Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)–Health Professional Version
Executive Summary
This executive summary reviews the topics covered in this PDQ summary on the genetics of kidney cancer (renal cell cancer), with hyperlinks to detailed sections below that describe the evidence on each topic.
- Inheritance and RiskRenal cell cancer (RCC), which is distinct from kidney cancer that involves the renal pelvis or renal medulla, occurs in both sporadic and heritable forms. Autosomal dominantly inherited pathogenic germline variants have been identified as the cause of inherited cancer risk in some RCC–prone families; these pathogenic variants are estimated to account for only 5% to 8% of RCC cases overall. It is likely that other undiscovered genes and background genetic factors contribute to the development of familial RCC in conjunction with nongenetic risk factors.
- Associated Genes and SyndromesThe following four major autosomal dominantly inherited RCC syndromes have been identified: von Hippel-Lindau disease (VHL, caused by pathogenic variants in VHL); hereditary leiomyomatosis and renal cell cancer (HLRCC, caused by pathogenic variants in FH); Birt-Hogg-Dubé syndrome (BHD, caused by pathogenic variants in FLCN); and hereditary papillary renal carcinoma (HPRC, caused by pathogenic variants in MET). Each of these syndromes, with the exception of HPRC, is associated with other benign or malignant tumors in other organs.
- Clinical ManagementRegular surveillance is a mainstay in individuals found to have or be at risk of carrying a pathogenic variant in VHL, FH, FLCN, or MET. Surveillance recommendations include regular screening for both renal and nonrenal manifestations of disease.VHL-associated renal tumors of 3 cm in size are commonly managed with surgery. Nephron-sparing techniques are typically employed as they have been shown to preserve renal function. Ablative techniques including radiofrequency ablation and cryoablation may be used in patients with smaller tumors who are at high operative risk. Chemotherapeutic agents such as sunitinib have been studied in the treatment of patients with VHL and found to be effective in treating VHL-associated RCC but not hemangioblastomas. Extrarenal manifestations of VHL, such as retinal hemangioblastomas, central nervous system lesions, pheochromocytomas, and pancreatic cysts and neuroendocrine tumors, often require subspecialty evaluation and may require surgical intervention.HLRCC-associated RCCs are biologically quite aggressive, so early and extensive surgical management (e.g., radical nephrectomy or partial nephrectomy with wide margins) may be necessary. Targeted therapies including the use of bevacizumab/erlotinib in a combination regimen and vandetanib are currently under investigation. HLRCC-associated cutaneous lesions generally need no intervention. If symptomatic, surgery, cryoablation, and/or laser therapy may be considered. A small randomized controlled trial has shown that botulinum toxin A may improve quality of life in HLRCC patients with painful skin lesions. Hormonal and/or pain management medications may be given to provide release from uterine leiomyoma-related pain. The leiomyomas may also be removed surgically.Both BHD-associated RCCs and HPRC-associated RCCs are typically managed with partial nephrectomy once they reach 3 cm. MET inhibition is being studied as a potential targeted therapy in individuals with HPRC-associated RCC. BHD-associated cutaneous lesions generally need no intervention. BHD patients are also at increased risk of spontaneous pneumothorax, which is managed as it would be in the general population.
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.]
[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]
Renal cell cancer (RCC) is among the more commonly diagnosed cancers in both men and women. In the United States in 2019, about 73,820 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to an estimated 14,770 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). Non-RCCs of the kidney, including cancer of the renal pelvis or renal medulla, are not addressed in this summary. Genetic pathogenic variants have been identified as the cause of inherited cancer risk in some RCC–prone families; these pathogenic variants are estimated to account for only 5% to 8% of RCC cases overall.[3,4] It is likely that other undiscovered genes and background genetic factors contribute to the development of familial RCC in conjunction with nongenetic risk factors.
RCC occurs in both sporadic and heritable forms. The following four major autosomal dominantly inherited RCC syndromes have been identified:
- von Hippel-Lindau disease (VHL).
- Hereditary leiomyomatosis and renal cell cancer (HLRCC).
- Hereditary papillary renal carcinoma (HPRC).
- Birt-Hogg-Dubé syndrome (BHD).
These genetic syndromes comprise the main focus of this summary. (Refer to the PDQ summary on Renal Cell Cancer Treatment and the PDQ summary on Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information about sporadic kidney cancer.)
Natural History
The natural history of each syndrome is distinct and influenced by several factors, including histologic features and underlying genetic alterations. 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.[5-7]
Family History as a Risk Factor for RCC
RCC accounts for about 4% of all adult malignancies in the United States.[8] Epidemiologic studies of RCC suggest that a family history of RCC is a risk factor for the disease.[4,9,10] 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 relative risk (RR) in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma.[9] 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 had either a first-degree relative or a second-degree relative with RCC, with an estimated RR of 2.5 for a sibling of an RCC-affected patient.[4] A study that evaluated 80,309 monozygotic twin individuals and 123,382 same-sex dizygotic twin individuals in Denmark, Finland, Norway, and Sweden found an excess cancer risk in twins whose co-twin was diagnosed with cancer.[10] The estimated cumulative risks were an absolute 5% higher (95% confidence interval [CI], 4%–6%) in dizygotic twins (37%; 95% CI, 36%–38%) and an absolute 14% higher (95% CI, 12%–16%) in monozygotic twins (46%; 95% CI, 44%–48%)—for twins whose co-twin also developed cancer—than that in the overall cohort (32%). Overall heritability of cancer, calculated by assessing the relative contribution of heredity versus shared environment, was estimated to be 33%. Heritability of kidney cancer was estimated to be 38% (95% CI, 21%–55%), with shared environmental factors not showing a significant contribution to overall risk.
