Considerations

There are several important measures that can be taken by the anaesthetist to
improve outcomes of liver resection for HCC. Intraoperatively a low central venous
pressure (CVP), preferably <5 cm H2O, is important in limiting blood loss. This can
be achieved by a combination of diuretics or nitroglycerine, reduction in tidal vol-
ume and positive end-expiratory pressure and placing the patient in the reverse
Trendelenburg position as well as minimal intravenous fluid infusion.
90 M. H. Sodergren and D. Sharma

a Overall survival

1.00
0.75
Proportion of survival
0.50
0.25
0.00

0 12 24 36 48 60 72
Months after resection
Number at risk
1870 1343 795 527 316 198 104
b Overall survival
1.00
Proportion of survival
0.75
0.50
0.25
0.00

0 12 24 36 48 60 72
Months after resection
Number at risk
0-A 933 712 434 283 162 105 51
B 663 465 280 189 126 72 41
C 274 166 81 55 28 21 12
0-A B C
c Overall survival
1.00
Proportion of survival
0.75
0.50
0.25
0.00

0 12 24 36 48 60 72
Months after resection
Number at risk
0-A 933 712 434 283 162 105 51
B-C 937 631 361 244 154 93 53
0-A B-C

Fig. 7.3 Survival after resection. (a) Overall survival of 2046 patients resected for HCC.
(b) Overall survival stratified according to the BCLC classification (P = 0.000). (c) Overall sur-
vival of patients in the very early and early stages (BCLC 0-A) versus patients in the intermediate
and advanced stages (BCLC B-C) (P = 0.000) Torzilli [10]
7 The Role of Liver Resection for the Treatment of Hepatocellular Carcinoma 91

Left PV

Tumour thrombus

Right PV

Main PV

Bilioarterial hilar
complex

Tumour thrombus in Left Main Portal Vein, Left Hepatectomy

Fig. 7.4 Liver resection with macroscopic portal vein extension

92 M. H. Sodergren and D. Sharma

Surgical Technique

Anatomical Resection or Not?

The aim of liver resection in patients with HCC and CLD is that it should be cura-
tive with resection of tumour vascular territories and also preserve as much liver
volume as possible to prevent postoperative liver failure. EASL guidelines recom-
mend anatomical resection of HCC, whereby the lines of resection match the limits
of one or more functional segments of the liver. This is based on evidence suggest-
ing superior oncological outcomes in addition to a reduction in the risk of bleeding
and biliary fistula. Although there are no randomised data, a meta-analysis includ-
ing 1829 patients from 12 non-randomised comparative trials did not show any
benefit of anatomical compared with non-anatomical resection in 1-, 3- and 5-year
survival, recurrence rate, postoperative morbidity or blood loss [11]. It is the authors’
practice to perform an anatomical resection for tumours >2 cm, and for smaller
tumours in anatomically favourable positions, a wedge with adequate margin is
often sufficient [12]. Modifying techniques to maximise parenchymal preservation
preserving adequate margins are often the key in these patients.

Anterior Approach

The anterior approach, as described by Professor Belghiti [13], has been advocated
for large right-sided tumours. This technique involves transection of the liver paren-
chyma to the IVC without mobilisation of the liver with the theoretical advantage of
less tumour seeding. A prospective randomised controlled trial compared the ante-
rior and conventional approach on 120 patients with large (>5 cm) HCCs. The ante-
rior approach group had less blood transfusion requirements and a significantly
longer overall survival (68.1 v 22.6 months; p = 0.006) [14].

Parenchymal Transection

As in liver resection for other indications, there is no good evidence to indicate that
a single method of parenchymal transection, application of fibrin sealants or inter-
mittent inflow occlusion is beneficial in surgery for HCC. There is also no evidence
to suggest that using special equipment for liver resection is of any benefit in
decreasing the mortality, morbidity, or blood transfusion requirements [15].
Surgeons should use techniques in which they have been trained and can demon-
strate acceptable outcomes.
7 The Role of Liver Resection for the Treatment of Hepatocellular Carcinoma 93

Laparoscopic Approach

Laparoscopic HCC resections are gaining popularity as the approach is more widely
adopted across centres. It is important that patients for laparoscopic resection are
selected based on the technical capabilities of the surgeon and centre, and the proper
mentoring takes place during the learning curve. A summary of published meta-­
analyses concluded that the laparoscopic approach was associated with improved
short-term outcomes (blood loss, complication rates and hospital length of stay)
without compromising long-term oncological outcomes. It is worth noting that there
are no randomised data; however a number of trials are in progress. Furthermore,
their analysis suggested that the incidence of postoperative ascites and liver failure is
decreased in the selected group of laparoscopic liver resections [16]. A further meta-
analysis of cirrhotic patients up to Child-Pugh B undergoing laparoscopic compared
with open liver resection for HCC confirmed these perioperative benefits [17].

Robotic Approach

Although still very much in its infancy, the application of robotic surgery to HCC
resection can theoretically yield similar advantages in short-term outcomes to the
laparoscopic technique. The only comparative study between robotic and open liver
resection for HCC included 183 patients undergoing robotic hepatectomy who were
compared using propensity scoring with a cohort of 275 open resections. The robotic
group required longer operating time (343 vs 220 min), shorter hospital stays (7.5 vs
10.1 days) and lower dosages of postoperative patient-controlled analgesia (350 vs
554 ng/kg). The 3-year disease-free survival of the robotic group was comparable
with that of the open group (72.2% vs 58.0%; p = 0.062), as was the 3-year overall
survival (92.6 vs 93.7%; p = 0.431) [18]. The associated financial costs of robotic
surgery still pose a limitation to its adoption, and it is unclear if this approach is asso-
ciated with any significant advantages over laparoscopic rather than open resection.

 ssociating Liver Partition with Portal Vein Ligation for Staged

A
Hepatectomy (ALPPS)/TAE/PVE

ALPPS is still considered an experimental technique in which a first-stage procedure

consisting of physical liver splitting and portal vein ligation is followed by a second
stage of resection of the HCC and associated liver segments. The advantage seen in
colorectal liver metastases is that of rapid hypertrophy for the FLR. There are only
limited data describing outcomes of ALPPS for HCC; however an analysis of 35
patients in the international ALPPS registry showed an impressive FLR hypertrophy
94 M. H. Sodergren and D. Sharma

of 47% following the first stage of the procedure that was associated with a 31% peri-
operative mortality rate. The majority of these patients were in the intermediate-­stage
category of the BCLC algorithm [19]. Further evaluation is required prior to routine
use of ALPPS for HCC resection, and it is the view of the authors that ALPPS may be
a procedure best reserved for carefully selected patients who have bilateral disease.

Combined Resection with RFA for Bilobar HCC

For patients with multiple or bilobar HCC in whom resection is contraindicated due
to inadequate FLR, combined resection and radiofrequency ablation (RFA) may
yield better results than alternative treatments. A single-centre study compared
patients with bilobar liver HCCs who underwent resection (n = 89), combination of
resection and RFA (n = 114) and TACE (n = 161). The results showed that 1-, 3- and
5-year survival was better in both resection and combined resection, and RFA
groups compared with TACE and survival and disease-free survival were compara-
ble between both surgical groups. They concluded that resection combined with
RFA provided a chance for cure in patients with bilobar HCC, and provided liver
function is preserved, aggressive treatment can improve prognosis [20].

Ruptured Hepatocellular Carcinoma

Ruptured HCC occurs in approximately 10% of patients and is a potentially life-­

threatening complication with a mortality rate of up to 50%. The initial concern is
often haemostasis, and this can be achieved in a number of ways including TACE,
bland embolisation and laparotomy with packing or liver resection. When possible
hepatic resection has the best outcome and should be the treatment of choice however
following haemostasis. The test of time is often useful to determine the biology of the
tumour prior to embarking on definitive treatment. A case-controlled propensity
matched study of 34 Western patients presenting with rupture was compared with a
cohort of HCC patient who did not present with rupture. There was no difference in
overall and disease-free survival between these groups; however underlying cirrhosis
was associated with significantly worse prognosis. Rupture in itself was not found to
be a risk factor for survival in selected patients who undergo hepatectomy [21].

Liver Resection for Recurrent Hepatocellular Carcinoma

Intrahepatic recurrence of HCC following resection or ablation is common, up to

70% at 5 years following primary resection comprising of both local recurrence and
de novo disease. Factors associated with an increased risk of recurrence include
7 The Role of Liver Resection for the Treatment of Hepatocellular Carcinoma 95

hepatitis C diagnosis, preoperative aspartate aminotransferase (AST) greater than

twice normal, large intraoperative blood transfusion and preoperative serum alpha-­
fetoprotein (AFP) of more than 10,000 ng/mL. Unlike in primary HCC, there are no
consensus guidelines to inform management decisions, and treatment options
include repeat hepatectomy, RFA, TACE or transplantation. A meta-analysis com-
paring hepatectomy, RFA and TACE including 2764 patients suggested a trend
towards improved survival following repeat hepatectomy compared with TACE
(HR = 1.61; p = 0.056) with similar outcomes to RFA (HR = 1.03; p = 0.897). Short
disease-free interval and multiple and larger hepatic metastases were all found to be
negative prognostic factors [22].

Conclusion

It is crucial that patients with HCC are treated in appropriate centres that have the
infrastructure and expertise available to manage this complex disease and ideally
who can offer all treatment modalities. The treatment approach followed at the
authors’ institution has been outlined. Surgical resection should be offered to
patients who are of good performance status with limited liver disease (single lesion
with Child-Pugh A cirrhosis with normal bilirubin and absence of portal hyperten-
sion). The EASL/AASLD guidelines provide a good framework on which to base
treatment strategies. Resection contemplated for more advanced disease or cirrhosis
may be carefully considered in a case-by-case basis by an expert multidisciplinary
team. However, despite retrospective nature of studies, it is likely that careful patient
selection may permit curative liver resection in groups outside the BCLC recom-
mendations such as those with multiple tumours, portal hypertension or even mac-
rovascular invasion. Available data regarding operative risks, alternative treatments
and oncological prognosis must be frankly discussed with the patient. Low CVP
during surgery may aid in reducing blood loss. The standard surgical approach is
that of an anatomical open liver resection with a minimum of 40% FLR in cirrhotic
patients. Portal vein ligation/embolisation may be useful in specific cases to increase
the FLR and decrease risk of postoperative liver decompensation. The anterior
approach may be useful for large lesions and may have some oncological benefits.
The laparoscopic approach is gaining popularity, particularly for anterior/left-sided
segmental liver resection, and appears to be associated with improved perioperative
outcomes. Techniques such as robotic surgery and ALPPS are still considered
experimental and should not be practised routinely outside clinical trials or regis-
tries. Ruptured HCC, once haemostasis has been established, should be treated
under the same oncological pathway as non-ruptured tumours including consider-
ation of surgical resection for appropriate patients. A large number of patients will
experience recurrence of HCC after resection. They should be re-evaluated for radi-
cal treatment with both reoperation and RFA producing improved outcomes to
TACE or supportive treatment.
96 M. H. Sodergren and D. Sharma

References

1. Boleslawski E, Petrovai G, Truant S, Dharancy S, Duhamel A, Salleron J, et al. Hepatic venous

pressure gradient in the assessment of portal hypertension before liver resection in patients
with cirrhosis. Br J Surg. 2012;99(6):855–63.
2. Lam CM, Fan ST, Lo CM, Wong J. Major hepatectomy for hepatocellular carcinoma in
patients with an unsatisfactory indocyanine green clearance test. Br J Surg. 1999;86:1012–46.
3. Ogata S, Belghiti J, Farges O, Varma D, Sibert A, Vilgrain V. Sequential arterial and portal
vein embolizations before right hepatectomy in patients with cirrhosis and hepatocellular car-
cinoma. Br J Surg. 2006;93:1091–8.
4. Huang J, Li BK, Chen GH, et al. Long-term outcomes and prognostic factors of elderly
patients with hepatocellular carcinoma undergoing hepatectomy. J Gastrointest Surg.
2009;13(9):1627–35.
5. Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepato-
cellular carcinoma: an update. Hepatology. 2011;53(3):1020–2.
6. European Association for the Study of the L, European Organisation for R, Treatment of
C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J
Hepatol. 2012;56(4):908–43.
7. Kudo M, Matsui O, Izumi N, et al. JSH consensus-based clinical practice guidelines for the
management of hepatocellular carcinoma: 2014 update by the liver cancer study group of
Japan. Liver Cancer. 2014;3(3-4):458–68.
8. Guglielmi A, Ruzzenente A, Conci S, et al. Hepatocellular carcinoma: surgical perspec-
tives beyond the Barcelona clinic liver cancer recommendations. World J Gastroenterol.
2014;20(24):7525–33.
9. Berzigotti A, Reig M, Abraldes JG, Bosch J, Bruix J. Portal hypertension and the outcome of
surgery for hepatocellular carcinoma in compensated cirrhosis: a systematic review and meta-­
analysis. Hepatology. 2015;61(2):526–36.
10. Torzilli G, Belghiti J, Kokudo N, et al. A snapshot of the effective indications and results of
surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/
AASLD recommendations?: an observational study of the HCC east-west study group. Ann
Surg. 2013;257(5):929–37.
11. Tang YH, Wen TF, Chen X. Anatomic versus non-anatomic liver resection for hepatocellular
carcinoma: a systematic review. Hepato-Gastroenterology. 2013;60(128):2019–25.
12. Eguchi S, Kanematsu T, Arii S, Okazaki M, Okita K, Omata M, Ikai I, Kudo M, Kojiro M,
Makuuchi M, et al. Comparison of the outcomes between an anatomical subsegmentectomy
and a non-anatomical minor hepatectomy for single hepatocellular carcinomas based on a
Japanese nationwide survey. Surgery. 2008;143:469–75.
13. Belghiti J, Guevara OA, Noun R, Saldinger PF, Kianmanesh R. Liver hanging maneu-
ver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg.
2001;193(1):109–11.
14. Liu CL, Fan ST, Cheung ST, Lo CM, Ng IO, Wong J. Anterior approach versus conventional
approach right hepatic resection for large hepatocellular carcinoma: a prospective randomized
controlled study. Ann Surg. 2006;244(2):194–203.
15. Moggia E, Rouse B, Simillis C, et al. Methods to decrease blood loss during liver resection: a
network meta-analysis. Cochrane Database Syst Rev. 2016;10:CD010683.
16. Morise Z, Ciria R, Cherqui D, Chen KH, Belli G, Wakabayashi G. Can we expand the indi-
cations for laparoscopic liver resection? A systematic review and meta-analysis of laparo-
scopic liver resection for patients with hepatocellular carcinoma and chronic liver disease. J
Hepatobiliary Pancreat Sci. 2015;22(5):342–52.
17. Twaij A, Pucher PH, Sodergren MH, Gall T, Darzi A, Jiao LR. Laparoscopic vs open approach
to resection of hepatocellular carcinoma in patients with known cirrhosis: systematic review
and meta-analysis. World J Gastroenterol. 2014;20(25):8274–81.
7 The Role of Liver Resection for the Treatment of Hepatocellular Carcinoma 97

18. Chen PD, Wu CY, Hu RH, et al. Robotic versus open hepatectomy for hepatocellular carci-
noma: a matched comparison. Ann Surg Oncol. 2016;24(4):1021–8.
19. D'Haese JG, Neumann J, Weniger M, et al. Should ALPPS be used for liver resection in
intermediate-­stage HCC? Ann Surg Oncol. 2016;23(4):1335–43.
20. Zhang T, Zeng Y, Huang J, Liao M, Wu H. Combined resection with radiofrequency ablation for
bilobar hepatocellular carcinoma: a single-center experience. J Surg Res. 2014;191(2):370–8.
21. Pinsker N, Papoulas M, Sodergren M, Quaglia A, Suddle A, Jassem W, Melendez HV,
Prachalias A, Srinivasan P, Menon K, Heaton N, et al. Outcomes following liver resection for
ruptured and non-ruptured hepatocellular carcinoma–a propensity matched analysis. In: 19th
Annual Scientific Meeting of the Association-of-Upper-Gastrointestinal-Surgeons-of-Great-
Britain-and-Ireland. Wiley-Blackwell. 2016; p. 17, ISSN: 0007-1323.
22. Erridge S, Pucher PH, Markar SR, Malietzis G, Athanasiou T, Darzi A, et al. Meta-analysis of
determinants of survival following treatment of recurrent hepatocellular carcinoma. Br J Surg.
2017;104:1433–42.
Chapter 8
Liver Transplantation for the Treatment
of Hepatocellular Carcinoma

Aileen Marshall

Introduction

Liver transplantation is established as an effective treatment for patients with

chronic liver diseases. Patients with primary liver cancer have been part of the
patient group since the first human liver transplants were performed in the 1960s.
The first report from Thomas Starzl of three successful liver transplants included
one paediatric patient with hepatic cell carcinoma [1]. This patient survived for
13 months and died of metastatic disease.
During the 1970s and 1980s as liver transplant programmes grew, HCC remained
an indication for transplant but with no clear selection criteria intended to optimise
the outcome for those recipients. It became evident that tumour recurrence post-­
transplant was a frequent occurrence, was difficult to treat, and had a high mortality.
Rapid HCC reoccurrence and death at a time when survival following liver trans-
plant for other indications was improving tempered enthusiasm to offer liver trans-
plantation to patients with HCC.
The importance of HCC stage to influence risk of recurrence was recognised. A
seminal paper published by Mazzaferro and colleagues in 1996 defined size and
number criteria that demonstrated a low risk of recurrence and patient and graft
survival comparable to other transplant indications [2]. The cohort of 48 patients,
predominantly HCV or HBV positive, had either a single HCC ≤ 5 cm or up to 3
HCC all in one lobe and the largest ≤3 cm. Radiological evidence of extrahepatic
disease or tumour invasion into a branch of the portal vein were exclusion criteria.
In this cohort 4/48 patients had HCC recurrence and 4 year recurrence-free sur-
vival was 83%, representing a significant improvement compared to historical

A. Marshall ()
The Sheila Sherlock Centre for Hepatology and Liver Transplantation, The Royal Free
Hospital, London, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 99

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_8
100 A. Marshall

series. Known as the Milan criteria, these size and number criteria were widely
adopted worldwide and remain the basis for patient selection for liver transplanta-
tion until now.
Whilst implementation of the Milan criteria renewed HCC as an indication for
liver transplantation, it is clear that one snapshot of tumour stage at one time point
does not capture the variability of tumour biology and prognosis for HCC. At one
end of the spectrum, there are patients with early-stage disease who still experience
post-transplant recurrence, and at the opposite end, there are patients with HCC
beyond the Milan criteria who had long-term recurrence-free survival. The chal-
lenge has been to optimise identification of patients who will benefit most from liver
transplantation. Histologically, the presence of microvascular invasion is the most
important predictor of recurrence. Microvascular invasion is defined as tumour
present within a blood vessel with a muscular wall >1 cm from the tumour margin
[3]. Additional factors impacting recurrence risk are grade of differentiation and the
presence of satellite nodules. All these factors can only be assessed fully following
transplantation so cannot be used in patient selection for transplantation.
The keys themes of research regarding patient selection for liver transplantation
have been:
1. Expansion of size and number criteria beyond Milan.
2. Pre-transplant radiological and serological parameters that predict post-­transplant
prognosis.
3. Change in radiological or serological parameters over time.
4. Response to locoregional treatment.

Pre-transplant Radiological Criteria

Table 8.1 summarises the proposed expansions to Milan criteria [4–8]. The first
proposal to modestly expand criteria was based on retrospective analysis of 70
patients receiving liver transplants between 1988 and 2000 at the University of
California, San Francisco (UCSF). They identified that overall survival was 90% at
1 year and 72.5% at 5 years for patients with 1 HCC < 6.5 cm, or up to 3 HCC, larg-
est <4.5 cm and total tumour diameter <8 cm [4]. In contrast, patients exceeding
these criteria had 50% 5 year survival. These data were obtained using histopathol-
ogy and subsequently were validated prospectively using pre-transplant radiology
in 168 patients and reporting 1- and 5-year recurrence-free survival of 92.1% and
80.7% [9].
In a study of 1556 patients exceeding Milan criteria, Mazzaferro and colleagues
proposed the concept of the “Metroticket” using HCC size and number [7]. The up-­
to-­seven criteria combine number of HCC with the size of the largest lesion so that
as number increases, the permitted size of the largest HCC decreases. Predicted
survival following transplantation decreases as the combined score increases, and it
was suggested that this graded approach could be used to identify patients with
8 Liver Transplantation for the Treatment of Hepatocellular Carcinoma 101

Table 8.1 Selection criteria for liver transplantation for patients with hepatocellular carcinoma.
TTD total tumour diameter, OS overall survival, RFS recurrence-free survival
Reference Name Criteria Outcome
Mazzaferro et al. [2] Milan 1 ≤ 5 cm OR 3 ≤ 3 cm 83% 4-year RFS
Yao et al. [4] UCSF 1 ≤ 6.5 cm OR 75.2% 5-year OS
3 ≤ 4.5 cm AND TTD ≤ 8 cm
Zheng et al. [5] Hangzhou TTD ≤ 8 cm OR 72.3% 5-year OS
TTD ≥ 8 cm and Grade I/II
differentiation and AFP ≤ 400 ng/
ml
Lee et al. [6] Asan Up to 6 HCC ≤ 5 cm and no 76.3% 5-year OS
macrovascular invasion (LDLT only)
Mazzaferro et al. [7] Up-to-­seven Sum of size of largest HCC and 71.2% 5-year OS
number of HCC < 7
Takada et al. [8] Kyoto Up to 10 HCC ≤ 5 cm AND 87% 5-year OS
PIVKA-II < 400 mAU/ml (LDLT only)

HCC beyond Milan criteria yet acceptable 5-year post-transplant survival. A revised
“Metroticket 2.0” model has just been published that also incorporated AFP.
Similarly, in populations where living donor transplant is more commonly per-
formed, expansion of size and number criteria have been proposed that are reported
to provide similar 5-year survival to the Milan criteria (Table 8.1) [6, 8].
Positron emission tomography (PET) is a combination of morphological and
functional imaging that relies on uptake of compounds by metabolically active
cells. FDG-PET has become part of the diagnostic algorithm for many solid can-
cers, but not HCC as a large proportion of HCC are non-avid. However, it may have
usefulness as a prognostic marker. In a Japanese cohort of patients receiving liver
donor transplant for HCC, pre-transplant PET-positive status was associated with
microscopic vascular invasion and with higher post-transplant recurrence [10].
In the UK, the liver transplant selection criteria are based on the Milan criteria
with minor modifications. A patient can be offered transplant if there is one
HCC < 5 cm or up to 5 HCC, largest ≤3 cm. The presence of extrahepatic disease,
radiological evidence of macrovascular invasion and AFP > 1000 IU/ml are exclu-
sion criteria. In addition, patients with a single HCC 5–7 cm in size that is stable
over 6 months can be offered transplantation.

Pre-transplant Serum Biomarkers for HCC

Alpha-fetoprotein (AFP) is the most well-known and widely used biomarker, origi-
nally linked to HCC in 1970. As a diagnostic marker for HCC, AFP is limited by
poor sensitivity and specificity. However, as a prognostic marker, numerous studies
have shown that a high pre-transplant AFP has been associated with an increased
risk of HCC recurrence. A systematic review and meta-analysis of published studies
102 A. Marshall

found the hazard ratio for recurrence was 2.69 (2.08–3.47) if the AFP was >400 IU/
ml [11]. In the UK, the cut-off for AFP has been reduced from 10,000 IU/ml to
1000 IU/ml.
Serial measurement of AFP pre-transplant also gives prognostic value; three
separate studies have identified that rising AFP whilst awaiting transplantation is
associated with adverse outcome. In Canadian patients, AFP increasing by >50 μg/l
per month was associated with 1-year recurrence-free survival of 40% [12]. A
French single-centre study reported 5-year recurrence-free survival 47% in patients
who had a pre-transplant AFP rising by 15 μg/l per month [13]. Similarly, a multi-
centre European study found that 5-year recurrence-free survival using the same
cut-off was 53.8% [14]. This study also showed that increasing AFP pre-transplant
conferred an increased risk of dropout from the transplant waiting list.
Des-gamma-carboxy prothrombin (DCP), also known as protein induced by
vitamin K absence (PIVKA), has been studied predominantly in Eastern popula-
tions. It is proposed as a diagnostic marker and to provide prognostic value for
patients with HCC treated with liver resection. In transplant populations, a meta-­
analysis of five published studies of HCC recurrence following liver transplantation
showed a strong correlation between pre-transplant DCP and post-transplant HCC
recurrence (HR 5.99, 3.27–10.98) [11].

Novel and Molecular Biomarkers in Liver Transplant Patients

Given the limitations of existing radiological criteria and serum biomarkers, there is
a great deal of interest in novel and molecular biomarkers as both diagnostic and
prognostic markers. As yet, none have been shown to perform well enough to be
implemented into clinical decision-making. A combination of clinical and serum
biomarkers (GALAD; Gender, Age, L3-AFP, AFP and DCP) has been shown to
improve sensitivity in HCC diagnosis, but this combination has not been evaluated
as a prognostic marker in liver transplant patients.

Non-coding RNA

Non-coding RNA, including long non-coding RNA (lncRNA) and microRNA

(miRNA), are molecules that have been discovered to play a critical role in the regu-
lation of gene expression. In recent years, non-coding RNA have been extensively
investigated for their role in carcinogenesis, as diagnostic markers and in cancer
therapeutics. Thousands of human miRNA are described with specific tissue pat-
terns and with specific alterations in many cancers. MiRNA are detectable in serum
which make them attractive biomarkers. A small number of studies, reviewed in
[15], found associations between pre-transplant miRNA profile and post-transplant
8 Liver Transplantation for the Treatment of Hepatocellular Carcinoma 103

recurrence. However, miRNA expression is also likely to be altered by the type and
stage of background liver disease or by comorbidities.
The earliest studies used standard extraction techniques to detect miRNA in
serum. It now appears that miRNA are found within circulating exosomes, small
membrane bound vesicles that are released into the circulation via fusion with the
cell membrane. Exosomes are thought to play a role in cell-cell communication of
genetic material. Therefore, extraction of miRNA from exosomes may improve the
sensitivity and specificity of detecting circulating cancer-derived miRNA. Using
this technique, decreased exosomal mir718 was found to be associated with more
HCC aggressiveness and recurrence post-transplant [16].
Tissue expression of two lncRNA (MALAT1 and HOTAIR) has been reported in
two cohorts to be associated with post-transplant recurrence. Circulating lncRNA
are now reported to be detectable in circulating exosomes, but as yet there is no date
on circulating lncRNA in patients with HCC.

 irculating Tumour Cells and Circulating

C
Cell-Free Tumour DNA

Circulating cancer cells and cell-free DNA have been described in several different
cancers, and in some cases, detection of circulating cells or DNA can lead to early
detection of recurrence or relapse following treatment. The extraction of such cells
relies on expression of cell surface markers, e.g., the stem cell marker EPCAM, or
detection of a known cancer mutation. For HCC, detection of p53 mutation in cell-­
free DNA has been described. At present, it is not known whether these markers
have a role in prognostication, early detection of recurrence or treatment decisions.
In the future it may be possible to identify an individual’s cancer mutation profile
using a biopsy or surgical specimen and then use that patient’s tumour-specific
mutations to detect recurrence.

 re-transplant Locoregional HCC Treatment

P
and Downstaging

In the UK approximately 22% of patients who receive a liver transplant have HCC
[17]. In common with other Western countries, most patients receiving liver trans-
plants for HCC will receive an organ from a deceased donor. The overall median
waiting time is 135 days, but there is a large range. For all patients, 18% are still
waiting 1 year after listing, and 5% are still waiting at 2 years. Given the uncertainty
about how long the patient will wait, it is common practice to offer locoregional
treatment (LRT) such as transarterial (chemo) embolisation (TA(C)E) or radiofre-
quency ablation (RFA) where possible. Some patients with decompensated liver
104 A. Marshall

disease will not be able to receive LRT. There are no randomised controlled clinical
trials comparing outcomes in patients who do not receive LRT whilst on the trans-
plant waiting list; however the United Network for Organ Sharing (UNOS) data
from North American transplant centres does demonstrate better post-transplant
outcomes in patients who are able to receive LRT.
Application of LRT to patients with HCC beyond Milan criteria has led to the
concept of downstaging, that is, using LRT to reduce the tumour size or number to
within accepted transplant criteria. In this context a response to LRT is thought to
be a surrogate marker for favourable tumour biology and hence an acceptable risk
of post-transplant recurrence. The published data is limited by heterogeneity in
patient selection, downstaging protocols, outcome assessment and study quality. A
systematic review of these studies concluded that the overall downstaging was
achieved in 40% of patients, and post-transplant recurrence was 16% [18].
Protocols and clinical outcomes have been published by two well-established
downstaging programmes conducted in UCSF [19] and French transplant centres
[20]. The UCSF group recently reported long-term outcomes in 118 patients ini-
tially outwith UCSF criteria entered into a downstaging protocol. Sixty-four patients
were successfully downstaged and received a transplant; of this group 7.5% had
HCC recurrence. Duvoux and colleagues have used pre-transplant AFP, tumour size
and tumour number to categorise patients as “low risk” or “high risk” (Table 8.2) for
recurrence and then re-categorise patients according to the response to LRT. Patients
who are initially high risk but following LRT meet low-risk criteria have the same
HCC recurrence, 14.3% over 4 years, as patients with low-risk HCC throughout.
Patients who are low risk and then progress to high risk had 58% 4-year recurrence,
and patients who were high risk throughout had 65% 4-year recurrence.
In the UK, there is a pilot programme to offer liver transplant to patients who
achieve downstaging to a Duvoux score of ≤2 and demonstrate stable tumour char-
acteristics over 6 months. At present, 12 patients are registered and have received
transplants in this ongoing pilot.

Table 8.2 Duvoux criteria for liver transplantation Variable Points

for patients with hepatocellular carcinoma
Largest Diameter (cm)
incorporating AFP. Patients with score ≤ 2 are
categorised as “low risk” and score > 2 high risk for ≤3 0
post-transplant recurrence [20] 3–6 1
>6 4
Number of nodules
1–3 0
≥4 2
AFP (ng/ml)
≤100 0
100–1000 2
>1000 3
8 Liver Transplantation for the Treatment of Hepatocellular Carcinoma 105

Types of Donor Liver

Most patients receiving a liver transplant receive a whole organ from a deceased
donor after brain death is confirmed. As the demand for organ transplant exceeds
supply, surgical innovations have been introduced to expand the donor pool.
These are:
1. Deceased donors after cardiac or circulatory death (DCD).
2. Split liver transplant, when the whole organ is separated and right and left lobes
transplanted into two recipients. Usually the left lobe is transplanted into a pae-
diatric recipient and the right lobe into an adult. Left lobe transplant into adult
recipient has been reported with successful outcome.
3. Adult-to-adult living donor liver transplant (LDLT). Again it is usually the right
lobe that is donated and transplanted into an adult recipient. In some countries,
such as Japan, deceased donors are very limited, and the most frequent trans-
plants are LDLT.
During DCD organ retrieval, there is an additional period when the liver is
exposed to warm ischaemia. There is a higher incidence of primary non-function
and ischaemic biliary injury, leading to an ischaemic cholangiopathy, in patients
receiving DCD transplants. As many patients with HCC undergoing transplants
have preserved synthetic liver function and performance status compared to patients
with decompensated cirrhosis, this group is more likely to receive a transplant from
one of these more marginal donors.
Inferior survival for patients with HCC receiving DCD organs has been demon-
strated using UNOS data [21]. Analysis of over 76,000 patients receiving trans-
plants between 1995 and 2011 compared outcomes in patients transplanted for HCC
or non-HCC and also patients receiving DBD or DCD donor livers in each group.
Patients with HCC had lower 5-year survival compared with non-HCC recipients
whether receiving DBD or DCD donors with the lowest 5-year survival in the HCC/
DCD group (Table 8.3). This may be influenced by differences in recipient charac-
teristics as patients transplanted for HCC were older and more were hepatitis C
positive. Furthermore, the time period studied includes the introduction of DCD
transplantation. In general, outcome improves with time, so this study includes
patients transplanted at the start of DCD programmes who would be expected over-
all to have an inferior outcome.

Table 8.3 1-, 3- and 5-year post-transplant survival in patients comparing patients receiving DBD
or DCD donor liver transplants and comparing HCC with non-HCC indication, UNOS data [21]
Group 1 Year 3 Years 5 Years
HCC-DBD 84.29% 72.23% 63.77%
Non-HCC–DBD 86.50% 78.97% 73.24%
HCC-DCD 75.98% 63.87% 55.86%
Non-HCC–DCD 85.79% 76.76% 70.52%
106 A. Marshall

UK transplant centres presented data for patients receiving liver transplants over
a 5-year period at the national British Liver Transplant Group meeting, Sept. 2017
(Data unpublished). The proportion of patients with HCC receiving DCD trans-
plants numerically exceeded each centre’s overall DCD rate. Overall, currently 28%
of UK patients receive a DCD transplant. In the seven UK centres, the proportion of
HCC patients receiving a DCD transplant ranged from 18 to 49%. The two centres
with the highest proportion of DCD transplants also reported lowest 5-year survival.
In UK recipients, the two commonest causes of graft loss are liver-related and recur-
rent HCC.
At present, the standard process for organ retrieval incorporates a period of cold
storage prior to organ implantation. A novel innovation is to use normothermic
machine perfusion (NMP) prior to implantation of the donor liver. This allows the
function of the donor organ to be observed, through measuring such factors as lac-
tate and ALT, which is not the case with standard retrieval. This has two main
advantages: to avoid transplanting an organ that does not function well and also may
allow transplantation of donor livers that appear too high risk but during observation
function adequately. Theoretically, NMP has potential to expand the donor pool and
improve transplant outcomes, and studies are underway to evaluate the technology.

 ffect of Immunosuppression on Outcome Following Liver

E
Transplant for HCC

Immune surveillance is now known to be critically important as a physiological

mechanism to prevent the development and progression of solid organ cancers.
Therefore, in patients receiving liver transplants for HCC, immunosuppression
could influence the risk of recurrence and death from recurrence. The goal of immu-
nosuppression is to prevent rejection but also to minimise the side effect. The most
frequent initial immunosuppression regime consists of a combination of corticoste-
roids, azathioprine or mycophenolate, and a calcineurin inhibitor, tacrolimus or
ciclosporin. Biological agents against IL2 receptors such as basiliximab are used in
patients with early renal dysfunction to reduce CNI exposure.
The mammalian target of rapamycin (mTOR) pathway is central to control of
cell proliferation. mTOR inhibitors are immunosuppressive (sirolimus and everoli-
mus) and theoretically might also have an effect on cancer occurrence in liver trans-
plant recipients. Retrospective analyses suggested an antineoplastic effect of mTOR
inhibition in liver transplant recipient. A randomised controlled trial comparing
early sirolimus immunosuppression vs. standard immunosuppression in over 500
LT/HCC recipients did not show a significant difference in recurrence-free survival
at the study end [22]. In the subgroup analyses, improved 3-year survival was noted
at 3 years post-transplant in the sirolimus group, and the greatest improvement was
seen in patients who were histologically within Milan criteria.
8 Liver Transplantation for the Treatment of Hepatocellular Carcinoma 107

Conclusion

Liver transplantation offers the prospect to treat both HCC and cirrhosis with good
medium- and long-term survival for patients with HCC. Key areas for research are
optimisation of patient selection, achieving good outcome with marginal donors and
prevention and treatment of HCC recurrence.

References

1. Starzl TE, Groth CG, Brettschneider L, Moon JB, Fulginiti VA, Cotton EK, Porter
KA. Extended survival in 3 cases of orthotopic homotransplantation of the human liver.
Surgery. 1968;63(4):549–63.
2. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna
M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular
carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–9.
3. Roayaie S, Blume IN, Thung SN, Guido M, Fiel M, Hiotis S, Labow DM, Llovet JN. Schwartz
MEA system of classifying microvascular invasion to predict outcome after resection in
patients with hepatocellular carcinoma. Gastroenterology. 2009;137(3):850–5.
4. Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, Ascher NL, Roberts JP. Liver
transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not
adversely impact survival. Hepatology. 2001;33(6):1394–403.
5. Zheng SS, Xu X, Wu J, Chen J, Wang WL, Zhang M, Liang TB, Wu LM. Liver trans-
plantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation.
2008;85(12):1726–32.
6. Lee SG, Hwang S, Moon DB, Ahn CS, Kim KH, Sung KB, Ko GY, Park KM, Ha TY, Song
GW. Expanded indication criteria of living donor liver transplantation for hepatocellular carci-
noma at one large-volume center. Liver Transpl. 2008;14(7):935–45.
7. Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, Camerini T, Roayaie S,
Schwartz ME, Grazi GL, Adam R, Neuhaus P, Salizzoni M, Bruix J, Forner A, De Carlis L,
Cillo U, Burroughs AK, Troisi R, Rossi M, Gerunda GE, Lerut J, Belghiti J, Boin I, Gugenheim
J, Rochling F, Van Hoek B, Majno P. Metroticket Investigator Study Group. Predicting survival
after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria:
a retrospective, exploratory analysis. Lancet Oncol. 2009;10(1):35–43.
8. Takada Y, Uemoto S. Liver transplantation for hepatocellular carcinoma: the Kyoto experi-
ence. J Hepatobiliary Pancreat Sci. 2010;17(5):527–32.
9. Yao FY, Xiao L, Bass NM, Kerlan R, Ascher NL, Roberts JP. Liver transplantation for hepato-
cellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging.
Am J Transplant. 2007;7(11):2587–96.
10. Takada Y, Kaido T, Shirabe K, Nagano H, Egawa H, Sugawara Y, Taketomi A, Takahara T,
Wakabayashi G, Nakanishi C, Kawagishi N, Kenjo A, Gotoh M, Toyoki Y, Hakamada K,
Ohtsuka M13, Akamatsu N, Kokudo N, Takeda K, Endo I, Takamura H, Okajima H, Wada
H, Kubo S, Kuramitsu K, Ku Y, Ishiyama K, Ohdan H, Ito E, Maehara Y, Honda M, Inomata
Y, Furukawa H, Uemoto S2, Yamaue H, Miyazaki M, Takada T. LTx-PET study group of the
Japanese Society of Hepato-Biliary-Pancreatic Surgery and the Japanese Liver Transplantation
Society. Significance of preoperative fluorodeoxyglucose-positron emission tomography in
prediction of tumor recurrence after liver transplantation for hepatocellular carcinoma patients:
a Japanese multicenter study. J Hepatobiliary Pancreat Sci. 2017;24(1):49–57.
108 A. Marshall

11. Pommergaard HC, Burcharth J, Rosenberg J, Rasmussen A. Serologic and molecular biomark-
ers for recurrence of hepatocellular carcinoma after liver transplantation: a systematic review
and meta-analysis. Transplant Rev. 2016;30:171–7.
12. Han K, Tzimas GN, Barkun JS, Metrakos P, Tchervenkov JI, Hilzenrat N, Wong P, Deschênes
M. Preoperative alpha-fetoprotein slope is predictive of hepatocellular carcinoma recurrence
after liver transplantation. Can J Gastroenterol. 2007;21:39–45.
13. Viberta E, Azoulay D, Hotia E, Iacopinellia S, Samuel D, Sallouma C, Lemoine A, Bismuth
H, Castaing D, Adam R. Progression of alphafetoprotein before liver transplantation for hepa-
tocellular carcinoma in cirrhotic patients: a critical factor. Am J Transplant. 2010;10:129–37.
14. Lai Q, Inostroza M, Rico Juri JM, Goffette P, Lerut J. Delta-slope of alpha-fetoprotein
improves the ability to select liver transplant patients with hepatocellular cancer. HPB
(Oxford). 2015;17:1085–95.
15. Farid WR, Verhoeven CJ, de Jonge J, Metselaar HJ, Kazemier G, Van der Laan LJW. The
ins and outs of microRNAs as biomarkers in liver disease and transplantation. Transpl Int.
2014;27(12):1222–32.
16. Sugimachi K, Matsumura T, Hirata H, Uchi R, Ueda M, Ueo H, Shinden Y, Iguchi T, Eguchi H,
Shirabe K, Ochiya T, Maehara Y, Mimori K. Identification of a bona fide microRNA biomarker
in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplanta-
tion. Br J Cancer. 2015;112(3):532–8.
17. NHS blood and transplant annual report 2017. https://nhsbtdbe.blob.core.windows.net/
umbraco-assets-corp/5007/annual_liver_transplantation_report_2017.pdf.
18. Parikh ND, Waljee AK, Singal AG. Downstaging hepatocellular carcinoma: a systematic
review and pooled analysis. Liver Transpl. 2015;21(9):1142–52.
19. Yao FY, Kerlan RK Jr, Hirose R, Davern TJ 3rd, Bass NM, Feng S, Peters M, Terrault N,
Freise CE, Ascher NL, Roberts JP. Excellent outcome following down-staging of hepato-
cellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology.
2008;48(3):819–27.
20. Duvoux C, Roudot-Thoraval F, Decaens T, Pessione F, Badran H, Piardi T, Francoz C,
Compagnon P, Vanlemmens C, Dumortier J, Dharancy S, Gugenheim J, Bernard PH, Adam
R, Radenne S, Muscari F, Conti F, Hardwigsen J, Pageaux GP, Chazouillères O, Salame E,
Hilleret MN, Lebray P, Abergel A, Debette-Gratien M, Kluger MD, Mallat A, Azoulay D,
Cherqui D, Liver Transplantation French Study Group. Liver transplantation for hepatocel-
lular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria.
Gastroenterology. 2012;143(4):986–94.
21. Croome KP, Wall W, Chandok N, Beck G, Marotta P, Hernandez-Alejandro R. Inferior sur-
vival in liver transplant recipients with hepatocellular carcinoma receiving donation after car-
diac death liver allografts. Liver Transpl. 2013;19(11):1214–23.
22. Geissler EK, Schnitzbauer AA, Zülke C, Lamby PE, Proneth A, Duvoux C, Burra P, Jauch
KW, Rentsch M, Ganten TM, Schmidt J, Settmacher U, Heise M, Rossi G, Cillo U, Kneteman
N, Adam R, van Hoek B, Bachellier P, Wolf P, Rostaing L, Bechstein WO, Rizell M, Powell J,
Hidalgo E, Gugenheim J, Wolters H, Brockmann J, Roy A, Mutzbauer I, Schlitt A, Beckebaum
S, Graeb C, Nadalin S, Valente U, Turrión VS, Jamieson N, Scholz T, Colledan M, Fändrich
F, Becker T, Söderdahl G, Chazouillères O, Mäkisalo H, Pageaux GP, Steininger R, Soliman
T, de Jong KP, Pirenne J, Margreiter R, Pratschke J, Pinna AD, Hauss J, Schreiber S, Strasser
S, Klempnauer J, Troisi RI, Bhoori S, Lerut J, Bilbao I, Klein CG, Königsrainer A, Mirza DF,
Otto G, Mazzaferro V, Neuhaus P, Schlitt HJ. Sirolimus use in liver transplant recipients with
hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial. Transplantation.
2016;100(1):116–25.
Chapter 9
The Role of Interventional Radiology
and Image-Guided Ablation in Primary
Liver Cancer

Jen-Jou Wong and Nabil Kibriya

Key Learning Points

1. Percutaneous ablation is a valid curative treatment in patients who meet
BCLC stages 0 or A.
2. Ablation should be considered where patients are not candidates for sur-
gery or liver transplantation.
3. There are a range of thermal and nonthermal techniques available, the
usage of which is dictated by local availability and expertise.
4. IRE provides an attractive ablation technique for preserving adjacent, heat
sensitive structures.
5. Lesions <3 cm, up to maximum of three nodules, are considered for ablation
in our institution; however these criteria continue to evolve with experience.

Areas of Controversy and Uncertainty

1. There is debate regarding the appropriateness of first-line ablation as pref-
erable to liver resection as a first curative treatment.
2. The role of IRE, while promising, is yet to be fully defined in treatment
algorithms.
3. Despite good evidence for effectiveness, treatment availability is variable
and affected by funding and a shortage of appropriately trained clinicians.

J.-J. Wong (*)

Department of Interventional Radiology, The Royal Liverpool University Hospital,
Liverpool, UK
N. Kibriya
Kings College Hospital, London, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 109

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_9
110 J.-J. Wong and N. Kibriya

Introduction

Hepatocellular carcinoma is the third most common cause of cancer deaths world-
wide and the leading cause of mortality amongst sufferers of cirrhosis and chronic
liver disease—the principal cause of death being liver failure. Over 500,000 patients
are affected worldwide [1], and the incidence is likely to rise in tandem with the
projected increase in the incidence of hepatitis B and C and excessive alcohol inges-
tion. While surgical resection remains the gold standard curative treatment, less
than a third of patients are eligible due to not meeting Milan criteria for liver trans-
plantation (one mass less than 5 cm, or up to three lesions less than 3 cm, without
extrahepatic disease or portal hypertension) [2]. Those eligible for liver transplanta-
tion are likely to face extended waits given the relative lack of donors—patients are
therefore at risk of progression without local disease control, although a period of
waiting after loco-regional treatment to assess response can be considered in select
patients who may best be served by liver transplantation. Median survival times are
4–6 months without treatment [3].
Percutaneous image-guided liver ablation has become established in the treat-
ment of patients who fall outside of treatment criteria for surgery or poor perfor-
mance status (PS > 1). Ablation carries a lower risk of complications and mortality
due to its minimally invasive nature. Localised ablative treatment also preserves
surrounding functional liver parenchyma. A lower procedural cost can be achieved
due to shorter inpatient stays compared to surgery. A number of technologies are
available, including radiofrequency, microwave, cryoablation and irreversible elec-
troporation to cater for different treatment environments; each of these will be dis-
cussed in this chapter.

Patient Selection

The diagnosis of HCC should be made in line with current guidelines—imaging

with either contrast-enhanced CT or dynamic contrast-enhanced MRI and correla-
tion with AFP should be diagnostic in most cases, with liver biopsy reserved for
cases where there remains diagnostic uncertainty.
All patients being considered for ablation should be discussed at a multidisci-
plinary team (MDT) meeting to ensure relevant clinical, biochemical and imaging
parameters are discussed and applied to an appropriate staging and treatment algo-
rithm and to ensure other modalities of treatment, in particular surgery and liver
transplantation, have been considered.
There are a number of staging and classification systems for HCC. Amongst
them, the Barcelona Clinic Liver Cancer staging criteria have been most commonly
referred to as the classification system of choice for determining staging, prognosis
and guiding treatment (Fig. 9.1) [4]. Percutaneous ablation can be included as part
of both curative and disease-control treatment paradigms. In summary, stage 0
9 The Role of Interventional Radiology and Image-Guided Ablation in Primary Liver 111

HCC
Staging

Stage 0 Stage A - C Stage D

PS 0 PS 0-2 PS >2
Child-Pugh A Child-Pugh A-B Child-Pugh C

Very early Early Intermediate Advanced Palliative

(Stage 0) (Stage A) (Stage B) (Stage C) (Stage D)
Single or Multinodular, Portal

Single
3 <3cm, PS 0 invasion, N1M1
nodules, PS1-2
<2cm
<3cm, PS
0
TACE Sorafenib Symptom control

Single 3 nodules, <3cm

Portal Raised Associated diseases

pressure/bilirubin

Normal No Yes

Curative Liver Ablation

resection Transplant
or curative ablation (?)
Downstage/Bridge

Fig. 9.1 The roles of ablation in the management of HCC, adapted from the Barcelona Clinic
Liver Criteria staging system [4]

patients who are fit and well with very early, single HCC are ideal for surgical resec-
tion. Stage A patients, with ≤3 nodules that are less than 3 cm may be suitable for
liver transplantation if portal pressure or bilirubin are raised but are otherwise well;
those with comorbidities are recommended to undergo ablation. Although not for-
mally included in the guidelines, ablation can also be used to achieve local tumour
control and either keep patients within or downgrade previously ineligible patients
to meet the Milan criteria for liver transplantation [5]. Ablative treatment can thus
provide the prospect of an extended window for waiting list viability given the
shortage of donor organs worldwide.
Current evidence points towards surgical resection being superior to RF ablation,
even in single small tumours (overall survival HR 0.56; 95% CI 0.40 to 0.78 and
2-year survival HR 0.38; 95% CI 0.17 to 0.84) [6]. Surgical resection should there-
fore be considered in the first instance, with ablation being reserved for patients who
are unsuitable for surgery. It should be noted that many studies have been performed
on Asian populations, where patient age and comorbidities are less—directly trans-
lating these results into treatment decisions for Western populations should there-
fore be considered with caution.
112 J.-J. Wong and N. Kibriya

Pre-assessment and Planning

After discussion at specialist MDT, patients should be assessed in a dedicated inter-

ventional oncology clinic by an interventional radiologist and hepatologist. The
opportunity to meet patients is of paramount importance; assessing the patient’s
overall health status and suitability as a candidate for ablation can be performed
with a direct clinical history and examination, in conjunction with review of the
patient notes. An explanation of procedural details can be given, and expectations of
the aim of treatment can also be managed (i.e., curative treatment versus disease
control). An assessment of the suitability of the target lesion for ultrasound-guided
intervention can be performed. Relevant biochemical workup such as full blood
count, clotting screen and renal function (at a minimum) can also be arranged.
The potential for complications must be assessed and discussed with the patient
(Fig. 9.2). Post-ablation syndrome is a relatively common occurrence, with around
a third of patients experiencing flu-like symptoms, including fever, delayed pain,
chills and nausea anywhere up to 2-weeks post-procedure. It is thought that ablation
leads to the release of cytokines and the resultant inflammatory response as a conse-
quence of necrotic tissue. The likelihood of disease recurrence grows with increas-
ing tumour size and the number of lesions treated in a single sitting. Infection and
abscess formation are known to occur post-ablation, and there are varying practices
between institutions with regard to the role of prophylactic antibiotics. In our insti-
tution, abscess formation is a rare complication and too low in incidence to justify
routine antibiotic administration, in line with available evidence [7]. If an abscess
does occur, percutaneous drainage maybe necessary in addition to systemic antibi-
otics. Haemorrhage may occur due to venous bleeding, or more significantly from
hepatic artery damage, and thus the possible need for emergency embolization

Potential complications of liver ablation:

Haemorrhage
Intraperitoneal
Liver parenchyma
Biliary damage
Biloma
Bile duct leak
Thoracic injury
Diaphragmatic perforation
Pneumothorax
Gastrointestinal tract perforation or thermal injury
Liver abscess
Portal vein thrombosis
Tumour seeding
Fig. 9.2 Complications of percutaneous
ablation Skin burns
9 The Role of Interventional Radiology and Image-Guided Ablation in Primary Liver 113

should be discussed with the patient. Non-target organ injury is unusual and not well
described in the literature. Thermal damage to surrounding organs (in most cases,
the gastrointestinal tract) should be avoided by reviewing previous planning or stag-
ing scans. It may be possible to hydro-dissect bowel away from the potential abla-
tion zone, using an 18 g needle and 5% dextrose solution—otherwise reconsidering
the appropriateness of thermal ablation against another treatment modality (such as
irreversible electroporation, discussed later) may be necessary. Other possible com-
plications include thermal damage to bile ducts, pneumothorax and skin burns.
A further consideration is for lesions adjacent to large vessels where thermal
energy at the treatment site can be diminished by a “heat-sink” effect, resulting in
less effective treatment and necrosis of the tumour.
Tumour seeding through the ablation tract is a significant possibility if tract abla-
tion is not carried out, as high as 12.5% [8]. However, if tract ablation is performed
correctly, tumour seeding incidence is around 1% [9]. If the needle is withdrawn too
briskly during tract ablation, or if inappropriately sized or misplaced grounding
pads are used in RF ablation, the possibility of superficial thermal burns is increased;
second- and third-degree burns have been reported at a rate of 3% [10].
The use of ultrasound or CT-guided techniques is dependent on operator prefer-
ence, the availability of imaging equipment and the optimum visualisation of the
target lesion in the selected imaging modality. Ultrasound is used where possible to
minimise radiation dose to both patient and operator and has the advantage of real-­
time needle guidance into the target lesion. Dual modality imaging can be per-
formed in a dedicated CT intervention scanner enabling placement of the treatment
needle with CT fluoroscopy performed during the procedure. An immediate post
procedure CT is performed with contrast (if renal function allows) to assess the
ablation zone and possible complications.
All available imaging should be reviewed to assess suitability for ablation and to
provisionally plan needle entry, route and position. Trans-pleural needle access
should be avoided due to patient discomfort and the risk of pneumothorax, haemo-
thorax and pleural seeding. Size should first be assessed—the generally agreed
upper limit for ablation is 3 cm. Tumours between 3 and 4.9 cm can still be consid-
ered but may require overlapping ablations, while those greater than 5 are at signifi-
cant risk of incomplete first ablations and recurrence if an appropriately sized
treatment margin of 1 cm cannot be achieved [11]. Lesions high in the hepatic
dome, while more technically challenging to perform, can still be targeted with an
approach starting beneath the thoracic cavity, with appropriate amount of cranial
angulation and use of anatomical landmarks.

Radiofrequency Ablation

Radiofrequency ablation (RFA) utilises the principle of an alternating electrical

field to generate radiofrequency waves, which dissipate their energy within the sur-
rounding target tissue as heat. This is achieved by an alternating electric current
114 J.-J. Wong and N. Kibriya

Fig. 9.3 Radiofrequency

ablation of an HCC. The
probe is initially inserted
with a single tip into the
lesion. Once a satisfactory
position is achieved,
multiple tines can be
extended to achieve an
appropriately sized
ablation zone

causing ionic agitation, generating frictional heat. Eventually, coagulative necrosis

of the target tissue is reached. The RFA probe is connected to the generator, which
in turn gives basic information such as probe temperature, total ablation time and
ablation efficiency. A target temperature of at least 50 °C must be maintained, with
the total ablation time dependent on the size of the target lesion and generally dic-
tated by the instructions for use of the machine being used.
Heat dissipates away from the tip of the probe, and heat conductance can be
significantly altered by varying impedance characteristics of treated, charred tissue.
Depending on the manufacturer, multiple arrays can be extended from within a
single delivery needle to achieve target temperatures at each tip within a different
portion of the target lesion (Fig. 9.3).
The effectiveness of RFA can be limited where the target area is adjacent to a
blood vessel with relatively high flow. A “heat-sink” effect may occur, whereby heat
generated is dissipated by adjacent flowing blood, limiting the target temperatures
achieved and increasing the risk of incomplete ablation or early recurrence. Caution
should therefore be exercised if the intended target lesion is adjacent either to
hepatic or portal veins.
When performed under CT fluoroscopy, an immediate assessment of the abla-
tion zone can be performed—low attenuation change and small bubbles of gas can
be discerned easily on non-contrast CT. Contrast-enhanced scanning can be per-
formed if complications are suspected. The same cannot be said of ultrasound-
guided treatment, where the presence of gas around and at the ablation zone
post-treatment makes it an unreliable modality to use in the immediate assessment
of the ablation zone.
9 The Role of Interventional Radiology and Image-Guided Ablation in Primary Liver 115

Microwave Ablation

Microwave ablation (MWA) aims to achieve coagulative necrosis of target lesions

by alternating electromagnetic waves in the spectrum between 900 and 2450 MHz.
Taking advantage of the asymmetrical polarity of water molecules, alternating elec-
tromagnetic waves cause adjacent water molecules to flip 2–5 billion times a sec-
ond, resulting in frictional heat that is required to achieve target temperatures [12].
The needle differs significantly from its RFA counterpart—there are no multiple
arrays, although systems do exist where several separate probes can be attached and
inserted. The ablation zone may be elliptically shaped or spherical depending on the
system selected. Additionally, the centre of the ablation zone may be located proxi-
mal to the probe tip, or near to it, depending on the way the technology has been
implemented (Fig. 9.4). Familiarity with the specific system utilised is therefore of
importance. The size of the ablation zone is controlled by the duration of ablation,
and also the power delivered to the antennae varied according to each manufactur-
er’s system.
The advantage of MWA over RFA is that the method of heat induction permits
target temperatures to be reached more quickly and that there is a reduced suscep-
tibility to heat-sink effects (at least in the immediate ablation zone—the margin
may still be susceptible to sub-treatment temperatures) [13, 14]. An upper limit of
approximately 4 cm is still generally accepted as the maximum size of a treatable
target lesion, although overlapping ablations of larger tumours is feasible. Lesions
greater than 5 cm are less likely to achieve initial complete response [11]. A recent
meta-analysis suggests that MWA performed similarly to RFA—complete response

Fig. 9.4 MWA needle

within the liver during
treatment. Low attenuation
surrounding the tip
represents gas generated
during thermal coagulative
necrosis. The dark band
proximal to the needle tip
indicates the central point
at which the ablation zone
will be generated
116 J.-J. Wong and N. Kibriya

and recurrence rates were superior on the MWA group though not statistically sig-
nificant, but MWA outperformed RFA in the sub-analysis of larger lesions
(p = 0.02) [15].

Cryoablation

Cryoablation (CA) relies on alternate freezing and thawing to destroy tissues. The
technique is based on the Joule-Thomson effect, where compressed argon gas is
forced through the tip of the probe, rapidly reducing in pressure and temperature. As
a consequence, ice crystals form in intra- and extracellular spaces, drawing water
molecules to either side of the cell membrane to form crystals and causing irrepa-
rable damage to the membrane and other cellular structures.
Use of CA in comparison to RFA and MWA has been less readily adopted in the
UK. The encapsulated structure of HCC has been proposed to lend itself to thermal
techniques, because heat is retained within the capsule, and therefore higher tem-
peratures can be achieved and sustained. But some studies suggest that similar com-
plete response and overall survival rates can be achieved with cryoablation as with
RFA or MWA [16–18]. A possible advantage over thermal ablation is that the ice
ball is more easily identified on CT or US guidance, permitting more reliable assess-
ment of the post-treatment zone and likely effectiveness. However, morbidity and
mortality may be slightly higher with this method, as the lack of vessel cauterisation
leads to a greater risk of bleeding and a lesser effect on coagulation may predispose
necrotic by-products of cryoablation to enter to bloodstream, causing thrombocyto-
penia and renal dysfunction [18]. The size of the ice ball generated is specific to
each needle, making equipment choice and availability more critical than for RFA
and MWA, which offer the flexibility of varying ablation zone sizes through adjust-
ing needle or system parameters. Additionally, it is not possible to tract ablate; thus
there is a theoretically increased risk of tract seeding.

Irreversible Electroporation (IRE)

IRE is a new technology that relies on the production of ultrashort but strong electri-
cal fields to create nanopores in cell membranes. Originally developed at a revers-
ible state to deliver DNA and other potential medicinal vectors into a cell, it was
realised that increasing the electrical field led to permanency of the open pores in the
cell membrane, disrupting cell homeostasis and inducing apoptosis, in contrast to
the coagulative necrosis induced by thermal ablation methods. Unlike thermal abla-
tion, IRE spares extracellular matrix and collagenous tissues—e.g., large blood ves-
sels and biliary ducts—making IRE an attractive option for those lesions near
sensitive structures, particularly near the liver hilum, colon and gallbladder (Fig. 9.5).
Furthermore, the method is not affected by a heat-sink effect of adjacent vessels.
9 The Role of Interventional Radiology and Image-Guided Ablation in Primary Liver 117

Fig. 9.5 IRE treatment of a central HCC. The location of this lesion, wrapped by the main portal
veins (top left) and also the biliary ducts (top right), raised concern for both heat-sink effect and
biliary damage if thermal ablation was chosen. Instead a four-needle IRE treatment was performed,
resulting in a successful ablation zone, with no collateral damage (bottom images)

At least two needle placements in parallel are required around the target lesion to
form the circuit through which the electrical current is delivered, with an optimised
needle distance of 2 cm. Larger lesions require more needles to maintain the 2 cm
maximum distance, with a maximum of six needles. Each needle combination is
tested to ensure the appropriate current (from 20 to 50 A) and voltages (1500 v/cm)
are achieved, before the final pulses between each needle combination are delivered
as the final treatment dose. General anaesthesia with muscle paralysis is required, as
well as ECG gating. Needle placement can be performed by either CT or ultrasound
guidance. Variables such as the voltage and degree of active needle tip exposure can
be varied between test pulses to optimise the final treatment dose. The current sys-
tem on the market is the NanoKnife™ system (Angiodynamics, NY, USA), utilising
19 gauge needles.
118 J.-J. Wong and N. Kibriya

IRE is not universally available to the extent thermal ablation and is generally
reserved for lesions that are deemed unsuitable for thermal ablation or surgical
resection. Its utility and position in treatment algorithms are still not fully deter-
mined. Despite ablative damage to surrounding biliary and vascular structures being
minimised by IRE itself, damage from needle placement remains a possibility and
increased by the fact that at least two separate punctures for the minimum two
­needles are required. Mortality secondary to cardiac arrhythmias has been reported—
this can be greatly reduced with the appropriate cardiac gating.

