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HEPATOCELLULAR
CARCINOMA
Diagnosis and Treatment
Second Edition

Edited by
BRIAN I. CARR, MD, FRCP, PhD
Professor of Medicine, Kimmel Cancer Center
Thomas Jefferson University, Philadelphia, PA, USA
Editor
Brian I. Carr, MD, FRCP, PhD
Kimmel Cancer Center
Thomas Jefferson University
Bluemle Building Room 519
233 S. 10th Street
Philadelphia, PA 19107
USA
[email protected]

ISBN 978-1-60327-373-2 e-ISBN 978-1-60327-376-3

DOI 10.1007/978-1-60327-376-3
Library of Congress Control Number: 2009934120

© Humana Press, a part of Springer Science+Business Media, LLC 2010

All rights reserved. This work may not be translated or copied in whole or in part without the written
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To my daughters, Ophira and Feridey
Preface to 2nd Edition

You are not obliged to complete the task,

Nor are you free to stop trying.
—Talmud, Avot
Hepatocellular carcinoma (HCC) used to be regarded as a rare disease.
The increasing numbers of chronic HCV carriers in the USA and subse-
quent increased incidence of HCC seen in most large medical centers mean
that it is no longer an uncommon disease for gastroenterologists or oncol-
ogists to encounter, and its incidence and epidemiology are changing (new
chapter). This has been enhanced by the appreciation that obesity (NASH or
NAFL)-associated cirrhosis is also a cause of HCC, as are many metabolic
syndromes (new chapter), in addition to carcinogens in the environment
(new chapter), hepatitis B (new chapter), and hepatitis C (new chapter).
Associated with this has been a clearer understanding of the many mech-
anisms involved in carcinogenesis of the liver (new chapter). During the
period when liver resection and systemic chemotherapy were the only real
therapeutic modalities available, the outcomes were generally dismal, espe-
cially since most patients presented with advanced-stage tumors. Several
recent factors seem to have changed this. They include the more frequent
use of aggressive surveillance by ultrasound and CT scanning in patients
who have chronic hepatitis or cirrhosis from any cause and thus are known
to be at risk for subsequent development of HCC in order to detect tumors
at an earlier and thus more treatable stage. Advances in CT scanning, par-
ticularly the introduction of multi-head fast helical scans, mean that these
vascular tumors can often be detected at an earlier stage or multiple lesions
can now be appreciated, when only large single lesions were formally seen,
so that unnecessary resections are not performed. Helical CTs have also
largely replaced the more invasive CT arteriography. Furthermore, advances
in MRI scanning (new chapter) have started to measure changes in tumor
blood flow as a result of anti-angiogenic therapies (new chapter); so has
dye-enhanced ultrasonography (new chapter). Liver transplantation has had
a profound effect on the therapeutic landscape. There have always been two
hopes for this modality, namely to eliminate cirrhosis as a limiting factor for
surgical resection and also to extend the ability of the surgeon to remove
ever-larger tumors confined to the liver. The organ shortage for patients
with HCC who could be transplanted has been alleviated in part by two

