








































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Key Words Competing Interests Article Information

Renal cancer, familial, genetics, syndrome, 
VHL, HLRCC, BHD, TSC, SHD, BAP1

None declared. Received on July 25, 2022 
Accepted on September 19, 2022 
This article has been peer reviewed.

Soc Int Urol J. 2022;3(6):397–406

DOI: 10.48083/CBTO5325

2022 WUOF/SIU International Consultation  
on Urological Diseases: Hereditary Renal Cell 
Carcinoma Syndromes

Jodi K. Maranchie,1 Brian M. Shuch,2 Gennady Bratslavsky,3 Eamonn R. Maher4

1Department of Urology, University of Pittsburgh and UPMC, Pittsburgh, United States 2 Department of Urology, University of California Los Angeles, Los Angeles, 
United States 3 Department of Urology, State University of New York (SUNY) Upstate Medical University, Syracuse, United States 4 Department of Medical Genetics, 
University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom

Abstract

A number of germline syndromes that predispose affected individuals to develop renal cancer have been described, 
each with unique manifestations, histopathology, and tumor behavior. Patients tend to present with early onset and/or 
multifocal tumors. Familiarity with these syndromes helps to identify at-risk patients and recommend genetic screening. 
Early detection is essential to direct appropriate cancer surveillance protocols for patients and other family members and 
care strategies that preserve lifelong renal function while minimizing risk of death from metastatic cancer.

Introduction

Hereditary syndromes represent 5% to 8% of all renal cell carcinomas (RCCs)[1]. It is important for urologists to 
recognize and solicit their features. Early detection facilitates appropriate cancer surveillance protocols and 
appropriate surgical planning[2], and helps identify other family members at risk. Positive family history, early age of 
onset, or multifocal tumor should trigger consideration for referral for genetic counseling and screening.

von Hippel-Lindau Disease (VHL)
VHL is caused by inheritance of one inactivated copy of the VHL tumor suppressor gene (TSG), located on 
chromosome 3 (3p25–26)[3]. Inheritance is autosomal dominant, occurring in 1 in 35 000 births, with estimated 
prevalence in the United States of 7000 to 8000 people. Affected patients develop renal cancer and cysts, 
pheochromocytomas or paragangliomas, central nervous system (CNS) hemangioblastomas of the brain or spine, 
retinal angiomas, neuroendocrine tumors or cysts of the pancreas, and endolymphatic sac tumors of the inner ear 
or papillary cystadenomas of the epididymis or broad ligament[4]. RCCs in VHL are uniformly clear cell histology 
(ccRCC). Tumors are multifocal and early onset, and some patients require a first RCC intervention in their 20s[5]. 
Due to its multiorgan nature of VHL, VHL patients are optimally managed by a multidisciplinary team managing 
routine retinal and CNS examination and imaging as well as adrenal and pancreatic functional testing. Cancer 
surveillance with abdominal ultrasound or cross-sectional imaging is recommended biannually starting at age 8. 
Magnetic resonance imaging (MRI) is preferred, when possible, to minimize risks for repeated radiation exposure. 
To prevent potentially lethal complications, pheochromocytoma must be excluded or managed prior to renal surgery.

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Historically, RCC was the leading cause of death 
in VHL. Though RCC resection can decrease risk for 
metastases, bilateral nephrectomy profoundly limits 
quality and quantity of life. To preserve renal func-
tion, a conservative approach of active surveillance 
until the largest renal tumor reaches 3 cm, followed by 
nephron-sparing surgery to remove all tumors from 
that kidney was established[6–8]. The safety of this 
“3 cm rule” for prevention of metastatic disease in VHL 
patients has been confirmed[9]. More than 80% of VHL 
patients will develop a recurrent de novo renal tumor 
within 10 years of resection[10]. The “3 cm rule” can 
be applied again to trigger a second[11] or even a third 
or fourth nephron-sparing surgery[12]. Alternatively, 
cutaneous ablation using radiofrequency, cryother-
apy, or microwave therapy has been reported in select 
patients with comparable functional and oncologic 
outcomes[13,14]. In 2021, the oral hypoxia-inducible 
factor 2α (HIF-2α) inhibitor belzutifan[15] was approved 
by the United States Food and Drug Administration 
(FDA) for systemic management of VHL associated 
RCC, CNS, or pancreatic tumors based on a 97% RCC 
response rate at 21 months. Belzutifan is generally well 
tolerated, with the most frequent side effects being 
anemia and fatigue[15].