Follow-Up and Prognosis

An approximation of the ablation zone can be made whether performed by ultra-

sound or CT guidance. Thermal ablation methods (i.e., RFA and MWA) when
viewed under ultrasound guidance produce gas, which localises the treatment area,
before spreading to obscure the field of view. When performed with CT fluoroscopy,
the presence of low attenuation change gives an early indication of the ablation
zone, although the changes may appear more extensive in the immediate aftermath
of treatment compared to the true treatment area as assessed on subsequent follow-
­up scans.
Most centres treating with ablation techniques do so under general anaesthesia.
Use of heavy sedation is possible, but high conversion rates to general anaesthetic
have been reported [19]. For IRE, electrical stimulation from the electrodes induces
muscles contractions and requires muscle paralysis. Thus, general anaesthesia is
mandated followed by an overnight hospital stay that is usually warranted to moni-
tor for possible complications.
At our institution a follow-up scan is performed at 4–6-week post-treatment.
This provides sufficient time for post-ablation inflammatory changes to settle, since
hyperaemic changes surrounding treated target lesions may otherwise be difficult to
differentiate from recurrence. Contrast-enhanced MRI with diffusion-weighted
imaging (DWI) is the preferred follow-up modality where there is no contraindica-
tion to MRI. Dynamic phase imaging is utilised to assess enhancement of residual
tumour. Peripheral hyperaemia may be present in the immediate post-ablation set-
ting; despite similar interpretation difficulties as with CT, DWI is extremely sensi-
tive to detecting recurrence that may not be discernible on CT. Earlier re-intervention
can therefore be planned, whether at previous treatment sites or against new target
lesions. Triple-phase CT can be performed if MRI is contraindicated or not possible
due to patient factors, e.g., the presence of claustrophobia, pacemakers or morbid
obesity, although it is less sensitive to early recurrence or new tumours. CT is most
useful in the immediate assessment of the macroscopic effects of the ablation zone,
evidenced as low attenuation change post-ablation. Peripheral enhancement due to
hyperaemic changes can be difficult to differentiate from recurrence or partial abla-
tion. A nodular or eccentric rim enhancement should raise the suspicion of recur-
rence (Fig. 9.6). Invariably CT is used to assess for complications, e.g., hepatic
9 The Role of Interventional Radiology and Image-Guided Ablation in Primary Liver 119

Fig. 9.6 Initial follow-up

scan in a patient treated
with MWA, showing
smooth, non-enhancing
low attenuation change in
keeping with matured
ablation zone. In the same
patient 18 months later,
peripheral nodular
enhancement surrounds the
old ablation site in keeping
with recurrence

artery bleed. PET CT has been used where successive CT or MRI follow-up scans
have been inconclusive in differentiating post-treatment change from viable tumour.
Post-ablation inflammation is FDG avid—delayed imaging by at least 2-month
post-procedure allows the initial inflammatory response to resolve, thus making
FDG avid abnormalities at this stage sensitive for viable tumour (Fig. 9.7). Yet its
cost remains prohibitive in making this the primary follow-up modality, as well as
having limited sensitivity to smaller changes that can be discerned only with
contrast-­enhanced cross axial imaging.
The literature regarding outcomes for liver ablation is significantly skewed
towards RFA and MWA as they are the more established modalities compared to
CA and IRE. There have been relatively few randomised controlled trials compar-
ing the effectiveness of thermal ablation versus other standards of care. Three RCTs
were included in a meta-analysis of randomised and non-randomised controlled
trials comparing ablation against hepatic resection. The three non-blinded trials
together showed similar recurrence-free survival rates at 1 and 3 years for RFA and
resection, but RFA performed less well when pooled 3- and 5-year recurrence-free
survival rates were reviewed (RR 1.48, 95% CI 1.14 to 1.94, and RR 1.52, 95% CI
1.18 to 1.97, respectively). Yet, the complication rates were lower in the RFA group
(RR 0.18, 95% CI 0.06–0.53, NNT = 3.5) [20]. A later Cochrane meta-analysis
120 J.-J. Wong and N. Kibriya

Fig. 9.7 A thin rind of enhancement on arterial phase MRI typically indicates hyperaemia, but
since this appearance was focal and had settled around the rest of the ablation margin, residual
disease was suspected, as proven on PET CT

confirmed hepatic resection was more effective than RFA regarding overall survival
(hazard ratio (HR) 0.56; 95% CI 0.40–0.78) and 2-year survival (HR 0.38; 95% CI
0.17–0.84) [6]. Surgical resection is considered the gold standard treatment where
possible, but where this is not an option [2], ablation is a viable second treatment
option. One of the most extensive retrospective reviews of 2982 ablations in 1170
HCC patients reported survival outcomes of 96.6%, 60.2% and 27.3% at 1, 5 and
10 years, respectively, demonstrating the effectiveness of thermal ablation [21].
Xu et al. reviewed 142 HCC patients with 294 treated nodules. Recurrence-free
survival rates at 1, 3 and 5 years were reported at 76.1%, 33.1% and 19.5%, respec-
tively [22]. Liang P, while not looking at recurrence-free survival, did report cumu-
lative survival of 93% at 1 year, 82% at 2 years, 72% at 3 years, 63% at 4 years and
51% at 5 years in 288 patients [23]. In a comparative retrospective analysis, Xu et
et al. reviewed 301 cases of MWA, reporting recurrence-free survival rates of
94.4%, 71.8% and 46.9% at 1, 3 and 5 years. Compared against 159 cases of RFA
(89.9%, 67.3% and 54.9%), no statistical difference was found in local recurrence
rates or overall survival [24]. Interestingly, lower rates of local tumour progression
in larger treated lesions have been reported in a meta-analysis comparing MWA
against RFA [25].
As the role of IRE is generally restricted to situations where tumours are con-
sidered to be not amenable to ablation or surgery, reports of effectiveness are
restricted to smaller numbers and observational studies. Thomson reported com-
plete ablation in 82% of patients who had HCC (n = 17) in an early human study
of the effectiveness of IRE. More recently Sutter et al. retrospectively analysed one
of the largest cohorts of HCC to date, treating 75 tumours in 58 patients; 6- and
12-month overall local tumour progression-free survival rates were 87% (95%
confidence interval [CI] 77%, 93%) and 70% (95% CI 56%, 81%), respectively
[26]. Our own unpublished bi-institutional data (n = 52, including both HCC and
colorectal liver metastases) reports a more modest median time to progression of
8 months. At 12 months, the percentage that was progression free was 49% (95%
CI 30%–66%) (N Kibriya - personal communication).
9 The Role of Interventional Radiology and Image-Guided Ablation in Primary Liver 121

Although multiple small studies have demonstrated the efficacy of IRE as a non-
thermal ablative treatment in HCC, these have mostly been part of a mix of aetiolo-
gies—further studies are required to further assess the impact of IRE and where it is
best used in the treatment armamentarium.

References

1. Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta

LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y
Acad Sci. 2002;963:13–20.
2. Belghiti J, Kianmanesh R. Surgical treatment of hepatocellular carcinoma. HPB (Oxford).
2005;7(1):42–9.
3. Nagase N, Yuki H, Hamada T, Hirose S, Kawashima R, Inokuchi K. The natural history of
hepatocellular carcinoma. A study of 100 untreated cases. Cancer. 1984;54(7):1461–5.
4. Llovet JM, Fuster J, Buix J. The Barcelona approach; diagnosis, staging and treatment of
hepatocellular carcinoma. Liver Transpl. 2004;10:115–20.
5. Pompili M, Francica G, Ponziani FR, Iezzi R, Avolio AW. Bridging and downstaging treat-
ments for hepatocellular carcinoma in patients on the waiting list for liver transplantation.
World J Gastroenterol. 2013;19(43):7515–30.
6. Weis S, Franke A, Mössner J, Jakobsen JC, Schoppmeyer K. Radiofrequency (thermal) abla-
tion versus no intervention or other interventions for hepatocellular carcinoma. Cochrane
Database Syst Rev. 2013;12:CD003046.
7. Bhatia S, et al. Is antibiotic prophylaxis for percutaneous radiofrequency ablation (RFA) of
primary liver tumors necessary? Results from a single-center experience. Cardiovasc Intervent
Radiol. 2015;38(4):922–8.
8. Llovet JM, Vilana R, Brú C, et al. Barcelona Clínic Liver Cancer (BCLC) Group Increased risk
of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carci-
noma. Hepatology. 2001;33(5):1124–9.
9. Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK. Seeding following percu-
taneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the
risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev.
2007;33(5):437–47.
10. Mulier S, Mulier P, Ni Y, et al. Complications of radiofrequency coagulation of liver tumours.
Br J Surg. 2002;89(10):1206–22.
11. Wang T, et al. Microwave ablation of hepatocellular carcinoma as first-line treatment: long
term outcomes and prognostic factors in 221 patients. Sci Rep. 2016;6:32728.
12. Brace C. Microwave ablation technology: What every user should know. Curr Probl Diagn
Radiol. 2009;38(2):61–7.
13. Simon CJ, Dupuy DE, Mayo-Smith WW. Microwave ablation: principles and applications.
Radiographics. 2005;25(Suppl 1):S69–83.
14. Wright AS, Sampson LA, Warner TF, Mahvi DM, Lee FT Jr. Radiofrequency versus micro-
wave ablation in a hepatic porcine model. Radiology. 2005;236(1):132–9.
15. Facciorusso A, Di Maso M, Muscatiello N. Microwave ablation versus radiofrequency abla-
tion for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis. Int
J Hyperth. 2016;32(3):339–44.
16. Wang C, et al. Multicenter randomized controlled trial of percutaneous cryoablation versus
radiofrequency ablation in hepatocellular carcinoma. Hepatology. 2015;61(5):1579–90.
17. Rong G, et al. Long-term outcomes of percutaneous cryoablation for patients with hepatocel-
lular carcinoma within Milan criteria. PLoS One. 2015;10(4):e0123065.
122 J.-J. Wong and N. Kibriya

18. Wu S, Hou J, Ding Y, Wu F, Hu Y, Jiang Q, Mao P, Yang Y. Cryoablation versus radiofrequency

ablation for hepatic malignancies. Medicine (Baltimore). 2015;94(49):e2252.
19. Chakravorty E, et al. Anaesthetic management of radiofrequency tumour ablation: or experi-
ence. Indian J Anaesth. 2006;50:123–7.
20. Wang Y, Luo Q, Li Y, Deng S, Wei S, Li X. Radiofrequency ablation versus hepatic resection
for small hepatocellular carcinomas: a meta-analysis of randomized and nonrandomized con-
trolled trials. PLoS One. 2014;9(1):e84484.
21. Shiina S, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and
prognostic factors. Am J Gastroenterol. 2012;107(4):569–77.
22. Xu Y, et al. Microwave ablation for the treatment of hepatocellular carcinoma that met
up-to-seven criteria: feasibility, local efficacy and long-term outcomes. Eur Radiol.
2017;27(9):3877–87.
23. Liang P, et al. Prognostic factors for survival in patients with hepatocellular carcinoma after
percutaneous microwave ablation. Radiology. 2005;235(1):299–307.
24. Xu Y, et al. Microwave ablation is as effective as radiofrequency ablation for very-early-stage
hepatocellular carcinoma. Chin J Cancer. 2017;36(1):14.
25. Chinnaratha MA, Chuang MY, Fraser RJ, Woodman RJ, Wigg AJ. Percutaneous thermal
ablation for primary hepatocellular carcinoma: A systematic review and meta-analysis. J
Gastroenterol Hepatol. 2016;31(2):294–301.
26. Sutter O, et al. Safety and efficacy of irreversible electroporation for the treatment of hepato-
cellular carcinoma not amenable to thermal ablation techniques: a retrospective single-center
case series. Radiology. 2017;284(3):877–86.
Chapter 10
Transarterial Embolization Therapies
in Hepatocellular Carcinoma:
Principles of Management

Tim Cross and Jonathan C. Evans

Key Learning Points

1. Transarterial embolization therapies are accepted as effective strategies for
patients with intermediate stage HCC (BCLC B).
2. They can be used as a palliative treatment to prolong overall survival, as a
bridge to curative treatments in particular liver transplantation or to down-
stage disease such that curative options including ablative therapies or
transplantation might be considered.
3. TACE should not be given where there is complete portal vein occlusion
due to the risk of significant liver ischaemia and subsequent liver decom-
pensation and death.
4. The overall fitness of the patient should be considered, and in the main
reserved for patients with child-Pugh a cirrhosis and performance status 0.
5. The use of tools such as HAP and ART may help identify patients unlikely
to benefit from TACE.

Areas of Controversy and Uncertainty

1. None of the embolic techniques (TAE, TACE, DEB-TACE) have been
shown to be consistently better than any other in terms of objective
response or patient survival. This suggests that it is the embolic component
of treatment and not the chemotherapeutic component that is key in deter-
mining response.

T. Cross (*) · J. C. Evans

Department of Hepatology, The Royal Liverpool Hospital, Liverpool, UK
Department of Radiology, The Royal Liverpool Hospital, Liverpool, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 123

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_10
124 T. Cross and J. C. Evans

2. How to treat patients without a radiological response to initial TACE

should be reviewed to determine if further TACE is beneficial or an alter-
native approach should be sought earlier.
3. The practice of giving TAE or SIRT when the patient is more frail and
­giving alternative forms of TACE in nonresponders, e.g., cisplatin and
­irinotecan, should be assessed to provide a more robust evidence base.

Introduction

Hepatocellular carcinoma (HCC) is the sixth commonest cancer worldwide and the
third commonest cause of cancer-related death [1, 2]. With a significant proportion
of patients presenting at this stage of disease, the use and refinement of transarterial
embolic therapies remain an area of interest and research. In the USA, it is esti-
mated that between 1976 and 1980 in comparison with 2011, the incidence of HCC
has risen from 1.4/100,0000 cases to 6.2/100,000 cases [1]. The intention of treat-
ment is primarily to prolong survival in comparison with doing nothing, but the
risks of toxicity; the potentially detrimental impact on liver function, which may
reduce rather than prolong survival; and the impact on quality of life of the patient
must be discussed honestly with the patient. Although HCC is seen in non-cirrhotic
patients (in particular those with chronic hepatitis B infection), in the UK cirrhosis
accounts for the majority of patients with chronic hepatitis C infection (CHC), and
non-alcoholic fatty liver disease (NAFLD) accounts for an increasing proportion of
HCC cases [3, 4]. The long-term survival is predicated by tumour stage at disease
presentation. Patients who have their cancer detected at an early stage have a wider
range of therapeutic choices and are more likely to live longer, when compared to
those who present late [5–7].
The most commonly used algorithm for the staging and treatment of patients
with HCC (as described earlier in the book) is that of the Barcelona Clinic Liver
Cancer (BCLC) [8]. In this classification, stages 0–A are considered curable. Stage
B is intermediate disease where palliative treatments may slow disease progression
or provide a route to curative therapies at a later time, e.g., liver transplantation
through downstaging where there is liver-confined disease. Thus, patients with
stage B disease at the time of first treatment are considered to be; unresectable,
untransplantable and unablatable. TACE is reserved for patients with unresectable
and unablatable disease or patients being bridged to liver transplant; thus the major-
ity of patients are BCLC stage B. Even with patients with technically incurable
disease, our treatment aim is to elicit a response and downstage the tumour such that
a curative option might be considered in the future, e.g., liver transplantation or
ablation. In this group of patients, resection is rarely, if ever possible, after
TACE. Thus, according to the algorithm, 20% of patients should be found at this
stage with a median survival of 20 months (range 14–45 months) [1]. In a UK sur-
vey of the provision of ultrasound surveillance for HCC, on a snapshot of 1-month
10 Transarterial Embolization Therapies in Hepatocellular Carcinoma: Principles 125

referrals for discussion of HCC multidisciplinary meetings (MDTs), 76 (24%) of

323 patients presented with BCLC stage B disease [9]. Stage C, advanced HCC
occurs when there are metastatic deposits (in bone, lymph nodes, lungs, portal vein
involvement) but, without liver decompensation, for who systemic therapies might
be considered, e.g., sorafenib, lenvatinib, and immunotherapies. Finally, stage D
disease occurs in patients with decompensated liver disease in who the prognosis is
very poor irrespective of any treatment offered.

Pathophysiology

The predominant blood supply to the liver parenchyma is from the portal vein.
Interestingly, this is not the case for hepatocellular carcinomas. These are predomi-
nantly hypervascular tumours that derive their circulation from the hepatic artery.
This is, therefore, something that can be exploited when treating patients. The ratio-
nale is that by targeting the arterial supply, the healthy “normal” liver tissue is
spared from significant liver injury. The analogy is that of a medieval-walled city
under siege, where the tumour is the city. The tumour has its “lines of supply” cut
off, and so the nutrients sustaining the cancer are removed, and so the tumour dies
from ischaemia and subsequently tissue necrosis. Transarterial embolization (TAE)
works using this mechanism alone, whereas transarterial chemoembolic therapies
(TACE) apply this approach whilst also providing a second hit from directly inject-
ing chemotherapeutic agents or drug-eluting beads laced with toxic drugs. It is pos-
tulated that the latter enhance cancer cell death.

Patient Workup

At our institution once HCC is suspected, the patient is seen in a dedicated liver
cancer clinic with a consultant hepatologist and a nurse specialist. A hepatologist
explains what has been found and what its implications may be and what the treat-
ment options are. The clinician takes a history and examines the patient to make an
assessment of the fitness of the patient as defined by their performance status (mea-
sured by the ECOG classification) (Table 10.1) [10]. The diagnostic and staging
tests begin with blood tests including full blood count, urea and electrolytes, liver
function tests, clotting, alpha-foetoprotein, ca19-9 and carcinoma embryonic anti-
gen (CEA) and a liver screen to try to determine underlying cause, e.g., viral hepa-
titis (hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody),
ferritin, alpha-1 antitrypsin and autoimmune liver screen and immunoglobulins.
Imaging tests consist of MRI liver, CT chest and, in cases where liver transplanta-
tion is the planned treatment, a bone scan to look for bone metastases. In patients
unable to tolerate a MRI, a triple-phase CT with intravenous contrast is performed.
126 T. Cross and J. C. Evans

Table 10.1 The ECOG performance status score [10]

Score Measures of performance
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work
of a light or sedentary nature, e.g. light housework and office work
2 Ambulatory and capable of all self-care but unable to carry out any work activities; up
and about more than 50% of waking hours
3 Capable of only limited self-care; confined to bed or chair more than 50% of waking
hours
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5 Dead

Once all the investigations have been performed, the case is discussed at the
weekly hepato-biliary cancer multidisciplinary team (MDT) meeting. This meeting
is attended by hepatologists, diagnostic radiologists, interventional radiologists,
hepatobiliary surgeons, medical oncologists, pathologists, clinical oncologists and
nurse specialists. At our institution there is a consultant anaesthetist who attends the
meeting. A management decision is made by the group.
If locoregional therapy is planned, including embolic therapies (ET), the patients
are reviewed in the interventional radiology clinic. This allows the interventional
radiologist to assess the patient and allows the patient to meet the person performing
their treatment and provide them with an opportunity to ask questions. It is impor-
tant to emphasize that this treatment of itself is not curative and the treatment may
disrupt liver function and may induce liver decompensation as demonstrated by
jaundice, ascites, spontaneous bacterial peritonitis and hepatic encephalopathy.

Contraindications to Treatment

Absolute Contraindications

Complete main branch portal vein thrombosis

Metastatic hepatocellular carcinoma
Ascites
Hepatic encephalopathy

Relative Contraindications (Applied in Our Unit)

Non-occlusive bland thrombus

Portal vein (tumour) thrombus of second-order branches
Bilirubin >30
Albumin <34
ECOG performance status ≥1
10 Transarterial Embolization Therapies in Hepatocellular Carcinoma: Principles 127

Treatment should be delivered within 4 weeks of the imaging to guide therapy to

ensure that the disease has not progressed to a level where ET would not deliver any
benefit to the patient. Further blood tests are performed no more than 1 week prior
to the treatment and should include full blood count, clotting studies (prothrombin
time (PT) and activated partial thromboplastin time (APTT), as well as repeat urea
and electrolytes (U&Es) and liver function tests (LFTs). The interventional radiolo-
gist performs the procedure using aseptic technique and at our centre blood product
replacement, if the platelets are <50 × 109, haemoglobin is <9 g/dl, the prothrombin
time is >18 s (INR > 1.5), and the fibrinogen level is <1.0. The eGFR should be
>30 ml/Kg/min. The patient is admitted on the morning of the procedure or the
night before if they have a time travel period of >1 h.

Assessing the Risk of Doing Harm

Although ET targets the arterial supply and hence should not incur any significant
parenchymal damage, in reality, this is a risk, and ET may lead to a deterioration in
liver synthetic function leading to liver failure and death. This constitutes a cata-
strophic outcome. To avoid this clinicians have been seeking tools that will help
identify those patients in who treatment may do more harm. Kadalayil and col-
leagues performed an assessment of outcomes of patients treated by TACE or TAE
at the Royal Free Hospital in London and the Queen Elizabeth Hospital in
Birmingham, UK [11]. Patients were assigned one point if albumin <36 g/dl, biliru-
bin >17 μmol/l, AFP >400 ng/ml or size of dominant tumour >7 cm. The hepatoma
arterial embolization prognostic (HAP) score was calculated by summing these
points. Patients were divided into four risk groups based on their HAP scores; HAP
A, B, C and D (scores 0, 1, 2 and >2, respectively). The median survival for the
groups A, B, C and D was 27.6, 18.5, 9.0 and 3.6 months, respectively. Thus,
patients with HAP C fared no better than patients with BCLC C disease, and patients
with HAP D performed no better than patients with BCLC D disease in who would
normally be offered best supportive care only [11]. A raised serum bilirubin which
has been persistent for months or years would be less concerning than a recent sud-
den sharp rise, and this should always prompt further investigation and perhaps
restaging of the disease. In our unit, TACE is rarely offered to patients with
HAP ≥ C, and alternative treatments such as systemic therapies or SIRT should be
considered where clinical intervention and performance status allow.

Selection of Transarterial Embolic Therapy

Once the decision has been made that embolic therapy (ET) is indicated, it is the
decision of the interventional radiologist, in conjunction with the MDT or their
hepatologist to decide what ET should be chosen. This is an area of considerable
discussion and controversy. The treatment options include conventional TACE
128 T. Cross and J. C. Evans

(cTACE) where chemotherapic agents such as doxorubicin, cisplatin or mitomycin

C are delivered by a feeding hepatic artery into the tumour and then the lesion is
embolized with foam or sponge particles. Another option is to embolize the feeding
vessel without the additional delivery of a chemotherapeutic agent by way of foam
or embolizing microspheres called transarterial embolization (TAE). The final
option is to deliver drug and embolization at the same time using microscopic beads
laced with drug-eluting beads—DEB-TACE. Some of the key studies assessing the
different modalities are summarized in Table 10.2 [12–21].
Since the introduction of embolic therapy, there have been ongoing studies to try
to demonstrate the superiority of one method over another. A previously published
meta-analysis did not demonstrate support of the use of either TAE or TACE in
patients with unresectable liver-confined HCC. This meta-analysis consisted of 9
trials with 645 participants. Six trials compared TACE with control, and three trials
compared TAE with control. The authors concluded that there was insufficient evi-
dence to support its use until further studies were available [22].

TACE Procedure

The procedure is performed with local anaesthesia at our institution. We use drug-­
eluting beads which are very well tolerated and rarely cause side effects. Patients
receive 1 g of intravenous paracetamol upon entering the intervention room.
Arterial access is achieved using a Seldinger technique. Most commonly the
femoral artery is used, but some centres prefer the brachial approach which allows
for quicker patient mobilization post-procedure. Following local anaesthesia, a 4 or
5 French sheath is inserted into the femoral artery. Coeliac axis and superior mesen-
teric arteriography is performed to evaluate liver supply and give a roadmap for
guiding more selective catheterization.
A microcatheter is then used to identify the tumour-feeding vessels, which may
be many and may have an extrahepatic source, especially when larger tumours are
close to the liver capsule or are exophytic. The internal mammary artery or inferior
phrenic artery may supply tumours close to the diaphragmatic surface, whereas
renal capsular branches or mesenteric branches may supply tumours near the infe-
rior surface of the liver.
Cone-beam CT fluoroscopy allows easier identification of all feeding vessels and
indicates how much liver parenchyma is going to be exposed to embolic material. If
there are many feeding branches of the right or left hepatic artery, then it may be
more practical to deliver the treatment in a lobar fashion rather than individually
select all of the individual feeding arteries. We try to be as selective as possible to
reduce the risk of post-embolization syndrome (PES), but it is important to ensure
that all of the tumour has been treated. Figure 10.1 shows an arteriogram used for a
chemoembolization.
We give a small bolus of intra-arterial nitrate before bead delivery to reduce the
risk of spasm, which could adversely affect treatment delivery. The prepared
­drug-­eluting beads are delivered from a 2 ml luer lock syringe in a pulsatile fashion
10 Transarterial Embolization Therapies in Hepatocellular Carcinoma: Principles 129

Table 10.2 Summary of evidence for trials for transarterial chemoembolization, DEB-TACE and
bland embolization
Treatment Authors Number Summary
TACE Solomon et al. [12] 38 Cisplatin, doxorubicin,
(conventional)
Mitomycin C, ethiodol
Polyvinyl alcohol
Biologic response 70% partial,
15% minor, 15% stable
Lo et al. [13] 40 Cisplatin, lipiodol, gelatin sponge
Particles vs symptomatic treatment
Treatment group: 1 and 3 year
Survival 57% and 26% versus 32%
And 3% (p0.002)
Marelli et al. [14] 175 Meta-analysis with 1, 3, 5 year
Survival of 62%, 30%, 19%
Median survival 18 months
Llovet et al. [15] 545 Meta-analysis TACE vs tamoxifen
No benefit bland embolization
Benefit TACE with cisplatin or
Doxorubicin OR 0.42 (95% CI
0.2–0.88)
DEB–TACE Lammer et al. [16] 212 CR 27% vs 22%, disease control
63% vs 42% (p = 0.11)
Reduced liver toxicity and side
Effects (p < 0.001)
Golfieri et al. [17] 177 DEB-TACE vs cTACE. No difference
Survival, tumour response or time
To progression
Less pain DEB-TACE. ECOG, albumin
And tumour number predict survival
Facciorusso et al. [18] 676 Meta-analysis TACE vs TAE. No
Difference 1, 2, or 3 year survival
No difference response or
Progression-free survival. Less
Toxicity with TAE
TAE Kluger et al. [19] 25 TACE vs TAE pre-OLT
TAE less procedures. Necrosis of
Explant 36% TAE vs 26% TACE
No difference 3-year recurrence and
Overall survival
Masarweh et al. [20] 405 TAE vs TACE. No difference in mean
Survival. 72% vs 74% (p = 0.66)
Brown et al. [21] 101 Microspheres vs DEB-TACE
No difference RECIST response or
Progression or overall survival
Abbreviations: TACE; DEB, TAE, OLT, RECIST
130 T. Cross and J. C. Evans

a b

Fig. 10.1 (a) MRI scan shows a large hypervascular right-sided liver lesion. This demonstrated
wash-out on the portal-venous phase of dynamic imaging. (b) The same patient scanned 10 years
later. There has been a marked reduction in size of the lesion

until there is “near stasis”. This means the contrast that is delivered with the beads
takes four to five heartbeats to clear the tip of the microcatheter. It is important to
use a microcatheter as it is less likely to cause arterial spasm, allows for a more
controlled delivery and does not significantly affect the laminar flow required to
carry the beads along the feeding artery.
When all planned treatment has been delivered the catheters are removed and
placed in a cytotoxic waste bin. We prefer not to perform post-treatment arteriography
as there is a risk of flushing out beads that may still be hovering in the delivered ves-
sel. A vessel closure device is used to seal the arterial puncture site. Figure 10.2 shows
a pre- and post-treatment response to transarterial chemoembolization (Fig. 10.2).
Patients are encouraged to drink plenty of fluid over the ensuing 24 h. Occasionally
intravenous fluids are required if the patient feels nauseous. The majority of patients
can be discharged the following morning.

Evidence Supporting Embolic Therapies

Despite concerns, ET has been pursued with enthusiasm by some clinicians. A

Bayesian network meta-analysis of 55 randomized controlled trials (12 with direct
comparisons) including 5763 patients with preserved liver function and unresect-
able HCC showed that all embolization strategies (TAE, TACE, DEB-TACE and
TARE) showed a significant survival gain when compared with a control group of
no treatment intervention. The median survival for controls was 13.9 months (11–
11.7), TACE 18.1 months (15.6–21.6), DEB-TACE 20.6 months (14.5–29.4), TAE
20.8 months (16.2–27.1), TARE 24.3 (16.8–37.3), TAC E + radiotherapy
30.1 months (24.6–37.3) and finally TACE + ablation 33.3 months (26.4–42.5) [23].
There is known to be a correlation between a radiological response to treatment
and survival. This is the supposition upon which assessing treatments with imaging
10 Transarterial Embolization Therapies in Hepatocellular Carcinoma: Principles 131

Fig. 10.2 Hepatic

arteriogram pre-TACE
shows a large vascular
lesion with feeding
arteries and smaller
tumour blushes within the
main body of the tumour.
The main outline of the
tumour can be clearly
delineated. The images
are from the same patient
from Fig. 10.1

is based. Objective response is the sum of complete response and partial response.
In the study by Lammer and colleagues comparing DEB-TACE with conventional
TACE, there was an objective response of 52% versus 44%. In the Katsanos study,
the most profound objective response was witnessed when patients had both TACE
with either an ablation technique or with external radiotherapy. The hierarchy of
effectiveness as defined by the surface area under the cumulative rankogram
(SUCRA) from least to most effective was TACE odds ratio (OR) (95% confidence
interval, CI) 13.9 (6.91–31.9), SUCRA 21%; TAE OR 16.2 (CI 7.78–38.8) SUCRA
35%; DEB-TACE OR 17.4 (CI 7.59–45.5), SUCRA 40%; TACE + adjuvant OR
18.7 (95% CI 8.25–49.3), SUCRA 47%; DEB-TACE + adjuvant OR 24.8 (7.78–
90), SUCRA 59%; TARE OR 26.9 (95% CI 8.44–93.8), SUCRA 62%; TACE + radio-
therapy OR 52.4 (95% CI 23.6–128.9) SUCRA 85%; and TACE + ablation OR 142
(95%CI 55.9–395.4), SUCRA 99%. DEB-TACE and TACE with adjuvant treatment
or radiotherapy gave rise to the greatest number of adverse events [23]. In terms of
overall survival, the most effective treatment was TACE with ablation or radiother-
apy. The meta-analysis can be criticized because the studies took place over two
decades and the management of chronic liver disease may have improved over that
time, e.g., hepatitis C treatment. A recurring challenge is that the majority of these
studies contain heterogeneous populations and may contain mixed tumour types,
with different disease aetiologies with different patient and tumour characteristics,
132 T. Cross and J. C. Evans

so clinicians should resist the temptation to infer too much from some of the data.
Moreover, the fact that TACE and ablation/radiotherapy had the best objective
response and overall survival may be indicative of greater tumour responsiveness,
and if this is a surrogate of survival, it is logical that they live longer.

Adverse Effects Associated with Embolic TACE

After TACE some patients experience pain. This is due to the localized liver isch-
aemia induced following treatment. This often settles with analgesia and tends to be
worst in the first 24 h after treatment. Many centres manage these patients within the
hospital for 24 h after their treatment. Some patients experience the post-­
embolization syndrome (PES). This arises when there is fever without sepsis
together with pain, nausea and sometimes vomiting. This often settles on its own but
can be very debilitating for patients and make them averse to future interventions.
Several strategies to mitigate its severity have been suggested, but none are univer-
sally followed. They can include antibiotics, intra-arterial lidocaine, acupuncture
and administration of 5-HT3 receptor antagonists [24].
Other complications of ET include:
• Bruising or bleeding at the skin puncture site
• Hair loss
• Immunosuppression and increased risk of infections
• Abnormal liver function and liver decompensation, e.g., jaundice and ascites
• Pulmonary embolism and deep vein thrombosis
• Inflammation of the gallbladder
• Liver abscess formation at the site of tumour necrosis
• Tumour lysis syndrome

Assessing Response to Treatment

At our centre, a contrast MRI liver (or dual-phase CT) is performed 4–6 weeks after
treatment. The images are reviewed by a multidisciplinary team meeting with inter-
ventional radiology, hepatology and oncology. The tumour nodules are compared
with their pretreatment scans and the area of arterialization and washout assessed.
Viable tumour shows arterialization in the arterial phase and then washout in the
portal venous phase. The radiologist assesses this, and a tumour with a complete
response will lose all arterialization, and a hypodense region will be observed on the
scan. Historically, response evaluation criteria in solid tumours (RECIST) guideline
criteria were used which were as follows [25].
RECIST to assess radiological response to treatment of hepatocellular
carcinoma
10 Transarterial Embolization Therapies in Hepatocellular Carcinoma: Principles 133

• Complete response (CR) is the disappearance of all target lesions.

• Partial response (PR) is defined as a minimum of a 30% decrease in the sum of
the longest diameter of target lesions, taking as reference the baseline sum lon-
gest diameter.
• Progressive disease (PD) occurs when there is at least a 20% increase in the sum
of the longest diameter of target lesions, taking as reference the smallest sum
longest diameter recorded since when treatment started or the appearance of one
or more new lesions.
• Stable disease (SD) is neither sufficient shrinkage to qualify for partial response
nor sufficient increase to qualify for progressive disease, taking as reference the
smallest sum longest diameter since the treatment started.
Tumours may respond but often show no size reduction 6 weeks after treatment.
This would be recorded as stable disease using the RECIST criteria when, in fact,
there may have been a complete response. Therefore the RECIST criteria have been
updated and are now termed the mRECIST criteria [25]. This is now the preferred tool
to determine a radiological response to treatment. They are summarized as follows:
mRECIST to assess radiological response to treatment of hepatocellular
carcinoma
• Complete response (CR): the disappearance of any intra-tumoural arterial
enhancement in all target lesions.
• Partial response (PR): at least a 30% decrease in the sum of diameters of viable
(contrast enhancement in the arterial phase) target lesions, taking as reference
the baseline sum of the diameters of target lesions.
• Progressive disease (PD): an increase of at least 20% in the sum of the diameters
of viable (enhancing) target lesions, taking as reference the smallest sum of the
diameters of viable (enhancing) target lesions recorded since the treatment
started.
• Stable disease (SD): any cases that do not qualify for either partial response or
progressive disease.
Additional terms which are used when assessing response to treatment include:
Target lesion: this is the lesion to which the locoregional therapy has been
applied.
Non-target lesion: this can include the development of markers of progressive
disease or hepatic decompensation and include portal vein thrombosis, local patho-
logical lymph.
nodes, lung and bone metastases and also new ascites or pulmonary effusions.
New lesion: a new HCC developing in a region separate to where HCC therapy
has been applied.
Overcalling of equivocal lesions as new HCC should be discouraged since it has
a major impact on the outcome of studies with a radiologic endpoint, such as tumour
response or time to progression [25]. More importantly, it could impact on patient
treatment and therapeutic options leading to incorrect choices becoming made for
the patient, e.g., palliative and not curative treatments being offered.
134 T. Cross and J. C. Evans

Decisionmaking for Further Treatments

If there has been a complete response to treatment, then no further treatment may be
necessary. If the lesion has reduced in size but remains greater than 3 cm at its maxi-
mal diameter, in the absence of features of liver decompensation or patient factors,
further TACE/TAE could be considered. If the dominant lesion reduces in size to
3 cm or less, it may be possible to use an ablation technique (radiofrequency abla-
tion, microwave ablation, cryoablation). There is evidence that combined therapies
such as TACE with ablation offer better survival than TACE alone, but this may just
be due to case selection and bias [23]. At our centre if there are a maximum of three
lesions post-TACE <3 cm, we would attempt to ablate those lesions pending discus-
sions of other therapies such as liver transplantation where appropriate. If there are
more than three lesions or one of the lesions is still >3 cm, TACE would be the first
choice of therapy. If there has been a partial response or no apparent response to
TACE, many centres, including our own, would consider a further attempt at
TACE. It would be useful to quantify what proportion of patients who do not respond
to a first TACE respond to a second treatment. If this response is low, the early adop-
tion of a different strategy might be beneficial to the patient. This is a research ques-
tion that should be addressed.
For lesions that do not respond despite a second treatment, the options include
offering a different embolic therapeutic approach such as selective internal radio-
therapy (SIRT) or using a different embolic approach, e.g., a different therapeutic
agent such as cisplatin or irinotecan beads or conventional TACE. There is no evi-
dence to support the use of the latter approach, and studies to evaluate this are
needed. The role of stereotactic body radiotherapy (SBRT) could be a useful alter-
native to TACE refractory liver-confined disease, for patients remaining within the
intermediate stage of HCC (BCLC B), and its role demands further evaluation in
this setting or perhaps in the long term as an alternative to TACE [26].

 atient Assessment Before Further Transarterial

P
Embolic Therapy

If a further TACE is planned, it is important to ensure there has been no significant

impact on the patient’s liver function. The appearance of ascites, of any volume, is
a contraindication to TACE in our unit, as is the onset of clinically detectable jaun-
dice. An assessment of the patient and biochemical variables is necessary before
any further treatment is undertaken. The HAP score [11] has not been validated in
sequential embolic therapies but is used in our centre as a guide. The ART strategy
has been validated in this setting and is a useful tool to use when considering further
ET [27]. In short, if the ART score before a second treatment is >2.5, that will iden-
tify patients who will not benefit from further TACE. This is summarized in
Table 10.3. Discussion with the patient is important. In the face of a post-TACE
10 Transarterial Embolization Therapies in Hepatocellular Carcinoma: Principles 135

Table 10.3 Models to predict risk of liver decompensation post-TACE

Kadalayil et al. [11] The HAP score AFP > 400 ng/mL = 1
Tumour >7 cm = 1
Albumin <36 g/dL = 1
Bilirubin >17 μmol/L = 1
Sum of scores
HAP A = 0 Median survival 27.6 months
HAP B = 1 Median survival 18.5 months
HAP C = 2 Median survival 9 months
HAP D > 2 Median survival 3.8 months
Permits identification at risk of liver decompensation after TACE
Hucke et al. [27] The ART strategy Radiologic tumour response
Present = 0, absent = 1 point
AST rise >25%
Present =4 points, absent = 0
Child-Pugh score increase
1 point rise = 1.5 points
≥2 points = 3 points
Absent = 0 points
A score of >2.5 identifies patients who do not benefit from further TACE

syndrome, some patients may not wish to have further treatment, although bland
embolization or SIRT may be a more “gentle” treatment that could be considered.
The balance between treating tumour and maintaining satisfactory liver synthetic
function and patient performance status is paramount. Our centre does not give ET
to patients with a performance status ≥2 and will be selective about patients with a
performance status of 1. Under the BCLC staging, these patients would be classified
as BCLC C (advanced disease) irrespective of the tumour disease burden. A new
rise in bilirubin >30 μmol/L, a drop in albumin to <34 g/DL, a rising AFP or increase
in tumour or new disease would prompt restaging prior to any treatment decision as
locoregional therapy may no longer be indicated and systemic therapies or best
­supportive treatments might need to be considered.

TACE Plus Treatments

There has been much interest in a combined approach with TACE/TAE plus other
therapies. The network meta-analysis performed by Katsanos and colleagues
showed the best responses were to be achieved in patients able to receive TACE with
either an ablative technique or an external radiotherapy technique [23]. The addi-
tions of adjuvant chemotherapies to TACE, including sorafenib, have offered no
survival advantage and cannot be supported at this time [23, 28]. But this strategy
remains an area of interest, and the evolving role of immune therapies such as the
136 T. Cross and J. C. Evans

checkpoint inhibitor, nivolumab, has sparked further interest, and a trial of DEB-­
TACE with nivolumab or placebo is recruiting in the USA (NCT03143270), and a
similar phase III study is planned in the UK.

Conclusions

Transarterial embolization therapies are accepted as effective strategies for patients

with intermediate stage HCC (BCLC B). They can be used as a palliative treatment
to prolong overall survival, as a bridge to curative treatments in particular liver
transplantation or to downstage disease such that curative options including ablative
therapies or transplantation might be considered. TACE should not be given where
there is complete portal vein occlusion due to the risk of significant liver ischaemia
and subsequent liver decompensation and death. It should be used with caution with
partial main branch portal vein thrombosis and where there is branch occlusion. The
overall fitness of the patient should be considered and in the main reserved for
patients with Child-Pugh A cirrhosis. Some centres might consider treatment for
patients with low Child-Pugh B, B7 disease, but the use of the HAP score and the
ART strategy has shown that even with liver-confined disease, the impact of liver
function as well as the tumour characteristics can have a significant impact in sur-
vival. The choice of ET may be determined by access and clinician preference;
despite each therapy being effective when compared to no intervention, none of the
embolic techniques have been shown to be consistently better than any other [23].
The adverse effects must be clearly explained to patients. Follow-up scan 4–6 weeks
after treatment is mandated to guide therapy, and the current consensus is that if a
lesion does not respond to two treatment cycles, alternatives should be considered,
e.g., alternative form of TACE, SIRT, SBRT or systemic therapy.

References

1. European Association for the Study of the Liver. EASL-EORTC clinical practice guidelines:
management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.
2. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology.
2012;142(6):1264–73 e1.
3. Njei B, Rotman Y, Ditah I, Lim JK. Emerging trends in hepatocellular carcinoma incidence
and mortality. Hepatology. 2015;61:191–9.
4. Dyson J, Jaques B, Chattopadyhay D, Lochan R, Graham J, Das D, et al. Hepatocellular
cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol.
2014;60(1):110–7.
5. Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso Mdel C, Sala M, et al. Natural history
of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of
therapeutic trials. Hepatology. 1999;29(1):62–7.
6. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–27.
10 Transarterial Embolization Therapies in Hepatocellular Carcinoma: Principles 137

7. Padhya KT, Marrero JA, Singal AG. Recent advances in the treatment of hepatocellular carci-
noma. Curr Opin Gastroenterol. 2013;29(3):285–92.
8. Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classifi-
cation. Semin Liver Dis. 1999;19(3):329–38.
9. Cross TJ, Villaneuva A, Shetty S, Wilkes E, Reeves H, et al. A national survey of the pro-
vision of ultrasound surveillance for the detection of hepatocellular carcinoma. Frontline
Gastroenterol. 2016;7:82–9.
10. Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative
Oncology Group. Am J Clin Oncol. 1982;5:649–55.
11. Kadalayil L, Benini R, Pallan L, O'Beirne J, Marelli L, et al. A simple prognostic scoring
system for patients receiving transarterial embolisation for hepatocellular cancer. Ann Oncol.
2013;24(10):2565–70.
12. Solomon B, Soulen MC, Baum RA, Haskal ZJ, Shlansky-Goldberg RD, Cope
C. Chemoembolization of hepatocellular carcinoma with cisplatin, doxorubicin, mitomycin-
­C, ethiodol, and polyvinyl alcohol: prospective evaluation of response and survival in a U.S.
population. J Vasc Interv Radiol. 1999;10(6):793–8.
13. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized con-
trolled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carci-
noma. Hepatology. 2002;35(5):1164–71.
14. Marelli L, Stigliano R, Triantos C, Senzolo M, Cholongitas E, Davies N, Tibballs J, Meyer
T, Patch DW, Burroughs AK. Transarterial therapy for hepatocellular carcinoma: which tech-
nique is more effective? A systematic review of cohort and randomized studies. Cardiovasc
Intervent Radiol. 2007;30(1):6–25. Review
15. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular
carcinoma: chemoembolization improves survival. Hepatology. 2003;37(2):429–42. Review
16. Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, et al. Prospective randomized study of
doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results
of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41–52.
17. Golfieri R, Giampalma E, Renzulli M, Cioni R, Bargellini I, et al. Randomised controlled
trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular car-
cinoma. Br J Cancer. 2014;111(2):255–64.
18. Facciorusso A, Di Maso M, Muscatiello N. Drug-eluting beads versus conventional chemo-
embolization for the treatment of unresectable hepatocellular carcinoma: a meta-analysis. Dig
Liver Dis. 2016;48(6):571–7.
19. Kluger MD, Halazun KJ, Barroso RT, Fox AN, Olsen SK, et al. Bland embolization ver-
sus chemoembolization of hepatocellular carcinoma before transplantation. Liver Transpl.
2014;20(5):536–43.
20. Massarweh NN, Davila JA, El-Serag HB, Duan Z, Temple S, et al. Transarterial bland ver-
sus chemoembolization for hepatocellular carcinoma: rethinking a gold standard. J Surg Res.
2016;200(2):552–9.
21. Brown KT, Do RK, Gonen M, Covey AM, Getrajdman GI, et al. Randomized trial of hepatic
artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres
compared with embolization with microspheres alone. J Clin Oncol. 2016;34(17):2046–53.
22. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolization for unresectable hepa-
tocellular carcinoma. Cochrane Database Syst Rev. 2011;Issue 3:Art. No CD004787.
23. Katsanos K, Kitrou P, Spiliopoulos S, Maroulis I, Petsas T, Karnabatidis D. Comparative effec-
tiveness of different transarterial embolization therapies alone or in combination with local
ablative or adjuvant systemic treatments for unresectable hepatocellular carcinoma: a network
meta-analysis of randomized controlled trials. PLoS One. 2017;12(9):e0184597.
24. Blackburn H, West S. Management of postembolization syndrome following hepatic
transarterial chemoembolization for primary or metastatic liver cancer. Cancer Nurs.
2016;39(5):E1–E18.
138 T. Cross and J. C. Evans

25. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carci-
noma. Semin Liver Dis. 2010;30(1):52–60.
26. Hasan S, Thai N, Uemura T, Kudithipudi V, Renz P, et al. Hepatocellular carcinoma with
child Pugh-a cirrhosis treated with stereotactic body radiotherapy. World J Gastrointest Surg.
2017;9(12):256–63.
27. Hucke F, Sieghart W, Pinter M, Graziadei I, Vogel W, Muller C, et al. The ART-strategy:
sequential assessment of the ART score predicts outcome of patients with hepatocellular car-
cinoma re-treated with TACE. J Hepatol. 2014;60(1):118–26.
28. Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, et al. Sorafenib in combination
with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma
(TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol
Hepatol. 2017;2(8):565–75.
Chapter 11
Radioembolisation in Hepatocellular
Carcinoma: Principles of Management

Bruno Sangro and Andrea Casadei Gardini

Key Learning Points

1. RE is currently used for the treatment of HCC patients when transarterial
chemoembolisation has failed to produce a tumour response or is not indi-
cated because the tumours are too large or too numerous or have invaded
the portal vein branches.
2. In the advanced HCC, RE can be an alternative to the systemic agent
sorafenib particularly when the drug is contraindicated or patients show
poor tolerability.
3. Additionally, RE can be used to induce hypertrophy of the contralateral
lobe to the tumour and rescue for surgery those patients that are unresect-
able due to small future liver remnant or to induce complete tumour abla-
tion in ‘radiation segmentectomy’.
4. Although radioembolisation is well tolerated, attention should be given
during the first 3 months to complications arising from excessive radiation
of the lungs, the liver or the GI tract, for which specific recommendation
about diagnostic workup and management are available.
5. A multidisciplinary team involving all relevant therapeutic disciplines such
as hepatologists, medical and radiation oncologists, interventional radiolo-
gists and liver surgeons is key to a successful radioembolisation program.

B. Sangro (*)
Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra,
IDISNA and CIBEREHD, Pamplona, Spain
e-mail: [email protected]
A. C. Gardini
Department of Medical Oncology, Istituto Scientifico Romagnolo per Lo Studio e Cura Dei
Tumori (IRST) IRCCS, Meldola, Italy
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 139

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_11
140 B. Sangro and A. C. Gardini

Areas of Controversy and Uncertainty

1. A standardised, validated dosimetric approach in which prescribed activity
is calculated on the basis of a target amount of radiation delivered to the
tumour and non-tumour liver volumes is lacking.
2. The role of RE as an alternative to sorafenib in the first-line treatment of
HCC patients with portal vein invasion is debatable.

Radioembolisation

Radioembolisation (RE), also called transarterial radioembolisation (TARE) or

selective internal radiotherapy therapy (SIRT), is an invasive, image-guided proce-
dure that delivers intra-arterial brachytherapy to cancer in the liver. RE is based on
the injection of microspheres loaded or labelled with yttrium-90 (Y90) into the
hepatic arterial circulation.
Contrary to healthy liver, 80–100% of the blood flow of hepatocellular carci-
noma (HCC) is supplied by branches of the hepatic arteries [1]. Besides, the vascu-
lar resistance of HCC vessels is low, and this increases the chances of particles
injected into a hepatic artery to reach the tumour vasculature [2]. RE takes advan-
tage of this situation to deliver most of the radiation emitted by Y90 inside liver
tumours, although a contributing therapeutic role of the embolisation of tumour
microvascularisation by millions of non-biodegradable particles cannot be ruled
out. Much experience has been obtained from two devices are approved for clinical
use in the EU including SIR-Spheres resin microspheres (Sirtex Medical) and
TheraSphere glass microspheres (BTG). QuiremSpheres is a new device that con-
sists in microparticles loaded with holmium 166 (Terumo), but there is very little
experience, and the consistent results observed with resin and glass microspheres
should not be extrapolated. The first two devices are loaded with Y90, a pure beta
emitter with a short half-life of 2.67 days and a short tissue penetration of 2.5 mm
as an average [3]. Their main differences are shown in Table 11.1.
RE and transarterial chemoembolisation (TACE) are both delivered through
catheterisation of the tumour-feeding vessels. However, they differ considerably in
the mechanism of action and procedural issues related to the requirement of
­superselective catheterisation. TACE works mainly by inducing tumour ischemia.

Table 11.1 Main differences between devices available for liver radioembolisation
SIR-Spheres TheraSphere
Material Resin Glass
Average size per particle 22 ± 10 μm 32 ± 10 μm
Average activity per particle 50 Bq 2500 Bq
Amount of microspheres in a typical 40–80 million 1–5 million
treatment
11 Radioembolisation in Hepatocellular Carcinoma: Principles of Management 141

TACE particles are in fact 3–10 times larger than RE microspheres (100–500 μm vs.
25–35 μm in diameter). A greater particle diameter results in occlusion of medium
to large arteries, and the radiological aim of TACE is indeed blood flow stagnation
or interruption. Contrary, RE is not followed by significant reduction in arterial
blood flow. The lack of significant ischemic effect allows lobar or even whole-liver
RE to be performed safely without inducing acute liver decompensation [4].
Otherwise, RE anti-tumour activity is based in delivering a tumouricidal dose of
radiation to tumour nodules while largely sparing non-tumoural liver from the effect
of radiation. Therefore, the therapeutic effect of RE largely depends on factors such
as hepatic arterial flow distribution, arterial vascularisation of the target tumour,
functional integrity of the uninvolved liver and relative radiosensitivities of tumour
and non-tumour tissues.

Patient Selection

Current Indications

RE is currently used in several situations where intra-arterial therapies could offer

potential benefits that will be discussed later in detail, including but not limited to:
• Single or multiple tumours with portal vein invasion (PVI).
• Multiple tumours that cannot be treated by superselective TACE.
• Tumours that show incomplete response after one or two sessions of TACE.
• Single large tumours, particularly when resection is contraindicated due to a
small future liver remnant.
• Small tumours in patients waiting for liver transplantation.
RE should be indicated after thorough discussion of alternative treatment options
in the setting of a multidisciplinary team involving all relevant therapeutic disci-
plines such as hepatologists, medical and radiation oncologists, interventional radi-
ologists and liver surgeons [3]. Particular attention should be paid to the relative
benefit of RE versus TACE for any specific patient condition. In this regard, there is
not much oncologic sense in using locoregional therapies such as RE to treat patients
with extrahepatic disease including those with regional lymph nodes. These patients
are likely better served by systemic therapies.

Contraindications

RE should be contraindicated in the presence of the following scenarios (although

specific contraindications have been developed by the manufacturers) summarised
in Table 11.2.
142 B. Sangro and A. C. Gardini

Table 11.2 Absolute and relative contraindications to radioembolisation

Absolute contraindications
A significant risk of microsphere deposition in the GI tract based on vascular anatomy and
MAA scan results
Lung shunt >20% (for resin microspheres) or estimated radiation to lung tissue >30 Gy (resin or
glass microspheres)
Decompensated cirrhosis (jaundice, ascites, encephalopathy, recent variceal haemorrhage)
Any technical contraindications to intra-arterial treatment including renal failure (serum
creatinine >2 mg/dl, glomerular filtration rate <30 ml/min)
Relative contraindications
Massive tumour involving both lobes (especially if tumour involvement >50%)
Bile duct occlusion or incompetent papilla due to stent or surgery
Lung shunt 10–20%, particularly if associated with reduced intra-tumoural MAA uptake
Lack of significant intra-tumoural uptake of MAA (also in the tumour thrombus)
Portal vein invasion involving the main trunk

A significant risk of radioactive microsphere deposition in the gastrointestinal

tract. Nowadays, injection of Y90 microspheres into the common hepatic artery is
formally contraindicated, while a double injection into the right and left hepatic
arteries is preferred to a single injection into the proper hepatic artery. If a single
injection into the proper hepatic artery is decided, the tip of the catheter should be
placed distally to the origin of the gastroduodenal artery, and/or this artery should
be coil embolised. Special attention should be paid if the left hepatic artery is
involved in the treatment plan to potential collaterals connecting this artery to the GI
tract. GI ulcerations are a frightful complication of RE that may impair patient qual-
ity of life for weeks or months [5]. Therefore, RE is better contraindicated when an
unequivocal GI uptake is observed in the MAA scan (particularly if SPECT-CT is
used). Contraindication is the best option even if no obvious collaterals are observed
during angiography since hemodynamic conditions under power contrast injection
may change blood flow patterns.
An excessive lung shunting that could result in the lungs absorbing a dose of
radiation that could cause pneumonitis. Glass and resin microspheres manufacturers
consider that any lung shunt fraction (LSF, as estimated by the MAA scan) that could
result in the delivery of 30 Gy to the lungs should be considered an absolute contra-
indication to RE. With resin microspheres, any LSF > 20% should also contraindi-
cate RE irrespective of the resulting dose of radiation absorbed by the lungs, while a
50% reduction in prescribed activity has to be implemented for LSF between 10%
and 20%. This additional precaution is likely beneficial since radiation pneumonitis
can rarely also occur in patients in which the 30 Gy threshold was s­ upposedly not
reached [6]. High LSF is usually observed in large primary liver tumours with vascu-
lar invasion. RE indication should be carefully individualised in these patients since
trans-tumoural shunt usually results in a lower delivery of radiation to the tumour that
may compromise treatment efficacy. A history of chronic obstructive pulmonary dis-
ease does not contraindicate RE unless severe pulmonary insufficiency is present.
11 Radioembolisation in Hepatocellular Carcinoma: Principles of Management 143

Significant liver dysfunction is an obvious contraindication for RE. However,

defining significant in this setting is not an easy task. Radioembolisation-induced
liver disease (REILD) is at the basis of this contraindication. Even in superselec-
tive RE, some non-tumoural liver tissue absorbs a certain amount of radiation.
This may lead to clinical liver decompensation or not depending on several fac-
tors including the severity of the damage induced (mostly related to the amount
of radiation delivered), volume of non-tumoural tissue involved and hepatic
functional reserve at baseline. The usual presentation of liver decompensation
after RE is REILD, which consists in the occurrence of ascites and jaundice
4–8 weeks after RE in the absence of tumour progression or bile duct occlusion
[7]. A conservative approach to patient selection and activity calculation is much
warranted in HCC patients. Ascites or a total bilirubin >2 mg/dl at the time of
evaluation should be considered an absolute contraindication. Since the risk of
REILD is higher in patients with a small liver volume (<1.5 l) or an abnormal
total bilirubin (>1.2 mg/dl), additional precautions could be considered in these
patients. An albumin level <3 g/dl and AST/ALT levels >5 times the upper limit
of normal also increase the risk of liver toxicity. The ALBI grade [8] is a good
indicator of liver functional reserve and patients in ALBI grade 3 are likely poor
candidates for RE.
A high tumour burden can make RE both ineffective due to reduced relative
amount of radiation for any given injected activity and dangerous due to compro-
mised functional reserve. RE is at least discouraged when tumour volume is >50%
of the total liver volume.
A high arterial blood flow to tumours provides the best chance of success after
RE. Arterial blood flow and vessel density may be heterogeneous, particularly in
large tumours. While dose estimates indicate the average dose per volume, different
parts of the tumour may absorb from massive to sublethal doses of radiation. Lesions
that achieve an objective response are those that absorb higher average doses of
radiation measured using intraoperative probes or estimated from pretreatment
MAA planar scintigraphy. More importantly, higher doses of tumour-absorbed radi-
ation are associated with improved survival in HCC patients and lack of significant
MAA uptake can be considered an argument against RE [9].
The use of RE for the treatment of HCC patients with portal vein thrombosis
(PVT) has been hindered by concerns about the risk of liver failure. Since Y90 is a
microembolic procedure causing no occlusion of large hepatic arteries, it can be
safely used in the setting of PVT, even when it involves the main portal trunk [10].
However, the low median survival observed after RE in patients with main trunk
portal vein invasion (<6 months) makes these patients poor candidates for RE. If RE
is nevertheless considered, lack of MAA uptake in the tumour thrombus should be
considered a contraindication to RE.
Other contraindications include any contraindication to angiography (bleeding
diathesis, vascular abnormalities, renal insufficiency), pregnancy or lactation. A
proposed algorithm for patient selection based on the results of the pretreatment
evaluation is shown on Fig. 11.1.
144 B. Sangro and A. C. Gardini

HCC patient

Risk of GI tract No risk of GI tract

Angiography irradiation irradiation

Risk of GI tract Poor MAA targeting in Good MAA targeting in

irradiation main tumours or PVI main tumours or PVI

MAA Scan

Non-therapeutic Therapeutic
Tumour dose Tumour dose

Suitability for Poor candidate Good candidate

Radioembolisation

Fig. 11.1 Algorithm for selecting the optimal candidates for radioembolisation based on the
results of the pretreatment evaluation

Pretreatment Evaluation and Treatment

The main purpose of RE is to reduce tumour burden as much as possible while pre-
serving the functional capacity of the non-tumoural liver. As mentioned before, sub-
clinical liver damage occurs as a result of the deployment of radioactive
microparticles in non-tumoural areas of the liver. REILD ensues only when the
extension and intensity of such damage is large enough to produce a clinically rel-
evant liver decompensation. Contrary to patients with metastatic liver disease from
colorectal or neuroendocrine tumours, those with HCC may develop REILD after
lobar RE or in the absence of prior chemotherapy. But this occurs rarely if a person-
alised approach to treatment planning and activity calculation is used [7].
One strategy is to spare as much liver volume as possible from liver damage. If
the lesion is located in a segment of the liver provided by a major arterial branch
without significant leakage, a high Y90 activity can be injected superselectively
safely in what has been called radiation segmentectomy [11]. Radiation absorbed by
the tumour in this approach can be as high as 1000 Gy, way above the tumouricidal
dose for epithelial tumours. Likewise, radiation lobectomy is an option when there
is extensive involvement of a single lobe. Radiation absorbed by the lobe is not as
high as in radiation segmentectomy, but it is high enough to frequently produce liver
atrophy and compensatory hypertrophy in the contralateral lobe [12]. Hypertrophy
is usually less intense in cirrhotic patients. When treating bilateral tumours, a single-­
session bilobar treatment can be safely performed at least using resin microspheres
[4] particularly if a conservative activity calculation is used [7]. Alternatively, some
centres prefer to treat both lobes in a sequential fashion although this practice is
11 Radioembolisation in Hepatocellular Carcinoma: Principles of Management 145

derived from a single retrospective study [13] and increases the cost significantly. In
any case, a multidisciplinary team discussion is crucial in the evaluation of these
patients to select the treatment design that is more appropriate to the individual
treatment aim.
Technically, RE consists of a two-step procedure. A pre-SIRT evaluation involv-
ing angiography and macroaggregated albumin (MAA) scan is completed prior to
the RE procedure. Although they are typically performed in two sessions separated
1–2 weeks, they can be performed as a sequential single-day procedure. In the pre-
RE evaluation, the abdominal arterial anatomy is explored, and any potentially
problematic collateral vessel is embolised to allow a full coverage of the tumour
volume and prevent extrahepatic microsphere deposition. Celiac and superior mes-
enteric artery angiograms allow recognition of variants such as aberrant or acces-
sory hepatic arteries and the identification of parasitic vessels that supply hepatic
tumours. High-power contrast injection is used to recognise small vessels and to
provide a supraphysiological flow that helps in detecting reflux that may occur dur-
ing the therapeutic procedure. All blood vessels that may be at risk of reflux are
embolised permanently using steel coils. Cystic artery embolisation is evaluated
case by case as the risk of cholecystitis from radiation is very low. Once the vascular
map is established, the planning procedure is completed by injecting MAA and
performing planar or preferably SPECT-CT MAA scan imaging. The size of MAA
is comparable to Y90 microspheres, and the MAA scan therefore enables to esti-
mate the LSF and the dose of radiation that will be absorbed by the lungs, any
extrahepatic uptake due to unnoticed collateral vessels, intrahepatic distribution of
Y90 microspheres and the dose of radiation that will be absorbed by the tumour and
the non-tumoural compartments [14]. Pre-RE evaluation minimises the potential for
non-target clinical toxicities, including gastric ulceration, pancreatitis, skin irrita-
tion and radiation pneumonitis.
The optimal 90Y activity is calculated differently for resin and glass micro-
spheres. For resin beads, it can be calculated using the body surface area (BSA)
formula or a partition model [15]. The BSA activity planning is the standard method
and is particularly suited for bilobar RE in metastatic disease. However, the activity
prescribed is usually considered too high for patients with metastatic tumours previ-
ously exposed to anticancer chemotherapy or those with primary tumours in the
setting of cirrhosis [16]. A more conservative approach with reduced prescribed
activities can be based on BSA tables used in pivotal clinical trials [17] or by reduc-
ing the activity provided by the formula by 10–20% depending on the perceived
potential frailty of the liver [7]. The partition model can be used as an alternative to
the BSA formula in tumours with a neat MAA uptake particularly when a lobar or
segmental approach is decided. In the partition model, the average doses of radia-
tion likely to be absorbed by the lungs, the non-tumoural liver and the tumours are
estimated from the activity of MAA measured in these compartments after MAA
injection. It is therefore essential to inject MAA at the same location where Y90
microspheres will be later injected if the partition model will be used for activity
calculation. The target is the dose of radiation absorbed by any given compartment
depending on treatment aim and patient condition. If both lobes are involved, the
target is to keep the dose absorbed by the non-tumoural liver below 40 Gy. If the
146 B. Sangro and A. C. Gardini

Treatment Whole-Liver Selective

Spared liver volume 0-1 Segments ≥ 2 Segments

Activity calculation BSA formula Partition Model

Additional conditions Liver volume < 1.5 L Size & Quality of

Tumour involvement < 5% spared segments
Cirrhosis (as for liver resection)
Prior Chemotherapy

No Yes Poor Good

Modifications Reduce activity Reduce activity Aim at 40 Gy in Aim at ≥ 100 Gy

by 10-20% towards 0.8 GBq/L non-tumour volume in tumour volume

Fig. 11.2 Activity calculation algorithm used at Clinica Universidad de Navarra (Modified from
Ref. [7])

amount of non-tumoural liver that can be spared from radiation is large and healthy
enough, the target is to keep the dose absorbed by the tumours above 120 Gy
(Fig. 11.1). As mentioned earlier, the dose absorbed by the lungs should be always
kept below 30 Gy. For glass beads, the volume of the targeted liver (segment, lobe
or entire liver) is calculated, and teams have to select the prescribed activity within
a range of 80–150 Gy of radiation absorbed by this volume irrespective of tumour
involvement. Attempts to use a dosimetric approach in which a specific target dose
to the tumour is calculated have been proposed and await validation. A proposed
algorithm for patient selection based on the results of the pretreatment evaluation is
show on Fig. 11.2.
Treatment should be performed within 2–4 weeks after the workup but can also
be on the same day. Collateral vessel patency and identification of new collaterals
should be explored before injection Y90 microspheres, especially when collaterals
have been embolised since changes in local haemodynamics may reverse flow in
previously unnoticed vessels. The location of the tip of the catheter close to a bifur-
cation increases the chances of mismatch between MAA and Y90 microspheres
distribution2 and should be avoided. Slow infusions are recommended. Analgesics
and anti-emetics should be given only to patients that experience symptoms during
or after the procedure.

