In English | En español
Questions About Cancer? 1-800-4-CANCER

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)

  • Last Modified: 02/14/2014

Page Options

  • Print This Page
  • Print This Document
  • View Entire Document
  • Email This Document

Major Heritable Renal Cell Cancer Syndromes

Von Hippel-Lindau Syndrome
        Molecular biology
        Clinical manifestations
        Tissue manifestations
        Future directions

Four major heritable renal cell cancer syndromes (von Hippel-Lindau syndrome [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt-Hogg-Dubé [BHD] syndrome, and hereditary papillary renal cancer [HPRC]) with autosomal dominant inheritance are listed in Table 1, along with their susceptibility genes. VHL is summarized in detail in the following sections of this summary. Sections describing the other major syndromes are in progress.

Table 1. Hereditary Renal Cell Cancer (RCC) Syndromes and Susceptibility Genes
Syndrome (Inheritance Pattern) Gene Locus, Gene Type (Protein) Renal Tumor Pathology (Cumulative Cancer Risk) Non-renal Tumors and Associated Abnormalities 
von Hippel-Lindau (VHL) syndrome (AD)VHL 3p26, tumor suppressor (pVHL)ccRCC (multifocal) (28%–45%)CNS hemangioblastoma, retinal angiomas, pheochromocytoma, pancreatic neuroendocrine tumor, endolymphatic sac tumor, cystadenoma of epididymis and broad ligament
Hereditary leiomyomatosis and renal cell cancer (HLRCC) (AD)FH 1q42.1, tumor suppressor (fumarase)‘HLRCC-type RCC’ may be new entity (formerly called papillary type 2) (unknown frequency)Cutaneous leiomyomas, uterine leiomyomas (fibroids)
Birt-Hogg-Dubé (BHD) syndrome (AD)FLCN 17p11.2, tumor suppressor (folliculin)Chromophobe oncolytic hybrid, papillary clear cell oncocytoma (8%–15%)Cutaneous: fibrofolliculomas, trichodiscomas, acrochordons
Pulmonary: lung cysts, spontaneous pneumothoraces
Hereditary papillary renal cancer (HPRC) (AD)MET 7q34, proto-oncogene (hepatocyte growth factor receptor)Papillary type 1 (19%)None known

AD = autosomal dominant; ccRCC = clear cell renal cell cancer; CNS = central nervous system.
Merck Manual 18th edition, 2006.[1].
Lindor et al.[2]; Rennebeck et al.[3]

Autosomal dominant mode of inheritance is the pattern of transmission reported within the families affected by these major RCC syndromes. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA) certified laboratories are available for VHL, BHDS, HLRCC, and HPRC. Genetic counseling is a prerequisite for genetic testing. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Von Hippel-Lindau Syndrome


VHL (OMIM) is an autosomal dominant, inherited disease with a predisposition to multiple neoplasms. Germline mutations in the VHL gene predispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems. These include CNS hemangioblastomas, retinal angiomas, clear cell renal carcinomas (ccRCCs) and cysts, pheochromocytomas, cysts and neuroendocrine tumors of the pancreas, endolymphatic sac tumors, and cystadenomas of the epididymis (males) and of the broad ligament (females).[4-7] A multidisciplinary approach is required for the evaluation, and in some cases the management, of individuals with VHL. Specialists involved in the care of individuals with VHL may include urologic oncology surgeons, neurosurgeons, general surgeons, ophthalmologists, endocrinologists, neurologists, medical oncologists, genetic counselors, and medical geneticists.


VHL gene

The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 at cytoband 3p25-26.[8] VHL disease-causing mutations occur in all three exons of this gene. Most affected individuals inherit a germline mutation of VHL from an affected parent and a normal ("wild type") VHL from their unaffected parent. VHL-associated tumors conform with Knudson’s “two-hit” hypothesis,[9,10] in which the clonal origin or first transformed cell of the tumor occurs only after both VHL alleles in a cell are inactivated. The inherited germline mutation in VHL represents the first "hit," which is present in every cell in the body. The second “hit” is a somatic mutation, one that occurs in a specific tissue at some point after a person's birth. It damages the normal, or wild-type, VHL allele, creating a clonal neoplastic cell of origin, which then proliferates into a tumor mass.

Prevalence and rare founder effects

The prevalence of VHL syndrome has been estimated to be 1 per 35,000 and 1 per 40,000 persons in the general population.[11,12] Thus, the number of VHL-affected individuals in the United States is estimated at between 6,000 and 7,000. Precise quantification of this number is a challenge because it requires comprehensive screening of potentially at-risk blood relatives of individuals diagnosed with VHL. Within this population, the large number of unique mutations in this small three-exon gene indicates that most family clusters have not arisen from a single founder. A founder effect was reported when a large U.S. family was compared with a family in Germany, both of whom had pheochromocytoma-predominant VHL.[13]

Penetrance of mutations

VHL mutations are highly penetrant and overall penetrance is greater than 90% by age 65 years.[11] Almost all carriers develop one or more types of syndrome-related neoplasms.

Risk factors for VHL

Each offspring of an individual with VHL has a 50% chance of inheriting the mutated VHL allele from their affected parent. The primary factors affecting the chances of developing VHL are: 1) a relative with VHL syndrome; 2) a germline mutation in the VHL gene; 3) a family member with one of the manifestations of VHL (e.g., CNS hemangioblastomas). (Refer to the Genetic diagnosis section of this summary for more information.)

