Renal Cancer Contemporary Management

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John A. Libertino
Editor

Renal Cancer
Contemporary Management
Editor
John A. Libertino
Institute of Urology, Lahey Clinic
Burlington, MA, USA

ISBN 978-1-4614-7235-3 ISBN 978-1-4614-7236-0 (eBook)

DOI 10.1007/978-1-4614-7236-0
Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2013938837

© Springer Science+Business Media New York 2013

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Contents

1 Epidemiology, Screening, and Clinical Staging ........................ 1

Michael J. Lipsky, Christopher M. Deibert,
and James M. McKiernan
2 Molecular Biology and Genetics ................................................ 19
Jeff Klomp, Karl Dykema, Bin Tean Teh, and Kyle Furge
3 Familial and Hereditary Syndromes ......................................... 39
Brian Shuch and Peter Pinto
4 Pathology of Renal Cell Carcinoma .......................................... 51
Fang-Ming Deng, Jonathan Melamed, and Ming Zhou
5 Imaging of Renal Cancer............................................................ 71
Jalil Afnan and Christoph Wald
6 Molecular Imaging for Renal Cell Carcinoma ......................... 93
Jian Q. Yu and Yamin Dou
7 History of Renal Surgery for Cancer ........................................ 113
Kamal Nagpal and Karim Hamawy
8 Natural History, Role of Biopsy, and Active Surveillance
of Renal Masses ........................................................................... 119
Anthony T. Corcoran, Marc C. Smaldone, Robert G. Uzzo,
and David Y.T. Chen
9 Interventional Radiology and Angioinfarction:
Transcatheter Embolization of Renal Tumors ......................... 143
Sebastian Flacke and Shams Iqbal
10 Unified Approaches to Surgery and Systemic Therapy
for Renal Cell Carcinoma........................................................... 155
Patrick A. Kenney and Christopher G. Wood
11 Rationale for Partial Nephrectomy ........................................... 179
Nicholas Donin and William Huang
12 Objectifying Complexity of Kidney Cancers:
Relationships of Tumor Anatomy and Outcomes .................... 201
Serge Ginzburg, Alexander Kutikov,
and Robert G. Uzzo

v
vi Contents

13 Open Partial Nephrectomy ........................................................ 211

Patrick A. Kenney, Matthew F. Wszolek, and John A. Libertino
14 Minimally Invasive Partial Nephrectomy
and Ablative Procedures for Small Renal Masses.................... 233
Casey G. Kowalik, David Canes, and Ali Moinzadeh
15 Surgery for Renal Cell Carcinoma with Thrombus
Extension into the Vena Cava .................................................... 251
Chad Wotkowicz and John A. Libertino
16 Role of Lymphadenectomy ......................................................... 271
Hein Van Poppel
17 Postoperative Surveillance Protocols
for Renal Cell Carcinoma........................................................... 283
Megan M. Merrill and Jose A. Karam
18 Role of Surgery in Locally Recurrent and Metastatic
Renal Cancer ............................................................................... 307
Paul Russo
19 Outcomes: Prognostic Factors, Models, and Algorithms ........ 323
Brandon K. Isariyawongse and Michael W. Kattan
20 Adjuvant Systemic Therapy, Immunotherapy,
and Targeted Treatment ............................................................. 335
Linda Cerbone and Cora N. Sternberg
21 Role for Radiation Therapy in Renal Cancer .......................... 349
Andrea McKee, Arul Mahadevan, and Timothy Walsh
22 Surgical Management for Transitional Cell Carcinoma
of the Upper Tract ....................................................................... 359
Jason R. Gee
23 Management of Non-clear Cell Renal Cell Carcinoma ........... 373
Henry J. Conter, Jose A. Karam, and Nizar M. Tannir

Index ..................................................................................................... 387

