Hindawi Publishing Corporation
International Journal of Surgical Oncology
Volume 2011, Article ID 658767, 11 pages
1Department of Urology, National Naval Medical Center, Bethesda, MD 20889, USA
2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health,
10 Center Drive, Building 10, Room 1-5940, Bethesda, MD 20892, USA
3Department of Urology, Upstate Medical University, SUNY, Syracuse, NY 13210, USA
Correspondence should be addressed to Gennady Bratslavsky, email@example.com
Received 1 March 2011; Accepted 31 May 2011
Academic Editor: Bernardo Garicochea
Copyright © 2011 Glen W. Barrisford et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Familial renal cancer (FRC) is a heterogeneous disorder comprised of a variety of subtypes. Each subtype is known to have unique
histologic features, genetic alterations, and response to therapy. Through the study of families affected by hereditary forms of
kidney cancer, insights into the genetic basis of this disease have been identified. This has resulted in the elucidation of a number of
kidney cancer gene pathways. Study of these pathways has led to the development of novel targeted molecular treatments for
patients affected by systemic disease. As a result, the treatments for families affected by von Hippel-Lindau (VHL), hereditary
papillary renal carcinoma (HPRC), hereditary leiomyomatosis renal cell carcinoma (HLRCC), and Birt-Hogg-Dub´ e (BHD) are
rapidly changing. We review the genetics and contemporary surgical management of familial forms of kidney cancer.
among men in developed countries in 2008 alone . In
2010, RCC ranked as the seventh and eighth most common
malignancy in men and women in the United States, respec-
tively, and 58,240 new cases and 13,040 deaths were expected
. Americans face a diagnosis of renal malignancy at a rate
of approximately 1 in 67 over the course of their lifetime .
The increased availability and use of cross-sectional imaging
as well as other imaging modalities tends to diagnose renal
tumors at earlier stages and often as incidental findings.
However, despite the increased and advanced detection, the
associated mortality rate has not declined . Unexpectedly,
the increased incidence of RCC cannot be entirely explained
by the more widespread use of imaging modalities .
Surgical resection has historically been the mainstay of
therapy as RCC is known to be resistant to radiation and
traditional chemotherapy [6, 7]. Although surgical resection
is often curative, up to 30% of patients will present with
systemic disease, while an additional 30% will develop
metastatic lesions in followup after an initial presentation of
organ confined disease . Treatment of systemic disease has
often been challenging due to the fact that RCC represents
a heterogeneous spectrum of diverse entities. Each subtype
of renal malignancy is known to possess unique clinical
characteristics, genetic alterations, and has varied responses
to therapy. The dominant malignant subtypes recognized by
the Heidelberg classification system include clear cell (con-
ventional) (70–80%), papillary (chromophile) (10–15%),
chromophobe (3–5%), and collecting duct (1%) tumors .
Papillary tumors are further stratified into type 1 (5%) and
type 2 (10%) based upon genetic and histologic variation
[10–12] (Figure 1).
RCC can exist as both hereditary and sporadic entities.
Sporadic RCC typically presents as a solitary lesion and will
occur more commonly in patients in the sixth decade and
beyond. Conversely, hereditary forms of kidney cancer often
present with multifocal, bilateral tumors and may present
2International Journal of Surgical Oncology
Figure 1: Histopathology of the most common malignant renal neoplasms. (a) Clear cell; (b) papillary type 1; (c) papillary type 2; and
(d) chromophobe. (From Linehan et al. , with permission.)
in far younger patients . Many cases of hereditary renal
malignancy go unrecognized or unreported as this spectrum
of diseases is not well understood . Moderate estimates
place hereditary disease forms at 3–5% of the overall number
of diagnoses [15, 16]. Liberally defined, familial renal cancer
(FRC) is noted to exist when more than one member of
a family presents with a single malignancy or collection of
The identification of FRC is critical in that it allows for
the early screening of families, vigilant followup for those
affected, appropriate and measured interventions when
needed, and the reduction of disease-related morbidity
and mortality. When a patient’s family history is positive
for kidney cancer, or a patient with one or more of the
physical/radiographic findings outlined in Table 1 is found
to have a renal mass, further investigation and referral to
a genetic counselor are often reasonable. The American
Society of Clinical Oncology’s recently published guidelines
on genetic testing for cancer susceptibility concisely identify
and explain many of the ethical issues associated with germ
line analysis .
FRC is a heterogeneous disease comprised of a spectrum
of varied histologic subtypes. The fundamental link among
the forms of FRC with a known genetic alteration is that they
are metabolic in nature, as the genes involved with FRC are
associated with abnormalities in oxygen, iron, glucose, and
energy sensing . The identification of genetic aberrations
associated with familial forms of kidney cancer has led to the
elucidation of a number of interrelated metabolic pathways.