Genotype-phenotype correlations

There are a few highly predictive, direct genotype -phenotype correlations.[14,15]

For example, pheochromocytoma without RCCs is the VHL pattern found in a large family with a single nucleotide change at position 505.[7,14,16] A similar family outside the United States was identified and found to have a common ancestor (i.e., a founder mutation).[16] However, no common ancestor was identified for several other mutations that occurred in multiple families. In general, founder mutations do not comprise a significant fraction of all VHL mutations. Single nucleotide changes at position 712 and 713 are “hot spots” for mutations leading to pheochromocytomas.[16] Mutation types leading to clinical VHL include missense, nonsense, frameshifts, insertions, partial and complete deletions, and splice site mutations of VHL.

De novo mutations and mosaicism

When a VHL diagnosis is made in an individual whose ancestors (biological parents and their kindred) do not have VHL, this may result from a de novo (new) VHL mutation in the affected individual. Patients diagnosed with VHL, who have no family history of VHL, have been estimated to comprise about 23% of VHL kindreds.[17] A new mutation is by definition a postzygotic event, because it is not transmitted from a parent.

Depending on the embryogenesis stage at which the new mutation occurs, there may be different somatic cell lineages carrying the mutation; this influences the extent of mosaicism. Mosaicism is the presence in an individual of two or more cell lines that differ in genotype but which arise from a single zygote.[18] If the postzygotic de novo mutation affects the gonadal cell line, there is a risk of transmitting a germline mutation to offspring.[17]

Allelic disorder

VHL-associated polycythemia (also known as familial erythrocytosis type 2 or Chuvash polycythemia) is a rare, autosomal recessive blood disorder caused by homozygous or compound heterozygous mutations in VHL in which affected individuals develop abnormally high numbers of red blood cells. The affected individuals have biallelic mutations in the VHL gene. The typical VHL syndromic tumors do not occur in these affected individuals.[19-21]

Other genetic lesions

In sporadic RCC, other genetic lesions have been found. These include PBRM1, SETD2, and BAP1 and may have relevance in RCC arising in VHL patients. Future studies will define their significance in the hereditary patient population.[22]

Molecular biology

The VHL gene product, pVHL, is a 213 amino acid protein that regulates hypoxia-inducible factors (HIFs), maintains a normal extracellular matrix, is involved in microtubule and centrosome regulation, and regulates the cell cycle.[23-25] These functions are described in more detail in the following paragraphs.

HIF1-alpha and HIF2-alpha

pVHL regulates protein levels of HIF1-alpha and HIF2-alpha in the cell by acting as an E3 ubiquitin ligase for HIF. In normoxic conditions, HIF1-alpha and HIF2-alpha are enzymatically hydroxylated. The hydroxylated HIF subunits are bound by the VHL protein complex, covalently linked to ubiquitin, and degraded by the S26 proteasome.

Under hypoxic conditions, hydroxylation does not occur; HIF1-alpha and HIF2-alpha are not bound to the VHL protein complex and are not ubiquinated. The resulting high levels of HIF1-alpha and HIF2-alpha drive increased transcription of a variety of proteins. Loss of functional pVHL creates a pseudohypoxic state, with uncontrolled HIF1-alpha and HIF2-alpha protein levels, and resultant inappropriate transcription of HIF-dependent genes.

HIF1-alpha and HIF2-alpha possess distinct functional characteristics, and a shift towards a HIF2-alpha–dominant phenotype occurs in RCC. HIF1-alpha and HIF2-alpha may preferentially upregulate Myc activity.[26] Hypoxia activated factor has been shown to increase HIF2-alpha transactivation [27] and HIF1-alpha instability.[28] Preferential loss of chromosome 14q, the locus for the HIF1-alpha gene, results in decreased levels of HIF1-alpha.[29]

Microtubule regulation and cilia centrosome control

Emerging data point to the importance of pVHL-mediated control of the primary cilium and the cilia centrosome cycle. The nonmotile primary cilium acts as a mechanosensor, is a regulator of cell signaling, and controls cellular entry into mitosis.[30] Loss of primary ciliary function results in the loss of the cell’s ability to maintain planar cell polarity, which results in cyst formation.[31] Loss of pVHL results in loss of the primary cilium.[32] pVHL binds to and stabilizes microtubules [33] in a glycogen synthase 3–dependent fashion.[34] Loss of pVHL or expression of mutated pVHL in cells also results in unstable astral microtubules, dysregulation of the spindle assembly checkpoint, and an increase in aneuploidy.[25]

Cell cycle control

pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL null cell lines.[23] Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to DNA damage.[35] Nuclear localization and intensity of p27 is inversely associated with tumor grade.[36] pVHL binds to, stabilizes, and transactivates p53 [37] in a phosphorylation-dependent fashion.[38] The importance of these findings is underscored by the findings that p53 is an important regulator of mitotic checkpoints, and loss of p53 permits aneuploid cells to survive.[39]

Extracellular matrix control

Functional pVHL is needed to form an extracellular fibronectin matrix.[40] Additionally, pVHL directly binds to, phosphorylates, and regulates fibronectin.[41] Collagen IV homeostasis is also regulated by pVHL. pVHL isoforms that are collagen IV binding–incompetent demonstrated a malignant phenotype.[24]

Animal models of VHL

No representative VHL animal models are currently available. Vhlh gene knockout in mice did not produce RCC or hemangioblastomas.[42] Murine homologues of the R200W-induced polycythemia in mice, phenocopying Chuvash polycythemia.[43] A R167Q homologue did not generate RCC.[44] Coordinate inactivation of Vhlh and Pten resulted in a higher rate of cyst formation, but, once again, no obvious RCC was observed.[45] The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including PBRM1,[46] SETD2,[47] and BAP1 [48] provide new avenues for developing relevant animal models of at least some VHL disease manifestations.

