[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 2016, about 62,700 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to more than 14,240 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 pathogenic variants have been identified as the cause of inherited cancer risk in some RCC cancerprone families; these pathogenic variants 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] Nonrenal 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:

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.)

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]

RCC accounts for about 4% of all adult malignancies in the United States.[7] 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.[8-10] 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 RR in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma.[8] 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.[9] 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.[11] 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 cancerthan 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,[12] compared with a median age at diagnosis of 64 years in the overall population.[13]. Bilaterality and multifocality are common in most heritable RCC, except in HLRCC.

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:

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.[16] 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.[17] 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.[18]

Four major heritable renal cell cancer (RCC) syndromes (von Hippel-Lindau syndrome [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt-Hogg-Dub syndrome [BHD], and hereditary papillary renal cancer [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. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories are available for 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.)

Von Hippel-Lindau syndrome (VHL) (OMIM) is an autosomal dominant, inherited disease with a predisposition to multiple neoplasms. Germline pathogenic variants in the VHL gene predispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems. These include central nervous system (CNS) hemangioblastomas, retinal angiomas, clear cell RCCs (ccRCCs) and cysts, pheochromocytomas, cysts and neuroendocrine tumors (NETs) of the pancreas, endolymphatic sac tumors (ELSTs), and cystadenomas of the epididymis (males) and of the broad ligament (females).[1,2,13,14] 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.

The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 at cytoband 3p25-26.[15] 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 from their unaffected parent. VHL-associated tumors conform to Knudsons two-hit hypothesis,[16,17] 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 then proliferates into a tumor mass.

The prevalence of VHL has been estimated to be 1 per 35,000 and 1 per 40,000 persons in the general population.[18,19] 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 pathogenic variants 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.[20]

VHL pathogenic variants are highly penetrant and overall penetrance is greater than 90% by age 65 years.[18] Almost all carriers develop one or more types of syndrome-related neoplasms.

Each offspring of an individual with VHL has a 50% chance of inheriting the VHL pathogenic variant allele from their affected parent. The primary factors affecting the chances of developing VHL are: 1) a relative with VHL; 2) a germline pathogenic variant 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.)

There are a few highly predictive, direct genotype -phenotype correlations.[21,22]

For example, pheochromocytoma without RCC is the VHL pattern found in a large family with a single nucleotide change at position 505.[14,21,23] A similar family outside the United States was identified and found to have a common ancestor (i.e., a founder pathogenic variant).[23] However, no common ancestor was identified for several other pathogenic variants that occurred in multiple families. In general, founder pathogenic variants do not comprise a significant fraction of all VHL variants. Single nucleotide changes at position 712 and 713 are hot spots for pathogenic variants leading to pheochromocytomas.[23] Pathogenic variant types leading to clinical VHL include missense, nonsense, frameshifts, insertions, partial and complete deletions, and splice-site variants of VHL.

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 history of VHL, have been estimated to comprise about 23% of VHL kindreds.[24] 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 genotype but which arise from a single zygote.[25] If the postzygotic de novo variant affects the gonadal cell line, there is a risk of transmitting a germline variant to offspring.[24]

VHL-associated polycythemia (also known as familial erythrocytosis type 2 or Chuvash polycythemia) is a rare, autosomal recessive blood disorder caused by homozygous or pathogenic variants in VHL in which affected individuals develop abnormally high numbers of red blood cells. The affected individuals have biallelic pathogenic variants in the VHL gene. The typical VHL syndromic tumors do not occur in these affected individuals.[26-28]

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.[29]

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.[30-32] These functions are described in more detail in the following paragraphs.

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 ubiquitinated. 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-alphadominant phenotype occurs in RCC. HIF1-alpha and HIF2-alpha may preferentially upregulate Myc activity.[33] Hypoxia activated factor has been shown to increase HIF2-alpha transactivation [34] and HIF1-alpha instability.[35] Preferential loss of chromosome 14q, the locus for the HIF1-alpha gene, results in decreased levels of HIF1-alpha.[36]

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.[37] Loss of primary ciliary function results in the loss of the cells ability to maintain planar cell polarity, which results in cyst formation.[38] Loss of pVHL results in loss of the primary cilium.[39] pVHL binds to and stabilizes microtubules [40] in a glycogen synthase 3dependent fashion.[41] 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.[32]

pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL null cell lines.[30] Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to DNA damage.[42] Nuclear localization and intensity of p27 is inversely associated with tumor grade.[43] pVHL binds to, stabilizes, and transactivates p53 [44] in a phosphorylation-dependent fashion.[45] 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.[46]