vii
viii Preface to 2nd Edition

new factors. They are the MELD criteria, which give extra points to patients
with small tumors, and the introduction of live donor transplants (new chap-
ter), which obviate the need for long waits for a cadaveric donor. Regional
chemotherapy and hepatic artery chemoembolization have been around for
a long time and have been practiced mainly in the Far East and in Europe.
There has not been a consensus on which drug or drug combinations are
best or even whether embolization is important, and if so, what type and size
of embolizing particle might be optimal. While there is still no consensus
on these matters, it has recently become clear from two randomized con-
trolled clinical trials that hepatic artery chemoembolization for unresectable,
non-metastatic HCC seems to bestow a survival advantage compared with
no treatment. The high recurrence rates after resection have led numerous
investigators to evaluate pre-resection and post-resection chemotherapy in
the hope of decreasing recurrence rates. Only recently have clinical trials
begun to provide evidence of enhanced survival for multimodality therapy
involving resection with added chemotherapy or 131 I lipiodol. The introduc-
tion of 90 Y microspheres (Theraspheres) appears to offer the promise of rel-
atively non-toxic tumoricidal internal radiotherapy to the liver and appears
to be a major therapeutic addition to our treatment choices, and its role alone
or in combination with other therapies is just beginning to be explored. The
advent of multiple clinical trials for new agents that inhibit either the cell
cycle or angiogenesis or both (new chapter) has diminished enthusiasm for
chemotherapy, since these agents appear to be less toxic and may enhance
survival, even for advanced disease. Some of these agents are taken orally,
which makes them even more attractive. In addition, we are beginning to
enter the phase of genomics (new chapter) and proteomics (new chapter) as
applied to many tumor types, including HCC. This raises the possibility of
being able to categorize patients into prognostic subsets, prior to any ther-
apy. We are just at the beginning of the age of cell cycle modulating factors
including hormones, growth factors, and growth factor receptor antagonists
and agents that specifically alter defined aspects of the cell cycle. Since the
mechanisms of many of these agents are known, we are entering the era of
personalized medicine and the rational selection of suitable treatment drugs
for an individual patient. For all these reasons, it seemed reasonable to us to
produce a book that presents much of current therapy and current thinking
on HCC. This is an exciting time to be in the field of HCC basic science
as well as clinical management, since so many changes are simultaneously
occurring at multiple levels of our understanding and management of the
disease, and suddenly there are many new choices of therapy to offer our
patients. All the original chapters have also been updated and enhanced.
Philadelphia, PA Brian I. Carr
March, 2009
Preface to 1st Edition

You are not obliged to complete the task,

nor are you free to desist from trying.
—Talmud, Avot
Hepatocellular carcinoma (HCC) used to be regarded as a rare disease.
The increasing numbers of chronic hepatitis C virus carriers in the United
States and subsequent increased incidence of HCC seen in most large med-
ical centers means that it is no longer an uncommon disease for most gas-
troenterologists or oncologists to encounter.
During the times when liver resection or systemic chemotherapy were
the only real therapeutic modalities available, the outcomes were gener-
ally dismal, especially because most patients presented with advanced-stage
tumors. Several recent factors seem to have changed this. They include the
more frequent use of aggressive surveillance by ultrasound and computed
tomography (CT) scanning in patients who have chronic hepatitis or cirrho-
sis from any cause (and thus are known to be at risk for subsequent devel-
opment of HCC) to detect tumors at an earlier and therefore more treatable
stage. Advances in CT scanning, particularly the introduction of multihead
fast helical scans, mean that this vascular tumor can often be detected at
an earlier stage, or multiple lesions can be diagnosed when only large sin-
gle lesions were formerly seen, so that unnecessary resections are not per-
formed.
Liver transplantation has had a profound effect on the therapeutic land-
scape. There have always been two hopes for this modality: namely, to elim-
inate cirrhosis as a limiting factor for surgical resection and also to extend
the ability of the surgeon to remove ever-larger tumors confined to the liver.
Regional chemotherapy and hepatic artery chemoembolization have been
around for a long time and have been practiced mainly in the Far East and
Europe.
There has not been a consensus for which drug or drug combination is
best or whether embolization is important and, if so, what type and size
of particle are optimal. Although there is still no consensus on these mat-
ters, it has recently become clear from two randomized controlled clin-
ical trials that hepatic artery chemoembolization for unresectable non-
metastatic HCC seems to bestow a survival advantage compared to no
treatment. The high recurrence rates after resection have led numerous

ix
x Preface to 1st Edition

investigators to evaluate preresection and postresection chemotherapy in

the hope of decreasing recurrence rates. Only recently have clinical trials
begun to provide evidence of enhanced survival for multimodality ther-
apy involving resection and either chemotherapy or 131I-lipiodol. The
introduction of 90Yttrium microspheres, which appear to offer the promise
of relatively nontoxic tumoricidal therapy to the liver, appears to be a major
therapeutic addition to our treatment choices, and its role alone or in combi-
nation with other therapies is just beginning to be explored.
In addition, we are beginning to enter the phase in which proteomics is
applied to many tumor types, including HCC. This raises the possibility of
being able to categorize patients into prognostic subsets, prior to any therapy.
We are also just at the beginning of the age of cell cycle modulating factors
including hormones, growth factors, and growth factor receptor antagonists
and agents that specifically alter defined aspects of the cell cycle.
For these reasons, it seemed reasonable to produce a book that represents
much of the current therapy and thinking on HCC. Admittedly, there is a
bias toward expressing the experience of one center, the Liver Cancer Cen-
ter at the University of Pittsburgh Starzl Transplant Institute, in which over
250 new cases of HCC have been seen each year for the last 15 years. This
is an exciting time to be in the field of HCC basic science as well as clini-
cal management because so many changes are simultaneously occurring at
multiple levels of our understanding and management of the disease.