Clinical manifestations

Age ranges and cumulative risk of different syndrome-related neoplasms

The age at onset of VHL varies both from family to family and between members of the same family. This fact informs the guidelines for starting age and frequency of presymptomatic surveillance examinations. The youngest age at onset of specific VHL syndrome components is observed for retinal hemangioblastomas and pheochromocytomas; targeted screening is recommended in children younger than 10 years. Examples of reported mean ages and age ranges of the following manifestations are summarized in Table 2.

Table 2. Neoplasms in von Hippel-Lindau Syndrome: Mean Age at Diagnosis and Cumulative Risk in Patients Affected
Neoplasm Mean Age (Range) in y  Cumulative Risk (%)  
Adapted from Choyke et al.[4] and Lonser et al.[5]
Renal cell cancer 37 (16–67)24–45
Pheochromocytoma 30 (5–58)10–20
Pancreatic tumor or cyst 36 (5–70)35–70
Retinal hemangioblastoma 25 (1–67)25–60
Cerebellar hemangioblastoma 33 (9–78)44–72
Brainstem hemangioblastoma 32 (12–4610–25
Spinal cord hemangioblastoma 33 (12–66)13–50
Endolymphatic sac tumor 22 (12–50)10

(Refer to the Clinical diagnosis section of this summary for more information.)

VHL familial phenotypes

Four clinical types of VHL syndrome have been described. In 1991, researchers classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma).[12] In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without RCC) and type 2B (with pheochromocytoma and RCC).[13] More recently, it was reported that VHL type 2C comprises patients with isolated pheochromocytoma without hemangioblastoma or RCC.[49] These specific VHL phenotypes are summarized below.

Table 3. Genotype-Phenotype Classification of Families With von Hippel-Lindau Syndromea
Type  Clinical Characteristics 
1Retinal hemangioblastomas
CNS hemangioblastomas
Renal cell cancers
Pancreatic neoplasms and cysts
Retinal hemangioblastomas
CNS hemangioblastomas
Retinal hemangioblastomas
CNS hemangioblastomas
Renal cell cancers
Pancreatic neoplasms and cysts
2CPheochromocytomas only

CNS = central nervous system.
aAdapted from Lonser et al.[5]

Tissue manifestations


More than 55% of VHL-affected individuals develop only multiple renal cell cysts. The VHL-associated RCCs that occur are characteristically multifocal and bilateral and present as a combined cystic and solid mass.[50] Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall. RCCs smaller than 3 cm in this disease tend to be low grade (Fuhrman nuclear grade 2 or 4) and minimally invasive,[51] and their rate of growth varies widely.[52] An investigation of 228 renal lesions in 28 patients who were followed up for at least 1 year showed that transition from a cyst to a solid lesion was rare.[50] Complex cystic and solid lesions contained neoplastic tissue that uniformly enlarged. These data may be used to help predict the progression of renal lesions in VHL syndrome.

Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[52,53] RCCs often remain asymptomatic for long intervals.


Risk assessment for Von Hippel-Lindau syndrome

The primary risk factor for VHL syndrome (or any of the hereditary forms of renal cancer under consideration) is the presence of a family member affected with the disease. Risk assessment should also consider gender and age for some specific VHL-related neoplasms. For example, pheochromocytomas may have onset in early childhood,[4] as early as 8 years of age.[54] Gender-specific VHL clinical findings include epididymal cystadenoma in males (10%–26%), which are virtually pathognomonic for VHL, especially when bilateral, and are rare in the general male population. Epididymal cysts are also common in VHL, but they are reported in 23% of the general male population, making them a poor diagnostic discriminator.[4] Females have histologically similar lesions to cystadenomas that occur in the broad ligament.[4]

Each offspring of an individual with VHL has a 50% chance of inheriting the mutated VHL allele from their affected parent. Diagnosis of VHL is frequently based on clinical criteria. If there is family history of VHL, then a patient with one or more specific VHL-type tumors (e.g., hemangioblastoma of the CNS or retina, pheochromocytoma, or ccRCC) may be diagnosed with VHL.

Genetic testing

At-risk family members should be informed that genetic testing for VHL is available. A family member with a clinical diagnosis of VHL or who is showing signs and symptoms of VHL is offered genetic testing initially. Germline mutations in VHL are detected in more than 99% of families affected by VHL. Sequence analysis of all three exons detect point mutations in the VHL gene (~72% of all mutations).[55] Using Southern blot analysis and/or quantitative polymerase chain reaction (PCR) to detect partial or complete gene deletions will detect deleterious mutations in the remaining 28% of VHL families.[55,56] The technique has a detection rate approaching 100%.[55] Newer techniques such as array comparative genomic hybridization (array CGH) are powerful tools for identifying genomic imbalances.