As a result, a number of targeted molecular therapies have
developed over the past half decade . This has altered the
management of advanced and systemic RCC and provided
additional approaches to cytokine-based therapies for the
systemic therapy of clear cell tumors [20, 21]. The treatment
of choice for nonclear cell histologies is presently less well
defined . Understanding the genetic abnormalities and
the pathways leading to the tumorigenesis of FRC provided
the opportunity for the development of novel forms of
therapies targeting these cancer gene pathways (Table 1).
Von Hippel-Lindau (VHL) is a hereditary renal cancer syn-
drome associated with clear cell renal tumors. The inheri-
tance pattern is autosomal dominant, and the incidence is 1
in 36,000 live births [10, 24, 25]. The disease can manifest
International Journal of Surgical Oncology3
Table 1: Familial renal cancer syndromes.
Syndrome PhenotypeRenal cancer manifestationGene Chromosome
Inheritance in Man
Renal tumors, adrenal
angiomas, central nervous
pancreatic cysts and
endolymphatic sac tumors,
epididymal and broad ligament
Clear cell renal cell carcinomaVHL 3p25 193300
and renal cell
Bilateral, multifocal renal tumors
Papillary renal cell carcinoma
MET 7q31 164860
Skin and uterine leiomyomas,
Papillary renal cell carcinoma
FH 1q42-43 605839
lung cysts, spontaneous
pneumothorax, renal tumors
chromophobe, and clear cell
renal cell carcinoma;
clinically with renal tumors, adrenal pheochromocytomas,
retinal angiomas, central nervous system hemangioblas-
tomas, pancreatic cysts, neuroendocrine tumors, endolym-
phatic sac tumors, and cystadenomas of the epididymis and
broad ligament. Each of these tumors is known to be highly
vascular. Improvement in treatment for central nervous
system tumors has had the effect of elevating metastatic
renal cell carcinoma to the leading cause of mortality among
these patients. Renal tumors appear in 35–45% of affected
individuals, can be solid or cystic, and are of clear cell
histology . Patients can develop up to 600 microscopic
tumors and over 1100 cysts per kidney [13, 24].
VHL-associated tumors were noted to have a consistent
loss of the short arm of chromosome 3 . Genetic linkage
studies in patients with hereditary and sporadic renal cancer
led to the identification of the VHL gene on the short arm
of chromosome 3 (3p26-25) [28, 29]. This gene is a tumor
in the VHL gene in kidney cancer tissue samples . This
observation suggested that there existed an inherited gene at
this location. This germline alteration was observed in VHL-
associated kidney cancer and is found in nearly 100% of
VHL families . Somatic VHL alterations are observed in
a high percentage of sporadic clear cell renal tumors but are
absent in papillary, chromophobe, or collecting duct tumors
. There are currently more than 300 known alterations
available for testing that involve the VHL gene [33, 34]. The
location and type of the VHL gene alteration can result in
the expression of different phenotypes. Penetrance is widely
varied, and certain traits (pheochromocytomas) tend to be
clustered in certain families while absent in others .
Patients with partial germline deletions are noted to have
a higher incidence of RCC and greater extent of involvement
among various organ systems as compared to those with
complete deletions [33, 36, 37].
VHL gene function has been rigorously studied. It is a
forms a complex with elongin B, elongin C, Cul 2, and Rbx1
[38–40]. This complex targets the hypoxia-inducible factors
(HIF), HIF-1α and HIF-2α, and is essential for ubiquitin-
mediated degradation [41, 42]. The transcription products
of HIF-1α and HIF-2α are known to regulate a number of
downstream genes that are involved in tumorigenesis. The
factor (VEGF), platelet derived growth factor (PDGF), epi-
dermal growth factor receptor (EGFR), transforming growth
factor (TGF-α), and glucose transporter (GLUT-1). During
conditions of normal tissue oxygen levels, the VHL complex
binds to HIF initiating ubiquitin-mediated degradation.
However, during conditions of low tissue oxygen levels,
the VHL complex does not degrade HIF which results in
a surge of HIF levels and an upregulation of transcrip-
tion of HIF-dependent genes [13, 43]. In the instance of
clear cell RCC, a VHL gene alteration changes the alpha
domain (which binds elongin C/B and Cul 2) or the beta
subunit (which targets HIF for breakdown). These changes
result in a buildup of HIF and consequently an increased
expression of the downstream genes (Figure 2). The pVHL
protein causes an effect similar to hypoxia and can activate
pathways for cellular proliferation and neovascularization.
