Von Hippel-Lindau disease (VHL) is an autosomal dominant disease with a predisposition to multiple neoplasms. Germline pathogenic variants in the VHLgene predispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems. These include central nervous system hemangioblastomas; retinal hemangioblastomas; clear cell renal cell carcinomas and renal cysts; pheochromocytomas, cysts, cystadenomas, and neuroendocrine tumors of the pancreas; endolymphatic sac tumors; and cystadenomas of the epididymis (males) and of the broad ligament (females).[1,2,3,4] 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.
The VHLgene is a tumor suppressor gene located on the short arm of chromosome 3 at cytoband 3p25-26.VHLpathogenic 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 an unaffected parent. Von Hippel-Lindau disease (VHL)-associated tumors conform to Knudson's "two-hit" hypothesis,[2,3] in which the clonal origin, or the first transformed cell of the tumor, occurs only after both VHLalleles are inactivated in a cell. 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 mutation, one that occurs in a specific tissue at some point after a person's birth. It damages the normal, or wild-type, VHL allele, creating a clonal neoplastic cell of origin, which 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.[4,5,6] The prevalence is estimated to be between 1 in 31,000 to 1 in 91,000 individuals.[5,6,7,8] Precise quantification of this number is a challenge because it requires comprehensive screening of potentially at-risk blood relatives of individuals diagnosed with VHL. 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
VHL pathogenic variants are highly penetrant, with manifestations found in more than 90% of carriers by age 65 years. Almost all carriers develop one or more types of VHL-related neoplasms.
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.)
Specific pathogenic variant types leading to VHL clinical manifestations include missense, nonsense, frameshifts, insertions, partial and complete deletions, and splice-site variants of VHL. The specific alteration may influence clinical manifestations. Two major clinical phenotypes of VHL have been described. Type 1, commonly associated with large gene deletions, is characterized by the development of all VHL-associated lesions except pheochromocytoma. Type 2, more commonly associated with missense variants, is characterized by the development of all clinical manifestations including pheochromocytoma. Type 2 clinical phenotype is subdivided into type 2A (low risk of renal cell carcinoma [RCC]), type 2B (high risk of RCC), and type 2C (no RCC development, where the predominant clinical picture is characterized by central nervous system hemangioblastoma and pheochromocytoma development). Overall, the risk of RCC correlates with the loss of hypoxia-inducible factor (HIF)2-alpha regulation by the specific VHLgermline variant.[9,10,11,12] 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 history of VHL, have been estimated to comprise about 23% of VHL kindreds. 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 occurs when two or more cell lines in an individual differ by genotype; these differing cell lines all arise from the same zygote. If the postzygotic de novo variant affects the gonadal cell line, there is a risk of transmitting a germline variant to offspring.
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.[15,16,17]
Other Genetic Alterations
In sporadic RCC, mutational inactivation of the VHL gene is the most frequent molecular event. In addition to VHL inactivation, sporadic clear cell renal cell carcinoma (ccRCC) tumors harbor frequent variants in other genes, including PBRM1, SETD2, and BAP1.[18,19] 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.[20,19] Germline pathogenic variants in PBRM1 and BAP1 result in the development of hereditary forms of ccRCC. The role of PBRM1, BAP1, and SETD2 in VHL-related ccRCC growth and progression is under investigation.
The VHLtumor suppressor gene encodes two proteins: a 213 amino acid protein (pVHL30) and a 154 amino acid protein, which is the product of internal translation. pVHL is best known for its regulation of hypoxia-inducible factor (HIF) activity, which is linked to tumor suppression. Other reported functions of pVHL include regulation of extracellular matrix formation, microtubule and centrosome maturation, and p53 inactivation.[2,3,4,5] 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. 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.[6,7]
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.
HIF1-alpha and HIF2-alpha possess distinct and partially contrasting functional characteristics. In the context of renal cell carcinoma (RCC), it appears that the EPAS1 gene, also known as HIF2A, acts as an oncogene, and HIF1A acts as a tumor suppressor gene. HIF2-alpha may preferentially upregulate Myc activity, whereas HIF1-alpha may inhibit Myc activity. Hypoxia-associated factor has been shown to increase HIF2-alpha transactivation  and HIF1-alpha instability. Preferential loss of chromosome 14q, the locus for the HIF1A gene, results in decreased levels of HIF1-alpha protein.