Genetic counseling is first provided, including discussion of the medical, economic, and psychosocial implications for the patient and their bloodline relatives. After counseling, the patient may choose to voluntarily undergo testing, after providing informed consent. Additional counseling is given at the time results are reported to the patient. When a VHL mutation is identified in a family member, their biologic relatives who then test negative for the same mutation are not carriers of the trait (i.e., they are true negatives) and are not predisposed to developing any VHL manifestations. Equally important, the children of true-negative family members are not as risk of VHL either. Clinical testing throughout their lifetime is therefore unnecessary.[6]

Genetic diagnosis

A germline mutation in the VHL gene is considered a genetic diagnosis. It is expected to carry a predisposition to clinical VHL and confers a 50% risk among offspring to inherit the VHL mutation. Approximately 400 unique mutations in the VHL gene have been associated with clinical VHL, and their presence verifies the disease-causing capability of the mutation. The diagnostic genetic evaluation in a previously untested family generally begins with a clinically diagnosed individual. If a VHL mutation is identified, that specific mutation becomes the DNA marker for which other biological relatives may be tested. In cases where there is a clear VHL clinical diagnosis without a VHL mutation by usual testing of peripheral blood lymphocytes and without a history of VHL in the biological parents or in the parents’ kindreds, then either a de novo mutation or mosaicism may be the cause. The latter may be detected by performing genetic testing on other bodily tissues, such as skin fibroblasts or exfoliated buccal cells.

Clinical diagnosis

Diagnosis of VHL is frequently based on clinical criteria (see Table 4). If there is family history of VHL, then a previously unevaluated family member may be diagnosed clinically if they present with one or more specific VHL-related tumors (e.g., CNS or retinal hemangioblastoma, pheochromocytoma, ccRCC, or endolymphatic sac tumor). If there is no family history of VHL, then a clinical diagnosis requires that the patient have two or more CNS hemangioblastomas or one CNS hemangioblastoma and a visceral tumor or endolymphatic sac tumor. See Table 4 for more diagnostic details.[5-7]

Since 1998, when a cohort of 93 VHL families in whom all germline mutations were identified was reported, diagnoses have included a combined approach of clinical and genetic testing within families. The diagnostic strategy differs among individual family members. Table 4 summarizes a combined approach of genetic testing and clinical diagnosis.

Table 4. Diagnostic Approaches to von Hippel-Lindau (VHL) Syndrome in Individuals With and Without a Family History
Family History of VHL  Genetic Testing  Clinical Diagnosis Requirements for Clinical Diagnosis 
With a family history of VHL Test DNA for the same VHL gene mutation as previously identified in affected biologic relative(s)When VHL gene mutation is unknown for a biologic relativeOne or more of the following is required for a clinical diagnosis:
- Epididymal or broad ligament cystadenomas
- CNS hemangioblastoma
- ccRCC, multifocal
- Pheochromocytoma
- Retinal angiomas
- Pancreatic neuroendocrine tumor
- Pancreatic cysts and/or cystadenomas
- Endolymphatic sac tumor
Without a family history of VHL May be negative if the VHL mutation occurred postzygotically (e.g., VHL mosaicism)When VHL mutation is unknown or germline negative, but there are clinical signs compatible for VHLEither or both of the following are required for a clinical diagnosis:
- CNS hemangioblastoma
- Retinal angiomas
If only one of the above is present, then also one of the following:
- ccRCC
- Pheochromocytoma
- Pancreatic cysts and/or cystadenomas
- Endolymphatic sac tumor
- Epididymal or broad ligament cystadenomas

CNS = central nervous system; ccRCC = clear cell renal cell cancer; VHL = von Hippel-Lindau syndrome.
Adapted and updated from Glenn et al., 1991 [7] and Pithukpakorn & Glenn, 2004.[6]


Surveillance guidelines that have been suggested for various manifestations of VHL are summarized in Table 5. In general, these recommendations are based on expert opinion and consensus; most are not evidence-based. These modalities may be used for the initial clinical diagnostic testing and also for periodic surveillance of at-risk individuals for early detection of developing neoplasm. Periodic presymptomatic screening is advised for at-risk individuals. At-risk individuals are those testing positive for a VHL mutation and those individuals who choose not to be tested for a VHL mutation but have biologic relatives affected by VHL. The risk of inheriting the VHL predisposition in such persons may be as high as 50%.