Contributors

Jalil Afnan Lahey Clinic Medical Center, Burlington, MA, USA

David Canes Institute of Urology, Lahey Clinic Medical Center, Burlington,
MA, USA
Linda Cerbone Department of Medical Oncology, San Camillo and
Forlanini Hospitals, Rome, Italy
David Y.T. Chen Department of Surgical Oncology, Fox Chase Cancer
Center of Temple University School of Medicine, Philadelphia, PA, USA
Henry J. Conter Division of Cancer Medicine, University of Texas MD
Anderson Cancer Center, Houston, TX, USA
Anthony T. Corcoran Department of Surgical Oncology, Fox Chase Cancer
Center of Temple University School of Medicine, Philadelphia, PA, USA
Christopher M. Deibert Department of Urology, College of Physicians and
Surgeons, Columbia University and New York Presbyterian Hospital, New
York, NY, USA
Fang-Ming Deng Departments of Pathology and Urology, New York
University Langone Medical Center, New York, NY, USA
Nicholas Donin Department of Urology, NYU Langone Medical Center,
New York, NY, USA
Yamin Dou Department of Radiology, Lahey Clinic Medical Center,
Burlington, MA, USA
Karl Dykema Van Andel Research Institute, Grand Rapids, MI, USA
Sebastian Flacke Professor of Radiology, Tufts University Medical School,
Lahey Clinic Medical Center, Burlington, MA, USA
Kyle Furge Van Andel Research Institute, Grand Rapids, MI, USA
Jason R. Gee Institute of Urology, Sophia Gordon Cancer Center, Lahey
Clinic Medical Center, Burlington, MA, USA
Serge Ginzburg Division of Urologic Oncology, Department of Surgical
Oncology, Fox Chase Cancer Center, Temple University, Philadelphia,
PA, USA

vii
viii Contributors

Karim Hamawy Department of Urology, Lahey Clinic Foundation,

Burlington, MA, USA
William Huang Department of Urology, Division of Urologic Oncology,
NYU Langone Medical Center, New York, NY, USA
Shams Iqbal Professor of Radiology, Tufts University Medical School,
Lahey Clinic Medical Center, Burlington, MA, USA
Brandon K. Isariyawongse Department of Urology, Glickman Urological
and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
Jose A. Karam Department of Urology, Division of Surgery, University of
Texas MD Anderson Cancer Center, Houston, TX, USA
Michael W. Kattan Department of Quantitative and Health Sciences,
Cleveland Clinic Foundation, Cleveland, OH, USA
Patrick A. Kenney Department of Urology, MD Anderson Cancer Center,
Houston, TX, USA
Jeff Klomp Van Andel Research Institute, Grand Rapids, MI, USA
Casey G. Kowalik Institute of Urology, Lahey Clinic Medical Center,
Burlington, MA, USA
Alexander Kutikov Division of Urologic Oncology, Department of Surgical
Oncology, Fox Chase Cancer Center, Temple University, Philadelphia,
PA, USA
John A. Libertino Institute of Urology, Lahey Clinic, Burlington,
MA, USA
Michael J. Lipsky Department of Urology, College of Physicians and
Surgeons, Columbia University and New York Presbyterian Hospital,
New York, NY, USA
Arul Mahadevan Department of Radiation Oncology, Sophia Gordon
Cancer Center, Lahey Clinic, Burlington, MA, USA
Andrea McKee Department of Radiation Oncology, Lahey Hospital and
Medical Center, Lahey Clinic, Burlington, MA, USA
James M. McKiernan Department of Urology, Columbia University
Medical Center, New York, NY, USA
Jonathan Melamed Departments of Pathology and Urology, New York
University Langone Medical Center, New York, NY, USA
Megan M. Merrill Department of Urology, MD Anderson Cancer Center,
Houston, TX, USA
Ali Moinzadeh Institute of Urology, Lahey Clinic Medical Center,
Burlington, MA, USA
Kamal Nagpal Resident, Department of Urology, Lahey Clinic, Burlington,
MA, USA
Contributors ix