Brian I. Carr, MD, FRCP, PhD

Contents

1 Epidemiology of Hepatocellular Carcinoma . . . . . . . . . . . 1

Donna L. White, Amir Firozi, and Hashem B. El-Serag
2 Environmental Carcinogens and Risk for Human
Liver Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 27
John D. Groopman, Kimberly Brodovicz, and Thomas W. Kensler
3 Primary Liver Cancer: Chemical Carcinogenesis . . . . . . . . . 55
Sheeno P. Thyparambil, Ricky D. Edmondson,
and Yvonne P. Dragan
4 Molecular Mechanisms of Hepatocellular Carcinoma:
Insights to Therapy . . . . . . . . . . . . . . . . . . . . . . 109
Marie C. DeFrances
5 Genomic Profiling of Human Hepatocellular Carcinoma . . . . . 131
Anuradha Budhu, Junfang Ji, and Xin Wei Wang
6 Pathologic Aspects of Hepatocellular Tumors . . . . . . . . . . 183
Michael A. Nalesnik, Tong Wu, Eizaburo Sasatomi,
and Anthony J. Demetris
7 Hepatocellular Carcinoma Associated with Hepatitis B Virus . . 235
Hie-Won L. Hann, and Mark Feitelson
8 Hepatitis C and Hepatocellular Carcinoma . . . . . . . . . . . . 259
Ryota Masuzaki, Haruhiko Yoshida, Naoya Kato,
and Masao Omata
9 Metabolic Disease and Hepatocellular Carcinoma . . . . . . . . 283
David H. Van Thiel and Giuliano Ramadori
10 Clinical Features and a Clinician’s Diagnostic
Approach to Hepatocellular Carcinoma . . . . . . . . . . . . 309
Gaurav Mehta and David A. Sass
11 Screening and Biomarkers for Hepatocellular
Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
Jorge A. Marrero
12 Use of Imaging Techniques to Screen for Hepatocellular
Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Michael P. Federle and Satoshi Goshima
xi
xii Contents

13 MRI for Detection and Evaluation of Hepatocellular

Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Donald G. Mitchell
14 Ultrasound of Hepatocellular Carcinoma: The
Important Contribution of Contrast Enhancement . . . . . . 387
Tae Kyoung Kim, Hyun-Jung Jang, and Stephanie R. Wilson
15 Percutaneous Ethanol Injection . . . . . . . . . . . . . . . . . . 407
Tito Livraghi, Maria Franca Meloni, and Anita Andreano
16 Radiofrequency Ablation of Hepatocellular Carcinoma . . . . . 421
Kevin Tri Nguyen and David A. Geller
17 Resection of Hepatocellular Carcinoma . . . . . . . . . . . . . . 453
Ronnie Tung Ping Poon
18 Liver Transplantation for Hepatocellular Carcinoma . . . . . . . 467
T. Clark Gamblin, Sydney D. Finkelstein, and J. Wallis Marsh
19 Living Donor Liver Transplantation for Hepatocellular
Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Hiroyuki Furukawa and Satoru Todo
20 Medical Therapy of HCC . . . . . . . . . . . . . . . . . . . . . 527
Brian I. Carr and Srikanth Nagalla
21 Percutaneous Interventional Technique for Intra-arterial
Chemoembolization . . . . . . . . . . . . . . . . . . . . . . 569
Nikhil B. Amesur and Albert B. Zajko
22 Molecular Targeted Therapies for HCC . . . . . . . . . . . . . . 589
Brian I. Carr and Susan Kralian
23 Radiation Therapy for Hepatocellular Carcinoma . . . . . . . . . 615
Andrew S. Kennedy
24 Psychosocial Issues in Hepatocellular Carcinoma . . . . . . . . 641
Jennifer L. Steel, Andrea DiMartini, and Mary Amanda Dew
25 Putting It All Together . . . . . . . . . . . . . . . . . . . . . . . 713
Brian I. Carr, J. Wallis Marsh, and David A. Geller
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
Contributors