Table 5. Practice Guidelines for Surveillance of von Hippel-Lindau Syndrome (VHL)
Examination/Test  Condition Screened For Starting Age/Frequencya 
OphthalmoscopyRetinal hemangioblastomaFrom infancy; every 6 to 12 mo
Fluorescein angioscopyRetinal hemangioblastomaIf needed (not routinely performed)
Plasma or 24-hour urinary catecholamines and metanephrinesPheochromocytomaFrom age 2 y; yearly and as clinically indicated when blood pressure is elevated
Enhanced MRI of brain/spinebCNS and peripheral hemangioblastomaFrom age 11 y; every 1 to 2 y and if symptoms appear
CT of abdomen with and without contrast (substitute MRI every other year)Renal, pancreatic, and adrenal neoplasms and cystsFrom age 18 y, earlier if indicated; yearly; alternate CT and MRI (reduces radiation)
Ultrasound of abdomenRenal, pancreatic, and adrenal neoplasms and cystsYearly from age 8 to 18 y, earlier if indicated; MRI as clinically indicated
MRI and CT of IACs, audiology, neurologyEndolymphatic sac tumorAny age for hearing loss, tinnitus, or vertigo

CNS = central nervous system; CT = computerized tomography; IACs = internal auditory canals; MRI = magnetic resonance imaging.
aFrequencies of exams or tests may be increased at organ sites of VHL lesions being monitored.
bBrain MRIs may be used to examine areas of the IACs for signs of endolymphatic sac tumors (ELSTs). If signs or symptoms of ELSTs are present, examine IACs by CT and MRI.
Adapted from Pithukpakorn and Glenn, 2004 [6]; Choyke et al, 1995 [4]; and Lonser et al, 2003.[5]

Surgical interventions

Nephron-sparing surgery (NSS) for VHL syndrome was introduced in about 1989 and continues to be widely used for the treatment of VHL-associated ccRCC that is 3 cm or smaller in diameter. One group reported that patients with tumors 3 cm or smaller who underwent NSS had no evidence of metastases and did not need dialysis or kidney transplantation at a median follow-up of 60 months (n = 52).[52]

The same group has since published details about the specific surgical techniques applied and the surveillance guidelines used for VHL ccRCCs that are 3 cm or smaller. In 2011, associated issues including repeat partial nephrectomy and routine removal of 20 or more tumors from a single unit in one setting in VHL ccRCC were also addressed. Of the 30 patients who underwent 34 partial nephrectomies, there were no mortalities during the median follow-up of 52 months (range, 4–187 months); more than 80% of the starting renal function was preserved in this cohort, with the exception of one patient.[57]

Although associated with increased complications, repeat and salvage partial nephrectomy can enable patients to maintain excellent renal functional outcomes and promising oncologic outcomes at intermediate follow-up.This challenging approach is generally executed at centers with significant experience in minimally invasive surgical and nonsurgical techniques.[58]

Ablative techniques

Radiofrequency ablation (RFA)

RCC treatment, which must prevent metastatic disease and spare nephrons, has changed in the last 2 decades with the emergence of ablative techniques, including RFA and cryoablation (CA).[59] A single-institution study evaluated RCC treatment between 1988 and 2009 in 113 patients with VHL. Renal anatomical survival was analyzed for the following three time periods: 1988 to 1994 (the learning phase of NSS); 1995 to 2003 (routine NSS); and 2004 to 2009 (the emergence of RFA). During a median follow-up of 7.2 years, 251 therapeutic procedures were performed in a total of 176 kidneys. A shift in first-line RCC treatment was observed over time. Between 1988 and 1994, 52% of cases underwent nephrectomy; 75% of cases underwent tumorectomy between 1995 and 2003; and 43% of cases underwent RFA between 2004 and 2009. The combination of NSS and, more recently, RFA has enabled earlier treatment of smaller tumors. This combination of NSS and RFA is associated with a significantly improved renal prognosis in patients with VHL syndrome.[59]

CA combined with NSS

There have been large increases in the detection of small renal masses as a result of advances in imaging techniques (computed tomography [CT] and magnetic resonance imaging [MRI]).[60] Clinicians commonly use minimally invasive ablative techniques for small tumors. There has been rapid development of laparoscopic partial nephrectomy and novel ablative techniques such as RFA and CA. The use of CA for small renal masses in particular has been advanced as it combines NSS with a minimally invasive approach. Five years of follow-up on these techniques have shown survival of 82% with RFA and 100% with CA.[60] Percutaneous cryoablation in kidneys advanced after the development of argon technology and ultrathin probes. Together with CT and open-access interventional MRI, percutaneous cryoablation allows real-time intraprocedural monitoring, providing the technical breakthroughs needed to make this approach safe and reproducible.[61] One study included patients with VHL syndrome and tumors 5 cm or smaller in a solitary kidney. The average follow-up was 16 months (range, 3–30 months); 3 of 12 patients (25%) required retreatment because of incomplete initial ablation. No cancer-related deaths were reported.[62]

Although clinical application and indications of cryoablation of small renal masses are still not clearly defined, available clinical evidence suggests that CA be reserved for small (<3 cm), solid-enhancing renal masses in older patients with high operative risk. Young age, tumor size larger than 4 cm, hilar tumors, intrarenal tumors, and cystic lesions can be regarded as relative contraindications. Irreversible coagulopathy is widely accepted as an absolute contraindication.[60,63]


A 2011 study evaluated the safety and efficacy of sunitinib in VHL patients.[64] Fifteen patients with VHL were given 50 mg of sunitinib daily for 28 days, followed by 14 days off for up to four cycles, with a primary endpoint of toxicity. Grade 3 toxicity included fatigue in five patients (33%); dose reductions were made in ten patients (75%). A significant response was observed in RCC but not in hemangioblastoma . Eighteen RCCs and 21 hemangioblastoma lesions were evaluable. Of these, six RCCs (33%) responded partially, versus none of the hemangioblastomas (P = .014). The expression of pFRS2 in hemangioblastoma tissue was also observed to be higher than in RCC, thus raising the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with hemangioblastoma.[64]

Case series and individual case reports have been published on an oral antiangiogenic agent, SU5416, in patients with VHL.[65-67] Modest improvement was observed in patients with retinal hemangioblastomas.[65,66] In a series of six VHL patients treated with SU5416, stabilization in CNS hemangioblastomas was observed in two patients.[67] A study of intravitreally administered anti–vascular endothelial growth factor therapy for a patient with retinal hemangioma yielded mixed results.[68] SU5416 is not licensed for human use.