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,[3] compared with a median age at diagnosis of 64 years in the overall population.[11]. Bilaterality and multifocality are common in most heritable RCC. A retrospective analysis of 1,235 patients with RCC who underwent genetic testing revealed that 6.1% of this population had positive genetic test results, 75.5% had negative test results, and 18.4% had a variant of unknown significance. The only variable associated with a positive test result was younger age at diagnosis of RCC.[12]
There is no consensus regarding whom to refer for genetic consultation for a possible hereditary kidney cancer syndrome, although the following organizations have offered guidance:
- American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.[13]
- VHL Alliance.
- Kidney Cancer Research Network of Canada.[14]
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.[15] In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably due to somatic variants in the VHL gene.[16] 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.[17]
References
- American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available online. Last accessed January 23, 2019.
- DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011.
- 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]
- 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]
- 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]
- Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PUBMED Abstract]
- 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]
- Siegel RL, Miller KD, Jemal A: Cancer statistics, 2016. CA Cancer J Clin 66 (1): 7-30, 2016 Jan-Feb. [PUBMED Abstract]
- 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]
- Mucci LA, Hjelmborg JB, Harris JR, et al.: Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 315 (1): 68-76, 2016. [PUBMED Abstract]
- National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 14, 2018.
- Nguyen KA, Syed JS, Espenschied CR, et al.: Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test. Cancer 123 (22): 4363-4371, 2017. [PUBMED Abstract]
- Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
- Reaume MN, Graham GE, Tomiak E, et al.: Canadian guideline on genetic screening for hereditary renal cell cancers. Can Urol Assoc J 7 (9-10): 319-23, 2013 Sep-Oct. [PUBMED Abstract]
- McLaughlin JK, Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 27 (2): 115-23, 2000. [PUBMED Abstract]
- 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]
- 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 (RCC) syndromes (von Hippel-Lindau disease [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt-Hogg-Dubé syndrome [BHD], and hereditary papillary renal carcinoma [HPRC]) with autosomal dominant inheritance are listed in Table 1, along with their susceptibility genes. These syndromes are summarized in detail in the following sections of this summary.
Autosomal dominant mode of inheritance is the pattern of transmission reported within the families affected by these major RCC syndromes. Autosomal dominant means that it is sufficient for the altered gene to be present in one of the parents and that the chances of transmitting this gene and the disease to the offspring is 50% for each pregnancy. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories are available for the genes associated with VHL, BHD, 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.)
References
- 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]
- Lonser RR, Glenn GM, Walther M, et al.: von Hippel-Lindau disease. Lancet 361 (9374): 2059-67, 2003. [PUBMED Abstract]
- Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98 (6): 3387-92, 2001. [PUBMED Abstract]
- Alam NA, Olpin S, Leigh IM: Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol 153 (1): 11-7, 2005. [PUBMED Abstract]
- Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003. [PUBMED Abstract]
- Wei MH, Toure O, Glenn GM, et al.: Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43 (1): 18-27, 2006. [PUBMED Abstract]
- Toro JR, Wei MH, Glenn GM, et al.: BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet 45 (6): 321-31, 2008. [PUBMED Abstract]
- Toro JR, Glenn G, Duray P, et al.: Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135 (10): 1195-202, 1999. [PUBMED Abstract]
- Zbar B, Alvord WG, Glenn G, et al.: Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev 11 (4): 393-400, 2002. [PUBMED Abstract]
- Pavlovich CP, Walther MM, Eyler RA, et al.: Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 26 (12): 1542-52, 2002. [PUBMED Abstract]
- Schmidt L, Duh FM, Chen F, et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16 (1): 68-73, 1997. [PUBMED Abstract]
- Schmidt LS, Nickerson ML, Angeloni D, et al.: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172 (4 Pt 1): 1256-61, 2004. [PUBMED Abstract]
Von Hippel-Lindau Disease
Introduction
Von Hippel-Lindau disease (VHL) (OMIM) is an autosomal dominant disease with a predisposition to multiple neoplasms. Germline pathogenic variants in the VHL genepredispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems. These include central nervous system (CNS) hemangioblastomas; retinal hemangioblastomas; clear cell renal cell cancers (ccRCCs) and renal cysts; pheochromocytomas, cysts, cystadenomas, and neuroendocrine tumors (NETs) of the pancreas; endolymphatic sac tumors (ELSTs); and cystadenomas of the epididymis (males) and of the broad ligament (females).[1-4] 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.[5] VHL pathogenic variants occur in all three exons of this gene. Most affected individuals inherit a germline pathogenic variant of VHL from an affected parent and a normal (wild-type) VHL copy from their unaffected parent. VHL-associated tumors conform to Knudson’s “two-hit” hypothesis,[6,7] 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 pathogenic variant in VHL represents the first "hit", which is present in every cell in the body. The second “hit” is a somatic pathogenic variant, 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 may proliferate into a tumor mass.
Prevalence and rare founder effects
The incidence of VHL is estimated to be between 1 per 27,000 and 1 per 43,000 live births in the general population.[8-10] The prevalence is estimated to be between 1 in 31,000 to 1 in 91,000 individuals.[9-12] 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 pathogenic variants in this small three-exon gene indicates that most family clusters have not arisen from a single founder.
Penetrance of pathogenic variants
Risk factors for VHL
Each offspring of an individual with VHL has a 50% chance of inheriting the VHL pathogenic variant allele from their affected parent. (Refer to the Genetic diagnosis section of this summary for more information.)
Genotype-phenotype correlations
Specific pathogenic variant types leading to VHL clinical manifestations include missense, nonsense, frameshifts, insertions, partial and complete deletions, and splice-site variantsof VHL. The specific alteration may influence clinical manifestations. Two major clinical phenotypes of VHL have been described. Type I, commonly associated with large gene deletions, is characterized by the development of all VHL-associated lesions except pheochromocytoma. Type II, more commonly associated with missense variants, is characterized by the development of all clinical manifestations including pheochromocytoma. Type II clinical phenotype is subdivided into Type IIA (low risk of RCC), Type IIB (high risk of renal cell cancer [RCC]), and Type IIC (no RCC development, where the predominant clinical picture is characterized by CNS hemangioblastoma and pheochromocytoma development). Overall, the risk of RCC correlates with the loss of hypoxia-inducible factor (HIF)2-alpha regulation by the specific VHL germline variant.[13-16] Specific alterations can be useful in segregating risks; however, significant overlap exists, and surveillance tailored according to phenotype is not generally advised.