Post-treatment Follow-Up

Although RE is by and large well tolerated, attention should be given during the first
3 months to signs and symptoms of complications. A summary of the current rec-
ommendations for the prevention, workup and treatment of such events is provided
11 Radioembolisation in Hepatocellular Carcinoma: Principles of Management 147

Table 11.3 Summary of recommendations for the prevention and treatment of complications of
RE (for a more detailed report see Ref. [6])
Prevention Workup Treatment
Pneumonitis
Reduce prescribed activity or Chest CT scan if hypoxemia, Steroids on a very empiric
contraindicate if lung shunt cough or dyspnoea within the first basis
>10% (if ≥15%, strongly 2 months post-SIRT Oxygen supply as needed
consider an alternative Functional tests to confirm
treatment) restrictive pattern and altered
Keep dose of radiation to lung carbon monoxide diffusion level
tissue <30 Gy
GI ulcerations
Avoid access of microspheres Upper endoscopy if upper High-dose proton pump
to GI tract by coil abdominal pain 4–8 weeks after inhibitors, sucralfate,
embolization, a more distal SIRT, particularly if associated anti-emetics, analgesics
injection or flow redistribution with nausea, loss of appetite or and gastric promotility
If a false-positive GI uptake of anaemia agents
MAA is suspected, consider Presumptive diagnosis based on If severe, consider total
repeating angiography and gross morphology parenteral nutrition or
MAA jejunostomy
REILD
Contraindicate RE if total Suspect REILD in any patient that Diuretics and monitor
bilirubin >2 mg/dL or develops jaundice and ascites liver function
non-tumoural ascites within the first 3 months after SIRT If liver function starts to
Consider reducing prescribed US-Doppler to check for bile duct decline, consider
activity for patients with obstruction, ascites and portal/ defibrotide
steatohepatitis or cirrhosis, hepatic vein patency. If bile duct If liver failure develops,
where the liver is <1.5 L, and obstruction is discarded, liver CT consider transjugular
in patients with intense or MRI to rule out tumour intra-hepatic
exposure to chemotherapy progression portosystemic stent-shunt
Spare as many liver segments Blood test to measure liver damage (TIPS) placement
as possible and function
Cholecystitis
If necessary, place the catheter Suspect radiation cholecystitis in Provide IV hydration and
distal to the cystic artery. If any patient with persistent right analgesics on demand
not feasible, perform upper quadrant tenderness Symptomatic therapy with
temporary occlusion of the 4–6 weeks following SIRT. Liver analgesics and
cystic artery during the US, CT or MRI to check for a anti-emetics
treatment procedure thickened wall, pericholecystic Consider cholecystostomy
(vasospasm or Gelfoam) fluid, intramural gas or hydrops (preferred) or
cholecystectomy if with
fever, intense pain or signs
of wall necrosis or rupture

in Table 11.3. The indiscriminate use of proton pump inhibitors, ursodeoxycholic

acid or even heparin and low-dose steroids is not supported by strong evidence
although it is common practice in many centres.
Assessing response to radioembolisation can be complex. As opposed to systemic
treatments where all tumours are simultaneously and homogeneously exposed to the
agent, in intra-arterial therapies tumours can be treated at different time points and
148 B. Sangro and A. C. Gardini

in a heterogeneous way. Size criteria such as those recommended by the Response

Evaluation Criteria in Solid Tumours (RECIST) guidelines are the most common
reporting standards. Criteria that take into account the volume of a tumour that lacks
contrast enhancement in the arterial phase of contrast-enhanced imaging because of
treatment-induced necrosis have been developed and are commonly used after TACE
and also serve well to RE. However, it usually takes longer to see changes in contrast
enhancement or tumour shrinkage after RE than it does after TACE. A minimum of
3 months is recommended before lack of response is declared after RE.

Specific Indications and Expected Outcomes

Most of the published experience with RE is focused on patients that were not con-
sidered appropriate candidates to TACE [1]. Since there were no effective systemic
anticancer agents until 2007, this group includes patients who failed TACE, had
tumours that were considered too large or too numerous to be treated by TACE or
showed vascular invasion into the portal or hepatic veins. Outcomes are consistent
depending on tumour stage at baseline and across devices as shown in Table 11.4.
In the largest multicentre study of 325 patients, median OS was 12.8 months,
varying by stage: 24.4 months for BCLC-A, 16.9 months for BCLC-B and
10.0 months for BCLC-C [4]. Independent prognostic factors were worse perfor-
mance status, higher tumour burden, worse liver function and extrahepatic disease.
The treatment was well tolerated, and there were very few treatment-emergent
CTCAE grade 3 events. For patients that were potential candidates for sorafenib
therapy as from the inclusion criteria in the pivotal SHARP trial, survival was quite
comparable [1]. Two recent phase 3 multicentre clinical trials conducted in France
[24] and the Asia-Pacific region [25] randomised patients to sorafenib or RE using
resin microspheres. There were no differences in the primary endpoint of overall
survival, but RE was associated with fewer adverse events and better quality of life.
In SARAH, RE resulted in delayed progression in the liver and a higher response
rate (19.0% vs. 11.6%) that were not translated into better overall survival (median
8.0 vs. 9.9 months) or PFS (4.1 vs. 3.7 months). In SIRveNIB, RE resulted in
delayed TTP at any site (6.41 vs 5.39 months, but only in the per-protocol analysis)
and higher RR (16.5% vs. 1.7%) that were not transferred into better OS. In both
studies around 20% of patients were randomised to RE but could not get the treat-
ment. This numbers are well above the 5–10% rate of contraindications due to find-
ings during the RE workup reported in most series from experienced centres.
Furthermore, the lack of differences in the pre-planned subgroup analysis of patients
with portal vein invasion was unexpected. In a previous retrospective study, RE was
associated with a longer OS than sorafenib (8.8 vs. 5.4 months) [26]. Two other tri-
als are exploring if combining RE with sorafenib can result in a better survival than
sorafenib alone (NCT01126645 and NCT01556490).
Most guidelines recommend TACE as first-line therapy for the intermediate stage
[27]. Expanding from the high rate of objective, durable remissions in advanced
 11

Table 11.4 Patient characteristics and long-term outcomes of large mixed-case series of HCC patients treated with radioembolisation
Tumour Performance Response Response Survival by BCLC
Staging Liver function burden status rate duration Survival stage
BCLC Child-Pugh Single EASL Median
Author, year N (A/B/C/D) (A/B) tumours ECOG >0 criteria TTP (months) (months) Median (months)
Salem [18]a 291 17/28/52 45/52 27% 44% 57% 7.9 A: 26.9
B: 17.2
C: 7.3
Hilgard [19] 108 2/51/55 77/22 Nr 49% 40% 10 16.4 B: 16.4
C: NR
Mazzaferro 52 0/33/67 83/17 3% 40% 40% 11 15 B: 18
[20] C: 13
Sangro [21] 325 16/27/56 268/57 24% 46% NR NR 12.8 A: 24.4
B: 16.9
C: 10
Vilgrain [22]b 174 7/53/114 153/20 46% 37% 19.5%c NR 9.9 NR
Chow [23]b 130 0/83/46 117/12 NR 18% 23.1%c 6.41 11.2 B: 13.5
C: 9.2
a
Data are for patients with no extrahepatic disease
b
Data are for the per-protocol population
c
By RECIST 1.1 criteria
Radioembolisation in Hepatocellular Carcinoma: Principles of Management

NR not reported
149
150 B. Sangro and A. C. Gardini

tumours, most experienced centres started exploring the use of RE in less advanced
cases. A number of retrospective series comparing TACE and RE showed similar
efficacy and suggested that a randomised trial with OS as primary endpoint should
recruit more than a thousand patients. Three small randomised trials have been
reported. The first one was a pilot trial with no statistical assumptions that randomised
24 patients and observed no difference in OS (592 days for RE vs. 788 days for
TACE) or TTP (371 days for RE versus 336 days for TACE) [28]. The second one had
quality of life as primary endpoint and randomised 28 patients [29]. No difference
was observed in quality of life, frequency of adverse events, PFS (3.6 months for RE
and 3.7 months for TACE) or OS. A third study had time to progression as primary
endpoint [30]. It was prematurely closed due to slow accrual after having randomised
45 patients. Patients treated with RE had a significantly longer TTP (HR, 0.122; 95%
CI, 0.027–0.557) although no difference was found in OS (17.7 months for RE vs.
18.6 months for SIRT). These three randomised trials differed in the patient popula-
tion. In the two first studies, patients were mostly in the intermediate stage with
bilobar tumours, while in the third most were in the early stage and unilobar.
Besides providing tumour control, SIRT can be used to induce hypertrophy of
the contralateral lobe to the tumour, which generally occurs within the first
3–6 months following RE [12]. A systematic review showed that the percentage of
hypertrophy after SIRT ranges from 29% to 47%. This effect may allow to bring
patients to surgery with good final outcomes. The safety of RE before surgery was
analysed in a retrospective study that showed how RE was not associated with wors-
ened safety outcomes after resection or transplantation [31].
Finally, RE can induce complete necrosis in small (<3 cm) tumours particularly
when a high Y90 activity is injected into a segmental tumour-feeding artery and
tumour-absorbed radiation is increased over 200 Gy in ‘radiation segmentectomy’
[32]. Local tumour ablation can therefore be the aim of RE for early tumours that
cannot be ablated due to their location in the dome or near the large vessels in
patients that are otherwise not candidates for resection or transplantation due to age,
cirrhosis or comorbidities (Fig. 11.3) [32].

a b c

Fig. 11.3 Superselective segmental radioembolisation or radiation segmentectomy. (a) CT scan

before treatment showing a multinodular tumour in segment VI. (b) PET scan showing intense
radiation in segment VI after superselective injection of Y90 resin microspheres into the segmental
artery. (c) Significant atrophy of segment VI and lack of tumour activity 1 year after treatment
11 Radioembolisation in Hepatocellular Carcinoma: Principles of Management 151

References

1. Sangro B, Iñarrairaegui M, Bilbao JI. Radioembolization for hepatocellular carcinoma. J

Hepatol. 2012 Feb;56(2):464–73.
2. Aramburu J, Antón R, Rivas A, Ramos JC, Sangro B, Bilbao JI, et al. Liver cancer arterial
perfusion modelling and CFD boundary conditions methodology: a case study of the haemo-
dynamics of a patient-specific hepatic artery in literature-based healthy and tumour-bearing
liver scenarios. Int J Numer Method Biomed Eng. 2016;32(11) https://doi.org/10.1002/
cnm.2764.
3. Kennedy A, Coldwell D, Sangro B. Radioembolization for the treatment of liver tumours:
general principles. Am J Clin Oncol. 2012;35(1):91–9.
4. Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, et al. Survival after
yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona
clinic liver cancer stages: a European evaluation. Hepatology. 2011;54(3):868–78.
5. Rodríguez-Lago I, Carretero C, Herráiz M, Subtil JC, Betés M, Rodríguez-Fraile M, et al.
Long-term follow-up study of gastroduodenal lesions after radioembolization of hepatic
tumors. World J Gastroenterol. 2013;19(19):2935–40.
6. Sangro B, Martínez-Urbistondo D, Bester L, Bilbao JI, Coldwell DM, Flamen P, et al.
Prevention and treatment of complications of selective internal radiation therapy: expert guid-
ance and systematic review. Hepatology. 2017 Sep;66(3):969–82.
7. Gil-Alzugaray B, Chopitea A, Iñarrairaegui M, Bilbao JI, Rodriguez-Fraile M, Rodriguez J,
et al. Prognostic factors and prevention of radioembolization-induced liver disease. Hepatology.
2013 Mar;57(3):1078–87.
8. Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeve HL, et al. Assessment of
liver function in patients with hepatocellular carcinoma: a new evidence-based approach—the
ALBI grade. J Clin Oncol. 2015;33(6):550–8.
9. Sangro B, Rodriguez M. Radioembolization for hepatocellular carcinoma: gaining insight on
a personalized approach. Liver Int. 2017;37(1):32–4.
10. Iñarrairaegui M, Thurston KG, Bilbao JI, D'Avola D, Rodriguez M, Arbizu J, et al.
Radioembolization with use of Yttrium-90 resin microspheres in patients with hepatocellular
carcinoma and portal vein thrombosis. J Vasc Interv Radiol. 2010;21(8):1205–12.
11. Riaz A, Gates VL, Atassi B, Lewandowski RJ, Mulcahy MF, Ryu RK, et al. Radiation segmen-
tectomy: a novel approach to increase safety and efficacy of radioembolization. Int J Radiat
Oncol Biol Phys. 2011;79(1):163–71.
12. Fernández-Ros N, Silva N, Bilbao JI, Iñarrairaegui M, Benito A, Davola D, et al. Partial liver
volume radioembolization induces hypertrophy in the spared hemiliver and no major signs of
portal hypertension. HPB (Oxford). 2014;16(3):243–9.
13. Seidensticker R, Seidensticker M, Damm R, Mohnike K, Schütte K, Malfertheiner P, et al.
Hepatic toxicity after radioembolization of the liver using 90Y-microspheres: sequential lobar
versus whole liver approach. Cardiovasc Intervent Radiol. 2012;35(5):1109–18.
14. Sancho L, Rodriguez-Fraile M, Bilbao JI, Beorlegui Arteta C, Iñarrairaegui M, Moran V, et al.
Is a technetium-99m macroaggregated albumin scan essential in the workup for selective
internal radiation therapy with yttrium-90? An analysis of 532 patients. J Vasc Interv Radiol.
2017;28(11):1536–42.
15. Lau WY, Kennedy AS, Kim YH, Lai HK, Lee RC, Leung TW, et al. Patient selection and activ-
ity planning guide for selective internal radiotherapy with yttrium-90 resin microspheres. Int J
Radiat Oncol Biol Phys. 2012;82(1):401–7.
16. Kennedy AS, Ball D, Cohen SJ, Cohn M, Coldwell DM, Drooz A, et al. Multicenter evalu-
ation of the safety and efficacy of radioembolization in patients with unresectable colorectal
liver metastases selected as candidates for (90)Y resin microspheres. J Gastrointest Oncol.
2015;6(2):134–42.
17. van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, et al. SIRFLOX:
randomized phase III trial comparing first-line mfolfox6 (plus or minus Bevacizumab) versus
152 B. Sangro and A. C. Gardini

mFOLFOX6 (plus or minus Bevacizumab) plus selective internal radiation therapy in patients
with metastatic colorectal cancer. J Clin Oncol. 2016;34(15):1723–31.
18. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular car-
cinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
Gastroenterology. 2010;138:52–64.
19. Hilgard P, Hamami M, Fouly AE, et al. Radioembolization with yttrium- 90 glass micro-
spheres in hepatocellular carcinoma: European experience on safety and long-term survival.
Hepatology. 2010;52:1741–9.
20. Mazzaferro V, Sposito C, Bhoori S, et al. Yttrium90 radioembolization for intermediate-
advanced hepatocarcinoma: a phase II study. Hepatology. https://doi.org/10.1002/hep.26014.
21. Sangro B, Carpanese L, Cianni R, European Network on Radioembolization with Yttrium-90
Resin Microspheres (ENRY). Survival after Yttrium-90 resin microsphere radioembolization
of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation.
Hepatology. 2011;54:868–78.
22. Vilgrain V, Pereira H, Assenat E, et al. Efficacy and safety of selective internal radiotherapy
with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoper-
able hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.
Lancet Oncol. 2017;18(12):1624–36. https://doi.org/10.1016/S1470-2045(17)30683-6.
23. Chow PKH, Gandhi M, Tan SB, et al. SIRveNIB: Selective Internal Radiation Therapy
Versus Sorafenib in Asia- Pacific Patients With Hepatocellular Carcinoma. J Clin Oncol.
2018;36(19):1913–21. https://doi.org/10.1200/JCO.2017.76.0892.
24. Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, et al. Efficacy and safety
of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib
in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label ran-
domised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624–36.
25. Pierce H, Chow W, Gandhi M, Asia-Paciifc Hepatocellular Carcinoma Trials Group. Phase
III multi-Centre open-label randomized controlled trial of selective internal radiation therapy
(SIRT) versus sorafenib in locally advanced hepatocellular carcinoma: the SIRveNIB study. J
Clin Oncol. 2017;35(15_suppl):4002.
26. de la Torre MA, Buades-Mateu J, de la Rosa PA, Lué A, Bustamante FJ, Serrano MT, et al.
A comparison of survival in patients with hepatocellular carcinoma and portal vein invasion
treated by radioembolization or sorafenib. Liver Int. 2016;36(8):1206–12.
27. European Association for the Study of the Liver. EASL–EORTC clinical practice guidelines:
management of hepatocellular carcinoma. Eur J Cancer. 2012;48(5):599–641.
28. Pitton MB, Kloeckner R, Ruckes C, Wirth GM, Eichhorn W, Wörns MA, et al. Randomized
comparison of selective internal radiotherapy (SIRT) versus drug-eluting bead transarterial
chemoembolization (DEB-TACE) for the treatment of hepatocellular carcinoma. Cardiovasc
Intervent Radiol. 2015;38(2):352–60.
29. Kolligs FT, Bilbao JI, Jakobs T, Iñarrairaegui M, Nagel JM, Rodriguez M, et al. Pilot random-
ized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepato-
cellular carcinoma. Liver Int. 2015;35(6):1715–21.
30. Salem R, Gordon AC, Mouli S, Hickey R, Kallini J, Gabr A, et al. Y90 Radioembolization
significantly prolongs time to progression compared with chemoembolization in patients with
hepatocellular carcinoma. Gastroenterology. 2016;151(6):1155–63.
31. Pardo F, Sangro B, Lee RC, Manas D, Jeyarajah R, Donckier V, et al. The post-sir-spheres sur-
gery study (p4s): retrospective analysis of safety following hepatic resection or transplantation
in patients previously treated with selective internal radiation therapy with yttrium-90 resin
microspheres. Ann Surg Oncol. 2017;24(9):2465–73.
32. Salem R, Mazzaferro V, Sangro B. Yttrium 90 radioembolization for the treatment of hepatocel-
lular carcinoma: biological lessons, current challenges, and clinical perspectives. Hepatology.
2013;58(6):2188–97.
Chapter 12
Oncotherapies for HCC

Alexa Childs and Tim Meyer

Key Learning Points

1. Forty percent of patients diagnosed with hepatocellular carcinoma (HCC)
are currently candidates for systemic therapy.
2. Sorafenib is a multi-targeted tyrosine kinase inhibitor and has been for
standard of care for advanced BCLC stage C disease since 2007.
3. Sorafenib improves median survival by nearly 3 months versus placebo
(10.7 vs 7.9 months) but has little benefit with patients beyond Child-Pugh
A cirrhosis.
4. There is currently no benefit from adjuvant or combination systemic and
surgical/locoregional therapies.
5. Lenvatinib could be used as an alternative to sorafenib as a first-line
therapy.
6. Regorafenib is the first approved second-line treatment for patients who
progress on first-line therapy.
7. The role of immune therapy is being explored, and outcomes for these tri-
als may significantly change the management of patients with advanced
HCC.

A. Childs · T. Meyer (*)

Department of Oncology, UCL Cancer Institute, University College London, London, UK
Department of Oncology, Royal Free Hospital, London, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 153

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_12
154 A. Childs and T. Meyer

Areas of Controversy and Uncertainty

1. The role of adjuvant and combination therapies has been an active area of
research, but the results of trials have been disappointing.
2. Immune therapy has revolutionized outcomes in patients with advanced
malignant melanoma and non-small cell lung cancer, but how and when it
might be used in patients with HCC has yet to be fully determined.
3. The ability to individualize treatment against specific tumour targets
remains an aspiration for clinicians managing HCC.

Introduction

Liver cancer is the second leading cause of cancer-related mortality worldwide and
accounted for 745,000 deaths in 2012, of which 50% occurred in China alone [1].
The incidence closely matches the prevalence reflecting the lethal nature of this
disease and very low rates of cure. Around 30% cases are eligible for curative inter-
ventions such as transplantation, resection or ablation, and a further 20% may be
suitable for transarterial therapy. Of the remaining 50%, 10% require symptomatic
supportive care, leaving 40% who are candidates for systemic therapy [2]. For the
last decade, the standard of care for advanced HCC has been sorafenib, an oral
multi-targeted tyrosine kinase inhibitor which is associated with a median survival
of around 11 months representing a 3-month improvement over placebo [3].
Numerous trials in the first- and second-line setting have failed, but in the past year,
there has finally been progress that will improve outcomes in patients with advanced
disease and has the potential to also improve outcomes in earlier-stage disease.

Chemotherapy

Chemotherapy has been used in the treatment of HCC for over 40 years, although
the evidence base for efficacy remains weak. Doxorubicin has historically been
regarded as the standard chemotherapy agent for HCC on the basis of an initial
single-arm study performed in 14 patients, which reported a response rate of 79%
[4]. Studies conducted subsequently were limited by the absence of an appropriate
control arm and the use of surrogate markers of response such as hepatomegaly and
AFP. Despite this, they still failed to reproduce the results seen in the initial study,
with reported response rates varying between 1 and 35% [5]. Only 1 randomized
trial of 106 patients has compared doxorubicin to best supportive care (BSC) and
reported a small benefit in median survival, despite lower-than-expected survival in
both arms (2.7 months for doxorubicin vs 1.9 months in those receiving BSC) [6].
Response rates were only 3% in the context of a 25% treatment-related mortality
12 Oncotherapies for HCC 155

rate, which is significantly higher than that seen in subsequent studies, where mor-
tality rates have been in the region of 3% or less [7].
There has been interest in alternative chemotherapeutic regimens, and four ran-
domized controlled trials have been performed in different patient populations using
doxorubicin as the control arm. The PIAF regimen (cisplatin, interferon, doxorubi-
cin and fluorouracil) was investigated after a promising response rate of 26% was
reported in an initial phase II study [8]. In a trial performed in Hong Kong, 188
patients were randomized to receive either PIAF or doxorubicin, and whilst the
superior response rate of PIAF was confirmed (10.5% vs 20.9%), there was no sig-
nificant difference seen in (OS) [7]. Nolatrexed, a thymidylate synthase inhibitor,
has been compared to doxorubicin in a study conducted across 445 patients recruited
from a Western population and shown to have a significantly worse OS (5.1 months
vs 7.4 months [HR 0.753 p = 0.0068]), along with increased toxicity [9]. A global
study of 339 patients investigating the microtubule inhibitor T138067 was also neg-
ative and failed to demonstrate any improvement in survival when compared to
doxorubicin (5.7 vs 5.6 months, respectively) [10]. The FOLFOX regime (fluoro-
uracil and oxaliplatin) has been compared to doxorubicin in 371 patients recruited
from Asian countries of which 70% were from mainland China [11]. Response rates
were higher with FOLFOX (8.2% vs 2.7%, p = 0.0233), and a small benefit in
median survival was also seen on long-term follow-up (6.4 months vs 5.0 months,
p = 0.0425).
In summary, the available evidence suggests that chemotherapy may provide a
modest survival benefit, but patient selection remains of key importance to limit
toxicity. The current data support the use of FOLFOX over doxorubicin.

Sorafenib

Sorafenib, an oral multi-targeted tyrosine kinase inhibitor against Raf, VEGFR,

PDGFR and c-Kit [12], was the first systemic treatment proven to have a survival
benefit in advanced HCC. It was approved in 2007 on the basis of two large multi-
centre, randomized, placebo-controlled studies. The phase III Sorafenib HCC
Assessment Randomized Protocol (SHARP) trial was performed in a predominantly
Western population recruited from Europe, North America, South America and
Australasia and demonstrated a significantly improved OS in patients with advanced
HCC and well-preserved liver function (>95% Child-Pugh A) [3]. Investigators
reported a median OS benefit of nearly 3 months with sorafenib therapy (10.7 vs
7.9 months; HR 0.69, [95% CI 0.55–0.87], p < 0.001) and improved time to pro-
gression (TTP) 5.5 months for sorafenib versus 2.8 months for placebo (0.58, [95%
CI 0.45–0.74] p < 0.001). This was despite an objective response rate of only 2%
according to response evaluation in solid tumours criteria (RECIST). The overall
incidence of treatment-related adverse events was 80% in the sorafenib arm
156 A. Childs and T. Meyer

compared to 52% in the placebo group, with grade 3 adverse events in the sorafenib
arm consisting predominantly of diarrhoea (8% vs 2%, p < 0.001), hand-foot skin
reaction (8% vs 1%, p < 0.001), hypertension (2% vs <1%, p = 0.28) and abdominal
pain (2% vs <1%, p = 0.17). The positive effect of sorafenib on OS and TTP was
confirmed by the results of the phase III Sorafenib Asia-Pacific trial [13], performed
in China, South Korea and Taiwan, thereby establishing sorafenib as the standard of
care in patients with advanced HCC. Child-Pugh class A was an entry criteria for
both the SHARP trial and the Asia-Pacific study, but data regarding sorafenib in
Child-Pugh B patients is now available from post-marketing studies and field of
practice audits. The GIDEON study is the largest prospective study to date and has
evaluated the impact of liver function in a cohort of >3000 patients treated with
sorafenib, including 666 with Child-Pugh class B [14]. In the final analysis, overall
adverse events were similarly observed in both Child A and B patients, but the rate
of sorafenib discontinuation in Child-Pugh B patients was higher as compared to
Child-Pugh A (40% vs 25%). More importantly, the median survival of patients
with a Child-Pugh class beyond A treated with sorafenib is extremely poor at around
3.6 months [15] suggesting that it is not cost effective to offer such patients therapy.
Similar findings were reported in a UK audit in which patients with Child-Pugh B
disease treated with sorafenib had a survival of only 4.6 months [16].
To establish if some subgroups benefit more than others, Bruix et al. conducted
an exploratory subgroup analysis of the SHARP data and found that sorafenib
­consistently improved OS across HCC patients, irrespective of disease aetiology,
baseline tumour burden, performance status and prior therapy [17]. OS in the
sorafenib arm appeared higher in those patients with HCV compared to those with
HBV (HBV sorafenib OS 9.7 months vs placebo 6.1 months; HCV sorafenib OS
14 months vs placebo 7.4 months), leading to the suggestion that patients with
HCV-related HCC may derive more clinical benefit from sorafenib treatment than
patients with HBV-related HCC. A subsequent pooled analysis of the SHARP and
Asia-Pacific trial confirmed that the greatest benefit for sorafenib was observed in
the patients with hepatitis C but also in those with no extrahepatic spread and a low
neutrophil-to-lymphocyte ratio [18].
Another study examined circulating biomarkers from SHARP study cohort and
found that high baseline plasma angiopoietin 2 (Ang2) and vascular endothelial
growth factor (VEGF) were independently associated with worse prognosis but had
no predictive value, whilst high c-KIT and low hepatocyte growth factor showed a
trend towards enhanced survival benefit from sorafenib [19]. Numerous other poten-
tial biomarkers have also been evaluated, including interleukin 6 and interleukin 8
[20], insulin-like growth factor (IGF) [21, 22], transforming growth factor (TGF-­
β1) [22] and hepatocyte growth factor (HGF) [19, 23], but their role remains
unproven.
The positive outcomes in advanced disease prompted the evaluation of sorafenib
in earlier-stage disease. The STORM trial randomized patients who had undergone
surgical resection or ablation to sorafenib 400 mg twice daily or match placebo for
a maximum of 4 years. There was neither difference in recurrence free survival
between the two arms at 33.3 and 33.7 months, respectively, nor was there evidence
12 Oncotherapies for HCC 157

of an improvement in OS [24]. Combining sorafenib with transarterial chemoembo-

lization has been similarly disappointing. Two trials, the global SPACE trial and the
UK TACE 2 trial, randomized patients receiving TACE, performed with doxorubi-
cin eluting beads, to combined therapy with sorafenib or matched placebo [25, 26].
Both trials were negative with no improvement in their respective primary end-
points, time to progression or progression-free survival. Hence, there remains a sig-
nificant unmet need for systemic therapy that is effective in the adjuvant setting or
in combination with locoregional therapy.
Sorafenib-based drug combinations have also been disappointing to date. Initially
encouraging data were reported by Abou-Alfa et al. who compared doxorubicin
alone with the combination of doxorubicin and sorafenib in 97 patients recruited
across North and South America and Europe [27]. OS was improved in the combi-
nation group as compared to doxorubicin alone (13.7 vs 6.5 months), but the absence
of a comparative sorafenib group precluded any assessment of synergism between
doxorubicin and sorafenib. A subsequent phase III trial comparing sorafenib with
sorafenib plus doxorubicin was conducted with the primary endpoint of OS [28].
The study was discontinued early at planned interim analysis when median OS was
found to be 9.3 months (95% CI 7.1–12.9) for combination therapy and 10.5 months
(95% CI 7.4–14.3) for sorafenib monotherapy [HR 1.06 (95% CI 0.8–1.4)] in the
context of increased toxicity in the combination arm. The SEARCH trial compared
the combination of sorafenib and the EGFR antagonist erlotinib with sorafenib and
placebo in a randomized, double-blind, placebo-controlled trial. There was no sig-
nificant difference in median OS at 9.5 months and 8.5 months, respectively [29].
In summary, sorafenib has been the only approved systemic therapy for the treat-
ment of advanced HCC for the past 10 years. The survival benefit is modest, and
response rate is negligible. It has no role as an adjuvant therapy and, to date, has not
demonstrated improvement when used in combination with locoregional therapy or
other systemic agents.

First-Line Phase III Trials

Since the approval of sorafenib in 2007, large randomized trials have sought to
improve the survival benefit seen with sorafenib monotherapy in the first-line set-
ting. Several have evaluated antiangiogenic therapies with limited success. Sunitinib
[30], linifanib [31] and brivanib [32] have all been compared with sorafenib in the
recently reported negative phase III studies. However, the impasse was broken by
the recently reported REFLECT trial in which lenvatinib was evaluated in the first-­
line setting. Lenvatinib is an orally active, tyrosine kinase inhibitor with multiple
targets, including VEGFR 1–3, FGFR 1–4, PDGFRα, RET and KIT. It was initially
evaluated in both phase I and II studies, the latter of which enrolled 46 advanced
HCC patients who had previously received treatment with sorafenib [33, 34]. The
primary endpoint of time to progression (TTP) was 7.4 months, 37% of patients
achieved a response, and the median OS was 18.7 months. In light of these results,
158 A. Childs and T. Meyer

a phase III non-inferiority trial (REFLECT study) was conducted comparing lenva-
tinib with sorafenib as first-line treatment in 954 patients with unresectable HCC
and preserved liver function (Child-Pugh A). The study met its primary endpoint
demonstrating that the median OS with lenvatinib was non-inferior to sorafenib
(13.6 vs 12.3 months; HR 0.92 95% CI 0.79–1.06) [35]. The study also showed
statistically significant improvements for secondary endpoints, including
progression-­free survival (7.4 vs 3.7 months; HR 0.66 95% CI 0.57–0.77
p < 0.00001), time to progression (8.9 vs 3.7 months; HR 0.63 95% CI 0.53–0.73
p < 0.00001) and objective response rate (24.1 vs 9.2% p < 0.00001). These findings
may lead to the approval of lenvatinib as a first-line agent for unresectable HCC, in
which case strategies for the differential use of lenvatinib and sorafenib in the clini-
cal setting will need to be determined.
On the basis of the currently available evidence, sorafenib remains the first-line
standard of care for patients with advanced HCC pending approval of lenvatinib.

Second-Line Phase III Trials

Several trials assessing targeted agents after progression on sorafenib have pro-
duced disappointing results. Brivanib, a selective inhibitor of VEGFR and FGFR,
was compared to placebo in a randomized phase III study recruiting HCC patients
who were refractory or intolerant to first-line treatment with sorafenib [36].
Although TTP was significantly longer in the brivanib arm, the primary endpoint of
OS was not met. The REACH trial randomized patients to receive ramucirumab, a
VEGFR-2 monoclonal antibody, or best supportive care following sorafenib, and
again, no significant difference in OS was reported (HR 0.87 [95% CI 0.72–1.05];
p = 0.14) [37]. Interestingly, however, a prespecified subgroup of patients with a
baseline AFP concentration of 400 ng/mL or greater exhibited a significantly
improved OS compared to placebo (7.8 months vs 4.2 months, respectively). The
hypothesis that ramucirumab is more effective in patients with a high AFP is being
tested in the ongoing REACH-2 trial (NCT02435433).
The mTOR pathway is activated in up to 45% of HCC [38] and is associated with
poorly differentiated tumours, early recurrence and worse prognosis [39, 40]. In
view of this, the mTOR inhibitor everolimus was evaluated in the second-line phase
III EVOLVE-1 trial which recruited a total of 546 HCC patients [41]. Unfortunately,
no significant difference was seen in OS, reported as 7.6 months in the experimental
arm compared to 7.3 months with placebo (HR 1.05; p = 0.67). Tuberous sclerosis
complex 2 (TSC2) functions as a negative regulator of the mTOR pathway, and sub-
sequent preclinical studies have suggested that tumours with loss of TSC2 expres-
sion may have enhanced sensitivity to mTOR inhibition. In a retrospective analysis
of the EVOLVE-1 data, investigators assessed patient TSC2 status by immunohisto-
chemistry and found that TSC2-null/low patients treated with everolimus tended to
have longer OS than those who received placebo or those patients with high TSC2
expression who received everolimus [42]. This preliminary data may justify further
12 Oncotherapies for HCC 159

investigation of TSC2 as a potential predictive biomarker for everolimus treatment.

Arginine depletion has also been explored in HCC based on the observation that
HCC is auxotrophic for this semi-essential amino acid. Patients who had failed or
were intolerant to sorafenib were randomized 2:1 to PEGylated arginine deiminase
(PEG-ADI 20) by weekly IM injection or matched placebo. The trial was negative
with a median OS of 7.8 and 7.4 months, respectively (HR = 1.022 (95% CI, 0.847,
1.233) p = 0.884) [43]. However, patients with arginine depletion beyond 8 weeks
had better survival than those with less than or equal to 4 weeks (12.3 vs 7.3 months),
suggesting that strategies to prolong arginine depletion could be pursued.
Most recently, a phase III trial of regorafenib, a multi-kinase inhibitor of VEGFR,
PDGFR, FGFR, TIE2, KIT, RET and RAF, has reported positive results in the
second-­line setting. An initial open-label phase II study assessed 36 patients pre-
treated with sorafenib and demonstrated an acceptable safety profile with median
OS of 13.8 months and disease control rate of 72% [44]. Following this, the phase
III RESORCE study recruited 573 patients with advanced HCC who had progressed
on sorafenib. Patients were required to have received sorafenib for at least 20 days
at a dose of at least 400 mg/day. Median OS, the primary endpoint of the study, was
significantly greater in patients who received regorafenib than placebo (10.6 vs
7.8 months; HR 0.63 95% CI 0.50–0.79; p < 0.0001) [45]. This phase III trial of
regorafenib is the first to show an OS benefit compared with placebo in patients who
have failed sorafenib treatment and has established a new standard of care for
second-­line therapy in HCC.

Molecularly Stratified Trials

The hepatocyte growth factor (HGF)-MET axis has been implicated in hepatocar-
cinogenesis, and high levels of c-MET expression have been associated with vascu-
lar invasion, tumour recurrence and reduced survival in several studies [46].
Overexpression of c-MET is reported in 20–80% of HCC tumours, making it a valid
potential target for therapy. Tivantinib, a selective c-MET receptor tyrosine kinase
inhibitor, has been investigated in advanced HCC as part of a randomized, placebo-­
controlled phase II trial, where patients were stratified according to level of c-MET
expression [47]. Patients with high c-MET expression treated with tivantinib had
significantly improved OS compared to those treated with placebo (median OS
7.2 months for tivantinib vs 3.8 months for placebo (HR 0.38; 95% CI 0.18–0.81).
For patients with c-MET low tumours, there were no differences in mTTP, mOS or
DCR. Disappointingly, a large second-line, placebo-controlled phase III study of
tivantinib in patients selected for high c-MET expression did not improve OS which
was 8.4 and 9.1 months for tivantinib and placebo, respectively [48]. There are sev-
eral other c-MET inhibitors of differing specificity in various stages of clinical
development for HCC at the current time, including cabozantinib, foretinib, capma-
tinib and tepotinib. Only the ongoing phase II study of tepotinib is actively recruit-
ing patients according to levels of c-MET expression (NCT02115373).
160 A. Childs and T. Meyer

The RAS/RAF/MEK/ERK pathway has a pivotal role in cellular proliferation,

and a small subset of HCC patients have tumour growth which is driven by constitu-
tive activation of a mutant RAS [49, 50] which can be targeted by the selective
inhibition of downstream targets such as MEK. In an initial phase II study evaluat-
ing refametinib in combination with sorafenib, only 5% of patients had evidence of
RAS mutations; however, three of these four patients went on to achieve a partial
response [51]. The combination therapy had a pronounced toxicity profile, however,
with an 80% rate of grade 3 and 4 adverse events and four treatment-related patient
deaths on study. In light of this, a phase II study is currently underway to explore the
efficacy and safety of refametinib monotherapy in advanced RAS-mutated HCC
(NCT01915589).
Whilst stratified trials have been disappointing to date, several studies have
defined molecular subclassifications in hepatocellular carcinoma, and these will
need to be carefully incorporated into future trial design [52].

Immunotherapy

Many different immunotherapeutic approaches have been investigated in HCC to

date; these include vaccine platforms based on RNA and dendritic cells, adoptive
T-cell therapy, cytokines and gene therapy [53]. The presence of tumour-infiltrating
lymphocytes in HCC [54] confirms the immunogenicity of this tumour type and
further rationale for this therapy can be found in the fact that relapse rates post trans-
plantation and resection are reduced in patients with dense lymphocytic infiltration
[55, 56]. Recently, the remarkable success of checkpoint inhibitors in tumour types
such as melanoma and non-small cell lung cancer [57–60] has stimulated great
interest in their potential role in HCC.
Tremelimumab, an anti-CTLA-4 monoclonal antibody, was the first checkpoint
inhibitor to be tested in patients with HCC and chronic HCV infection. In a phase II
study of 21 patients, it achieved a response rate of 17%, disease control rate of 76%
and a median time to progression of 6.5 months [61]. Interestingly, a significant
drop in viral load was also seen on treatment. Local tumour destruction during abla-
tion or chemoembolization could potentially enhance tumour-specific antigen pre-
sentation, and in view of this tremelimumab has also been evaluated in combination
with TACE/RFA in a pilot study of 32 patients which confirmed the feasibility of the
approach [62]. Again, a significant antiviral effect was observed with 12 out of 14
patients experiencing reduction in HCV viral load. Together, these studies demon-
strate that tremelimumab can be administered safely to a cirrhotic patient popula-
tion and has a potential antitumour and antiviral effect warranting further
investigation.
Targeting the PD-1/PD-L1 has also been explored. Nivolumab is a fully human
IgG4 anti-PD-1 monoclonal antibody and has been evaluated in an HCC-specific
multicentre phase I/phase II trial which recruited a total of 262 patients [63]. In the
dose expansion cohort, an overall response rate of 20% by RECIST 1.1 was reported,
12 Oncotherapies for HCC 161

and the survival rate at 9 months was 74%, with some patients achieving durable
responses exceeding 12 months. The response rate was similar across the hepatitis
B and C infected and the uninfected cohorts. Prior sorafenib did not affect response
rate, and there was no clear relationship between response and tumour PD-L1
expression. With extended follow-up, the median survival of patients treated second-­
lines was 15.6 months which compares favourably with previously reported second-­
line trials [64]. A first-line phase III study comparing nivolumab with sorafenib has
completed recruitment, and results are expected in 2018 (NCT02576509).
Many ongoing trials are evaluating other checkpoint-targeting molecules and
combinations thereof. A key priority is the identification of biomarkers to define the
responsive subpopulation.

Conclusion

Sorafenib represented a modest but important step forward in the treatment of

advanced HCC, but it has taken 10 years to make further meaningful advances. In
the first-line setting, the REFLECT study has demonstrated that lenvatinib has a
non-inferior OS to sorafenib and has clinically significant antitumour effects. The
improved ORR with lenvatinib may favour its use over sorafenib in patients who
remain symptomatic due to heavy disease burden and potentially allow downstag-
ing of disease, but the optimum sequence of these therapies remains unknown. In
the second-line setting, the RESORCE trial has proven the activity of regorafenib
with a manageable safety profile and provides a treatment option to those patients
who remain fit enough for further therapy after progression on sorafenib. There is an
increasing interest in the role of immunotherapy in advanced HCC, and phase III
evidence on the role of nivolumab is expected within the next year which might
further change the care of patients with advanced HCC.

References

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence

and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J
Cancer. 2015;136(5):E359–86.
2. European Association for the Study of the L, European Organisation for R, Treatment of
C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J
Hepatol. 2012;56(4):908–43.
3. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced
hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.
4. Olweny CL, Toya T, Katongole-Mbidde E, Mugerwa J, Kyalwazi SK, Cohen H. Treatment
of hepatocellular carcinoma with adriamycin. Preliminary communication. Cancer.
1975;36(4):1250–7.
5. Burroughs A, Hochhauser D, Meyer T. Systemic treatment and liver transplantation for hepa-
tocellular carcinoma: two ends of the therapeutic spectrum. Lancet Oncol. 2004;5(7):409–18.
162 A. Childs and T. Meyer

6. Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inop-
erable hepatocellular carcinoma. A prospective randomized trial. Cancer. 1988;62(3):479–83.
7. Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, et al. A randomized phase III study
of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) com-
bination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst.
2005;97(20):1532–8.
8. Leung TW, Patt YZ, Lau WY, Ho SK, Yu SC, Chan AT, et al. Complete pathological remission
is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma.
Clin Cancer Res. 1999;5(7):1676–81.
9. Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, et al. Phase III randomized controlled
trial comparing the survival of patients with unresectable hepatocellular carcinoma treated
with nolatrexed or doxorubicin. J Clin Oncol. 2007;25(21):3069–75.
10. Posey J, Johnson P, Mok T, Hirmand M, Dahlberg S, Kwei L, et al. Results of a phase 2/3
open-label, randomized trial of T138067 versus doxorubicin (DOX) in chemotherapy-naïve,
unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2005;23(90160):4035.
11. Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, et al. Randomized, multicenter, open-­
label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative che-
motherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol.
2013;31(28):3501–8.
12. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of
sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine
kinase signaling. Mol Cancer Ther. 2008;7(10):3129–40.
13. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib
in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III ran-
domised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.
14. Lencioni R, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L, et al. GIDEON (Global
Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with
sorafeNib): second interim analysis. Int J Clin Pract. 2014;68(5):609–17.
15. Edeline J, Blanc JF, Johnson P, Campillo-Gimenez B, Ross P, Ma YT, et al. A multicentre com-
parison between Child Pugh and Albumin-Bilirubin scores in patients treated with sorafenib
for Hepatocellular Carcinoma. Liver Int. 2016;36(12):1821–8.
16. King J, Palmer DH, Johnson P, Ross P, Hubner RA, Sumpter K, et al. Sorafenib for the
treatment of advanced hepatocellular cancer–a UK audit. Clin Oncol (R Coll Radiol).
2017;29(4):256–62.
17. Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of
sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial.
J Hepatol. 2012;57(4):821–9.
18. Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and
predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase
III studies. J Hepatol. 2017;67(5):999–1008.
19. Llovet JM, Pena CE, Lathia CD, Shan M, Meinhardt G, Bruix J, et al. Plasma biomarkers as
predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res.
2012;18(8):2290–300.
20. Shao Y, Hsu C, Huang C, Cheng A. Use of plasma angiogenesis-related factors to investigate
the association of interleukin 8 and interleukin 6 levels with efficacy of sorafenib-based anti-
angiogenic therapy in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol.
2011;29(4_suppl):199.
21. Shao YY, Huang CC, Lin SD, Hsu CH, Cheng AL. Serum insulin-like growth factor-1 levels
predict outcomes of patients with advanced hepatocellular carcinoma receiving antiangiogenic
therapy. Clin Cancer Res. 2012;18(14):3992–7.
22. Lin TH, Shao YY, Chan SY, Huang CY, Hsu CH, Cheng AL. High serum transforming growth
factor-beta1 levels predict outcome in hepatocellular carcinoma patients treated with sorafenib.
Clin Cancer Res. 2015;21(16):3678–84.
12 Oncotherapies for HCC 163

23. Miyahara K, Nouso K, Tomoda T, Kobayashi S, Hagihara H, Kuwaki K, et al. Predicting the
treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular
carcinoma. J Gastroenterol Hepatol. 2011;26(11):1604–11.
24. Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, et al. Adjuvant sorafenib for
hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-­
blind, placebo-controlled trial. Lancet Oncol. 2015;16(13):1344–54.
25. Lencioni R, Llovet JM, Han G, Tak WY, Yang J, Guglielmi A, et al. Sorafenib or placebo plus
TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol.
2016;64(5):1090–8.
26. Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, et al. Sorafenib in combination
with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma
(TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol
Hepatol. 2017;2(8):565–75.
27. Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, et al. Doxorubicin plus
sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a random-
ized trial. JAMA. 2010;304(19):2154–60.
28. Abou-Alfa GK, Niedzwieski D, Knox JJ, Kaubisch A, Posey J, Tan BR, Kavan P, Goel R,
Murray JJ, Bekaii-Saab TS, Tam VC, Rajdev L, Kelley RK, Siegel A, Balletti J, Harding JJ,
Schwartz LH, Goldberg RM, Bertagnolli MM, Venook AP. Phase III randomized study of
sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carci-
noma (HCC): CALGB 80802 (Alliance). J Clin Oncol. 2016;34(suppl 4S):Abstr 192.
29. Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, et al. SEARCH: a phase
III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients
with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33(6):559–66.
30. Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib versus sorafenib
in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol.
2013;31(32):4067–75.
31. Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus Sorafenib in
patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin
Oncol. 2015;33(2):172–9.
32. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, et al. Brivanib versus sorafenib
as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results
from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31(28):3517–24.
33. Ikeda M, Okusaka T, Mitsunaga S, Ueno H, Tamai T, Suzuki T, et al. Safety and pharmaco-
kinetics of lenvatinib in patients with advanced hepatocellular carcinoma. Clin Cancer Res.
2016;22(6):1385–94.
34. Ikeda K, Kudo M, Kawazoe S, Osaki Y, Ikeda M, Okusaka T, et al. Phase 2 study of lenvatinib
in patients with advanced hepatocellular carcinoma. J Gastroenterol. 2017;52(4):512–9.
35. Cheng A-L, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. Phase III trial of lenvatinib
(LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocel-
lular carcinoma (uHCC). J Clin Oncol. 2017;35(15_suppl):4001.
36. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, et al. Brivanib in patients
with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom
sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol.
2013;31(28):3509–16.
37. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, et al. Ramucirumab versus placebo
as second-line treatment in patients with advanced hepatocellular carcinoma following first-­
line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.
Lancet Oncol. 2015;16(7):859–70.
38. Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M. mTOR and P70 S6 kinase
expression in primary liver neoplasms. Clin Cancer Res. 2004;10(24):8421–5.
39. Zhou L, Huang Y, Li J, Wang Z. The mTOR pathway is associated with the poor prognosis of
human hepatocellular carcinoma. Med Oncol. 2010;27(2):255–61.
164 A. Childs and T. Meyer

40. Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, et al. Pivotal role of mTOR
signaling in hepatocellular carcinoma. Gastroenterology. 2008;135(6):1972–83, 83 e1-11.
41. Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, et al. Effect of everolimus on sur-
vival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 random-
ized clinical trial. JAMA. 2014;312(1):57–67.
42. Huynh H, Hao HX, Chan SL, Chen D, Ong R, Soo KC, et al. Loss of tuberous sclerosis
complex 2 (TSC2) is frequent in hepatocellular carcinoma and predicts response to mTORC1
inhibitor everolimus. Mol Cancer Ther. 2015;14(5):1224–35.
43. Abou-Alfa GK, Qin S, Ryoo B-Y, Lu S-N, Yen C-J, Feng Y-H, et al. Phase III randomized
study of second line ADI-peg 20 (A) plus best supportive care versus placebo (P) plus best
supportive care in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol.
2016;34(15_suppl):4017.
44. Bruix J, Tak WY, Gasbarrini A, Santoro A, Colombo M, Lim HY, et al. Regorafenib as second-­
line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label,
phase II safety study. Eur J Cancer. 2013;49(16):3412–9.
45. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with
hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised,
double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66.
46. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. Targeting MET in cancer: rationale
and progress. Nat Rev Cancer. 2012;12(2):89–103.
47. Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, et al. Tivantinib
for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-­
controlled phase 2 study. Lancet Oncol. 2013;14(1):55–63.
48. Rimassa L, Assenat E, Peck-Radosavljevic M, Zagonel V, Pracht M, Caremoli ER, et al. Second-­
line tivantinib (ARQ 197) vs placebo in patients (Pts) with MET-high hepatocellular carcinoma
(HCC): results of the METIV-HCC phase III trial. J Clin Oncol. 2017;35(15_suppl):4000.
49. Yea S, Narla G, Zhao X, Garg R, Tal-Kremer S, Hod E, et al. Ras promotes growth by alterna-
tive splicing-mediated inactivation of the KLF6 tumor suppressor in hepatocellular carcinoma.
Gastroenterology. 2008;134(5):1521–31.
50. Challen C, Guo K, Collier JD, Cavanagh D, Bassendine MF. Infrequent point mutations
in codons 12 and 61 of ras oncogenes in human hepatocellular carcinomas. J Hepatol.
1992;14(2–3):342–6.
51. Lim HY, Heo J, Choi HJ, Lin CY, Yoon JH, Hsu C, et al. A phase II study of the efficacy
and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus
sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clin Cancer Res.
2014;20(23):5976–85.
52. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of
hepatocellular carcinoma. Gastroenterology. 2015;149(5):1226–39 e4.
53. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular
carcinoma. Nat Rev Gastroenterol Hepatol. 2015;12(12):681–700.
54. Unitt E, Rushbrook SM, Marshall A, Davies S, Gibbs P, Morris LS, et al. Compromised
lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology.
2005;41(4):722–30.
55. Unitt E, Marshall A, Gelson W, Rushbrook SM, Davies S, Vowler SL, et al. Tumour lympho-
cytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J
Hepatol. 2006;45(2):246–53.
56. Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M. Clinicopathological study on hepa-
tocellular carcinoma with lymphocytic infiltration. Hepatology. 1998;27(2):407–14.
57. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab
versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med.
2015;373(2):123–35.
58. Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in
untreated melanoma. N Engl J Med. 2015;373(13):1270–1.
12 Oncotherapies for HCC 165

59. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously
untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.
60. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival
with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.
61. Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, et al. A
clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carci-
noma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8.
62. Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, et al.
Tremelimumab in combination with ablation in patients with advanced hepatocellular carci-
noma. J Hepatol. 2016;66(3):545–51.
63. Sangro B, Melero I, Yau TC, Hsu C, Kudo M, Crocenzi TS, Kim T-Y, Choo S, Trojan J,
Meyer T, Kang Y-K, Anderson J, Dela Cruz CM, Lang L, Neely J, El-Khoueiry AB. Safety
and ­antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carci-
noma (HCC): Interim analysis of dose-expansion cohorts from the phase 1/2 CheckMate-040
study. J Clin Oncol. 2016;34(Suppl):Abstract 4078.
64. Crocenzi TS, El-Khoueiry AB, Yau TC, Melero I, Sangro B, Kudo M, et al. Nivolumab (nivo)
in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC):
CheckMate 040 study. J Clin Oncol. 2017;35(15_Suppl):4013.
 Part II
Cholangiocarcinoma
Chapter 13
Mixed Hepatocellular/
Cholangiocarcinomas: Current
Perspectives and Management

Ray Tan, Alberto Quaglia, and Paul J. Ross

Key Learning Points

1. cHCC-CC accounts for 0.4–14% of primary liver tumours.
2. Diagnosis is based on histology. This uses a combination of morphology,
immunohistochemistry, in situ hybridization and molecular biology.
3. Diagnosis is optimally established on whole tumours.
4. Tumours are classified according to 2010 WHO classification.
5. Genetics reflect those of classical HCC and cholangiocarcinoma.
6. Hepatic resection with hilar nodal dissection is the optimal management
resulting in 5-year survival of approximately 28%.

R. Tan
Department of Medical Oncology, Guy’s Cancer, Guy’s and St Thomas’ NHS Foundation
Trust, London, UK
e-mail: [email protected]
A. Quaglia
The Institute of Liver Studies, King’s College Hospital, London, UK
e-mail: [email protected]
P. J. Ross (*)
Department of Medical Oncology, Guy’s Cancer, Guy’s and St Thomas’ NHS Foundation
Trust, London, UK
Department of Oncology, King’s College Hospital NHS Foundation Trust, London, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 169

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_13
170 R. Tan et al.

Areas of Controversy and Uncertainty

1. Incidence of the tumour is poorly understood due to the management of
HCC based on imaging and AFP.
2. Aetiological factors are poorly defined; the current view is that these are
similar to other primary liver tumours.
3. Growing understanding of the complexity of the spectrum of these
tumours. However, much to be learnt as molecular biology is studied that
will influence classification and management.
4. Can cHCC-CC be distinguished from classical HCC by imaging?
5. In advanced disease can diagnosis be established using needle biopsy?
6. Is there a need for repeat biopsy as disease progresses?
7. Data from liver transplantation are low in volume. Is there a role for liver
transplantation?
8. What are the optimal locoregional and systemic therapies for advanced
disease?

Pathology

The term combined or mixed hepatocellular-cholangiocarcinoma (cHCC-CC)

refers to a rare variant of primary malignant epithelial liver tumours in which both
hepatocellular carcinoma and cholangiocarcinoma are present in the same lesion. It
accounts for 0.4–14% of all primary liver tumours. The diagnosis is currently histo-
logical and is based on tumour cell morphology and immunohistochemistry.
The first known description of tumours with both hepatocellular and cholangio-
cellular differentiation is in the paper by Wells in 1903 [1]. The histological classi-
fication of cHCC-CC has evolved considerably over the years and has included the
occurrence of hepatocellular and cholangiocellular differentiation in separate
lesions in the same liver, in separate lesions coming into contact with each other and
within a single tumour mass [2–4]. Early studies were based purely on morphologi-
cal observations. The resemblance of tumour cells to hepatocytes or cholangiocytes
or their conventional neoplastic counterparts would define the tumour phenotype.
More recent studies have used a combination of morphology and techniques such as
immunohistochemistry, in situ hybridization, electron microscopy and molecular
biology to demonstrate lineage-specific markers. New concepts in liver embryol-
ogy, observations in animal models of liver carcinogenesis and regeneration, the
characterisation of the hepatic progenitor/stem cell compartment and advances in
the understanding of cell plasticity led to the concept that at least a proportion of
these tumours may derive from progenitor/stem cells with the potential of dual
hepatocellular and cholangiocellular differentiation. The current understanding is
that the spectrum of primary liver carcinoma has pure (by morphological and
­immunohistochemical criteria) hepatocellular carcinoma and cholangiocellular car-
cinoma at its two ends and a plethora of tumours exhibiting various combinations of
hepatocellular, biliary and progenitor cell morphological and immunohistochemical
13 Mixed Hepatocellular/Cholangiocarcinomas: Current Perspectives and Management 171

Table 13.1. 2010 WHO classification

Classical Histologically typical areas of HCC together with
cHCC-CC those of CC in the same tumour
cHCC-CC with
stem cell features
Typical Nests of mature hepatocyte-like tumour cells
surrounded by small cells exhibiting IHC markers of
progenitor cells
Intermediate Small homogeneous cells comprising most of the
tumour that are intermediate between hepatocytes and
cholangiocytes and showing immunohistochemical
markers of both
Cholangiocellular Small cells with a high nuclear/cytoplasmic ratio and
hyperchromatic oval-shaped nuclei arranged in a
tubular anastomosing (antler-like) pattern within a
dense, sclerotic stroma and also expressing
progenitor/stem cell markers

phenotypes in between. The reader is referred to the comprehensive review by Brunt

and colleagues, where a detailed description of the immunomarkers commonly used
in the interpretation of cHCC-CC is given [5]. Whether cHCC-CC derives from
transformed hepatocytes or cholangiocytes acquiring stem cell features, trans-
formed progenitor/stem cell maintaining dual differentiation potential, or even hep-
atoblasts, remains to be proven. cHCC-CC occurs often in tumour previously treated
by local ablation therapy and in particular transarterial chemoembolization [6–8].
This observation raises the possibility that tumour progenitor/stem cells resistant to
chemotherapy and hypoxia may gain a selective growth advantage and cause tumour
progression.
The currently used WHO 2010 classification (Table 13.1.) encapsulates this
complexity. It classifies cHCC-CCs into two main categories: classical cHCC-CC
and cHCC-CC with stem cell features.
Of note, coexistence of hepatocellular and cholangiocellular carcinoma as two
separate lesions in the same liver is not considered as cHCC-CC. Fibrolamellar car-
cinoma and hepatoblastoma are not included in the currently accepted definition of
cHCC-CC.

Genetics

Genetic studies looking into the genetic signature and molecular biology of cHCC-­
CCs are currently few in number. Further studies are needed in order to help better
understand the pathogenesis and clinical presentation of cHCC-CCs. Genomic and
genetic analyses of cHCC-CC have similar molecular characteristics with both
intrahepatic cholangiocarcinoma and classic HCC. Frequent alterations in primary
liver cancers include genes such as TP53, WNT, CTNNB1 and cell cycle-related
genes such as CCND1 and CDKN2A [9]. Recently, IDH1/IDH2 mutations have
172 R. Tan et al.

been observed in four different HCC tumours [10]. An additional 11 tumours with
gene expression patterns similar to the IDH1-/IDH2-mutated samples were
observed. These tumours histopathologically resemble HCC but have clinical and
genetic features of cholangiocarcinomas and HCCs suggestive of a possible biphe-
notypic stem cell origin. This observation is supportive of the concept that HCC and
iCCA represent two ends of a spectrum, and the presence of IDH1/IDH2 mutations
shifts a tumour towards a biliary phenotype.

