Clinical features, diagnosis, and management of von Hippel-Lindau disease

INTRODUCTION — Von Hippel-Lindau (VHL) disease is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors. A pathogenic variant in the VHL gene diagnostic for VHL disease is present in approximately 1 in 36,000 individuals [1-3].

The initial manifestations of disease can occur in childhood, adolescence, or adulthood, with a mean age at initial presentation of approximately 26 years [1]. The spectrum of VHL-associated tumors includes:

●Hemangioblastomas of the brain (cerebellum) and spine

●Retinal capillary hemangioblastomas (retinal angiomas)

●Clear cell renal cell carcinomas (RCCs)

●Pheochromocytomas

●Endolymphatic sac tumors of the middle ear

●Serous cystadenomas and neuroendocrine tumors of the pancreas

●Papillary cystadenomas of the epididymis and broad ligament

The different types of VHL disease, their clinical manifestations and management, the genetic diagnosis of VHL, and appropriate surveillance protocols will be reviewed here. The molecular biology and pathogenesis of VHL disease are discussed separately. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)

TYPES OF VHL DISEASE — Families with VHL disease have been divided into types 1 and 2, based upon the likelihood of developing pheochromocytoma [4]. Type 2 families are more likely to have a pathogenic variant encoding a missense change in the VHL gene.

●Type 1 – Patients in kindreds with type 1 disease have a substantially lower risk of developing pheochromocytomas (type 1A) and a lower risk of both pheochromocytomas and renal cell carcinoma (RCC; type 1B), although they are at high risk for the other VHL-associated lesions. Type 1B is due to a specific type of deletion that includes the nearby BRK1 gene.

●Type 2 – Kindreds with type 2 disease are at high risk for developing pheochromocytoma. Type 2 disease is subdivided based upon the risk of developing RCC. Type 2A and 2B families have a low and high incidence of RCC, respectively, while type 2C kindreds are characterized by the development of pheochromocytomas only, without RCC or hemangioblastoma. These subclassifications should be used as a guide and are not absolute. Continued surveillance for other VHL-related lesions should continue, for example, in individuals who present with type 2C characteristics.

The goal of improving survival and quality of life in patients with VHL disease has been aided by a better understanding of the natural history of VHL-associated tumors [5]. As a result, surveillance strategies have been developed and regularly updated for individuals with VHL, which have led to the detection of small, asymptomatic tumors prior to the development of metastases or other complications. In addition, therapeutic advances (eg, renal-sparing surgery in RCC) have improved outcomes by decreasing the incidence of renal failure when therapy is required. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)

The molecular pathogenesis of VHL disease follows a "two-hit" model. Affected patients have a germline loss of function variant that inactivates one copy of the VHL gene in all cells. For disease to occur, there must be loss of expression of the second, normal allele through somatic pathogenic variants or deletion of the second allele, or through hypermethylation of its promoter. Further details on the molecular pathogenesis of VHL disease is discussed separately. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)

OCCURRENCE AND AGE OF ONSET OF VHL-RELATED LESIONS — VHL-related lesions occur over a wide range of ages, as outlined in the table (table 1) [6]. Age of onset of screening varies by lesion, with screening for retinal lesions commencing in infancy and screening for other lesions starting slightly later. (See 'Surveillance protocols' below.)

RENAL CELL CARCINOMAS

Clinical presentation — Patients with VHL disease are at risk for developing multiple renal cysts and renal cell carcinomas (RCC), which occur in approximately two-thirds of patients [1]. Virtually all VHL-associated RCCs are clear cell tumors [2]. RCCs of predominant papillary, chromophobe, or oncocytic histology are not associated with VHL disease, but can be associated with other cancer susceptibility syndromes [7,8]. (See "Hereditary kidney cancer syndromes".)

Although the diagnosis of RCC is rare in VHL disease prior to age 20, there are teenage cases of RCC, and thus, screening is now recommended to begin at age 15. RCC occurs with increasing frequency thereafter [1,2,9]. The mean age at onset in one large series was 44 years and it was estimated that 69 percent of patients surviving to age 60 would develop RCC [1]. The incidence of RCC is lower in patients who carry missense changes in the VHL gene in which pheochromocytoma is prominent, although the same surveillance recommendations apply independently of the type of pathogenic variant [4]. (See 'Types of VHL disease' above.)

RCCs are often multicentric and bilateral, and can arise either in conjunction with cysts or de novo from noncystic renal parenchyma. Although renal cysts may be benign, they are thought to represent a premalignant lesion; solid components within otherwise benign-appearing renal cysts almost always contain RCC [10]. (See "Simple and complex kidney cysts in adults".)

Histopathologic changes in the renal parenchyma are widespread and are not limited to renal cysts [11]. Systematic microscopic analysis identified numerous clear cell abnormalities, which are thought to be precursors for clear cell RCC. Similar clear cell precursors were not seen in the renal parenchyma from patients with sporadic RCC or from patients without RCC.