Functional pVHL is needed to form an extracellular fibronectin matrix.[47] Additionally, pVHL directly binds to, phosphorylates, and regulates fibronectin.[48] Collagen IV homeostasis is also regulated by pVHL. pVHL isoforms that are collagen IV bindingincompetent demonstrated a malignant phenotype.[31]

No representative VHL animal models are currently available. Vhlh gene knockout in mice did not produce RCC or hemangioblastomas.[49] Murine homologues of the R200W-induced polycythemia in mice, phenocopying Chuvash polycythemia.[50] A R167Q homologue did not generate RCC.[51] Coordinate inactivation of Vhlh and Pten resulted in a higher rate of cyst formation, but, once again, no obvious RCC was observed.[52] The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including PBRM1,[53] SETD2,[54] and BAP1 [55] provide new avenues for developing relevant animal models of at least some VHL disease manifestations.

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. 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.[56] 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.)

Four clinical types of VHL have been described. In 1991, researchers classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma).[19] In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without RCC) and type 2B (with pheochromocytoma and RCC).[20] More recently, it was reported that VHL type 2C comprises patients with isolated pheochromocytoma without hemangioblastoma or RCC.[57] These specific VHL phenotypes are summarized below.

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.[58] 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,[59] and their rate of growth varies widely.[60] 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.[58] 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.

Enlarge

Figure 1. von Hippel-Lindau syndromeassociated renal cell cancers are characteristically multifocal and bilateral and present as a combined cystic and solid mass. Red arrow indicates a lesion with a solid and cystic component, and white arrow indicates a predominantly solid lesion.

Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[60,61] 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).[62] A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.[63]

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.[64] Retinal involvement is one of the earliest manifestations of VHL, with a mean age at onset of 35.9 years.[65] These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children younger than 10 years.[65,66]

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.[64] The median number of lesions per affected eye is approximately six.[67] Other retinal lesions in VHL can include retinal vascular hamartomas, flat vascular tumors located in the superficial aspect of the retina.[68]

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 [64] having blindness caused by various mechanisms, including secondary maculopathy, contributing to retinal detachment, or possibly directly causing retinal neurodegeneration.[69] 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.[67,70]

Hemangioblastomas are the most common disease manifestation in patients with VHL, potentially affecting more than 70% of individuals. A prospective study assessed the natural history of hemangioblastomas.[71] After a mean follow-up of 7 years, 75% of the 225 patients studied developed new lesions. 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.

Enlarge

Figure 2. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau syndrome. The left panel shows a sagittal view of brainstem and cerebellar lesions. The middle panel shows an axial view of a brainstem lesion. The right panel shows a cerebellar lesion (red arrow) with a dominant cystic component (white arrow).

Enlarge

Figure 3. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau syndrome. Multiple spinal cord hemangioblastomas are shown.

The rate of pheochromocytoma formation in the VHL patient population is 25% to 30%,[72,73] with bilaterality occurring in some patients. Of patients with VHL pheochromocytomas, 44% developed disease in both adrenal glands.[74] One study reported a mean age at onset for pheochromocytoma in VHL patients of 30 years.[2] Rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL disease,[75] and approximately two-thirds will experience physical manifestations.[72] Missense VHL gene pathogenic variants correlated with the risk of pheochromocytoma in patients with VHL,[72] with a low incidence of pheochromocytoma in patients with complete deletion of the VHL gene. 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 disease.[76]

Paragangliomas are rare in VHL patients but can occur in the head and neck or abdomen.[77] A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and 19% presented with a paraganglioma.[74]

The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas is approximately 30 years,[73,78] and patients with multiple tumors were diagnosed more than a decade earlier than patients with solitary lesions in one series (19 vs. 34 years; P < .001).[78] Diagnosis of pheochromocytoma was made in patients as young as 5 years in one cohort,[73] providing a rationale for early testing. All 21 pediatric patients with pheochromocytomas in this 273-patient cohort had elevated plasma normetanephrines.[73]

ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone.[79] 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.[79,80] Approximately 30% of VHL patients with ELSTs have bilateral lesions.[79,81]

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%).[79,80] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage.[80] 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.[79]

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.[82,83] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss and improve vestibular symptoms.[80,82]

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.[84] Papillary cystadenomas are histologically identical to epididymal cystadenomas commonly observed in males with VHL.[85] One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas in men can occur sporadically.[86] Therefore, any female with a broad ligament papillary cystadenoma should be referred for genetic counseling. These tumors are frequently cystic, and although they become large, they generally have a fairly indolent behavior.