Clinical Features

The rarity of this cancer has made it difficult to define epidemiologically. A

population-­level analysis using the Surveillance, Epidemiology and End Results
(SEER) database for the period 1988–2009 included 465 patients with cHCC-CC
[11]. This occurred more frequently in patients who were white, male and older than
65 years. In a US population of patients undergoing liver transplantation for cHCC-
­CC, hepatitis C and alcoholic cirrhosis were the most frequent secondary diagnoses,
similar to patients with HCC [12]. cHCC-CC is considered an aggressive tumour
with poor long-term survival. Good quality clinical data remains limited. cHCC-
­CC, similarly to both HCC and CC, usually develops asymptomatically until it
becomes more advanced, at which point it may cause symptoms such as right upper
quadrant abdominal pain, weight loss, pruritus, fever and fatigue. Clinical signs
may include hepatomegaly or abdominal distension due to ascites.

Diagnosis

The majority of series have found no major differences in the presentation of cHCC-
­CC with those of classical HCC or iCCA. The tumour markers alpha-fetoprotein
(AFP) and carbohydrate antigen 19-9 (Ca 19-9) have been found to be serum mark-
ers for HCC and CC, respectively. Both may also be elevated in cHCC-CC, and a
simultaneous increase in both along with clinical and radiological suspicion of
malignancy should make one consider cHCC-CC as a potential diagnosis. It is
worth noting that AFP is elevated less frequently and also tends to be lower in
cHCC-CC compared to HCC.
The accepted dogma has been that preoperative non-invasive diagnosis of cHCC-
­CC with conventional imaging is almost impossible. The majority based on imag-
ing resemble classical HCC. However, Potretzke and colleagues reviewed imaging
of 61 patients with histologically confirmed cHCC-CC according to the diagnostic
imaging criteria recommenced by the American College of Radiology Liver
Imaging Reporting and Data System (Li-RADS) (Table 13.2) [13]. Multiphasic
contrast-­
enhanced MRI scans (48 patients) and CT scans (13 patients) were
obtained pretreatment. According to Li-RADS major features in 33 (54%) patients
met major criteria for HCC. However, 29 of 33 had at least 1 ancillary feature
13 Mixed Hepatocellular/Cholangiocarcinomas: Current Perspectives and Management 173

Table 13.2 Li-RADS ancillary features favouring malignancy and features favouring non-­
hepatocellular (HCC) malignancy over HCC
Ancillary features favouring
malignancy Features favouring non-HCC malignancy over HCC
Midmoderate T2 hyperintensity Rim or peripheral arterial phase hyperenhancement
Restricted diffusion Portal venous and delayed phase progressive central
enhancement
Distinctive rima Peripheral washout appearance
Corona enhancementa Marked diffusion restriction
Mosaic architecturea Liver surface retraction
Nodule-in-nodule architecturea Biliary obstruction disproportionate to that expected on basis
of size of mass
Intralesional fata
Lesional iron sparing
Lesional fat sparing
Hepatobiliary phase
hypointensity
Feature specifically favours HCC over malignancy in general
a

favouring non-­HCC malignancy. Overall 54 of 61 (88%) of cHCC-CC in this study

could be categorised as non-HCC malignancy indicating the importance of an algo-
rithm such as Li-RADS for assessment of liver lesions.
Although definitive diagnosis of cHCC-CC based on tumour markers and imag-
ing alone is challenging, certain findings should prompt strong consideration of
cHCC-CC pre-biopsy. These would be imaging features of both HCC and CC,
raised AFP as well as Ca 19-9 and imaging appearances which contradict the tumour
marker (e.g. CC features on imaging but a raised AFP).
The definitive diagnosis of cHCC-CC requires histological examination.
Extensive sampling of surgically resected tumours is necessary to ensure that the
microscopy examination is carried out on a sufficient amount of tissue and that areas
of divergent differentiation are not missed. Sampling error remains a major concern
when interpreting core needle biopsy specimens, particularly with small and/or sin-
gle pass samples as they may not be representative. Multiple biopsies from different
areas of the tumour mass would be necessary to minimise sampling error.

Management

Surgical resection and liver transplantation are the only curative options. Hepatic
resection with hilar lymph node dissection is the recommended treatment for cHCC-
­CC in non-cirrhotic patients. In common with all surgery, this is dependent on the
general medical condition of the patient, tumour extent and local anatomical condi-
tions. The aim should be complete excision with negative margins and minimal
impact on liver function. For patients with liver cirrhosis, hepatic resection should
be carefully considered based on their functional reserve.
174 R. Tan et al.

cHCC-CC tends to behave like HCC with respect to portal and hepatic venous
infiltration and like CC with respect to lymph node metastasis. In fact, lymph node
metastasis is a more significant problem in cHCC-CC than in either HCC or CC. The
Liver Cancer Study Group of Japan studied the frequency of distant metastasis in
autopsied patients with primary liver cancer and found that lymph node metastasis
was observed in 30.3% of patients with HCC, 68.6% of patients with CC and 76.2%
of patients with cHCC-CC [14]. However, despite this it remains controversial with
regards to whether lymph node dissection improves prognosis.
The role of liver transplantation in cHCC-CC, unlike in HCC, is not well-defined.
Outcomes following liver transplantation are difficult to interpret because of the low
number of reported cases. Most of the available data is based on patients who were
initially misdiagnosed with HCC.
Groeschl et al. performed a retrospective comparative cohort study of surgical
treatment using the SEER database for the period 1973–2008 [15]. Fifty-four
patients diagnosed with cHCC-CC were included, 19 (35%) underwent liver trans-
plantation and 35 (65%) hepatic resection. One-year overall survival was 89% fol-
lowing transplantation compared to 71% with hepatic resection; 3-year overall
survivals were 48% and 46%, respectively. Median overall survival for all the
patients with cHCC-CC was 36 months. (95% CI, 19–89, P = 0.01). A more recent
analysis of patients using the United Network for Organ Sharing (UNOS) database
between 1994 and 2013 included 94 patients with cHCC-CC [12]. Overall survival
rates following liver transplantation for cHCC-CC at 1, 3 and 5 years were 82%,
47% and 40%. These were significantly inferior to those observed for classical HCC
but similar to those for cholangiocarcinoma.
In the population-level analysis, Garacini et al. observed that most patients had
no interventional treatment, 13.1% liver transplantation, 10.0% major hepatectomy,
7.6% minor hepatectomy and 4% ablative therapy [11]. Five-year overall survival
rates were 41.1% with liver transplantation, 28.1% with major hepatectomy, 27.1%
with minor hepatectomy and 0 for those treated with ablative therapies or without
interventional treatment. Whilst a univariate analysis demonstrated a better 5-year
survival for patients treated with liver transplantation compared to hepatectomy, this
was not confirmed in a multivariate analysis.
This data clearly demonstrates that patients with tumours amenable to surgical
intervention have superior survival to those treated with local ablative therapy or
non-interventional therapy. However, the outcomes from liver transplantation are
inferior to those of patients with HCC. Indeed, two retrospective studies have
observed no definitive survival advantage for liver transplantation compared to
resection. It remains to be seen with better selection criteria to these studies whether
there is a role for liver transplantation in cHCC-CC. Currently, major hepatic resec-
tion remains the best option for those with tumours amenable to same.
Patients treated with liver resection or transplantation with curative intent
management of recurrence need to be informed by histology from the recurrence.
Our group have described the histological pattern of surgically resected primary
and metastatic classic cHCC-CC in four patients [16]. This emphasised the het-
erogeneous presentation and unpredictable behaviours of these tumours. The first
13 Mixed Hepatocellular/Cholangiocarcinomas: Current Perspectives and Management 175

case had a primary tumour and subsequent bilateral adrenal metastases demon-
strating a similar combined phenotype. Further metastases had a purely HCC
component. A second case demonstrated that only one component metastasised
with a histological pattern similar to the predominant and less-differentiated HCC
component (Fig. 13.1). In another cases it was the minor cholangiocellular com-
ponent that recurred. In the fourth case, the two components showed a different
tropism, with HCC metastasising to paravertebral tissue and brain and cholangio-
carcinoma to the lung. Consequently, when considering systemic therapy, it is
important to have an understanding of which component is predominant. Indeed,
systemic therapies could give a selective advantage of one component on the
other over time.
Data on non-surgical treatment of cHCC-CC is extremely limited, and no clini-
cal trial data is available. Non-surgical options include transarterial chemoemboli-
zation (TACE), radioembolisation, hepatic arterial infusion chemotherapy, ablative
therapies and systemic chemotherapy. One of the few studies reporting on outcomes

a b

c d

Fig. 13.1 Sixty-eight year old female patient. Surgical resection specimen containing a 50 mm
diameter mixed hepatocellular-cholangiocellular caracinoma, classic-type. (a) Haematoxylin and
eosin (H&E) stain show an area of cholangiocellular differentiation in the top left corner, adjacent
to an area of hepatocellular differentiation with clear cell changes in the lower part of the field.
This is supported by immunohistochemistry which shows that the hepatoid tumour cells stain for
Hep-Par-1 (b) and arginase-1 (c), whereas the tubulo-glandular structures do not stain for these
markers but stain instead for CA 19-9 (d). Magnification: 200× in each picture
176 R. Tan et al.

in patients not suitable for surgical management included 18 patients treated with
liver-directed therapy from a cohort of 79 patients with cHCC-CC [17]. The liver-­
directed therapy group received either TACE, radioembolisation or hepatic arterial
infusion chemotherapy. Typically, patients treated with liver-directed therapy had
larger tumours than those managed with surgery (mean tumour size 8.9 cm vs
5.8 cm), more frequent satellite lesions (83% vs 32%) and more frequent presence
of lymph node metastases (33% vs 8%). Liver-directed therapy resulted in a partial
response rate of 47%; 50% with radioembolisation, 20% with TACE and 66% with
hepatic arterial infusion chemotherapy. However, the differences needed to be
treated with caution due to the small numbers in each group. Median progression-­
free and overall survival with liver-directed therapy were 8.3 and 16.0 months,
respectively.
Systemic chemotherapy remains the only option for metastatic disease. The lit-
erature is predominantly limited to case reports. Fowler and colleagues included 28
patients treated with systemic chemotherapy alone in their retrospective study [17].
Patients generally had more advanced tumours than those treated with liver-directed
therapy: tumour thrombus (24% vs 5%), nodal metastases (83% vs 33%) and distant
metastases (57% v 12%). No details of regimens used are reported. Response data
was only available for 18 of the 28 patients with an observed partial response rate of
6% and 33% achieving stable disease. Median progression-free and overall surviv-
als were 5.0 and 5.6 months, respectively. A series published from the MD Anderson
Cancer Center group in 2017 provided a retrospective analysis of seven patients
treated from 2009 to 2014 [18]. Four patients were treated with first-line gemcitabine-­
based therapy, whilst three received sorafenib. Three patients proceeded to second-­
line therapy. This series again demonstrated the poor outcomes with systemic
therapy with initial progression-free survival of 3.4 months and median overall sur-
vival of 8.3 months.

Future Prospects

Work continues to better understand the histogenesis of cHCC-CC. Govaere and

Roskams have been studying how differentiation or dedifferentiation leads to a phe-
notypic switch and subsequent heterogeneity in the same tumour [19]. In particular,
they have been looking at how the cell of origin and time-dependent dedifferentia-
tion can contribute to the different phenotypes found in hepatic cancer, as well as
the signals involved.
Understanding of the mutational landscape that leads to the development of pri-
mary liver cancers continues to increase. This in turn will hopefully lead to more
targeted treatments aimed at those genetic mutations in order to prevent the devel-
opment of or treat these cancers. For example, recent sequencing approaches have
emphasised the importance of early genetic events that affect telomere maintenance,
epigenetic mechanisms and RNA editing; this in turn is opening the door for pos-
sible novel therapeutic opportunities.
13 Mixed Hepatocellular/Cholangiocarcinomas: Current Perspectives and Management 177

Conclusions

cHCC-CC is a rare primary liver cancer with an aggressive nature and a poor
prognosis. Due to its similar clinical presentation to HCC and CC and its ambigu-
ous imaging features, preoperative diagnosis is difficult. It should be considered
as a differential diagnosis when imaging and tumour marker patterns do not fit
with either HCC or CC and should prompt multiple biopsies from different areas
of the tumour. Improved initial diagnosis rates of cHCC-CC may facilitate more
aggressive neoadjuvant therapies for these patients and hopefully improve
outcomes.
Hepatic resection with hilar lymph node resection remains the current standard
of care in localised disease, as a benefit of liver transplantation over hepatic resec-
tion has not been proved conclusively. Literature regarding non-surgical treatments
of cHCC-CC is extremely limited and limited mainly to case reports.
Further work is undoubtedly needed to further evaluate current treatments, as
well as to better understand the histogenesis of cHCC-CC in order to develop novel
therapeutics.

References

1. Wells HG. Primary carcinoma of the liver. Am J M Sc. 1903;126:403–17.

2. RA A, Lisa JR. Combined liver cell and bile duct carcinoma. Am J Surg Pathol.
1949;25:647–55.
3. Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among
48,900 necropsies. Cancer. 1954;7(3):462–503.
4. Akiba J, Nakashima O, Hattori S, Tanikawa K, Takenaka M, Nakayama M, Kondo R,
Nomura Y, Koura K, Ueda K, Sanada S, Naito Y, Yamaguchi R, Yano H. Clinicopathologic
analysis of combined hepatocellular-cholangiocarcinoma according to the latest
WHO classification. Am J Surg Pathol. 2013;37(4):496–505. https://doi.org/10.1097/
PAS.0b013e31827332b0.
5. Brunt EM, Paradis V, Sempoux C, Thiese ND. Biphenotypic (hepatobiliary) primary liver
carcinomas: the work in progress. Hepatic Oncol. 2015;2(3):255–73.
6. Zen C, Zen Y, Mitry RR, Corbeil D, Karbanová J, O’Grady J, Karani J, Kane P, Heaton N,
Portmann BC, Quaglia A. Mixed phenotype hepatocellular carcinoma after transarterial che-
moembolization and liver transplantation. Liver Transpl. 2011;17(8):943–54. https://doi.
org/10.1002/lt.22314.
7. Nishihara Y, Aishima S, Kuroda Y, Iguchi T, Taguchi K, Asayama Y, Taketomi A, Kinukawa
N, Honda H, Tsuneyoshi M. Biliary phenotype of hepatocellular carcinoma after preopera-
tive transcatheter arterial chemoembolization. J Gastroenterol Hepatol. 2008;23(12):1860–8.
https://doi.org/10.1111/j.1440-1746.2008.05601.x.
8. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A, Roberts
LR, Demetris AJ, Sun Z, Nevens F, Roskams T, Thorgeirsson SS. A novel prognostic sub-
type of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med.
2006;12(4):410–6.
9. Marquardt JU, Andersen JB, Thorgeirsson SS. Functional and genetic deconstruction of the
cellular origin in liver cancer. Nat Rev Cancer. 2015;15(11):653–67. https://doi.org/10.1038/
nrc4017.
178 R. Tan et al.

10. Cancer Genome Atlas Research Network. Comprehensive and integrative genomic char-
acterization of hepatocellular carcinoma. Cell. 2017;169(7):1327–1341.e23. https://doi.
org/10.1016/j.cell.2017.05.046.
11. Garancini M, Goffredo P, Pagni F, Romano F, Roman S, Sosa JA, Giardini V. Combined
hepatocellular-­cholangiocarcinoma: a population-level analysis of an uncommon primary liver
tumor. Liver Transpl. 2014;20(8):952–9. https://doi.org/10.1002/lt.23897.
12. Vilchez V, Shah MB, Daily MF, Pena L, Tzeng CW, Davenport D, Hosein PJ, Gedaly R,
Maynard E. Long-term outcome of patients undergoing liver transplantation for mixed hepa-
tocellular carcinoma and cholangiocarcinoma: an analysis of the UNOS database. HPB
(Oxford). 2016;18(1):29–34. https://doi.org/10.1016/j.hpb.2015.10.001.
13. Potretzke TA, Tan BR, Doyle MB, Brunt EM, Heiken JP, Fowler KJ. Imaging features of
biphenotypic primary liver carcinoma (Hepatocholangiocarcinoma) and the potential to mimic
hepatocellular carcinoma: LI-RADS analysis of CT and MRI features in 61 cases. AJR Am J
Roentgenol. 2016;207(1):25–31. https://doi.org/10.2214/AJR.15.14997.
14. The Liver Cancer Study Group of Japan. Primary liver cancer in Japan: clinicopathologic
features and results of surgical treatment. Ann Surg. 1990;211:277–87.
15. Groeschl RT, Turaga KK, Clark Gamblin T. Transplantation versus resection for patients with
combined hepatocellular carcinoma-cholangiocarcinoma. J Surg Oncol. 2013;107(6):608–12.
https://doi.org/10.1002/jso.23289.
16. De Vito C, Sarker D, Ross P, Heaton N, Quaglia A. Histological heterogeneity in primary and
metastatic classic combined hepatocellular-cholangiocarcinoma: a case series. Virchows Arch.
2017; https://doi.org/10.1007/s00428-017-2196-x.
17. Fowler K, Saad NE, Brunt E, Doyle MB, Amin M, Vachharajani N, Tan B, Chapman
WC. Biphenotypic primary liver carcinomas: assessing outcomes of hepatic directed therapy.
Ann Surg Oncol. 2015;22(13):4130–7. https://doi.org/10.1245/s10434-015-4774-y.
18. Rogers JE, Bolonesi RM, Rashid A, Elsayes KM, Elbanan MG, Law L, Kaseb A, Shroff
RT. Systemic therapy for unresectable, mixed hepatocellular-cholangiocarcinoma: treat-
ment of a rare malignancy. J Gastrointest Oncol. 2017;8(2):347–51. https://doi.org/10.21037/
jgo.2017.03.03.
19. Govaere O, Roskams T. Pathogenesis and prognosis of hepatocellular carcinoma at the cel-
lular and molecular levels. Clin Liver Dis. 2015;19(2):261–76. https://doi.org/10.1016/j.
cld.2015.01.002.
Chapter 14
Epidemiology and Pathogenesis
of Cholangiocarcinoma

Stephen McClements and Shahid A. Khan

Introduction

Cholangiocarcinoma is the second most common primary liver cancer after hepa-
tocellular carcinoma and is associated with a high mortality, often attributed to late
diagnosis when the opportunity for curative therapies has passed.
Cholangiocarcinoma accounts for approximately 3% of all gastrointestinal cancers
worldwide, with a prevalence in autopsy studies of 0.01–0.46% [1].

Clinical Anatomy and Classification

The term cholangiocarcinoma (CCA) refers to cancers arising in the intrahepatic, peri-
hilar or extrahepatic (distal) biliary tree and excludes cancers of the gallbladder and
ampulla (Fig. 14.1) [2]. Intrahepatic cholangiocarcinoma (iCCA) originates in the
peripheral ductules or large ducts within the liver; this represents less than 10% overall.
Extrahepatic cancers are classified as either perihilar cholangiocarcinoma (pCCA) rep-
resenting 50% or distal cholangiocarcinoma (dCCA) representing 40% [3]. The transi-
tion zone between perihilar and distal disease is the insertion point of the cystic duct.
Cancers arising in the perihilar region, also referred to as Klatskin tumours in the
International Classification of Diseases (ICD), have been further classified accord-
ing to their patterns of involvement of the hepatic ducts (the Bismuth-Corlette clas-
sification) (Fig. 14.2):
• Type I: tumours below the confluence of the left and right hepatic ducts.
• Type II: tumours reaching the confluence but not involving left or right hepatic
ducts.

S. McClements · S. A. Khan (*)

Liver Unit, St Mary’s Hospital Campus, Imperial College London, London, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 179

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_14
180 S. McClements and S. A. Khan

RHD: Right Hepatic Duct LHD: Left Hepatic Duct

Intrahepatic CCA
Liver

Perihilar CCA
CHD: Common Hepatic Duct
Cystic Duct
Common Bile Duct

Extrahepatic CCA

Distal CCA
Gall Bladder

Pancreatic Duct
Sphincter of Oddi

Ampulla of Vater Pancreas

Duodenum

Fig. 14.1 Sites of the different sub-types of cholangiocarcinoma (CCA)

Fig. 14.2 Bismuth

classification of biliary
strictures [4]

I IIIa IV

II IIIb IV

• Type III: tumours occluding the common hepatic duct and either the right (IIIa)
or the left (IIIb) hepatic duct.
• Type IV: tumours that are multicentric or involving both right and left hepatic
ducts.
14 Epidemiology and Pathogenesis of Cholangiocarcinoma 181

Epidemiology

The incidence of cholangiocarcinoma (CCA) increases with age and typically pres-
ents in the fifth or sixth decade; the noteworthy exceptions to this trend are the
tumours presenting in patients with primary sclerosing cholangitis (PSC) and cho-
ledochal cysts which can present much earlier (see section “Risk Factors” below).
There is a slight male predominance, which appears to reflect the higher incidence
of risk factors (particularly PSC) in men.
The emerging concept is that the three anatomical groups (iCCA, pCCA and
dCCA) differ significantly in their tumour biology, clinical characteristics, and epi-
demiology. Overall rates of cholangiocarcinoma diagnoses appear to be rising glob-
ally; however, there is not a balanced distribution between the subtypes.
Many countries including North America, Japan, Europe and Australia have
reported an increased incidence of intrahepatic disease (iCCA) coupled by a
decreasing incidence of extrahepatic disease (pCCA and dCCA); however, the data
are inconsistent and must be viewed cautiously, and actually this trend is seemingly
reversed in other countries.
There is clearly some geographical variation in incidence largely attributed to
the distribution of risk factors in different countries; for instance, South East
Asia has an increased incidence of iCCA related to endemic liver fluke infection
(see below).
The distribution of risk factors, however, does not fully explain the global vari-
ability in incidence, and several confounding factors have been identified that con-
tribute to the data inconsistencies.
Although biologically these three subsets of CCA appear to represent distinct
clinical entities, International classifications have not consistently distinguished
between pCCA and dCCA and instead distinguish only intrahepatic disease (iCCA)
and extrahepatic disease (where pCCA and dCCA are combined).
Additionally the nomenclature of periductal disease (pCCA) (previously
referred to as Klatskin tumours) has evolved in sequential editions of the
International Classification of Diseases (ICD); initially they were considered as a
distinct entity (within the intrahepatic spectrum), then laterally could be placed
within either the intrahepatic or extrahepatic classification dependant on tumour
margins. This phenomenon means that pCCAs are classified differently, according
to which edition of ICD is applied and as different countries adopt the updated
editions of the ICD at different times (often over long time periods). True represen-
tation of incidence based on retrospective international data is extremely
challenging.
The apparent rise in iCCA may also be artefactual when historic misclassifica-
tion is taken into account; as diagnostic tests have become more sophisticated and
widely available, the risk of CCA being misclassified has been reduced. The distinc-
tion between iCCA and HCC requires detailed investigations, and the importance of
making this distinction is now clinically more relevant as treatment modalities and
outcomes have advanced. This change has undoubtedly altered the rates of accurate
182 S. McClements and S. A. Khan

iCCA diagnosis. There has also been an observed dichotomy of increased rates of
iCCA diagnosis coupled with a decreased incidence of ‘cancer of unknown ­primary’,
and this again adds weight to the argument that much of the apparent increase inci-
dence of iCCA may in fact reflect more accurate diagnosis rather than a greater
number of total cancers per se.
The summary of current epidemiological data therefore is difficult to reconcile
given the heterogeneity of recording and classification practices employed interna-
tionally, and the apparent rise in incidence needs to be interpreted with caution until
more consistent and uniform data recording practices are adopted.

Risk Factors

Although the majority of cases of cholangiocarcinoma are sporadic with no clear

predisposing factors, several risk factors have been identified which share the com-
mon property of precipitating chronic inflammation of the biliary tree [5].

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is the commonest known predisposing condition for

cholangiocarcinoma in the west. It tends to present earlier in PSC patients than in
sporadic cases, typically affecting the 30–50-year age group. About a third of
patients with primary sclerosing cholangitis who develop cholangiocarcinoma do so
within 2 years of diagnosis, and the risk of cholangiocarcinogenesis seems unre-
lated to the duration of the inflammatory disease. Two-thirds of patients with pri-
mary sclerosing cholangitis have associated inflammatory bowel disease, especially
ulcerative colitis. No association has been shown between the risk of cholangiocar-
cinoma and the presence, severity, and extent of inflammatory bowel disease in this
group of patients [6].

Parasitic Infection

A large body of experimental and epidemiological data suggests a pathogenic

association between liver fluke infestation, especially Opisthorchis viverrini (and
less definitively Clonorchis sinensis), and cholangiocarcinoma [7]. Eating under-
cooked fish infects humans with adult worms inhabiting and laying eggs in the
biliary system. These parasites are endemic in parts of South East Asia and are
largely attributed to the marked increase in iCCA observed in countries such as
Thailand.
14 Epidemiology and Pathogenesis of Cholangiocarcinoma 183

Fibropolycystic Liver Disease

Caroli’s syndrome (congenital biliary cysts), congenital fibrosis and choledocal

cysts (cystic dilatations of the biliary tree) carry a 15% risk of malignant change
after the second decade, at an average age of 34 years [8]. The mechanism of carci-
nogenesis is unclear but could be related to biliary stasis, reflux of pancreatic juice
causing chronic inflammation or activation of bile acids and deconjugation of car-
cinogens [9]. Bile duct adenomas and biliary papillomatosis are also associated
with the development of cholangiocarcinoma.

Intrahepatic Biliary Stones

Hepatolithiasis is rare in the west, but relatively common in parts of Asia, and is
associated particularly with peripheral intrahepatic cholangiocarcinoma. Up to 10%
of patients with hepatolithiasis develop cholangiocarcinoma [10]. In Taiwan, up to
70% of patients with cholangiocarcinoma undergoing resection reportedly have
intrahepatic biliary stones, and in Japan this figure is 6–18% [11]. Biliary stones are
thought to cause bile stasis, predisposing to recurrent bacterial infections and sub-
sequent inflammation, a potential cofactor for cholangiocarcinogenesis.

Chemical Carcinogen Exposure

Several chemical toxins have been associated with cholangiocarcinoma. Promutagenic

DNA adducts have been identified in cholangiocarcinoma tissue, indicating exposure
to DNA-damaging agents [12]. Thorotrast, a radiological contrast agent banned in
the 1960s for its carcinogenic properties, has been strongly associated with the devel-
opment of cholangiocarcinoma many years after exposure, increasing the risk to 300
times that of the general population [13]. Associations have also been made with
exposure to by-products from the rubber and chemical industries, including dioxins
and nitrosamines [14], as well as with alcohol and smoking [15].

Viral Hepatitis

Cirrhosis, of any cause, has also been associated with cholangiocarcinoma; a large
cohort study of over 11,000 patients with cirrhosis, followed up over 6 years,
showed a tenfold risk compared with the general population [15]. More specifically,
hepatitis B and C viruses have been linked to the cancer. A case-control study from
Korea reported that 12.5% of patients with cholangiocarcinoma tested positive for
184 S. McClements and S. A. Khan

hepatitis C virus and 13.8% for hepatitis B virus surface antigen (HBsAg), com-
pared with 3.5% and 2.3% of controls [15]. In a second case-control study from
Italy, 23% of patients with cholangiocarcinoma were positive for antihepatitis C
virus, and 11.5% were HbsAg-positive with odds ratios of 6.1 for hepatitis C virus
and 5.9 for HIV infection [16].

Metabolic Disease

The metabolic syndrome (clinically represented by dyslipidemia, central obesity,

impaired glucose tolerance and hypertension) has been associated with an increased
risk of intrahepatic CCA [17]. Several cohort and case-controlled studies have also
demonstrated both type 2 diabetes mellitus and obesity as independent risk factors
associated with increased incidence of iCCA, and this has been substantiated by
meta-analyses of such studies [18, 19].
It remains unclear, however, whether diabetes and obesity are direct drivers of
carcinogenesis or are merely surrogate markers for molecular derangement associ-
ated with the metabolic syndrome.

Molecular Pathogenesis

Carcinogenesis involves specific cell genome derangements; the genetic pathways

contributing to the selective growth advantage of cancer cells can be organised into
those governing cell fate and differentiation, proliferation, cell survival, and main-
tenance of genome integrity [20]. The transition from normal biliary epithelium to
malignant tissue occurs through a precursor lesion: intraductal papiliary neoplasia
(IPMN) of the bile duct or biliary intraepithelial neoplasia (BilN). These lesions like
pancreatic IPMN are classified due to the extent of cellular atypia [5].
A proposed model for carcinogenesis in cholangiocarcinoma showing interac-
tion between environmental factors and host genetics is presented in Fig. 14.3. As
with many cancers, there is a stepwise progression from normal cell biology to
neoplasia, influenced by interplay between environmental and host factors.
Genetic polymorphisms in the cytochrome P450 enzymes or in the bile salt trans-
porter proteins, for example, could lead to alterations in the efficiency with which
environmental toxins (xenobiotics) are handled by the liver. The development of
cholangiocarcinoma probably needs a ‘second hit’ to deconjugate such xenobiotics
and to expose the bile duct epithelium to damage. Such secondary hits include chronic
inflammation, viral hepatitis, worm infections, and recurrent cholangitis [21].
Recent molecular analysis has delineated the genomic landscape in CCA, and
the diverse genetic targets identified have reinforced the evidence for heterogeneity.
These concepts are explored in more depth in chapter “Oncotherapies for
Cholangiocarcinoma”.
14 Epidemiology and Pathogenesis of Cholangiocarcinoma 185

Normal
cholangiocyte Environmental agents:
metabolised by or deposited in,
the hepatobiliary system:
• Genotoxic chemicals
—eg. nitrosamines, dioxins
• Genotoxic physical agents
—eg. thorotrast

Host factors Initiation

Individual genes Cholangiocyte DNA
• DNA repair enzymes mutation in key gene—eg,
• Toxin metabolising enzymes p53, mdm–2, k-ras, APC (Repair/apoptosis)
• Defects in oncogenes, tumour
suppressor genes, and genes
controlling cell cycle and
apoptosis Persistence of mutation
• loss of antigrowth signalling and cell division
• bile salt transporter Risk factors cholangiocyte
polymorphisms turnover—eg.
Individual environment • liver flukes
• Macro—eg, chemical exposure Promotion • primary sclerosing cholangitis
from smoking, occupation, Proliferation of the initiated • chronic intraductal gallstones
pollution etc, and infection cholangiocyte • biliary cystic disease
• Macro—eg, growth factors and
hormones, immune system, Chemicals and drugs in bile—eg,
nitric oxide PCBs, oestrogens, oral
(Preneoplastic lesion) contraceptive

Micro environment—eg. bile

acids, oestrogens

Progression
Further DNA mutations—eg,
p53, mdm-2, k-ras, cell-cycle
control genes—leading to • Spontaneous events
genetic heterogenity, • Chemical/physical agents
karyotype instability and • Epigenetic alterations
selection of clones with
growth advantage,
angiogenesis

Clinical
cholangiocarcinoma

Further genetic changes

Metastasis

Fig. 14.3 Proposed model for carcinogenesis in cholangiocarcinoma showing interaction between
environmental factors and host genetics (Bridgewater et al. [2])
186 S. McClements and S. A. Khan

References

1. Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas.

Semin Liver Dis. 1994;14(2):109.
2. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park J-W, Patel T, Pawlik TM, Gores
GJ. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
J Hepatol. 2014;60(6):1268–89 pii: S0168-8278(14)00067-1. https://doi.org/10.1016/j.
jhep.2014.01.021.
3. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year
experience with 564 patients at a single institution. Ann Surg. 2007;245:755.
4. Kato T, Tsukamoto E, Kuge Y, et al. Clinical role of (18)F-FDG PET for initial staging of
patients with extrahepatic bile duct cancer. Eur J Nucl Med Mol Imaging. 2002;29:1047–54.
5. Zen Y, Adsay NV, Bardadin K, et al. Biliary intraepithelial neoplasia: an international interob-
server agreement study and proposal for diagnostic criteria. Mod Pathol. 2007;20:701.
6. Broome U, Olsson R, Loof L, et al. Natural history and prognostic factors in 305 Swedish
patients with primary sclerosing cholangitis. Gut. 1996;38:610–5.
7. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg.
2002;89:962–70.
8. Simeone DM. Gallbladder and biliary tree: anatomy and structural anomalies. In: Yamada T,
editor. Textbook of gastroenterology. Philadelphia: Lippincott Willimas and Wilkins; 1999.
p. 2244–57.
9. Ohtsuka T, Inoue K, Ohuchida J, et al. Carcinoma arising in choledochocele. Endoscopy.
2001;33:614–9.
10. Kubo S, Kinoshita H, Hirohashi K, Hamba H. Hepatolithiasis associated with cholangiocarci-
noma. World J Surg. 1995;19:637–41.
11. Chen MF. Peripheral cholangiocarcinoma (cholangiocellular carcinoma): clinical features,
diagnosis and treatment. J Gastroenterol Hepatol. 1999;14:1144–9.
12. Khan SA, Carmichael PL, Taylor-Robinson SD, Habib N, Thomas HC. DNA adducts, detected
by 32P postlabelling, in human cholangiocarcinoma. Gut. 2003;52:586–91.
13. Sahani D, Prasad SR, Tannabe KK, Hahn PF, Mueller PR, Saini S. Thorotrast-induced cholan-
giocarcinoma: case report. Abdom Imaging. 2003;28:72–4.
14. Hardell L, Bengtsson NO, Jonsson U, Eriksson S, Larsson LG. Aetiological aspects on pri-
mary liver cancer with special regard to alcohol, organic solvents and acute intermittent por-
phyria: an epidemiological investigation. Br J Cancer. 1984;50:389–97.
15. Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with
cirrhosis: a nationwide cohort study in Denmark. Hepatology. 1998;28:921–5.
16. Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B
virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes
Control. 2001;12:959–64.
17. Welzel TM, Graubard BI, Zeuzem S, et al. Metabolic syndrome increases the risk of pri-
mary liver cancer in the United States: a study in the SEER-medicare database. Hepatology.
2011;54:463.
18. Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver
cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol.
2012;57(1):69–76.
19. Jing W, Jin G, Zhou X, et al. Diabetes mellitus and increased risk of cholangiocarcinoma: a
meta-analysis. Eur J Cancer Prev. 2012;21:24.
20. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383:2168–79.
21. Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet.
2005;366:1303–14.
Chapter 15
Diagnosis and Staging
of Cholangiocarcinoma

Jessica R. Hale and Olusola O. Faluyi

Key Learning Points

1. Cholangiocarcinoma (CCA), the most common biliary tract malignancy, is
unfortunately often diagnosed late with resultant poor survival outcomes.
2. Accurate staging is of paramount importance both for identifying patients
with potentially curable disease amenable to resection and for guiding
treatment in patients with locally advanced or metastatic disease.
3. Radiological evaluation usually involves CT staging, with the option of
MRI, PET, EUS, US and cholangiography for further clarification of dis-
ease status.
4. To guide treatment, CCA can be classified into early, locally advanced or
metastatic stages. More detailed staging can also be achieved using the
AJCC/UICC TNM system or other staging methods. Laparoscopic evalu-
ation is capable of detecting sub-radiological disease.
5. Future considerations include the development of biomarkers to enhance
early and specific diagnosis as well as to guide systemic treatment.
Furthermore, improved imaging techniques to allow accurate identifica-
tion of patients who may benefit from potentially curative surgical
intervention.

J. R. Hale (*) · O. O. Faluyi

Clatterbridge Cancer Centre, Wirral, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 187

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_15
188 J. R. Hale and O. O. Faluyi

Areas of Controversy and Uncertainty

1. Due to the scirrhous nature of lesions as well as the histological and
molecular features shared with other malignancies, the pathological diag-
nosis of Cholangiocarcinoma (CCA) can be challenging.
2. Currently there is no universal staging system in use for CCA; the AJCC/
UICC system incorporates information on survival and is the most com-
monly used. Accurate staging is vital to guide treatment.
3. Radiological evaluation of CCA can be a challenge even with the most
modern CT imaging techniques. Radiological distinction between CCA,
HCC and metastases to the liver from non-hepatobiliary sites can be diffi-
cult; this often requires complex evaluation of arterial uptake of index
lesions and the assessment of surrounding tissue as well as further imaging
techniques such as MRI or possibly PET.
4. Meaningful improvement in outcomes for patients with CCA necessitates
systematic evaluation, often requiring a multimodal approach to patient
workup.

Introduction

Cholangiocarcinoma (CCA) is the broad term for malignancies originating from

biliary epithelial cells. CCA is the most common malignancy of the biliary tract.
CCA can be classified based on anatomical location into intrahepatic (iCCA),
perihilar (pCCA, Klatskin tumours), distal (dCCA, extrahepatic tumours) and gall
bladder cancer. iCCA is located proximal to the second-degree bile ducts, pCCA
is defined as tumour in the area between the second-degree bile ducts and the
insertion of the cystic duct into the common bile duct, while dCCA is defined as
tumour in the area between the insertion of the cystic duct to the bile duct and the
ampulla of Vater [1].
The majority of CCAs occur in the perihilar region (60–70%) with the remainder
occurring in the distal common bile duct (20–30%) or within the liver (5–15%) [2].
pCCA which accounts for the majority of tumours can be classified using the
Bismuth-Corlette classification (Table 15.1; [3]).

Table 15.1 Bismuth–Corlette classification of Perihilar (Klatskin) tumours (adapted from

Bismuth and Corlette [3])
Type Description
Type I Limited to the common hepatic duct, below the level of the confluence of the right
and left hepatic ducts
Type II Tumour extends into the bifurcation but not into intraphepatic bile ducts
Type IIIa Tumour occlusion of the common hepatic duct and the right hepatic duct
Type IIIb Tumour occlusion of the common hepatic duct and left hepatic duct
Type IV Tumour involving the confluence and both right and left hepatic ducts
15 Diagnosis and Staging of Cholangiocarcinoma 189

Diagnosis

Clinical Presentation

The clinical presentation of CCA can be fairly unspecific. Extrahepatic tumours usu-
ally present with painless jaundice, steatorrhoea, dark urine and pruritus related to
biliary obstruction. Conversely, iCCA can present with pain, most commonly local-
ised to the right upper quadrant of the abdomen. Other clinical features include
fatigue, weight loss and fever. Differential diagnosis is wide, including hepatocellular
carcinoma (HCC), pancreatic carcinoma, cholangitis, cholelithiasis, parasitic infesta-
tions or metastases to the liver from non-hepatobiliary (non-HB) malignancies. While
the definitive diagnosis of cholangiocarcinoma is histological, various less invasive
tests are useful for the exclusion of differential diagnosis and staging of the disease.

Radiological Imaging Investigations

Ultrasonography (US)

Abdominal ultrasonography, although cheap, non-invasive and often the first line of
investigation, is of limited value in the diagnosis of CCA. Large intrahepatic mass
lesions may be identified on US. However, smaller intrahepatic, p­ erihilar and gall
bladder lesions can be more difficult to visualise. The s­ ensitivity of US in detecting
pCCA ductal masses or thickening is operator-dependent and reported to range
from 87 to 96% [4]. Irregular thickening of the duct wall and polypoid intraluminal
masses can also be seen in some cases of iCCA [5]. Despite its limitations, contrast-­
enhanced US can be utilised in the radiological exclusion of HCC for patients
unable to tolerate contrast-enhanced CT or MRI [6].

Endoscopic Ultrasound (EUS)

EUS allows clear visualisation of the distal biliary tree, gall bladder, local blood
supply and regional lymph nodes. This modality can be utilised to facilitate fine
needle aspiration of suspicious areas, allowing differentiation between malignant
and benign lesions. However, the sensitivity and specificity of EUS are variable-
and user-dependent. Meta-analysis has found a sensitivity of between 59 and 80%
for EUS-FNA in the diagnosis of CCA [7].

Computerised Axial Tomography (CT)

Triple-phase contrast-enhanced hepatobiliary CT is the routine initial test for

assessment of HB tumours in many centres. Furthermore, thoraco-abdominal CT
is a particularly useful tool in the perioperative evaluation and staging of early HB
190 J. R. Hale and O. O. Faluyi

tumours (including CCA). Besides visualising masses and showing biliary duct
stricturing or dilatation, CT allows clear delineation of macrovascular invasion
which is imperative for estimating operative feasibility. In these respects, meta-
analysis has suggested that CT has a sensitivity of over 80% and specificity of
over 90% for staging CCA [8]. However, its sensitivity is lower for smaller lesions
(<3 cm), excluding distant metastases (63%) and identifying regional lymph node
metastases (54%) [9, 10].
As regards diagnosis, even with triple-phase (arterial, portal venous and delayed/
washout phase) imaging on the most modern CT scanners, the radiological distinction
between CCA, HCC and metastases to the liver from non-HB sites can be challenging.
The best validated criteria are for distinguishing HCC where in a cirrhotic liver, HCC
appears hypervascular compared with liver parenchyma on the hepatic arterial phase of
scans. This hypervascularity diminishes during the washout phase. According to the
American Association for the Study of Liver Diseases (AASLD) [11] and the European
Association for the Study of the Liver (EASL) [12], in a cirrhotic liver, demonstration of
intense arterial uptake followed by washout is diagnostic of HCC. However, these crite-
ria are not diagnostic of HCC in non-cirrhotic livers. In comparison, CCA (more com-
mon in non-cirrhotic livers) appears as a hypo-dense lesion with rim enhancement, often
accompanied by biliary duct dilatation and contrast enhancement on delayed images,
similar to non-HB metastases. A previous study reported that iCCA in patients with cir-
rhosis had varied enhancement patterns on triple-phase contrast CT [13]. Additionally,
the study suggested that even though most iCCA did not display the same radiological
characteristics as HCC, the rate of misdiagnosis of iCCA for HCC was significant [13].
Consequently, histological confirmation of CT findings would be recommended when
feasible. Nevertheless, typical radiological features of CCA and its common differential
diagnoses are outlined in Table 15.2.

Table 15.2 Summary of histological and molecular markers of the most common primary and
secondary hepatobiliary malignancies
Cholangiocarcinoma Hepatocellular Metastatic
Malignancy (CCA) carcinoma (HCC) adenocarcinoma
Expressed Common: CK7, CK19, Common: Hep Par1, Common:
MOC31, Claudin 4, albumin (by in-situ Gastro-oesophaeal and
Ber-Ep4, mCEA, hybridization), AFP, pancreatic: similar to
pCEA (non- pCEA (canalicular), GPC3 CCA
canalicular), Mucin Rare: CK7, CK19, Lower GI: CK19, CK20,
(Extra-hepatic): CK20 MOC31, claudin 4, Ber-Ep4, pCEA
Rare: GPC3 Ber-Ep4, mucin (non-canalicular)
Radiology Hypo-dense hepatic In a cirrhotic liver, lesion Hypo-dense hepatic lesion
lesion with rim with arterial phase with rim enhancement on
enhancement on portal enhancement and portal venous or washout
venous or washout washout in portal venous phase (primary tumour
phase or washout phase may be evident)
Serological Ca19-9, CEA AFP Multiple markers
marker including AFP, Ca19-9
and CEA
Not expressed Hep Par1, AFP mCEA Hep Par1, AFP
15 Diagnosis and Staging of Cholangiocarcinoma 191

Magnetic Resonance Imaging (MRI)

Triple-phase gadolinium-enhanced images of the liver can also be obtained during MRI
evaluation. Better separation of the MRI phases can be achieved compared with CT,
allowing hypervascular lesions and washout to be identified more clearly for radiologi-
cal exclusion of HCC. During the arterial phase of gadolinium-­enhanced MRI, iCCAs
tend to appear hypointense compared with liver tissue on T1-weighted images. However,
iCCAs tend to look hyperintense on T2-weighted images, due to fibrosis and the pres-
ence of mucin within tumours [14]. Given that the distinction between smaller iCCA
and HCC on CT scans of cirrhotic livers remains a challenge [15], lesion intensity on
T1-and T2-weighted MRI may help to further clarify the nature of such liver masses. In
a study of the accuracy of MRI distinction between HCC and CCA (for lesions > 2 cm),
MRI had a sensitivity of 85% and specificity of 89.7% [16]. However, MRI is less accu-
rate for the differential diagnoses of smaller lesions or metastases from non-hepatobili-
ary primary sites. Furthermore, in livers with chronic biliary stricturing conditions such
as primary sclerosing cholangitis, the specificity of typical MRI appearances for CCA
can be as low as 37% [17]. As regards CCA staging, trials comparing the accuracy of
contrast-­enhanced CT with MRI (including MRCP) are yet to be conducted. However,
from small studies, their overall accuracy is considered broadly equivalent [18].
Nevertheless, MRI may provide more detail on hepatic architecture and smaller iCCA
particularly when radical surgery is feasible.

Positron Emission Tomography (PET)

For lesions which remain indeterminate for malignancy after CT and MRI evalua-
tion, PET may be useful, providing metabolic rather than anatomical information on
tumours. The main limitations of PET imaging include poor resolution and ana-
tomical localisation. The development of PET-CT fusion images has been of help in
overcoming this issue to some degree. Studies evaluating the accuracy of PET-CT
in staging CCA are fairly limited. However, they seem to suggest its utility for
exclusion of distant metastatic disease. One small study found that only 25% of
distant metastases detected on PET were evident on contrast-enhanced CT scan
[19]. Another study has reported a sensitivity of 95% for detection of distant metas-
tases by PET compared with 63% for CT [9]. Nevertheless, PET is less reliable for
the detection of lymph node and peritoneal metastases. While PET may be a poten-
tial tool for preventing unnecessary radical surgery for cholangiocarcinoma, ade-
quately powered studies are required to validate its role.

Cholangiography

Magnetic resonance cholangiopancreatography (MRCP) is the most accurate non-­

invasive means of imaging of the entire biliary tree and is as sensitive as ERCP for
detecting extrahepatic CCA [20]. This could be of value when selective bile duct
dilatation is crucial to the differential diagnosis of periampullary lesions. Invasive
192 J. R. Hale and O. O. Faluyi

cholangiography permits direct visualisation of the biliary tree utilising various tech-
niques such as endoscopic retrograde cholangiopancreatography (ERCP), single-­
operator peroral cholangiopancreatography (SpyGlass endoscopy) or percutaneous
transhepatic cholangiography (PTC). ERCP is useful in the diagnosis of pCCA and
dCCA as well as obtaining brush samples of epithelium for cytological analysis.
Specificity of cytology is high (60–100%); however, sensitivity is low (9–24%) [21].
In addition, ERCP and PTC both facilitate therapeutic stent deployment to relieve
biliary obstruction. SpyGlass endoscopy is utilised as an option to overcome some of
the limitations of standard ERCP. It provides a useful alternative technique of stent
deployment and obtains a tissue diagnosis when ERCP is unsuccessful [22]. However,
diagnostic radiological imaging is recommended to be obtained prior to any inter-
vention, to prevent anatomical distortion precluding interpretation of imaging.

Laboratory Investigations

Serology
Liver Function Tests

Common biochemical abnormalities associated with CCA typically reflect biliary

obstruction which include raised levels of bilirubin, alkaline phosphatase and
gamma-glutamyltransferase. In more advanced cases, aspartate aminotransferase
and alanine aminotransferase can also become deranged, along with impaired clot-
ting and falling albumin levels indicative of failing synthetic liver function. However,
these are non-specific for a cholangiocarcinoma diagnosis.

Tumour Markers

The value of tumour markers in the diagnosis of CCA is limited. Carbohydrate anti-
gen (CA) 19-9 remains one of the best studied markers. Carcinoembryonic antigen
(CEA) is another well-studied marker. Both markers are, however, rather non-­
specific and can be raised in a multitude of inflammatory conditions such as cholan-
gitis and with other malignancies. On the other hand, patients who are Lewis antigen
negative will not be able to produce CA 19-9. Thus the sensitivity and specificity of
currently studied tumour markers are low for a cholangiocarcinoma diagnosis.

Histopathology

CCA is thought to develop through a series of stages from early biliary glandu-
lar hyperplasia, through metaplasia, to dysplasia and finally carcinoma. CCAs
are adenocarcinomas comprising tubules, acini, solid nests or trabeculae,
15 Diagnosis and Staging of Cholangiocarcinoma 193

embedded in desmoplastic stroma [23]. As they can be surrounded by extensive

fibrosis, it is often difficult to distinguish cholangiocarcinoma from chronically
inflamed tissue morphologically. iCCA is usually found in non-cirrhotic livers.
However, in the setting of an intrahepatic lesion on a background of cirrhosis,
differentiation of CCA from HCC morphologically is sometimes problematic.
Morphologically, iCCA can be classified into mass-forming, periductal-infil-
trating, intraductal, superficial spreading and undefined subtypes [24].
Furthermore, pCCAs can be classified into exophytic mass-forming and intra-
ductal subtypes. Periductal and mass-forming types harbour the poorest
prognosis.
CCAs can range from being undifferentiated to well-differentiated. Papillary
adenocarcinoma is by far the commonest variant. Subtypes of CCA other than pap-
illary adenocarcinoma account for <10% of tumours and include mucinous, adeno-
squamous, squamous cell, signet-ring cell, mucoepidermoid, glycogen-rich
clear-cell and spindle cell or undifferentiated carcinomas. Adenosquamous and
spindle cell carcinomas are thought to have a worse prognosis than adenocarcinoma
[23]. The difference between poorly differentiated CCA, HCC with a pseudoglan-
dular pattern of differentiation and metastases to the liver from non-HB sites can be
challenging. Immunohistochemical and molecular markers which could be of assis-
tance in this respect are shown in Table 15.2.

Staging

The staging of CCA guides management and helps with prognostication. The com-
plexities of staging this tumour group are well documented due to the variation in
anatomical location of the tumour as well as the limited sensitivity of even the most
modern imaging modalities. To guide treatment, CCA can be simply classified into
early, locally advanced (LA) or metastatic stages. Early CCA is potentially resect-
able, dependent upon patient suitability. LA CCA is deemed surgically unresectable
due to macrovascular or lymph node involvement. However, there is ongoing inter-
est in the role of locoregional ablative treatment approaches and the potential for
conversion to resectable disease (particularly when LA by virtue of macrovascular
invasion). Finally, metastatic CCA occurs with spread to adjacent or more distant
organs, only amenable to palliative systemic treatment.
While no staging system has been universally adopted, at least three well-known
comprehensive staging systems are currently available which incorporate prognos-
tic factors to expand on the basic classification. Variations exist in each of these
staging systems according to the anatomical location of tumour. These include the
American Joint Committee on Cancer/Union for International Cancer Control
(AJCC/UICC), the Liver Cancer Study Group of Japan (LCSGJ) and the National
Comprehensive Cancer Network (NCCN) staging systems. The AJCC/UICC is the
only system which has shown correlation between stage and survival, is the most
often used and will be discussed in more detail. This staging system underwent
194 J. R. Hale and O. O. Faluyi

recent revision with an 8th edition projected to come into effect globally in January
2018 [25].

Radiological Staging

Intrahepatic CCA

For iCCA, T classification (AJCC/UICC staging) is dependent upon the number of

lesions present, the presence of macrovascular invasion and invasion of adjacent
structures. Tumour size has been controversial as a prognostic factor; however, size
has been shown to correlate with tumour grade which could confound such analysis
[26]. The AJCC/UICC system for intrahepatic CCA (8th edition; [27]):
T Stage
T1a: solitary tumour, <5 cm without macrovascular involvement
T1b: solitary tumour >5 cm, also without macrovascular involvement
T2: solitary tumour with intrahepatic macrovascular invasion or multiple tumours,
with or without macrovascular invasion
T3: tumours perforating visceral peritoneum
T4: tumours directly invading local extrahepatic structures
N Stage
N0: refers to no regional lymph node involvement
N1: refers to regional lymph node involvement
M Stage
M0: refers to no distant metastases or nodal involvement
M1: refers to distant metastatic spread or distant nodal involvement
The 8th edition (AJCC system) has been shown to be better able to stratify
the risk of death for stage III and T3 patients [28]. A further study claimed the
8th edition provided more discrete stratification of patient prognostic groups in
general [29].

Perihilar CCA

For pCCA, the presence of lymph node metastases, differentiation, macrovascular

invasion, perineural invasion and surgical resection margins has been shown to be
of prognostic relevance [30, 31]. The Bismuth-Corlette system (Table 15.1) is not
a staging system but can help guide surgical management. The two main staging
systems in common use include AJCC/UICC and the Memorial Sloan Kettering
Cancer Centre (MSKCC) staging system. The AJCC/UICC system for pCCA (8th
Edition):
15 Diagnosis and Staging of Cholangiocarcinoma 195

T Stage
T1: tumour confined to the bile duct, with extension up to the muscle layer or fibrous
tissue
T2: tumours which invade beyond the wall of the bile duct to surrounding adipose
tissue or adjacent hepatic parenchyma
T3: tumours which invade unilateral branches of the portal vein or hepatic artery
T4: tumours which invade the main portal vein or its branches bilaterally, the com-
mon hepatic artery, the unilateral second-order biliary radicals with contralateral
portal vein or hepatic artery involvement
N Stage
N0: refers to no lymph node involvement
N1: refers to involvement of one to three lymph nodes within the hilar, cystic duct,
common bile duct, hepatic artery, posterior pancreatoduodenal and/or portal vein
lymph node groups
N2: refers to involvement of four or more lymph nodes from the sites mentioned for
N1 (above)
M Stage
M0: refers to no distant metastases or nodal involvement
M1: refers to distant metastases or distant nodal involvement

Distal CCA

For distal CCA, factors such as depth of invasion, the presence of lymph node
metastases, microscopic vascular invasion, direct invasion into the pancreas/adja-
cent structures, resection margins and perineural invasion have been suggested to be
independent prognostic factors [31, 32]. The AJCC/UICC 8th edition is currently
the only accepted staging system for distal CCA [33].
T Stage
T1: tumours invading the bile duct wall with a depth less than 5 mm
T2: tumours invadeing the bile duct wall with a depth of 5–12 mm
T3: tumours invadeing the bile duct wall with a depth greater than 12 mm
T4: tumours are classed as involving the celiac axis, superior mesenteric artery and/
or common hepatic artery
N Stage
N1: disease encompasses metastasis in one to three regional lymph nodes
N2: disease is classed as four or more regional lymph nodes involved
M Stage
M0: refers to no distant metastases or nodal involvement
M1: distant metastasis or distant nodal involvement
196 J. R. Hale and O. O. Faluyi

Laparoscopy and Surgical Staging

Laparoscopy has been shown to be able to detect sub-radiological intra-abdominal

metastases by facilitating closer evaluation of the liver surface, which may allow
detection of occult hepatic metastases. Staging laparoscopy can also detect occult
peritoneal metastases. A previous study [34] found that in patients with CCA that
initially appeared resectable after combined imaging modalities, staging laparos-
copy detected peritoneal and liver metastasis in one third of patients (accuracy was
found to be 92% and 71%, respectively). It could not however detect lymph node or
vascular involvement which was only observed during laparotomy [34]. Consequently
preoperative laparoscopy has been said to prevent unnecessary laparotomy in up to
30% of patients. Expert consensus recommends preoperative laparoscopy in patient
with high-risk localised CCA, such as defined by T stage and Ca 19-9 levels in
secretors [35]. Nevertheless, a previous study suggested that the presence of metas-
tases on laparoscopy was not contingent with radiological staging [36].
Furthermore, laparoscopy allows biopsy of lesions which appear indeterminate
on imaging, providing histological confirmation in case of uncertainty. The addition
of laparoscopic ultrasound also aids the diagnosis of hepatic metastases and should
be combined with staging laparoscopy to determine local stage and rule out meta-
static disease [37]. Nevertheless, surgical resectability cannot be guaranteed with-
out complete abdominal exploration at the time of surgery.

Future Considerations

With respect to the diagnosis of cholangiocarcinoma, further research into potential

biomarkers to enhance early diagnosis with a high degree of sensitivity and specific-
ity is ongoing [38]. Furthermore, improved resolution of imaging is crucial for accu-
rate selection of cases which are potentially curable by surgery. Techniques such as
PET-CT and PET-MR and the use of cholangiocyte-specific contrast media are cur-
rently undergoing evaluation [39]. Finally, in this era of genomic and precision medi-
cine, molecular biomarkers to distinguish liver metastatic upper gastrointestinal
malignancies from CCA and to identify clinically relevant subsets of cholangiocarci-
noma may be crucial to optimising the benefit from systemic therapy for cancer [40].

References

1. Razumilava N, Gores GJ. Combination of gemcitabine and cisplatin for biliary tract cancer: a
platform to build on. J Hepatol. 2011;54:577–8.
2. Ahrendt SA, Pitt HA. Biliary tract. In: Townsend C, editor. Sabiston textbook of surgery.
Philadelphia: W.B. Saunders Company; 2001. p. 1076–111.
3. Bismuth H, Corlette MB. Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus
of the liver. Surg Gynecol Obstet. 1975;140:170–8.
15 Diagnosis and Staging of Cholangiocarcinoma 197

4. Hann LE, Greatrex KV, Bach AM, et al. Cholangiocarcinoma at the hepatic hilus: sonographic
findings. AJR Am J Roentgenol. 1997;168(4):985–9.
5. Van Beers BE. Diagnosis of cholangiocarcinoma. HPB (Oxford). 2008;10(2):87–93.
6. Giorgio A, Montesarchio L, Gatti P, et al. Contrast-enhanced ultrasound: a simple and effec-
tive tool in defining a rapid diagnostic work-up for small nodules detected in cirrhotic patients
during surveillance. J Gastrointestin Liver Dis. 2016;25(2):205–11.
7. Navaneethan U, Njei B, Venkatesh PG, Lourdusamy V, Sanaka MR. Endoscopic ultrasound in
the diagnosis of cholangiocarcinoma as the etiology of biliary strictures: a systematic review
and meta-analysis. Gastroenterol Rep (Oxf). 2015;3(3):209–15.
8. Ruys AT, van Beem BE, Engelbrecht MR, et al. Radiological staging in patients with hilar chol-
angiocarcinoma: a systematic review and meta-analysis. Br J Radiol. 2012;85(1017):1255–62.
9. Lee SW, Kim HJ, Park JH, et al. Clinical usefulness of 18F-FDG PET-CT for patients with
gallbladder cancer and cholangiocarcinoma. J Gastroenterol. 2010;45(5):560–6.
10. Lee HY, Kim SH, Lee JM, et al. Preoperative assessment of resectability of hepatic hilar
cholangiocarcinoma: combined CT and cholangiography with revised criteria. Radiology.
2006;239(1):113–21.
11. Tan CH, Low SC, Thng CH. APASL and AASLD consensus guidelines on imaging diagnosis
of hepatocellular carcinoma: a review. Int J Hepatol. 2011;2011:519783.
12. Pugacheva O, Matsui O, Kozaka K, et al. Detection of small hypervascular hepatocellular
carcinomas by EASL criteria: comparison with double-phase CT during hepatic arteriography.
Eur J Radiol. 2011;80(3):e201–6.
13. Li R, Cai P, Ma KS, et al. Dynamic enhancement patterns of intrahepatic cholangiocarcinoma
in cirrhosis on contrast-enhanced computed tomography: risk of misdiagnosis as hepatocel-
lular carcinoma. Sci Rep. 2016;6:26772. https://doi.org/10.1038/srep26772.
14. Vilgrain V, Van Beers BE, Flejou JF, et al. Intrahepatic cholangiocarcinoma: MRI and patho-
logic correlation in 14 patients. Comput Assist Tomogr. 1997;21(1):59–65.
15. Huang B, Wu L, Lu XY, et al. Small intrahepatic cholangiocarcinoma and hepatocellular car-
cinoma in cirrhotic livers may share similar enhancement patterns at multiphase dynamic MR
imaging. Radiology. 2016;281(1):150–7.
16. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrho-
sis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.
Hepatology. 2008;47(1):97–104.
17. Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD. Utility of serum tumor markers,
imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholan-
gitis. Hepatology. 2008;48(4):1106–17.
18. Ryoo I, Lee JM, Park HS, Han JK, Choi BI. Preoperative assessment of longitudinal extent of
bile duct cancers using MDCT with multiplanar reconstruction and minimum intensity projec-
tions: comparison with MR cholangiography. Eur J Radiol. 2012;81(9):2020–6.
19. Petrowsky H, Wildbrett P, Husarik DB, et al. Impact of integrated positron emission tomogra-
phy and computed tomography on staging and management of gallbladder cancer and cholan-
giocarcinoma. J Hepatol. 2006;45:43–50.
20. Park MS, Kim TK, Kim KW, et al. Differentiation of extrahepatic bile duct cholangiocar-
cinoma from benign stricture: findings at MRCP versus ERCP. Radiology. 2004;233(1):
234–40.
21. Harewood GC, Baron TH, Stadheim LM, Kipp BR, Sebo TJ, Salomao DR. Prospective,
blinded assessment of factors influencing the accuracy of biliary cytology interpretation. Am J
Gastroenterol. 2004;99:1464–9.
22. Navaneethan U, Hasan MK, Lourdusamy V, Njei B, Varadarajulu S, Hawes RH. Single-­
operator cholangioscopy and targeted biopsies in the diagnosis of indeterminate biliary stric-
tures: a systematic review. Gastrointest Endosc. 2015;82(4):608–14.
23. Esposito I. Schirmacher pathological aspects of cholangiocarcinoma. HPB (Oxford).
2008;10(2):83–6.
24. Nakanuma Y, Sato Y, Harada K, Sasaki M, Xu J, Ikeda H. Pathological classification of intra-
hepatic cholangiocarcinoma based on a new concept. World J Hepatol. 2010;2:419–27.
198 J. R. Hale and O. O. Faluyi

25. Blechacz B. Cholangiocarcinoma: current knowledge and new developments. Gut Liver.
2017;11(1):13–26.
26. Spolverato G, Ejaz A, Kim Y, Sotiropoulos GC, Pau A, Alexandrescu S, et al. Tumor size
predicts vascular invasion and histologic grade among patients undergoing resection of intra-
hepatic cholangiocarcinoma. J Gastrointest Surg. 2014;18:1284–91.
27. Nagorney DM, Pawlik TM, Chun YS, et al. Perihilar bile ducts. In: Amin MB, editor. AJCC
cancer staging manual. 8th ed. Chicago: AJCC; 2017. p. 311.
28. Spolverato G, Bagante F, Weiss M, et al. Comparative performances of the 7th and the 8th
editions of the American Joint Committee on Cancer staging systems for intrahepatic cholan-
giocarcinoma. J Surg Oncol. 2017; https://doi.org/10.1002/jso.24569. [Epub ahead of print].
29. Aloia T, Pawlik TM, Taouli B, et al. Intrahepatic bile ducts. In: Amin MB, editor. AJCC cancer
staging manual. 8th ed. Chicago: AJCC; 2017. p. 295.
30. Ercolani G, Zanello M, Grazi GL, et al. Changes in the surgical approach to hilar cholangio-
carcinoma during an 18-year period in a Western single center. J Hepatobiliary Pancreat Sci.
2010;17(3):329–37.
31. Ghouri YA, Mian I, Boris Blechacz B. Cancer review: cholangiocarcinoma. J Carcinog.
2015;14:1. Published online 23 Feb 2015. https://doi.org/10.4103/1477-3163.151940.
32. Hong SM, Pawlik TM, Cho H, et al. Depth of tumor invasion better predicts prognosis than the
current American Joint Committee on Cancer T classification for distal bile duct carcinoma.
Surgery. 2009;146(2):250–7.
33. Krasinskas A, Pawlik TM, Mino-Kenudson M, Vauthey J-N. Distal bile duct. In: Amin MB,
editor. AJCC cancer staging manual. 8th ed. Chicago: AJCC; 2017. p. 317.
34. Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging laparoscopy in subsets of biliary
cancers: laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder
carcinoma. Surg Endosc. 2006;20(5):721–5.
35. Weber SM, Ribero D, O'Reilly EM, Kokudo N, Miyazaki M, Pawlik TM. Intrahepatic cholan-
giocarcinoma: expert consensus statement. HPB (Oxford). 2015;17(8):669–80.
36. Bird N, Elmasry M, Jones R, et al. Role of staging laparoscopy in the stratification of patients
with perihilar cholangiocarcinoma. Br J Surg. 2017;104(4):418–25.
37. Joseph S, Connor S, Garden OJ. Staging laparoscopy for cholangiocarcinoma. HPB (Oxford).
2008;10(2):116–9.
38. Macias RIR, Banales JM, Sangro B, et al. The search for novel diagnostic and prognostic
biomarkers in cholangiocarcinoma. Biochim Biophys Acta. 2018;1864(4 Pt B):1468–77. pii:
S0925-4439(17):30275-2.
39. Kirchner J, Sawicki LM, Deuschl C, et al. 18 F-FDG PET/MR imaging in patients with sus-
pected liver lesions: value of liver-specific contrast agent Gadobenate dimeglumine. PLoS
One. 2017;12(7):e0180349.
40. Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis of intrahepatic
cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology.
2013;144(4):829–40.
Chapter 16
Cholangiocarcinoma: From Mechanisms
to Management

Leonard M. Quinn, Nicholas Bird, Robert Jones, David Vass,

and Hassan Malik

Key Learning Points

1. Symptomatically silent in the early stages, cholangiocarcinoma manifests
a very poor prognosis with many patients having advanced disease at
presentation.
2. None of the staging systems accurately predict survival. The most impor-
tant staging and predictive issue is surgical resectability which represents
the only treatment with curative intent.
3. Survival following resection is largely dependent on tumour-negative mar-
gin status, the absence of vascular invasion and lymph node metastasis and
adequate functional liver remnant.
4. The UK BILCAP Phase III trial found improved median survival with
adjuvant capecitabine following successful resection compared to obser-
vation alone.
5. Preoperative (neoadjuvant) chemotherapy and orthotopic liver transplanta-
tion are not standard treatment protocol at the current time.

