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

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Last Modified: 06/05/2014

Introduction

 [Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

Renal cell cancer (RCC) is among the more commonly diagnosed cancers in both men and women. In the United States in 2014, about 63,920 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to more than 13,860 deaths.[1] This cancer accounts for about 4% of all the adult malignancies. The male-to-female ratio is 1.5:1.[2] RCC is distinct from kidney cancer that involves the renal pelvis or renal medulla, and it only applies to cancer that forms in the lining of the kidney bed (i.e., in the renal tubules). Genetic mutations have been identified as the cause of inherited cancer risk in some RCC cancer–prone families; these mutations are estimated to account for only 1% to 2% of RCC cases overall.[3] It is likely that other undiscovered genes and background genetic factors contribute to the development of familial RCC in conjunction with nongenetic risk factors. About 80% of sporadic RCC is of clear cell histopathology.[2] Non–renal cell cancers of the kidney, including cancer of the renal pelvis or renal medulla, are not addressed in this summary.

RCC occurs in both sporadic and heritable forms. The following four major autosomal dominantly inherited RCC syndromes have been identified:

  • von Hippel-Lindau (VHL) syndrome.
  • Hereditary papillary renal cancer (HPRC).
  • Birt-Hogg-Dubé (BHD) syndrome.
  • Hereditary leiomyomatosis and renal cell cancer (HLRCC).

These genetic syndromes comprise the main focus of this summary. (Refer to the PDQ summary on Renal Cell Cancer Treatment for more information and the PDQ summary on Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information about sporadic kidney cancer.)

Natural History Varies by Histopathology

The natural history of each of the RCCs varies according to the characteristic histopathology of the renal tumors that arise in the specific syndrome. Although it is useful to follow the predominant reported natural history of each syndrome, each individual affected will need to be evaluated and monitored for occasional individual variations. The individual prognosis will depend upon the characteristics of the renal tumor at the time of detection and intervention and will differ for each syndrome (VHL, HPRC, BHD, and HLRCC). Prognostic determinants at diagnosis include the stage of the RCC, whether the tumor is confined to the kidney, primary tumor size, Fuhrman nuclear grade, and multifocality.[4-6]

Family History as a Risk Factor for RCC

Epidemiologic studies of RCC suggest that a family history of RCC is a risk factor for the disease. The relative risk (RR) is estimated to be 2.5 for a sibling of an RCC-affected patient. This observation was reproducible in a number of studies.[7,8] Analysis of renal carcinomas up to the year 2000 in the Sweden Family-Cancer Database, which includes all Swedes born since 1931 and their biological parents, led to the observation that risk of RCC was particularly high in the siblings of those affected with RCC. The higher RR in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma.[7] Investigators in Iceland studied all patients in Iceland who developed RCC between 1955 and 1999 (1,078 cases). In addition, they used an extensive computerized database to perform a unique genealogic study that included more than 600,000 Icelandic individuals. The results revealed that nearly 60% of RCC patients in Iceland during this time period had either a first-degree relative or a second-degree relative with RCC.[8]

Because RCC accounts for only about 4% of all adult malignancies in the United States,[2,9] the presence of two or more family members with RCC may suggest a hereditary etiology. Having a relative affected with kidney cancer is one of the known epidemiologic risk factors for this disease. There is a 2.5 times greater chance of RCC arising in a sibling of an affected individual than in someone in the general population.[7,8,10] Young age at onset is also a clue to possible hereditary etiology. In contrast with sporadic RCC, which is generally diagnosed during the fifth to seventh decades of life, hereditary forms of kidney cancer are generally diagnosed at an earlier age. In a review from the National Cancer Institute of over 600 cases of hereditary kidney cancer, the median age at diagnosis was 37 years, with 70% of the cases being diagnosed at age 46 years or younger,[11] compared with a median age at diagnosis of 64 years in the overall population.[12]. Bilaterality and multifocality are common in most heritable RCC, except in HLRCC.

Other Risk Factors for RCC

Studies of environmental and lifestyle factors contributing to the risk of RCC focus almost exclusively on sporadic (i.e., nonhereditary) RCC. Smoking, hypertension, and obesity are the major environmental and lifestyle risk factors associated with RCC.[9] In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably due to somatic mutations in the VHL gene.[13] Dietary intake of vegetables and fruits has been inversely associated with RCC. Greater intake of red meat and milk products have been associated with increased RCC risk, although not consistently.[14]

References
  1. American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014. 

  2. DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011. 

  3. Hung RJ, Moore L, Boffetta P, et al.: Family history and the risk of kidney cancer: a multicenter case-control study in Central Europe. Cancer Epidemiol Biomarkers Prev 16 (6): 1287-90, 2007.  [PUBMED Abstract]

  4. Vira MA, Novakovic KR, Pinto PA, et al.: Genetic basis of kidney cancer: a model for developing molecular-targeted therapies. BJU Int 99 (5 Pt B): 1223-9, 2007.  [PUBMED Abstract]

  5. Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003.  [PUBMED Abstract]

  6. Zbar B, Glenn G, Merino M, et al.: Familial renal carcinoma: clinical evaluation, clinical subtypes and risk of renal carcinoma development. J Urol 177 (2): 461-5; discussion 465, 2007.  [PUBMED Abstract]

  7. Hemminki K, Li X: Familial risks of cancer as a guide to gene identification and mode of inheritance. Int J Cancer 110 (2): 291-4, 2004.  [PUBMED Abstract]

  8. Gudbjartsson T, Jónasdóttir TJ, Thoroddsen A, et al.: A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas. Int J Cancer 100 (4): 476-9, 2002.  [PUBMED Abstract]

  9. McLaughlin JK, Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 27 (2): 115-23, 2000.  [PUBMED Abstract]

  10. Teh BT, Giraud S, Sari NF, et al.: Familial non-VHL non-papillary clear-cell renal cancer. Lancet 349 (9055): 848-9, 1997.  [PUBMED Abstract]

  11. Shuch B, Vourganti S, Ricketts CJ, et al.: Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 32 (5): 431-7, 2014.  [PUBMED Abstract]

  12. National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, MD: National Cancer Institute, 2014. Available online. Last accessed June 6, 2014. 

  13. Brauch H, Weirich G, Hornauer MA, et al.: Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma. J Natl Cancer Inst 91 (10): 854-61, 1999.  [PUBMED Abstract]

  14. Chow WH, Devesa SS: Contemporary epidemiology of renal cell cancer. Cancer J 14 (5): 288-301, 2008 Sep-Oct.  [PUBMED Abstract]

Major Heritable Renal Cell Cancer Syndromes

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

Introduction

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.

Genetics

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
2APheochromocytomas
Retinal hemangioblastomas
CNS hemangioblastomas
2BPheochromocytomas
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

Histopathology

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.

Management

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

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 two 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]

Chemotherapy

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.

Prognosis

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.

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Changes to This Summary (06/05/2014)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Introduction

Added text to state that hereditary forms of kidney cancer are generally diagnosed at an earlier age; in a review from the National Cancer Institute (NCI) of over 600 cases of hereditary kidney cancer, the median age at diagnosis was 37 years, with 70% of the cases being diagnosed at age 46 years or younger (cited Shuch et al. and NCI as references 11 and 12, respectively).

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary



Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of kidney cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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