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 disease.[87] Among symptomatic patients, the most common presentation 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.[88]

One group of investigators observed that epididymal tumorigenesis in VHL disease occurred in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells caused by developmental arrest of progenitor cells, followed by neoplastic papillary proliferation with activation/up-regulation of HIF and VEGF, associated with continuous reactive fibrovascular proliferation.[89] 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. 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.[85]

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 8 years of age.[90] 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.

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).[91] Using Southern blot analysis and/or quantitative polymerase chain reaction to detect partial or complete gene deletions will detect pathogenic variants in the remaining 28% of VHL families.[91,92] The technique has a detection rate approaching 100%.[91] Newer techniques such as array comparative genomic hybridization (array CGH) are powerful tools for identifying genomic imbalances. Anecdotal evidence exists for the utility of next-generation sequencing in cases of suspected mosaicism with a negative VHL genetic test.[93]

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 pathogenic 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.[13]

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.

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.[2,13,14]

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 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%.

Level of evidence: 5

The management of VHL has changed significantly as clinicians have learned how to best 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.[94,95] 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.[96,97] In 1995, a large, multi-institutional series demonstrated how NSS could produce excellent cancer-specific survival in patients with RCC.[98] Because of multiple reports of excellent outcomes, when feasible, NSS is now considered the surgical standard of care. Over time, the technique of NSS in this population has been refined to minimize damage to the adjacent normal parenchyma. To avoid the taking of a wide margin, enucleative resection was developed and allows the tumor and pseudocapsule to be shelled off the surrounding adjacent normal parenchyma.[99]

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 specific timing for intervention was questioned. The National Cancer Institute evaluated a specific size threshold to trigger surgical intervention. An evaluation of 52 patients treated before the largest lesion reached 3 cm demonstrated no evidence of distant metastases or need for renal replacement therapy at a median follow-up of 60 months.[60] Later 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.[100] For patients with tumors larger than 3 cm, a total of 27.3% (20 of 73) developed distant recurrence.[100] 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 more than a dozen renal tumors may be necessary.[101] The use of intraoperative ultrasound to identify and then remove smaller lesions may delay the need for further surgical interventions.[102]

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 is still 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 functional outcomes and provide promising oncologic outcomes at intermediate follow-up.[103,104] These surgeries may be best handled at a specialized center with significant experience with this surgical approach.[105]

Level of evidence: 3di

Thermal ablative techniques utilize either heating or cooling of a mass in an effort to destroy the tumor. Cryoablation (CA) and radiofrequency ablation (RFA) were introduced into the management of small renal masses in the late 1990s.[106,107] For sporadic renal masses, both thermal ablative techniques have a nearly 90% recurrence-free survival rate, leading the American Urologic Association to consider this as a recommendation in high-risk patients with a small renal mass.[108] For patients with VHL, the clinical applications of ablative techniques are still not clearly defined, and surgery is still 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.[109] Since this time, some centers have utilized thermal ablative techniques for primary and salvage management in patients with VHL with good success.[110] Other centers have found that techniques such as RFA have a higher failure rate and should be reserved for patients with marginal renal function.[111] 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.[112]

Thermal ablation may play an increasing role in the salvage therapy setting for individuals with a high risk of morbidity from surgery. Cryoablation 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 treated.[113] 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.[114-116] In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management.[105,117]

The clinical applications of ablative techniques in VHL are still not clearly defined, and surgery is still 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. Irreversible coagulopathy is widely accepted as an absolute contraindication.[118,119]

Level of evidence: 3di

A 2011 study prospectively evaluated the safety and efficacy of sunitinib in VHL patients.[120] 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.[120] A retrospective study of 14 patients with VHL, 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 hemangioblastomas.[121]

Case series and individual case reports have been published on an oral antiangiogenic agent, SU5416, in patients with VHL.[122-124] Modest improvement was observed in patients with retinal hemangioblastomas.[122,123] In a series of six VHL patients treated with SU5416, stabilization in CNS hemangioblastomas was observed in two patients.[124] A study of intravitreally administered antivascular endothelial growth factor therapy for a patient with retinal hemangioma yielded mixed results.[125] SU5416 is not licensed for human use.