L. M. Quinn · N. Bird · D. Vass

Hepatobiliary Surgery, Digestive Diseases Unit, Aintree University Hospital, Liverpool, UK
e-mail: [email protected]
R. Jones · H. Malik (*)
Department of Liver Surgery, Aintree University Hospital NHS Foundation Trust,
Liverpool, UK
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2019 199

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_16
200 L. M. Quinn et al.

Areas of Controversy and Uncertainty

1. Disease staging and prediction of surgical resectability.
2. Preoperative biliary drainage and staging laparoscopy.
3. Neoadjuvant chemotherapy.
4. Neoadjuvant radiotherapy.
5. Adjuvant chemotherapy.
6. Orthotopic liver transplantation.

Introduction

In this chapter we explore the following areas pertaining to cholangiocarcinoma

(CCA):
• Anatomy, tumour classification and staging
• Epidemiology and risk factors
• Molecular spectrum of disease
• Clinical presentation
• Approach to investigation and staging
• Treatment for localized cholangiocarcinoma
• Treatment for advanced disease
• Future research perspectives
• References

Anatomy

Intrahepatic cholangiocarcinoma (iCCA) originates in the small peripheral intrahe-

patic bile ducts or the large intrahepatic ducts proximal to the bifurcation of the left
and right hepatic ducts.
In extrahepatic cholangiocarcinoma, the disease may arise in the large bile ducts
of the perihilar region (pCCA), including the confluence itself, proximal to the inser-
tion of the cystic duct into the common bile duct (CBD) or distal to the insertion of
the cystic duct into the CBD down to but not including the ampulla of Vater (dCCA).
Tumours involving the common hepatic duct bifurcation are termed hilar cholan-
giocarcinoma or Klatskin tumours. These two terms do not account for whether or
not the tumour originated from the intrahepatic or extrahepatic components [1].
In Western populations pCCA comprises 50%, dCCA 40% and iCCA 10% of
cases, respectively [2].
Perihilar disease is subdivided according to the Bismuth-Corlette classification.
Tumours located below the confluence of the left and right hepatic ducts are classi-
fied as Type I. Tumours reaching the confluence are Type II. Those tumours occlud-
ing the common hepatic duct and either the right or left hepatic duct are termed
Type IIIa and IIIb, respectively. Multicentric tumours are Type IV [3].
16 Cholangiocarcinoma: From Mechanisms to Management 201

Staging of Disease

A number of staging systems are used to stage cholangiocarcinoma. The most com-
monly used is the Union for International Cancer Control/American Joint Committee
on Cancer (UICC/AJCC) 2010 revision of the tumour, node and Metatasis (TNM)
classification that separates cholangiocarcinoma into intrahepatic, hilar and distal
disease, respectively [4]. A full description of TNM staging follows.
None of the staging systems accurately predict survival. The most important
staging and predictive issue is surgical resectability. The AJCC system is based on
pathological outcome following resection—this is therefore of use only for prog-
nostication and not for predicting resectability.
Clinical staging systems for pCCA include the Bismuth-Corlette and Memorial
Sloan Kettering Cancer Centre (MSKCC) systems.
The Bismuth-Corlette system (described previously) classifies patients on the
extent of biliary involvement but does not incorporate important features such as
vascular involvement or lobar atrophy. As such it cannot be used for predicting
resectability.
MSKCC staging for pCCA, first proposed in 1998, builds on Bismuth-Corlette
and includes longitudinal and radial extension of the tumour to more accurately
predict resectability. Specifically the T staging compromises local tumour involve-
ment, portal vein involvement and hepatic lobar atrophy (Table 16.3). This staging
system has been externally validated and accurately predicted resectability, proba-
bility of metastatic disease and long-term survival in the preoperative setting [5].

iCCA Tumour Classification (Table 16.1)

• Tis—Carcinoma in situ
• T1—Solitary tumour without vascular invasion
• T2a—Solitary tumour with vascular invasion
• T2b—Multiple tumours with or without vascular invasion
• T3—Tumour perforating visceral peritoneum or involving local extrahepatic
structures through direct invasion
• T4—Tumour with periductal invasion (longitudinal)

Table 16.1 UICC/AJCC TNM classification of intrahepatic cholangiocarcinoma

Stage T N M
0 Tis N0 M0
I T1 N0 M0
II T2 N0 M0
III T3 N0 M0
IVa T4 N0 M0
Any T N1 M0
IVb Any T Any N M1
202 L. M. Quinn et al.

pCCA Tumour Classification (Table 16.2)

• Tis—Tumour in situ
• T1—Tumour confined to bile duct with extension to muscle or fibrous tissue
• T2a—Tumour invading beyond bile duct to surrounding adipose tissue
• T2b—Tumour invading adjacent hepatic parenchyma
• T3—Tumour invading unilateral branches of portal vein or hepatic artery
• T4—Tumour invading main portal vein or its branches bilaterally, the common
hepatic artery and second biliary radicals bilaterally, or second-order biliary
radicals unilaterally with contralateral portal vein or hepatic artery involvement

MSKCC T Staging Classification (Table 16.3)

dCCA Tumour Classification (Table 16.4)

• Tis—Tumour in situ
• T1—Tumour confined to bile duct
• T2—Tumour invades beyond wall of bile duct
• T3—Tumour invades adjacent structures but without involvement of superior
mesenteric artery or coeliac axis
• T4—Tumour involves the coeliac axis or superior mesenteric artery.

Table 16.2 UICC/AJCC TNM classification of peri-hilar cholangiocarcinoma

Stage T N M
0 Tis N0 M0
I T1 N0 M0
II T2a-b N0 M0
IIIa T3 N0 M0
IIIb T1–3 N1 M0
IVa T4 N0–1 M0
IVb Any T N1 M0
Any T Any N M1

Table 16.3 MSKCC T Staging classification

T-stage Description
T1 Tumour involving biliary confluence ± unilateral extension to 2nd-order biliary radicles
T2 Tumour involving biliary confluence ± unilateral extension to 2nd-order biliary radicles
and ipsilateral portal vein involvement ± ipsilateral hepatic lobar atrophy
T3 Tumour involving biliary confluence and bilateral extension to 2nd-order biliary
radicles or unilateral extension to 2nd-order biliary radicles with contralateral portal
vein involvement, or unilateral extension to 2nd-order biliary radicles with contralateral
hepatic lobar atrophy or main or bilateral portal venous involvement
16 Cholangiocarcinoma: From Mechanisms to Management 203

Table 16.4 UICC/AJCC TNM classification of distal cholangiocarcinoma

Stage Tumour Nodes Metastasis
0 Tis N0 M0
Ia T1 N0 M0
Ib T2 N0 M0
IIa T3 N0 M0
IIb T1 N1 M0
T2 N1 M0
T3 N1 M0
III T4 Any N M0
IV Any T Any N M1

Regional Lymph Nodes

• N0—No regional lymph node metastasis

• N1—Regional lymph node metastasis present

Distant Metastasis

• M0—No evidence of distant metastasis

• M1—Distant metastasis present

Histologic Grading

• G1—Well differentiated
• G2—Moderately differentiated
• G3—Poorly differentiated
• G4—Undifferentiated

Epidemiology

Cholangiocarcinoma is a rare malignancy accounting for 3% of gastrointestinal

cancers with an incidence of 1–2 per 100,000 population [6].
The incidence of iCCA is rising globally, whilst extra-hepatic is decreas-
ing. This may be related to increases in cirrhosis, alcoholic liver disease and
hepatitis C [7].
Cholangiocarcinoma occurs more frequently in males and increases with
age [8].
204 L. M. Quinn et al.

Risk Factors

There are well-recognized risk factors. However, in the vast majority of patients, no
one specific risk factor is identified [9].
Risk factors in Western cohorts include primary sclerosing cholangitis [10], con-
genital fibropolycystic liver disease, e.g. choledochal cysts [11]; chronic intrahe-
patic ductal stones [12], and hepatitis C infection [13].
Asian cohorts demonstrate strong associations with parasitic liver fluke infection
(genera Clonorchis and Opisthorcis) [14].

Mechanisms of Disease

The molecular understanding of CCA is far less understood and described com-
pared to other gastrointestinal cancers and exhibits marked heterogeneity on the
basis of location. iCCA has been more fully examined at the present time.
Currently, there are no molecular markers for early diagnosis, prognostication or
therapy selection. With the advent of next-generation sequencing and multi-omics
approaches, it is hoped that advances in understanding CCA biology will lead to
biomarker development and personalized medicine.
Diverse candidates for cellular origin include hepatic stem cells, immature neu-
ral cell adhesion molecule-positive cholangiocytes, mature interlobular cholangio-
cytes and peri-biliary glands [15].
CCA expresses cancer stem cells (with capacity for self-renewal) in >30% of
tumour mass [16].
Precursor biliary epithelial lesions harbour mutations in p53 [17].
The most prevalent tumour genetic alterations affect key networks such as DNA
repair (TP53) and tyrosine kinase signalling (KRAS, BRAF, SMAD4, FGFR) and
chromatin remodelling (ARID1A, BAP1) and lead to more aggressive phenotypes.
One third of tumours overexpress TP53 suggesting mutation in this suppressor.
Abnormal K-ras expression is found in 45–54% of iCCA and 10–15% of extrahe-
patic [18].
Fusion gene products involving the kinase receptor FGFR2 gene drive cell pro-
liferation and are well described in iCCA and are suppressed with FGFR kinase
inhibitors [19].
Epigenetic profiles differ. iCCA demonstrates mutated isocitrate dehydrogenase-
­1 (associated with CpG shore hypermethylation) in 25% of cases. It is not present
in extrahepatic [20].
Immunohistochemistry demonstrated epidermal growth factor receptor is over-
expressed. EGFR activation triggers the MAPK-ERK pathway in cholangiocytes
and is targetable [21]. CCAs are oestrogen sensitive with increased expression of
alpha- and beta-oestrogen receptors [22].
CCA arises in biliary inflammation with overexpression of interleukin-6, crucial
in activating MAPK [23]. TGF-B receptors promote invasion and migration [24].
16 Cholangiocarcinoma: From Mechanisms to Management 205

CCA is characterized by a prominent desmoplastic stroma with high densities of

tumour-associated macrophages suggesting a role in CCA progression through the
Wnt pathway. Wnt inhibition in animal CCA models increases apoptosis [25].

Clinical Presentation

Both iCCA and extrahepatic cholangiocarcinomas present late with subtle early
symptoms [26].
iCCA is often detected during surveillance in cirrhosis and hepatitis B and C
infection. Jaundice is unlikely without significant metastatic burden. The symptoms
include:
• Dull right upper quadrant pain
• Weight loss
Extrahepatic cholangiocarcinoma presents when the bile ducts are occluded.
Cholangitis is a rare presentation. The symptoms and signs include:
• Jaundice
• Pale stools
• Dark urine
• Pruritus
• Night sweats/malaise
• Right upper quadrant pain/tenderness/mass.
• Hepatomegaly
• Weight loss

Investigation and Workup

Laboratory Analyses

Extrahepatic CCA reflects biliary obstruction with elevation of bilirubin and alka-
line phosphatase. Transaminases are normal in early stages but may elevate as bili-
ary obstruction progresses. The prothrombin time and international normalized
ratio similarly elevate.
iCCA will demonstrate elevated alkaline phosphatase levels but normal
bilirubin.
The tumour marker CA 19-9 is suggestive of CCA but not specific [27]. CA 19-9
has significant overlap with pancreatic cancer and may also rise in the presence of
biliary obstruction alone [28]. CA 19-9 levels greater than 1000 units/ml are sugges-
tive of advanced disease [29].
CEA is associated with colorectal cancer and liver metastases [30]. AFP suggests
hepatocellular carcinoma [31].
206 L. M. Quinn et al.

Investigation and Staging

Most jaundiced patients will undergo transabdominal ultrasound initially. This con-
firms the presence or absence of ductal dilatation, helps localize site of biliary
obstruction and determines the presence of gallstones [32]. When US cannot con-
firm benign causation, cross-sectional imaging is required.
Multiphase contrast CT can detect intrahepatic tumours, clarify the level of bili-
ary obstruction and assist in differentiating benign and malignant strictures [33].
Ductal dilatation in both liver lobes, with a contracted gall bladder or non-union
of left and right ducts, with or without a thickened wall, suggests perihilar. A dis-
tended gall bladder with both dilated intrahepatic and extrahepatic ducts is typical
of tumours involving CBD, ampulla of Vater or head of the pancreas.
For intra-hepatic lesions in the non-cirrhotic liver, iCCA (hypodense) must be dif-
ferentiated from distant metastasis. In the cirrhotic liver, HCC hyperenhances [34].
CT visualizes lymph node basins but with low sensitivity. Preoperative lymph
node enlargement is not evidence of non-curability [35]. CT has limited sensitivity
for extra-regional metastases, particularly peritoneal [36].
MRI and MRCP provide non-invasive assessment with CCA appearing
hypodense on T1 and heterogeneously hyperintense on T2 imaging [37].
In extra-hepatic, if CT and MRI fail to confirm diagnosis, endoscopic ultrasound
(EUS) or ERCP (endoscopic retrograde cholangiopancreatography) permits direct
visualization and enables biopsy or brush cytology for tissue diagnosis. ERCP
enables therapeutic stenting.
Tissue diagnosis is not absolutely necessary prior to curative or palliative inter-
vention, provided characteristic radiology is present [38].
Positron emission tomography (with fluorodeoxyglucose) scanning offers greater
sensitivity for detection of occult metastases [39].
Where staging radiology is satisfactory, patients proceed to staging laparoscopy.
This identifies many patients with unresectable disease and peritoneal metastases
not found on radiology [40]. Unfortunately, true resectability can often only be
determined at laparotomy [41].
Biliary drainage is indicated in cholangitis or jaundice in conjunction with mal-
nutrition, hepatic/renal insufficiency and portal vein embolization [42]. In the pal-
liative setting, biliary drainage may prolong survival. Self expanding metal stents
offer higher patency duration [43].

Surgical Resection of Localized Cholangiocarcinoma

Complete surgical resection of CCA represents the only treatment with curative
intent.
In iCCA, resection of affected liver segments or of the affected lobe is under-
taken. pCCA resection is dependent on the extent of disease but may mandate
16 Cholangiocarcinoma: From Mechanisms to Management 207

resection of involved intra- and extrahepatic bile ducts, ipsilateral liver, gallbladder
and regional lymph nodes. Pancreatoduodenectomy is performed for dCCA with
pylorus-­preserving procedures preferable.
Unfortunately, a minority of patients have disease considered to be resectable at
time of diagnosis due to local tumour infiltration, peritoneal or distant metastases,
lack of biliary reconstructive options or inadequate future liver remnant. dCCA has
a higher resectability rate than more proximal pCCA and iCCA [26].
Traditional guidance on the resectability of CCA is as follows [44]:
• Absence of retropancreatic and paracoeliac nodal metastases or distant liver
metastases
• Absence of invasion of portal vein and main hepatic artery (some centres do sup-
port en bloc resection with vascular reconstruction)
• Absence of adjacent extrahepatic organ invasion
• Absence of disseminated disease
Resectability is ultimately determined at the time of surgery particularly in
pCCA, as these tumours often extend into the liver and major vascular structures
and accurate preoperative evaluation of these areas is difficult. Therefore, surgical
exploration with or without trial resection is appropriate for potentially resectable
disease [41].
Survival following resection is largely dependent on tumour-negative margin sta-
tus, the absence of vascular invasion and lymph node metastasis and adequate func-
tional liver remnant [45].
The majority of cases still recur despite complete resection. Relapse patterns are
local and distant, forming the basis for adjuvant chemotherapy.
Overall 5-year survival following resection is reported as 22–44% for iCCA,
11–41% for pCCA and 27–37% for dCCA.

Orthotopic Liver Transplantation

Liver transplantation is not considered a standard treatment approach due to issues

surrounding donor allocation and the poor sensitivity of invasive staging for CCA
[46]. Transplantation for iCCA is associated with rapid metastatic formation and
has thus been abandoned [47].
The US Mayo Clinic considers liver transplantation in highly selected cases of
early stage local unresectable perihilar CCA, in patients who have completed
­thorough staging, assessment and neoadjuvant chemoradiotherapy [48]. Vascular
encasement of the hilar vessels is not a contraindication to transplantation. The
upper limit of tumour size is 3 cm and with the absence of intra- or extrahepatic
metastases and excludes iCCA or GB cancer. Prior to resection patients undergo
exploratory laparotomy. Regional lymph node metastases and peritoneal and locally
extensive disease preclude surgery.
208 L. M. Quinn et al.

The published Mayo experience found a statistically significant improved sur-

vival following their transplantation protocol with 92% 1 year, 82% 3 year and 82%
5 year survival. This compared to 82%, 48% and 21%, respectively, following
resection only [49]. The ongoing French Phase III Transphil trial compares this
strategy with standard surgical resection.

Adjuvant Therapy

The role of adjuvant therapy remains ill defined. The European Society for Medical
Oncology and the National Comprehensive Cancer Network suggest chemotherapy
for both margin-negative and margin-positive resected patients [50].
On the basis of improved survival in periampullary cancer in the ESPAC-3 trial,
gemcitabine or flurouracil is considered acceptable adjuvant chemotherapy for
CCA [51].
The U.K. BilCap Phase III trial found improved median survival with
Capecitabine compared to observation which was not statistically significant. This
included large numbers of R1 resections but was deemed clinically relevant. Per
protocol analysis demonstrated a statistically significant survival benefit. The
authors recommend adjuvant capecitabine as standard of care [52].
No prospective clinical trials have identified if benefit is achieved with adjuvant
radiotherapy.

Systemic Therapy for Advanced Disease

In advanced disease, for first-line treatment, the UK ABC-01 and ABC-02 trial
found the gemcitabine in combination with cisplatin was superior to gemcitabine
alone with improved tumour control rate, time to progression and progression free
survival [53]. If cisplatin is not well tolerated, oxaliplatin is an excellent alterna-
tive (GEMOX) [54]. Gemcitabine and capecitabine combinations are also benefi-
cial [55]. In patients with borderline performance status, monotherapy is
reasonable.
The second line treatment can be offered and include FOLFOX (Folinic acid,
flurouracil, oxaliplatin) [56], capecitabine and oxaliplatin [57] or GEMOX plus
bevacizumab/rituximab [58], or FOLFIRI (folinic acid, flurouracil and irinotecan)
and Bevacizumab [59].
In selected cases, improved outcomes were found using erlotinib (targets epider-
mal growth factor receptor), an oral tyrosine kinase inhibitor [60]. The monoclonal
antibody bevacizumab can be added as salvage (targeting vascular endothelial
growth factor) [61].
16 Cholangiocarcinoma: From Mechanisms to Management 209

Future Perspectives

Neoadjuvant Therapy

Preoperative chemotherapy or radiotherapy is not considered a routine treatment.

Many patients are jaundiced and malnourished.
However, the potential benefit cannot be ignored in selected patients. A small
study identified complete pathological response and margin-negative resection in
extrahepatic CCA [62]. Further work identified survival benefit despite the neoad-
juvant cohort having more advanced disease [63].
These promising early findings warrant further investigation with appropriately
powered clinical trials.

References

1. Nagorney DM, Pawlik TM, Chun YS, et al. Perihilar bile ducts. In: Amin MB, editor. AJCC
cancer staging manual. 8th ed. Chicago: AJCC; 2017. p. 312.
2. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year
experience with 564 patients at a single institution. Ann Surg. 2007;245(5):755.
3. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangio-
carcinoma. Ann Surg. 1992;215(1):31.
4. Edge SB, Byrd DR, Compton CC, et al., editors. American Joint Committee on Cancer staging
manual. 7th ed. New York: Springer; 2010. p. 201.
5. Janargin WR, Fong Y, DeMatteo RP, et al. Staging, resectability and outcome in 225 patients
with hilar cholangiocarcinoma. Ann Surg. 2001;234(4):507–17.
6. Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas.
Semin Liver Dis. 1994;14(2):109.
7. Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA. Risk factors of intrahe-
patic cholangiocarcinoma in the United States: a case-control study. Gastroenterology.
2005;128(3):620.
8. Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the extrahepatic bile ducts. Histologic
types, stage of disease, grade, and survival rates. Cancer. 1992;70(6):1498.
9. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol. 1999;10(Suppl
4):308.
10. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary
sclerosing cholangitis. J Hepatol. 2002;36(3):321.
11. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease. A
changing pattern of presentation. Ann Surg. 1994;220(5):644.
12. Hsing AW, Gao YT, Han TQ, et al. Gallstones and the risk of biliary tract cancer: a population-­
based study in China. Br J Cancer. 2007;97(11):1577.
13. Mahale P, Torres HA, Kramer JR, Hwang LY, Li R, Brown EL, Engels EA. Hepatitis C virus
infection and the risk of cancer among elderly US adults: a registry-based case-control study.
Cancer. 2017;123(7):1202. Epub 2017 Jan 24.
14. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg.
2002;89(8):962.
210 L. M. Quinn et al.

15. Cardinale V, Carpino G, Reid L, Gaudio E, Alvaro D. Multiple cells of origin in cholangiocar-
cinoma underlie biological, epidemiological and clinical heterogeneity. World J Gastrointest
Oncol. 2012;4:94–102.
16. Cardinale V, et al. Profiles of cancer stem cell subpopulations in cholangiocarcinomas. Am J
Pathol. 2015;185:1724–39.
17. Nakanishi Y, Zen Y, Kondo S, Itoh T, Itatsu K, Nakanuma Y. Expression of cell cycle-related
molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intra-
ductal papillary neoplasm. Hum Pathol. 2008;39(8):1153.
18. Isa T, Tomita S, Nakachi A, Miyazato H, Shimoji H, Kusano T, Muto Y, Furukawa M. Analysis
of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahe-
patic cholangiocarcinoma. Hepatogastroenterology. 2002;49(45):604.
19. Arai Y, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molec-
ular subtype of cholangiocarcinoma. Hepatology. 2014;59:1427–34.
20. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase
(IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.
Oncologist. 2012;17(1):72–9. Epub 2011 Dec 16.
21. Yoshikawa D, et al. Clinicopathological and prognostic significance of EGFR, VEGF and
HER2 expression in cholangiocarcinoma. Br J Cancer. 2008;98:418–25.
22. Alvaro D, et al. Estrogens and insulin-like growth factor 1 modulate neoplastic cell growth in
human cholangiocarcinoma. Am J Pathol. 2006;169:877–88.
23. Webhe H, Henson R, Meng F, Mize-Berge J, Patel T. Interleukin-6 contributes to growth in
cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res.
2006;66:10517–24.
24. Sato Y, et al. Epithelial-mesenchymal transition induced by transforming growth fac-
tor B-1/Snail activation aggravates invasive growth of cholangiocarcinoma. Am J Pathol.
2010;177:141–52.
25. Boulter L, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologi-
cally inhibited. J Clin Invest. 2015;125:1269–85.
26. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar,
and distal tumors. Ann Surg. 1996;224(4):463.
27. Malaguarnera G, Paladina I, Giordano M, Malaguarnera M, Bertino G, Berretta M. Serum
markers of intrahepatic cholangiocarcinoma. Dis Markers. 2013;34(4):219.
28. Kim HJ, Kim MH, Myung SJ, et al. A new strategy for the application of CA19-9 in the differ-
entiation of pancreaticobiliary cancer: analysis using a receiver operating characteristic curve.
Am J Gastroenterol. 1999;94(7):1941.
29. Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ. The utility of CA 19-9 in the
diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J
Gastroenterol. 2000;95(1):204.
30. Siqueira E, Schoen RE, Silverman W, et al. Detecting cholangiocarcinoma in patients with
primary sclerosing cholangitis. Gastrointest Endosc. 2002;56(1):40.
31. Maeda T, Adachi E, Kajiyama K, Sugimachi K, Tsuneyoshi M. Combined hepatocellular and
cholangiocarcinoma: proposed criteria according to cytokeratin expression and analysis of
clinicopathologic features. Hum Pathol. 1995 Sep;26(9):956–64.
32. Saini S. Imaging of the hepatobiliary tract. N Engl J Med. 1997;336(26):1889.
33. Choi SH, Han JK, Lee JM, et al. Differentiating malignant from benign common bile duct
stricture with multiphasic helical CT. Radiology. 2005;236(1):178. Epub 2005 Jun 13.
34. Iavarone M, Piscaglia F, Vavassori S, et al. Contrast enhanced CT-scan to diagnose intrahe-
patic cholangiocarcinoma in patients with cirrhosis. J Hepatol. 2013;58(6):1188–93. Epub
2013 Feb 26.
35. Adachi T, Eguchi S, Beppu T, et al. Prognostic impact of preoperative lymph node enlargement
in intrahepatic cholangiocarcinoma: a multi-institutional study by the Kyushu Study Group of
Liver Surgery. Ann Surg Oncol. 2015;22(7):2269–78. Epub 2015 Jan 13.
36. Tillich M, Mischinger HJ, Preisegger KH, Rabl H, Szolar DH. Multiphasic helical CT in diag-
nosis and staging of hilar cholangiocarcinoma. AJR Am J Roentgenol. 1998;171(3):651.
16 Cholangiocarcinoma: From Mechanisms to Management 211

37. Manfredi R, Barbaro B, Masselli G, Vecchioli A, Marano P. Magnetic resonance imaging of

cholangiocarcinoma. Semin Liver Dis. 2004;24(2):155.
38. Pelsang RE, Johlin FC. A percutaneous biopsy technique for patients with suspected biliary or
pancreatic cancer without a radiographic mass. Abdom Imaging. 1997;22(3):307.
39. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose positron emission
tomography influences management decisions in patients with biliary cancer. J Am Coll Surg.
2008;206(1):57. Epub 2007 Oct 1.
40. Weber SM, RP DM, Fong Y, Blumgart LH, Jarnagin WR. Staging laparoscopy in
patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg.
2002;235(3):392.
41. Su CH, Tsay SH, Wu CC, et al. Factors influencing postoperative morbidity, mortality, and
survival after resection for hilar cholangiocarcinoma. Ann Surg. 1996;223(4):384.
42. Khan SA, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update.
Gut. 2012;61:1657–69.
43. Liberato MJ, Canena JM. Endoscopic stenting for hilar cholangiocarcinoma: efficacy of uni-
lateral and bilateral placement of plastic and metal stents in a retrospective review of 480
patients. BMC Gastroenterol. 2012;12:103.
44. Tsao JI, Nimura Y, Kamiya J, et al. Management of hilar cholangiocarcinoma: comparison of
an American and a Japanese experience. Ann Surg. 2000;232(2):166.
45. Edge SB, Byrd DR, Compton CC, et al., editors. American Joint Committee on Cancer staging
manual. 7th ed. New York: Springer; 2010. p. 219.
46. Panjala C, Nguyen JH, Al-Hajjaj AN, et al. Impact of neoadjuvant chemoradiation on the
tumor burden before liver transplantation for unresectable cholangiocarcinoma. Liver Transpl.
2012;18(5):594.
47. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207
patients. Transplantation. 2000;69:1633–7.
48. Croome KP, Rosen CB, Heimbach JK, Nagorney DM. Is liver transplantation appropriate
for patients with potentially resectable De Novo hilar cholangiocarcinoma? J Am Coll Surg.
2015;221(1):130–9. Epub 2015 Mar 11.
49. Rea DJ, Heimback JK, Rosen CB, et al. Ann Surg. 2005;242(3):451–8.
50. Eckel F, Brunner T, Jelic S, ESMO Guidelines Working Group. Biliary cancer: ESMO clini-
cal practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(Suppl
6):vi40–4.
51. Neoptolemos JP, Moore MJ, Cox TF, et al. European Study Group for Pancreatic Cancer.
Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observa-
tion on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 peri-
ampullary cancer randomized trial. JAMA. 2012;308(2):147.
52. Primrose JN, Fox R, Palmer DH, et al. Adjuvant capecitabine for biliary tract cancer: the
BILCAP randomized study (abstract). J Clin Oncol. 2017; 35 (suppl; abstr 4006).
53. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary
tract cancer. N Engl J Med. 2010;362(14):1273.
54. André T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with oxalipla-
tin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol.
2004;15(9):1339.
55. Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine in patients with
advanced biliary cancer: a phase II trial. J Clin Oncol. 2005;23(10):2332.
56. Novarino AM, Satolli MA, Chiappino I, et al. FOLFOX-4 regimen or single-agent gem-
citabine as first-line chemotherapy in advanced biliary tract cancer. Am J Clin Oncol.
2013;36(5):466–71.
57. Nehls O, Oettle H, Hartmann JT, et al. Capecitabine plus oxaliplatin as first-line treatment
in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II
trial. Br J Cancer. 2008;98(2):309. Epub 2008 Jan 8.
58. Zhu AX, Meyerhardt JA, Blaszkowsky LS, et al. Efficacy and safety of gemcitabine, oxali-
platin, and bevacizumab in advanced biliary-tract cancers and correlation of changes
212 L. M. Quinn et al.

in 18-­fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol.

2010;11(1):48–54. Epub 2009 Nov 20.
59. Guion-Dusserre JF, Lorgis V, Vincent J, Bengrine L, Ghiringhelli F. FOLFIRI plus bevaci-
zumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma. World J
Gastroenterol. 2015;21(7):2096–101.
60. Philip PA, Mahoney MR, Allmer C, et al. Phase II study of erlotinib in patients with advanced
biliary cancer. J Clin Oncol. 2006;24(19):3069.
61. Lubner SJ, Mahoney MR, Kolesar JL, et al. Report of a multicenter phase II trial testing a
combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary
cancer: a phase II Consortium study. J Clin Oncol. 2010;28(21):3491. Epub 2010 Jun 7.
62. McMasters KM, Tuttle TM, Leach SD, et al. Neoadjuvant chemoradiation for extrahepatic
cholangiocarcinoma. Am J Surg. 1997;174(6):605.
63. Nelson JW, Ghafoori AP, Willett CG, et al. Concurrent chemoradiotherapy in resected
extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2009;73(1):148. Epub
2008 Sep 19.
Chapter 17
Oncotherapies for Cholangiocarcinoma

Oliver Pickles and Yuk Ting Ma

Key Learning Points

1. Although biliary tract cancers are relatively rare tumours, large-scale ran-
domised clinical trials are feasible with multicentre collaboration and have
helped to inform the evidence base.
2. First-line chemotherapy for patients with advanced disease should be with
gemcitabine and cisplatin.
3. There is no proven second-line chemotherapy and patients should be
enrolled into clinical trials where possible.
4. Adjuvant capecitabine chemotherapy should be considered in all patients
following surgical resection.
5. The role of adjuvant radiotherapy and adjuvant chemoradiotherapy remains
uncertain, and further randomised trials in this setting are indicated.

Areas of Controversy and Uncertainty

1. Conflicting data exists for the role of radiotherapy and chemoradiotherapy
in the management of biliary tract cancers and randomised trials in this
setting are indicated.

O. Pickles · Y. T. Ma (*)
Department of Medical Oncology, Queen Elizabeth Hospital, Birmingham, UK

© Springer Nature Switzerland AG 2019 213

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_17
214 O. Pickles and Y. T. Ma

Chemotherapy for Advanced Disease

Cholangiocarcinoma is frequently diagnosed at a late and therefore inoperable stage

and the aims of treatment in this setting are to palliate symptoms and to control
disease. Management of patients with advanced disease is often complicated by the
presence of biliary obstruction and sepsis as well as age-related comorbidities. For
patients with a good performance status, chemotherapy has been shown to improve
cancer-related symptoms and median survival, although the overall median survival
still remains poor (less than 1 year).
Due to the rarity of these tumours, nearly all of the clinical trials performed have
broadened their eligibility to include all biliary tract cancers. Two randomised phase
III trials have demonstrated a survival benefit of chemotherapy over best supportive
care (BSC) in patients with advanced disease [1, 2]. The first study by Glimelius
et al., compared 5-fluorouracil (5FU), leucovorin and etoposide with BSC in patients
with pancreatic and biliary tract cancers. Chemotherapy significantly improved
median survival (6 vs 2.5 months, p < 0.01) and quality of life [1]. The second study
by Sharma et al., randomised patients with unresectable gallbladder cancer to gem-
citabine and oxaliplatin (GEMOX), 5FU and folinic acid or BSC. Chemotherapy
with GEMOX significantly improved survival compared with 5-fluorouracil and
folinic chemotherapy or BSC (9.5 vs 4.6 vs 4.5 months, p = 0.39) and was associ-
ated with a much higher response rate [2].
Many chemotherapeutic agents have been investigated in biliary tract cancers,
although the majority have been small single-arm phase II studies. A pooled analy-
sis comprising 104 trials and 2810 patients revealed fluoropyrimidines, gemcitabine
and platinum analogues to be the most active agents, with the highest response and
disease-control rates observed with gemcitabine in combination with cisplatin or
oxaliplatin [3].
The UK phase III Advanced Biliary tract Cancer (ABC)-02 study finally estab-
lished combination chemotherapy with gemcitabine and cisplatin as the first-line
standard-of-care chemotherapy for advanced biliary tract cancers in 2010 [4]. This
study was initiated as a randomised phase II study (ABC-01), which was then
extended to a phase III study [5]. Four hundred and ten patients with locally
advanced or metastatic cholangiocarcinoma, gallbladder cancer or ampullary can-
cer were randomised to either cisplatin (25 mg/m2) followed by gemcitabine
(1000 mg/m2) each given on days 1 and 8 every 21 days for eight cycles, or gem-
citabine alone (1000 mg/m2) given on days 1, 8 and 15 every 28 days for six cycles.
This study demonstrated a statistically improved median overall survival in patients
treated with the gemcitabine-cisplatin doublet compared to gemcitabine alone (11.7
vs 8.1 months, HR 0.64, 95% CI 0.52–0.80; p < 0.001), without the addition of
significant toxicity [4]. A similar magnitude of benefit was seen in the parallel ran-
domised phase II Biliary Tract (BT)-22 study performed in Japan using the same
treatment regimen (median overall survival 11.2 vs 7.7 months, HR 0.69, 95% CI
0.42–1.13) [6]. The BT-22 trial was developed to evaluate the same dose and regi-
mens used in the ABC-02 trial in Japanese patients with advanced biliary tract
17 Oncotherapies for Cholangiocarcinoma 215

cancer. In a subsequent pre-planned meta-analysis of both studies, representing the

largest prospectively evaluated patient pool with nearly 500 patients, gemcitabine
and cisplatin chemotherapy was confirmed to significantly improve progression-­
free survival (8.8 vs 6.7 months, HR 0.64, p < 0.001) and overall survival (11.6 vs
8.0 months, HR 0.65, p < 0.001) [7]. Exploratory subgroup analyses demonstrated
that all subgroups benefit from treatment but patients with ampullary tumours and
poor performance status [2] were least likely to benefit [7]. The ABC-02 and BT22
studies have shown that even though biliary tract cancers are relatively rare tumours,
large-scale prospective studies can be successfully undertaken with multicentre and
multinational collaboration.

Second Line Chemotherapy

There is no phase III data to support any chemotherapy regimen over best support-
ive care after failure of first-line chemotherapy in advanced disease. A number of
regimes have been used, most notably fluoropyrimidine-based where patients have
been treated with gemcitabine in the first line. In the ABC-02 study, 15% of patients
received second-line chemotherapy, whereas in the BT-22 study, 75% of patients
received second-line chemotherapy. Despite this difference, the median overall sur-
vival observed in both studies was very similar, suggesting that subsequent lines of
treatment may be of limited benefit. Prospective randomised trials are clearly
needed to answer this question definitively [8].
In the absence of randomised phase III studies, a systematic review was under-
taken to evaluate the level of evidence supporting the use of second-line chemo-
therapy in patients with advanced biliary tract cancers [8]. Twenty-five studies
comprising 761 patients were included in the final analysis: 14 phase II clinical tri-
als, 9 retrospective analyses and 2 case reports. There was marked heterogeneity
with respect to both first- and second-line chemotherapies used in these studies, and
it was concluded that there is a poor level of evidence (level C) to recommend a
second-line chemotherapy schedule in patients with advanced biliary tract cancer.
Of note, the weighted mean overall survival in the 20 studies with survival data
available was 7.2 months (95% CI 6.2–8.2), which is much higher than the 4-month
expected median overall survival following progression observed in the ABC-02
study. This clearly reflects a highly selected population as patients eligible for
second-­line chemotherapy usually have a better performance status and thus better
prognosis, and combined with the observation that 15–25% of patients may be fit
enough for second-line treatment, it is evident that a cohort of patients exist who
may benefit from second-line treatment. This issue will hopefully be addressed in
the ongoing UK ABC-06 (NCT 01926236) study, a randomised phase III clinical
trial that is comparing combination chemotherapy with oxaliplatin and 5FU against
active symptom control alone in patients with advanced biliary tract cancers, follow-
ing progression on first-line gemcitabine and cisplatin chemotherapy. With recruit-
ment likely to complete in late 2017, the results of this study are eagerly awaited.
216 O. Pickles and Y. T. Ma

Summary

• First-line systemic treatment for unresectable biliary tract cancer should be with
gemcitabine and cisplatin chemotherapy.
• The role of target therapy will be discussed in the next chapter.
• At present, in the second line, no treatment can be recommended with a robust
evidence base over best supportive care. Where possible these patients should be
enrolled into clinical trials.

Chemotherapy in the Adjuvant Setting

The outcome following surgery for biliary tract cancer remains poor, with the
majority of patients succumbing to local recurrent or metastatic disease. Until
recently, there was sparse data supporting the routine use of adjuvant therapy. Due
to the relative rarity of these tumours and the even fewer patients who are eligible
for surgical resection, one of the challenges is the difficulty in completing a large
randomised controlled trial that is adequately powered to show a survival advan-
tage. Consequently the majority of the publications consist of uncontrolled institu-
tional series and registry analyses.
The first prospective study was published in 2002. Takada et al. randomised 508
patients with resected pancreatic (n = 173), bile duct (n = 139), gallbladder (n = 140)
or ampullary carcinoma (n = 56) to chemotherapy with mitomycin C and 5FU (MF)
or to surgery alone [9]. In a per-protocol analysis, the 5-year survival in patients
with gallbladder cancer was significantly better in the MF group compared to sur-
gery alone (26% vs 14.4%, p = 0.0367), but this was no longer statistically signifi-
cant in the intention-to-treat analysis. There were no significant differences found in
the 5-year survival in patients with pancreatic, bile duct or ampullary carcinomas.
Major limitations of this study include the inclusion of patients who underwent both
curative and non-curative resections, as well as a large number of ineligible patients
who were imbalanced between the two gallbladder carcinoma groups.
The ESPAC-3 periampullary trial was a randomised phase III trial designed to
compare the survival benefit of adjuvant chemotherapy versus observation follow-
ing resection for patients with periampullary cancers and to compare 5FU plus
folinic acid chemotherapy to that of gemcitabine alone [10]. Four hundred and
twenty-eight patients with resected ampullary (n = 297), bile duct (n = 96) or other
periampullary (n = 35) cancers were randomised in a 1:1:1 ratio to 5FU and folinic
acid, gemcitabine or to observation alone. In the primary analysis, no difference in
median overall survival was observed between the three groups, but after correcting
for independent prognostic variables (age, bile duct cancer, poor differentiation,
positive lymph nodes), a statistically significant survival benefit was observed for
chemotherapy (HR 0.75, 95% CI 0.57–0.98, p = 0.03) and specifically for gem-
citabine (HR 0.70, 95% CI 0.51–0.97, p = 0.03) compared to observation. This
study also revealed significant differences in survival based on tumour type with a
17 Oncotherapies for Cholangiocarcinoma 217

median survival of 53.1 months for ampullary cancers, 20.9 months for bile duct
cancers and 32.6 months for patients with other cancers. This study was not pow-
ered to reveal a survival advantage for each specific tumour type due to the rela-
tively low incidence of each tumour type, but it is notable that amongst the patients
with bile duct cancers, the median survival was 27.2 months in those randomised to
observation alone, 18.3 months in the 5FU and folinic acid group and 19.5 months
in the gemcitabine group; thus, the value of adjuvant chemotherapy specifically in
bile duct cancers remains uncertain from this trial, and the authors recommend
investigating bile duct cancers as a separate entity in future studies.
Horgan et al. performed a systematic review of all the published, mainly nonran-
domised, studies evaluating adjuvant therapy for biliary tract cancers up to 2010 to
try and inform the design of subsequent prospective randomised controlled trials
[11]. Twenty studies involving 6712 patients were included, and the pooled analysis
revealed a non-significant improvement in overall survival with any adjuvant ther-
apy compared with surgery alone (pooled OR 0.74, p = 0.06), with the greatest
benefit observed in those with lymph node-positive disease (OR 0.49, p = 0.004)
and R1 disease (OR 0.36, p = 0.002). There was no difference observed between
gallbladder and bile duct cancers [11].
Recently, two randomised phase III trials of adjuvant chemotherapy, designed
specifically for patients with biliary tract cancers, have been presented. The French
PRODIGE 12-ACCORD 18 study was presented at the 2016 ASCO GI meeting [12].
This study randomised 196 patients to GEMOX chemotherapy or to surveillance
alone following an R0 or R1 resection of a localised biliary tract cancer (intrahepatic,
perihilar, extrahepatic cholangiocarcinoma or gallbladder cancer). Tolerability of
treatment was satisfactory, and although there was a trend towards an improvement
in relapse-free survival with GEMOX chemotherapy (30.4 vs 22 months, HR 0.83,
95% CI 0.58–1.19, p = 0.31), this was not statistically significant. This study was
also underpowered to detect an overall survival difference. The second, the UK
BILCAP study, is the first adequately powered randomised trial of adjuvant chemo-
therapy in patients with resected biliary tract cancer, and was presented at the 2017
ASCO meeting [13]. This study randomised 447 patients with a completely resected
cholangiocarcinoma or gallbladder cancer to oral capecitabine (1250 mg/m2 twice
daily on days 1–14 of a 21 day cycle for 24 weeks) or to surveillance alone. The
primary analysis was not statistically significant (51.1 vs 36.4 months, HR 0.80, 95%
CI 0.63–1.04, p = 0.097) but in the pre-planned sensitivity analysis adjusting for
prognostic factors (nodal status, grade of disease and gender), a statistically signifi-
cant improvement in median overall survival was observed (HR 0.70, 95% CI 0.55–
0.91, p = 0.007). The full publication of both datasets is awaited but it is likely that
oral capecitabine will now become the standard-­of-care adjuvant therapy.
The ongoing ACTICCA-1 (NCT02170090) trial is a European randomised
phase III trial comparing chemotherapy with gemcitabine and cisplatin (as per the
ABC-­02 study) with surveillance alone, in patients with curatively resected cholan-
giocarcinoma or gallbladder cancer. Following the publication of the results of the
BILCAP study, a substantial amendment has been submitted to replace the surveil-
lance arm with oral capecitabine, providing an opportunity to compare the two
218 O. Pickles and Y. T. Ma

regimens head-to-head. The primary end point is disease-free survival, and the
study plans to enrol 280 patients with cholangiocarcinoma and 80 patients with
gallbladder cancer. The UK-wide BILCAP study took 10 years to complete, and it
is hoped that with more collaborative working, future adjuvant studies will be com-
pleted more quickly.

Summary

• There is a high risk of recurrence following surgery in biliary tract cancer and
poor 5-year survival.
• Given the results of the BILCAP trial, patients with resected biliary tract cancer
should be offered adjuvant capecitabine. Full results from this study will likely
be published shortly.

Radiotherapy in Cholangiocarcinoma

The role of radiotherapy remains poorly defined in biliary tract cancers, and efforts
to study the effectiveness of treatment have been hampered by small patient numbers
and heterogeneous patients and trial designs. Currently no randomised phase III data
exists. Besides the usual palliative role of radiotherapy, e.g. treating painful bone
metastases, groups have sought to establish the effectiveness in the palliative, adju-
vant and neoadjuvant setting, with conflicting data frequently seen in the literature.

Adjuvant Radiotherapy

There is limited evidence to support the use of radiotherapy alone following surgical
resection. There has been no prospective clinical trial investigating its role as a sole
adjuvant modality, and given the results from adjuvant chemotherapy, it is unlikely
that such a study will be performed in the future. The available data comes from
retrospective series and population-based registries only.
In the systematic review of nonrandomised studies undertaken by Horgan et al.,
pooled analysis suggested a significant benefit of adjuvant therapy in patients with
R1 disease (OR 0.36, 95% CI 0.19–0.68, p = 0.004). Sixty-three percent of these R1
patients received radiotherapy alone, compared to mostly chemoradiotherapy in the
R0 studies. A significant benefit was observed with adjuvant radiotherapy in patients
with R1 disease, irrespective of disease site (OR 0.33, 95% CI 0.014–0.81, p = 0.01),
whereas treatment with radiotherapy was associated with a nonsignificant odds of
harm (OR 1.26, 95% CI 0.88–1.79, p = 0.20) in those with R0 status. This difference
in effect size was statistically significant suggesting that adjuvant radiotherapy may
be of benefit only in patients with R1 disease [11].
17 Oncotherapies for Cholangiocarcinoma 219

Population-based analyses using data from the US Surveillance, Epidemiology

and End Results (SEER) database have formed the largest datasets to examine the
role of adjuvant radiotherapy. Hyder et al. reported on the outcomes of 5011 patients
with gallbladder cancer who underwent surgical resection between 1988 and 2009.
Eight hundred ninety-nine (18%) patients received external beam radiotherapy;
these patients were more likely to be younger, have more extensive disease, poorly
differentiated tumours and lymph node involvement. On a propensity-matched mul-
tivariate model, radiotherapy was associated with a better long-term survival at
1 year (HR 0.45; p < 0.001) but not at 5 years (HR 1.06; p = 0.50) [14]. The lack of
information regarding chemotherapy administration and the inclusion of patients
with metastatic disease in these datasets means that it is difficult to draw any conclu-
sions regarding the role of adjuvant radiotherapy.

Summary

• Given the limited available evidence, adjuvant radiotherapy is not routinely

recommended.

Adjuvant Chemoradiotherapy

Adjuvant chemoradiotherapy (CRT) has been investigated by some groups in an

attempt to combine the local control effect of radiotherapy with the systemic effects
of adjuvant chemotherapy. There is a lack of randomised data in this area, and con-
flicting results have been reported from pooled analyses of retrospective series and
population registries.
Wang et al. performed an analysis of patients treated in the SEER-Medicare
database with adjuvant chemoradiotherapy for gallbladder cancer between 1995
and 2005. Of the 1137 patients included in this analysis, 126 patients (11%) had
received adjuvant chemoradiotherapy. The authors developed a nomogram to help
make individualised survival estimates and found that in their model, adjuvant
chemoradiotherapy outperformed adjuvant chemotherapy for virtually all patient
subsets [15].
Conversely, in the systematic review by Horgan et al., subgroup analysis of the
different adjuvant modalities showed the greatest benefit with adjuvant chemother-
apy (OR 0.39, 95% CI 0.23–0.66, p < 0.01) followed by chemoradiotherapy (OR
0.61, 95% CI 0.38–0.99, p = 0.049) with no benefit observed with adjuvant radio-
therapy alone (OR 0.98, 95% CI 0.67–1.43, p = 0.90) [11].
Recently, the results from the SWOG S0809 study have been published [16].
This was a prospective, multicentre (intergroup) nonrandomised phase II study that
assessed the efficacy of adjuvant chemoradiotherapy with four cycles of adjuvant
gemcitabine (1000 mg/m2 on days 1 and 8) in combination with capecitabine
(1500 mg/m2 on days 1–14) every 21 days, followed by concurrent capecitabine
220 O. Pickles and Y. T. Ma

(1330 mg/m2 per day) with radiotherapy (45Gy to regional lymphatics, 54–59.4 Gy
to tumour bed). High-quality radiotherapy with either three-dimensional planning
or intensity-modulated radiotherapy (IMRT) was used in this study. Per protocol
radiotherapy was given in 85% of patients. A total of 79 patients were enrolled and
encouraging 2 year survival of 65% (95% CI 53–74%) for all patients was observed.
Treatment was also well tolerated; the most common grade 3 or 4 toxicity was neu-
tropenia in 44%, and other grade 3 toxicities were rare. One patient died from GI
haemorrhage [16]. The main limitation of this study is the absence of a control arm,
but this study demonstrates the feasibility of conducting a national clinical trial for
a relatively rare tumour, and future randomised phase III clinical trials in this setting
are indicated.

Neoadjuvant Chemoradiotherapy

At present the role of neoadjuvant, as well as downstaging techniques, remains

poorly defined in biliary tract cancer and is generally only performed in an experi-
mental setting. Chemotherapy, CRT and other techniques, e.g. photodynamic ther-
apy, have all been considered. Given the lack of clear guidance on this topic, it is
not uncommon for patients with unresectable disease at presentation to be com-
menced on standard palliative therapy. During routine response assessment, it is
important to consider those with significant response for surgical exploration fol-
lowing MDT discussion. One systemic review of neoadjuvant therapy in hilar chol-
angiocarcinoma prior to standard resection was limited by study quality and
heterogeneity but was unable to favourably recommend neoadjuvant therapy in this
group [17].
A notable exception to this is with hilar cholangiocarcinoma where an approach
with neoadjuvant CRT followed by liver transplantation has been compared to liver
transplantation alone. This approach developed by the Mayo Clinic involved patients
initially receiving external beam irradiation with bolus 5FU, followed by brachy-
therapy with iridium and concomitant 5FU infusion, and then continuous 5FU until
laparoscopy. The early results from this pilot study revealed a prolonged disease-­
free survival (DFS) in those undergoing liver transplantation after neoadjuvant
treatment (92% after a median follow-up of 37 months). However, these patients
were highly selected with 40% of patients being excluded following exploratory
laparotomy due to progressive disease [18]. A retrospective multicentre analysis of
this approach from 12 large-volume transplant centres in the United States con-
firmed these initial findings. Of the 287 patients included who received neoadjuvant
CRT followed by liver transplantation, 65% remained recurrence free at 5 years. In
total 25% of patients starting CRT dropped out prior to transplantation [19]. The
French phase III TRANSPHIL study (NCT02232932) is ongoing and looks to for-
mally assess the effectiveness of this approach in this highly selected group of
patients (using CRT with capecitabine followed by liver transplantation vs surgical
resection alone).
17 Oncotherapies for Cholangiocarcinoma 221

Summary

• Adjuvant chemoradiotherapy is not routinely recommended in biliary tract

cancers.
• Promising results have been observed in a prospective phase II trial but there is a
need for randomised controlled studies in this area.
• A role for neoadjuvant CRT in hilar cholangiocarcinoma prior to liver transplan-
tation may exist for highly selected patients, though remains specialised, and
further trial data is awaited.

Chemoradiotherapy for Locally Advanced Disease

The role of chemoradiotherapy in a palliative setting for locally advanced disease is

poorly defined. As with many treatment modalities in the biliary tract, there is a lack
of randomised prospective evidence. One French randomised phase II study has
been performed comparing CRT (EBRT 50Gy in 25 fractions with cisplatin and
5FU) with GEMOX chemotherapy. Unfortunately the study closed early due to
slow recruitment, with only 34 patients included [20]. Further retrospective analy-
ses have been performed including a single-centre retrospective analysis of CRT
(with either 5FU or gemcitabine) against best supportive care alone. One hundred
six patients were treated with CRT versus 70 with BSC, and the CRT patients were
on average 5 years younger with lower T stage (T2) compared to the BSC group.
Median overall survival was better in the CRT group (OS 42.6 weeks vs 13.3 weeks,
p < 0.001) [21].
At present there is insufficient evidence to recommend the routine use of CRT
in locally advanced biliary tract disease. Emerging techniques including stereotactic
body radiotherapy (SBRT) will need to be assessed in the coming years. In the UK,
a feasibility study which hopes to extend to a randomised phase II is currently
recruiting (ABC-07). This looks at randomising to SBRT versus two further cycles
of chemotherapy in patients who have disease control following six cycles of gem-
citabine and cisplatin chemotherapy.

Summary

• It is not possible to recommend CRT for locally advanced biliary tract cancer at
present.
• Data in existing retrospective series is unlikely to be comparable with modern
radiotherapy techniques and emerging technologies (e.g. SBRT), and direct com-
parison with standard-of-care gemcitabine and cisplatin chemotherapy is
required.
222 O. Pickles and Y. T. Ma

References

1. Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom H, Enander LK, et al.

Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer.
Ann Oncol. 1996;7(6):593–600.
2. Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, et al. Best supportive care
compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled
study. J Clin Oncol. 2010;28(30):4581–6.
3. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of
clinical trials. Br J Cancer. 2007;96:896–902.
4. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus
gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–81.
5. Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R, et al. Gemcitabine alone or in
combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or
other biliary tract tumours: a multicentre randomised phase II study—The UK ABC-01 study.
Br J Cancer. 2009;101(4):621–7.
6. Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, et al. Gemcitabine
alone or in combination with cisplatin in patients with biliary tract cancer: a comparative mul-
ticentre study in Japan. Br J Cancer. 2010;103(4):469–74.
7. Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, et al. Cisplatin and gemcitabine
for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol.
2014;25(2):391–8.
8. Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced
biliary cancer: a systematic review. Ann Oncol. 2014;25(12):2328–38.
9. Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, et al. Is postoperative adju-
vant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective
randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer.
2002;95(8):1685–95.
10. Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, et al. Effect of
adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on
survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary
cancer randomized trial. JAMA. 2012;308(2):147–56.
11. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract
cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30(16):1934–40.
12. Edeline J, Bonnetain F, Philip JM, Watelet J, Hammel P, Joly JP, et al. GEMOX versus surveil-
lance following surgery of localized biliary tract cacner: results of the PRODIGE 12-ACCORD
18 (UNICANCER GI) phase III trial. J Clin Oncol. 2017;35(4 suppl):225.
13. Primrose JN, Fox R, Palmer DH, Prasad R, Mirza D, Anthoney DA, et al. Adjuvant capecitabine
for biliary tract cancer: the BILCAP randomized study. J Clin Oncol. 2017;35(15 suppl):4006.
14. Hyder O, Dodson RM, Sachs T, Weiss M, Mayo SC, Choti MA. Impact of adjuvant exter-
nal beam radiotherapy on survival in surgically resected gallbladder adenocarcinoma: a
propensity score-matched Surveillance, Epidemiology, and End Results analysis. Surgery.
2014;155(1):85–93.
15. Wang SJ, Lemieux A, Kalpathy-Cramer J, Ord CB, Walker GV, Fuller CD, et al. Nomogram
for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin
Oncol. 2011;29(35):4627–32.
16. Ben-Josef E, Guthrie KA, El-Khoueiry AB, Corless CL, Zalupski MM, Lowy AM, et al.
SWOG S0809: a phase II intergroup trial of adjuvant capecitabine and gemcitabine followed
by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallblad-
der carcinoma. J Clin Oncol. 2015;33(24):2617–22.
17. Grendar J, Grendarova P, Sinha R, Dixon E. Neoadjuvant therapy for downstaging of locally
advanced hilar cholangiocarcinoma: a systematic review. HPB. 2014;16(4):297–303.
17 Oncotherapies for Cholangiocarcinoma 223

18. De Vreede I, Steers JL, Burch PA, Rosen CB, Gunderson LL, Haddock MG, et al. Prolonged
disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for
cholangiocarcinoma. Liver Transpl. 2000;6(3):309–16.
19. Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, et al. Efficacy
of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarci-
noma at 12 US centers. Gastroenterology. 2012;143(1):88–98.
20. Phelip JM, Vendrely V, Rostain F, Subtil F, Jouve JL, Gasmi M, et al. Gemcitabine plus cisplatin
versus chemoradiotherapy in locally advanced biliary tract cancer: Federation Francophone de
Cancerologie Digestive 9902 phase II randomised study. Eur J Cancer. 2014;50(17):2975–82.
21. Yi SW, Kang DR, Kim KS, Park MS, Seong J, Park JY, et al. Efficacy of concurrent chemora-
diotherapy with 5-fluorouracil or gemcitabine in locally advanced biliary tract cancer. Cancer
Chemother Pharmacol. 2014;73(1):191–8.
 Part III
Neueoendocrine Tumours
Chapter 18
Novel Treatments for Advanced
Cholangiocarcinoma

Jenny Cotton, Angela Lamarca, Mairéad G. McNamara, and Juan W. Valle

Key Learning Points

1. A modest gain in survival in advanced cholangiocarcinoma using systemic che-
motherapy highlights the need for improved therapies at all stages of treatment.
2. Locoregional therapies show promising results in locally advanced and
palliative settings; however liver toxicity can occur in up to 40% of patients.
3. The use of targeted therapies remains investigational; to date none have
demonstrated an improvement in patient outcomes.
4. The use of antiangiogenic agents has not yet resulted in a significant
improvement in survival.
5. As the field of molecular medicine advances, systemic therapies may now
focus on targeted therapies and immunotherapies.
6. Further research into novel treatments is warranted and further targeted
molecular profiling developments may result in improved survival in
advanced cholangiocarcinoma in the future.
7. Palliative care needs to be introduced earlier in the disease for better over-
all outcomes and quality of life.