Birt-Hogg-Dubé Syndrome (BHD)
BHD is an autosomal dominant, familial syndro-
me[16 –18] caused by inactivating mutations of 
folliculin (FLCN)[19,20]. Manifestations include 
cutaneous fibrofolliculomas (hair follicle tumors) or 
trichodiscomas. Present in at least 70% of patients by 40 
years, these benign skin lesions are raised white papules 

on the nose and malar region and less commonly on the 
neck, ears, forehead, or trunk. Pulmonary cysts occur 
in about 80% and may rupture, with a 30% lifetime risk 
for spontaneous pneumothorax[21]. All individuals with 
pathogenic FLCN variants should be considered at risk 
for developing RCC regardless of family history[19]. 
Lifetime risk for RCC is 25% to 30%, presenting as early 
as 20 years, with mean age at diagnosis of 50 years[21,22]. 
The most characteristic BHD histopat holog y is 
a hy br id ch romophobe/oncoc y t ic pat ter n, but 
chromophobe, clear cell, and papillary RCC have all 
been described[22,23]. Other potential manifestations 
include colorectal polyps and cancer, thyroid cancer, and 
melanoma, though these have not yet been confirmed. 
Colonoscopy is indicated if there is a family history of 
colorectal cancer[24].

Affected or at-risk individuals should begin surveil-
lance for RCC with annual MRI at 20 years. Ultrasonog-
raphy can be used if MRI is unavailable or not tolerated. 
When a solid renal lesion is detected, it is managed using 
the “3 cm rule,” followed by nephron-sparing surgery 
or ablation[23]. Although mouse and cell-based models 
of FLCN inactivation demonstrate mammalian target 
of rapamycin (mTOR) pathway activation[25], a clini-
cal trial of mTOR inhibition with topical rapamycin for 
fibrofolliculomas did not demonstrate therapeutic effi-
cacy[26] and additional study is required.

Hereditary Leiomyomatosis and Renal Cell 
Carcinoma (HLRCC)
HLRCC was f irst described 50 years ago as the 
autosomal dominant familial Reed ’s syndrome of 
cutaneous leiomyomas[27]. Recognition of associated 
uterine leiomyomas and RCC led to the designation 
of HLRCC[28]. In 2002, fumarate hydratase (FH) was 
identified as the causal TSG[29]. HLRCC was initially 
thought to be a rare disease with high penetrance, 
but recent data suggests that HLRCC may have an 
incidence as high as 1 in 1000[30] with highly variable 
penetrance[31,32]. Cutaneous leiomyomas are observed 
in 50% to 80% as raised skin papules that may be 
painful. Uterine leiomyomas are reported in 30% to 
80%. Though benign, they can present with heavy 
vaginal bleeding and early hysterectomy. FH-deficient 
RCC occurs in 10% to 20% and is notoriously aggressive, 
with early progression to metastatic disease[31–33]. 
Median age of onset is 36 to 40 years (range, 11–90 
years)[17,34] and 7% present under the age of 20. If not 
detected by screening, RCC presents with symptoms 
from advanced disease (Figure 1)[33,35]. To date, most 
RCCs have been unifocal. However, with screening 
and effective early treatment, metachronous tumors 
have now been reported. FH-deficient RCC histology is 
variable and includes type 2 papillary, collecting duct, 

Abbreviations 
AML angiomyolipoma
BAP1-TPDS BAP1 tumor predisposition syndrome 
BHD Birt-Hogg-Dubé syndrome
ccRCC clear cell renal cell carcinoma 
CNS central nervous system 
CS Cowden syndrome 
CT computed tomography
ESC RCC eosinophilic solid cystic RCC
FH fumarate hydratase 
HLRCC hereditary leiomyomatosis and renal cell carcinoma 
MRI magnetic resonance imaging
mTOR mammalian target of rapamycin
PHTS PTEN hamartoma tumor syndrome
RCC renal cell carcinoma
TSC tuberous sclerosis complex 
TSG tumor suppressor gene 
VHL von Hippel-Lindau disease

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or tubulocystic morphology[32,35], frequently with two 
or more growth patterns, and pleiomorphic eosinophilic 
nucleoli surrounded by a clear halo[32].