Peter Pinto Urologic Oncology Branch, Center for Cancer Research, NCI,
NIH, Bethesda, MD, USA
Paul Russo Department of Surgery, Urology Service, Weill Cornell College
of Medicine, Memorial Sloan Kettering Cancer Center, New York,
NY, USA
Brian Shuch Urologic Oncology Branch, Center for Cancer Research, NCI,
NIH, Bethesda, MD, USA
Marc C. Smaldone Department of Surgical Oncology, Fox Chase Cancer
Center of Temple University School of Medicine, Philadelphia, PA, USA
Cora N. Sternberg Department of Medical Oncology, San Camillo and
Forlanini Hospitals, Rome, Italy
Nizar M. Tannir Department of Genitourinary Medical Oncology, Division
of Cancer Medicine, University of Texas MD Anderson Cancer Center,
Houston, TX, USA
Bin Tean Teh NCCS-VARI Translational Research Laboratory, National
Cancer Centre Singapore, Singapore
Robert G. Uzzo Department of Surgical Oncology, Fox Chase Cancer
Center of Temple University School of Medicine, Philadelphia, PA, USA
Hein Van Poppel Department of Urology, University Hospital, Leuven,
Belgium
Christoph Wald Lahey Clinic Medical Center, Burlington, MA, USA
Timothy Walsh Tufts University School of Medicine, Boston, MA, USA
Christopher G. Wood Department of Urology, MD Anderson Cancer
Center, Houston, TX, USA
Chad Wotkowicz Department of Urology, Lahey Clinic, Burlington,
MA, USA
Matthew F. Wszolek Department of Urologic Oncology, MD Anderson
Cancer Center, Houston, TX, USA
Jian Q. Yu Fox Chase Cancer Center, Philadelphia, PA, USA
Ming Zhou Departments of Pathology and Urology, New York University
Langone Medical Center, New York, NY, USA
 Epidemiology, Screening,
and Clinical Staging 1
Michael J. Lipsky, Christopher M. Deibert,
and James M. McKiernan

of about 3:2 [4]. In fact, these are estimated to be

Epidemiology the sixth and eighth most commonly diagnosed
tumors in males and females, respectively. Based
Worldwide, kidney tumors account for 2 % of all on data from the SEER (Surveillance,
newly diagnosed malignancies with approxi- Epidemiology, and End Results) program, it has
mately 271,000 new cases diagnosed annually. In been estimated that approximately 1 in 69 males
addition, 116,000 deaths were attributed to kidney and 1 in 116 females will be diagnosed with a kid-
cancer globally in 2008 [1]. There is a predomi- ney tumor in their lifetime [5]. Additionally, about
nance of kidney cancers in more developed areas 13,500 deaths in the United States alone will be
with greater than four times the number of kidney due to these cancers in 2012 [3].
tumors diagnosed and greater than three times the The differential diagnosis of a renal mass is
number of deaths attributed to renal malignancies given in Table 1.1 and includes benign and malig-
when compared to less developed areas. In fact, nant renal parenchymal tumors as well as tumors
kidney cancers are the sixth most common malig- of the upper urinary tract. Renal cell carcinoma
nancy among males in developed countries with (RCC) accounts for about 85 % of all tumors of
more than 110,000 new cases and about 43,000 the kidney, with benign renal tumors and other
deaths annually [2]. Within the United States, malignant tumors occurring less commonly [6].
tumors of the kidney and renal pelvis account for Renal cell carcinoma encompasses a variety of
about 4 % of all cancer diagnoses [3]. In 2012, different histologic subtypes, each of which por-
there will be an estimated 64,770 new cases tends a different prognosis. Conventional or
diagnosed with a male-to-female predominance clear-cell renal cell carcinoma is the most com-
mon form of RCC, accounting for 70–85 % of all
cases [7, 8]. There are reports that patients with
clear-cell RCC have an increased rate of metasta-
sis post-surgery compared to other histologic
subtypes such as papillary or chromophobe, even
M.J. Lipsky, M.D. • C.M. Deibert, M.D.
Department of Urology, College of Physicians after controlling for tumor stage [9]. This, how-
and Surgeons, Columbia University and New York ever, is controversial, as other studies show no
Presbyterian Hospital, New York, NY, USA prognostic significance of histological subtype
J.M. McKiernan, M.D. (*) [8, 10]. Non-clear-cell histologic subtypes include
Department of Urology, Columbia University Medical chromophobe, papillary, and collecting duct RCC
Center, 161 Fort Washington Ave, 11h floor, and occur in about 10–15 %, 5 %, and <1 % of all
New York, NY 10024, USA
e-mail: jmm23@[Link] RCC cases, respectively [7].

J.A. Libertino (ed.), Renal Cancer: Contemporary Management, 1

DOI 10.1007/978-1-4614-7236-0_1, © Springer Science+Business Media New York 2013
2 M.J. Lipsky et al.