VHL in pregnancy

Two studies suggest that pregnancy is associated with hemangioblastoma progression in patients with VHL.[69,70] One study retrospectively examined the records of 29 patients with VHL from the Netherlands who became pregnant 48 times (49 newborns) between 1966 and 2010 (40% became pregnant before 1990); imaging records were available for 31% of the pregnancies. Researchers reported that 17% of all pregnancies had VHL-related complications, including three patients who had craniospinal hemangioblastoma that significantly (P = .049) changed in progression score before and after pregnancy.[69] This study's findings are in contrast with a small, prospective investigation.[70] Until a large-scale, international, prospective investigation is conducted, all investigations suggest using a conservative approach that includes medical surveillance during pregnancy.


Morbidity and mortality in VHL vary and are influenced by the individual and the family’s VHL phenotype (e.g., Type 1, 2A, 2B, or 2C). (Refer to the VHL familial phenotypes section of this summary for more information.)

In the past, metastatic RCC has caused about one-third of deaths in patients with VHL, and in some reports, it was the leading cause of death.[54,71-73] With increased surveillance of mutation-positive individuals, the RCC mortality rate is thought to have diminished.

Hemangioblastomas of the CNS, although histologically benign, are a major cause of morbidity and arise anywhere along the craniospinal axis, including the brainstem.[5] Pancreatic neuroendocrine tumors, formerly called pancreatic islet cell tumors, in some cases, may grow rapidly and metastasize to liver and bone.[71,74] Hearing and vision may also be decreased or lost as a result of VHL tumors. Periodic screening allows early detection and may prevent advanced disease.

Future directions

Currently, the renal manifestations of VHL are still generally managed surgically or with thermal ablation. There is a clear unmet need for better management strategies. These will include defining the molecular biology and genetics of kidney cancer development, which may result in the development of effective prevention or early intervention therapies. In addition, the evolving understanding of the molecular biology of established kidney cancers may provide opportunities to phenotypically normalize the cancer by modulating residual VHL function, identifying new targets, or discovering synthetic lethal strategies that can effectively eradicate RCC.

  1. Beers M, Porter R, Jones T: The Merck Manual of Diagnosis and Therapy. 18th ed. Rahway, NJ: Merck Sharp & Dohme Research Laboratories, 2006. 

  2. Lindor NM, McMaster ML, Lindor CJ, et al.: Concise handbook of familial cancer susceptibility syndromes - second edition. J Natl Cancer Inst Monogr (38): 1-93, 2008.  [PUBMED Abstract]

  3. Rennebeck G, Kleymenova EV, Anderson R, et al.: Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc Natl Acad Sci U S A 95 (26): 15629-34, 1998.  [PUBMED Abstract]

  4. Choyke PL, Glenn GM, Walther MM, et al.: von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194 (3): 629-42, 1995.  [PUBMED Abstract]

  5. Lonser RR, Glenn GM, Walther M, et al.: von Hippel-Lindau disease. Lancet 361 (9374): 2059-67, 2003.  [PUBMED Abstract]

  6. Pithukpakorn M, Glenn G: von Hippel-Lindau syndrome. Community Oncology 1 (4): 232-43, 2004. 

  7. Glenn GM, Daniel LN, Choyke P, et al.: Von Hippel-Lindau (VHL) disease: distinct phenotypes suggest more than one mutant allele at the VHL locus. Hum Genet 87 (2): 207-10, 1991.  [PUBMED Abstract]

  8. Latif F, Tory K, Gnarra J, et al.: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260 (5112): 1317-20, 1993.  [PUBMED Abstract]

  9. Knudson AG Jr, Strong LC: Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum Genet 24 (5): 514-32, 1972.  [PUBMED Abstract]

  10. Knudson AG Jr: Genetics of human cancer. Annu Rev Genet 20: 231-51, 1986.  [PUBMED Abstract]

  11. Maher ER, Iselius L, Yates JR, et al.: Von Hippel-Lindau disease: a genetic study. J Med Genet 28 (7): 443-7, 1991.  [PUBMED Abstract]

  12. Neumann HP, Wiestler OD: Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet 337 (8749): 1052-4, 1991.  [PUBMED Abstract]

  13. Brauch H, Kishida T, Glavac D, et al.: Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect. Hum Genet 95 (5): 551-6, 1995.  [PUBMED Abstract]

  14. Bender BU, Eng C, Olschewski M, et al.: VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality. J Med Genet 38 (8): 508-14, 2001.  [PUBMED Abstract]

  15. Woodward ER, Wall K, Forsyth J, et al.: VHL mutation analysis in patients with isolated central nervous system haemangioblastoma. Brain 130 (Pt 3): 836-42, 2007.  [PUBMED Abstract]