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 von Hippel-Lindau disease (VHL)-related malignancies.[13,14,15] Specific HIF2-alpha inhibitors are in preclinical and clinical testing.[16,17,18]
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, regulates cell signaling, and controls cellular entry into mitosis. The loss of primary ciliary function results in the loss of the cell's ability to maintain planar cell polarity; thus ultimately results in cyst formation. The loss of pVHL results in the loss of the primary cilium. pVHL binds to and stabilizes microtubules  in a glycogen synthase 3–dependent fashion. The 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.
Cell Cycle Control
pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL-null cell lines. Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to DNA damage. Nuclear localization and intensity of p27 is inversely associated with tumor grade. pVHL binds to  and facilitates phosphorylation of p53 in an ATM-dependent fashion.
Extracellular Matrix Control
Functional pVHL is needed for appropriate assembly of an extracellular fibronectin matrix. Additionally, phosphorylation of pVHL regulates binding of fibronectin and secretion into the extracellular space.
Regulation of Oncogenic Autophagy
In clear cell renal cell carcinoma (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.[30,31]
Animal Models of VHL
Vhl-knockout mice die in utero. Heterozygous Vhl mice develop vascular liver lesions reminiscent of hemangioblastomas. Conditional targeted inactivation of the Vhl gene in the mouse kidney results in the generation of VHL-resembling cysts but not RCC. Coordinate inactivation of Vhl and Pten results in a higher rate of cyst formation, but no obvious RCC. Murine homologues of the Vhl R200W pathogenic variant induced polycythemia in mice, phenocopying Chuvash polycythemia. The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including PBRM1,SETD2, and BAP1, provide new avenues for developing relevant animal models of at least some VHL manifestations.
Age Ranges and Cumulative Risk of Different Syndrome-related Neoplasms
The age of onset for von Hippel-Lindau disease (VHL) varies both between different families and between members of the same family. This fact informs the guidelines for starting age and frequency of presymptomatic surveillance examinations. Of all VHL manifestations, retinal hemangioblastomas and pheochromocytomas have the youngest age of onset; hence, 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. Examples of reported mean ages and age ranges of VHL clinical manifestations are summarized in Table 1.
|Neoplasm||Mean Age (Range) in y||Cumulative Risk (%)|
|a Adapted from Choyke et al.and Lonser et al.|
|b Limited data are available for cystadenomas of the broad/round ligament and epididymis.|
|Renal cell carcinoma||37 (16–67)||24–45|
|Pancreatic tumor or cyst||36 (5–70)||35–70|
|Retinal hemangioblastoma||25 (1–67)||25–60|
|Cerebellar hemangioblastoma||33 (9–78)||44–72|
|Brainstem hemangioblastoma||32 (12–46)||10–25|
|Spinal cord hemangioblastoma||33 (12–66)||13–50|
|Endolymphatic sac tumor||22 (12–50)||10|
(Refer to the Clinical diagnosis section of this summary for more information.)
VHL Familial Phenotypes
Four clinical types of VHL have been described. In 1991, researchers classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma). In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without renal cell carcinoma [RCC]) and type 2B (with pheochromocytoma and RCC). In 2001, VHL type 2C (with isolated pheochromocytoma, but without hemangioblastoma or RCC) was reported. These specific VHL phenotypes are summarized in Table 2.
|RCC = renal cell carcinoma.|
|a Each of the VHL subtypes can include other manifestations, such as central nervous system hemangioblastomas; retinal hemangioblastomas; renal cysts; cysts, cystadenomas, and neuroendocrine tumors of the pancreas; endolymphatic sac tumors; and cystadenomas of the epididymis (males) and of the broad ligament (females).|
|1||Absence of pheochromocytomas|
|Low risk of RCC|
|High risk of RCC|
|Absence of RCC|
More than 55% of von Hippel-Lindau disease (VHL)-affected individuals only develop multiple renal cell cysts. The VHL-associated renal cell carcinomas (RCCs) that occur are characteristically multifocal and bilateral; these RCCs present as combined cystic and solid masses. Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall. In VHL, RCCs smaller than 3 cm tend to be low grade (Fuhrman nuclear grade 2) and minimally invasive; however, their growth rate varies widely. 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. Complex cystic and solid lesions contained neoplastic tissue that was uniformly enlarged. These data may be used to help predict the progression of renal lesions in patients with VHL. Figure 1 depicts bilateral renal tumors in a patient with VHL.