Table 1.1 The differential diagnosis of a renal mass Elsevier Saunders: Wein A, Kavoussi L, Novick A, Partin
(Reproduced with permission from Thieme Medical: A, Peters C. Campbell-Walsh Urology, 10th ed.,
Barbaric ZL. Principles of genitourinary radiology. 2nd Philadelphia, PA Elsevier Saunders, 2012, pg. 141)
ed. New York, NY. Thieme Medical, 1994, pg. 154 and
Malignant Benign Inflammatory
Renal cell carcinoma Simple cyst Abscess
Clear cell Angiomyolipoma Focal pyelonephritis
Papillary Oncocytoma Xanthogranulomatous pyelonephritis
Chromophobe Renal adenoma Infected renal cyst
Collecting duct Metanephric adenoma Tuberculosis
Urothelium based Cystic nephroma Rheumatic granuloma
Transitional cell carcinoma Mixed epithelial/stromal tumor
Squamous cell carcinoma Reninoma (JG cell tumor)
Adenocarcinoma Leiomyoma
Sarcoma Fibroma
Leiomyosarcoma Hemangioma
Liposarcoma Vascular
Angiosarcoma Renal artery aneurysm
Hemangiopericytoma Arteriovenous malformation
Malignant fibrous histiocytoma Pseudotumor
Synovial sarcoma
Osteogenic sarcoma
Clear cell sarcoma
Rhabdomyosarcoma
Wilms tumor
Primitive neuroectodermal tumor
Carcinoid
Lymphoma
Leukemia
Metastasis
Invasion by adjacent neoplasm

RCC Incidence over Time the increasing number of asymptomatic renal

tumors diagnosed, there has also been a rise in the
From 1999 to 2008, there was a steady increase in incidence of advanced renal tumors (tumors with
the incidence of malignancies of the kidney and regional extension and distant metastases) and an
renal pelvis in the United States [11]. These rates increase in the kidney cancer mortality rates [14].
increased most dramatically for clinically local- As the incidence of RCC increases, its prevalence
ized tumors, likely in part due to the increased use is estimated to increase from 308,000 in 2010 to
of abdominal imaging [11]. This is supported by 426,000 in 2020 in the United States alone [15].
the fact that the number of renal masses discovered
only at autopsy is decreasing, whereas the rate of
occult kidney cancers per 100 autopsies did not Demographic Factors in Renal Cell
change significantly over time in one study [12]. In Carcinoma
conjunction with the increase in overall incidence,
there has been a relative increase in stage I renal Renal cell carcinoma is predominantly a cancer of
tumors with a subsequent improvement in relative the elderly. In fact, review of the SEER database
survival [13]. However, other factors may be from 1996 to 2000 suggests that only about 10 %
involved in the increasing incidence of renal of all kidney tumors are diagnosed <45 years of
tumors. While imaging has certainly contributed to age, with 75 % of renal tumor diagnosed in patients
1 Epidemiology, Screening, and Clinical Staging 3