Once a germline FH mutation is identified, all first-
degree relatives should be tested—ideally prior to age 
10. Any patient with multiple cutaneous leiomyomas, 
early-onset fibroids, or non-clear cell RCC by the age of 
46 should also be considered for testing[36–38]. Current 
management strategy for FH-deficient RCC is early 
detection with immediate intervention. Annual cross-
sectional imaging with MRI (preferred) or computed 
tomography (CT) is necessary, as renal ultrasound can 
easily miss a small papillary tumor. Fluorodeoxyglucose 
positron emission tomography (FDG-PET) imaging 
may be useful due to the increased metabolic activity of 
FH-deficient RCC[39]. Tumors may demonstrate solid 
and cystic elements and are frequently infiltrative in 
appearance[40]. Once detected, prompt excision with 

clear margins is required regardless of tumor size. The 
“3 cm rule” does not apply to HLRCC, and nephron-
sparing surgery should be performed only if a negative 
margin is reasonably possible. Regional retroperitoneal 
recurrences are common, and consideration should be 
given to regional node dissection even if the nodes are 
clinically negative[40].

Efficacy of available systemic therapy for dissem-
inated HLRCC is limited. National Comprehensive 
Cancer Network (NCCN) guidelines currently recom-
mend bevacizumab plus erlotinib as first-line therapy 
based on response rates of 70%, with a median progres-
sion-free survival (PFS) of 21 months[41]. Outcomes 
with other tyrosine kinase inhibitors have been variable. 
One series reported promising partial response rates 
approaching 50% for sunitinib or cabozantinib[42], 
but others found that most patients progressed within 
6 months[43]. Checkpoint inhibitors have similarly 

FIGURE 1. 

Gross inspection of a radical nephrectomy specimen showing hereditary leiomyomatosis and renal cell carcinoma 
(HLRCC) with an infiltrative tumor appearance

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shown mixed outcomes, with reports ranging from no 
response to complete response[44]. An ongoing trial 
(NCT03914742) is investigating whether DNA damage 
repair inhibitors may have therapeutic benefit[45].

Hereditary Papillary Renal Cell Carcinoma 
(HPRC)
HPRC is a rare autosomal dominant disease (incidence 1 
in 500 000)[46], caused by germline-activating mutations 
of the MET proto-oncogene (chromosome 7). MET in 
turn activates multiple signaling pathways to promote 
RCC proliferation and survival[47]. HPRCs are typically 
multifocal and indolent with an International Society 
of Urologic Pathologists (ISUP) grade 1 or 2. They 
demonstrate predominantly papillary/tubulopapillary 
features with type 1 papillary histology[46], though 
concurrent ccRCC has been reported[47,48]. The median 
age of tumor presentation is 41 years[1] with earliest 
onset at 30 years. Penetrance approaches 100% by the 
age of 80. Advanced HPRC tumors may present with the 
classic triad of flank pain, hematuria, and an abdominal 
mass or, rarely, with lung metastasis[49,50]. No nonrenal 
manifestations of HPRC have been observed.