Level of evidence: 2

Two studies suggest that pregnancy is associated with hemangioblastoma progression in patients with VHL.[126,127] 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.[126] This study's findings are in contrast with a small, prospective investigation.[127] Until a large-scale, international, prospective investigation is conducted, all investigations suggest using a conservative approach that includes medical surveillance during pregnancy.

Morbidity and mortality in VHL vary and are influenced by the individual and the familys 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.[90,128-130] With increased surveillance of pathogenic variantpositive 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.[2] Pancreatic NETs, formerly called pancreatic islet cell tumors, in some cases, may grow rapidly and metastasize to liver and bone.[128,131] 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.

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.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) (OMIM) is characterized by the presence of one or more of the following: cutaneous leiomyomas (or leiomyomata), uterine leiomyomas (fibroids) in females, and RCC. Germline pathogenic variants in the fumarate hydratase (FH) gene are responsible for the susceptibility to HLRCC. FH encodes fumarate hydratase, the enzyme that catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle (Krebs cycle).

Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis. In 1973, two kindreds were described in which multiple members over three generations exhibited cutaneous leiomyomas and uterine leiomyomas and/or leiomyosarcomas inherited in an autosomal dominant pattern.[132] That report also described a woman aged 20 years with uterine leiomyosarcoma and metastatic RCC. Subsequently, the association of cutaneous and uterine leiomyomas became known as Reed syndrome. However, the clear association of cutaneous leiomyomas and RCC was not described until 2001, when a study reported two Finnish families in whom cutaneous and uterine leiomyomas and papillary type 2 RCC co-segregated.[3] The name hereditary leiomyomatosis and renal cell cancer was then assigned. The term HLRCC is preferred because it is impossible to distinguish between individuals with cutaneous leiomyomas who do or do not have an increased risk of renal cancer.

The FH gene consists of ten exons encompassing 22.15 kb of DNA. The gene is highly conserved across species. The human FH gene is located on chromosome 1q42.3-43.

HLRCC is an autosomal dominant syndrome; a single variant FH allele is sufficient to cause the disease.[133] Inherited biallelic pathogenic variants cause fumarate hydratase deficiency (FHD), a disorder characterized by rapidly progressive neonatal neurologic impairment including hypotonia, seizures, and cerebral atrophy. (Refer to the Genetically related disorders section of this summary for more information.)

Germline pathogenic variants in FH, plus somatic variants and loss of heterozygosity (LOH) in RCC, suggest that loss of function in the fumarate hydratase protein is the basis of tumor formation in HLRCC and, further, that FH functions as a tumor suppressor gene.[3,134]

Various pathogenic variants in FH have been identified in families with HLRCC. Most are missense pathogenic variants, but nonsense, frameshift, and splice-site variants have been described.[5,6,134,135] Recently, whole-gene or partial deletions have been identified.

The prevalence of HLRCC is unknown. It is estimated that more than 100 families with HLRCC have been seen at the National Institutes of Health, but it is likely that HLRCC remains an underrecognized entity (R. Srinivasan, MD, PhD, oral communication, April 2014).

Considering the three major clinical manifestations combined, the penetrance of HLRCC is considered to be very high. However, the estimated cumulative incidence of RCC varies widely, from between 2% and 7% to 15%, and perhaps as high as 32%, in families with germline FH pathogenic variants, depending on ascertainment method and the imaging modalities used.[3-6,136]

No genotype-phenotype correlations have been described. Thus, no correlation has been observed between specific FH variants and the occurrence of cutaneous lesions, uterine leiomyomas, or RCC in HLRCC.[6]

Although smaller studies have suggested the presence of different variant spectra in FHD and HLRCC,[5,134] a study that included a larger cohort of patients indicated that the variant distribution is fairly similar in these two entities.[133] The predisposition to HLRCC versus FHD likely results from a difference in gene dosage, rather than the location of the FH variant as originally suggested.[134]