above the age of 55 [5]. Studying the age-related Registry between 1998 and 2004 showed that
trend of RCC, the mean age as well as the propor- African Americans not only had an increased
tion of patients diagnosed >65 years has increased incidence but also had a decreased survival rela-
from 1982 to 1997 [16]. In review of the 1996– tive to all other races. In contrast, Asians and
2000 SEER database, the median age of diagnosis Pacific Islanders had a lower incidence rate and a
was 64 and 67 years for males and females, respec- higher survival [23]. Other studies suggest that
tively [5]. While the reasons remain unclear, a there are racial differences in the RCC subtype
recent study suggests that RCC diagnosed at a incidence, with African Americans more likely to
young age may in fact have different tumor biol- have papillary tumors and less likely to have
ogy than those diagnosed in the elderly. In a retro- tumors of clear-cell histology [24].
spective review of greater than 4,000 patients with In addition to the racial differences in RCC
RCC, RCC diagnosed in young patients tended to incidence, there have been reports regarding dis-
have favorable stages, grades, as well as histologic crepancies in RCC survival. Controlling for stage
subtypes [17]. The true implications of RCC biol- and age, African Americans have a lower median
ogy and patient age remain to be elucidated. disease-specific survival than Caucasians [22].
There is a male predominance of RCC incidence Reviewing treatment patterns of patients with RCC
as well as mortality, with an approximate 3:2 ratio by race, African Americans were less likely to
[3, 18]. While the incidence rates have increased in undergo nephrectomy (risk ratio = 0.93, p < 0.001)
the past 40 years, the relative prevalence by gender for local disease or receive IL-2 for metastatic dis-
does not seem to have changed significantly over ease [25, 26]. In addition, the overall survival was
time [19, 20]. The reasons for this discrepancy are worse for African American patients even after
not well understood but may be explained in that controlling for cancer-specific factors. This differ-
males tend to present with more aggressive forms ence in survival, however, was negated when con-
of RCC with higher grade and higher stage, leading trolling for comorbidities as well as nephrectomy.
to a lower survival rate [18, 21]. The authors concluded that the survival discrep-
Race is an important factor in the epidemiol- ancy may be due to increased comorbidity rate as
ogy of RCC. Using SEER data between 1975 and well as the decreased rate of nephrectomy in the
1995, the incidence of RCC increased by 3.9 % African American population [25].
among African American males whereas it only
increased by 2.3 % among Caucasian males.
Similarly, there was a 4.3 % increase in the inci- RCC in Children
dence of RCC among African American females
and by only 3.1 % among Caucasian females Renal cell carcinoma is a rare entity in childhood
[14]. While imaging may have been a factor in and accounts for only 2–5 % of all renal tumors in
the overall increase, it is only likely to have children. The median age at diagnosis in this popu-
caused the discrepant increase among African lation is 12 years, though there have been reports
Americans if an imaging bias exists in this popu- of RCC occurring during infancy [27, 28]. A num-
lation. Similarly, expanding the SEER data to ber of genetic abnormalities have been associated
include patients between 1975 and 1998, there with pediatric RCC, with translocation morpholo-
was a disproportionate rise in the estimated gies including Xp11 and 6p21 being the most com-
annual percent change of RCC in the African mon abnormalities [29, 30]. In addition, childhood
American population relative to the Caucasian RCC has been associated with genetic syndromes
population (4.46 % vs. 2.87 % for patients such as tuberous sclerosis and Beckwith-
20–59 years and 4.35 % vs. 3.06 % for patients Wiedemann syndrome [28, 31]. Prognostic vari-
60+ years). While the reasons for this discrep- ables in childhood RCC are similar to those in
ancy remain unclear, it has been suggested that adult RCC with tumor stage being the strongest
perhaps it is due to exposure to RCC risk factors prognostic variable [32]. Younger patients with
or inherent biologic differences between popula- sporadic RCC have better survival rates following
tions [22]. A review of the California Cancer treatment when compared to adults [33].
4 M.J. Lipsky et al.

Obesity
Risk Factors for the Development
of RCC A number of studies have been conducted to inves-
tigate an association between obesity and RCC.
A number of factors have been reported to In 1984, McLaughlin et al. conducted case-control
increase risk of the development of RCC. The analyses and observed that BMI seemed to be
most commonly cited risk factors are smoking, associated with RCC in women [38]. Since that
hypertension, and obesity, though other expo- point, other studies have been performed which
sures exist (or have been linked). suggested that increasing BMI puts one at an
increased risk for RCC, regardless of sex [39, 40].
In fact, a quantitative analysis of all studies regard-
Smoking ing obesity and RCC between 1966 and 1998 cal-
culated a relative risk of 1.07 per increase in unit
Smoking has long been associated with RCC. In BMI. They conclude that 27 % of cases of RCC
one Italian case-control study, ex-smokers had a among men and 29 % of cases among women can
relative risk of 1.7 of having RCC compared to be attributed to obesity [41]. A further analysis of
never-smokers. A dose-response relationship was 11 studies from 1966 to 2008 similarly concluded
also observed with a RR of 1.1 for moderate smok- that increasing BMI increases the risk of renal
ers and 2.3 for heavy smokers relative to never- cancer, with a stronger effect in females than males
smokers. Further, there was a relationship between [42]. While the mechanism remains to be eluci-
duration of smoking, as well as age at starting to dated, there have been a number of proposed theo-
smoke and time since quitting, and the risks of ries involving hyperinsulinemia, sex hormone
RCC [34]. In a larger case-control series, Yuan dysregulation, and impaired immune function [43,
et al. found that patients with RCC had a 35 % 44]. Not only has obesity been associated with risk
increased odds of having smoked cigarettes [35]. for the development of RCC, but it has also been
Further, risk increased with increasing smoking associated with histologic subtype. Higher BMI
habits and decreased with increasing time from was found to have an association with clear-cell
the last cigarette. In this study, they attributed histology [45]. The increase in the obesity rate
17 % of Los Angeles-based RCC to smoking. must be considered when analyzing the increased
To more directly assess the relationship incidence of RCC [46]. While much of the
between smoking and the development of RCC, increased incidence has been attributed to increased
McLaughlin et al. conducted a 26-year study on imaging use, the relative increase in RCC risk fac-
the smoking habits of US veterans with develop- tors such as obesity may also play a role.
ment of RCC as an outcome [36]. They found
that smokers had a 47 % increase in the relative
risk of the development of RCC compared to Hypertension
nonsmokers. In addition, the risk increased with
the number of cigarettes smoked per day. In a Hypertension, smoking, and obesity are the three
recent meta-analysis of the relationship between largest risk factors for the development of RCC.
smoking and RCC, the authors analyzed 19 case- Yuan et al. have previously demonstrated an asso-
control studies as well as 5 cohort studies. They ciation between RCC and hypertension [39]. They
found a 38 % increased risk in current or former found that patients with RCC had 2.2 times the
smokers versus never-smokers. They confirmed odds of having a diagnosis of hypertension than
the previously mentioned dose-response relation- the matched controls. In a prospective study from
ship between cigarette use and RCC develop- 1982 to 1989, an association was found between
ment. In addition, longer time of smoking the rate of fatal renal cancer and presence of
cessation (>10 years vs. 1–10 years) reduced sub- hypertension in females; however, this did not
sequent risk of RCC [37]. hold true for males [47]. This is consistent with
1 Epidemiology, Screening, and Clinical Staging 5