Genetic screening should be considered for any indi-
vidual who has a known family history of HPRC or who 
develops type 1 papillary RCC prior to age 45 or multi-
focal papillary tumors[51]. Testing requires bidirec-
tional DNA sequencing. To date, all identified mutations 
reside in 4 of 21 MET exons[47,52–54]. Because papillary 
tumors are frequently isoechoic and missed by ultra-
sound, routine cross-sectional imaging with CT or MRI 
is recommended every 2 years[55,56]. Tumors are char-
acteristically hypovascular with enhancement of 10–30 
Hounsfield units. Management of RCC follows the “3 
cm rule,” with nephron-sparing surgery as in VHL[55]. 
Good preservation of renal function is documented for 
partial nephrectomy even with more than 20 tumors[57]. 
Several agents targeting the MET pathway have been 
studied for potential efficacy against HPRC[47]. Fore-
tinib, a multikinase inhibitor of MET, VEFGR2, RON, 
AXL, and TIE-2 receptors, showed responses in 50% of 
patients with germline HPRC[52]. Other MET-targeting 
agents including cabozantinib are being explored[58], 
potentially opening new therapeutic options for these 
patients.

Tuberous Sclerosis Complex (TSC)
TSC is a multiorgan syndrome with autosomal dominant 
inheritance. Estimated incidence is 1 in 6 000 to 10 000 
new births. Although penetrance in TSC is over 95%, 
there is significant variability in the disease phenotype, 
including rare cases with no overt manifestations[59]. 
Dermatologic (facial angiofibromas, hypomelanotic 
macules, fibrous cephalic plaques, shagreen patches, and 

ungual fibromas) and CNS manifestations (cognitive/
behavioral impairment or structural issues leading to 
epilepsy or nodules of the ventricular walls) present 
in 90% in early childhood[60]. Renal manifestations 
include angiomyolipomas (AMLs) in nearly 70% and 
RCC in 2% to 4%[61]. A pathogenic alteration can be 
found in the genes for TSC (TSC1-hamartin and TSC2-
tuberin) in approximately 80% with both somatic and 
germline mosaicism described[62]. Up to 50% are 
de novo alterations[63]. TSC2 germline defects are 
associated with greater disease burden and severity than 
TSC1[64].

AMLs (mesenchymal tumors of the PEComa family) 
are typically bilateral and multifocal. They develop 
in late childhood at a median age of 16.9 years[65]. 
Bulky AMLs may merge, making it difficult to distin-
guish clear boundaries between lesions. The majority 
are benign, consisting of vascular, smooth muscle, and 
fatty elements. A rare but important variant, epitheli-
oid AML, is composed of epithelioid cells with minimal 
to no fat. Epithelioid AMLs may grow rapidly and are 
more prone to necrosis and hemorrhage and progres-
sion, with distant metastases observed in up to 33% in 
multiple series (Figure 2). Screening recommendations 
include baseline abdominal imaging with CT or MRI 
at diagnosis and then every 1 to 3 years[66]. AMLs are 
usually easily identified by the presence of macroscopic 
fat, though fat-poor lesions may require confirmatory 
biopsy. Ultrasound does not adequately assess tumor 
size or presence of fat. Contrast-enhanced MRI should 
be coordinated with brain MRI whenever possible to 
minimize number of procedures under sedation. With 
prospective surveillance, more than 80% of TSC AMLs 
are identified prior to onset of symptoms or hemor-
rhage[65]. They can be safely observed until they reach 
4 cm, at which time embolization or resection is indi-
cated. Epithelioid variants should be considered for 
earlier resection given their risk for malignant behavior. 
Alternatively, everolimus is approved for the medical 
management of AML and has also shown efficacy in the 
setting of metastatic epithelioid AML[67].

TSC RCCs occur at a median age of 28 years (range, 7– 
59)[61]. Perhaps due to routine surveillance imaging, the 
majority are small (median size, 2.9 cm), incidental[61], 
and localized. Nearly 50% are multifocal[61,68]. Our 
understanding of TSC RCC has evolved as more cases 
have been reported. Initially, histology was believed 
to be similar to sporadic RCC, including ccRCC[63] 
molecularly distinct from VHL[69]. In recent years, 
common morphologic patterns have emerged including 
chromophobe and hybrid oncocy tic/chromophobe 
tumors (HOCT), RCC with smooth muscle stroma 
(also known as renal angiomyoadenomatous tumors), 
and eosinophilic unclassified variants[61,68]. Notably, 
the latter are reminiscent of sporadic eosinophilic solid 

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cystic RCC (ESC RCC), which harbors somatic mTOR/
TSC mutations. There are limited data to suggest that 
TSC RCC should be treated differently than other 
forms of RCC. However, renal preservation should be 
prioritized with use of partial nephrectomy or ablation 
when feasible.