NIKHIL B. AMESUR , MD • Department of Radiology, University of

Pittsburgh Medical Center, Pittsburgh, PA, USA
ANITA ANDREANO MD • Ospedale di Monza, Italy
KIMBERLY BRODOVICZ • Merck Research Laboratories, Epidemiology
Department, Merck & Co., Inc., North Wales, PA, USA
ANURADHA BUDHU • Liver Carcinogenesis Section, Laboratory of
Human Carcinogenesis, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD, USA
BRIAN I. CARR, MD , FRCP, PhD • Department of Medical Oncology, Liver
Tumor Program, Thomas Jefferson University, Philadelphia PA, USA
MARIE C. DEFRANCES, MD, PhD • Department of Pathology, University
of Pittsburgh School of Medicine, Pittsburgh, PA, USA
ANTHONY J. DEMETRIS, MD • Division of Transplantation and Hepatic
Pathology, Department of Pathology, University of Pittsburgh Medical
Center, Pittsburgh, PA, USA
MARY AMANDA DEW, PhD • Clinical Epidemiology Program, Advanced
Center for Interventions and Services Research in Late Life Mood
Disorders, Quality of Life Research, and Artificial Heart Program,
University of Pittsburgh School of Medicine and Medical Center,
Pittsburgh, PA, USA
ANDREA DIMARTINI, MD • Starzl Transplant Institute, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
YVONNE P. DRAGAN, PhD • Division of Safety Assessment-US,
AstraZeneca Pharmaceuticals, Wilmington, DE, USA
RICKY D. EDMONDSON, PhD • University of Arkansas Medical School,
Little Rock, AR, USA
HASHEM B. EL-SERAG, MD, MPH • Michael E. DeBakey Veterans
Administration Medical Center and Baylor College of Medicine, Sections
of Gastroenterology and Health Services Research and the Clinical
Epidemiology and Outcomes Program, Houston Center for Quality of
Care and Utilization Studies, Houston, Texas, USA
MICHAEL P. FEDERLE, MD • Department of Radiology, University of
Pittsburgh School of Medicine, Pittsburgh, PA, USA
MARK FEITELSON, PhD • Temple Biotechnology Center, College of
Science and Technology, Temple University, Philadelphia, PA, USA

xiii
xiv Contributors

SYDNEY D. FINKELSTEIN, MD • Chief Scientific Officer, RedPath

Integrated Pathology, Pittsburgh, PA, USA
AMIR FIROZI, MD • Michael E. DeBakey Veterans Administration Medical
Center and Baylor College of Medicine, Sections of Gastroenterology and
Health Services Research and the Clinical Epidemiology and Outcomes
Program, Houston Center for Quality of Care and Utilization Studies,
Houston, Texas, USA
HIROYUKI FURUKAWA, MD • Department of Organ Transplantation and
Regenerative Medicine, Hokkaido University School of Medicine,
Sapporo, Japan
T. CLARK GAMBLIN, MD, MS • Department of Transplantation Surgery,
University of Pittsburgh Medical Center, Pittsburgh, PA, USA
DAVID A. GELLER, MD • University of Pittsburgh Medical Center Liver
Cancer Center and Starzl Transplant Institute, Pittsburgh, PA, USA
SATOSHI GOSHIMA, MD, PhD • Department of Radiology, Gifu University
Hospital, Gifu, Japan
JOHN D. GROOPMAN • Department of Environmental Health Sciences,
Bloomberg School of Public Health, Johns Hopkins University, Baltimore,
MD, USA
HIE-WON L. HANN, MD • Division of Gastroenterology and Hepatology,
Thomas Jefferson University Hospital, Philadelphia, PA, USA
HYUN-JUNG JANG, MD • Department of Medical Imaging, Toronto
General Hospital, University of Toronto, Toronto, ON, Canada
JUNFANG JI, MD, PhD • Liver Carcinogenesis Section, Laboratory of
Human Carcinogenesis, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD, USA
NAOYA KATO, MD • Department of Gastroenterology, University of Tokyo,
Tokyo, Japan
ANDREW S. KENNEDY, MD, FACRO • Wake Radiology Oncology, Cary,
NC, USA
THOMAS W. KENSLER, PhD , MIT • Department of Environmental Health
Sciences, Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, MD, USA
TAE KYOUNG KIM, MD • Department of Medical Imaging, Toronto
General Hospital, University of Toronto, Toronto, ON, Canada
SUSAN KRALIAN, PhD • Researcher Scientist, New York, NY, USA
TITO LIVRAGHI, MD • Istituto Clinico Humanitas, Rozzano(Milan), Italy
JORGE A. MARRERO, MD, MS • Department of Medicine, University of
Michigan, Ann Arbor, MI, USA
J. WALLIS MARSH, MD • Department of Transplantation Surgery,
University of Pittsburgh Medical Center, Pittsburgh, PA, USA
RYOTA MASUZAKI, MD • Department of Gastroenterology, University of
Tokyo, Tokyo, Japan
Contributors xv