De novo pathogenic variants 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 pathogenic variant in the affected individual. Patients diagnosed with VHL, who have no family historyof VHL, have been estimated to comprise about 23% of VHL kindreds.[17] A new variant is by definition a postzygotic event, because it is not transmitted from a parent.
Depending on the embryogenesis stage at which the new variant occurs, there may be different somatic cell lineages carrying the variant; this influences the extent of mosaicism. Mosaicism is the presence in an individual of two or more cell lines that differ in genotypebut which arise from a single zygote.[18] If the postzygotic de novo variant affects the gonadal cell line, there is a risk of transmitting a germline variant 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 pathogenic variants in VHL in which affected individuals develop abnormally high numbers of red blood cells (polycythemia). The affected individuals have biallelic pathogenic variants in the VHL gene. It had been originally thought that the typical VHL syndromic tumors do not occur in these affected individuals.[19-21]
Other genetic alterations
In sporadic RCC, mutational inactivation of the VHL gene is the most frequent molecular event. In addition to VHL inactivation, sporadic ccRCC tumors harbor frequent variants in other genes, including PBRM1, SETD2, and BAP1.[22,23] Mutational inactivation of PBRM1, SETD2, and BAP1 are “second hit” events occurring after VHL alterations in sporadic ccRCC, and they contribute to development and growth of ccRCC.[24,23] Germline pathogenic variants in PBRM1 and BAP1 result in the development of hereditary forms of ccRCC.[25] The role of PBRM1, BAP1, and SETD2 in VHL-related ccRCC growth and progression is under investigation.
Molecular Biology
The VHL tumor suppressor gene encodes two proteins: a 213 amino acid protein (pVHL30) and a 154 amino acid protein, which is the product of internal translation.[26] The best-studied function of pVHL, linked to its ability to suppress tumor formation, is the regulation of HIF activity. Other reported functions of pVHL include regulation of extracellular matrix formation, microtubule and centrosome maturation, and inactivation of p53.[27-30] 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 a substrate recognition site for HIF as part of an E3 ubiquitin ligase complex.[30] In normoxic conditions, HIF1-alpha and HIF2-alpha are enzymatically hydroxylated by intracellular prolyl hydroxylases. The hydroxylated HIF subunits are bound by the VHL protein complex, covalently linked to ubiquitin, and degraded by the S26 proteasome.[31,32]
Hypoxia inactivates prolyl hydroxylases, leading to lack of HIF hydroxylation. Nonhydroxylated HIF1-alpha and HIF2-alpha are not bound to the VHL protein complex for ubiquitination, and, therefore, accumulate. The resulting constitutively high levels of HIF1-alpha and HIF2-alpha drive increased transcription of a variety of genes, including growth and angiogenic factors, enzymes of the intermediary metabolism, and genes promoting stemness-like cellular phenotypes.[33]
HIF1-alpha and HIF2-alpha possess distinct and partially contrasting functional characteristics. In the context of RCC, it appears that HIF2-alpha acts as an oncogene, and HIF1-alpha acts as a tumor suppressor gene. HIF2-alpha may preferentially upregulate Myc activity, whereas HIF1-alpha may inhibit Myc activity.[34] Hypoxia-associated factor has been shown to increase HIF2-alpha transactivation [35] and HIF1-alpha instability.[36] Preferential loss of chromosome 14q, the locus for the HIF1-alpha gene, results in decreased levels of HIF1-alpha protein.[37]
Numerous studies using xenografted or transgenic animal models have shown that inactivation of HIF2-alpha by pVHL is necessary and sufficient for tumor suppression by the pVHL proteins. HIF2-alpha is now an established therapeutic target for VHL-related malignancies.[38-40] Specific HIF2-alpha inhibitors are in preclinical and clinical testing.[41-43]
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.[44] Loss of primary ciliary function results in the loss of the cell’s ability to maintain planar cell polarity, which results in cyst formation.[45] Loss of pVHL results in loss of the primary cilium.[46] pVHL binds to and stabilizes microtubules [47] in a glycogen synthase 3–dependent fashion.[48] Loss of pVHL or expression of variant pVHL in cells also results in unstable astral microtubules, dysregulation of the spindle assembly checkpoint, and an increase in aneuploidy.[29]
Cell cycle control
pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL null cell lines.[27] Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to DNA damage.[49] Nuclear localization and intensity of p27 is inversely associated with tumor grade.[50] pVHL binds to [51] and facilitates phosphorylation of p53 in an ATM-dependent fashion.[52]
Extracellular matrix control
Regulation of oncogenic autophagy
In ccRCC, oncogenic autophagy dependent on microtubule-associated protein 1 light chain 3 alpha and beta (LC3A and LC3B) is stimulated by activity of the transient receptor potential melastatin 3 (TRPM3) channel through multiple complementary mechanisms. The VHL tumor suppressor represses this oncogenic autophagy in a coordinated manner through the activity of miR-204, which is expressed from intron 6 of the gene encoding TRPM3. TRPM3 represents an actionable target for ccRCC treatment.[55,56]
Animal models of VHL
VHL knockout mice die in utero. Heterozygous VHL mice develop vascular liver lesions reminiscent of hemangioblastomas.[57] Conditional targeted inactivation of the Vhlh gene in the mouse kidney results in the generation of VHL-resembling cysts but not RCC. Coordinate inactivation of Vhlh and Pten results in a higher rate of cyst formation, but no obvious RCC.[58] Murine homologues of the VHL R200W pathogenic variant induced polycythemia in mice, phenocopying Chuvash polycythemia.[59] The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including PBRM1,[60] SETD2,[61] and BAP1 [62] provide new avenues for developing relevant animal models of at least some VHL 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 components is observed for retinal hemangioblastomas and pheochromocytomas; targeted screening is recommended in children younger than 10 years. At least one study has demonstrated that the incidence of new lesions varies depending on patient age, the underlying pathogenic variant, and the organ involved.[63] Examples of reported mean ages and age ranges of VHL clinical manifestations are summarized in Table 2.