  16. Chen F, Kishida T, Yao M, et al.: Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat 5 (1): 66-75, 1995.  [PUBMED Abstract]

  17. Sgambati MT, Stolle C, Choyke PL, et al.: Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet 66 (1): 84-91, 2000.  [PUBMED Abstract]

  18. Austin KD, Hall JG: Nontraditional inheritance. Pediatr Clin North Am 39 (2): 335-48, 1992.  [PUBMED Abstract]

  19. Ang SO, Chen H, Hirota K, et al.: Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32 (4): 614-21, 2002.  [PUBMED Abstract]

  20. Pastore YD, Jelinek J, Ang S, et al.: Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood 101 (4): 1591-5, 2003.  [PUBMED Abstract]

  21. Cario H, Schwarz K, Jorch N, et al.: Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis. Haematologica 90 (1): 19-24, 2005.  [PUBMED Abstract]

  22. Popova T, Hebert L, Jacquemin V, et al.: Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 92 (6): 974-80, 2013.  [PUBMED Abstract]

  23. Pause A, Lee S, Lonergan KM, et al.: The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci U S A 95 (3): 993-8, 1998.  [PUBMED Abstract]

  24. Kurban G, Hudon V, Duplan E, et al.: Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res 66 (3): 1313-9, 2006.  [PUBMED Abstract]

  25. Thoma CR, Toso A, Gutbrodt KL, et al.: VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol 11 (8): 994-1001, 2009.  [PUBMED Abstract]

  26. Gordan JD, Bertout JA, Hu CJ, et al.: HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11 (4): 335-47, 2007.  [PUBMED Abstract]

  27. Koh MY, Lemos R Jr, Liu X, et al.: The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res 71 (11): 4015-27, 2011.  [PUBMED Abstract]

  28. Koh MY, Darnay BG, Powis G: Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation. Mol Cell Biol 28 (23): 7081-95, 2008.  [PUBMED Abstract]

  29. Monzon FA, Alvarez K, Peterson L, et al.: Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis. Mod Pathol 24 (11): 1470-9, 2011.  [PUBMED Abstract]

  30. Pan J, Snell W: The primary cilium: keeper of the key to cell division. Cell 129 (7): 1255-7, 2007.  [PUBMED Abstract]

  31. Simons M, Walz G: Polycystic kidney disease: cell division without a c(l)ue? Kidney Int 70 (5): 854-64, 2006.  [PUBMED Abstract]

  32. Thoma CR, Frew IJ, Hoerner CR, et al.: pVHL and GSK3beta are components of a primary cilium-maintenance signalling network. Nat Cell Biol 9 (5): 588-95, 2007.  [PUBMED Abstract]

  33. Hergovich A, Lisztwan J, Barry R, et al.: Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol 5 (1): 64-70, 2003.  [PUBMED Abstract]

  34. Hergovich A, Lisztwan J, Thoma CR, et al.: Priming-dependent phosphorylation and regulation of the tumor suppressor pVHL by glycogen synthase kinase 3. Mol Cell Biol 26 (15): 5784-96, 2006.  [PUBMED Abstract]

  35. Roe JS, Kim HR, Hwang IY, et al.: von Hippel-Lindau protein promotes Skp2 destabilization on DNA damage. Oncogene 30 (28): 3127-38, 2011.  [PUBMED Abstract]

  36. Kim J, Jonasch E, Alexander A, et al.: Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Clin Cancer Res 15 (1): 81-90, 2009.  [PUBMED Abstract]

  37. Roe JS, Youn HD: The positive regulation of p53 by the tumor suppressor VHL. Cell Cycle 5 (18): 2054-6, 2006.  [PUBMED Abstract]

  38. Lai Y, Song M, Hakala K, et al.: Proteomic dissection of the von Hippel-Lindau (VHL) interactome. J Proteome Res 10 (11): 5175-82, 2011.  [PUBMED Abstract]

  39. Li M, Fang X, Baker DJ, et al.: The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc Natl Acad Sci U S A 107 (32): 14188-93, 2010.  [PUBMED Abstract]

  40. Ohh M, Yauch RL, Lonergan KM, et al.: The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell 1 (7): 959-68, 1998.  [PUBMED Abstract]

  41. Lolkema MP, Gervais ML, Snijckers CM, et al.: Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain. J Biol Chem 280 (23): 22205-11, 2005.  [PUBMED Abstract]

  42. Haase VH, Glickman JN, Socolovsky M, et al.: Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A 98 (4): 1583-8, 2001.  [PUBMED Abstract]

  43. Hickey MM, Lam JC, Bezman NA, et al.: von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest 117 (12): 3879-89, 2007.  [PUBMED Abstract]

  44. Lee CM, Hickey MM, Sanford CA, et al.: VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo. Oncogene 28 (14): 1694-705, 2009.  [PUBMED Abstract]

  45. Frew IJ, Thoma CR, Georgiev S, et al.: pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J 27 (12): 1747-57, 2008.  [PUBMED Abstract]

  46. Varela I, Tarpey P, Raine K, et al.: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469 (7331): 539-42, 2011.  [PUBMED Abstract]

  47. Dalgliesh GL, Furge K, Greenman C, et al.: Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463 (7279): 360-3, 2010.  [PUBMED Abstract]

  48. Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, et al.: BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44 (7): 751-9, 2012.  [PUBMED Abstract]