J. Cotton
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
Department of Medical Oncology, The Clatterbridge Cancer Centre, Wirral, UK
A. Lamarca
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
e-mail: [email protected]
M. G. McNamara · J. W. Valle (*)
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
Division of Cancer Sciences, University of Manchester, Manchester, UK
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2019 227

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_18
228 J. Cotton et al.

Areas of Controversy and Uncertainty

1. High-level evidence for the efficacy of locoregional therapy in cholangio-
carcinoma is lacking.
2. Where locoregional therapies will be included in a patient’s disease man-
agement plan is uncertain.
3. To date, the addition of targeted therapy to the treatment algorithm for
cholangiocarcinoma has not resulted in increases in overall survival, and
novel agents are needed.
4. The use of immunotherapy has demonstrated encouraging response rates
in numerous cancers, and final results of prospective clinical trials in
patients with a diagnosis of cholangiocarcinoma are awaited.

Introduction

Cholangiocarcinoma, which may be intrahepatic, hilar or extrahepatic (distal bile

duct), according to primary location, is an aggressive malignancy with unmet treat-
ment needs in advanced stages. The incidence and mortality rates for intrahepatic
cholangiocarcinoma (ICC), in particular, have risen steeply over recent decades [1].
Radical surgery with lymphadenectomy (tailored for the site of primary) is the only
option which provides the possibility of cure, but most patients have advanced dis-
ease at presentation, and disease relapse is common, with 5-year survival rates of
only 38.8% [2, 3].
With the rise in cholangiocarcinoma incidence, and the anticipation that novel
agents will improve overall survival (OS), symptom palliation will become an ever-­
increasing challenge. Stenting to relieve biliary obstruction provides essential palliation
of cholangiocarcinoma involving the main bile ducts and is associated with improved
quality of life, particularly for patients with unresectable disease [4]. Patient education
and encouragement of self-reporting of symptoms may help with early detection of
obstructive and/or infective disease-related complications and lead to improved out-
comes such as OS and quality of life, as has been shown in other cancer types [5]. Early
palliative care should be considered for all patients with advanced cholangiocarcinoma,
so that optimal benefit with systemic treatment, where appropriate, is achieved.
The current standard treatment for patients with locally advanced or metastatic
biliary tract cancer is cisplatin plus gemcitabine (CisGem) chemotherapy [6]. The
median survival in patients with advanced biliary tract cancers who receive CisGem
is 11.7 months with a median progression-free survival (PFS) of 8 months [6].
There is no second-line therapy with established benefit for patients with advanced
cholangiocarcinoma [7].
Whilst there is evidence to support the use of standard-of-care treatments, a num-
ber of novel treatments remain in early phases of clinical trial development [8, 9].
These trials are required to establish the efficacy of novel treatments and identify
associated toxicity, the role of biomarkers and their place in the patient therapeutic
pathway. This chapter will highlight novel treatments and some ongoing clinical
18 Novel Treatments for Advanced Cholangiocarcinoma 229

trials in locally advanced and metastatic cholangiocarcinoma and identify where

they might be used in the disease trajectory. Locoregional approaches are discussed
first, followed by systemic therapy options.

Locoregional Approaches in Cholangiocarcinoma

Locoregional therapies are used for the treatment of ICC, although high-level evi-
dence for their efficacy is lacking [3]. Transcatheter arterial chemoembolisation
(TACE) and radioembolisation have been used for some years to treat cancer in the
liver (primary or secondary). Technical advances over the last decade have allowed
more precise tumour treatment with focused delivery of chemotherapy and radio-
therapy, whilst sparing adjacent normal tissues as much as possible.
Novel approaches such as hepatic arterial-based therapies (HAT) now focus on
minimising toxicity and improving quality of life. A meta-analysis of 20 studies of
the use of HAT in ICC suggested that hepatic arterial infusion offered the best out-
comes in terms of tumour response and survival, compared to other locoregional
therapies. However, its use is limited by hepatic toxicity, including raised liver
enzymes, hepatic abscess formation and hepatic failure [10].

Chemotherapy-Based Therapies

Chemosaturation

Most recently, chemosaturation allows delivery of potentially lethal doses of melpha-

lan to the liver via an indwelling hepatic artery catheter, followed by external filtering
of the drug before blood is returned to the systemic circulation. By this mechanism,
the liver can be exposed to doses of chemotherapy that are not feasible by conven-
tional infusion. It is associated with a degree of bone marrow suppression due to the
limited systemic escape of melphalan (approx. 3% of the total delivered dose) [11].
It is resource-intensive, requiring an expert team including interventional radiology,
perfusionist and anaesthetist, with oncological and surgical backup, if necessary.
Chemosaturation has resulted in improved PFS in liver metastases in patients
with cutaneous or ocular melanoma. A phase III trial comparing the use of chemo-
saturation with best standard of care reported that patients had an improved median
hepatic PFS of 7.0 months compared to 1.6 months with standard-of-care treatment,
with an overall PFS of 5.4 months compared to 1.6 months. Median OS, however,
was not significantly different [12]. It has been investigated in patients with cholan-
giocarcinoma [13], as well as primary liver tumours [14] and unresectable hepatic
metastases [12]. There has been one documented case of a complete response when
used in metastatic cholangiocarcinoma [14]. In order to clarify the potential role of
this treatment in cholangiocarcinoma, randomised-controlled trials are needed.
230 J. Cotton et al.

 rug-Eluting Bead Transcatheter Arterial Chemoembolisation

D
(DEB-TACE) in Unresectable Cholangiocarcinoma

Drug-eluting bead transcatheter arterial chemoembolisation is a procedure where

drug-eluting microspheres can be delivered directly to the tumour via an arterial cath-
eter. This process allows sustained delivery of chemotherapy into the liver, therefore
avoiding peak concentrations which may be associated with toxicity, as well as arterial
embolisation. In a small study of 11 patients with ICC using doxorubicin drug-eluting
beads (loaded with 100–150 mg), there was a 100% response rate according to
response evaluation criteria in solid tumours (RECIST), with a median OS of
13 months [15]. In a further study where 26 patients were given irinotecan DEB-
TACE and ten patients were given mitomycin-C DEB-TACE, irinotecan produced a
better PFS of 3.9 months and OS of 11.7 months versus a PFS of 1.8 months and OS
of 5.7 months in the mitomycin-C group. Doxorubicin appears to be the most effective
agent in DEB-TACE. A recognised risk of such therapy is “post-embolisation syn-
drome” which is characterised by a low-grade fever, nausea and abdominal pain [16].

Ablative Therapies

Irreversible Electroporation in Unresectable Cholangiocarcinoma

Irreversible electroporation (IRE) is a novel image-guided ablation technique that

has been used in the treatment of metastatic or primary tumours in the liver, kidney,
lung and prostate [17, 18]. It uses a pulsed electric current to create irreversible
pores in the cell membrane causing cell death through non-thermal ablation.
Patients who have undergone palliative metal stenting are required to have the
metal stent changed for a plastic one before the procedure can be performed, as
power conduction tissue heating may lead to thermal complications. Currently, a
single-arm pilot clinical trial focussing on the effectiveness of IRE for the treatment
of metastatic cholangiocarcinoma or liver cancer is evaluating the response of IRE-
treated lesions according to modified RECIST evaluation (clinicaltrials.gov identi-
fier, NCT02807181). Case reports on the use of this technique in cholangiocarcinoma
exist, but no randomised trial data is available yet.

 adiofrequency Ablation in Unresectable or Advanced

R
Cholangiocarcinoma

Several small studies in recent years have suggested that percutaneous ultrasound-­
guided thermal ablation for unresectable ICC is safe and potentially effective, par-
ticularly for primary and relatively small tumours (see Table 18.1). The evidence
demonstrates that smaller tumours, particularly those <5 cm [19] and a small
18 Novel Treatments for Advanced Cholangiocarcinoma 231

Table 18.1 Retrospective studies including patients with intrahepatic cholangiocarcinoma treated
with radiofrequency ablation
Median f/u No. of Successful Largest OS at Median OS
Treatment intent N (months) nodules ablation nodule 6 months (months)
Curative /palliative 10 19.5 12 8 (75%) 7 cm 83.3% –
(Giorgio et al.) [19]
Curative 18 8.7 25 23 (92%) 4.3 cm 30% –
(Xu et al.) [20]
Curative /palliative 17 29 26 – 4.4 cm – 33
(Fu et al.) [21]
Curative 13 19.5 17 15 (88%) 8 cm 15%. 38.5
(Kim et al.) [22]
N number of participants; f/u follow-up; OS overall survival

number of nodules [20], have a better recurrence-free survival but not

OS. Identification of prognostic factors might allow better patient selection and out-
comes with this technique [19]. This suggests that radiofrequency ablation may be
an option for the treatment of small lesions.

Radiation-Based Therapies

 tereotactic Body Radiation Therapy (SBRT) in Locally

S
Advanced Cholangiocarcinoma

Stereotactic body radiation therapy allows safe delivery of one to five fractions of
high-dose radiotherapy compared with small fractions of daily radiotherapy over
many weeks. It has been used in the treatment of unresectable, locally advanced
ICC, though experience is limited. There are, to date, no randomised trials compar-
ing this technique with conventional radiotherapy in biliary tract cancer.
Toxicity may limit use, but case reports and retrospective case series have shown
that SBRT can give good local control [23, 24]. One report of ten patients with hilar
cholangiocarcinoma, where 30 Gy in three fractions was delivered with gem-
citabine, resulted in 80% local control and 80% 2-year survival [25]. A phase I study
of 41 patients receiving individualised SBRT for unresectable hepatocellular carci-
noma and ICC, who were not suitable for standard therapies, received 6 fractions of
SBRT over a 2-week period. Seventeen of the 41 patients had received no prior
therapy, and patients who had received previous radiotherapy to the right upper
abdomen were excluded. This study reported a median survival of 15.0 months in
the ICC group. No radiotherapy-induced liver disease or treatment-related grade 4/5
toxicity was seen within 3 months of SBRT [26].
The ongoing multicentre UK randomised phase II, ABC-07, clinical trial ran-
domises patients in a 2:1 ratio between CisGem chemotherapy + SBRT and CisGem
chemotherapy alone. If feasibility of recruitment is demonstrated (feasibility phase),
the study will then continue to full accrual. It will evaluate the efficacy of six cycles
232 J. Cotton et al.

of CisGem chemotherapy followed by SBRT (experimental arm) compared to

eight cycles of CisGem chemotherapy (control arm). The primary endpoint is
improvement in PFS at 12 months (EudraCT number 2014-003656-31).

 elective Internal Radiation Therapy (SIRT) in Unresectable

S
Cholangiocarcinoma

Selective internal radiation therapy consists of the injection of millions of tiny beads
or microspheres into the hepatic artery feeding the tumour or region of the liver
containing malignancy. They embed and irradiate surrounding tissue with
yttrium-90, via radioembolisation. A meta-analysis of 12 relevant studies demon-
strated a partial radiological-based tumour response in 28% of patients, and stable
disease in 54%, at three months, in the setting of unresectable disease. The compli-
cation profile of radioembolisation is similar to that of other intra-arterial treatment
modalities with elevated liver enzymes, radiotherapy-induced hepatitis and ascites
[27]. The SIRCCA trial (clinicaltrials.gov identifier, NCT02807181) is a first-line
randomised phase II trial for patients with inoperable ICC, investigating standard of
treatment CisGem in one arm versus SIRT preceding CisGem in the other arm; this
study is currently recruiting.

Proton Beam Irradiation in Locally Advanced Cholangiocarcinoma

Proton beam therapy, a method of delivering high-dose radiotherapy, minimising

normal tissue dose because of the unique physical properties of heavy particles, has
been used as a successful method of gaining local control in cholangiocarcinoma. A
phase II multi-institutional study of 83 evaluable patients has been conducted to
determine the efficacy and safety of proton beam therapy in patients with hepatocel-
lular carcinoma and unresectable ICC. Thirty-seven of these patients had ICC, and
OS at 2 years was 46.5% for this patient population [28]. As expected, the larger
tumour sizes and worse performance status were associated with inferior survival.
The most common associated toxicities were gastrointestinal symptoms and chol-
angitis (seen in 40% of patients).

 onclusion on Use of Locoregional Therapies

C
in Cholangiocarcinoma

Locoregional therapies can be used in the locally advanced or palliative settings in

cholangiocarcinoma, and Fig. 18.1 demonstrates where they can potentially be
included in a patient’s disease trajectory. These treatments have only been assessed
18 Novel Treatments for Advanced Cholangiocarcinoma 233

Cholangiocarcinoma

Early stage Locally advanced or metastatic

Surgery Is there an appropriate clinical trial available?

No Yes

Is there an appropriate clinical trial available? Standard of care Clinical trial

treatment with • Loco-regional therapy (see
No Yes CisGem below)
• Chemotherapy +/-targeted
Standard adjuvant Adjuvant therapy/novel agents
chemotherapy clinical trial

Stability following 1st line

treatment

Surveillance Is loco-regional therapy appropriate?

Yes

Progression following 1st line

Is there an appropriate clinical trial available? treatment

Yes No

Loco-regional trial Consider

Introduce palliative care if unfit
• Chemosaturation SBRT/SIRT
• TACE/ DEB-TACE
• SBRT/SIRT If fit, is there an appropriate clinical trial
• IRE Surveillance
• RFA No Yes
• Proton beam Progression Treatment at Clinical trial
discretion of • Chemotherapy
Surveillance
clinician • Targeted therapy/
novel agents

Key
Standard treatment Clinical question Clinical trial

Fig. 18.1 Algorithm for the potential future management of patients with cholangiocarcinoma
(modified from ESMO guidelines, Ann Oncol (2016) 27 (suppl 5): v28-v3, Valle et al.). TACE
transcatheter arterial chemoembolisation, DEB-TACE drug-eluting bead transcatheter arterial che-
moembolisation, SBRT Stereotactic body radiation therapy, SIRT selective internal radiation ther-
apy, IRE irreversible electroporation, RFA radiofrequency ablation

in small, early phase trials and retrospective series, but have shown some promise
in local control and OS. Toxicity to the liver and other abdominal organs is prevalent
(occurring in up to 40% of patients). Clinical trials and good patient selection, con-
sidering performance status and tumour size, are imperative prior to offering these
novel treatments. Results of prospective randomised trials will evaluate the magni-
tude of benefit compared to currently available options.
234 J. Cotton et al.

Systemic Therapies in the Treatment of Cholangiocarcinoma

Advances in technology for drug delivery and an improved understanding of

advanced cholangiocarcinoma and its microenvironment are aiding researchers in
identification of potential future treatment options, including targeted agents and
immunotherapies. This section will review the current evidence supporting these
potential treatment options. For standard systemic therapy options, please refer to
the previous Chap. 16 in this book.

 ome Targeted Therapies Investigated in Biliary Tract

S
Cancers

 argeting Epidermal Growth Factor Receptor (EGFR)

T
Mutations in Biliary Tract Cancer

Common carcinoma-associated gene mutations are found in the epidermal growth

factor receptor (EGFR), providing a rationale for targeting EGFR-tyrosine kinase
(EGFR-TK) with novel treatment approaches. The EGFR-TK is strictly controlled
in normal cells and activated in many tumour cells, and it provides signals that drive
dysregulated proliferation, invasion and metastasis, angiogenesis and enhanced cell
survival [29]. The use of agents to inhibit this pathway has been investigated as a
therapeutic strategy in cholangiocarcinoma [30, 31]. Erlotinib is an oral tyrosine
kinase inhibitor which acts on the intracellular kinase domain. Cetuximab and pani-
tumumab are intravenously administered anti-EGFR monoclonal antibodies; they
act on the extracellular receptors of the same pathway.
The use of EGFR-TK inhibitors and anti-EGFR antibodies in biliary tract can-
cers has led to mixed results. Some of the randomised phase II and III studies utilis-
ing these agents are summarised in Table 18.2.
Although the data reported in Table 18.2 include all biliary tract cancers, there
have been further subgroup analyses of the use of EGFR-TK inhibitors within some
of these studies.
An early phase II trial suggested that there could be therapeutic benefit for EGFR
blockade with erlotinib as a monotherapy in biliary tract cancer [36]. However,
erlotinib compared with standard chemotherapy in a phase III trial [32] showed no
OS advantage and no significant difference in PFS. A subgroup analysis of the 180
patients with cholangiocarcinoma reported that those who received erlotinib with
gemcitabine and oxaliplatin (GEMOX), versus GEMOX alone, had a significantly
better PFS of 5.9 months versus 3 months (p = 0.049). Although grade 3 and 4 tox-
icities were not significantly more frequent in the erlotinib group, toxicity-related
dose reductions were more common in the combination therapy arm (64% versus
43%) [32]. In a randomised phase II trial subgroup analysis [34] of the use of pani-
tumumab in cholangiocarcinoma, patients with ICC treated with panitumumab plus
 18

Table 18.2 Trials using EGFR inhibitors in patients with advanced biliary tract cancers
Phase Median f/u EGFR PFS OS
Name of study Drug (dose) of trial N (months) expression Most common toxicity (months) (months) ORR
NCT01149122 Erlotinib (100 mg) and III 268 15 Not Febrile neutropenia 5.8 vs. 9.5 in both 40 (30%)
GEMOX versus GEMOX reported 4.2 groups vs. 21
alone [32] (16%)
BINGO Cetuximab and GEMOX II 150 31.1 23% Peripheral neuropathy, 6.1 vs. 11.0 vs. 24% vs.
versus GEMOX alone [33] neutropenia and 5.5 12.4 23%
aminotransferase elevation
TCOG T1210 Cetuximab (500 mg/m2) II 122 – (KRAS)- – 6.7 vs. 10.6 vs. 27% vs.
and GEMOX versus 36.1% 4.1 9.8 17%
GEMOX alone [31]
Vecti-BIL Panitumumab (6 mg/kg) II 89 10.1 Not Skin toxicity 5.3 vs. 9.9 vs. 26.6% vs.
Novel Treatments for Advanced Cholangiocarcinoma

and GEMOX versus reported 4.4 10.2 18.1%

GEMOX alone [34]
PICCA Panitumumab (6 mg/kg) II 93 – (p53 34%) Skin toxicity 6.7 vs. 12.4 vs. 45% vs.
and Cis/Gem versus Cis/ 8.2 21.4 39%
Gem alone [35]
Abbreviations: N number of participants; f/u follow-up; PFS progression-free survival; OS overall survival; ORR objective response rate; EGFR epidermal
growth factor receptor; GEMOX gemcitabine plus oxaliplatin; Cis/Gem cisplatin and gemcitabine
235
236 J. Cotton et al.

chemotherapy had a non-significant survival benefit in comparison with chemo-

therapy alone (15.1 vs. 11.8 months, p = 0.13).
Cetuximab has been associated with improved outcomes in various malignan-
cies including colorectal, lung and head and neck cancer [37]. Cetuximab and
panitumumab have shown antitumour activity in RAS wild-type colorectal cancer
[35, 37]. The KRAS or EGFR mutation status is not related to outcome in advanced
ICC [33, 34].
The use of EGFR-targeted agents in combination with chemotherapy in this dis-
ease group has shown no benefit in OS compared to standard chemotherapy, and
only one study showed a significant difference in PFS [31]. With no effective tar-
geted therapy for cholangiocarcinoma identified in the face of several negative tri-
als, further investigation of chemotherapy in combination with EGFR-targeted
agents is not yet warranted.

Targeting Angiogenesis in Biliary Tract Cancer

Vascular endothelial growth factor (VEGF) is overexpressed in biliary tract cancers

and has been proposed as a therapeutic target [38]. It is one of the main growth fac-
tors regulating angiogenesis. Receptors for this ligand are also expressed in the
adjacent endothelial cells and are named VEGF receptor-1 (VEGFR1) and VEGFR2.
Bevacizumab is a recombinant humanised monoclonal antibody that blocks
angiogenesis by inhibiting vascular endothelial growth factor-A (VEGF-A). It has
demonstrated efficacy in a number of other solid tumours, including colorectal can-
cer, renal cell cancer, non-small cell lung cancer and metastatic breast cancer [39].
In phase I and II trials, bevacizumab in combination with erlotinib demonstrated no
pharmacokinetic interaction [40, 41]; but there are no randomised trials to establish
whether bevacizumab can improve standard-of-care outcomes in biliary tract can-
cer. A phase II trial exploring its use in patients diagnosed with advanced cholangio-
carcinoma in combination with erlotinib reported a small response rate of just 12%,
with a median OS of 9.9 months and median time to disease progression of
4.4 months [39].
Cediranib is an oral tyrosine kinase inhibitor acting on VEGFR1, VEGFR2 and
VEGFR3, with additional activity against platelet-derived growth factor (PDGF)
receptors and the proto-oncogene c-KIT. A multicentred, placebo-controlled, ran-
domised phase II trial [38] of 124 patients (ABC-03) reported that PFS did not
improve with the addition of cediranib to CisGem chemotherapy (median PFS
7.4 months vs. 8.0 months in the standard CisGem and placebo group). The study
did not meet its primary endpoint (to detect an improvement in PFS), maybe due to
lack of efficacy, but also perhaps due to the fact that patients on cediranib discontin-
ued treatment at a median of 4.6 months, mainly due to toxic effects. The most
common grade 3 toxicity was hypertension (37%). The partial response rate of 41%
in the cediranib group and improved 6-month PFS of 70.5% in the cediranib group
versus 61.3% in the placebo group suggest that cediranib may have had some ben-
18 Novel Treatments for Advanced Cholangiocarcinoma 237

eficial effect. However, its toxicity profile, and therefore limited exposure to treat-
ment, prevents longer-term benefit.
The role of VEGF inhibition in addition to chemotherapy for patients with
advanced biliary tract cancer remains investigational. Whether a better-tolerated
anti-VEGF treatment can improve overall survival in combination with chemother-
apy remains to be seen.

 he Use of Isocitrate Dehydrogenase 1 (IDH-1) Mutation

T
Inhibitors in Cholangiocarcinoma.

Somatic mutations in IDH-1 produce the oncometabolite D-2-hydroxyglutarate

(2-HG) which promotes oncogenesis. Mutant IDH-1 (mIDH-1) was first detected in
an integrated genomic analysis of human glioblastoma. Mutations in IDH-1 occur
in up to 25% of ICC [9]. The ongoing ClarIDHy trial is a phase III multicentred,
randomised, placebo-controlled trial of AG-120, an inhibitor of the mIDH-1
enzyme; it plans to enrol 186 patients with an IDH-1 mutation [9]. In the small
phase I trial (500 mg daily versus placebo) in advanced cholangiocarcinoma,
AG-120 demonstrated a favourable safety profile and some clinical activity (with
40% PFS rate at 6 months) (clinicaltrials.gov identifier, NCT02073994).

 he Role of Fibroblast Growth Factor Receptor 2 (FGFR2)

T
Fusion Mutations in Cholangiocarcinoma

Fibroblast growth factor receptor (FGFR) alterations are implicated in the develop-
ment and progression of ICC. There are four subtypes of FGFR identified in mul-
tiple cancers, including breast, bladder, lung, gastric, endometrial and multiple
myeloma [42]. Using fluorescent in situ hybridisation (FISH) or next-generation
sequencing (NGS), mutations are seen in up 20% of ICC [43], with FGFR2 translo-
cations occurring in approximately 13% of patients [44]. The presence of FGFR
fusions is therefore a potential therapeutic target and is currently being investigated
in clinical trials.
The highly potent and selective irreversible FGFR inhibitor, TAS-120, inhibits
all four FGFR subtypes. It has been shown in vitro to inhibit growth of human can-
cer cell lines with FGFR gene abnormalities selectively, cellular phosphorylation of
FGFR, intercellular signalling pathways downstream of FGFR and tumour growth
in human tumour xenograft mouse models [42].
Other FGFR inhibitors, such as ARQ 087 and INCB054828 are currently being
investigated in clinical trials in this patient group [8, 43]. The pan-FGFR inhibitor,
ARQ 087, is undergoing a phase I/phase II open-label clinical trial for patients
with identified FGFR2 status positivity in ICC. An interim analysis following
238 J. Cotton et al.

p­ ost-­treatment radiographic assessment has reported partial response, stable disease

and progressive disease in 20%, 57% and 23% of patients, respectively. This indi-
cates encouraging antitumour activity with a manageable safety profile.
A selective FGFR inhibitor to FGFR1, FGFR2 and FGFR3, INCB054828 [8] is
being investigated in a phase II open-label study recruiting patients with unresect-
able cholangiocarcinoma.
A phase I study by Nogova et al. has recently reported that oral BGJ398, a selec-
tive FGFR1-3 tyrosine kinase inhibitor, demonstrated antitumour activity in several
advanced solid tumour types. Common adverse effects at the maximum tolerated
dose were hyperphosphataemia (82.5%), constipation (50.9%), decreased appetite
(45.6%) and stomatitis (45.6%) [45]. A phase II study has evaluated BGJ398 antitu-
mor activity in patients with advanced or metastatic cholangiocarcinoma containing
FGFR2 fusions or other FGFR alterations whose disease had progressed whilst
receiving prior therapy, and promising antitumor activity was demonstrated, with an
overall response rate of 14.8% (18.8% FGFR2 fusions only), disease control rate of
75.4% (83.3% FGFR2 fusions only) and estimated median PFS of 5.8 months (95%
CI, 4.3 to 7.6 months) [46].

 itogen-Activated Protein/Extracellular Signal-Regulated

M
Kinase Kinase (MEK) Inhibitors in Biliary Tract Cancer

Trametinib is a MEK inhibitor which acts downstream in the mitogen-activated

protein kinase (MAPK) pathway. Mitogen-activated protein kinase pathway altera-
tions have been identified in biliary cancers [47]. A randomised phase II trial of 80
patients with cholangiocarcinoma or gallbladder cancer who failed platinum/gem-
citabine therapy, and then received oral trametinib versus chemotherapy with oral
capecitabine or infusional 5-fluorouracil, reported that survival was not improved in
a planned interim analysis of objective response of 14 patients registered to the
trametinib arm. Consequently, the study was interrupted early [47]. Further research
is required to ascertain if there is a strong enough scientific rationale for pursuing
MEK inhibition with or without chemotherapy in this disease group.

Immunotherapies in Biliary Tract Cancer

Immune checkpoint inhibitors have demonstrated encouraging response rates in

numerous cancer groups including melanoma, renal cell cancer, colorectal, bladder
and urothelial carcinoma and non-small cell lung cancer [48]. This negative feed-
back pathway supresses the T-cell immune response and is upregulated in many
tumours and their surrounding microenvironment. Expression of programmed
death-ligand-1 (PD-L1) and programmed death-ligand-2 (PD-L2) on the surface of
tumour cells is important. However, it is not an entirely reliable predictive marker of
18 Novel Treatments for Advanced Cholangiocarcinoma 239

response to treatment with immune checkpoint inhibitors [49]. Another factor which
may be used as a predictive marker of response is mismatch repair (MMR) defi-
ciency in cholangiocarcinoma, which is strongly associated with therapeutic
response to PD-1 blockade in colorectal cancer [50]. The presence of MMR defi-
ciency leads to a high mutational load and microsatellite instability (MSI) (accumu-
lation of numerous insertion/deletion mutations affecting microsatellites). This, in
turn, leads to T-cell neoantigen production with a pronounced antitumour immune
response resulting in successful immune checkpoint blockade [50]. The MSI phe-
notype is most frequently found in colorectal and endometrial cancers, but also
occurs in a variety of other malignancies [51]. The availability of MSI analysis may
open new therapeutic options for biliary tract cancer after (or even prior to) standard
treatment.

Targeting Programmed Death-1 and Programmed Death-Ligand 1

Even tumours without PD-L1 expression or dense infiltration with cytotoxic cells
can show a good response to immunotherapies. A case series characterising PD-L1
and PD-1 expression and density of tumour-infiltrating lymphocytes (TILs) in 99
cholangiocarcinoma specimens reported that PD-L1 expression by neoplastic cells
was observed in only nine patients, but PD-L1 positive inflammatory cell aggre-
gates were identified in 46. Expression of PD-L1 by either neoplastic or inflamma-
tory cells was associated with a high density of CD3-positive TILs. The results
highlight that cholangiocarcinomas with dense intra-tumoral lymphocytic infiltra-
tion might represent good candidates for PD-L1/PD-1 blocking agents [48].
There is a case report of a patient with extrahepatic cholangiocarcinoma who had
a strong and durable response to the immune checkpoint inhibitor pembrolizumab
(a highly selective humanised monoclonal antibody against PD-1 and its ligands,
PD-L1 and PD-L2) [50]. The patient’s tumour displayed deoxyribonucleic acid
(DNA) MMR deficiency and MSI, but lacked other features commonly discussed as
predictors of response to checkpoint blockade, such as PD-L1 expression or dense
infiltration with cytotoxic T cells. Notably, high levels of human leukocyte antigen
(HLA) class I and II expression were detected in the tumour, suggesting a potential
causal relationship between functionality of the tumour’s antigen presentation
machinery and the success of immune checkpoint blockade. This suggests that it is
worthwhile to determine MSI status in combination with HLA class I and II antigen
expression in tumours potentially eligible for immune checkpoint blockade, even in
the absence of conventional markers predictive for anti-PD-1/PD-L1 therapy or in
entities not commonly linked to MSI phenotype [50]. Defects in HLA class I expres-
sion may allow tumour cells to escape immune recognition [52]. A phase II trial to
evaluate the clinical activity of pembrolizumab (anti-PD-1 immune checkpoint
inhibitor), in patients with progressive metastatic disease, identified MMR defi-
ciency in one case of cholangiocarcinoma; however the response to pembrolizumab
was not discussed [53].
240 J. Cotton et al.

No large phase II/III clinical trials have been conducted to ascertain if PD-L1/
PD-1 blockade results in improved survival in cholangiocarcinoma. KEYNOTE-028
is a phase Ib multicohort trial designed to assess the safety and antitumour activity
of pembrolizumab in patients with PD-L1-positive advanced biliary tract cancer.
Preliminary results report that 17% had a partial response, 17% had stable disease,
and 52% had progressive disease. The treatment was generally well tolerated, but
these data again demonstrate that targeting the PD-L1 ligand does not guarantee
response to treatment, even in the presence of PD-L1 expression [54].

Mesothelin in Cholangiocarcinoma

Mesothelin is a tumour differentiation antigen present at low levels in a restricted

set of normal adult tissues and is expressed at high levels in mesothelioma and also
in ovarian, pancreatic and lung cancers [55]. Its use as a therapeutic target in chol-
angiocarcinoma has yet to be fully investigated. An anti-mesothelin recombinant
immunotoxin, SS1P, has been found to be active in cholangiocarcinoma in vitro and
may be a relevant antigenic target for future immunotherapies [55].

 onclusion on the Use of Systemic Therapy Options

C
in Cholangiocarcinoma

Understanding of cholangiocarcinoma biology, the oncogenic landscape of this dis-

ease and its complex interaction with the tumour microenvironment and immune
response could lead to optimum therapies with improvement in patient survival.
Studies to characterise the mutational landscape of cholangiocarcinoma further may
help to identify appropriate future lines of treatment following standard of care.
However, there have been instances where genetic alterations do not stratify risk of
disease recurrence or death. More research is required to understand the tumour
microenvironment and relevant antigenic targets better. The use of immunotherapy
and targeted therapy in cholangiocarcinoma in the UK remains investigational, and
therefore these agents remain available only to those patients eligible for clinical
trials.

References

1. Khan SA, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update.
Gut. 2012;61(12):1657–69.
2. Tabata M, et al. Surgical treatment for hilar cholangiocarcinoma. J Hepato-Biliary-Pancreat
Surg. 2000;7(2):148–54.
3. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383(9935):2168–79.
18 Novel Treatments for Advanced Cholangiocarcinoma 241

4. Salgado SM, Gaidhane M, Kahaleh M. Endoscopic palliation of malignant biliary strictures.

World J Gastrointest Oncol. 2016;8(3):240–7.
5. Basch E, et al. Overall survival results of a trial assessing patient-reported outcomes for symp-
tom monitoring during routine cancer treatment. JAMA. 2017;318(2):197–8.
6. Valle J, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J
Med. 2010;362(14):1273–81.
7. Lamarca A, et al. Second-line chemotherapy in advanced biliary cancer: a systematic review.
Ann Oncol. 2014;25(12):2328–38.
8. Borad MJ, et al. Phase 2, open-label, multicenter study of the efficacy and safety of
INCB054828 in patients (pts) with advanced, metastatic, or surgically unresectable
cholangiocarcinoma (CCA) with inadequate response to prior therapy. J Clin Oncol.
2017;35(15_suppl):TPS4145.
9. Lowery MA, et al. ClarIDHy: a phase 3, multicenter, randomized, double-blind study of
AG-120 vs placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation.
J Clin Oncol. 2017;35(15_suppl):TPS4142.
10. Boehm LM, et al. Comparative effectiveness of hepatic artery based therapies for unresectable
intrahepatic cholangiocarcinoma. J Surg Oncol. 2015;111(2):213–20.
11. Vogel A, et al. Chemosaturation percutaneous hepatic perfusion: a systematic review. Adv
Ther. 2017;33(12):2122–38.
12. Hughes MS, et al. Results of a randomized controlled multicenter phase III trial of percuta-
neous hepatic perfusion compared with best available care for patients with melanoma liver
metastases. Ann Surg Oncol. 2016;23(4):1309–19.
13. Vogl TJ, et al. Chemosaturation with percutaneous hepatic perfusions of melphalan for hepatic
metastases: experience from two European centers. Rofo. 2014;186(10):937–44.
14. Pingpank JF, et al. Phase I study of hepatic arterial melphalan infusion and hepatic venous
hemofiltration using percutaneously placed catheters in patients with unresectable hepatic
malignancies. J Clin Oncol. 2005;23(15):3465–74.
15. Aliberti C, et al. Chemoembolization (TACE) of unresectable intrahepatic cholangiocarci-
noma with slow-release doxorubicin-eluting beads: preliminary results. Cardiovasc Intervent
Radiol. 2008;31(5):883–8.
16. Kuhlmann JB, et al. Treatment of unresectable cholangiocarcinoma: conventional transarterial
chemoembolization compared with drug eluting bead-transarterial chemoembolization and
systemic chemotherapy. Eur J Gastroenterol Hepatol. 2012;24(4):437–43.
17. Ball C, Thomson KR, Kavnoudias H. Irreversible electroporation: a new challenge in “out of
operating theater” anesthesia. Anesth Analg. 2010;110(5):1305–9.
18. Onik G, Mikus P, Rubinsky B. Irreversible electroporation: implications for prostate ablation.
Technol Cancer Res Treat. 2007;6(4):295–300.
19. Giorgio A, et al. Radiofrequency ablation for intrahepatic cholangiocarcinoma: retrospective
analysis of a single centre experience. Anticancer Res. 2011;31(12):4575–80.
20. Xu HX, et al. Percutaneous ultrasound-guided thermal ablation for intrahepatic cholangiocar-
cinoma. Br J Radiol. 2012;85(1016):1078–84.
21. Fu Y, et al. Radiofrequency ablation in the management of unresectable intrahepatic cholan-
giocarcinoma. J Vasc Interv Radiol. 2012;23(5):642–9.
22. Kim JH, et al. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocar-
cinoma. AJR Am J Roentgenol. 2011;196(2):W205–9.
23. Jung DH, et al. Outcomes of stereotactic body radiotherapy for unresectable primary or recur-
rent cholangiocarcinoma. Radiat Oncol J. 2014;32(3):163–9.
24. Mahadevan A, et al. Stereotactic body radiotherapy (SBRT) for intrahepatic and hilar cholan-
giocarcinoma. J Cancer. 2015;6(11):1099–104.
25. Polistina FA, et al. Chemoradiation treatment with gemcitabine plus stereotactic body radio-
therapy for unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma. Results
of a five year experience. Radiother Oncol. 2011;99(2):120–3.
26. Tse RV, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular
carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2008;26(4):657–64.
242 J. Cotton et al.

27. Al-Adra DP, et al. Treatment of unresectable intrahepatic cholangiocarcinoma with

yttrium-90 radioembolization: a systematic review and pooled analysis. Eur J Surg Oncol.
2015;41(1):120–7.
28. Hong TS, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam
therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic
cholangiocarcinoma. J Clin Oncol. 2016;34(5):460–8.
29. Ritter CA, Arteaga CL. The epidermal growth factor receptor-tyrosine kinase: a promising
therapeutic target in solid tumors. Semin Oncol. 2003;30(1 Suppl 1):3–11.
30. Paule B, et al. Cetuximab plus gemcitabine-oxaliplatin (GEMOX) in patients with refractory
advanced intrahepatic cholangiocarcinomas. Oncology. 2007;72(1–2):105–10.
31. Chen L-T, et al. KRAS mutation status-stratified randomized phase II trial of GEMOX with
and without cetuximab in advanced biliary tract cancer (ABTC): The TCOG T1210 trial. J
Clin Oncol. 2013;31(15_suppl):4018.
32. Lee J, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract can-
cer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012;13(2):181–8.
33. Malka D, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-­
tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol.
2014;15(8):819–28.
34. Leone F, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not pro-
long survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial
(Vecti-BIL study). Cancer. 2016;122(4):574–81.
35. Vogel A, et al. Panitumumab in combination with gemcitabine/cisplatin (GemCis) for
patients with advanced kRAS WT biliary tract cancer: a randomized phase II trial of the
Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol. 2015;33(15_suppl):4082.
36. Philip PA, et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin
Oncol. 2006;24(19):3069–74.
37. Gruenberger B, et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable
advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol. 2010;11(12):1142–8.
38. Valle JW, et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemo-
therapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.
Lancet Oncol. 2015;16(8):967–78.
39. Lubner SJ, et al. Report of a multicenter phase II trial testing a combination of biweekly beva-
cizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium
study. J Clin Oncol. 2010;28(21):3491–7.
40. Herbst RS, et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor mono-
clonal antibody bevacizumab in combination with the HER-1/epidermal growth factor recep-
tor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J
Clin Oncol. 2005;23(11):2544–55.
41. Thomas MB, et al. Phase II trial of the combination of bevacizumab and erlotinib in patients
who have advanced hepatocellular carcinoma. J Clin Oncol. 2009;27(6):843–50.
42. Ochiiwa H, et al. Abstract A270: TAS-120, a highly potent and selective irreversible FGFR
inhibitor, is effective in tumors harboring various FGFR gene abnormalities. Mol Cancer Ther.
2013;12(11 Supplement):A270.
43. Mazzaferro V, et al. ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor,
in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic
aberrations. J Clin Oncol. 2017;35(15_suppl):4017.
44. Arai Y, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molec-
ular subtype of cholangiocarcinoma. Hepatology. 2014;59(4):1427–34.
45. Nogova L, et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor,
in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor
receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol.
2017;35(2):157–65.
18 Novel Treatments for Advanced Cholangiocarcinoma 243

46. Javle M, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangio-
carcinoma. J Clin Oncol. 2018;36(3):276–82.
47. Kim RD, et al. SWOG S1310: randomized phase II trial of single agent MEK inhibitor tra-
metinib vs. 5-fluorouracil or capecitabine in refractory advanced biliary cancer. J Clin Oncol.
2017;35(15_suppl):4016.
48. Fontugne J, et al. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma.
Oncotarget. 2017;8(15):24644–51.
49. Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N
Engl J Med. 2012;366(26):2443–54.
50. Czink E, et al. Successful immune checkpoint blockade in a patient with advanced stage mic-
rosatellite unstable biliary tract cancer. Cold Spring Harb Mol Case Stud. 2017;3(5)
51. Hause RJ, et al. Classification and characterization of microsatellite instability across 18 can-
cer types. Nat Med. 2016;22(11):1342–50.
52. Sabbatino F, et al. PD-L1 and HLA Class I antigen expression and clinical course of the dis-
ease in intrahepatic cholangiocarcinoma. Clin Cancer Res. 2016;22(2):470–8.
53. Le DT, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med.
2015;372(26):2509–20.
54. Bang YJ, et al. 525 Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with
advanced biliary tract cancer: interim results of KEYNOTE-028. Eur J Cancer. 2015;51:S112.
55. Yu L, et al. Mesothelin as a potential therapeutic target in human cholangiocarcinoma. J
Cancer. 2010;1:141–9.
Chapter 19
Making the Diagnosis of Neuroendocrine
Tumour Disease

Vandana M. Sagar, Mona Elshafie, and Tahir Shah

Key Learning Points

1. The incidence of neuroendocrine tumours (NETs) is rising in the United
Kingdom.
2. NETs are slow-growing tumours that are often discovered incidentally on
imaging or histology. Their presentation is dependent on location of dis-
ease and hormone-related symptoms.
3. Majority of pancreatic NETs (panNETs) are ‘non-functioning’.
Functioning panNETs present with symptoms related to the hormone they
may secrete—such as insulin or gastrin.
4. Bronchial carcinoids usually present early with usual chest symptoms—
cough, infection and haemoptysis.
5. Expert histopathological assessment is essential. Cross-sectional and func-
tional imaging modalities are used for staging and planning treatments.
6. NET management can be complex and should always be arranged in con-
junction with a centre with comprehensive expertise.
7. All cases should be discussed in a multidisciplinary neuroendocrine
tumour multidisciplinary meeting (NET MDM) in order to deliver optimal
care.

V. M. Sagar (*) · M. Elshafie · T. Shah

Birmingham Neuroendocrine Tumour Centre, Queen Elizabeth Hospital, Birmingham, UK
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2019 245

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_19
246 V. M. Sagar et al.

Areas of Controversy and Uncertainty

1. Strategies for earlier diagnosis: most patients continue to be diagnosed
with metastatic disease such that cure is not possible. However there is no
agreement on ways to improve this situation through the use of available
diagnostic modalities as screening tools.

Areas of Likely Future Progress

1. Somatostatin receptor-targeted imaging modalities such as DOTA PET
are improving resolution and accuracy. There will likely be further
improvement through the use of somatostatin receptor antagonists as
tracers.
2. Telotristat may be licenced in the near future as a new therapy for carci-
noid syndrome.
3. There is a need for highly effective systemic treatments that can either cure
or effectively control the disease for very long periods, hence providing a
normal or near normal life expectancy.

Introduction

Epidemiology

Neuroendocrine tumours (NETs) are rare, but their incidence is on the rise in the
United Kingdom. Public Health England identified 8726 neuroendocrine neoplasms
(3978 NETs) diagnosed between 2013 and 2014 in England yielding an overall
incidence rate of 8 per 100,000 persons [1]. According to the World Health
Organisation (WHO) 2010 classification, NETs are graded from 1 to 3 (G1–G3)
which is based on the cellular proliferation rate (i.e. Ki-67 index) and the mitotic
count [2, 3]. G1 and G2 tumours are generally well-differentiated NETs, and G3 can
either be well-differentiated NETs or poorly differentiated neuroendocrine carcino-
mas (NECs) [2]. It is important to identify the G3 NETs from poorly differentiated
NECs as treatments used will differ markedly. There are as many NECs diagnosed
as NETs. There is a growing body of evidence to aid the management of NETs,
whereas very little evidence exists to help manage NECs. The NECs are often
referred to the neuroendocrine tumour multidisciplinary meeting (NET MDM) for
treatment decision. Much smaller groups consist of the mixed adenoneuroendocrine
carcinomas, Merkel cell carcinomas and a few rarer morphologies [1].
The majority of well-differentiated NETs arise in the gastrointestinal (GI)
tract and pancreas. The lung is the second commonest site of origin. Other, albeit
rarer, primary sites for NETs include the breast, ovaries, head and neck, renal
tract and skin. The primary site is unknown in approximately 8.7% [1]. There is
equal distribution between males and females. Even at an advanced stage of
19 Making the Diagnosis of Neuroendocrine Tumour Disease 247

disease at diagnosis, NETs have a better overall 1-year survival (at least 90%)
compared to NECs and other subtypes (as low as 40%) [1]. Unsurprisingly, sur-
vival for patients with NECs and other subtypes is dependent on the stage of the
tumour at diagnosis [1].

Aetiology

NETs are slow-growing tumours originating from cells containing neuroendocrine

properties (known as enterochromaffin or Kulchitsky cells) [4, 5]. These cells
express particular proteins including neuron-specific enolase and synaptophysin,
which are classically identified in neural cells. In addition, they produce certain
amines and peptide hormones including serotonin, somatostatin, substance P and
vasoactive intestinal peptide (VIP) [5].
NETs originating in the GI tract were traditionally classified into tumours of the
foregut, midgut and hindgut according to their embryological origin but now com-
monly follow the WHO 2010 classification system as described above [4]. There is
currently emerging data on the molecular biology of NETs suggesting the presence
of a role for molecular profiling and common genetic characteristics that may play
a pivotal role in the classification of these tumours, in addition to identifying pos-
sible molecular targets involved in tumour progression [4].

Genetics

The majority of NETs occur sporadically, but a small group of patients will have an
inheritable condition [4]. NETs may be associated with familial endocrine cancer
syndromes such as multiple endocrine neoplasia 1 (MEN1), multiple endocrine
neoplasia 2 (MEN2), Von Hippel-Lindau (VHL) and tuberous sclerosis (TS) [2, 4].
In gastroenteropancreatic (GEP) NETs, the incidence of MEN1 varies from nearly
nil in GI NETs to 5% in insulinomas and 25–30% in gastrinomas [6]. Some patients
with midgut NETs have shown mutations in the succinate-ubiquinone oxidoreduc-
tase subunit D (SDHD) gene which is usually associated with phaeochromocyto-
mas and paragangliomas [7]. It is therefore imperative to take a detailed family
history and perform a thorough examination in patients with NETs and attempt to
identify patients at risk for inherited conditions. Appropriate patients should then be
referred for genetic testing to confirm the diagnosis [4]. A diagnosis of MEN1,
MEN2, TS, neurofibromatosis type 1 (NF1) or a paraganglioma syndrome should
necessitate screening for other associated tumours and genetic testing of patients’
relatives [4].
Another significant risk factor for developing any type of NET is a family history
of cancer, with the risk found to be greater in females than in males [8]. It has also
been shown that pre-existing diabetes mellitus, particularly in women, has a strong
248 V. M. Sagar et al.

association with gastric NETs, with one study showing the development of synchro-
nous cancer (mostly colon adenocarcinoma) occurring in 25% of patients with a GI
NET [8, 9].

Clinical Features

In this chapter, the clinical features of the two commonest sites for NETs to occur
(GEP NETs and pulmonary NETs) will be explained.

GEP NETs

GI NETs can present with symptoms related to local mass effect or desmoplasia.
Symptoms from distant metastases, commonly to the liver, can also occur. Around
60% of pancreatic NETs are non-functioning, which may present with symptoms
from the pancreatic mass and/or liver metastases. Functioning pancreatic NETs
have clinical features resulting from peptide and hormone release, and these are
discussed below [4].

Gastric NETs

Gastric NETs (g-NETs) are the most frequently diagnosed digestive NETs, with an
increasing recognition related to growing performance of upper GI endoscopies for
various diagnostic purposes [10]. They are usually benign in nature but can occa-
sionally be malignant. They are classified into three types: type 1, type 2 and type 3.
Type 1 is the commonest g-NET representing around 70–80% of all g-NETs and
is related to atrophic gastritis that leads to chronic hypergastrinaemia. Type 2 is due
to raised gastrin from a gastrinoma and is associated with Zollinger-Ellison syn-
drome (ZES) and MEN1. Type 1 and 2 are diagnosed relatively early due to symp-
toms related to underlying conditions, such as abdominal discomfort, reflux,
diarrhoea and GI haemorrhage. Type 1 g-NET is usually asymptomatic, diagnosed
on histology taken endoscopically. Type 1 and 2 g-NETs are well-differentiated
tumours. Type 3 are sporadic and do not cause symptoms until the tumour has
metastasised. They can be more aggressive with some expressing features of G3
NEC histologically. Around 50–100% of type 3 have evidence of metastases, com-
pared to 2–5% of type 1 and 10–30% of type 2 [10, 11].

Proximal Small Bowel NETs

These include the duodenal NETs (d-NETs), whereas distal small bowel NETs
include the jejunal and ileal NETs which will later be explained.
19 Making the Diagnosis of Neuroendocrine Tumour Disease 249

The d-NETs are usually sporadic but can be associated with MEN1. They are
usually non-functioning but may also present with a functional syndrome: ZES
occurring in duodenal gastrinomas [10, 12].

Distal Small Bowel NETs

These represent at least the third largest cohort within the GEP NETs. The most
frequent clinical symptom encountered is abdominal pain, which may be as a result
of small bowel obstruction (SBO), small bowel wall dysmotility or secondary to
transient mesenteric ischaemia from mesenteric fibrosis due to a desmoplastic reac-
tion. Other non-specific symptoms that can occur including nausea and vomiting in
SBO, weight loss, fatigue and occasionally GI bleeding [13]. Approximately 20%
of cases may present with carcinoid syndrome: diarrhoea, flushing, palpitations,
intermittent abdominal pain and occasionally lacrimation and rhinorrhoea [4]
(Fig. 19.1).

Colorectal NETs

Colorectal NETs are usually diagnosed incidentally on histology from tissue taken
at the time of colonoscopy or sigmoidoscopy. Common indications for performing
these endoscopic investigations include diarrhoea, abdominal pain, GI bleeding,
change in bowel habit, anorectal symptoms or weight loss. Some patients (more so
in colon NETs) may present with bowel obstruction. Colonic NETs usually present
late with extensive metastatic disease, whereas 75–80% of rectal carcinoids are
localised at diagnosis [14].

Fig. 19.1 Haematoxylin and eosin (H&E) staining. Histology specimen demonstrating a polypoid
ileal neuroendocrine tumour. Nests and trabecular growth pattern of neuroendocrine tumour cells
(A) infiltrating the mucosa (B), submucosa (C) and muscularis propria (D)
250 V. M. Sagar et al.

Functioning Pancreatic NETs

Table 19.1 summarises the symptoms associated with functioning pancreatic NETs
(F-P-NETs).

Pulmonary NETs

Pulmonary NETs encompass the typical carcinoids that are low-grade NETs and
atypical carcinoids that are intermediate-grade NETs. We will not be considering
the large cell neuroendocrine carcinomas and small cell lung carcinomas which are
the most aggressive and are high-grade malignant tumours with neuroendocrine dif-
ferentiation. Typical and atypical carcinoids may be detected incidentally on imag-
ing, or patients may present with symptoms of haemoptysis, recurrent chest
infections, shortness of breath and wheezing [15]. These tumours may also be rarely
associated with Cushing’s syndrome or ectopic adrenocorticotropic hormone secre-
tion [4, 15]. The majority of bronchial carcinoids are diagnosed at an early stage
where surgical cure is possible (Fig. 19.2).

Carcinoid Syndrome

Carcinoid syndrome is commonest in GI NET patients with sizeable metastases in

the liver. It also occurs with advanced bronchial carcinoids. Carcinoid syndrome is
rare in NETs of pancreatic origin. It usually results from the release of vasoactive
compounds, such as serotonin and tachykinins, into the systemic circulation, via the
hepatic vein, from liver metastases. However, in bronchial carcinoids, retroperito-
neal or ovarian metastases, carcinoid syndrome may occur due to direct hormone
release into the systemic venous system, bypassing the degradation capacity of the
liver [4, 16]. Another presenting feature may be of right upper quadrant pain

Table 19.1 F-P-NETs

Type of F-P-NET Symptoms
Insulinoma Hypoglycaemic symptoms including sweating, confusion,
loss of consciousness and dizziness. Improvement with
eating
Gastrinoma Profound peptic ulceration and diarrhoea in ZES or
diarrhoea alone
Glucagonoma Diabetes mellitus, rash (necrolytic migratory erythema),
weight loss
Vasoactive intestinal peptide-­ Verner-Morrison syndrome with marked watery diarrhoea
secreting tumour: VIPoma and hypokalaemia
Somatostatinoma Cholelithiasis, diabetes mellitus and diarrhoea/steatorrhoea
Adapted from Ramage JK et al. [4]
19 Making the Diagnosis of Neuroendocrine Tumour Disease 251

Fig. 19.2 Haematoxylin and eosin (H&E) staining. Histology specimen demonstrating back-
ground lung tissue (A) with an ill-defined bronchial carcinoid lesion with trabecular (B) and micro-
cystic (C) growth pattern of neuroendocrine tumour cells. Background fibrosis (D) and fresh
haemorrhage (E) with chronic inflammation (F)

secondary to hepatic enlargement, haemorrhage into the tumour or necrosis of

hepatic secondaries. Around 20% of patients with carcinoid syndrome present with
features of carcinoid heart disease (CHD) at diagnosis [4].

Carcinoid Heart Disease

CHD results from high levels of serotonin, in addition to other vasoactive sub-
stances, secreted by the metastatic tumour cells in the liver, reaching the right side
of the heart and causing deposition of carcinoid plaques. The resulting fibrosis and
thickening of the endocardial surface of the heart and valves lead to incompetence
of tricuspid and pulmonary valves [17]. Left-sided lesions occur in around 15% of
patients with carcinoid heart disease [4]. Foramen ovale patency is commonly
involved in those with a left-sided lesion [4].

Diagnosis

Biochemical Assessment

Measuring secretory biomarkers can assist clinicians in various ways: firstly, to aid
in making the diagnosis in functional duodenal or pancreatic NETs, by measuring
the secretory peptides or hormones, secondly to monitor the efficacy of treatments,
and thirdly to help determine the prognosis [2, 4]. Biochemical levels of calcium,
252 V. M. Sagar et al.

phosphate, parathyroid hormone and prolactin, in addition to taking a thorough fam-

ily history, may help in diagnosing MEN1. If Cushing’s syndrome is suspected in
pulmonary NETs, biochemical analysis of serum cortisol, 24-h urinary-free cortisol
and ACTH should be performed. Chromogranin A (CgA), a secretory protein found
in neuroendocrine cells, is currently the sole generic marker for all NETs, with lev-
els related to tumour bulk rather than neuroendocrine tumour type or symptoms [2].
Chromogranin B (CgB) has also been raised but is perhaps less clinically relevant
[4]. Pancreatic polypeptide (PP), normally secreted by cells in the endocrine pan-
creas, is found to be secreted in high concentrations from GEP NETs: 50–80% of
pancreatic NETs and >30% of GI NETs. PP can therefore be a useful biomarker in
certain cases, especially when CgA and CgB are within normal values [4].
Serotonin is secreted by the majority of NETs (>70%) found in the distal small
bowel (jejunum and ileum), proximal colon and appendix, as well as 10–35% of
gastric and pulmonary NETs. 5-Hydroxyindoleacetic acid (5-HIAA) is the break-
down product of serotonin which can be measured in the urine usually over a
24-hour collection. However, there are specific dietary restrictions and drug interac-
tion problems associated with serotonin and the detection of 5-HIAA, and therefore
careful instructions need to be provided to the patient to exclude certain foods and
drugs prior to urine collection [4]. Rising tumour markers after surgery, particularly
CgA, can be early indicators of tumour recurrence. Many NETs in the ileum and
colon are diagnosed histopathologically after presentation with bowel obstruction.
Biochemical samples are therefore taken post-operatively when the serum markers
and 24-hour urinary 5-HIAA levels may have normalised. CgA together with neu-
rokinin A and 24-hour urinary 5-HIAA will point towards residual disease in >90%
of patients [4]. Excluding small appendiceal NETs, surgical cure is rare, and there-
fore patients should be followed up long term with serial laboratory and radiological
investigations [4].
24-hour urinary 5-HIAA has a high sensitivity but low specificity in diagnosing
CHD and is therefore not an appropriate marker for this indication. Neurohormones
(called natriuretic peptides) released by the atria and ventricles secondary to wall
stress are a useful screening tool for CHD [4]. Levels of NTproBNP that are above
the normal range are an indication for an echocardiogram followed by a specialist
cardiology review if appropriate.

Histopathology

Histopathology is essential in the diagnosis and classification of NETs. A large

proportion of NETs are diagnosed histologically after presentation with non-spe-
cific signs and symptoms. NETs should be classified in accordance with the WHO
2010 classification, which takes into consideration the malignant potential of all
NETs. The WHO 2010 classification has a grading system: grade 1 (G1), grade 2
(G2) or grade 3 (G3), depending on their differentiation and proliferative activity
as measured by Ki-67 immunostaining and mitotic count. Whilst tumours are
graded according to the WHO 2010 classification, they should also follow the
19 Making the Diagnosis of Neuroendocrine Tumour Disease 253

Table 19.2 WHO 2010 classification

Type Grade Ki-67 index (%) Mitotic count (per 10HPF)
NET G1 ≤2 <2
NET G2 3–20 2–20
NET or NEC G3 >20 >20
NET neuroendocrine tumour; NEC neuroendocrine carcinoma; HPF high-power field. Adapted
from Niederle B et al. [13]

Union for International Cancer Control (UICC) TNM staging system. For appen-
diceal, stomach and pancreas NETs, the ENETS TNM staging system should be
used where the T-staging criteria differs from the UICC TNM staging system [4]
(Table 19.2).

Radiological Assessment

The radiological assessment of NETs can be divided into ‘anatomic imaging’ and
‘functional imaging’. Computed tomography (CT), ultrasound (US) and magnetic
resonance imaging (MRI) are examples of anatomic imaging modalities that can
provide information on the extent and staging of disease. Functional imaging,
including somatostatin receptor scintigraphy (SRS), positron emission tomography
(PET)/CT scan and tracers that mark NET metabolism, such as 3,4-dihydroxy-6-
18
F-fluoro-­
l-phenylalanine (18F-FDOPA) and 18F-fluoro-2-deoxyglucose (18F-
FDG), gives evidence of biologic behaviour and targets for specific medical
treatment in managing the disease [4, 18].
Patients at risk of genetic conditions, such as those with a family history of
MEN1, should be considered for screening according to MEN syndrome guidelines.
Generally, asymptomatic individuals should be screened with investigations that
avoid exposure to radiation, and therefore MRI is often most appropriate in this
group [4].
A number of imaging modalities may be required to diagnose and detect lesions
(in particular small lesions), stage the disease and assess response to treatment.

Anatomic Imaging

CT is the most widely used anatomic imaging modality for NETs. It shows evidence
of avid early enhancement on biphasic and triphasic contrast-enhanced CT (CECT),
in particular with pancreatic NETs. In around 20% of pancreatic NETs, an isodense
lesion with calcification can be seen on unenhanced scans in contrast to pancreatic
adenocarcinomas that lack calcification [18].
More than 40% of pulmonary NETs can be detected incidentally on a chest
x-ray. A CECT is the gold standard showing common features of a round or ovoid
shape peripheral lung nodule with lobular or smooth margins. Pulmonary NETs are
very vascular and typically show enhancement following administration of intrave-
254 V. M. Sagar et al.

nous contrast [15]. If the tumour is located centrally, features of obstruction includ-
ing obstructive pneumonitis, atelectasis or air trapping may be seen. High-resolution
CT (HRCT) with an expiration study is the modality of choice for diffuse interstitial
pulmonary neuroendocrine cell hyperplasia (DIPNECH) which shows air trapping
and nodules [15].
Small bowel NETs are often associated with mesenteric nodules and mesenteric
fibrosis due to desmoplastic reaction resulting in stranding, tethering and fat changes
seen on CT. Radiological signs of bowel ischaemia can also be identified occurring
as a result of nodal metastases encasing key vessels such as the superior mesenteric
vein and superior mesenteric artery. Liver metastases enhance in a similar way to
the primary NET, and the hepatic arterial phase of the scan will help identify these
lesions [18].
Given the regular imaging surveillance required for patients with NETs, MRI
may be preferred to reduce the risk of ionising radiation exposure. MRI has a 94%
sensitivity in diagnosing pancreatic lesions. Pancreatic NETs show hyperintensity
in T2-weighted images and hypointensity in T1-weighted images [4, 18]. Two-­
thirds of small bowel NETs can be detected on MRI and are better identified on
postgadolinium contrast T1-weighted fat-suppressed images [18]. MRI is signifi-
cantly better than CT for imaging NET liver metastases, including assessing
response to liver targeted therapy [18].