(Refer to the Clinical diagnosis section of this summary for more information.)
VHL familial phenotypes
Four clinical types of VHL have been described. In 1991, researchers classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma).[11] In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without RCC) and type 2B (with pheochromocytoma and RCC).[64] More recently, it was reported that VHL type 2C comprises patients with isolated pheochromocytoma without hemangioblastoma or RCC.[65] These specific VHL phenotypes are summarized in Table 3.
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.[66] 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) and minimally invasive,[67] and their rate of growth varies widely.[68] An investigation of 228 renal lesions in 28 patients who were followed up for at least 1 year showed that transition from a simple cyst to a solid lesion was infrequent.[66] 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. Figure 1 depicts bilateral renal tumors in a patient with VHL.
Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[68,69] RCCs often remain asymptomatic for long intervals.
Patients can also develop pancreatic cysts, cystadenomas, and pancreatic NETs.[2] Pancreatic cysts and cystadenomas are not malignant, but pancreatic NETs possess malignant characteristics and are typically resected if they are 3 cm or larger (2 cm if located in the head of the pancreas).[70] A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.[71]
Retinal hemangioblastomas
Retinal manifestations, first reported more than a century ago, were one of the first recognized aspects of VHL. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most frequent manifestations of VHL and are present in more than 50% of patients.[72] Retinal involvement is one of the earliest manifestations of VHL, with a mean age at onset of 25 years.[1,2] These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children as young as 1 year.[2,73,74]
Retinal hemangioblastomas occur most frequently in the periphery of the retina but can occur in other locations such as the optic nerve, a location much more difficult to treat. Retinal hemangioblastomas appear as a bright orange spherical tumor supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas.[72] The median number of lesions per affected eye is approximately six.[75] Other retinal lesions in VHL can include retinal vascular hamartomas, flat vascular tumors located in the superficial aspect of the retina.[76]
Longitudinal studies are important for the understanding of the natural history of these tumors. Left untreated, retinal hemangioblastomas can be a major source of morbidity in VHL, with approximately 8% of patients [72] having blindness caused by various mechanisms, including secondary maculopathy, contributing to retinal detachment, or possibly directly causing retinal neurodegeneration.[77] Patients with symptomatic lesions generally have larger and more numerous retinal hemangioblastomas. Long-term follow-up studies demonstrate that most lesions grow slowly and that new lesions do not develop frequently.[75,78]
Cerebellar and spinal hemangioblastomas
Hemangioblastomas are the most common disease manifestation in patients with VHL, affecting more than 70% of individuals. A prospective study assessed the natural history of hemangioblastomas.[79] The mean age at onset of CNS hemangioblastomas is 29.1 years (range, 7–73 y).[80] After a mean follow-up of 7 years, 72% of the 225 patients studied developed new lesions.[81] Fifty-one percent of existing hemangioblastomas remained stable. The remaining lesions exhibited heterogeneous growth rates, with cerebellar and brainstem lesions growing faster than those in the spinal cord or cauda equina. Approximately 12% of hemangioblastomas developed either peritumoral or intratumoral cysts, and 6.4% were symptomatic and required treatment. Increased tumor burden or total tumor number detected was associated with male sex, longer follow-up, and genotype (all P < .01). Partial germline deletions were associated with more tumors per patient than were missense variants (P < .01). Younger patients developed more tumors per year. Hemangioblastoma growth rate was higher in men than in women (P < .01). Figures 2 and 3 depict cerebellar and spinal hemangioblastomas, respectively, in patients with VHL.
Pheochromocytomas and paragangliomas
The rate of pheochromocytoma formation in the VHL patient population is 25% to 30%.[82,83] Of patients with VHL-associated pheochromocytomas, 44% developed disease in both adrenal glands.[84] The rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL,[85] and approximately two-thirds will experience physical manifestations such as hypertension, tachycardia, and palpitations.[82] Patients with a partial loss of VHL function (Type 2 disease) are at higher risk of pheochromocytoma than are VHL patients with a complete loss of VHL function (Type 1 disease); the latter develop pheochromocytoma very rarely.[13,14,82,86] The rate of VHL germline pathogenic variants in nonsyndromic pheochromocytomas and paragangliomas was very low in a cohort of 182 patients, with only 1 of 182 patients ultimately diagnosed with VHL.[87]
Paragangliomas are rare in VHL patients but can occur in the head and neck or abdomen.[88] A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and 19% presented with a paraganglioma.[84]
The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas is approximately 30 years,[83,89] and patients with multiple tumors were diagnosed more than a decade earlier than patients with solitary lesions in one series (19 vs. 34 y; P < .001).[89] Diagnosis of pheochromocytoma was made in patients as young as 5 years in one cohort,[83] providing a rationale for early testing. All 21 pediatric patients with pheochromocytomas in this 273-patient cohort had elevated plasma normetanephrines.[83]
Pancreatic manifestations
VHL patients may develop multiple serous cystadenomas, pancreatic NETs, and simple pancreatic cysts.[1] VHL patients do not have an increased risk of pancreatic adenocarcinoma. Serous cystadenomas are benign tumors and warrant no intervention. Simple pancreatic cysts can be numerous and rarely cause symptomatic biliary duct obstruction. Endocrine function is nearly always maintained; occasionally, however, patients with extensive cystic disease requiring pancreatic surgery may ultimately require pancreatic exocrine supplementation.