Between 80% and 100% of individuals with HLRCC have identifiable, deleterious sequence alterations in FH.[5,6,137]

FHD, resulting from the inheritance of biallelic pathogenic variants in FH, is an autosomal recessive inborn error of metabolism characterized by rapidly progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy. Homozygous or compound heterozygous germline pathogenic variants in FH are found in individuals with FHD.[138,139] To date, RCC has not been reported in FHD-affected individuals. Most individuals with FHD survive only a few months; very few survive to early adulthood.[140] However, a parent (heterozygous carrier) of an individual with FHD developed cutaneous leiomyomas similar to those observed in HLRCC.[134]

LOH around the FH locus has been identified in two early-onset sporadic uterine leiomyomas and a soft tissue sarcoma of the lower limb without other associated tumor characteristics of the heritable disease.[141,142] All three tumors displayed biallelic inactivation of FH. In sporadic forms of kidney cancer, there have been no somatic pathogenic variants identified in FH to date.[141]

The mechanisms by which alterations in FH lead to HLRCC are still being elucidated. Biallelic inactivation of FH has been shown to result in loss of oxidative phosphorylation and reliance on aerobic glycolysis to meet cellular energy requirements. Blockage of the Krebs cycle at FH results in increased levels of intracellular fumarate, inhibiting HIF prolyl hydroxylases. Inactivating variants of FH also appear to result in the generation of reactive oxygen species, further contributing to the stabilization of HIF.[143] This upregulation of the HIF pathway leads to a pseudohypoxic state and upregulation of a transcriptional program contributing to aggressive tumor biology.[144] Others have demonstrated upregulation of the antioxidant response pathway due to posttranslational modification of KEAP1. The resultant NRF-2 dysregulation leads to upregulation of antioxidant response elementcontrolled genes such as aldo-keto reductase family 1 member, B10 (AKR1B10), possibly contributing to the neoplastic process.[145]

The clinical characteristics of HLRCC include cutaneous leiomyomas, uterine leiomyomas (fibroids), and RCC. Affected individuals may have multiple cutaneous leiomyomas, a single skin leiomyoma, or no cutaneous lesion; an RCC that is typically solitary, or no renal tumors; and/or uterine leiomyomas. Disease severity shows significant intrafamilial and interfamilial variation.[3,5,6]

Cutaneous leiomyomas present as firm pink or reddish-brown papules and nodules distributed over the trunk and extremities and, occasionally, on the face. These lesions occur at a mean age of 25 years (age range, 1047 years) and tend to increase in size and number with age. Lesions are sensitive to light touch and/or cold temperature and are, less commonly, painful. Pain is correlated with severity of cutaneous involvement.[5] The presence of multiple cutaneous leiomyomas is associated with HLRCC until proven otherwise and should prompt a genetic workup; a solitary leiomyoma requires careful analysis of family history. (Refer to the Clinical diagnosis and Differential diagnosis sections below for more information.)

The onset of uterine leiomyomas in women with HLRCC occurs at a younger age than in women in the general population. The age at diagnosis ranges from 18 to 52 years (mean age, 30 years). Uterine leiomyomas are usually large and numerous. Most women experience symptoms including irregular or heavy menstruation and pelvic pain, thus requiring treatment at a younger age than females with leiomyomas in the general population. Women with HLRCC and uterine leiomyomas undergo hysterectomy or myomectomy for symptomatic uterine leiomyomas at a younger age (<30 years) than do women in the general population (median age, 45 years).[5,137,146,147]

The symptoms of RCC may include hematuria, lower back pain, and a palpable mass. However, a large number of individuals with RCC are asymptomatic. Furthermore, not all individuals with HLRCC present with or develop RCC. Most RCCs are unilateral and solitary; in a few individuals, they are multifocal. Approximately 10% to 32% of individuals with HLRCC who presented with multiple cutaneous leiomyomas had RCC at the time that renal imaging was performed.[5,137] The median age at detection of RCC was 37 years,[148] although some cases have been reported to occur as early as age 10 years.[149] In contrast to other hereditary renal cancer syndromes, RCCs associated with HLRCC are aggressive,[150,151] with Fuhrman nuclear grade 3 or 4 in many cases and 9 of 13 individuals dying from metastatic disease within 5 years of diagnosis.[5] Figure 4 depicts RCCs in a patient with HLRCC.

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