Figure 1. von Hippel-Lindau disease–associated 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.
Patients can also develop pancreatic cysts, cystadenomas, and pancreatic neuroendocrine tumors (NETs). 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). A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.
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. Retinal involvement is one of the earliest manifestations of VHL, with a mean age of onset at 25 years.[5,9] These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children as young as 1 year.[5,10,11]Sporadic retinal hemangioblastomas are rare; one registry study reported that 84% of these tumors were associated with VHL.
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 bright orange spherical tumors supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas. The median number of lesions per affected eye is approximately six. Other retinal lesions in patients with VHL can include retinal vascular hamartomas and flat vascular tumors located in the superficial aspect of the retina.
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 patients with VHL. Approximately 8% of patients  will develop blindness caused by various mechanisms like secondary maculopathy; this can contribute to retinal detachment or directly cause retinal neurodegeneration. Patients with symptomatic lesions will generally have a greater number of retinal hemangioblastomas, which will often be larger in size. Long-term follow-up studies demonstrate that most lesions grow slowly and that new lesions do not develop frequently.[13,16]
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. The mean age at onset of central nervous system (CNS) hemangioblastomas is 29.1 years (range, 7–73 y). CNS hemangioblastomas were most commonly seen in the cerebellum (45%), spinal cord (36%), cauda equina (11%), and brain stem (7%). While sporadic hemangioblastomas are generally solitary in nature, the VHL-associated CNS lesions are often multifocal. After a mean follow-up of 7 years, 72% of the 225 patients studied developed new lesions. Figures 2 and 3 depict cerebellar and spinal hemangioblastomas, respectively, in patients with VHL.
Figure 2. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau disease. 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).
Figure 3. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau disease. Multiple spinal cord hemangioblastomas are shown.
Pheochromocytomas and Paragangliomas
The rate of pheochromocytoma formation in the VHL patient population is 25% to 30%.[20,21] Of patients with VHL-associated pheochromocytomas, 44% developed disease in both adrenal glands. The rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL, and approximately two-thirds will experience physical manifestations such as hypertension, tachycardia, and palpitations. Patients with a partial loss of VHL function (type 2 disease) are at a higher risk of developing pheochromocytomas than VHL patients with a complete loss of VHL function (type 1 disease); the latter develop pheochromocytoma very rarely.[20,24,25,26] In a cohort of 182 patients with pheochromocytomas and paragangliomas that were not associated with a VHL diagnosis, only one patient had a VHLgermline pathogenic variant.
Paragangliomas are rare in VHL patients but can occur in the head and neck or in the abdomen. A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and only 19% presented with a paraganglioma.
The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas is approximately 30 years.[21,29] 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). Diagnosis of pheochromocytoma was made in patients as young as age 5 years in one cohort, providing a rationale for early testing. All 21 pediatric patients with pheochromocytomas in this 273-patient cohort had elevated plasma normetanephrines.
VHL patients may develop multiple serous cystadenomas, pancreatic NETs, and simple pancreatic cysts. VHL patients do not have an increased risk of pancreatic adenocarcinoma. Serous cystadenomas are benign tumors and warrant no intervention. VHL patients can develop many pancreatic cysts, but these rarely cause symptomatic biliary duct obstruction. Endocrine function is nearly always maintained; however, patients with extensive cystic disease may require pancreatic surgery and pancreatic exocrine supplementation.
Pancreatic NETs are usually nonfunctional, but they can metastasize (to the lymph nodes and the liver). The risk of pancreatic NET metastasis was analyzed in a large cohort of patients, in which the mean age of pancreatic NET diagnosis was 38 years (range, 16–68 y). 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 monitored 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. 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.[31,32] Approximately 30% of VHL patients with ELSTs have bilateral lesions.[31,33]
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%).[31,32] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage. 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.
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.[34,35] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss; this procedure can also improve vestibular symptoms.[32,34]
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. Papillary cystadenomas are histologically identical to epididymal cystadenomas, which are commonly observed in males with VHL. One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas can occur sporadically. These tumors are frequently cystic, and although they can become large, they generally have fairly indolent behavior.
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. These well-circumscribed lesions have variable amounts of cystic and papillary components that are lined with epithelial cuboidal or columnar clear cells. 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.
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.