Pancreatic NETs are usually nonfunctional but can metastasize (to lymph nodes and the liver). The risk of pancreatic NET metastasis was analyzed in a large cohort of patients, in which the mean age at diagnosis of a pancreatic NET was 38 years (range, 16–68 y).[90] The risk of metastasis was lower in patients with small primary lesions (≤3 cm), in patients without an exon 3 pathogenic variant, and in patients whose tumor had a slow doubling time (>500 days). Nonfunctional pancreatic NETs can be followed by imaging surveillance with intervention when tumors reach 3 cm. Lesions in the head of the pancreas can be considered for surgery at a smaller size to limit operative complexity.
Endolymphatic sac tumors (ELSTs)
ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone.[91] ELSTs are rare in the sporadic setting, but are apparent on imaging in 11% to 16% of patients with VHL. Although these tumors do not metastasize, they are locally invasive, eroding through the petrous bone and the inner ear structures.[91,92] Approximately 30% of VHL patients with ELSTs have bilateral lesions.[91,93]
ELSTs are an important cause of morbidity in VHL patients. ELSTs evident on imaging are associated with a variety of symptoms, including hearing loss (95% of patients), tinnitus (92%), vestibular symptoms (such as vertigo or disequilibrium) (62%), aural fullness (29%), and facial paresis (8%).[91,92] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage.[92] Hearing loss or vestibular dysfunction in VHL patients can also present in the absence of radiologically evident ELSTs (approximately 60% of all symptomatic patients) and is believed to be a consequence of microscopic ELSTs.[91]
Hearing loss related to ELSTs is typically irreversible; serial imaging to enable early detection of ELSTs in asymptomatic patients and resection of radiologically evident lesions are important components in the management of VHL patients.[94,95] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss and improve vestibular symptoms.[92,94]
Broad/round ligament papillary cystadenomas
Tumors of the broad ligament can occur in females with VHL and are known as papillary cystadenomas. These tumors are extremely rare, and fewer than 20 have been reported in the literature.[96] Papillary cystadenomas are histologically identical to epididymal cystadenomas commonly observed in males with VHL.[97] One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas in men can occur sporadically.[98] These tumors are frequently cystic, and although they become large, they generally have a fairly indolent behavior.
Epididymal cystadenomas
Fluid-filled epididymal cysts, or spermatoceles, are very common in adult men. In VHL, the epididymis can contain more complex cystic neoplasms known as papillary cystadenomas, which are rare in the general population. More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL.[99] These well-circumscribed lesions have variable amounts of cystic and papillary components that are lined with epithelial cuboidal or columnar clear cells.[100] Among symptomatic patients, the most common presentation of epididymal cystadenoma is a painless, slow-growing scrotal swelling. The differential diagnoses of epididymal tumors include adenomatoid tumor (which is the most common tumor in this site), metastatic ccRCC, and papillary mesothelioma.[101]
In a small series, histological analysis did not reveal features typically associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis. Lesions were strongly positive for CK7 and negative for RCC. Carbonic anhydrase IX (CAIX) was positive in all tumors. PAX8 was positive in most cases. These features were reminiscent of clear cell papillary RCC, a relatively benign form of RCC without known metastatic potential.[97]
Management
Risk assessment for VHL
The primary risk factor for VHL (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,[1] as early as age 8 years.[102] 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.[1] Females have histologically similar lesions to cystadenomas that occur in the broad ligament.[1]
Each offspring of an individual with VHL has a 50% chance of inheriting the VHL variant 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 initially offered genetic testing. Germline pathogenic variants in VHL are detected in more than 99% of families affected by VHL. Sequence analysis of all three exons detect point variants in the VHL gene (~72% of all pathogenic variants).[103] Deletions are detected mainly by using next-generation sequencing (NGS), with confirmation using targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification. Array comparative genomic hybridization is also being used to identify genomic imbalances. Anecdotal evidence exists for the utility of NGS in cases of suspected mosaicism with a negative VHL genetic test.[104]
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 VHLpathogenic variant is identified in a family member, their biologic relatives who then test negative for the same pathogenic variant 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.[3]
Genetic diagnosis
A germline pathogenic variant 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 pathogenic variant. Approximately 400 unique pathogenic variants in the VHL gene have been associated with clinical VHL, and their presence verifies the disease-causing capability of the variant. The diagnostic genetic evaluation in a previously untested family generally begins with a clinically diagnosed individual. If a VHL pathogenic variant is identified, that specific pathogenic variant 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 pathogenic variant 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 pathogenic variant 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 (refer to 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. Refer to Table 4 for more diagnostic details.[2-4]
Since 1998, when a cohort of 93 VHL families in whom all germline pathogenic variants 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.
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 pathogenic variant and those individuals who choose not to be tested for a VHL pathogenic variant but have biologic relatives affected by VHL. The risk of inheriting the VHL predisposition in such persons may be as high as 50%.