the results of a case-control study performed by Diet

Shapiro et al. [48]. Results from a prospective
study from 1971 to 1992 demonstrate that not Several theories regarding differential food intake
only is the presence of hypertension a risk factor in relation to RCC risk have been posited.
for the development of RCC, but both increasing Consumption of fruits and vegetables decreases
diastolic and/or systolic blood pressures are asso- the risk of RCC [54]. This finding was confirmed
ciated with increasing relative risks of RCC [40]. in a meta-analysis reviewing 13 prospective stud-
In their analysis, patients with a diastolic blood ies [55]. Similarly, there have been reports regard-
pressure 90–99 mmHg had more than double the ing increased risk in patients with high-fat,
risk of developing RCC when compared to high-protein diets [56]. Benzo(a)pyrene, a poly-
patients with a diastolic blood pressure <70 mmHg. cyclic aromatic hydrocarbon present in barbe-
This association was not found for tumors of the cued red meats, was found to be associated with
renal pelvis. In another meta-analysis of 13 case- RCC in one case-control study [57]. In a prospec-
control studies from 1966 to 2000, hypertensive tive analysis of meat intake with the outcome of
patients were found to have a pooled odds ratio of RCC, red meat consumption was found to be
1.75 of having RCC [49]. Further, there has been associated with RCC development [58]. Further,
evidence that RCC risk increases with increasing there was an association with meat intake and the
time from hypertension diagnosis [50]. papillary histologic subtype of RCC. Alcohol has
been identified as a factor that decreases risk for
RCC. A pooled analysis of 12 prospective studies
Medications demonstrated that those who drank slightly more
than one alcoholic drink per day had a RR of 0.72
Antihypertensive Agents compared to nondrinkers [59]. Furthermore, this
As hypertension has been associated with RCC, association with alcohol intake was not noted for
there have been numerous studies to determine if other liquids, implying that alcohol specifically is
drugs treating hypertension modulate RCC risk. the modifying factor [60]. While data exists
The results of a meta-analysis of 29 prospective regarding risk of RCC based on diet profile,
studies demonstrate a pooled OR of 1.54 between mechanistic pathways must still be clarified.
diuretics and RCC [51]. No other antihyperten-
sive agents analyzed in this study, including beta-
blockers, calcium channel antagonists, and Trichloroethylene Exposure
angiotensin converting enzyme inhibitors, were
associated with increased risk of RCC. Trichloroethylene, a degreaser used for the clean-
ing of metal, has been identified as a risk factor for
Analgesics RCC. In a case-control analysis of 134 patients
Multiple studies implicate chronic use of analge- with RCC, trichloroethylene was found to be asso-
sics in the development of RCC [52, 53]. Using ciated with an increased risk of RCC (OR = 5.57)
prospective data from the Nurses’ Health Study [61]. In an additional case-control study, exposure
and the Health Professionals Follow-up Study, a to trichloroethylene was found to be associated
longer duration of non-aspirin nonsteroidal anti- with RCC when controlling for age, obesity,
inflammatory drug use may increase the risk of smoking, hypertension, and diuretic use [62].
RCC [53]. This trend was not observed for aspi-
rin or acetaminophen. The authors suggest that
the analgesic-mediated RCC carcinogenesis is Screening for Malignant Disease
due to inhibition of prostaglandin synthesis lead-
ing to chronic subacute renal injuries. This in Screening for the detection and treatment of
turn could lead to DNA damage and uncontrolled malignant renal disease is enticing. An ideal
cell proliferation. screening program has several components.
6 M.J. Lipsky et al.