Functional Imaging

Functional imaging was used to corroborate the findings of anatomic imaging in

terms of the visible lesions being likely NET and complement the findings in terms
of lesions such as small bowel primaries that are not normally well seen on ana-
tomic imaging. However, the advent of DOTA PET imaging has made functional
imaging pre-eminent in terms of sensitivity and specificity for highlighting various
cancer lesions. DOTA PET is particularly useful as part of staging imaging prior to
surgery.
NETs overexpress somatostatin receptors (SSTRs) of subtypes 1–5. Most soma-
tostatin receptor scintigraphy (SSRS) agents target the SSTR2 and SSTR5 subtypes.
The sensitivity and specificity of SSRS are improved with the use of single-photon
emission computed tomography (SPECT) or with SPECT-CT imaging. The diag-
nostic performance for pancreatic NETs using SSRS varies between specific tumour
types, gastrinomas, VIPomas and glucagonomas, and non-functioning tumours
have a sensitivity of around 75–100% compared to 50–60% sensitivity for primary
insulinomas [19]. This is mainly because insulinomas can present with symptoms
when too small for resolution by any of these imaging modalities. There are a few
limitations associated with SSRS: firstly, the scan is performed over 2 days; sec-
ondly there is a reduced sensitivity in detecting <1 cm lesions; thirdly concurrent
use of somatostatin analogues (SSAs) can interfere with SSTR imaging; and lastly
the tumours may not express SSTRs [4].
19 Making the Diagnosis of Neuroendocrine Tumour Disease 255

Imaging using 111Indium (111I)-octreotide, or 123I or 131I-meta-iodobenzylguanidine

(mIBG), is used to identify patients with inoperable or metastatic disease who may
benefit from targeted radiotherapy with radiolabelled mIBG [4, 18]. The main indi-
cation for performing mIBG imaging is to identify patients where 131I-mIBG-­
targeted radionuclide therapy would be an option. Pancreatic NETs rarely take up
mIBG, and small bowel NETs have a better sensitivity for 111In scintigraphy than
123
I-mIBG scintigraphy [4]. Lutetium and yttrium peptide receptor radionuclide
therapy (PRRT) has superseded the use of mIBG treatment, and mIBG imaging is
mostly used in locating phaeochromocytomas.
PET/CT imaging with 68Gallium-labelled somatostatin analogues, such as
DOTA-octreotide (DOTATOC) and DOTA-octreotate (DOTATATE), bind avidly to
SSTR2 and SSTR5. In addition to these SSTR subtypes, DOTA-Nal-octreotide
(DOTANOC) also binds to SSTR3 [4]. One study showed an improved diagnostic
efficacy of using 68Ga-DOTATOC as a radiotracer with PET imaging compared with
SPECT and diagnostic CT imaging in detecting the primary lesion, the staging of
disease and follow-up [20]. 68Ga-DOTATATE PET has been found to have a greater
sensitivity and specificity compared to 111In-octreotide scintigraphy [18]. The major
disadvantage of 68Ga-peptide PET/CT is the limited availability in the United
Kingdom and elsewhere [4].
18
F-FDG PET/CT imaging is commonly used in bronchial NETs as part of stan-
dard workup for bronchial lesions. It is often not positive in well-differentiated
bronchial NETs; however, if the scan is positive, then this indicates a poorer prog-
nosis, as the tumour will usually then be of a less well-differentiated phenotype
(Figs. 19.3 and 19.4).

Fig. 19.3 Multiplanar reconstructions of an octreotide SPECT-CT scan demonstrating strong

radiotracer uptake in a focal liver neuroendocrine metastatic deposit (crosshairs). Less avid uptake
in other neuroendocrine metastatic deposits seen around this lesion
256 V. M. Sagar et al.

Fig. 19.4 Multiplanar reconstructions of 68Ga-DOTA-PET/CT scan demonstrating focal radio-

tracer uptake (arrow) in a loop of small bowel representing a neuroendocrine lesion

Table 19.3 Summary Type of diagnostic technique Type of NET diagnosed

of diagnostic
Upper GI endoscopy and biopsy Gastric and duodenal
modalities for primary
NET detection Lower GI endoscopy and biopsy Colonic and rectal
Bronchoscopy and biopsy Pulmonary
Endoscopic ultrasound (EUS) and biopsy Pancreatic
Capsule endoscopy Small bowel
DSA with intra-arterial calcium Gastrinomas
stimulation
GI Gastrointestinal, Lower GI endoscopy includes colonoscopy and flex-
ible sigmoidoscopy. DSA digital subtraction angiography. Information
from Ramage JK et al. [4]

Other Diagnostic Assessments

In addition to the diagnostic tools listed above, various other diagnostic modalities
may be used when clinically indicated. The table below summarises some of these
investigations (Table 19.3).

Strategies for Earlier Diagnosis

Unless associated with hormonal symptoms, such as due to insulin or gastrin, NETs
present late with non-specific GI symptoms or are discovered incidevntally. The
majority of patients have metastatic disease at diagnosis. Unfortunately, we do
not have accurate and easy-to-administer screening tools for diagnosing
19 Making the Diagnosis of Neuroendocrine Tumour Disease 257

neuroendocrine tumours. Nevertheless, there has been a steady increase in diagno-

sis and a perceived improvement in earlier discovery of cancer, i.e. before the onset
of carcinoid or other tumour-related symptoms. This is very likely due to the
increased general use of imaging in the general population and a lowering of thresh-
old for using US or CT imaging for abdominal symptoms after negative endoscopic
tests. Whether earlier diagnosis could be achieved without causing severe harm to
population under review remains debatable. At present there is lack of consensus on
possible strategies for earlier diagnosis.

Acknowledgements We would like to thank Dr. Salil Karkhanis for his contribution in writing
this chapter.

References

1. Incidence and survival in neuroendocrine tumours and neuroendocrine carcinomas (NETs/

NECs) in England, 2013–2014. Public Health England. 2016.
2. Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine
tumors. Cancer Metastasis Rev. 2011;30(Suppl 1):3–7.
3. Jernman J, Välimäki MJ, Louhimo J, Haglund C, Arola J. The Novel WHO 2010 classifica-
tion for gastrointestinal neuroendocrine tumour correlates well with the metastatic potential of
rectal neuroendocrine tumours. Neuroendocrinology. 2012;95(4):317–24.
4. Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, et al. Guidelines for the man-
agement of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs).
Gut. 2012;61(1):6–32.
5. Xavier S, Rosa B, Cotter J. Small bowel neuroendocrine tumors: from pathophysiology to
clinical approach. World J Gastrointest Pathophysiol. 2016;7(1):117–24.
6. Debas HT, Mulvihill SJ. Neuroendocrine gut neoplasms. Important lessons from uncommon
tumors. Arch Surg. 1994;129(9):965–71.
7. Kytölä S, Nord B, Elder EE, Carling T, Kjellman M, Cedermark B, et al. Alterations of the
SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and
abdominal paragangliomas. Genes Chromosomes Cancer. 2002 Jul;34(3):325–32.
8. Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Risk factors associated with
neuroendocrine tumors: A U.S.-based case-control study. Int J Cancer. 2008;123(4):
867–73.
9. Saha S, Hoda S, Godfrey R, Sutherland C, Raybon K. Carcinoid tumors of the gastrointestinal
tract: a 44-year experience. South Med J. 1989;82(12):1501–5.
10. Delle Fave G, O’Toole D, Sundin A, Taal B, Ferolla P, Ramage JK, et al. ENETS consen-
sus guidelines update for gastroduodenal neuroendocrine neoplasms. Neuroendocrinology.
2016;103(2):119–24.
11. Li TT, Qiu F, Qian ZR, Wan J, Qi XK, Wu BY. Classification, clinicopathologic features and
treatment of gastric neuroendocrine tumors. World J Gastroenterol. 2014;20(1):118–25.
12. Hoffmann KM, Furukawa M, Jensen RT. Duodenal neuroendocrine tumors: Classification,
functional syndromes, diagnosis and medical treatment. Best Pract Res Clin Gastroenterol.
2005;19(5):675–97.
13. Niederle B, Pape UF, Costa F, Gross D, Kelestimur F, Knigge U, et al. ENETS consensus guide-
lines update for neuroendocrine neoplasms of the jejunum and ileum. Neuroendocrinology.
2016;103(2):125–38.
14. Ramage JK, Goretzki PE, Manfredi R, Komminoth P, Ferone D, Hydrel R, et al. Consensus
guidelines for the management of patients with digestive neuroendocrine tumours: well-­
differentiated colon and rectum tumour/carcinoma. Neuroendocrinology. 2008;87(1):31–9.
258 V. M. Sagar et al.

15. Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, et al. Pulmonary neuro-
endocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and
recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol.
2015;26(8):1604–20.
16. Bhattacharyya S, Davar J, Dreyfus G, Caplin ME. Carcinoid heart disease. Circulation.
2007;116(24):2860–5.
17. Bhattacharyya S, Burke M, Caplin ME, Davar J. Utility of 3D transoesophageal echocardiog-
raphy for the assessment of tricuspid and pulmonary valves in carcinoid heart disease. Eur J
Echocardiogr. 2011;12(1):E4.
18. Basuroy R, Srirajskanthan R, Ramage JK. Neuroendocrine tumors. Gastroenterol Clin N Am.
2016;45(3):487–507.
19. Dde Herder WW, Kwekkeboom DJ, Valkema R, Feelders RA, van Aken MO, Lamberts SW,
et al. Neuroendocrine tumors and somatostatin: imaging techniques. J Endocrinol Invest.
2005;28(11 Suppl International):132–6.
20. Gabriel M, Decristoforo C, Kendler D, Dobrozemsky G, Heute D, Uprimny C, et al.
68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin
receptor scintigraphy and CT. J Nucl Med. 2007;48(4):508–18.
Chapter 20
Treatment of Neuroendocrine
Tumour Disease

Andrew R. Moore and Vincent S. Yip

Key Learning Points

1. NENs are increasing in incidence and, taken as a group, are more common
than either oesophagogastric or pancreatic/hepatobiliary cancers.
2. The management of neuroendocrine tumours should be coordinated by
specialist multidisciplinary teams.
3. Treatment is based on careful multimodal assessment to characterise and
accurately stage NEN disease.
4. Tumours should be graded using the WHO 2010 classification and staged
using a validated TNM classification such as that proposed by ENETS.
5. Resection of primary lesions and—in selected cases—of metastases poten-
tiates the effectiveness of medical treatment.
6. Somatostatin receptor-positive NENs should be treated with somatostatin
analogues as first line.

A. R. Moore
Liverpool Regional Neuroendocrine Tumour Service, Royal Liverpool University Hospital,
Liverpool, UK
e-mail: [email protected]
V. S. Yip (*)
Department of Hepatobiliary and Pancreatic Surgery, Royal Liverpool University Hospital,
Liverpool, UK
Department of Hepatobiliary and Pancreatic Surgery, Royal London Hospital, London, UK
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 259

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_20
260 A. R. Moore and V. S. Yip

Areas of Controversy and Uncertainty

1. The timing of initiation of somatostatin analogues in metastatic grade 1
and 2 NEN disease
2. The tumour size above which colorectal NENs should be resected surgically
3. The follow-up protocol for patients following resection of duodenal,
appendix and colorectal NENs
4. The role of novel targeted molecular therapies in combination with other
agents
Areas of Likely Future Progress
1. Use of telotristat for carcinoid syndrome in functional NENs
2. Use of pasireotide for refractory carcinoid syndrome
3. Use of gastrin antagonist agents for types 1 and 2 gastric NENs and in
Zollinger-Ellison syndrome

Introduction

Neuroendocrine neoplasms (NENs) are a diverse group of uncommon tumours with

widely divergent behaviour dependent on their site of origin, degree of cellular dif-
ferentiation and proliferative activity. Their heterogeneity and relative scarcity have
made their management challenging and have historically limited opportunities for
large-scale research. In the past decade, however, the publication of several phase 3
trials has altered the landscape of treatment for NENs.
The treatment for NENs is dependent on various patient and disease characteris-
tics. In this chapter, we outline the treatments commonly used for NEN disease of
the gastrointestinal (GI) tract and pancreas and the means by which specialist mul-
tidisciplinary teams classify disease to determine the appropriate treatment.

Gastroduodenal Neuroendocrine Neoplasms

Characteristics

Gastric neuroendocrine neoplasms (g-NENs), though said to be rare, are the most
prevalent of the GI NENs, and their incidence is increasing as a result of increased
usage of upper GI fibre-optic endoscopy [1, 2]. They are most commonly found
incidentally and can be classified according to their endoscopic, histopathological
and clinical features (Table 20.1).
Types 1 and 2 g-NENs are both derived from the enterochromaffin-like (ECL)
cells native to the proximal gastric mucosa and arise as the result of chronic
hypergastrinaemia due to chronic autoimmune gastritis and Zollinger-Ellison
20 Treatment of Neuroendocrine Tumour Disease 261

Table 20.1 Characteristics of the types of gastric NET

Type 1 Type 2 Type 3
Associated pathology AIG and PA ZES and Sporadic
MEN-1
Proportion of gastric NETs 46% 6% 15%
(from La Rosa et al. [3])
Site Corpus/ Corpus/fundus Any
fundus
Typical number Multiple Multiple Single
Typical size of tumours <10 mm <10 mm 20–50 mm
Serum gastrin concentration Increased Increased Normal
Gastric acid production Decreased Increased Normal
Prognosis Very good Good Poor
Typical WHO grade Grade 1 Grade 1 Grade 2 > grade1 > NEC
AIG autoimmune atrophic gastritis, PA pernicious anaemia, ZES Zollinger Ellison syndrome,
MEN-1 multiple endocrine neoplasia type 1. Adapted from Burkitt et al. [4]

s­ yndrome, respectively. They typically appear as multiple, small nodules or pol-

yps in the proximal stomach and are generally found to have a low proliferative
index (WHO grade 1).
In contrast, type 3 g-NENs are typically sporadic, large and solitary lesions of
higher WHO grade and with a polypoidal appearance.

Disease Classification and Staging

The initial assessment of g-NENs is accomplished by means of upper GI endoscopy.

Careful inspection of visible gastric lesions and the background mucosa is made
with representative biopsies taken. Endoscopic ultrasonography (EUS) is of value
when assessing larger lesions prior to resection. Cross-sectional and functional
imaging are not routinely recommended for small type 1 g-NENs but are employed
for the staging of types 2 and 3 tumours to facilitate treatment selection [5, 6].
Haematological and biochemical analyses should be performed including full
blood count, serum B12 concentration, fasting serum gastrin concentration and anti-­
gastric parietal cell/intrinsic factor antibody serology.

Treatment

In type 1 tumours, the overall risk of metastases is low though the risk increases
with tumour size. Lesions ≥10 mm have a significantly greater potential for malig-
nant behaviour, and so endoscopic resection is recommended for these [7].
Other strategies for treatment of type 1 g-NENs include surgical antrectomy (to
obviate endogenous gastrin secretion), the use of somatostatin analogues (SSAs)
262 A. R. Moore and V. S. Yip

and administration of gastrin-receptor antagonists. All have been shown to bring

about regression of type 1 tumours in small series, but there are no randomised
controlled trials (RCTs) to support their use in what is generally considered to be a
relatively benign, indolent disease, and so these are not recommended for use in
routine clinical practice [8–10].
The treatment of type 2 g-NENs is generally directed towards the treatment of
the associated gastrin-secreting NENs arising in the setting of multiple endocrine
neoplasia type-1 (MEN-1) though larger gastric tumours are managed endoscopi-
cally as described for type 1 lesions [11].
Type 3 g-NENs are staged and managed along the same lines as more common
gastric malignancies such as adenocarcinoma. Staging by means of computed
tomography (CT) and diagnostic laparoscopy are employed prior to surgical resec-
tion with formal lymph node dissection in suitable cases [7].
Duodenal NENs (d-NENs) are generally treated by resection after staging using
EUS and CT (and functional imaging where indicated). Small tumours can be safely
resected endoscopically, whilst larger lesions or those involving the submucosa are
resected surgically. The treatment of functional d-NENs associated with Zollinger-­
Ellison syndrome (ZES) is discussed along with pancreatic gastrinomas later [12, 13].

Follow-Up

There are limited data to support any given surveillance regime for g-NENs and
d-NENs, but the pragmatic approach adopted in international guidelines is to rec-
ommend biennial upper GI endoscopy [13, 14].

Small Intestinal Neuroendocrine Neoplasms

Overview

NENs of the jejunum and ileum (small intestinal NENs, si-NENs) arise from native
enterochromaffin cells and are typically of low grade (WHO grades 1–2). Despite
their innate indolence, the majority present following the development of locally
advanced or metastatic disease [1].

Disease Classification and Staging

Staging is achieved using cross-sectional (CT or MR) and functional (68Ga-labelled

somatostatin analogue PET-CT) imaging, whilst prognostic (and monitoring) informa-
tion can be gleaned from the measurement of serum chromogranin A (CgA) concentra-
tion. In the majority of cases, tissue is obtained for diagnostic and grading purposes.
20 Treatment of Neuroendocrine Tumour Disease 263

Treatment

In patients with disease limited to the primary site, with or without involved regional
lymph nodes, curative surgery with primary tumour resection and lymph node dis-
section should be considered. This surgical approach has been shown to confer
5-year survival rates of 100% for T1–T3 disease and >95% for T4 or regional nodal
disease [15]. International guidelines advocate opportunistic cholecystectomy at the
time of surgery, particularly for patients likely to be treated with somatostatin ana-
logues (SSAs) to mitigate the risk of the complications of treatment-related choleli-
thiasis [16].
In patients with distant metastases, surgical resection may be employed as a pal-
liative measure when the primary tumour or associate mesenteric fibrosis threatens
small bowel obstruction.

Appendix Neuroendocrine Neoplasms

Appendiceal NENs are most commonly identified incidentally following appendi-

cectomy and are generally asymptomatic except in rare cases of locally advanced or
widely metastatic disease. Treatment selection therefore is largely dependent on
postoperative staging and disease characterisation. The most important features
appear to be anatomical location, tumour size and local stage. Small (<10 mm)
tumours at the tip of the appendix (hence more likely to be completely resected)
without infiltration beyond the muscularis propria (ENETS stage T1) are thought to
confer a very small risk of disease recurrence or metastases and do not usually
require additional surgery [17]. CT/MRI can be used to complete staging and
exclude metastatic disease in such cases. Large (<20 mm) tumours or those with
significant (>3 mm) subserosal/mesoappendix invasion are uncommon but carry a
substantial risk of metastases. For these, CT and functional imaging are used to
complete staging and to exclude metastatic disease prior to formal oncological
resection by means of right hemicolectomy with lymph node dissection. The appro-
priate treatment for intermediate disease (tumour size 1–2 cm, minimal subserosal/
mesoappendix invasion) is less clear. In this group, the presence of adverse disease
characteristics such as lymphovascular invasion or WHO grade 2 proliferative index
should prompt consideration of completion right hemicolectomy.
Follow-up is not routinely recommended for patients in whom a curative resec-
tion of a small appendiceal NEN without adverse features has been accomplished
by means of appendicectomy. Similarly, no follow-up is advised for patients whose
treatment was by right hemicolectomy and in whom resection was complete and
without lymph node metastases.
Suitable follow-up regimes for other groups are less clear. For patients with
lymph node invasion or those in whom there were adverse tumour characteristics
(tumour >2 cm, subserosal invasion, >WHO grade 1, lymphovascular invasion,
etc.), long-term follow-up with cross-sectional imaging seems prudent though there
are no data showing improved outcomes with such a strategy. ENETS guidelines
264 A. R. Moore and V. S. Yip

suggest minimising the exposure to ionising radiation by utilising biomarker moni-

toring and alternative imaging such as ultrasound or MR [17].

Colorectal Neuroendocrine Neoplasms

Overview

Colorectal NENs are another group of tumours whose incidence is rising due to the
expanding use of GI endoscopy, not least in the context of population-based screening
programmes. These neoplasms appear to represent two distinct clinical entities. Rectal
NENs are typically small, well differentiated and of low proliferative index (WHO
grades 1–2), whereas colonic NENs are more commonly poorly differentiated, of
higher grade and more advanced stage at diagnosis. Rectal NENs are often diagnosed
following endoscopic resection performed as part of routine colonoscopy [18, 19].

Disease Classification, Staging and Treatment

As for other gastroenteropancreatic (GEP) NENs, treatment is dependent on accu-

rate risk stratification. Tumour size, stage and grade are the most important predic-
tors of behaviour. For small (<10 mm) rectal NENs, local staging is performed
using EUS and early stage (T1/T2) tumours resected endoscopically or by means of
transanal endoscopic microsurgery (TEMS). For tumours between 10 and 20 mm,
cross-sectional imaging (pelvic MRI) may be employed to augment EUS staging
prior to local resection. Larger (>20 mm), locally advanced (T3) or high-grade
(WHO grade 3) are fully staged using cross-sectional and functional imaging to
exclude metastatic disease prior to resection [19, 20].

Pancreatic Neuroendocrine Neoplasms

Overview

This group of neuroendocrine neoplasms can be divided into those associated with
a syndrome resulting from the secretion of bioactive peptides—functional pancre-
atic neuroendocrine tumours (F-p-NETs)—and those without such clinical mani-
festations, non-functional pancreatic neuroendocrine tumours (NF-p-NETS). The
commonest F-p-NETs are gastrinomas and insulinomas, whilst there are a disparate
group of rare tumours known to secrete other bioactive peptides, which are further
sub-classified as rare functional tumours (RFTs). F-p-NETs are frequently associ-
ated with MEN-1 (20–30% of gastrinomas, <5% insulinomas and RFTs) [21–23].
20 Treatment of Neuroendocrine Tumour Disease 265

Whilst F-p-NETs typically present with symptoms attributable to the action of

their secreted peptides, NF-p-NETs are more commonly found incidentally or else
present following the development of locally advanced or metastatic disease. The
incidental diagnosis of NF-p-NETs is an increasingly common event owing to the
expanding use and improving performance of cross-sectional imaging techniques.

Disease Classification and Staging

As well as biochemical studies to measure the circulating levels of F-p-NET related

peptides, staging of p-NETs is performed using CT, MRI and EUS (± guided fine-­
needle aspiration). 68Ga-labelled somatostatin analogue PET-CT is both sensitive and
specific for p-NETs and is therefore recommended for use to improve the accuracy of
staging and tumour localisation prior to surgery. This modality is less useful in imag-
ing insulinomas however. In patients whose symptoms are poorly controlled and in
whom surgery is warranted, tumour localisation can be achieved using functional
imaging techniques which utilise radiolabelled glucagon-like peptide-1 (GLP-1) or
selective intra-arterial calcium injection and hepatic venous insulin gradients [24, 25].

Treatment

In the absence of MEN-1, metastatic disease or patient-related contraindications,

surgical exploration with a view to tumour resection and lymph node dissection is
recommended for F-p-NETs. In those patients thought not to be suitable surgical
candidates, techniques such as radiofrequency ablation are thought to be effective
alternatives.
The role for a surgical approach in NF-p-NETs is not routinely recommended
unless there are adverse tumour characteristics (size >20 mm, higher grade, etc.)

 edical Treatment of Gastrinomas and Zollinger-Ellison

M
Syndrome (ZES)

The development of effective anti-secretory agents, notably the proton-pump inhibi-

tors (PPIs), has greatly improved the outlook for patients with ZES and form the
cornerstone of medical treatment. When used in sufficiently high dosage, adequate
control of acid secretion is achieved in almost all patients. The gastrin antagonist
netazepide may be of benefit in refractory cases, but this is not yet commercially
available. In a substantial proportion of patients thought to have had all gastrinomas
surgically resected, acid hypersecretion can persist for several years, and so caution
should be exercised in the withdrawal of PPIs following surgery [26, 27].
266 A. R. Moore and V. S. Yip

Medical Treatment of Insulinomas

Prior to surgical resection or in patients not suitable for surgery, the treatment of
insulinoma-related hypoglycaemia is with regular meals and administration of the
potassium channel activator diazoxide [28].

Metastatic Neuroendocrine Tumour Disease

Overview

A substantial proportion of NENs (particularly those arising in the small intestine,

right colon and pancreas) are found to have metastasised at the time of diagnosis
with the liver the predominant site for distant metastatic disease. The rate of metas-
tasis is unsurprisingly greater in tumours of higher grade (WHO grade 3) than in
those of lower grade, and carcinoid syndrome is a common feature in metastatic
disease arising from small intestinal primaries [29, 30].

Liver-Targeted Treatment

Therapies directed at liver-predominant disease should be considered early in the

management of unresectable, metastatic NENs. Care must be exercised in the setting
of functional tumour disease where prior treatment with somatostatin analogues is
recommended to avoid the precipitation of carcinoid crises following treatment [30].
There are no large trials comparing the use of the varied methods of liver-­targeted
therapy with one another or with systemic treatment, and—to some degree—the
treatment selected is dependent on local expertise and resource availability.
Debulking liver surgery might be considered in patients with functional tumours
refractory to systemic treatment or in those whose symptoms are related to bulky
liver disease [31]. Loco-regional or ablative treatments such as bland embolisation,
chemoembolisation and radiofrequency ablation are considered in patients whose
liver-predominant disease is unsuitable for surgical debulking or in whom surgery
is contraindicated. These techniques can be used repeatedly in recurrent or progres-
sive disease [30].

Somatostatin Analogues

Somatostatin analogues (SSAs) are used as first-line treatment in patients with

symptoms of carcinoid syndrome and/or as a cytostatic treatment in midgut or
p-NENs and where somatostatin receptor positivity is demonstrated by means of
functional imaging.
20 Treatment of Neuroendocrine Tumour Disease 267

There are two commercially available long-acting agents—lanreotide autogel

(60–120 mg subcutaneous injection monthly) and octreotide LAR (10–30 mg intra-
muscular injection monthly). They are equally efficacious in the treatment of carci-
noid syndrome with a symptomatic response rate of approximately 65–70%.
Refractory symptoms can be managed by dose escalation and/or increased fre-
quency of administration without intolerable side effects [32].
SSAs are employed for their antiproliferative effects in both midgut and pancre-
atic NENs with Ki67 indices of ≤10%. Two large RCTs have provided evidence of
significantly extended progression-free survival with SSAs. Both agents are used in
the treatment of intestinal NETs, whilst lanreotide is recommended for the treat-
ment of p-NEN. The decision to commence SSA treatment in non-functional NENs
is usually predicated on the presence of extensive disease volume or after disease
progression is observed though some expert advocate treatment initiation at the time
of diagnosis [33, 34].

Interferon

Interferon-alpha (IFN-α) may be used for treatment of carcinoid syndrome in addi-

tion to SSAs when monotherapy has not brought about complete symptom control
and where the combination may have a synergistic effect. IFN is less efficacious for
the treatment of carcinoid syndrome when used alone and its use is further limited
by the high incidence of adverse effects such as fever, lethargy and myelosuppres-
sion [35, 36].

Telotristat

Telotristat is an oral serotonin synthesis inhibitor which has been shown to improve
symptomatic control in carcinoid syndrome when added to SSA. It is also posited
that its direct effect on circulating 5HIAA levels may reduce the development of
carcinoid heart disease [37].

Molecular Targeted Therapies

Everolimus and sunitinib are novel targeted agents whose use has been evaluated in
several recent phase III trials.
Everolimus is an oral mTOR inhibitor shown to increase median progression-­
free survival (PFS) in WHO grades 1–2 p-NENS and si-NENs compared with pla-
cebo. Unfortunately, side effects prompting withdrawal of treatment is reported in
12–19% of trial subjects with diarrhoea and stomatitis among the symptoms com-
monly reported [38–40].
268 A. R. Moore and V. S. Yip

Sunitinib is a tyrosine kinase inhibitor acting to inhibit angiogenesis and prolifera-

tive activity via vascular endothelial growth factor (VEGF) and platelet-derived growth
factor (PDGF). In a recent phase III randomised controlled trial, PFS was significantly
increased in patients with progressive p-NENs when compared with placebo [41].
The role of combining these novel drugs with SSAs for tumour control and car-
cinoid syndrome treatment is not yet supported by robust data.

Peptide Receptor Radionuclide Therapy (PRRT)

Targeted therapy with radionuclide is considered second-line therapy for SSTR-­

positive NEN disease following progression or symptoms refractory to treatment
with SSAs. SSA labelled with a radioactive isotope is administered with the inten-
tion of establishing radiation-induced tumour DNA damage. The recent NETTER-1
trial compared 177Lu-Dotatate to octreotide LAR for the treatment of progressive
midgut NENs and showed markedly increased PFS and response rate in the PRRT
group. PRRT is limited to provision in specialist centres [42, 43].

Cytotoxic Chemotherapy

Systemic chemotherapy is usually reserved for the treatment of progressive pNET or

high-grade NEN. Other indications for treatment include large-volume disease, refrac-
tory symptoms and rapid tumour progression. The treatment of non-­pancreatic NENs
with chemotherapy is not usually recommended unless the tumours are of high grade
(Ki67 >15%), rapidly growing or if functional imaging demonstrates paucity of tracer
avidity suggesting SSTR-negative disease. Combination therapy with streptozotocin
(STZ) and fluorouracil (5-FU) has been shown to be superior to STZ monotherapy.
Chemotherapy treatment for neuroendocrine carcinomas (NECs) is well estab-
lished and is typically inclusive of platinum-based drugs with etoposide [30, 44].

Resection

Resection remains the only curative option for neuroendocrine liver metastases
(NLMs). Complete resection (R0/1) of NLM can offer a 5-year survival of 60–80%
[31, 45–47], as compared to around 30% 5-year survival for the non-resected group
[48]. There are two main indications in offering resection in NLM, namely, curative
intent with R0/1 resection and debulking resection for symptomatic control. Few
elements have to be factored in before the consideration of liver resection for this
group of patient. These elements are histological grade of the NLM, distribution of
the liver metastases, presence of extra-hepatic metastases, status and resectability of
the primary tumour and functionality of the neuroendocrine tumour.
20 Treatment of Neuroendocrine Tumour Disease 269

Liver resection is generally only offered in well-differentiated neuroendocrine

tumour (NET) (G1/G2), with only very few exception in solitary high-grade
NLM. For liver resection with “curative intent”, absence of extra-hepatic metastases
and resectability of the primary tumour must be confirmed by high-resolution con-
trast computer tomography and functional imaging such as SPECT/CT or much
more sensitive Gallium-68 PET/CT prior to surgical intervention.
Technical resectability for NLM is dependent on the distribution of liver lesions,
which can be broadly categorised into three main types: (1) simple pattern (unilobar
or limited), (2) complex pattern (bilobar) and (3) diffuse pattern. Liver resection is
associated with low mortality rate of less than 5% and an overall morbidity of
around 30% [49]. For simple pattern NLM, minor resection (less than 3 or more
segments) or non-anatomical resections are normally sufficient to achieve a R0
resection margin. When surgery is contraindicated, curative therapy in the form
microwave or radiofrequency ablation can be offered.
For complex pattern distribution, it is normally associated with bilobar disease
or tumour location involving main intrahepatic vasculature requiring major hepa-
tectomy in combination with or without intraoperative ablation technique. When
the estimated future liver remnant after major hepatectomy is less than 30%, a
two-step liver resection with ipsilateral inflow occlusion prior to resection can be
employed to augment the remnant liver volume. A two-stage ALPPS approach has
also been suggested to improve the feasibility of resecting borderline NLM [50].
When surgery is contraindicated, liver-only metastases can be managed by che-
moembolisation or selective internal radiation therapy [51]. Surgical option is
generally limited for diffuse pattern disease. Other treatment in the form of sys-
temic therapy is normally required. These treatment pathways are summarised in
Fig. 20.1.

Morphological and
functional imaging

Resection of primary No extrahepatic spread

A. Simple pattern of LMs B. Complex pattern of

C. Diffuse LMs
G1/G2 LMs G1/G2
G1/G2
(unilobar or limited) (bilobar)

Or surgery Selected cases

contraindicated (<1%)

Resection Two-step surgery Small intestinal Pancreatic

Surgery
(minor or One-step surgery 1. Minor resection ± -SSA (IFN) -SSA (IFN)
contraindicated
anatomical) Major liver resection RFA, RPVE, RPVL -PRRT -Chemotherapy
± RFA 2. Sequential major -(Everolimus) -Everolimus
liver resection -Sunitinib
-PRRT

Ablation
(RFA, LITT) TACE Liver
TACE TAE transplantation

Fig. 20.1 Treatment approach to neuroendocrine liver metastases without extra-hepatic spread
(Need approval from ENET consensus guideline [11])
270 A. R. Moore and V. S. Yip

The other indication for liver resection (debulking procedure) is for symptomatic
control secondary to functioning tumours. Debulking procedures involve hepatecto-
mies, primary tumour resection and lymphadenectomy, with or without ablative
therapies aiming to remove >90% of tumour burden [52, 53]. Although debulking
procedure is mainly for palliative setting, studies have demonstrated an improve-
ment in quality of life in patients’ refractory to medical treatment [46, 53]. However,
it is debatable regarding the extent of tumour burden that should be resected in
debulking procedure.

Liver Transplantation

With limited evidence on the long-term outcome of liver transplantation in NLM,

transplantation is currently not indicated in the UK. The benefit for liver transplan-
tation has to be weighted out against the peri-operative morbidities and mortali-
ties, the long-term immunosuppression for an underlying malignant condition and
the ethical distribution of already scarce liver graft. In addition to the criteria for
resection above, ENET consensus guideline has also suggested a limited age of
50 years old and a low Ki-67 level to be included as part of the criteria for liver
transplantation [30]. Nonetheless, the small percentage of tumour-free patients
after 5 years in liver transplantation would be more realistically a palliation rather
than a curative goal.

References

1. Niederle MB, Hackl M, Kaserer K, Niederle B. Gastroenteropancreatic neuroendocrine

tumours: the current incidence and staging based on the WHO and European Neuroendocrine
Tumour Society classification: an analysis based on prospectively collected parameters.
Endocr Relat Cancer. 2010;17(4):909–18.
2. Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, et al. TNM staging
of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading
system. Virchows Arch. 2007;451(4):757–62.
3. La Rosa S, Inzani F, Vanoli A, Klersy C, Dainese L, Rindi G, et al. Histologic characterization
and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms. Hum Pathol.
2011;42(10):1373–84.
4. Burkitt MD, Pritchard DM. Review article: pathogenesis and management of gastric carcinoid
tumours. Aliment Pharmacol Ther. 2006;24(9):1305–20.
5. Cavallaro A, Zanghì A, Cavallaro M, Menzo EL, Carlo ID, Vita MD, et al. The role of
68-Ga-DOTATOC CT-PET in surgical tactic for gastric neuroendocrine tumors treatment: our
experience: a case report. Int J Surg. 2014;12:S225–31.
6. Thomas D, Tsolakis AV, Grozinsky-Glasberg S, Fraenkel M, Alexandraki K, Sougioultzis S,
et al. Long-term follow-up of a large series of patients with type 1 gastric carcinoid tumors:
data from a multicenter study. Eur J Endocrinol. 2013;168(2):185–93.
7. Rindi G, Azzoni C, Rosa SL, Klersy C, Paolotti D, Rappel S, et al. ECL cell tumor and poorly
differentiated endocrine carcinoma of the stomach: prognostic evaluation by pathological anal-
ysis. Gastroenterology. 1999;116(3):532–42.
20 Treatment of Neuroendocrine Tumour Disease 271

8. Campana D, Nori F, Pezzilli R, Piscitelli L, Santini D, Brocchi E, et al. Gastric endocrine

tumors type I: treatment with long-acting somatostatin analogs. Endocr Relat Cancer.
2008;15(1):337–42.
9. Murugesan SV, Steele IA, Dimaline R, Poston GJ, Shrotri M, Campbell F, et al. Correlation
between a short-term intravenous octreotide suppression test and response to antrec-
tomy in patients with type-1 gastric neuroendocrine tumours. Eur J Gastroenterol Hepatol.
2013;25(4):474–81.
10. Moore AR, Boyce M, Steele IA, Campbell F, Varro A, Pritchard DM. Netazepide, a gastrin
receptor antagonist, normalises tumour biomarkers and causes regression of Type 1 gastric
neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis.
PLoS One. 2013;8(10):e76462.
11. Moore AR, Varro A, Pritchard DM. Zollinger-Ellison syndrome. Gastrointest Nurs.
2012;10(5):44–9.
12. Jensen RT, Niederle B, Mitry E, Ramage JK, Steinmüller T, Lewington V, et al. Gastrinoma
(duodenal and pancreatic) ENETS guidelines. Neuroendocrinology. 2006;84(3):173–82.
13. Delle Fave G, Kwekkeboom DJ, Van Cutsem E, Rindi G, Kos-Kudla B, Knigge U, et al.
ENETS consensus guidelines for the management of patients with gastroduodenal neoplasms.
Neuroendocrinology. 2012;95(2):74–87.
14. Sato Y, Hashimoto S, Mizuno K, Takeuchi M, Terai S. Management of gastric and duodenal
neuroendocrine tumors. World J Gastroenterol. 2016;22(30):6817–28.
15. Jann H, Roll S, Couvelard A, Hentic O, Pavel M, Müller-Nordhorn J, et al. Neuroendocrine
tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical
outcome. Cancer. 2011;117(15):3332–41.
16. Pape UF, Perren A, Niederle B, Gross D, Gress T, Costa F, et al. ENETS consensus guide-
lines for the management of patients with neuroendocrine neoplasms from the jejuno-­
ileum and the appendix including goblet cell carcinomas—abstract. Neuroendocrinology.
2012;95(2):135–56.
17. Pape U-F, Niederle B, Costa F, Gross D, Kelestimur F, Kianmanesh R, et al. ENETS consensus
guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas).
Neuroendocrinology. 2016;103(2):144–52.
18. Jung YS, Yun KE, Chang Y, Ryu S, Park JH, Kim HJ, et al. Risk factors associated with
rectal neuroendocrine tumors: a cross-sectional study. Cancer Epidemiol Prev Biomark.
2014;23(7):1406–13.
19. Ramage JK, Herder WWD, Fave GD, Ferolla P, Ferone D, Ito T, et al. ENETS consen-
sus guidelines update for colorectal neuroendocrine neoplasms. Neuroendocrinology.
2016;103(2):139–43.
20. Shen C, Yin Y, Chen H, Tang S, Yin X, Zhou Z, et al. Neuroendocrine tumors of colon and rec-
tum: validation of clinical and prognostic values of the World Health Organization 2010 grad-
ing classifications and European Neuroendocrine Tumor Society staging systems. Oncotarget.
2016;8(13):22123–34.
21. Niina Y, Fujimori N, Nakamura T, Igarashi H, Oono T, Nakamura K, et al. The current strategy
for managing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1. Gut
Liver. 2012;6(3):287–94.
22. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. Clinical prac-
tice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab.
2012;97(9):2990–3011.
23. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, et al. Consensus:
guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab.
2001;86(12):5658–71.
24. Sharma J, Duque M, Saif MW. Emerging therapies and latest development in the treat-
ment of unresectable pancreatic neuroendocrine tumors: an update for clinicians. Ther Adv
Gastroenterol. 2013;6(6):474–90.
25. McKenna LR, Edil BH. Update on pancreatic neuroendocrine tumors. Gland Surg.
2014;3(4):258–75.
272 A. R. Moore and V. S. Yip

26. Wilcox CM, Seay T, Arcury JT, Mohnen J, Hirschowitz BI. Zollinger–Ellison syndrome: pre-
sentation, response to therapy, and outcome. Dig Liver Dis. 2011;43(6):439–43.
27. Boyce M, Dowen S, Turnbull G, van den Berg F, Zhao C-M, Chen D, et al. Effect of netaz-
epide, a gastrin/CCK2 receptor antagonist, on gastric acid secretion and rabeprazole-induced
hypergastrinaemia in healthy subjects. Br J Clin Pharmacol. 2015;79(5):744–55.
28. Kittah NE, Vella A. Management of endocrine disease: pathogenesis and management of
hypoglycemia. Eur J Endocrinol. 2017;177(1):R37–47.
29. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after
“carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825
cases in the United States. J Clin Oncol. 2008;26(18):3063–72.
30. Pavel M, O’Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, et al. ENETS consen-
sus guidelines update for the management of distant metastatic disease of intestinal, pan-
creatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site.
Neuroendocrinology. 2016;103(2):172–85.
31. Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG. Surgical treatment
of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll
Surg. 2003;197(1):29–37.
32. O’Toole D, Ducreux M, Bommelaer G, Wemeau JL, Bouché O, Catus F, et al. Treatment
of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in
terms of efficacy, patient acceptability, and tolerance. Cancer. 2000;88(4):770–6.
33. Rinke A, Muller H-H, Schade-Brittinger C, Klose K-J, Barth P, Wied M, et al. Placebo-­
controlled, double-blind, prospective, randomized study on the effect of octreotide lar in the
control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report
from the PROMID study group. J Clin Oncol. 2009;27(28):4656–63.
34. Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, et al. Lanreotide in
metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224–33.
35. Faiss S, Pape U-F, Böhmig M, Dörffel Y, Mansmann U, Golder W, et al. Prospective, random-
ized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their
combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—The
International Lanreotide and Interferon Alfa study group. J Clin Oncol. 2003;21(14):2689–96.
36. Arnold R, Rinke A, Klose K-J, Müller H-H, Wied M, Zamzow K, et al. Octreotide versus
octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized
trial. Clin Gastroenterol Hepatol. 2005;3(8):761–71.
37. Pavel M, Hörsch D, Caplin M, Ramage J, Seufferlein T, Valle J, et al. Telotristat etiprate for carci-
noid syndrome: a single-arm, multicenter trial. J Clin Endocrinol Metab. 2015;100(4):1511–9.
38. Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, et al. Everolimus
plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours
associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase
3 study. Lancet. 2011;378(9808):2005–12.
39. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced
pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23.
40. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treat-
ment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal
tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet Lond Engl.
2016;387(10022):968–77.
41. Faivre S, Sablin M-P, Dreyer C, Raymond E. Novel anticancer agents in clinical trials for well-­
differentiated neuroendocrine tumors. Endocrinol Metab Clin N Am. 2010;39(4):811–26.
42. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of
177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.
43. Cives M, Strosberg J. Radionuclide therapy for neuroendocrine tumors. Curr Oncol Rep.
2017;19(2):9.
20 Treatment of Neuroendocrine Tumour Disease 273

44. Alexandraki KI, Karapanagioti A, Karoumpalis I, Boutzios G, Kaltsas GA. Advances and
current concepts in the medical management of gastroenteropancreatic neuroendocrine neo-
plasms. Biomed Res Int. 2017;2017:9856140.
45. Chamberlain RS, Canes D, Brown KT, Saltz L, Jarnagin W, Fong Y, et al. Hepatic neuroendo-
crine metastases: does intervention alter outcomes? J Am Coll Surg. 2000;190(4):432–45.
46. Chen H, Hardacre JM, Uzar A, Cameron JL, Choti MA. Isolated liver metastases from neu-
roendocrine tumors: does resection prolong survival? J Am Coll Surg. 1998;187(1):88–92.
discussion-3
47. Elias D, Lasser P, Ducreux M, Duvillard P, Ouellet JF, Dromain C, et al. Liver resection (and
associated extrahepatic resections) for metastatic well-differentiated endocrine tumors: a
15-year single center prospective study. Surgery. 2003;133(4):375–82.
48. Kianmanesh R, O'Toole D, Sauvanet A, Ruszniewski P, Belghiti J. Surgical treatment of
gastric, enteric pancreatic endocrine tumors. Part 2. Treatment of hepatic metastases. J Chir
(Paris). 2005;142(4):208–19.
49. Glazer ES, Tseng JF, Al-Refaie W, Solorzano CC, Liu P, Willborn KA, et al. Long-term
survival after surgical management of neuroendocrine hepatic metastases. HPB (Oxford).
2010;12(6):427–33.
50. Alvarez FA, Ardiles V, de Santibanes M, Pekolj J, de Santibanes E. Associating liver parti-
tion and portal vein ligation for staged hepatectomy offers high oncological feasibility with
adequate patient safety: a prospective study at a single center. Ann Surg. 2015;261(4):723–32.
51. Grozinsky-Glasberg S, Kaltsas G, Kaltsatou M, Lev-Cohain N, Klimov A, Vergadis V, et al.
Hepatic intra-arterial therapies in metastatic neuroendocrine tumors: lessons from clinical
practice. Endocrine. 2018;60(3):499–509.
52. Ahlman H, Wangberg B, Jansson S, Friman S, Olausson M, Tylen U, et al. Interventional treat-
ment of gastrointestinal neuroendocrine tumours. Digestion. 2000;62(Suppl 1):59–68.
53. Sarmiento JM, Que FG. Hepatic surgery for metastases from neuroendocrine tumors. Surg
Oncol Clin N Am. 2003;12(1):231–42.
 Part IV
Colo-Rectal Metastases and Benign Liver
Tumours
Chapter 21
Colorectal Liver Metastasis

Rafael Diaz-Nieto and Graeme J. Poston

Key Learning Points

1. Up to 60% of patients with colorectal cancer will develop colorectal liver
metastases.
2. Irrespective of the extension of the disease, all patients with colorectal
liver metastases must be discussed in a specialized multidisciplinary
committee.
3. Intervention for liver metastases can provide long-term survival benefit.
4. Surgical resection remains the best curative intent treatment.
5. Combination of systemic chemotherapy and locoregional therapies to the
liver can offer survival benefits even in the palliative settings.

Introduction

Colorectal cancer (CRC) is the third most common cause of cancer in both men and
women and the third cause of cancer-related deaths in the United States [1]. Twenty-­
five percent of patients diagnosed with CRC present with synchronous liver metas-
tasis (LM), and up to 60% of patients will develop liver metastases at some point in
their course of their disease [2]. Metastases identified at the time of the diagnosis of
the primary tumour are defined as synchronous, and those identified after the diag-
nosis of the original colorectal cancer are considered to be metachronous.

R. Diaz-Nieto (*) · G. J. Poston

Hepatobiliary Surgery, Digestive Diseases Unit, Aintree University Hospital, Liverpool, UK
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2019 277

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_21
278 R. Diaz-Nieto and G. J. Poston

The liver is a very common site for metastases, not only from colorectal can-
cer but also from many other tumours including pancreatic cancer, breast cancer
and gastric cancer. Intuitively, the tumour cells reach the liver microcirculation
via the portal circulation and then seed into the hepatic parenchyma. However,
most of these cells fail in metastasizing successfully. Factors determining the
progression of these stem cells into new tumours include adhesion, angiogene-
sis and final cell survival [3]. Carcinogenesis and progression of CRC involve
multiple genetic and epigenetic changes in many genes. Recent investigations
have demonstrated that at least 46 genes are significantly related to the liver
metastasis process of CRC: KRAS, p53, APC, B-catenin and AXIN being the
most common [4]. However, the whole underlying process remains poorly
understood.

Tumour Biology

The understanding of tumour biology is evolving but is now being introduced into
clinical practice based on the molecular and genetic analysis of the different
tumours. The recent research on these genetic markers has introduced a deeper
understanding of molecular variations between tumours, so bringing tumour biol-
ogy further into clinical practice. Advances in the knowledge of KRAS, NRAS,
BRAF and PIK3CA mutations have shown the importance of their roles as prognos-
tic factors following surgery [5]. Our group, for example, has added KRAS muta-
tion into the traditional clinical risk score for prediction of survival for colorectal
liver metastasis, resulting in a modified clinical score that stratifies patients overall
survival with disease-free survival [6].
A good example of how tumour biology impacts on clinical practice is KRAS
mutational status. KRAS status (wild- vs mutant-type) implies sensitivity or
resistance to treatment using anti-epidermal growth factor receptor (EGFR)
monoclonal antibodies (such as cetuximab and panitumumab) and is also associ-
ated with poorer overall survival (OS) and disease-free survival (DFS) and worse
pattern of unresectable extrahepatic recurrence [7]. Additionally mutation of
KRAS and BRAF predicts poorer survival outcomes after surgical resections [8,
9]. However this is even more complex as, based on a recent analysis, there is no
100% concordance in KRAS mutation between the primary tumour and the
metastases [10].

Management

Management of colorectal liver metastasis is now an extremely complex multidisci-

plinary process. There is now strong evidence suggesting that despite being previ-
ously considered incurable metastatic disease, interventions to colorectal liver
metastases can achieve long-term survival benefit and high rates of cure [11].
21 Colorectal Liver Metastasis 279

The complexity of patient management now relies on more detailed diagnoses,

careful preoperative assessment and multidisciplinary approaches with combina-
tions of systemic treatments and locoregional treatments to the liver, all in combina-
tion with the already complex management of the primary tumour.

Diagnosis

Clinical diagnosis remains the mainstay in managing the primary colorectal cancer.
However liver metastasis can be completely asymptomatic. Imaging modalities are
therefore essential in the diagnosis of colorectal liver metastasis, irrespective of the lack
of clinical suspicion. These modalities are also of extreme importance not only for the
diagnosis itself but also in the context of planning liver surgery. Assessment of the qual-
ity of the background liver, evaluation of resectability, estimation of liver volumes prior
to surgery and assessment of response to systemic therapies are additional requirements
for the appropriate management of colorectal liver metastasis. Figure 21.1 illustrates the
most common modalities used for the diagnosis of colorectal liver metastasis.

a b

c d

Fig. 21.1 Comparison between different diagnostic modalities for colorectal liver metastasis.
Clinical scenario of bilateral liver metastasis from colorectal cancer. (a) Contrast-enhanced com-
puter tomography (CT). (b) Contrast-enhanced magnetic resonance (diffusion-weighted images).
Arrows pointing metastatic deposits. (c) Functional study with fluorodeoxiglucose positron emis-
sion tomography (FDG-PET). (d) Combination of FDG-PET and CT (PET-CT)
280 R. Diaz-Nieto and G. J. Poston

Ultrasound Scanning

Ultrasound (US) is frequently used for the diagnosis of hepatobiliary diseases.

Some patients with colorectal liver metastasis may present with non-specific symp-
toms and deranged liver function test, and therefore US may be the front-line inves-
tigation. However, US itself is not adequate to differentiate between colorectal liver
metastasis and other solid liver tumours. It is helpful when characterizing cystic
liver lesions, and it is of paramount importance as an intraoperative technique at the
time of liver resections, both for diagnosis and location of tumours, but also for
planning the anatomy of the liver resection [12].
Additionally, the current use of contrast-enhanced US (CEUS) can be helpful
when the diagnosis is unclear, and it is becoming a very important tool for the sur-
geon in the operative management of disappearing metastasis (lesions that are not
further visible after a course of chemotherapy). CEUS improves US sensitivity from
67.4–71.6% to 93.4–95.8%. On a lesion-by-lesion analysis, CEUS improves the
sensitivity of US from 60.9–64.9% to 85.3–92.8% and increased its specificity from
50–60% to 76.7–83.3% [13]. CEUS can be therefore an adequate alternative to MRI
or CT in cases of contra-indication [14].

Computed Tomography

Computed tomography (CT) is the gold standard for staging colorectal cancer.
Contrast-enhanced CT is the standard technique that most commonly will identify
hypodense lesions both in the arterial and portal phases with a pooled sensitivity of
80.5% (67.0–89.4%) [12]. Atypical characteristics as hypervascular or cystic metas-
tases are also possible and may require further characterization with complementary
tests. Calcification can be also an atypical presentation, but is more common in
patients who have received systemic chemotherapy [15].

Magnetic Resonance

Magnetic resonance (MR) increases the detection of metastases within the liver,
especially when adding specific hepatobiliary contrast with combination of
diffusion-­weighted imaging [16]. Again, with some exceptions, colorectal liver
metastasis will be shown on MR as hypovascular lesions, and it has a sensitivity of
85.7% (69.7–94.0%) [17]. Not all hepatobiliary centres routinely use MR as part of
staging and diagnosis of colorectal cancer, but MR increases the sensitivity and
specificity of CT for smaller metastases. Another limitation of CT that MR is able
to overcome is the presence of background liver disease (steatosis, fatty infiltration,
cirrhosis).
21 Colorectal Liver Metastasis 281

Positron Emission Tomography

Positron emission tomography (PET) is the only functional test applicable to colorec-
tal liver metastasis. Identification of hypermetabolic hepatic tumours in the context
of colorectal cancer can be diagnostic of metastatic disease; however PET does not
have the morphological/anatomical characteristic of other imaging modalities. It has
however a valuable role in the identification of widespread metastatic disease as it
scans the whole body. The combination of PET and CT overcomes its limitations as
simply a functional investigation. Some reports have also correlated the grade of
contrast uptake on PET with long-term outcomes [18]. However, limitations include
small tumours (sub-centimetre) that are not visible with this modality and atypical
metastases such as mucinous tumours; hypometabolic metastasis will not necessarily
be PET avid, and it may be affected by recent chemotherapy [17]. The most common
modality used in PET is fluorodeoxiglucose (FDG-PET), with a pooled sensitivity of
81.3% (64.1–91.4%) for FDG-PET and 71.0% (64.3–76.9%) for FDG-PET/CT,
whilst in patients who have received chemotherapy, sensitivity rates were 54.5%
(46.7–62.1%) for FDG-PET and 51.7% (37.8–65.4%) for FDG-PET/CT [17].
This diagnostic modality however is not available in every centre and is not usu-
ally included in the routine diagnostic or staging algorithm for colorectal cancer.
Our group however uses PET-CT in patients with colorectal liver metastasis in cases
of diagnostic doubts, clarification of postoperative/post-ablation changes in the liver
and especially for identification of extrahepatic and occult metastasis [19].
Alternatively the development of MR-PET may play a role in the future staging
of colorectal cancer, but this modality is not currently available in most centres, and
there are no data to support its routine application [20].
With all this in mind, it is important to define adequate diagnostic algorithms that
are cost-effective and provide the most accurate diagnosis. In our centre, CT of the
chest abdomen and pelvis is the first diagnostic test, and in liver-limited disease, it
can help to determine curative intent management for around 25% of patients.
Those patients who are considered for curative intent treatment (potential surgical
candidates) are then further investigated with FDG-PET and liver MRI. Our experi-
ence showed that FDG-PET identified an extra 12% of patients who had extrahe-
patic disease missed on the initial CT, and MRI precluded surgery in an additional
4% of patients considered resectable by CT. This staged model (or so-called hybrid
model) proved to be the most cost-effective and has the shortest time to decision
regarding definitive liver resection [21].

Treatment

Historically, only liver resection offered the possibility of cure for these patients;
however only one third of patients with liver-limited disease are presently consid-
ered surgically resectable at the time of diagnosis [2]. Five-year survival rates
282 R. Diaz-Nieto and G. J. Poston

following successful liver resection are around 50% and 10-year survival approaches
25% [22, 23]. On the contrary median survival from the diagnosis of patients receiv-
ing no treatment is 6–12 months, with no 5 year survival [22, 24].
Available treatments for colorectal liver metastasis include surgery, ablation, sys-
temic chemotherapy and regional chemotherapy and radiation therapy [25]. A
recently published randomized clinical trial has demonstrated the real survival ben-
efit of ablation of such liver metastases combined with chemotherapy in comparison
with chemotherapy alone, and there are extensive data from non-randomized clini-
cal trials demonstrating that surgical resections of colorectal liver metastasis pro-
vide long-term survival benefits [23, 26, 27]. However, such good long-term survival
is a result of the combination of multimodal therapies to provide the highest survival
rates. Every single patient with colorectal liver metastases must be discussed in a
multidisciplinary team meeting where gastroenterologists, colorectal surgeons, hep-
atobiliary surgeons, thoracic surgeons, oncologist, radiologists and histopatholo-
gists can determine a structured treatment plan that may combine systemic
chemotherapy, surgical resections and/or locoregional interventions.

Surgery

Surgical resection of liver metastases from colorectal cancer remains the best treat-
ment with curative intent. Advances in liver surgery have dramatically improved
outcomes for this procedure and allow more patients to benefit. The last few years
have also seen the introduction of minimally invasive surgery in the field of liver
resections. Awaiting stronger evidence comparing open and laparoscopic surgery, it
seems that both are equally feasible and safe in terms of survival outcomes, with
laparoscopic surgery offering advantages in terms of reduced postoperative morbid-
ity and blood loss [28].
Appropriate patient selection is essential. Patient fitness is crucial, and detailed
anaesthetic assessment is strongly advised prior to surgery; however nowadays
there is no single factor, including age, that is considered a contraindication to
surgery.
The aim of surgery should be the complete removal of all the tumours within the
liver. Whilst there are recent debates around debulking surgery [29], there is still
lack of evidence to support surgery which doesn’t remove all of the disease.
Resection margins should be free of tumour; however the acceptable width of the
margin remains unclear. It is commonly accepted that 1 mm is enough and can be
considered an R0 resection. However when tumours are in contact with c­ ontralateral
portal pedicles, then R1 resections are acceptable and can be considered as curative
intent surgery and have proven long-term survival benefit [23, 30]. Indeed, R1
resection might have less impact on long-term survival than other more recently
considered prognostic factors such as KRAS mutational status [31]. However most
authors consider R1 resection to be associated with decreased OS and DFS [32],
and so the surgical resection should be planned for a complete resection of the
21 Colorectal Liver Metastasis 283

tumour with at least 1 mm margin. Macroscopic presence of tumour at the resection

margin (R2 resection) has definitely poorer survival outcomes when compared with
R0/R1 resections [11].
The definition of resectability is a constantly evolving concept. The current defi-
nition of resectability is the removal of all tumours whilst preserving an adequate
remnant (25–30%) of the viable, disease-free healthy liver. Nevertheless even in
some circumstances where there is not enough future liver remnant, new strategies
are currently used to increase and optimize liver volumes and hence turning initially
non-resectable patients into resectable. With this objective in mind, the surgical
technique can vary. From typical anatomical (resection of anatomical segments or
sectors of the liver), we have now moved into more parenchymal-sparing hepatec-
tomies where a more limited resection is performed in order to preserve more rem-
nant liver, thus decreasing operative morbidity [33].
Some of the strategies to convert unresectable patients to resectability include
two-stage hepatectomy (TSH)–clearance of the metastases in one or two sectors
of the liver combined with intraoperative or postoperative ligation/embolization
of the contralateral portal vein, followed by a second hepatectomy to clear the
rest of the disease. Portal vein embolization (PVE)–occlusion of portal vein
branches to that part of the liver to be subsequently resected aims at increasing
the future liver remnant volume by leading to hypertrophy of the other side in the
subsequent weeks (Fig. 21.2). A combination of both as associated liver partition
and portal vein ligation for staged hepatectomy (ALLPS)–where at the time of
the first stage, the transection of the liver parenchyma is combined with ligation
of the contralateral portal vein. This technique is meant to reduce the cross flow
of blood through the liver parenchyma to the contralateral liver, in addition to the
occlusion of the portal vein flow. All these techniques aim to occlude the inflow
(portal vein) to the sector of the liver that would be potentially removed, so
allowing the future remnant liver to hypertrophy prior to the resection. ALLPS
results in a quicker growth rate than the other techniques, which could poten-
tially reduce the risk of disease progression between the two stages, leading to
irresectability, whilst on the other hand it is associated with higher mortality and
morbidity rates [34].
Median overall survival following two-stage hepatectomy is 38.9 months with a
median disease-free survival of 15.7 months. However, up to 30% of patients will
not reach the second stage of surgery mainly because of disease progression during
the interval between embolization and resection [35]. Staged hepatectomy has a
postoperative morbidity and mortality after the first stage of around 17% and 0.5%,
respectively and of 40% and 3%, respectively, after the second stage [36]. Again in
this setting, 20–30% of patients will not reach the second stage mainly because of
tumour progression, but for those who complete both stages, R0 resection rate is of
75%, and median overall survival is 37 months (range, 24–44) months [36]. The
concept of ALPPS is to reduce the interval time between stages, ideally increasing
the number of patients who will reach the second stage. This shorter period of time
should avoid the development of new metastases whilst carrying with it increased
morbidity and mortality [34].
284 R. Diaz-Nieto and G. J. Poston

a1 a2

b1 b2

c1 c2

d1 d2

Fig. 21.2 Examples of portal vein embolization for insufficient future liver remnant prior to liver
resection. Clinical scenarios a and b of insufficient future liver remnant volume in the left hemi-­
liver prior to liver resection. a1/b1: Initial scans before intervention. a2/b2: Venograms before and
after right-sided portal vein embolization. c1/c2: Post-embolizaton scans showing left-sided
hypertrophy. d1/d2: Scans after liver resection showing final liver volume
21 Colorectal Liver Metastasis 285

All these strategies are in the setting of initially unresectable disease, and most
protocols include the use of systemic chemotherapy (sometimes known as conver-
sion chemotherapy) in order to reduce the bulk of the disease in the liver and subse-
quently proceed with surgery. An additional advantage of this approach is the
treatment of micrometastases and also the selecting out of patients with more
aggressive biology.