Treatment
Treatment of renal tumors
Surgical interventions
The management of VHL has changed significantly as clinicians have learned how to balance the risk of cancer dissemination while minimizing renal morbidity. Some of the initial surgical series focused on performing a bilateral radical nephrectomy for renal tumors followed by a renal transplantation.[106,107] Nephron-sparing surgery (NSS) for VHL was introduced in the 1980s after several groups demonstrated a low risk of cancer dissemination with a less-radical surgical approach.[108,109] In 1995, a large multi-institutional series demonstrated how NSS could produce excellent cancer-specific survival in patients with RCC.[110] Because of multiple reports of excellent outcomes, NSS is now considered the surgical standard of care when technically feasible. Over time, the technique of NSS in this population has been refined to minimize damage to the adjacent normal parenchyma. Instead of taking a wide margin traditionally described for NSS, enucleation was developed to allow the tumor and pseudocapsule to be shelled off the surrounding adjacent normal parenchyma.[111]
Patients with VHL can have dozens of renal tumors; therefore, resection of all evidence of disease may not be feasible. To minimize the morbidity of multiple surgical procedures, loss of kidney function, and the risk of distant progression, a method to balance over- and under-treatment was sought. The National Cancer Institute (NCI) evaluated a specific size threshold to trigger surgical intervention. An evaluation of 52 patients treated when the largest solid lesion reached 3 cm demonstrated no evidence of distant metastases or need for renal replacement therapy at a median follow-up of 60 months.[68] Later retrospective series reinforced that this was an important threshold because 0 of 108 patients with tumors managed at 3 cm or smaller had evidence of distant spread.[112] For patients with tumors larger than 3 cm, a total of 27.3% (20 of 73) developed distant recurrence.[112] This threshold is now widely used to trigger surgical intervention for VHL-associated ccRCC. When surgery is performed on a patient with VHL, resection of as many renal tumors as is clinically feasible may delay the need for further surgical interventions.[113] The use of intraoperative ultrasound is helpful to identify and then remove smaller lesions.[114]
Many patients with VHL develop new RCCs on an ongoing basis and may require further intervention. Adhesions and perinephric scarring make subsequent surgical procedures more challenging. While a radical nephrectomy could be considered, NSS remains the preferred approach, when feasible. While there may be a higher incidence of complications, repeat and salvage NSS can enable patients to maintain excellent renal function outcomes and provide promising oncologic outcomes at intermediate follow-up.[115,116] These surgeries may be best handled at a specialized center with significant experience with the management of hereditary forms of kidney cancer.[117]
Ablative techniques
Radiofrequency ablation (RFA) and cryoablation (CA)
Thermal ablative techniques utilize either extreme heating or cooling of a mass in an effort to destroy the tumor. CA and RFA were introduced into the management of small renal masses in the late 1990s.[118,119] For sporadic renal masses, both thermal ablative techniques have a recurrence-free survival rate of nearly 90%, leading the American Urologic Association to consider this as a recommendation in high-risk patients with a small renal mass (≤4 cm).[120] For patients with VHL, the clinical applications of ablative techniques are still not clearly defined, and surgery remains the most-studied intervention. Ablative techniques were first introduced into the management of VHL-associated RCC in a phase II trial investigating the effects of ablation at the time of lesion resection. In this study, 11 tumors were treated, and an intra-operative ultrasound showed complete elimination of blood flow to the tumors; on final pathology, there was evidence of treatment effect on all tumors.[121] Since that time, some centers have utilized thermal ablative techniques for primary and salvage management in patients with VHL with good success.[122] Other centers have found that techniques such as RFA have a higher failure rate and should be reserved for patients with marginal renal function.[123] Despite limited long-term data, these techniques have been increasingly utilized in the treatment of RCC in patients with VHL. A single-institution study evaluated treatment trends in RCC in 113 patients with VHL. Between 2004 and 2009, 43% of cases were managed with RFA at this center.[124]
Thermal ablation may play an increasing role in the salvage therapy setting for individuals with a high risk of morbidity from surgery. CA as salvage therapy was evaluated in a series of 14 patients to avoid the morbidity of repeat NSS. There was minimal change in renal function; at a median follow-up of 37 months, there was suspicion for lesion recurrence in only 4 of 33 tumors (12.1%).[125] However, it must be cautioned that surgery after thermal ablation is a very challenging endeavor, with a significantly higher rate of postoperative complications due to adhesions and scarring, especially along the tract of the ablative probes.[126-128] In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management.[117,129]
The clinical applications of ablative techniques in VHL are not clearly defined, and surgery remains the most-studied intervention. The available clinical evidence suggests that ablative approaches be reserved for small (≤3 cm) solid-enhancing renal masses in older patients with high operative risk, especially in patients facing salvage renal surgery because of a higher complication rate. Young age, tumor size larger than 4 cm, hilar tumors, and cystic lesions can be regarded as relative contraindications.[130,131]
Chemotherapy
Much of the preclinical data that form the basis for current systemic treatment strategies stem from the study of VHL alteration. All the large randomized phase III trials investigating aldesleukin, vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, mTOR inhibitors, and checkpoint inhibitors are based on data from the treatment of sporadic clear cell kidney cancer. Despite limited studies investigating these agents in the VHL population with metastatic kidney cancer, they are believed to be efficacious and are available as treatment options. Systemic therapy to limit the development or progression of VHL manifestations has been of interest to many groups.
A 2011 study prospectively evaluated the safety and efficacy of sunitinib in patients.[132] Fifteen patients 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%) had partial responses, versus none of the hemangioblastomas (P = .014). Archival VHL-related tumor specimens were evaluated to determine expression of relevant sunitinib targets. The expression of pFRS2 in hemangioblastoma tissue was 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.[132] A retrospective study of 14 VHL patients with RCC, 10 of whom had metastatic disease, demonstrated significant response in metastatic and primary RCC lesions. Eleven patients had cerebellar hemangioblastomas, and eight had spinal hemangioblastomas. No response was seen in patients with hemangioblastomas.[133]
A study of intravitreally administered pegaptanib, an anti-VEGF therapy, was evaluated in five patients with VHL-associated retinal hemangioblastomas.[134] Only two patients were able to complete the intended therapy, and no responses were seen in the primary tumors. Two patients had decreased retinal thickening and reduced hard exudates. Although the agent is approved by the U.S. Food and Drug Administration for macular degeneration, it is not approved for the treatment of VHL retinal lesions.
Treatment of pheochromocytomas
Surveillance of pheochromocytomas
Pheochromocytomas can be a source of significant morbidity in patients with VHL due to the cardiovascular effects of excess catecholamines. In individuals that undergo surgery or childbirth without proper medical management, the results can be catastrophic due to massive surges in catecholamine release. Because tumors can also undergo malignant transformation, it is imperative that surveillance and early intervention are performed in this patient population. Available surveillance guidelines are shown in Table 5. Assessment of catecholamines/metanephrines and cross-sectional abdominal imaging are key to early detection.