GAURAV MEHTA, MD • Department of Gastroenterology, Drexel

University College of Medicine, Philadelphia, PA, USA
MARIA FRANCA MELONI, MD • Ospedale di Monza, Italy
DONALD G. MITCHELL, MD, FACR • Department of Radiology, Thomas
Jefferson University, Philadelphia, PA, USA
SRIKANTH NAGALLA, MD, MS • Department of Medical Oncology,
Thomas Jefferson University Hospital, Philadelphia, PA, USA
MICHAEL A. NALESNIK, MD • Division of Transplantation and Hepatic
Pathology, Department of Pathology, University of Pittsburgh Medical
Center, Pittsburgh, PA, USA
KEVIN TRI NGUYEN, MD, PhD • University of Pittsburgh Medical Center
Liver Cancer Center and Starzl Transplant Institute, Pittsburgh, PA, USA
MASAO OMATA, MD • Department of Gastroenterology, University of
Tokyo, Tokyo, Japan
RONNIE TUNG PING POON, MS, PhD, FRCS (EDIN), FACS • Department
of Surgery & Centre for Cancer Research, University of Hong Kong
Medical Centre, Queen Mary Hospital, Hong Kong, China
GIULIANO RAMADORI, MD, PhD • Zentrum Innere Medizin, Leiter der
Abteilung, Gastroenterologie und Endokrinologie, Göttingen, Germany
EIZABURO SASATOMI, MD • Division of Transplantation and Hepatic
Pathology, Department of Pathology, University of Pittsburgh Medical
Center, Pittsburgh, PA, USA
DAVID A. SASS, MD , FACP, FACG • Department of Medicine and Surgery,
Drexel University College of Medicine and Medical Director of Liver
Transplantation, Hahnemann University Hospital, Philadelphia, PA, USA
JENNIFER L. STEEL, PhD • Center for Excellence in Integrated Behavioral
Medicine and Starzl Transplantation Institute, University of Pittsburgh
School of Medicine, Pittsburgh PA, USA
SHEENO P. THYPARAMBIL, PhD • University of Arkansas Medical School,
Little Rock, AR, USA
SATORU TODO, MD • Department of General Surgery, Hokkaido
University School of Medicine, Sapporo, Japan
DAVID H. VAN THIEL, MD • Department of Medicine, Division of
Hepatology, Rush University Medical Center, Chicago, IL, USA
XIN WEI WANG, PhD • Liver Carcinogenesis Section, Laboratory of
Human Carcinogenesis, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD, USA
DONNA L. WHITE, PhD, MPH • Michael E. DeBakey Veterans
Administration Medical Center and Baylor College of Medicine, Sections
of Gastroenterology and Health Services Research and the Clinical
Epidemiology and Outcomes Program, Houston Center for Quality of
Care and Utilization Studies, Houston, Texas, USA
xvi Contributors

STEPHANIE R. WILSON, MD • Department of Diagnostic Imaging,

Foothills Medical Centre, University of Calgary, Calgary, AB, Canada
TONG WU, MD, PhD • Division of Transplantation and Hepatic Pathology,
Department of Pathology, University of Pittsburgh Medical Center,
Pittsburgh, PA, USA
HARUHIKO YOSHIDA, MD • Department of Gastroenterology, University
of Tokyo, Tokyo, Japan
ALBERT B. ZAJKO, MD • Department of Radiology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
 1 Epidemiology of Hepatocellular
Carcinoma