Risk Assessment for von Hippel-Lindau Disease (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, as early as age 8 years. Gender-specific VHL clinical findings include epididymal cystadenoma in males (10%–26%), which are virtually pathognomonic for VHL, especially when bilateral; these are also 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. Females have histologically similar lesions to cystadenomas that occur in the broad ligament.
Each offspring of an individual with VHL has a 50% chance of inheriting the VHLvariant 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 central nervous system [CNS] or retina, pheochromocytoma, or clear cell renal cell carcinoma [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 VHLgene (~72% of all pathogenic variants).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.
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, this person's 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 VHL manifestations. Equally important, the children of true-negative family members are not at risk of VHL either. Clinical testing throughout their lifetime is therefore unnecessary.
A germline pathogenic variant in the VHL gene is considered a genetic diagnosis. Hence, it predisposes an individual 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. Cases can present where an individual meets VHL clinical criteria for diagnosis, but this individual does not test positive for a VHL pathogenic variant; when these individuals also do not have family history of VHL, 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 (refer to Table 3). If there is family history of VHL, then a previously unevaluated family member may be clinically diagnosed if this person presents 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 has two or more CNS hemangioblastomas or one CNS hemangioblastoma and a visceral tumor or endolymphatic sac tumor. Refer to Table 3 for more diagnostic details.[5,6,7]
In 1998, all germline pathogenic variants identified in a cohort of 93 VHL families were reported. Since then, VHL diagnosis has based on a combination of clinical manifestations and genetic testing for VHL pathogenic variants identified within families. The diagnostic strategy differs among individual family members. Table 3 summarizes a combined approach of genetic testing and clinical diagnosis.
|Family History of VHL||Genetic Testing||Clinical Diagnosis||Requirements for Clinical Diagnosis|
|CNS = central nervous system; ccRCC = clear cell renal cell carcinoma.|
|Adapted and updated from Glenn et al.and Pithukpakorn and Glenn.|
|With a family history of VHL||Test DNA for the sameVHLgene pathogenic variant as previously identified in affected biologic relative(s)||WhenVHLgene pathogenic variant is unknown for a biologic relative||One or more of the following is required for a clinical diagnosis:|
|- Epididymal or broad ligament cystadenomas|
|- CNS hemangioblastoma|
|- ccRCC, multifocal|
|- Retinal hemangioblastomas|
|- Pancreatic neuroendocrine tumor|
|- Pancreatic cysts and/or cystadenomas|
|- Endolymphatic sac tumor|
|Without a family history of VHL||May be negative if theVHLpathogenic variant occurred postzygotically (e.g.,VHLmosaicism)||WhenVHLpathogenic variant is unknown or germline negative, but there are clinical signs compatible for VHL||Either or both of the following are required for a clinical diagnosis:|
|- CNS hemangioblastoma|
|- Retinal hemangioblastomas|
|If only one of the above is present, then also one of the following:|
|- Pancreatic cysts and/or cystadenomas|
|- Endolymphatic sac tumor|
|- Epididymal or broad ligament cystadenomas|
Screening for Early Detection of Disease Manifestations
Screening guidelines that have been suggested for various manifestations of VHL are summarized in Table 4. 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 neoplasms. Periodic presymptomatic screening is advised for at-risk individuals. At-risk individuals include those who tested positive for a VHL pathogenic variant and those who chose not to be tested for a VHL pathogenic variant but have biologic relatives with VHL. The risk of inheriting a VHL pathogenic variant in such persons may be as high as 50%.