The disease must have a significant impact on Physicians performed renal USG, and 79 % of
public health, be detectable while asymptomatic, patients returned for a second exam a year later.
and have improved outcomes if treated early. The Thirteen cases of renal mass (0.1 %) were
disease must also be of sufficiently high preva- detected, of which nine were RCC. In an even
lence in the population of interest, and if detected, larger study, 219,640 Japanese adults received
patients must be willing to comply with further abdominal USG screening for any malignancy
evaluation and treatment [63]. RCC remains a [70]. Of the total, 638 (0.3 %) had a renal mass,
disease that is amenable to local therapy for cure, and RCC was identified in 192 people (0.09 %).
especially when the disease is discovered at an No persons had regional or distant metastatic dis-
early stage. ease, and 35 % had T1 lesions. In their analysis,
The evolution and increased use of CT scan- they found that USG would only be cost-effective
ning has increased RCC detection. Serendipitously if applied to the entire abdomen, to detect any
discovered renal tumors are smaller, lower stage, abdominal malignancy.
and have significantly better survival (94 % vs. Dialysis patients represent a large group of peo-
35 %) than those that present symptomatically ple with known increased risk of RCC [71].
[64]. Reviewing available SEER data, Parsons Ishikawa and colleagues examined patients on
et al. discuss that early detection may not in fact dialysis who developed symptomatic renal masses
decrease mortality. Rather, it may only generate a compared to dialysis patients detected by USG to
lead time bias [65]. RCC only occurs in about have a renal mass. Risk of death was reduced by
1/10,000 people per year in the USA [21, 66]. 35 % in the USG-detected population [72]. For
With such a rare disease and the possibility of patients on dialysis, Sarasin et al. performed a
detecting benign renal neoplasms, the sensitivity decision analysis to evaluate a hypothetical screen-
and specificity of any screening test would need ing program with USG or CT. They relate that
to be nearly 100 %. This is likely not a cost-effec- screening for renal malignancy would only be
tive strategy for malignant renal disease. beneficial to the youngest and healthiest patients,
Several screening strategies have been investi- as others are more likely to succumb to renal fail-
gated. The presence of asymptomatic micro- ure than to renal malignancy [73]. Following renal
scopic hematuria was associated with a urologic transplantation, the risk of malignancy in the native
malignancy, including bladder or renal cell carci- kidneys is about 1.1–3.2 %, which is 10 times
noma in only 0.2–0.5 % of screened cohorts [67]. higher than the general population [66, 74, 75].
In a contemporary cohort, RCC invaded the col- At the Brigham and Women’s Hospital in Boston,
lecting system in only 14 % of patients. Therefore, transplant recipients generally undergo ipsilateral
microscopic or gross hematuria from this disease native nephrectomy at the time of transplantation.
would be expected to be rare, despite the fact that Four percent of these native kidneys contained
it has been described as part of the classic triad of RCC [76]. Therefore, screening of the native
RCC presentation [64]. kidneys in both the pre- and post-renal transplant
Renal ultrasonography (USG) has been pro- settings may be beneficial in this group.
posed for use as a screening device. It is noninva- Computed tomography (CT) is another imag-
sive, delivers no radiation, and is relatively ing modality that can be used for screening.
inexpensive. With detection by CT scan as the Fenton and Weiss performed a meta-analysis of
reference, USG detects greater than 82 % of CT screening programs [77]. These programs
tumors larger than 2 cm [68]. In association with included screening for coronary artery disease,
the large Aneurysm Detection and Management whole-body CT, lung carcinoma in former smok-
study, 6,678 adults age 50–79 self-referred for ers, and 2 colon cancer case series. The pooled
abdominal and renal ultrasound. A solid renal prevalence of preclinical renal carcinoma was 2.1
mass was detected in 0.33 % [69]. In the German cases per 1,000 persons screened (0.21 %).
cities of Mainz and Wuppertal, a 2-year screen- In addition to imaging modalities, urine and
ing program for RCC recruited 9,959 volunteers. serum biomarkers may also provide a means of
1 Epidemiology, Screening, and Clinical Staging 7