Growth kinetics of RCC in VHL patients were described in a series of 96 renal tumors in 64 VHL patients with analyzed germline pathogenic variants (54 out of 64 treated, 10 out of 64 active surveillance) over a mean follow-up of 55 months [12]. In this series, the mean growth rate of 96 tumors was 4.4 mm/year (standard deviation [SD] 3.2, median 4.1 mm/year), and mean volume doubling time was 25.7 months (SD 20.2, median 22.2 months). Obviously, patients with larger lesions or faster growth rates need to have a tailored approach to their follow-up.

The recommended surveillance strategy for early detection of suspicious renal cystic lesions in patients with VHL disease is discussed below. (See 'Surveillance protocols' below.)

Management — The management of patients with VHL disease and RCC is evolving. Patients with VHL disease and renal masses should seek multidisciplinary care from clinicians familiar with VHL management guidelines [13], including a nephrologist, urologist, medical oncologist, and interventional radiologist. At the time of diagnosis, a clinical geneticist should also be involved to ensure that the genetic diagnosis is secure and appropriate strategies are in place to assess risk to other family members and offer predictive genetic testing, where appropriate. Our approach to the management of these patients is outlined below.

Locoregional tumors <3 cm

Surveillance — For patients with VHL disease and solid locoregional renal tumors <3 cm who are asymptomatic, we suggest initial surveillance rather than immediate surgery or medical therapy (algorithm 1). These tumors can be monitored every three to six months with magnetic resonance imaging (MRI) of the abdomen; once stability of the lesions is confirmed over at least three consecutive scans, surveillance imaging can be extended to every two years [13].

Solid renal tumors <3 cm in diameter that remain stable can be safely monitored as they generally have very low metastatic potential. As an example, in one study, serial imaging studies were performed in 96 patients with VHL disease and small renal tumors [14]. Surgery was performed in 52 patients when a tumor reached a threshold size of 3 cm in diameter. At median follow-up of 60 months, only two patients required nephrectomy, and none developed metastatic disease. In the remaining 44 patients, this size threshold was not used as an indication for immediate surgery. In this group, at median follow-up of 66 months, 12 patients required nephrectomy, and 11 developed metastatic disease. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass".)

Belzutifan — For patients with VHL disease and solid locoregional renal tumors <3 cm with accelerated tumor growth or for those who desire a more aggressive management strategy, we offer belzutifan as an alternative to surveillance (algorithm 1). Although there are no formal criteria, some experts define accelerated tumor growth as greater than 5 millimeters per year. In these patients, belzutifan is effective, has durable responses, and may be used to potentially postpone or avoid future surgical interventions.

Belzutifan specifically inhibits hypoxia-inducible factor-2alpha (HIF-2alpha), a key protein regulated by the VHL pathway (figure 1). Belzutifan is administered orally at 120 mg daily until disease progression or unacceptable toxicity. Hypoxia and anemia are common on-target toxicities associated with therapy and are managed as follows: (See "Molecular biology and pathogenesis of von Hippel-Lindau disease", section on 'Molecular biology and pathogenesis'.)

●Management of anemia – Anemia can be managed by withholding belzutifan for hemoglobin <9 g/dL, if a red blood cell transfusion is indicated, or in the event of an urgent surgical intervention. Upon recovery of the hemoglobin to ≥9 g/dL, belzutifan may be resumed at 120 mg daily. Belzutifan may be reduced to a dose of 80 mg for anemia that is refractory to therapy or permanently discontinued, depending upon the severity of the anemia. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Oncology patient'.)

For patients who develop anemia on belzutifan, we also offer the use of erythropoiesis-stimulating agents (ESAs), as these agents are highly effective in treating anemia and can reduce the need for red blood cell transfusion in our clinical experience. However, this approach diverges from the US Food and Drug Administration label, which does not recommend the use of ESAs with this drug due to limited safety data [15]. The indications for ESAs in the treatment of anemia in patients with cancer are discussed separately. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer".)

●Management of hypoxia – For patients with asymptomatic hypoxia, we continue belzutifan and closely monitor oxygen saturation. For patients with persistent or symptomatic hypoxia (pulse oximeter <88 percent or partial pressure of oxygen [PaO2] <55 mmHg at rest or with exercise), we offer a dose reduction of belzutifan to 80 mg and oxygen therapy as indicated. (See "Long-term supplemental oxygen therapy", section on 'Prescribing oxygen'.)

In an open-label phase II trial (Study 004) of 61 patients with VHL disease and systemic therapy-naïve RCC, at median follow-up of 22 months, belzutifan demonstrated an objective response rate of 49 percent, which were all partial responses [15,16], and two-year progression-free survival of 97 percent. The median time to response was eight months, and over half of patients (56 percent) experienced ongoing durable responses lasting one year or longer. Grade ≥3 treatment-related toxicities included anemia and hypertension (8 percent each), fatigue (5 percent), as well as dyspnea and myalgias (2 percent each) [16].