|Examination/Test||Condition Screened For||Starting Age/Frequencya|
|CNS = central nervous system; CT = computed tomography; IACs = internal auditory canals; MRI = magnetic resonance imaging.|
|a Frequencies of exams or tests may be increased at organ sites of VHL lesions being monitored.|
|b Brain MRIs may be used to examine areas of the IACs for signs of endolymphatic sac tumors (ELSTs). If signs or symptoms of ELSTs are present, examine IACs by CT and MRI.|
|Adapted from VHL Alliance.|
|Ophthalmoscopy||Retinal hemangioblastoma||Annually from age 1 y|
|Plasma or 24-hour urinary catecholamines and metanephrines||Pheochromocytoma||From age 5 y; annually and as clinically indicated when blood pressure is elevated|
|Enhanced MRI of brain/spineb||CNS and peripheral hemangioblastoma||From age 16 y; every 2 y and if symptoms appear|
|MRI of abdomen with and without contrast||Renal, pancreatic, and adrenal neoplasms and cysts||From age 16 y; annually alternating with ultrasound|
|Ultrasound of abdomen||Renal, pancreatic, and adrenal neoplasms and cysts||From age 16 y; annually alternating with MRI|
|Audiology; MRI and CT of IACs; neurology||Endolymphatic sac tumor||Audiology from age 5 y; every 2–3 y or annually if hearing loss, tinnitus, or vertigo. Imaging as needed at any age for hearing loss, tinnitus, vertigo. Annual neurological assessment from age 5 y|
Level of evidence: 5
Treatment of Disease Manifestations
Treatment of renal tumors
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.[9,10] Nephron-sparing surgery (NSS) was introduced in the 1980s for VHL after several groups demonstrated a low risk of cancer dissemination with a less-radical surgical approach.[11,12] In 1995, a large multi-institutional series demonstrated how NSS could produce excellent cancer-specific survival in patients with renal cell carcinoma (RCC). Because of multiple reports of excellent outcomes, NSS is now considered the surgical standard of care when technically feasible. Over time, NSS technique has been refined for VHL patients in order to minimize damage to the adjacent normal parenchyma. In traditional NSS, a wide margin of tissue is taken; however, in a newer type of NSS, called enucleation, much of the adjacent normal parenchyma can be preserved.
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. Subsequent retrospective series reinforced the importance of this 3 cm threshold: in one study, none of the 108 patients showed evidence of distant spread when tumors were managed at 3 cm or smaller. In patients with tumors larger than 3 cm, 27.3% (20 of 73) developed distant recurrence. This threshold is now widely used in the United States to trigger surgical intervention for VHL-associated ccRCC, although some international groups have published data supporting active surveillance of tumors smaller than 4 cm.[17,18,19,20] 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. The use of intraoperative ultrasound is helpful to identify and remove smaller lesions.
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 and provide promising oncologic outcomes at intermediate follow-up.[23,24] These surgeries may be best handled at a specialized center with significant experience with the management of hereditary forms of kidney cancer.
Level of evidence: 3di
Radiofrequency ablation (RFA) and cryoablation (CA)
Thermal ablative techniques utilize either extreme heating or cooling of a mass to destroy it. CA and RFA were introduced into the management of small renal masses in the late 1990s.[26,27] For sporadic renal masses, both thermal ablative techniques achieved 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). 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 to VHL-associated RCC management 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. Since that time, some centers have successfully utilized thermal ablative techniques for primary and salvage management in patients with VHL. Other centers have found that techniques such as RFA have a higher failure rate and should be reserved for patients with marginal renal function. 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.
Thermal ablation may play an increasing role in the salvage therapy setting for individuals with a high risk of morbidity from surgery. CA was evaluated as a salvage therapy 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%). However, it must be cautioned that surgery after thermal ablation is a very challenging endeavor, with a significantly higher rate of postoperative complications because of adhesions and scarring, especially along the tract of the ablative probes.[34,35,36] In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management.[25,37]
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 for thermal ablation.[38,39]
Level of evidence: 3di
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. Many groups are interested in systemic therapies that can limit the development or progression of VHL manifestations.
A 2011 prospective study evaluated the safety and efficacy of sunitinib in VHL patients. 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. Fatigue, as a grade 3 toxicity, was observed in five patients (33%); dose reductions were made in ten patients (75%). A significant response was observed in RCC but not in hemangioblastoma. Among the 18 evaluable RCC lesions and the 21 evaluable hemangioblastoma lesions, 6 RCC lesions (33%) achieved partial responses while none of the hemangioblastoma lesions did (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 tissue, thus raising the hypothesis that treatment with fibroblast growth factor pathway–blocking agents may benefit patients with hemangioblastoma. A retrospective study of 14 VHL patients with RCC, 10 of whom had metastatic disease, demonstrated significant response to sunitinib in patients with metastatic and primary RCC lesions. Eleven patients had cerebellar hemangioblastomas, and eight had spinal hemangioblastomas. No response was seen in patients with hemangioblastomas.
A study of intravitreally administered pegaptanib, an anti-VEGF therapy, was evaluated in five patients with VHL-associated retinal hemangioblastomas. 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.