This effect takes place under normoxic conditions and
has been termed “pseudohypoxia” [12, 44]. Many of the
current therapeutic management approaches for clear cell
4 International Journal of Surgical Oncology
HIF-1α and HIF-2α
HIF-1α and HIF-2α
HIF-1α and HIF-2α
Figure 2: The VHL complex targets HIF-1α and HIF-2α for ubiquitin-mediated degradation. In clear cell RCC, an alteration in the VHL
gene in the α or β domain disrupts HIF degradation. HIF overaccumulates leading to increased transcription of downstream genes. (a) VHL
alteration; (b) VHL/HIF pathway molecular targeting; and (c) VHL/HIF downstream molecular targeting. (From Linehan and Zbar ,
RCC are based upon the targeting of the receptors for HIF-
regulated genes . The agents currently approved by the
US Food and Drug Administration to treat metastatic clear
cell RCC via the targeting of VHL transcription products
include sunitinib, sorafenib, bevacizumab plus interferon-α,
pazopanib, temsirolimus, and everolimus . These agents
form the foundation for systemic therapy in a disease that
has been resilient in the face of cytotoxic chemotherapy and
radiotherapy [6, 7, 21]. Despite the great progress in the
arena of targeted therapy, the bulk of the work has been
in clear cell histology, and treatment for other histologic
subtypes is presently less well established .
Hereditary papillary renal carcinoma (HPRC) is an inherited
renal cancer syndrome in which affected individuals are at
risk of developing multifocal bilateral type 1 papillary renal
carcinoma. It follows an autosomal dominant inheritance
pattern with very high penetrance, meaning that there is
a high likelihood of a person developing papillary RCC by
age 80 . Affected individuals are generally at risk of
developing tumors in the sixth through eighth decades .
The only involved organ in HPRC is the kidney. The tumors
are typically well differentiated but are malignant and can
International Journal of Surgical Oncology5
papillary kidney cancer
Figure 3: Alterations in the intracellular tyrosine kinase domain of
the MET proto-oncogene are found in patients with HPRC. These
mutations result in the activation of the MET pathway. (From Line-
han et al. , with permission.)
metastasize. Initial descriptions of the disease describe it
as “late onset”, occurring in the later decades of life [46,
48]. However, within the last decade, an early onset form
of HPRC has been identified . Renal tumors in these
patients are often diagnosed incidentally .
Computed tomography (CT) and magnetic resonance
imaging (MRI) are the imaging modalities of choice when
evaluating patients with HPRC as they demonstrate greater
sensitivity when compared to renal ultrasound . How-
ever, these lesions are typically small and hypovascular with
poor enhancement on CT imaging. HPRC lesions can easily
be mistaken for renal cysts, and a high index of suspicion
is needed. In these cases, ultrasound is a useful adjunct
to differentiate cystic from solid lesions, although the solid
lesions may be isoechoic to normal renal parenchyma.
HPRC-affected families were evaluated and found to be
devoid of abnormalities on chromosome 3. However, within
the first few years of the identification of the syndrome,
research yielded the gene responsible for HPRC on chro-
mosome 7q31 [46, 48]. The germline alteration in HPRC
activates a proto-oncogene. The missense mutations in the
tyrosine kinase domain of the MET proto-oncogene at 7q31
are responsible for the constitutive activation of the MET
protein. The MET transmembrane protein is located at a
hepatocyte growth factor receptor site, and a tyrosine kinase
domain is located intracellularly . Hepatocyte growth
factor activates MET tyrosine phosphorylation which in
turn induces proliferation and differentiation of epithelial
and endothelial cells, cell branching, and invasion [13, 53]
(Figure 3). MET alterations in somatic cells have been iden-
tified in a division of patients with sporadic papillary type 1
renal cancer . Changes in the MET gene involve ligand-
independent activation of the intracytoplasmic tyrosine
factor (HGF)/MET pathway resulting in tumor formation
[55, 56]. HPRC families retain germline changes in the MET
altered MET allele .
Molecular targeting aimed to inhibit HGF, and the sub-
sequent downstream pathways could be a potential therapy
of papillary type 1 RCC in patients with HPRC .
For example, foretinib is an oral tyrosine kinase receptor
inhibitor that targets c-MET and VEGFR2 that has been
studied in a phase II multicenter trial .