Donna L. White, PhD, MPH, Amir

Firozi, MD, and Hashem B. El-Serag,
MD, MPH

CONTENTS
G LOBAL I NCIDENCE OF H EPATOCELLULAR
C ARCINOMA
R ISK FACTORS OF H EPATOCELLULAR
C ARCINOMA
G ENETIC E PIDEMIOLOGY OF HCC
R EFERENCES

ABSTRACT
Hepatocellular carcinoma (HCC) affects more than half a million indi-
viduals per year worldwide. It is a largely preventable disease. Most cases
are related to hepatitis B virus infection in sub-Saharan Africa and Eastern
Asia (except Japan). Hepatitis C virus has emerged as an important cause
of HCC particularly in North America and some parts of Europe, where a
recent sharp increase in HCC has been reported. There is growing evidence
of an association between obesity and diabetes and increased risk of HCC;
however, the causal link is still unclear. The striking geographic and racial
variations in the occurrence of HCC are partly explained by the distribution
of HBV and HCV infections. Additional established risk factors for HCC
include older age, male sex, heavy alcohol intake, aflatoxin exposure, iron
overload related to hemochromatosis, and possibly tobacco smoking. The

B.I. Carr (ed.), Hepatocellular Carcinoma, Current Clinical Oncology

DOI 10.1007/978-1-60327-376-3_1

C Humana Press, a part of Springer Science+Business Media, LLC 2010

1
2 D.L. White et al.

role of diet except for alcohol drinking and aflatoxin contamination in the
etiology of HCC in human populations is largely unknown. Host genetic
factors are being examined but definitive data are lacking. Most of these risk
factors operate by promoting the development of cirrhosis which is present
in most HCC cases. The annual risk of HCC in cirrhosis ranges between 1
and 7%. This review discusses in detail the epidemiology of HCC from a
global perspective.

Key Words: Hepatitis C; hepatitis B; cirrhosis; incidence; prevalence; risk;

genetic association; coffee; insulin resistance; liver cancer; epidemiology;
determinants; risk factors

1. GLOBAL INCIDENCE OF HEPATOCELLULAR

CARCINOMA
1.1. Overview
Primary liver cancer is the fifth most common cancer worldwide and the
third most common cause of cancer mortality (1). Globally, over 560,000
people develop liver cancer each year and an almost equal number, 550,000,
die of it. Liver cancer burden, however, is not evenly distributed through-
out the world (Fig. 1). Most HCC cases (>80%) occur in either sub-
Saharan Africa or in Eastern Asia. China alone accounts for more than
50% of the world’s cases (age-standardized incidence rate (ASR) male:
35.2/100,000; female: 13.3/100,000). Other high-rate (>20/100,000) areas
include Senegal (male: 28.47/100,000; female: 12.2/100,000), The Gam-
bia (male: 39.67/100,000; female: 14.6/100,000), and South Korea (male:
48.8/100,000; female: 11.6/100,000).
North and South America, Northern Europe, and Oceania are low-
rate (< 5.0/100,000) areas for liver cancer among most populations. Typ-
ical incidence rates in these areas are those of the United States (male:
4.21/100,000; female: 1.74/100,000), Canada (male: 3.2/100,000; female:
1.1/100,000), Colombia (male: 2.2/100,000; female: 2.0/100,000), the
United Kingdom (male: 2.2/100,000; female: 1.1/100,000), and Australia
(male: 3.6/100,000; female: 1.0/100,000). Southern European countries,
typified by rates in Spain (male: 7.5/100,000; female: 2.4/100,000), Italy
(male: 13.5/100,000; female: 4.6/100,000), and Greece (male: 12.1/100,000;
female: 4.6/100,000), are of medium rate (5.0–20.0/100,000) (2).
HCC accounts for between 85 and 90% of primary liver cancer. One note-
worthy exception is the Khon Kaen region of Thailand, which has one of
the world’s highest rates of liver cancer (ASR1993–1997 male: 88.0/100,000;
female: 35.4/100,000) (3). However, due to endemic infestation with liver