Level of evidence: 2
Treatment of pheochromocytomas
Surveillance of pheochromocytomas
Pheochromocytomas can be a source of significant morbidity in patients with VHL because of the cardiovascular effects of excess catecholamines. In individuals that undergo surgery or childbirth without proper medical management, the results can be catastrophic as a result of 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 4. Assessment of catecholamines/metanephrines and cross-sectional abdominal imaging are key to early detection.
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 4). Clinicians have the option of performing plasma testing, urinary testing, or both. The levels of catecholamines can greatly vary as a result of diet and medications; measurement of their metabolites, metanephrines, is suggested because of higher performance metrics. A fourfold, or greater, elevation of metanephrines is suggestive of the presence of a pheochromocytoma or paraganglioma. Individuals with VHL pheochromocytomas often have isolated normetanephrines while other endocrine syndromes show a different functional profile. 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 and methods of biochemical testing for pheochromocytomas.
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%. Additional imaging studies may be of clinical utility when there is clinical suspicion based on biochemical studies and there are no lesions visible. While most tumors arising from chromaffin tissue in VHL are pheochromocytomas, paragangliomas can also occur in the chest, abdomen, pelvis, and head and neck. 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 locating 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%). Other modalities such as fluorine F 18 (18F)-fluorodopa and 18F-fludeoxyglucose PET/CT are also very useful for tumor localization.
Surgical resection is the mainstay of management for pheochromocytoma in individuals with VHL. Prior to surgical resection, it is important that all patients have a detailed endocrine evaluation and preoperative alpha-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. 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. Leaving at least 15% to 30% of the residual gland volume is necessary to allow sufficient hormone production. With modern techniques, the majority of glands can maintain functional cortisol production after cortical-sparing partial adrenalectomy. In a solitary gland, a series demonstrated that 1 of 13 (8%) patients required lifelong steroid replacement.
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%). 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.
In a 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. 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 gland with amputation of that region, while tumors in the body of the adrenal gland had a thin rim of normal parenchyma included with the resection 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, which is similar to the approach of renal tumor enucleation. This may maximally preserve cortical tissue and limit vascular compromise to the residual gland. 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.[54,55] 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. 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. 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 from laparoscopy, which is technically difficult to perform within the confined space. (Refer to the Surgery section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for a discussion of the surgical approaches to pheochromocytoma.)
Treatment of pancreatic manifestations
VHL-related tumors such as pancreatic neuroendocrine tumors (NETs) may be identified during incidental imaging or during lifelong surveillance protocols.[58,59] One study reported that 15% of patients with VHL developed pancreatic NETs. The clinical characteristics of the pancreatic lesions (cystic vs. solid, symptomatic vs. asymptomatic, size) determine whether patients are eligible for conservative management with imaging surveillance or whether they require surgical intervention.
Workup and imaging
Pancreatic cysts are benign and rarely require any intervention. Pancreatic cysts in VHL demonstrate no enhancement in imaging and have no malignant potential regardless of size. Diffuse cystic disease rarely affects endocrine function. Infrequently, cystic replacement of the normal pancreas can lead to loss of exocrine function. When bloating, cramping, diarrhea, or abdominal pain occurs with fatty meals, enzymatic studies on the stool could be employed to determine if exocrine supplementation is indicated. Solid or mixed pancreatic lesions require specialized evaluation and treatment as they may represent cystadenomas or pancreatic NETs. The majority of pancreatic NETs are nonfunctional but laboratory evaluation with biochemical markers such as chromogranin A could be considered during the workup or during follow-up. Imaging evaluation with a contrast-enhanced CT or MRI are both excellent modalities to characterize pancreatic lesions. Gallium Ga 68-DOTATATE PET/CT has also been used in the detection of VHL-associated tumors. The performance metrics may depend on the lesion size and optimization of the timing of contrast administration. Functional imaging with nuclear medicine modalities may be useful with inconclusive cross-sectional imaging, to diagnose metastatic disease, or to distinguish solid microcystic adenomas versus solid pancreatic NETs. Endoscopic ultrasound is a highly sensitive modality; this procedure may be offered when intravenous contrast cannot be given or when there is concern that a lesion represents a solid microcystic serous adenoma, rather than a cancer. Tissue sampling can be performed during an endoscopic procedure but is rarely indicated.