Biochemical testing
Biochemical testing remains critical to the evaluation of individuals with VHL as levels can often be elevated in the absence of anatomic imaging findings. Assessment begins in childhood with some guidelines recommending initiation at age 5 years (see Table 5). Clinicians have the option of performing plasma testing, urinary testing, or both. Because the levels of catecholamines can greatly vary due to diet and medications, measurement of their metabolites, metanephrines, is suggested due to higher performance metrics. A fourfold, or greater, elevation of metanephrines is suggestive of the presence of a pheochromocytoma or paraganglioma.[135] Individuals with VHL pheochromocytomas often have isolated normetanephrines while other endocrine syndromes have a different functional profile.[88] Refer to the Clinical Diagnosis of Paraganglioma (PGL) and Pheochromocytoma (PHEO) section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information regarding diet methods of testing.
Imaging of pheochromocytomas
Cross-sectional imaging is initiated early in the second decade of life to evaluate the kidneys, adrenal glands, and pancreas. Both magnetic resonance imaging (MRI) and computed tomography (CT) scans have excellent performance characteristics for the detection of pheochromocytomas with a sensitivity of greater than 90%.[136] When there is clinical suspicion on the basis of biochemical studies and there are no lesions visible, additional imaging studies may be of clinical utility. While most tumors arising from chromaffin tissue in VHL are pheochromocytomas, paragangliomas can also occur in the chest, abdomen, pelvis, and head and neck.[88] Dedicated cross-sectional imaging can be performed in those areas in addition to a whole-body functional imaging. Refer to the Clinical Diagnosis of PGL and PHEO section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for a detailed discussion of nuclear medicine imaging modalities for both sporadic and various hereditary pheochromocytomas. In patients with VHL, functional imaging studies such as scintigraphy (nuclear medicine) or positron emission tomography (PET) scans are useful in the localization of pheochromocytomas when there is high suspicion and CT or MRI fails to detect a tumor. Imaging performance can vary on the basis of tumor location and by the genetic background. Iodine I 123 (123I)-metaiodobenzylguanidine scintigraphy coupled with CT imaging provides anatomic and functional information with good sensitivity (80%–90%) and specificity (95%–100%).[137] Other modalities such as fluorine F 18 (18F)-fluorodopa and 18F-fludeoxyglucose PET/CT are also very useful for tumor localization.[138]
Surgery
Surgical resection is the mainstay of management of pheochromocytoma in individuals with VHL. Prior to surgical resection, all patients should have a detailed endocrine evaluation and perioperative blockade. Often, medications need to be initiated and carefully titrated preoperatively to prevent potentially life-threatening cardiovascular complications. Refer to the Preoperative management section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.
Pheochromocytomas in patients with VHL may have different management than in individuals with sporadic tumors or other hereditary cancer syndromes. The incidence of bilaterality and multifocality is nearly 50% and historically many patients underwent bilateral adrenalectomy and required lifelong steroid replacement.[139] The morbidity of adrenal replacement and development of Cushing syndrome raised the interest in pursuing cortical-sparing partial adrenalectomy in this population. Even after extensive adrenal mobilization and tumor resection, the adrenal gland has extensive collateral arterial supply and venous drainage that can permit organ survival.[140] Leaving at least 15% to 30% of the residual gland volume is necessary to allow sufficient hormone production.[141] With modern techniques, the majority of glands can maintain functional cortisol production. In a solitary gland, a series demonstrated that 1 of 13 (8%) patients required lifelong steroid replacement.[142]
Leaving residual cancer behind is a concern with a partial adrenalectomy in patients with a malignant pheochromocytoma; however, in the VHL population, the malignancy rate is extremely low (<5%).[143] The local recurrence rate with partial adrenalectomy appears low (0%–33%). Therefore, when feasible and safe from an oncologic perspective, most guidelines advocate for partial adrenalectomy for the management of pheochromocytoma in VHL patients.
With total adrenalectomy, the adrenal vein is generally divided early to limit catecholamine release with gland mobilization. In a partial adrenalectomy, this can lead to venous congestion and gland compromise.[144] In a patient with an effective preoperative catecholamine block, it may be possible to only clamp the adrenal vein during the resection and unclamp it after tumor excision. The optimal amount of adjacent normal parenchyma to remove is unclear. The initial surgical approach to partial adrenalectomy described surgery for patients with tumors in the tail/head of the adrenal with amputation of that region, while tumors in the body of the adrenal had a thin rim of normal parenchyma included with the specimen. As further data have clarified the risk of malignancy and local recurrence in patients with VHL, an enucleative resection of the tumor pseudocapsule has been described that is similar to the renal tumor approach. This may maximally preserve cortical tissue and limit vascular compromise to the residual gland.[139] Concerns over a higher rate of local recurrence may limit this approach.
Both open resection and laparoscopic approaches are safe, but if feasible, laparoscopic removal is preferred.[145,146] Means of exposure and approach are based on the anatomic location of the tumor. Direct access to the adrenal and para-aortic region can be achieved with the posterior approach. It is direct, safe, and efficient.[147] Adequate exposure of the complete tumor is important for complete removal. Robotic assistance can be utilized in select cases because it offers a three-dimensional, magnified view of the anatomy.[148] With multiple abdominal procedures, a minimally invasive approach may often not be feasible because of adhesions. Open resection is commonly recommended for patients with large tumors because of the increased risk of complications owing to the surgical technical difficulty within the confined space of laparoscopy. (Refer to the Surgerysection in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for a discussion of the surgical approaches to pheochromocytoma.)
Treatment of retinal hemangioblastomas
Treatment of retinal hemangioblastomas includes laser treatment, photodynamic therapy, and vitrectomy. Efforts have also been made to use either local or systemic therapy.