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is
in 2001 by Launonen et al. . Individuals affected with
this syndrome are at risk of developing papillary type 2 renal
tumors as well as cutaneous and uterine leiomyomas. These
aggressive renal lesions can be mistaken for collecting duct
RCC tumors . Although papillary type 2 lesions can
occur in a sporadic fashion, those associated with HLRCC
tend to occur as unilateral solitary lesions that are very
aggressive, prone to metastasis, and lethal if afforded the
opportunity to progress [62, 63]. The gene responsible for
HLRCC was identified by Tomlinson et al. on chromosome
1 (1q42-44) and is known as fumarate hydratase (FH). This
gene functions as a tumor suppressor, and both alleles are
inactivated in tumor tissue . The FH gene is inherited in
an autosomal dominant fashion with high penetrance.
Fumarate hydratase is a critical enzyme in aerobic me-
tabolism. Its role in the Krebs cycle is the conversion of
fumarate to malate. Alteration to FH upregulates HIF and
VHL. When FH is inactivated, fumarate levels build up and
competitively inhibit HIF prolyl hydroxylase (HPH). HPH
is a key enzymatic regulator of intracellular HIF levels .
When HPH is inactivated, HIF levels rise and transcription
no known sporadic counterpart to HLRCC renal malignancy
and no evidence to support a relationship between the FH
mutation and tumorigenesis in nonfamilial cancers. How-
were identified in the FH gene .
Potential areas of systematic therapy for HLRCC will
likely be designed to prevent increased HIF levels or target
the transcription products of VHL-independent HIF accu-
mulation, such as VEGF and TGF-α/EGFR. One attempt to
block the downstream affects of FH inactivation is through
the use of erlotinib, an oral EGFR tyrosine kinase inhibitor
(TKI). A multicenter phase II trial of this agent in patients
with locally advanced and metastatic papillary RCC reported
an overall RECIST response rate of 11% with an additional
24 patients (53%) experiencing stable disease .
Combination therapy with an mTOR inhibitor or VEGF
pathway antagonist may potentiate the single agent activity
of erlotinib. A phase II trial of erlotinib (EGFR TKI) in com-
bination with bevacizumab (monoclonal antibody against
to evaluate this strategy .
Birt-Hogg-Dub´ e (BHD) is a hereditary renal cancer syn-
drome that is associated with chromophobe renal tumors.
The inheritance pattern is autosomal dominant, and affected
6International Journal of Surgical Oncology
Figure 4: In a normoxic environment, HIF is hydroxylated by HPH allowing the VHL complex to initiate ubiquitin-mediated breakdown
in the proteosome. In HLRCC, FH alteration results in a buildup of fumarate. Fumarate competitively inhibits HPH allowing a rise in HIF
levels and subsequent transcription of downstream genes. (From Pfaffenroth and Linehan , with permission.)
individuals develop cutaneous fibrofolliculomas, pulmonary
cysts, spontaneous pneumothoraces, and renal tumors .
In identified genetic carriers, renal tumors were observed
in 14–34%, spontaneous pneumothoracies in 23%, and
pulmonary cysts in 83% . The majority of the renal
tumors are of chromophobe histology (33%), hybrid tumors
(50%), and oncocytomas (5%). Multifocal oncocytosis is
seen in the surrounding renal parenchyma in 50% of the
affected individuals. In addition, clear cell RCC is seen in
patients with BHD .
The BHD gene, folliculin (FLCN), was localized to chro-
mosome 17 and was subsequently identified at 17p11.2
[72, 73]. FLCN is altered as a result of insertions, deletions,
or nonsense mutations . FLCN deficiency activates the
mammalian target of rapamycin (mTOR) pathway . The
FLCN gene has the traits of a tumor suppressor and requires
two mutations with the second hit inactivating the gene .
FLCN forms a complex with folliculin-interacting pro-
teins (FNIP1 and FNIP2). These components intern bind to
AMP-activated protein kinase (AMPK). AMPK acts to sense
cellular energy and assists in the regulation of the mTOR
activity level [75, 77]. In tumors that are noted to have FLCN
alterations in both alleles, mTOR activation (mTORC1 and
mTORC2) has been observed . Rapamycin inhibits the
mTOR pathway and has been noted to prolong survival
and reduce renal manifestations of BHD in FLCN knockout
mice . This represents a potential therapeutic role for
mTOR inhibitors in patients affected by BHD-related renal
tumors. At present, the role of mTOR pathways in sporadic
chromophobe tumors is under investigation (Figure 5).
Patients with FRC are likely to develop multifocal, bilateral,
and recurrent renal tumors. In managing these patients, two
goals are paramount: prevention of metastatic disease and
preservation of renal function. At the National Cancer Insti-
tute, the first goal has been achieved largely through diligent
surveillance serial cross-sectional imaging and observation
lesion becomes 3cm, surgical intervention is recommended.