Surveillance of pancreatic manifestations
Serous cystadenomas do not have malignant potential and can be safely observed. Local obstruction of the bile or pancreatic duct is rare. Solid pancreatic NETs have low metastatic potential and if localized, small, and asymptomatic, can be safely observed without concerns. The duration and modality for imaging is center dependent, but the general principles are to perform imaging every 1 to 2 years with the same examination method to allow meaningful comparisons. Lesions with slow doubling times, sizes less than 3 cm, and no exon 3 pathogenic variants have the most favorable outcomes. In a review of 175 VHL patients with pancreatic NETs, patients with tumors less than 1.2 cm in diameter did not develop metastases or need surgery. Patients with larger tumors (1.2–3 cm in diameter) with a missense variant in VHL, as opposed to other variant types, were more likely to develop metastases or require surgical invention. Tumor size, variant type, and exon location may eventually play a role in determining surveillance in VHL patients.
Pancreatic cysts rarely need intervention except when exerting a mass effect. Aspiration or decortication can be considered in these rare cases. Indications for surgery for pancreatic NETs can vary, but intervention is offered to lower the risk of dissemination. Tumor enucleation is safe and effective if the lesion is away from the pancreatic duct. Lesions in the body or tail of the pancreas are removed when they are 3 cm or larger in diameter. If it is not safe to enucleate, a distal pancreatectomy is performed. Tumors of the head that are 2 cm or larger are also evaluated for resection, as larger lesions in this location are more challenging to enucleate. If there is concern with regards to the location of the pancreatic duct, a Whipple procedure is offered. For rare situations where there are large multifocal lesions, a total pancreatectomy could be considered. After surgery, if patients develop exocrine dysfunction, enzyme supplementation may improve gastrointestinal symptoms and nutritional status.
Positive lymph nodes should be removed when found at the time of surgery. For individuals with locally advanced or metastatic pancreatic NETs, surgery is still considered if significant debulking can be offered. Metastatic liver lesions can often be treated with local ablative techniques or resection in select VHL patients.
In the setting of locally advanced or metastatic pancreatic NETs, the systemic medical treatments for VHL-related pancreatic NETs are primarily extrapolated from studies in sporadic pancreatic NETs. Specifically, VEGF inhibitors, such as sunitinib and pazopanib, have been described in VHL-related pancreatic NETs. Retrospective case studies of five patients have reported either a partial response or stable disease after sunitinib treatment of VHL-related pancreatic NETs.[66,67,68] In a prospective phase II trial of sunitinib in VHL-related tumors, the best response in patients with pancreatic NETs was stable disease, as assessed by Response Evaluation Criteria In Solid Tumors (RECIST). Patients underwent treatment for up to four cycles (4 weeks of sunitinib followed by a 2-week treatment break per cycle). The primary endpoint of the study was tolerability, and 9 of the 15 patients completed all four cycles of therapy.
In a prospective phase II trial of pazopanib in VHL-related tumors, the best RECIST responses in pancreatic lesions (n = 17) were 53% with a partial response and 47% with stable disease. Patients underwent treatment for six cycles (28 days of pazopanib per cycle). The partial responses occurred in nonmalignant pancreatic serous cystadenomas, and the heterogeneity of the pancreatic lesions (inclusion of nonmalignant pancreatic cystadenomas and malignant pancreatic NETs) confounded the RECIST responses of VHL-related pancreatic NETs to pazopanib.
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.
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. Pars plana vitrectomy was shown to improve or preserve visual function in 23 patients with advanced VHL eye disease; however, postoperative progression of ocular VHL disease was possibly accelerated in cases where a retinotomy was performed.
Photodynamic therapy reduced macular edema in a case series of two patients with bilateral retinal hemangioblastoma involvement; these patients had minimal, if any, benefit in visual acuity. In a second series of five patients, including four with VHL disease, photodynamic therapy was performed on six eyes. This resulted in tumor regression or stabilization for all patients; all cases showed improvement of subretinal fluid and lipid exudation as well. However, stabilization or improvement of visual acuity was observed in only 50% of the cases.
Case reports of intravitreal treatment with bevacizumab resulted in stabilization for over 2 years in one case report, and improvement in vision in one of five treated eyes in a second case report. Intravitreal ranibizumab did not provide consistent benefit in a case series of five patients. Systemic bevacizumab provided marginal benefit in individual case reports.[78,79] Treatment with sunitinib resulted in possible visual stabilization in three patients, but with significant concomitant toxicity.
A case study of proton therapy of eight eyes in eight patients demonstrated resolution of macular edema in seven of eight patients, and all treated eyes experienced preservation of vision after a median follow-up of 84 months.