PTEN hamartoma tumor syndrome (PHTS)
PHTS is a spectrum of autosomal dominant disorders 
caused by germline mutations in the PTEN TSG. The 
best recognized form is Cowden syndrome (CS), but 
others include Bannayan-Riley-Ruvalcaba syndrome 
(BRRS), Proteus-like syndrome, and macrocephaly with 
autism and/or learning disability. Major manifestations 
of CS include mucocutaneous papillomatous papules 
and trichilemmomas, macrocephaly, multinodular 
goiter, follicular adenomas of the thyroid, and increased 
lifetime risks for breast (>80%), nonmedullary thyroid 
(~35%), and endometrial cancers (~30%)[70,71]. RCC, 
most commonly papillary and chromophobe subtypes, 
occurs in 15% to 24%, with median age at diagnosis of 

50 years[70,72,73]. CS RCC is usually unilateral[73], with 
reported age at onset as early as 20 years. At least one 
manifestation of CS will be evident in 90% by age 30 
years[74].

When clinical diagnostic criteria for Cowden 
syndrome are met[74], diagnosis of PHTS is confirmed 
by germline testing for a PTEN pathogenic variant[75]. 
PTEN is now included on many multigene cancer test-
ing panels. A positive test should trigger testing of at-risk 
relatives. Comprehensive PHTS surveillance protocols 
are recommended starting at age 18 years[74,76]. For 
women, annual mammography or breast MRI starts at 
age 30 years and endometrial cancer screening at age 35 
years. Prophylactic mastectomy may be offered. Annual 
thyroid examinations and biannual dermatologic assess-
ments begin at time of diagnosis and regular colonos-
copy at 35 years. Biannual RCC screening is started at 
20 years[77]. Treatment of PHTS RCC is the same as for 
sporadic RCC, and available data suggest that the “3 cm 
rule” can be applied.

BAP1 Tumor Predisposition Syndrome 
(BAP1-TPDS)
BAP1-TPDS is an autosomal dominant, multiorgan 
cancer syndrome caused by germline loss or mutation 
of BAP1, which is located on 3p21.1 and frequently 
codeleted with VHL in ccRCC[78]. BAP1 codes for 
ubiquitin carboxyl-terminal hydrolase BAP1, a nuclear 
deubiquitinating enzy me involved in chromatin 
remodeling and repair of double-stranded DNA 
breaks[79]. The prevalence of germline BAP1-TPDS is 
unknown, but it is estimated to represent 1% to 1.5% 
of all ccRCCs and nearly 20% of patients who develop 
both RCC and uveal melanoma[80]. Nonrenal BAP1-
TPDS manifestations include pigmented skin lesions 
(BAP1-inactivated melanocytic tumors), aggressive 
uveal melanoma with high risk for metastasis and poor 
survival, and early-onset malignant mesothelioma 
(MM) of the pleura or peritoneum[81]. Less commonly, 
c ut a ne ou s  me l a nom a ,  b a s a l  c e l l  c a rc i nom a , 
meningioma, cholangiocarcinoma, and breast cancer 
are observed. Penetrance is variable but high, with at 
least one tumor observed in nearly 90% of affected 
individuals[81].

RCC occurs in 10% of BAP1-TPDS patients and 
is often bilateral and multifocal[55,82]. Tumors are 
predominantly ccRCC, though papillary and chromo-
phobe have been reported[55,81]. Median age at onset is 
47 years. BAP1-TPDS RCC is typically high grade with 
poor clinical outcome, and the “3 cm rule” may not be 
appropriate. Close surveillance of affected individuals 
with early excision is recommended until the syndrome 
is better characterized[82].

FIGURE 2. 