Laser photocoagulation is extensively used for retinal hemangioblastomas in patients with VHL disease. A retrospective review of 304 treated retinal hemangioblastomas in 100 eyes showed that laser photocoagulation had a control rate greater than 90%, and was most effective in smaller lesions measuring up to 1 disk diameter.[149]
Twenty-one patients with severe retinal detachment achieved varying degrees of visual preservation when treated with pars plana vitrectomy with posterior hyaloid detachment, epiretinal membrane dissection, and silicone oil or gas injection with retinectomy or photocoagulation/cryotherapy to remove the retinal hemangioblastoma.[150] Pars plana vitrectomy in advanced VHL eye disease was shown to improve or preserve visual function in a second group of 23 patients, but postoperative progression of ocular VHL disease was possibly accelerated in cases where a retinotomy was performed.[151]
Photodynamic therapy reduced macular edema in a case series of two patients with bilateral retinal hemangioblastoma involvement, but with minimal, if any, benefit in visual acuity.[152] In a second series of five patients, including four with VHL disease, photodynamic therapy was performed on six eyes, resulting in tumor regression or stabilization and the improvement of subretinal fluid and lipid exudation in all cases. However, stabilization or improvement of visual acuity was observed in only 50% of the cases.[153]
Case reports of intravitreal treatment with bevacizumab resulted in stabilization for over 2 years in one case report,[154] and improvement in vision in one of five treated eyes in a second case report.[155] Intravitreal ranibizumab did not provide consistent benefit in a case series of five patients.[156] Treatment with systemic bevacizumab provided marginal, if any, benefit in individual case reports.[157,158] Treatment with sunitinib resulted in possible visual stabilization in three patients, but with significant concomitant toxicity.[159]
A case study of proton therapy of eight eyes in eight patients demonstrated resolution of macular edema in seven of eight patients, and preservation of vision in all treated eyes after a median of 84 months of follow-up.[160]
Treatment of CNS hemangioblastomas
Surgical resection of cerebellar or spinal hemangioblastomas has been the standard treatment approach. While it is generally accepted that surgical resection of tumors be performed prior to the onset of neurologic symptoms,[161] when to intervene on asymptomatic individuals varies by center and may be influenced by patient factors and tumor factors including edema, location, hydrocephalus, and growth rate. Spinal lesions are often approached posteriorly and require a laminectomy. Because patients often require multiple operations during their lifetime, removal of support can lead to progressive spinal instability requiring stabilization/fusion.[162] For cerebellar lesions, the approach depends on the lateral orientation of the tumor, but many can be approached through a midline suboccipital incision. Preoperative embolization can be performed to reduce bleeding, but this approach is dependent on surgeon preference.[163]
Because patients may have multiple tumors and require several surgical procedures, external beam radiation therapy has emerged as an alternative when surgical resection is not feasible. Stereotactic radiosurgery has become a commonly utilized approach to hemangioblastoma treatment.[164] Retrospective series have demonstrated that treatment was associated with a size reduction in more than 50% of treated lesions, with a low rate of complications.[164] A prospective study at the NCI evaluated local control of treated lesions. As tumors can have a saltatory growth pattern, long-term series may be necessary to assess the effectiveness of this modality. In this series, 33% of treated subcentimeter, asymptomatic tumors progressed during follow-up. Because of concerns of long-term local control, the authors concluded that treatment with stereotactic radiosurgery should be reserved for the treatment of tumors not amenable to surgical resection.[165] Systemic therapy for CNS hemangioblastomas with pazopanib has been used in select cases with success when surgical options were not feasible.[166,167] Use of another tyrosine kinase inhibitor, sunitinib, was shown to be ineffective for treating cerebellar or spinal hemangioblastomas in a phase II trial of 15 patients with VHL.[132] Further research is required to continue to reduce the morbidity of these benign but often problematic tumors.
Treatment of ELSTs
There are limited data on the management of ELSTs, consisting largely of case series detailing surgical management of sporadic and VHL-associated tumors. The largest series details the outcomes in 31 patients treated with surveillance and surgical resection.[168] In this retrospective analysis, complete surgical resection with preservation of hearing and vestibular function was feasible in most patients; when complete resection was achieved, the risk of recurrence was low. Because audiovestibular compromise is not dependent on tumor size and can occur with small tumors, early intervention is generally preferred. Early intervention may also minimize the risk of spread to surrounding structures and increase the probability of complete resection. Preoperative embolization was used effectively in this series in select cases to minimize the risk of perioperative morbidity and hemorrhage.
VHL in pregnancy
Two studies have examined the effect of pregnancy on hemangioblastoma progression in patients with VHL.[169,170] 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.[169] This study's findings are in contrast with a small, prospective investigation.[170] 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.[102,171-173] With increased surveillance of pathogenic variant–positive individuals, the RCC mortality rate is thought to have diminished significantly because of adherence to RCC treatment recommendations including the 3 cm rule. A Danish study compared the life expectancy of individuals with VHL disease with that of their unaffected siblings, and demonstrated a median survival of 67 years in men and 60 years in women with VHL disease. The study reported an increased hazard ratio for death of 2.25 (95% confidence interval [CI], 1.02–4.95; P = .045) in men and 8.09 (95% CI, 4.88–13.40; P < .001) in women.[174] The risk of VHL-related death decreased with younger age. Genotype did not have an effect on survival probability. The main cause of VHL disease–related death was due to complications arising from hemangioblastomas. Patients with truncating pathogenic variants benefitted more from surveillance than individuals with missense variants.
Hemangioblastomas of the CNS, although histologically benign, are a major cause of morbidity and arise anywhere along the craniospinal axis, including the brainstem.[2] Pancreatic NETs, formerly called pancreatic islet cell tumors, in some cases, may grow rapidly and metastasize to liver and bone.[171,175] 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 generally managed surgically or with thermal ablation. There is a clear unmet need for better management strategies and development of targeted systemic therapy. 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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