Treatment of CNS hemangioblastomas
Surveillance of CNS hemangioblastomas
Many small lesions are found incidentally with screening, and patients may remain asymptomatic for a long period of time. In a study with a short-term follow-up, 35.5% to 51% of CNS hemangioblastomas remained stable.
In a National Institutes of Health series, the researchers noted that the pattern of growth for CNS hemangioblastoma can vary with saltatory growth most commonly observed (72%), but other patterns such as linear growth (6%) and exponential growth (22%) were also observed. Determinants of growth have been assessed. Lesion location may matter, since cerebellar and brain-stem lesions grow faster than those in the spinal cord or cauda equina. Approximately 12% of patients with 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). Other interesting findings were observed such as increased tumors per year in younger patients and a more rapid tumor growth rate in men (P < .01).
Another small series (n = 52) aimed to evaluate growth rates under surveillance. Researchers identified symptomatic presentation as the only independent predictor of growth. As most lesions eventually grow and become symptomatic, the rate of treatment also increases, with the rates of intervention at 1-, 3-, and 7-year reaching 11.5%, 50.1%, and 73%, respectively.
Surgical resection of cerebellar or spinal hemangioblastomas has been the standard treatment approach. While surgical resection of tumors is generally performed prior to the onset of neurologic symptoms, this 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. 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.
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 for hemangioblastoma treatment. Retrospective series have demonstrated that radiosurgery was associated with a size reduction in more than 50% of treated lesions, with a low complication rate. A prospective study at the NCI evaluated local control of treated lesions. Long-term series may be necessary to assess the effectiveness of radiosurgery, since tumors can have a saltatory growth pattern. 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 stereotactic radiosurgery should be reserved for the treatment of tumors not amenable to surgical resection. Other series have shown better outcomes; however, it is unclear if this is dependent on the definition of local control, which varies across studies.
In select cases when surgery was not feasible, CNS hemangioblastomas were treated with pazopanib successfully.[90,91] 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. Further research is required to reduce the morbidity of these benign but often problematic tumors.
Treatment of endolymphatic sac tumors (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. 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. In select cases, preoperative embolization was used effectively in this series 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.[93,94] 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 with craniospinal hemangioblastoma in whom the progression score of the tumors changed significantly (P = .049) before and after pregnancy. Findings from this study are in contrast with that from a small, prospective investigation. Until a large-scale, international, prospective study is conducted, all investigations suggest using a conservative approach that includes medical surveillance during pregnancy.
Historically, patients with von Hippel-Lindau disease (VHL) had poor survival when compared with the general population, because of the morbidity and mortality of the various disease manifestations and the resultant management. With improved understanding of the disease and modern management strategies, the outcomes may be improving. A Danish study compared the life expectancy of individuals with VHL with that of their unaffected siblings; this demonstrated a median survival of 67 years in men and 60 years in women with VHL disease. A second study from China involving 340 patients with VHL disease estimated a median life expectancy of 62 years of age.
In the past, metastatic renal cell carcinoma (RCC) has caused about one-third of deaths in patients with VHL and, in some reports, it was the leading cause of death in VHL patients.[1,4,5,6] 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. The study from China demonstrated that 97% of deaths in patients with VHL were disease related, with central nervous system (CNS) hemangioblastoma and RCC accounting for 67.7% and 27.8% of deaths, respectively. The Danish study demonstrated 79% of deaths were VHL related with 51% attributed to CNS hemangioblastoma and 36% attributed to RCC.
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.) The Danish study reported an increased hazard ratio for death in women,  but this was not observed in the Chinese series. The age and type of presentation may influence outcome; this is perhaps reflective of disease aggressiveness. Genotype did not have an effect on survival probability in the Danish series but, for the Chinese study, those with type 2 disease had improved survival (compared with type 1) and those with a missense variant had improved survival (compared with a truncating variant).
Currently, the renal manifestations of von Hippel-Lindau disease (VHL) are generally managed surgically or with thermal ablation. There is a clear need for better management strategies and development of targeted systemic therapy. These will include defining the molecular biology and genetics of kidney cancer formation, which may lead to 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 VHLgene function, identifying new targets for treatment, and discovering synthetic lethal strategies that can effectively eradicate renal cell carcinoma.
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of von Hippel-Lindau disease. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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