  49. Hoffman MA, Ohh M, Yang H, et al.: von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 10 (10): 1019-27, 2001.  [PUBMED Abstract]

  50. Choyke PL, Glenn GM, Walther MM, et al.: The natural history of renal lesions in von Hippel-Lindau disease: a serial CT study in 28 patients. AJR Am J Roentgenol 159 (6): 1229-34, 1992.  [PUBMED Abstract]

  51. Poston CD, Jaffe GS, Lubensky IA, et al.: Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von Hippel-Lindau disease: clinical and molecular genetic implications. J Urol 153 (1): 22-6, 1995.  [PUBMED Abstract]

  52. Walther MM, Choyke PL, Glenn G, et al.: Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol 161 (5): 1475-9, 1999.  [PUBMED Abstract]

  53. Walther MM, Lubensky IA, Venzon D, et al.: Prevalence of microscopic lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinoma and no renal disease: clinical implications. J Urol 154 (6): 2010-4; discussion 2014-5, 1995.  [PUBMED Abstract]

  54. Maher ER, Yates JR, Harries R, et al.: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77 (283): 1151-63, 1990.  [PUBMED Abstract]

  55. Stolle C, Glenn G, Zbar B, et al.: Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 12 (6): 417-23, 1998.  [PUBMED Abstract]

  56. Hoebeeck J, van der Luijt R, Poppe B, et al.: Rapid detection of VHL exon deletions using real-time quantitative PCR. Lab Invest 85 (1): 24-33, 2005.  [PUBMED Abstract]

  57. Fadahunsi AT, Sanford T, Linehan WM, et al.: Feasibility and outcomes of partial nephrectomy for resection of at least 20 tumors in a single renal unit. J Urol 185 (1): 49-53, 2011.  [PUBMED Abstract]

  58. Shuch B, Linehan WM, Bratslavsky G: Repeat partial nephrectomy: surgical, functional and oncological outcomes. Curr Opin Urol 21 (5): 368-75, 2011.  [PUBMED Abstract]

  59. Joly D, Méjean A, Corréas JM, et al.: Progress in nephron sparing therapy for renal cell carcinoma and von Hippel-Lindau disease. J Urol 185 (6): 2056-60, 2011.  [PUBMED Abstract]

  60. Dominguez-Escrig JL, Sahadevan K, Johnson P: Cryoablation for small renal masses. Adv Urol : 479495, 2008.  [PUBMED Abstract]

  61. Shingleton WB, Sewell PE Jr: Percutaneous renal cryoablation of renal tumors in patients with von Hippel-Lindau disease. J Urol 167 (3): 1268-70, 2002.  [PUBMED Abstract]

  62. Shingleton WB, Sewell PE Jr: Cryoablation of renal tumours in patients with solitary kidneys. BJU Int 92 (3): 237-9, 2003.  [PUBMED Abstract]

  63. Aron M, Gill IS: Minimally invasive nephron-sparing surgery (MINSS) for renal tumours. Part II: probe ablative therapy. Eur Urol 51 (2): 348-57, 2007.  [PUBMED Abstract]

  64. Jonasch E, McCutcheon IE, Waguespack SG, et al.: Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. Ann Oncol 22 (12): 2661-6, 2011.  [PUBMED Abstract]

  65. Girmens JF, Erginay A, Massin P, et al.: Treatment of von Hippel-Lindau retinal hemangioblastoma by the vascular endothelial growth factor receptor inhibitor SU5416 is more effective for associated macular edema than for hemangioblastomas. Am J Ophthalmol 136 (1): 194-6, 2003.  [PUBMED Abstract]

  66. Aiello LP, George DJ, Cahill MT, et al.: Rapid and durable recovery of visual function in a patient with von hippel-lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor su5416. Ophthalmology 109 (9): 1745-51, 2002.  [PUBMED Abstract]

  67. Madhusudan S, Deplanque G, Braybrooke JP, et al.: Antiangiogenic therapy for von Hippel-Lindau disease. JAMA 291 (8): 943-4, 2004.  [PUBMED Abstract]

  68. Dahr SS, Cusick M, Rodriguez-Coleman H, et al.: Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina 27 (2): 150-8, 2007.  [PUBMED Abstract]

  69. Frantzen C, Kruizinga RC, van Asselt SJ, et al.: Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease. Neurology 79 (8): 793-6, 2012.  [PUBMED Abstract]

  70. Ye DY, Bakhtian KD, Asthagiri AR, et al.: Effect of pregnancy on hemangioblastoma development and progression in von Hippel-Lindau disease. J Neurosurg 117 (5): 818-24, 2012.  [PUBMED Abstract]

  71. Lamiell JM, Salazar FG, Hsia YE: von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore) 68 (1): 1-29, 1989.  [PUBMED Abstract]

  72. Horton WA, Wong V, Eldridge R: Von Hippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med 136 (7): 769-77, 1976.  [PUBMED Abstract]

  73. Neumann HP: Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 16 (3): 220-6, 1987.  [PUBMED Abstract]

  74. Karsdorp N, Elderson A, Wittebol-Post D, et al.: Von Hippel-Lindau disease: new strategies in early detection and treatment. Am J Med 97 (2): 158-68, 1994.  [PUBMED Abstract]