Epithelioid variant angiomyolipoma (AML) in a patient 
with tuberous sclerosis complex (TSC) who had failed 
two attempts at angioembolization of large vessel  
(coil seen) 

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Genetic consultation and screening should be offered 
to any individual with a personal or family history of two 
or more BAP1-TPDS tumors[83], with testing of at-risk 
relatives if positive. Current guidelines for affected indi-
viduals require annual fundus and full body dermato-
logic examination annually starting at 2 years, MRI of 
the brain every other year starting at age 18, and MRI of 
the chest, abdomen, pelvis, and breast every other year 
starting at age 30 with annual mammography starting 
at age 40[84]. Once a renal tumor is identified, however, 
annual abdominal imaging is advised due to the docu-
mented rapid growth rate of BAP1-TPDS RCC[85].

Succinate Dehydrogenase (SDH)- 
Deficient RCC
SDH-deficient RCC is a rare autosomal dominant 
syndrome caused by germline mutations of the succinate 
dehydrogenase complex (SDHA: 5p15.33; SDHB: 
1p36.13; SDHC: 1q23.3; and SDHD: 11q23)[86].  
In addition to early-onset RCC, affected individuals may 
develop paragangliomas (commonly of the head and 
neck), pheochromocytoma, wild-type (negative for 
mut ations of t he KIT and PD GFRA genes) 
gast rointest ina l stromal tumor (GIST), and, less 
commonly, prolactin-secreting pituitary adenoma[55,82]. 
Renal masses may be multifocal and bilateral and are 
morphologically distinct from other RCCs[87]. Germline 
SDH defects can be detected in up to 15% of all 
pheochromocytomas and paragangliomas and 1% to 1.5% 
of all RCCs[55,88].

SDH is a complex enzyme composed of four subunits: 
SDHA, SDHB, SDHC, and SDHD. It is often referred 
to as Mitochondrial Complex II and is anchored on the 
inner mitochondrial membrane where it participates in 
both the Krebs cycle (oxidation of succinate to fumarate) 
and the electron transport chain[89]. Loss of SDH func-
tion leads to accumulation of succinate and a metabolic 
shift to aerobic glycolysis[82]. Most cases of SDH-defi-
cient RCC involve germline mutations of SDHB, though 
all subunits have been reported[55].

SDH-deficient RCCs are tan to brown with well-cir-
cumscribed “pushing” margins[90]. Cystic features are 
common. Tumors have a distinctive histologic appear-
ance of cuboidal cells with inconspicuous nucleoli 
arranged in nests or tubules, with eosinophilic cyto-
plasm containing vacuoles and cytoplasmic inclu-
sions[55,86]. Although the majority are low grade, 
high-grade SDH-deficient RCCs are aggressive[86,91] 
and known for early metastasis[82]. At-risk individuals 
should be screened annually with abdominal MRI or 
CT. The “3 cm rule” does not apply, and prompt excision 
regardless of size is recommended using nephron-sparing 
surgery where possible.

Hereditary Hyperparathyroidism  
Jaw Tumor Syndrome (HPT-JT)
HPT-JT is a syndrome of parathyroid adenoma and 
cancer, benign ossifying fibromas of the jawbone, and 
renal and uterine cancers. It commonly presents as 
early-onset primary hyperparathyroidism, with an 
estimated penetrance of 65% by age 50[92]. Inheritance 
is autosomal dominant and conferred by germline 
mutations of the CDC73 gene, which encodes the 
nuclear protein parafibromin. Renal manifestations 
include renal cysts and tumors, with both ccRCC and 
Wilm’s tumor reported[93]. Though there are currently 
no consensus guidelines, renal screening by abdominal 
ultrasound every 5 years has been recommended for at-
risk individuals[55].

Conclusion
Hereditary RCC syndromes are a diverse group with 
varying penetrance, histology, and clinical behavior. 
Although hereditary RCCs are uncommon, most 
urologists will encounter them, and it is important to 
remain vigilant, take an appropriately detailed history, 
make use of genetic counselors when indicated, and 
select a surveillance and management strategy that 
addresses the tumor biology and lifelong risk for 
recurrence.

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