screening or surveillance in RCC. This strategy tumor suppressor features of TSC2 is related to
to date has not been substantiated via any large an increase in RCC risk [83, 85]. Though no
population-based prospective trials. Recently, the screening trials in the disease have been con-
detection of aberrant hypermethylation of tumor ducted, with the high frequency of renal involve-
suppressor genes (including APC, p16, RAR- ment, periodic ultrasonographic review will help
beta2, ARF) has shown initial viability for renal to follow the extent of renal disease.
cancer detection with high sensitivity [78, 79]. Autosomal dominant polycystic kidney dis-
ease (ADPKD) is characterized by multifocal
renal cysts. There is no increased risk of RCC
Screening of Target Populations [86]. Imaging is difficult to interpret given the
complexity of the cystic structures of the renal
A collaborative approach to care of the patient with parenchyma. Contrast-enhanced CT or MRI may
a known renal syndrome is invaluable. Screening provide the enhanced resolution necessary to sep-
in these populations has been evaluated. arate RCC from the other ubiquitous renal cysts,
The von Hippel-Lindau gene, VHL, is a tumor but this has not been used in any formal screening
suppressor gene on chromosome 3p that is nor- process [87, 88]. All patients with ADPKD dis-
mally involved in the degradation of HIF, play hemorrhagic renal cysts on imaging [87].
hypoxia-inducible factor. When inactivated, VHL For children with a family history of ADPKD,
causes overexpression of pro-growth and angio- USG screening has a high rate of cystic detection
genic factors either directly or via loss of HIF in a series of 420 children, but the ability to define
suppression. Loss of VHL is highly penetrant and RCC in early lesions is not discussed [89].
affects 1 in 36,000 live births [80]. Affected indi- Transformation from simple cyst to solid mass is
viduals may manifest disease with benign or rare, though the solid components of complex
malignant tumors or cystic lesions of the kidney, cysts nearly always have RCC at pathologic
adrenal gland, pancreas, or central nervous sys- review [82]. Given the minimal risk of RCC in
tem [80]. Annual US screening in this population ADPKD and difficulty in detecting these lesions,
for abdominal malignancy has been suggested to screening is not recommended in the population.
begin at age 8 with a switch to annual CT at age Families with hereditary papillary RCC may
18 [80]. Hypermethylation of the VHL gene is carry mutations in the c-MET proto-oncogene.
found in up to 80 % of RCC [81]. Choyke and Asymptomatic family members may be screened
colleagues followed 28 patients with VHL by with noninvasive USG, though this only detects a
yearly CT scan. With at least 1 year of follow-up, small number of tumors [90].
they identified 228 total renal lesions and found The United States Preventive Services Task
that they have a variable growth rate. While they Force does not have a position statement related
note that the transition from simple cyst to solid to kidney cancer screening. Screening for RCC in
mass is rare, complex cysts examined pathologi- the general population cannot be endorsed at this
cally almost always contain RCC [82]. time. However, indications to screen selected
Tuberous sclerosis is an autosomal dominant subpopulations do exist.
neurocutaneous syndrome which can manifest in
many organ systems [83]. While most affected
patients present with dermatologic changes Clinical Staging
including hypopigmented macules, facial
angiofibromas (adenoma sebaceum), and lum- Clinical staging systems are developed to classify
bosacral angiofibromas, renal lesions are seen in malignant diseases in a uniform manner with
up to 58 % of affected patients. Angiomyolipoma prognostic capability. They are used to guide treat-
is the most common lesions, seen in 85 % of ment and planning decisions and manage expected
cases, with cysts and RCC seen in 44 % and outcomes by stratifying the risk of cancer progres-
4.2 % of cases, respectively [84]. Loss of the sion. Finally, uniform staging systems allow for