In patients adhering to this “3cm rule”, none developed
metastatic disease with more than 10 years followup .
It should be noted, however, that the 3cm rule was initially
developed in the VHL population and later expanded to
include HPRC and BHD patients. Patients with HLRCC and
any evidence of solid tumor are offered surgical extirpation
given the highly aggressive nature of their disease. Active
surveillance is not recommended for HLRCC patients with
renal tumors. The second goal of renal preservation has
International Journal of Surgical Oncology7
negative feedback loop
complex is phosphorylated by a rapamycin-sensitive kinase (mTORC1). (b) When FLCN is altered, it fails to complex and allows activation
of AKT, mTORC1, and mTORC2. (From Hasumi et al. , with permission.)
been achieved with a committed approach to nephron-
sparing surgery (NSS) using open, laparoscopic, and robotic
The development of locallyrecurrent renal tumorsis rare
in sporadic disease but more common in patients with FRC,
although it is difficult to distinguish recurrent disease from
adjacent de novo tumor in the majority of cases. Disease
recurrence in the ipsilateral renal unit has been described
at the same site or elsewhere in the kidney after both
partial nephrectomy and ablative therapy (cryoablation or
radio frequency ablation) [84–86]. This scenario presents
a complicated management dilemma, and this particular
situation is occurring with greater frequency as a result of
the increased use of nephron sparing surgery . In the
setting of local recurrence, management options include
observation, initial or repeat ablation, repeat or salvage
partial nephrectomy, radical nephrectomy, or systemic ther-
apy. Each management option presents a unique array of
risks and benefits. The majority of renal units can be
salvaged in the face of disease recurrence. However, it comes
at the cost of increased perioperative complication rates
8International Journal of Surgical Oncology
Reoperation for locally recurrent disease is often associ-
ated with a difficult dissection due to disruption of normal
anatomic tissue planes as well as perinephric scarring. Com-
plication rates increase with the number and complexity
of repeated interventions on the ipsilateral kidney. Greater
operative times, blood loss, and perioperative complications
are typically observed . The overall major complication
rate approaches 20% with repeat partial nephrectomy ,
whereas complication rates in surgically na¨ ıve patients range
from 11% to 13% [89, 90]. The most common complication
noted to resolve in all patients . Other complications
include bowel injury, renovascular injury, and, rarely, loss
of a renal unit or death. Although the risks associated with
repeated surgical intervention on the same renal unit are
significant, they are offset by the benefits of avoiding the
morbidity and mortality associated with renal replacement
therapy. While the treatment algorithm offers many branch
points, the complexity and increased risk associated with
these procedures demand referral to an experienced sur-
geon at a medical center that can provide comprehensive
In cases of metastatic disease, surgical treatment options
alone are typically inadequate. Systemic therapies that target
VEGF, VEGFR, and mTOR are commonly used. While the
agents in these drug classes have been shown to improve
progression-free survival and overall survival, durable com-
plete responses are uncommon. For patients with clear cell
RCC and a good performance status, treatment with IL-2
is often considered as it is the only systemic therapy shown
to provide the opportunity for durable complete responses
. Given the improving yet limited efficacy of systemic
therapy for RCC, aggressive surgical extirpation, including
lymphadenectomy and metastectomy in select patients,
should remain the treatment of choice whenever technically
feasible [92, 93].
FRC is a heterogeneous disease and represents a spectrum of
cancer gene pathways. Having a high suspicion for the pres-
and surveillance of the patient and other potentially affected
kindred. The complexity of these pathways requires unique
therapeutic management strategies for each cancer syn-
drome. Understanding these pathways has led to improved
management of affected patients. Using a strategy aimed
at renal preservation and prevention of systemic disease,
the care of FRC patients and families has been optimized.
However, it is clear that no single strategy offers a compre-
hensive solution. The continuation of translational research,
diligent surveillance programs, NSS, and the management
of systemic disease with immunotherapy and novel-targeted
therapies appears to be the most efficacious contemporary
This paper was supported by the Intramural Research Pro-
gram of the NIH, National Cancer Institute, Center for Can-
The views expressed in this paper are those of the authors
and do not necessarily reflect the official policy or position of
the Department of the Navy, Army, Department of Defense,
nor the US Government.
The authors certify that all individuals who qualify as
authors have been listed; that each has participated in the
conception and design of this work, the analysis of data
(when applicable), the writing of the document, and the
represents valid work; that if we used information derived
from another source, they obtained all necessary approvals
to use it and made the appropriate acknowledgments in
the document; that each takes public responsibility for
it. Nothing in the presentation implies any Federal/DOD/
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