Systemic Therapies

There is now a wide range of drugs and regimens available to treat advanced
colorectal cancer. Systemic therapy has evolved from single agent fluorouracil
(5-FU) to multiple combinations of antineoplastic agents in addition to anti-­
angiogenic drugs (bevacizumab, regorafenib and aflibercept) and anti-epidermal
growth factor receptor agents (anti-EGFR), such as cetuximab and panitumumab.
Most of the standard regimens include 5-FU modulated by folinic acid, oxaliplatin
or irinotecan. Nomenclature is also complex, and the traditional concept of neoad-
juvant chemotherapy can be confusing if the patient has undergone an earlier bowel
resection with subsequent adjuvant chemotherapy which could be considered as
neoadjuvant to the resection of the liver metastases. Perioperative chemotherapy
includes all regimens given either before or after surgery.
The most reliable evidence supporting perioperative chemotherapy and showing
survival benefit in terms of disease-free survival comes from the use of FOLFOX4
[37, 38].
Neoadjuvant systemic chemotherapy prior to liver resection for resectable liver
metastases has many theoretical advantages, such as assessing tumour sensitivity,
decreasing large or multiple liver lesions, increasing resectability, and treating
micrometastases [39]. However there are inherit risks related to delaying the surgi-
cal resection specially the risk of disease progression (6%) and 30% of patients who
don’t respond to chemotherapy [40], induction of liver toxicity (steatohepatitis with
irinotecan and sinusoidal congestion syndrome with oxaliplatin) and increasing
postoperative morbidity [38] and mortality [41]. There is a need for stronger evi-
dence therefore to support the routine use of systemic chemotherapy for resectable
liver metastasis prior to liver resection, both in the setting of synchronous presenta-
tion and metachronous presentation.
Adjuvant chemotherapy is even more controversial. There are discrepancies
between trials regarding benefits in OS and DFS; however as mentioned before,
the use of perioperative chemotherapy (rather than adjuvant only chemotherapy)
is justified, supported by the fact that recurrence after liver resection remains
around 60% [41]. Based on the publication of the randomized clinical trial for
resectable liver metastasis (EORTC 40983), perioperative administration of
FOLFOX4 (six 14-day cycles of oxaliplatin 85 mg/m2, folinic acid 200 mg/m2
286 R. Diaz-Nieto and G. J. Poston

(DL form) or 100 mg/m2 (L form) on days 1–2 plus bolus and fluorouracil
400 mg/m2 (bolus) and 600 mg/m2 (continuous 22 h infusion), before and after
surgery) has become the standard regimen. This trial reported a significant DFS
benefit in those patients who underwent liver resection [38] but failed to demon-
strate long-term OS benefit as it was insufficiently powered [42]. A more recent
meta-analysis has suggested that the routine use of adjuvant systemic chemo-
therapy after resection of liver metastasis improved OS rates for 23% of the
patients versus surgery alone (HR, 0.77; 95% confidence interval [CI] 0.67–0.88;
p < 0.001) and improved DFS for 29% of the patients (HR, 0.71; 95% CI 0.61–
0.83; p < 0.001) [43].
Up to 70% of patients will have unresectable disease at the time of presenta-
tion. This is where conversion chemotherapy plays a very important role.
Recently the METHEP trial reported that the FOLFIRINOX regimen (combina-
tion of folinic acid, 5-FU, oxaliplatin and irinotecan) resulted in a very good
response in patients with unresectable liver-limited disease with up to 67% of the
patients become resectable [44]. More recent addition of bevacizumab or other
regimens including capecitabine may also increase this resection rate and offer
alternatives for initial nonresponders [45, 46]. Median pooled overall survival for
patients who underwent liver resection after FOLFIRINOX-Bev was 30.2 months,
and median DFS was 12.4 months [47]. The addition of cetuximab to standard
systemic chemotherapy significantly improves the outcomes in RAS wild-type
patients with unresectable liver-limited colorectal metastases in terms of OS,
DFS and also conversion to resectable and improved R0 rates after surgery [48].
However postoperative administration of FOLIRI after R0 resection of liver
metastases did not show any benefit in overall survival but increased the rate of
chemotherapy-related toxicity [41, 44].
In the palliative setting, chemotherapy remains the basis of management for
the majority of patients with stage 4 colorectal cancer. Surgery has traditionally
only played a role in these patients for the treatment of symptoms related to the
primary tumour [49]. Administration of the chemotherapy regimens discussed
above provides a survival benefit to patients of 24 months OS [49]. Further
results from randomized clinical trials suggest that, when possible, liver-targeted
interventions for the liver metastases (mainly ablation techniques) offer a sur-
vival benefit when compared to chemotherapy alone [26]. Alternative therapies
for patients with liver-limited disease when systemic treatment (following one or
more treatment lines) has failed to control the disease, include regional treatment
to the liver such as hepatic artery infusional (HAI) chemotherapy and radioem-
bolization (yttrium-90 (Y90)) [50, 51]. However current evidence to support
such treatment strategies is limited. Drug-eluting beads with irinotecan (DEBIRI)
may offer equivalent effect with potentially reduced side effects. Its use as neo-
adjuvant treatment has recently proved to be as effective as systemic chemo-
therapy for resectable liver metastases [52].
21 Colorectal Liver Metastasis 287

Thermal Ablation

Thermal ablation (TA) technologies destroy neoplastic tissue by coagulative necro-

sis. Radiofrequency ablation (RFA) and microwave ablation (MWA) use extremely
high temperatures (>60 °C), whilst cryotherapy (CA) uses liquid nitrogen to disrupt
the tissue by freezing [53, 54].
A recent systematic review compared these three techniques, and in accordance
with most of the available literature, it seems that CA has the highest local recur-
rence rates (12–39%), RFA local recurrence rates ranged between 10 and 31%, and
MWA had the lowest (5–13%) [55–57]. More recently, the use of irreversible elec-
troporation (IRE) has reported similar outcomes [58], but there remains a need for
well-designed trials to compare these different techniques. However, IRE seems to
be beneficial for tumours very close to the main portal pedicles and major hepatic
veins, where others types of thermal ablations are considered unsafe [58].
The advantage of TA over liver resection (LR) is lower morbidity/mortality [59,
60]; however there are limitations relating to tumour location and size and number
of metastases [61]. A recent consensus concluded that less than five tumours, all
smaller than 3 cm, are acceptable for percutaneous ablation, if more than a 5 mm
ablation margin can be achieved [62].
Despite the lack of strong evidence and the heterogeneity of clinical trials, it
seems that liver resection, when feasible, is superior to TA in achieving local control
[63]. Recent reports suggest that LR was superior to RFA in the treatment of patients,
irrespective of solitary or multiple metastases and the size of the tumours [64–67].
However, in the setting of the multidisciplinary team and complementary to surgery
and chemotherapy, TA has a very important role in the management of colorectal
liver metastasis, both for curative intent treatment and palliative management [61].

Liver Transplantation

Liver transplantation is, in concept, an alternative treatment to colorectal liver metas-

tasis. It was actually one of the initial indications for transplantation; however poor
outcomes and early recurrence made centres abandon these techniques for liver malig-
nancies, and only hepatocellular carcinoma remains as a standard indication for liver
transplantation [25]. The lack of donor organs for transplantation to treat end-stage
chronic liver diseases precluded for the indications of transplantation for malignan-
cies. Some centres however have explored this field and innovations in some immune-
modulating agents, rather than immunosuppressive drugs may change this indication
[25]. Despite remaining a unique outcome, Hagness et al. reported a 1-, 3- and 5-year
OS of 95%, 68% and 60%, respectively, following orthotopic liver transplantation for
patients with unresectable liver-limited colorectal liver metastases [68].
288 R. Diaz-Nieto and G. J. Poston

Recurrence After Treatment

In the lack of strong evidence, most commonly used follow-up protocols after
curative intended liver resection for colorectal liver metastases include regular CTs
of the chest abdomen and pelvis every 6 months to a year for a minimum of 5 years.
In addition, CEA has proven to be an adequate tumour marker to monitor
recurrence.
If the disease recurs in the liver, then all of the therapies discussed above can
be reconsidered. Surgery remains the ideal treatment option despite the limita-
tions of a previous liver resection. In this setting, if technically possible then
repeated hepatectomies have proven to be as effective in survival outcomes as
the first hepatectomy, despite the surgical limitations of adhesions from previ-
ous surgeries [69]. There is no limit to the number of hepatectomies that can be
performed, with large series reporting long-term survival benefits after repeated
hepatectomies [70]. The limitation is related however to the future liver remnant
that would be progressively compromised. Alternatively, thermal ablation can
be considered. However our recent experience shows that despite being feasible,
ablation has a poorer outcome when compared to surgery for recurrent colorec-
tal liver metastases [71].

Presence of Extrahepatic Disease

Although the liver is the most common site for metastatic colorectal cancer, up to
38% of patients will develop metastases at other sites. Lung, peritoneum and lymph
nodes are the most common site for extrahepatic metastases. The complexity of
management is obviously greater, but long-term survival is still possible. Extrahepatic
disease is no longer an absolute contraindication, and if R0 resection is possible at
all anatomical sites, then treatment strategies to achieve this objective should be
considered [72].
From our experience a multidisciplinary approach is of key importance.
Tumours that have initially responded to chemotherapy can be re-challenged
using the same chemotherapy regimen. Following a lack of response, then con-
sideration should be given to second-line chemotherapy. Nowadays it is manda-
tory that every patient with colorectal liver metastases, irrespective of the extent
of disease or the concomitance of disease at other sites, is discussed in a special-
ized liver centre where a liver surgeon can assess resectability [73]. Even more
so, multidisciplinary management of patients with colorectal cancer has proven
to diagnose and stage patients more accurately with a subsequent positive impact
in OS [74].
21 Colorectal Liver Metastasis 289

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.
2. Sag AA, Selcukbiricik F, Mandel NM. Evidence-based medical oncology and interventional
radiology paradigms for liver-dominant colorectal cancer metastases. World J Gastroenterol.
2016;22(11):3127–49.
3. Rudmik LR, Magliocco AM. Molecular mechanisms of hepatic metastasis in colorectal can-
cer. J Surg Oncol. 2005;92(4):347–59.
4. Ki DH, Jeung HC, Park CH, Kang SH, Lee GY, Lee WS, et al. Whole genome analysis for liver
metastasis gene signatures in colorectal cancer. Int J Cancer. 2007;121(9):2005–12.
5. Palomba G, Doneddu V, Cossu A, Paliogiannis P, Manca A, Casula M, et al. Prognostic
impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a
population-­based study. J Transl Med. 2016;14(1):292.
6. Brudvik KW, Jones RP, Giuliante F, Shindoh J, Passot G, Chung MH, et al. RAS mutation clini-
cal risk score to predict survival after resection of colorectal liver metastases. Ann Surg. 2017.
7. Andreatos N, Ronnekleiv-Kelly S, Margonis GA, Sasaki K, Gani F, Amini N, et al. From
bench to bedside: Clinical implications of KRAS status in patients with colorectal liver metas-
tasis. Surg Oncol. 2016;25(3):332–8.
8. Passiglia F, Bronte G, Bazan V, Galvano A, Vincenzi B, Russo A. Can KRAS and BRAF muta-
tions limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic
review and meta-analysis. Crit Rev Oncol Hematol. 2016;99:150–7.
9. Brudvik KW, Kopetz SE, Li L, Conrad C, Aloia TA, Vauthey JN. Meta-analysis of
KRAS mutations and survival after resection of colorectal liver metastases. Br J Surg.
2015;102(10):1175–83.
10. Mao C, Wu XY, Yang ZY, Threapleton DE, Yuan JQ, Yu YY, et al. Concordant analysis of
KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer
and matched metastases. Sci Rep. 2015;5:8065.
11. Allard MA, Adam R, Giuliante F, Lapointe R, Hubert C, Ijzermans JNM, et al. Long-term out-
comes of patients with 10 or more colorectal liver metastases. Br J Cancer. 2017;117(5):604–11.
12. Torzilli G, Procopio F. State of the art of intraoperative ultrasound in liver surgery: current use
for resection-guidance. Chirurgia (Bucur). 2017;112(3):320–5.
13. Cantisani V, Ricci P, Erturk M, Pagliara E, Drudi F, Calliada F, et al. Detection of hepatic metas-
tases from colorectal cancer: prospective evaluation of gray scale US versus SonoVue(R) low
mechanical index real time-enhanced US as compared with multidetector-CT or Gd-BOPTA-­
MRI. Ultraschall Med. 2010;31(5):500–5.
14. Cantisani V, Grazhdani H, Fioravanti C, Rosignuolo M, Calliada F, Messineo D, et al. Liver
metastases: contrast-enhanced ultrasound compared with computed tomography and magnetic
resonance. World J Gastroenterol. 2014;20(29):9998–10007.
15. Hale HL, Husband JE, Gossios K, Norman AR, Cunningham D. CT of calcified liver metasta-
ses in colorectal carcinoma. Clin Radiol. 1998;53(10):735–41.
16. Zech CJ, Herrmann KA, Reiser MF, Schoenberg SO. MR imaging in patients with suspected
liver metastases: value of liver-specific contrast agent Gd-EOB-DTPA. Magn Reson Med Sci.
2007;6(1):43–52.
17. van Kessel CS, Buckens CF, van den Bosch MA, van Leeuwen MS, van Hillegersberg R,
Verkooijen HM. Preoperative imaging of colorectal liver metastases after neoadjuvant chemo-
therapy: a meta-analysis. Ann Surg Oncol. 2012;19(9):2805–13.
18. Xia Q, Liu J, Wu C, Song S, Tong L, Huang G, et al. Prognostic significance of (18)FDG
PET/CT in colorectal cancer patients with liver metastases: a meta-analysis. Cancer Imaging.
2015;15:19.
290 R. Diaz-Nieto and G. J. Poston

19. Yip VS, Poston GJ, Fenwick SW, Wieshmann H, Athwal T, Malik HZ. FDG-PET-CT is effec-
tive in selecting patients with poor long term survivals for colorectal liver metastases. Eur J
Surg Oncol. 2014;40(8):995–9.
20. Lee DH, Lee JM. Whole-body PET/MRI for colorectal cancer staging: is it the way forward?
J Magn Reson Imaging. 2017;45(1):21–35.
21. Yip VS, Collins B, Dunne DF, Koay MY, Tang JM, Wieshmann H, et al. Optimal imaging
sequence for staging in colorectal liver metastases: analysis of three hypothetical imaging
strategies. Eur J Cancer. 2014;50(5):937–43.
22. Wilson SM, Adson MA. Surgical treatment of hepatic metastases from colorectal cancers.
Arch Surg. 1976;111(4):330–4.
23. Hosokawa I, Allard MA, Gelli M, Ciacio O, Vibert E, Cherqui D, et al. Long-term survival
benefit and potential for cure after R1 resection for colorectal liver metastases. Ann Surg
Oncol. 2016;23(6):1897–905.
24. Scheele J, Stangl R, Altendorf-Hofmann A, Gall FP. Indicators of prognosis after hepatic
resection for colorectal secondaries. Surgery. 1991;110(1):13–29.
25. Moris D, Tsilimigras DI, Chakedis J, Beal EW, Felekouras E, Vernadakis S, et al. Liver trans-
plantation for unresectable colorectal liver metastases: a systematic review. J Surg Oncol.
2017;116(3):288–97.
26. Ruers T, Punt C, Van Coevorden F, Pierie JP, Borel-Rinkes I, Ledermann JA, et al.
Radiofrequency ablation combined with systemic treatment versus systemic treatment alone
in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup
phase II study (EORTC 40004). Ann Oncol. 2012;23(10):2619–26.
27. Ruers T, Punt CJA, Van Coevorden F, Pierie JPEN, Borel-Rinkes I, Ledermann JA, Poston G,
et al. Long-term survival results of a randomised phase II study of the EORTC-NCRI CCSG-­
ALM intergroup 40004 (CLOCC). J Clin Oncol. 2015;33(Suppl).
28. Hallet J, Beyfuss K, Memeo R, Karanicolas PJ, Marescaux J, Pessaux P. Short and long-term
outcomes of laparoscopic compared to open liver resection for colorectal liver metastases.
Hepatobiliary Surg Nutr. 2016;5(4):300–10.
29. Tanaka K, Murakami T, Yabushita Y, Hiroshima Y, Matsuo K, Endo I, et al. Maximal debulking
liver resection as a beneficial treatment strategy for advanced and aggressive colorectal liver
metastases. Anticancer Res. 2014;34(10):5547–54.
30. de Haas RJ, Wicherts DA, Flores E, Azoulay D, Castaing D, Adam R. R1 resection by
necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg.
2008;248(4):626–37.
31. Truant S, Sequier C, Leteurtre E, Boleslawski E, Elamrani M, Huet G, et al. Tumour biology of
colorectal liver metastasis is a more important factor in survival than surgical margin clearance
in the era of modern chemotherapy regimens. HPB (Oxford). 2015;17(2):176–84.
32. Tranchart H, Chirica M, Faron M, Balladur P, Lefevre LB, Svrcek M, et al. Prognostic impact
of positive surgical margins after resection of colorectal cancer liver metastases: reappraisal in
the era of modern chemotherapy. World J Surg. 2013;37(11):2647–54.
33. Alvarez FA, Sanchez Claria R, Oggero S, de Santibanes E. Parenchymal-sparing liver sur-
gery in patients with colorectal carcinoma liver metastases. World J Gastrointest Surg.
2016;8(6):407–23.
34. Moris D, Ronnekleiv-Kelly S, Kostakis ID, Tsilimigras DI, Beal EW, Papalampros A, et al.
Operative results and oncologic outcomes of Associating Liver Partition and Portal Vein
Ligation for Staged Hepatectomy (ALPPS) versus Two-Stage Hepatectomy (TSH) in patients
with unresectable colorectal liver metastases: a systematic review and meta-analysis. World J
Surg. 2017.
35. Ironside N, Bell R, Bartlett A, McCall J, Powell J, Pandanaboyana S. Systematic review of
perioperative and survival outcomes of liver resections with and without preoperative portal
vein embolization for colorectal metastases. HPB (Oxford). 2017;19(7):559–66.
21 Colorectal Liver Metastasis 291

36. Lam VW, Laurence JM, Johnston E, Hollands MJ, Pleass HC, Richardson AJ. A systematic
review of two-stage hepatectomy in patients with initially unresectable colorectal liver metas-
tases. HPB (Oxford). 2013;15(7):483–91.
37. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and
fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J
Clin Oncol. 2000;18(16):2938–47.
38. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative
chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases
from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet.
2008;371(9617):1007–16.
39. Nordlinger B, Benoist S. Benefits and risks of neoadjuvant therapy for liver metastases. J Clin
Oncol. 2006;24(31):4954–5.
40. Masi G, Loupakis F, Pollina L, Vasile E, Cupini S, Ricci S, et al. Long-term outcome of ini-
tially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin,
oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg.
2009;249(3):420–5.
41. Fiorentini G, Sarti D, Aliberti C, Carandina R, Mambrini A, Guadagni S. Multidisciplinary
approach of colorectal cancer liver metastases. World J Clin Oncol. 2017;8(3):190–202.
42. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative
FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases
from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase
3 trial. Lancet Oncol. 2013;14(12):1208–15.
43. Araujo RL, Gonen M, Herman P. Chemotherapy for patients with colorectal liver metastases
who underwent curative resection improves long-term outcomes: systematic review and meta-­
analysis. Ann Surg Oncol. 2015;22(9):3070–8.
44. Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, et al. A ran-
domized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in
patients following complete resection of liver metastases from colorectal cancer. Ann Oncol.
2009;20(12):1964–70.
45. Okines A, Puerto OD, Cunningham D, Chau I, Van Cutsem E, Saltz L, et al. Surgery with
curative-intent in patients treated with first-line chemotherapy plus bevacizumab for meta-
static colorectal cancer First BEAT and the randomised phase-III NO16966 trial. Br J Cancer.
2009;101(7):1033–8.
46. Wong R, Cunningham D, Barbachano Y, Saffery C, Valle J, Hickish T, et al. A multicentre
study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients
with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann Oncol.
2011;22(9):2042–8.
47. Tomasello G, Petrelli F, Ghidini M, Russo A, Passalacqua R, Barni S. FOLFOXIRI plus beva-
cizumab as conversion therapy for patients with initially unresectable metastatic colorectal
cancer: a systematic review and pooled analysis. JAMA Oncol. 2017;3(7):e170278.
48. Lv W, Zhang GQ, Jiao A, Zhao BC, Shi Y, Chen BM, et al. Chemotherapy plus cetuximab versus
chemotherapy alone for patients with KRAS wild type unresectable liver-confined metastases
colorectal cancer: an updated meta-analysis of RCTs. Gastroenterol Res Pract. 2017;2017:8464905.
49. Costi R, Leonardi F, Zanoni D, Violi V, Roncoroni L. Palliative care and end-stage
colorectal cancer management: the surgeon meets the oncologist. World J Gastroenterol.
2014;20(24):7602–21.
50. Cercek A, Gendel V, Jabbour S, Moore D, Chen C, Nosher J, et al. A comparison of Yttrium-90
microsphere radioembolization to hepatic arterial infusional chemotherapy for patients with
chemo-refractory hepatic colorectal metastases. Curr Treat Options in Oncol. 2017;18(7):42.
51. Bhutiani N, Martin RC 2nd. Transarterial therapy for colorectal liver metastases. Surg Clin
North Am. 2016;96(2):369–91.
292 R. Diaz-Nieto and G. J. Poston

52. Jones RP, Malik HZ, Fenwick SW, Terlizzo M, O'Grady E, Stremitzer S, et al. PARAGON
II—a single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead
in patients with resectable liver metastases from colorectal cancer. Eur J Surg Oncol.
2016;42(12):1866–72.
53. Wu ZB, Si ZM, Qian S, Liu LX, Qu XD, Zhou B, et al. Percutaneous microwave ablation com-
bined with synchronous transcatheter arterial chemoembolization for the treatment of colorec-
tal liver metastases: results from a follow-up cohort. Onco Targets Ther. 2016;9:3783–9.
54. Poston G. Cryosurgery for colorectal liver metastases. Hepato-Gastroenterology.
2001;48(38):323–4.
55. Pathak S, Jones R, Tang JM, Parmar C, Fenwick S, Malik H, et al. Ablative therapies for
colorectal liver metastases: a systematic review. Color Dis. 2011;13(9):e252–65.
56. Correa-Gallego C, Fong Y, Gonen M, D'Angelica MI, Allen PJ, DeMatteo RP, et al. A retro-
spective comparison of microwave ablation vs. radiofrequency ablation for colorectal cancer
hepatic metastases. Ann Surg Oncol. 2014;21(13):4278–83.
57. Martin RC, Scoggins CR, McMasters KM. Safety and efficacy of microwave ablation of hepatic
tumors: a prospective review of a 5-year experience. Ann Surg Oncol. 2010;17(1):171–8.
58. Scheffer HJ, Melenhorst MC, Echenique AM, Nielsen K, van Tilborg AA, van den Bos W,
et al. Irreversible electroporation for colorectal liver metastases. Tech Vasc Interv Radiol.
2015;18(3):159–69.
59. Hammill CW, Billingsley KG, Cassera MA, Wolf RF, Ujiki MB, Hansen PD. Outcome after
laparoscopic radiofrequency ablation of technically resectable colorectal liver metastases. Ann
Surg Oncol. 2011;18(7):1947–54.
60. Jakobs TF, Hoffmann RT, Trumm C, Reiser MF, Helmberger TK. Radiofrequency abla-
tion of colorectal liver metastases: mid-term results in 68 patients. Anticancer Res.
2006;26(1B):671–80.
61. Diaz-Nieto R, Fenwick S, Malik H, Poston G. Defining the optimal use of ablation for meta-
static colorectal cancer to the liver without high-level evidence. Curr Treat Options in Oncol.
2017;18(2):8.
62. Gillams A, Goldberg N, Ahmed M, Bale R, Breen D, Callstrom M, et al. Thermal ablation of
colorectal liver metastases: a position paper by an international panel of ablation experts, The
Interventional Oncology Sans Frontieres meeting 2013. Eur Radiol. 2015;25(12):3438–54.
63. de Meijer VE, Verhoef C, Kuiper JW, Alwayn IP, Kazemier G, Ijzermans JN. Radiofrequency
ablation in patients with primary and secondary hepatic malignancies. J Gastrointest Surg.
2006;10(7):960–73.
64. Wu YZ, Li B, Wang T, Wang SJ, Zhou YM. Radiofrequency ablation vs hepatic resection for
solitary colorectal liver metastasis: a meta-analysis. World J Gastroenterol. 2011;17(36):4143–8.
65. Abdalla EK, Vauthey JN, Ellis LM, Ellis V, Pollock R, Broglio KR, et al. Recurrence and out-
comes following hepatic resection, radiofrequency ablation, and combined resection/ablation
for colorectal liver metastases. Ann Surg. 2004;239(6):818–25. discussion 25-7
66. Lee KH, Kim HO, Yoo CH, Son BH, Park YL, Cho YK, et al. Comparison of radiofrequency
ablation and resection for hepatic metastasis from colorectal cancer. Korean J Gastroenterol.
2012;59(3):218–23.
67. Lee H, Heo JS, Cho YB, Yun SH, Kim HC, Lee WY, et al. Hepatectomy vs radiofrequency
ablation for colorectal liver metastasis: a propensity score analysis. World J Gastroenterol.
2015;21(11):3300–7.
68. Hagness M, Foss A, Line PD, Scholz T, Jorgensen PF, Fosby B, et al. Liver transplantation for
nonresectable liver metastases from colorectal cancer. Ann Surg. 2013;257(5):800–6.
69. Wurster EF, Tenckhoff S, Probst P, Jensen K, Dolger E, Knebel P, et al. A systematic review
and meta-analysis of the utility of repeated versus single hepatic resection for colorectal cancer
liver metastases. HPB (Oxford). 2017;19(6):491–7.
70. Adam R, Pascal G, Azoulay D, Tanaka K, Castaing D, Bismuth H. Liver resection for colorec-
tal metastases: the third hepatectomy. Ann Surg. 2003;238(6):871–83. discussion 83-4
21 Colorectal Liver Metastasis 293

71. Dupre A, Jones R, Diaz-Nieto R, Fenwick S, Poston G, Malik H. Curative-intent treatment of

recurrent colorectal liver metastases: a comparison between ablation and resection. Eur J Surg
Oncol. 2017;43(10):1901–7.
72. Hadden WJ, de Reuver PR, Brown K, Mittal A, Samra JS, Hugh TJ. Resection of colorectal
liver metastases and extra-hepatic disease: a systematic review and proportional meta-analysis
of survival outcomes. HPB (Oxford). 2016;18(3):209–20.
73. Jones RP, Vauthey JN, Adam R, Rees M, Berry D, Jackson R, et al. Effect of specialist decision-­
making on treatment strategies for colorectal liver metastases. Br J Surg. 2012;99(9):1263–9.
74. Ye YJ, Shen ZL, Sun XT, Wang ZF, Shen DH, Liu HJ, et al. Impact of multidisciplinary team
working on the management of colorectal cancer. Chin Med J. 2012;125(2):172–7.
Chapter 22
Benign Liver Tumours

James Pape and Charles Imber

Key Learning Points

1. Benign liver lesions can offer challenging dilemmas for clinicians.
2. Hepatic adenomas have the potential for malignant change determined by
size and patient gender.
3. The mechanism and classification of hepatic adenomas are increasingly
understood.
4. Haemangiomas, FNH and cysts are often asymptomatic but may cause
problems due to pressure effects.
5. Surgical intervention must weigh up the risks to the patient and the poten-
tial benefits.
6. Liver transplantation may be indicated in a small number of polycystic
liver disease cases, where patients are very symptomatic and the quality of
life poor.

Hepatocellular Adenoma

Hepatocellular adenoma (HCA) is a rare benign liver tumour derived from the pro-
liferation of mature hepatocytes, with an incidence of 1 case for 1,000,000 people
[1]: the incidence increases to 1–3 cases for 100,000 in females which use or have
used an oral contraceptive long term.

J. Pape (*) · C. Imber

Centre For HPB Surgery and Liver Transplantation, Royal Free Hospital,
London, UK
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2019 295

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4_22
296 J. Pape and C. Imber

Presentation and Clinical Features

More than 50% of adenomas are asymptomatic and identified incidentally; large
lesions (6–30 cm) can cause right upper quadrant discomfort or pain due to expan-
sion of the liver capsule. A potentially acute and life-threatening presentation occurs
if a large peripheral or exophytic tumour breaks and bleeds into the abdominal
cavity.
The main risk factor for HCA development is oestrogen exposure, explaining the
predominance of female cases and the association with oral contraception. Also
some congenital diseases such as glycogen storage diseases, as well as some meta-
bolic syndrome manifestations such as diabetes mellitus, insulin resistance, dyslipi-
daemia and obesity, are considered as risk factors for the development and
progression of HCA.
Men with metabolic syndrome are at a much higher risk (ten times more likely
than females) for malignant degeneration of liver adenomas (anyway rare, <5%).
Other risk factors for degeneration are androgen use, large tumours (>5 cm) and
histological subtype (β-catenin-mutated).

Pathophysiology

HCAs usually are solitary, well-delineated and, occasionally, pedunculated tumours

with parenchyma composed of plates of hepatocytes separated by sinusoids without
portal tract elements or bile ductules, a key feature in the histological distinction of
HCA from focal nodular hyperplasia (FNH).
With regard to the morphomolecular aspects of the disease, the great leap for-
ward was the discovery that hepatocellular adenoma was not a single entity and that
at least three different subtypes exist, with specific underlying gene mutations [2].
These mutations affect the HNF1A gene, several genes leading to JAK/STAT3 path-
way activation and the CTNNB1 gene. All of them are associated with more or less
specific histopathological characteristics and can be recognised using immunohisto-
chemistry either with specific antibodies or with surrogate markers.

Diagnostic Workup

Confronted with a potentially benign liver tumour, the first key clinical point is to
perform a precise and unambiguous diagnosis. Abnormal liver function tests may
occur in patients with large HCA tumours including increased γ-glutamyl trans-
ferase levels, alkaline phosphatase secondary to cholestasis or an increase in
transaminase levels as a result of hepatic steatosis. Serum biomarkers of
22 Benign Liver Tumours 297

inflammation including fibrinogen and C-reactive protein were increased in 90%

of patients with inflammatory HCA and returned to normal after surgical resec-
tion of the tumour.
Imaging is useful to rule out focal nodular hyperplasia (FNH) and hepatic hae-
mangioma. Most HCAs are diagnosed on contrast-enhanced, multiphase computed
tomography (CT) or magnetic resonance imaging (MRI). Multiphase dynamic
contrast-­enhanced MRI is considered the modality of choice in the diagnosis of
HCA and its subtypes [3]. Histological analysis after percutaneous image-driven
biopsy remains the gold standard of HCA diagnosis and can also help to rule out
differential diagnoses, such as hepatocellular carcinoma (HCC) or FNH.

Management and Complications

Classically, HCAs have been considered an indication for surgical resection due to
their potential for both bleeding and malignant transformation. Yet, growing knowl-
edge of this condition has showed that bleeding and malignant transformation were
mainly observed in lesions >5 cm and rarely in lesions less than this size. It has also
been shown that malignant transformation is ten times more frequent in males,
especially in the presence of steroid intake. These features have led to the manage-
ment of hepatic adenomas based on size and gender, with resection of HCAs >5 cm
in females and of all HCAs in males. The surgical approach does not require a wide
resection margin or a regional lymphadenectomy even in the case of suspected
malignancy owing to the minimal risk of vascular invasion or lymph node involve-
ment, and a laparoscopic approach may be considered for a non-haemorrhagic
HCA. Intraoperative ultrasound is useful because HCA tumours often are soft and
non-palpable with ill-defined margins between the tumour and the adjacent steatotic
hepatic parenchyma.
Recent molecular subtyping of adenomas has revolutionised the field and fur-
ther refined indications for resection of HCAs [4]. In several reference centres, it
has revived the use of preoperative biopsies for more personalised management.
Thus, liver surgeons must be fully educated on the molecular subtypes of hepatic
adenomas. HCA molecular subtypes drive the prognosis and natural history of
these lesions, have a good correlation with imaging; and can be studied on biopsy
specimens using specific immunochemistry. Obesity is a risk factor for inflamma-
tory HCA and ‘sonic hedgehog’ HCA, which also has a high risk of bleeding.
Hepatocyte nuclear factor 1 alpha HCA has a low potential for malignant transfor-
mation, while b-catenin-activated HCA has a high potential for progressing to
malignancy. Less than 10% of HCAs are not characterised by imaging or immuno-
histochemistry. All are precipitated by oral contraceptives in females and the size
and gender rule (higher risk of bleeding and malignancy in lesions >5 cm and of
malignancy in males) remains valid in all subtypes. These findings are summarised
in Table 22.1.
298 J. Pape and C. Imber

Table 22.1 Classification and significance of different subtypes of hepatic adenoma

Bordeaux group risk prediction tool for adenoma
HCC Immunohistochemical
Tumour subtype Prevalence association Bleeding risk markers
Hepatocyte nuclear 30–50% Rare N/A Liver fatty acid-binding
factor 1α protein
β-Catenin activated 10–15% 46% N/A β-Catenin
association
Inflammatory 35% None N/A Serum amyloid A
Sonic hedgehog 4% Rare High GLI1 activation
Unclassified 5–10% N/A N/A None

Prognosis

Most patients are asymptomatic, and small lesions in women have an excellent
prognosis. In men or women with larger tumours, histological subtyping and/or
consideration of resection is necessary.

Haemangioma

Presentation and Clinical Features

Hepatic haemangiomas account for up to 70% of benign liver lesions. Estimated

prevalence varies from 0.4 to 20%, making them the most common liver lesion.
Most are discovered incidentally during laparotomy or imaging for an unrelated
indication.
Haemangiomas are typically asymptomatic, but larger lesions may cause symp-
toms which are most commonly right upper quadrant pain or fullness. Nausea, loss
of appetite and early satiety are less common and may occur due to compression of
adjacent structures. If there is thrombosis or bleeding within the tumour, sudden
severe abdominal pain may result, associated with liver function derangement and
fever. Rarely, rupture into the biliary tree leads to haemobilia.
In children, giant haemangiomas have been associated with high-output cardiac
failure.
Generally physical examination is unremarkable, but occasionally a liver mass is
palpable.
Haemangiomas of the liver may be associated with haemangiomas of other
organs, focal nodular hyperplasia and bile duct hamartomas.
22 Benign Liver Tumours 299

Pathophysiology

Haemangiomas range in size from a few millimetres to more than 20 cm diameter.

They are often solitary but may be multiple in up to 40% of patients [5]. Lesions
larger than 5 cm are referred to as giant haemangiomas and are more likely to grow
or cause symptoms.
The tumour is made up of different sizes of cavernous vascular spaces lined with
a single layer of endothelium and filled with blood which may thrombose.
This thrombosis may lead to the development of a collagenous scar or fibrous nod-
ule. Lesions are surrounded by a thin capsule.
Sex hormones may influence tumour growth as haemangiomas enlarge in preg-
nancy and during administration of oestrogen or progesterone. The lesions often regress
after withdrawal of the therapy. However, oestrogen receptors have not been found in
all haemangiomas, and tumour growth has been reported in the absence of oestrogen
therapy and in postmenopausal women, and so the association is not yet entirely defined.

Diagnostic Workup

In the absence of compressive effects, liver function tests are normal unless there is
acute bleeding or thrombosis within the haemangioma. Alpha-fetoprotein (AFP) is
normal.
Ultrasound usually strongly suggests haemangioma, but other modalities are
added to confirm the diagnosis if the patient has a history of malignancy or chronic
liver disease, as malignant tumours have similar patterns on ultrasound. Smaller
lesions are usually easier to identify, but the thrombosis and fibrosis in larger lesions
make confident diagnosis more challenging. Contrast agents used in conjunction
with ultrasound improve the detection rate [6].
CT scanning with contrast and a portal venous phase shows initial peripheral
enhancement of the lesion and the centre filling in thereafter. Larger lesions may
opacify atypically due to differing sizes of vascular spaces, scar tissue and the pres-
ence of cystic spaces.
MRI is highly accurate and may be further enhanced when combined with liver-­
specific IV contrast.
Technetium-99 m pertechnetate-labelled red blood cells are highly specific, but
sensitivity is affected by the presence of fibrosis and thrombosis. Single-photon
emission CT (SPECT) has an accuracy close to that of MRI.
Angiography is rarely used for diagnosis but may assist for atypical tumours that
elude definitive diagnosis after non-invasive imaging.
Percutaneous needle biopsy has been associated with fatal haemorrhage, and as
the diagnostic yield is low its value is debatable and use is best avoided.
300 J. Pape and C. Imber

Management

Patients with asymptomatic small lesions may be reassured and observed. Lesions
<5 cm are often not followed up provided there is diagnostic certainty. Larger
lesions are more likely to grow and should have repeat imaging in 6–12 months.
Prophylactic resection cannot be justified as the risk of bleeding is low.
There is controversy as to whether patients with haemangiomas should be
advised against pregnancy. Oral contraceptives and pregnancy seem associated with
haemangioma development and growth, but there is insufficient evidence to make a
conclusive link.
Indications for treatment include failure to exclude malignancy radiologically,
incapacitating symptoms or complications including rupture and intraperitoneal
bleeding. The management of asymptomatic lesions that are large or growing is
controversial, as complications of observing these remain mild and do not outweigh
the risk of surgery [7].
Where the indication is pain, other causes should be ruled out beforehand as a
number of patients have persistent pain after haemangioma treatment.
Surgical treatment options are resection, enucleation, hepatic artery ligation and
transplantation.
Non-surgical treatments include arterial embolisation, radiotherapy and inter-
feron alpha-2a.
Arterial embolisation may be used for acute bleeding control and treatment, or to
reduce the size of lesions preoperatively.
Radiotherapy is used occasionally for the treatment of childhood haemangiomas
but is rarely a first-line therapy due to risks of secondary malignancy and effects on
growth [8].
Interferon alpha-2a is used for treatment of infants with life-threatening extrahe-
patic haemangiomas but with limited success, and it has not been well studied for
hepatic haemangiomas [9].

Natural History and Complications

The natural history of hepatic haemangioma is not completely understood, with

variable results reported in available studies. This makes it challenging to determine
what proportion of the lesions will progress. Spontaneous rupture is a rare but seri-
ous complication and occurs usually in large haemangiomas that are located periph-
erally. Rupture following abdominal trauma is also possible but uncommon.

Prognosis

Most patients are asymptomatic, and the lesions have an excellent prognosis.
22 Benign Liver Tumours 301

Focal Nodular Hyperplasia

Focal nodular hyperplasia (FNH) is a generally benign liver lesion that usually
occurs in a normal liver and only occasionally becomes symptomatic. It can be chal-
lenging to differentiate radiologically from some more sinister liver pathology.

Presentation and Clinical Features

The incidence of FNH is estimated at 0.3% [10]. It occurs most commonly in adults,
especially women of childbearing age. It is more common in females with reported
ratios varying from 8 to 15:1 [11, 12]. Lesions in men are often smaller and more
likely to be atypical.
FNH accounts for approximately 8% of primary liver tumours and is between
three and ten times more common than hepatocellular adenoma.
Most FNH are found incidentally in patients without symptoms. 12–13% are
discovered when abnormal liver function tests are investigated.
Symptoms are rare but include abdominal pain, a palpable mass (2–4%) or
hepatomegaly.
Differential diagnosis is challenging, especially with other hypervascular entities
such as hepatocellular adenoma, hepatocellular carcinoma and hypervascular
metastases, which appear similar on imaging. MRI and CT can lead to diagnosis
when typical features are demonstrated, but these are not always present [11].

Pathogenesis

FNH probably develops secondary to local hemodynamic instability in the liver. An

arterial malformation leads to hyperperfusion of an area of the liver causing a regen-
erative response. At present the pathophysiology remains unclear, but FNH is
accepted to be truly benign and is not expected to bleed spontaneously or undergo
malignant transformation [10, 13].
FNH has been associated with hepatic haemangiomas and various vascular mal-
formations, leading to the hypothesis that it may result from a congenital vascular
abnormality [11].
Oral contraceptives do not cause FNH, but established FNH may further develop
in response to oestrogens. Patients taking oral contraceptives tend to have larger
more vascular tumours. The reports of haemorrhage and rupture of FNH that have
occurred have all been in patients taking oral contraceptives. FNH are well-­
differentiated lesions without a capsule and contain scar tissue. Fibrous stroma
divides the lesion into small hepatocellular nodules. The stroma is prominent and
forms a central stellate scar. There is disruption of the central veins and portal tracts
of the normal hepatic lobule and large dystrophic arteries.
302 J. Pape and C. Imber

Arteries drain into adjacent hepatic veins producing a ‘spoke and wheel’ pattern
that is seen on angiography. FNH can be differentiated from hepatocellular ade-
noma by the presence of sinusoids and Kupffer cells [11].

Diagnostic Workup

Laboratory testing is often unremarkable, but mild disruption of hepatic enzymes

may occur. Alpha-fetoprotein is normal [11].
Ultrasound often incidentally detects FNH, but its appearance varies greatly.
Lesions may appear hypo- or isoechoic and rarely as hyperechoic. The central scar
is only seen in about 20% of cases, and it may be difficult to distinguish FNH from
adenoma or malignant lesions. Ultrasound becomes more informative when com-
bined with IV contrast, which may show arterial phase enhancement of the central
stellate arteries. Emerging research suggests that the ability of contrast-enhanced
ultrasound to differentiate solid liver tumours is comparable with MRI.
CT is often suggestive of the diagnosis and should be performed without contrast
and then with hepatic arterial and portal venous phases. The lesion is iso- or
hypodense before contrast and then hyperdense with contrast. The central scar often
enhances prominently. CT has been shown to have a sensitivity of 75% and specific-
ity of 92% [14].
MRI is considered highly accurate in diagnosis of FNH and useful when other
imaging techniques are inadequate for diagnosis. The use of IV contrast allows for
definitive diagnosis if typical behaviour is present [13].
In FNH behaving atypically, differentiation can be difficult. Gadolinium-based
hepato-specific contrast agents may assist—these are taken up by the liver and
excreted in the biliary system. Since adenomas and metastases do not contain bile
ducts, they can be distinguished from FNH.
Angiography may reveal the diagnostic ‘spoked wheel’ but is rarely indicated [14].
If doubt still exists, image-guided biopsy may be undertaken, but existing data
shows a poor correlation between a biopsy diagnosis of FNH and the histology of
subsequently resected specimens [15].

Management

Management remains controversial due to the lack of randomised trials comparing

elective resection with conservative management. However the absence of malig-
nant transformation and the relative rarity of complications support a conservative
approach if sufficient diagnostic certainty can be achieved. This is especially true
for small asymptomatic lesions that do not enlarge at follow-up [15].
22 Benign Liver Tumours 303

Suggested indications for resection include diagnostic doubt, tumour enlarge-

ment (3–5 cm/year) and symptomatic lesions, although no randomised controlled
trials have studied the benefit of elective surgery [13]. Surgery for FNH has been
demonstrated to be safe. Moreover, it is associated with both a low morbidity and in
providing long-term relief from symptoms [13, 15].
Angio-embolisation has been described and may be considered when symptom-
atic lesions are not resectable.

Prognosis

FNH generally runs a benign course and has a very good prognosis.

Hepatic Cysts

Hepatobiliary cystic lesions are more common than previously thought. With
advances in modern cross-sectional imaging, the prevalence of hepatobiliary cystic
lesions has increased from a presumed 2–3% historically to 18%. The differential
diagnosis of hepatobiliary cystic lesions is broad, and it ranges from benign, asymp-
tomatic lesions to infectious lesions and aggressive malignancies.

Presentation and Clinical Features

In many cases, hepatobiliary cysts are asymptomatic and are found incidentally on
imaging for other reasons. This is especially true for simple hepatic cysts, although
large simple cysts may produce abdominal pain, vague discomfort or fullness, early
satiety, palpable mass or abdominal distention. In the setting of polycystic liver
disease (PCLD), patients often present with a protuberant abdomen from massive
hepatomegaly with or without associated autosomal dominant polycystic kidney
disease.
Infectious hepatic cysts, including parasitic, amoebic and pyogenic abscesses,
often present with fever, malaise, right upper quadrant pain and even sepsis.
Additionally, there is often a history of antecedent intra-abdominal infection or bili-
ary tract manipulation. Pyogenic liver abscesses can result from haematogenous
seeding from extra-abdominal infections, especially in immunosuppressed individ-
uals. Parasitic liver abscesses are most commonly due to echinococcal infection
(hydatid disease), which is endemic in the Middle East, Asia, Australia, New
Zealand and South America.
304 J. Pape and C. Imber

Neoplastic hepatic cysts which include cystadenoma, cystadenocarcinoma and

intraductal papillary mucinous neoplasm of biliary origin (IPMN-B) are rare and
are thought to account for <1% of all cystic lesions. Diagnosis is typically delayed
for these lesions because symptoms are indolent and nonspecific. They include
abdominal pain or discomfort, abdominal swelling and jaundice.

Diagnostic Workup

Blood tests will normally be unrevealing in this situation. Patients with infectious
cysts may have leukocytosis and elevated alkaline phosphatase, gamma-glutamyl
transferase and transaminases. Erythrocyte sedimentation rate and C-reactive pro-
tein are also frequently elevated. The armamentarium for diagnosis and characteri-
sation of hepatobiliary cystic neoplasms includes ultrasound, cross-sectional
imaging (CT and MRI), magnetic resonance cholangiopancreatography (MRCP)
and endoscopic retrograde cholangiopancreatography (ERCP).
Cyst fluid is typically acellular and is not helpful in distinguishing simple cysts
from other cysts, including neoplastic cysts. Multiple recent studies have demon-
strated that cyst and serum concentrations of CEA and CA 19-9 in patients with
simple cysts and cystadenoma are comparable [16].

Management

Asymptomatic simple cysts do not require intervention. If symptomatic the primary

treatment modalities for simple hepatic cysts include sclerotherapy and laparo-
scopic or open fenestration. Aspiration is not recommended as definitive therapy
due to a nearly 100 percent recurrence rate.
In symptomatic patients with polycystic liver disease, the goal of therapy is to
reduce liver volume to the greatest extent possible. In this setting, cyst recurrence
is the rule. Medical therapies include octreotide, lanreotide and sirolimus, all of
which have been shown to achieve modest reductions in liver volume by inhibiting
cyst fluid secretion and are of limited value. Additional options include aspiration
and sclerotherapy, cyst fenestration or liver resection in cases where one area of the
liver is predominantly affected, and there is little to no functional parenchyma in
that area. Liver transplant is rarely indicated for PCLD as the uninvolved liver
parenchyma functions normally, but for quality of life improvement if extremely
­symptomatic, it can be considered. If the patient is losing weight and muscle mass,
this may lend weight to the indication or if combined liver kidney transplant is
required because of worsening renal function due to coexistent polycystic kidney
disease.
22 Benign Liver Tumours 305

In patients presenting with pyogenic liver abscess, blood cultures should be

obtained immediately, and broad-spectrum IV antibiotics should be administered as
soon as possible. If the abscess is secondary to an intra-abdominal infection, the
source should be addressed (i.e. appendicitis, diverticulitis, cholangitis, etc.). As
with any abscess, the key to successful treatment is drainage. Ultrasound-guided
percutaneous drainage can be achieved by simple aspiration or catheter drainage
and is generally recommended as the first therapeutic approach. Aspiration is well-­
suited for multiple small abscesses, whereas catheter drainage is recommended for
large abscesses with loculation. If percutaneous drainage fails, surgical drainage is
required and can be performed via a laparoscopic or open approach.
Recommended treatment for hydatid cysts includes chemotherapy combined
with surgery or percutaneous aspiration, injection and re-aspiration (PAIR).
Neoplastic hepatic cysts include biliary cystadenoma, cystadenocarcinoma and
the more recently recognised IPMN-B. There is as of yet no way to distinguish
between cystadenoma, a premalignant lesion, and cystadenocarcinoma in the
absence of metastatic disease. Regardless, both lesions should be treated with com-
plete resection by enucleation, partial hepatectomy or bile duct resection with bilio-
enteric reconstruction for extrahepatic lesions [15]. Partial resection and drainage
are inadequate due to high recurrence rates.

Prognosis

Hepatobiliary cystic lesions encompass a range of benign and malignant conditions.

Clinical presentation, laboratory investigations and imaging can often lead to a
diagnosis prior to surgical intervention. In more complex cases, patients should be
presented and discussed in a multidisciplinary setting.

Conclusion

Benign liver tumours are not infrequently seen, and a robust diagnostic approach is
necessary to avoid missing malignancies and also to prevent harm being done from
unnecessary medical interventions. The natural history of hepatic adenomas and
their underlying pathophysiology are being increasingly understood. Haemangiomas,
FNH and cysts often require no intervention, but should the patient become symp-
tomatic, the harms and benefits must be carefully considered and fully discussed
with the patient prior to any intervention. Treatment, including surgery and embolic
procedures, should only be offered in centres with experience in managing these
patients. Table 22.2 summarises the key differences between the most commonly
seen benign liver tumours.
306 J. Pape and C. Imber

Table 22.2 Summary of clinical features of the common benign liver tumours
Features of benign liver tumours
Adenoma Haemangioma FNH Simple liver cyst
Prevalence Very rare Common Infrequent Common
Presentation >50% Asymptomatic Mostly incidental Simple cysts
asymptomatic generally
asymptomatic.
Infective cysts
with features of
inflammation
Pathology Plates of Cavernous Fibrous central Variety of
hepatocytes vascular spaces stellate scar pathologies—
3 morphological with single layer simple, infective,
subtypes of endothelium. neoplastic
Thrombosis may
lead to
collagenous scar
Laboratory Large lesions may Normal unless Occasional mild Usually normal,
tests cause cholestasis compressive hepatic enzyme infective cysts
Increased effects disruption with
fibrinogen and appropriately
CRP raised makers.
Radiological Variable per Homogenous. Hypodense Fluid-filled lesion
and other subtypes Peripheral becoming with distinct
investigations No capsule enhancement with hyperdense with capsule
Consider biopsy contrast followed contrast, with
for molecular by central filling. visible central
subtyping No capsule scar
Management Surgical resection Conservative if Conservative— Conservative, or
(males, or >5 cm asymptomatic resect if large or sclerotherapy or
lesion in females) symptomatic fenestration if
due to risk of symptomatic
bleeding and
malignant
transformation

References

1. Rooks JB, Ory HW, Ishak KG, et al. Epidemiology of hepatocellular adenoma. The role of oral
contraceptive use. JAMA. 1979;242:644–8.
2. Bioulac-Sage P, Rebouissou S, Thomas C, et al. Hepatocellular adenoma subtype classification
using molecular markers and immunohistochemistry. Hepatology. 2007;46:740–8.
3. Ronot M, Bahrami S, Calderaro J, et al. Hepatocellular adenomas: accuracy of magnetic reso-
nance imaging and liver biopsy in subtype classification. Hepatology. 2011;53:1182–91.
4. Bioulac-Sage P, Laumonier H, Couchy G, et al. Hepatocellular adenoma management and
phenotypic classification: the Bordeaux experience. Hepatology. 2009;50:481–9.
5. Tait N, Richardson AJ, Muguti G, Little JM. Hepatic cavernous haemangioma: a 10 year
review. Aust N Z J Surg. 1992;62(7):521–4. http://www.ncbi.nlm.nih.gov/pubmed/1610320.
[cited 2018 Jan 14]
22 Benign Liver Tumours 307

6. Leifer DM, Middleton WD, Teefey SA, Menias CO, Leahy JR. Follow-up of patients at low risk
for hepatic malignancy with a characteristic hemangioma at US. Radiology. 2000;214(1):167–
72. http://pubs.rsna.org/doi/10.1148/radiology.214.1.r00ja09167. [cited 2018 Jan 14]
7. Miura JT, Amini A, Schmocker R, Nichols S, Sukato D, Winslow ER, et al. Surgical man-
agement of hepatic hemangiomas: a multi-institutional experience. HPB. 2014;16(10):924–8.
http://www.ncbi.nlm.nih.gov/pubmed/24946109. [cited 2018 Jan 14]
8. Gaspar L, Mascarenhas F, da Costa MS, Dias JS, Afonso JG, Silvestre ME. Radiation therapy
in the unresectable cavernous hemangioma of the liver. Radiother Oncol. 1993;29(1):45–50.
http://www.ncbi.nlm.nih.gov/pubmed/8295987. [cited 2018 Jan 14]
9. Ezekowitz RAB, Mulliken JB, Folkman J. Interferon Alfa-2a therapy for life-threatening hem-
angiomas of infancy. N Engl J Med. 1992;326(22):1456–63. http://www.ncbi.nlm.nih.gov/
pubmed/1489383. [cited 2018 Jan 14]
10. Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of
the liver. Hepatology. 1985;5(6):1194–200. http://www.ncbi.nlm.nih.gov/pubmed/4065824.
[cited 2018 Jan 4]
11. Nguyen BN, Fléjou JF, Terris B, Belghiti J, Degott C. Focal nodular hyperplasia of the liver: a
comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am
J Surg Pathol. 1999;23(12):1441–54. http://www.ncbi.nlm.nih.gov/pubmed/10584697. [cited
2018 Jan 5]
12. Luciani A, Kobeiter H, Maison P, Cherqui D, Zafrani E-S, Dhumeaux D, et al. Focal nod-
ular hyperplasia of the liver in men: is presentation the same in men and women? Gut.
2002;50(6):877–80. http://www.ncbi.nlm.nih.gov/pubmed/12010893. [cited 2018 Jan 5]
13. Cristiano A, Dietrich A, Spina JC, Ardiles V, de Santibañes E. Focal nodular hyperplasia and
hepatic adenoma: current diagnosis and management. Updates Surg. 2014;66(1):9–21. http://
www.ncbi.nlm.nih.gov/pubmed/23807711. [cited 2018 Jan 3]
14. Rogers JV, Mack LA, Freeny PC, Johnson ML, Sones PJ. Hepatic focal nodular hyperplasia:
angiography, CT, sonography, and scintigraphy. AJR Am J Roentgenol. 1981;137(5):983–90.
http://www.ajronline.org/doi/10.2214/ajr.137.5.983. [cited 2018 Jan 6]
15. Vogt DP, Henderson JM, Chmielewski E. Cystadenoma and cystadenocarcinoma of the liver:
a single center experience. J Am Coll Surg. 2005;200:727–33.
16. Seo JK, Kim SH, Lee SH, et al. Appropriate diagnosis of biliary cystic tumors: comparison
with atypical hepatic simple cysts. Eur J Gastroenterol Hepatol. 2010;22:989–96.
Appendix

New Directions in the Management of Hepatocellular

Carcinoma

The majority of patients with HCC present with non-curative disease, i.e. BCLC
stage B–D disease [1]. As mentioned in earlier chapters, there has been an expan-
sion in the treatments available from ablation therapies (microwave, radio fre-
quency, cryoablation and irreversible electroporation (IRE) for early-stage disease
patients not fit for surgery) to embolic therapies (transarterial embolization (TAE),
transarterial chemoembolization (TACE) and selective internal radiation therapy
(SIRT)) for patients with intermediate-stage disease through to the introduction of
sorafenib [2] and the new generation of systemic therapies for first-line (lenvatinib
[3]) or second-line therapies (regorafinib [4]). Yet, the only way a clinician can
assess response is to give treatment and follow the patient up. Surely, it would be
better if the clinician knew beforehand that the treatment being offered was very
likely to be successful. The ‘holy grail’ for much of medicine and not just peculiar
to oncology is the development of personalized medicine.
The historical reluctance to biopsy liver tumours due to the overstated risk of
tumour seeding and bleeding has, in retrospect, hindered our understanding of this
malignancy and in the process allowed potential targets for treatment to remain
elusive. In the future, particularly when cure with resection or liver transplantation
is not considered possible, it may become standard practice to biopsy dominant liver
lesions and perform DNA sequencing to identify targets best suited to treat and
individualize care based on those findings. With refinements in technique, it may be
possible to identify circulating markers and DNA accurately from peripheral blood.
This in turn may lead to the identification of new biomarkers that permit earlier
detection of the disease to improve the quality and sensitivity of surveillance and
also provide a further way to assess response to treatment (provided that the test is
cheap, effective and readily available in a target population).

© Springer Nature Switzerland AG 2019 309

T. Cross, D. H. Palmer (eds.), Liver Cancers,
https://doi.org/10.1007/978-3-319-92216-4
310 Appendix

Patients with intermediate-stage disease who progress on treatments such as

TACE have few options for liver-confined disease. Some centres use alternative
chemotherapeutic against or bland embolizations, but these are not proven to be
superior and data is lacking. For lesions too large for ablation or unresponsive to
TACE/TAE and where TARE, as in the UK, is not universally available, the
options for patients and clinicians are limited. Unlike other forms of malignancy,
the role of radiotherapy had taken a back seat and was not considered a viable or
relevant treatment option. But the development of stereotactic body radiotherapy
(SBRT) is changing this perception. At present, this technique does not fit in any-
where among the algorithms applied by BCLC or AASLD guidelines although it
has been proposed that SBRT could be applied across the HCC spectrum of dis-
ease from very early to very advanced stages [5]. This treatment requires careful
staging and planning on how to deliver multiple beams of radiation to be deliv-
ered in a highly targeted and focussed way. It is thought that radiation may have
a directly ablative effect on the tumour as well as have direct effects on the endo-
thelium (fuKs). A further intriguing mechanism is whether radiation induces a
tumour antigen-­specific immune response that enhances the effectiveness of
tumour cell death [6].
This degree of accuracy was not previously possible, and the concern was that
excessive toxicity and local tissue damage might be incurred. Several observational
studies from around the world have suggested this technique may be a further tool
to be added to the armamentarium directed against HCC. Sanuki and colleagues
assessed outcomes in a retrospective series of 185 patients. Dose of radiation was
35 Gy for patients with Childs-Pugh B disease or 40 Gy if the patient had Childs-­
Pugh A disease, in five fractions. In short, the 3-year local control rate and overall
survival were 91% and 70%, respectively. Equivalent outcomes were observed
regardless of the dose of radiation administered [7]. A similar study was done by
Wahl and colleagues when outcomes were compared between radio-frequency abla-
tion or SBRT for small inoperable HCC. Two hundred patients were identified of
which 161 (249 tumours) underwent RFA and 63 had SBRT (83 tumours). The rates
of freedom from local progression at 1 and 2 years was 83.6% and 80.2% for RFA
and 97.4 and 83.8% for SBRT. The overall survival at 1 and 2 years was 70% and
53% for RFA versus 74% and 46% after SBRT [8].
In the UK, several centres have been involved in a service evaluation of the
role of HCC in selected cases. A trial is planned in the future, and it is likely that
SBRT may be compared against lesions that fail to respond to TACE. A study in
South Korea showed that patients with an incomplete response to TACE had
similar survival outcomes after SBRT to those patients who had an initial good
response to TACE, suggesting this approach might be an alternative for patients
not having an initial response to chemoembolization [9]. There is also emerging
evidence that SBRT might have an emerging role in treating patients with portal
vein tumour thrombosis related to HCC [10]. The procedure does require multi-
ple visits to the hospital, but it does obviate the need for a hospital admission.
Unfortunately, in the UK, the centres in England are predominantly in the south
of the country, and there is only one centre in the North of England in Leeds.
Appendix 311

Thus, many patients are some distance from these centres, and this might be
disadvantageous, particularly as one of the highest UK prevalences of HCC is in
North West of England.
The development of immune therapies has revolutionized the outcome for
patients diagnosed with lung cancer, malignant melanoma and renal cell carci-
noma. Given the historically poor outcomes in these patients, it is not too optimis-
tic to expect that similar outcomes could be delivered in HCC or its cousin in young
adults, fibrolamellar HCC, when surgical resection is not possible. The future man-
agement of patients with or at risk of HCC is likely to include better targeting of
patients who will benefit from surveillance; the introduction of better biomarkers
to help diagnose, assess tumour biology and acquire a more rapid assessment of
treatment response, with a further understanding of the tumour, liver and patient
characteristics, that better select treatment regimens with scientifically selected tar-
gets. Like other forms of malignancy, tumour cells in the liver cause subversion of
the immune system that ultimately leads to full-blown HCC. The place of immune
checkpoints, including programmed cell death protein 1, programmed cell death
ligand 1 and cytotoxic T lymphocyte antigen 4, is increasingly being recognised
as targets for treatments and to modify the disease process [11]. For patients with
incurable disease, this could offer improved patient survival, and the additional
prospect of regenerative medicine and methods to downstage liver scarring (fibro-
sis) could further reduce the likelihood of cancer development in the future.
In the past, the diagnosis of hepatocellular carcinoma was met with a sense of
nihilism, but in the future, rather than being one of despair, we can look ahead with
cautious optimism.

References

1. European Association for the Study of the L, European Organisation for R, Treatment of
C. Clinical practice guidelines: EASL–EORTC clinical practice guidelines: management of
hepatocellular carcinoma. J Hepatol. 2012;56:908–43.
2. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced
hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.
3. Cheng A-L, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. Phase III trial of lenvatinib
(LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocel-
lular carcinoma (uHCC). J Clin Oncol. 2017;35(15_Suppl):4001.
4. Bruix J, Qin S, Merle P, Granito A, Huang YH, et al. Regorafenib for patients with hepatocel-
lular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-­
blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66.
5. Dawson LA. Overview: where does radiation therapy fit in the spectrum of cancer loco-
regional therapies? Semin Radiat Oncol. 2011;21(4):241–6.
6. Finkelstein SE, Timmerman R, McBride WH, Schaue D, Hoffe SE, et al. The confluence
of sterotactic ablative radiotherapy and tumour immunology. Clin Dev Immunol. 2011.; ID
439752
7. Sanuki N, Takeda A, Oku Y, Mizuno T, Aoki Y, et al. Stereotactic body radiotherapy for small
hepatocellular carcinoma: a retrospective outcome analysis in 185 patients. Acta Oncol.
2014;53(3):399–404.
312 Appendix

8. Wahl DR, Stenmark MH, Tao Y, Pollom EL, Caoili EM, et al. Outcomes after stereotactic
body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol.
2016;34(5):452–9.
9. Paik EK, Kim MS, Jang WI, Seo YS, Cho CK, et al. Benefits of stereotactic ablative radio-
therapy combined with incomplete transcatheter arterial chemoembolization in hepatocellular
carcinoma. Radiat Oncol. 2016;11:22.
10. Yu JI, Park HC, Lim DH, Park W, Yoo BC, Paik SW, Koh KC, Lee JH. Prognostic index for
portal vein tumor thrombosis in patients with hepatocellular carcinoma treated with radiation
therapy. J Korean Med Sci. 2011;26(8):1014–22.
11. Elsegood CL, Tirnitz-Parker JE, Olynuy JK, Yeoh GCT. Immune checkpoint inhibition:
prospects for prevention and therapy of hepatocellular carcinoma. Clin Transl Immunol.
2017;6(11):e161.