Based on these data, the FDA granted regulatory approval to belzutifan in adult patients with VHL disease who require therapy for associated RCC and do not require immediately surgery [15]. Belzutifan also has FDA approval for VHL-associated central nervous system hemangioblastomas and pancreatic neuroendocrine tumors. (See 'Hemangioblastomas' below and 'Pancreatic tumors' below.)

Locoregional tumors ≥3 cm

Nephron-sparing approaches — For patients with VHL and locoregional RCC greater than or equal to 3 cm, we recommend a nephron-sparing approach rather than radical nephrectomy (algorithm 1). We offer partial nephrectomy to patients who elect a surgical approach. For those who elect nonsurgical therapy, options include cryotherapy and radiofrequency ablation.

The therapeutic approach to locoregional RCC in patients with VHL disease has shifted from radical nephrectomy to nephron-sparing approaches (eg, partial nephrectomy, cryotherapy, and radiofrequency ablation) to preserve as much kidney parenchyma as possible and reduce the risk of chronic kidney dysfunction [9,14,17,18]. Nephron-sparing approaches are preferred for those with VHL disease, who are at risk for bilateral and recurrent tumors, and are also extrapolated from data in those with sporadic RCCs. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy' and "Definitive surgical management of renal cell carcinoma".)

Several factors have contributed to this change:

●Improved imaging modalities (eg, computed tomography [CT], MRI, and ultrasound), combined with regular surveillance programs, have led to the identification of more RCCs at an early stage.

●Partial nephrectomy appears to be as effective as total nephrectomy for early stage RCC. Repeated partial nephrectomies may be feasible in carefully selected patients to preserve kidney parenchyma and avoid dialysis [18]. The rationale and results with partial nephrectomy for patients with RCC are discussed separately. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)

●Other nephron-sparing approaches, particularly cryoablation and radiofrequency ablation, may permit the eradication of multiple small tumors while minimizing damage to the normal kidney. (See "Radiofrequency ablation, cryoablation, and other ablative techniques for renal cell carcinoma".)

Continued close surveillance is required after treatment of RCC in VHL patients. New kidney tumors are detected in approximately 30 percent of patients by five years and 85 percent by 10 years. The risk of metastatic disease appears to be low as long as the patient is carefully monitored. However, in one report of 21 such patients, two developed metastatic disease at a median follow-up of 29 months [9].

Indications for belzutifan — For patients who are not candidates for further surgery or other nephron-sparing approaches, we alternatively offer systemic therapy with belzutifan (algorithm 1). Candidates for this approach include patients with multiple prior surgeries, or those with lesions in a solitary remaining kidney where further locoregional interventions would render the patient anephric. The use of this agent is discussed above. (See 'Belzutifan' above.)

Indications for kidney transplantation — Kidney transplantation has been used in patients with VHL disease who required bilateral nephrectomy for RCC or developed end-stage kidney disease. Experience is limited, because of concerns that immunosuppressive therapy might enhance the risk of tumor recurrence. However, this concern was not borne out in at least one study of 32 patients with VHL disease who received kidney transplants and 32 matched transplant recipients without VHL disease [19]. At an average follow-up of four years, no differences were observed between the two groups in graft and patient survival or kidney function. (See "Overview of care of the adult kidney transplant recipient".)

Metastatic disease — There are limited clinical trials evaluating systemic therapy in patients with VHL disease and metastatic RCC, and the management of these patients is extrapolated from the approach used for sporadic metastatic RCC. (See "Systemic therapy of advanced clear cell renal carcinoma" and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)

Data from early phase clinical trials suggest that antiangiogenic agents such as sunitinib and pazopanib are effective in patients with VHL disease and metastatic RCC [20,21]. With the advent of vascular endothelial growth factor (VEGF)-targeted therapy that can decrease the size of RCC lesions, it may be possible to decrease the frequency of surgical intervention through chronic or intermittent use of certain agents.

●Sunitinib – In a clinical trial of 15 patients with VHL disease treated with sunitinib, partial responses were seen in 6 of 18 patients with RCC (33 percent) [21].

●Pazopanib – In a phase II trial of 31 patients with VHL disease treated with pazopanib, the RCC lesional response rate was 52 percent [20].

●Is there a role for belzutifan? – Belzutifan, a HIF-2alpha inhibitor, does not have regulatory approval in patients with metastatic RCC, and further data are necessary in this patient population.

HEMANGIOBLASTOMAS

Clinical presentation — Hemangioblastomas are well-circumscribed, capillary vessel-rich benign neoplasms, which do not invade locally or metastasize. However, they can cause symptoms through pressure on adjacent structures and through hemorrhage, due to either the hemangioblastoma itself or cyst formation around the lesion. The clinical presentation and management of sporadic hemangioblastomas are discussed elsewhere. (See "Hemangioblastoma".)

Hemangioblastomas are the most common lesions associated with VHL disease, affecting 60 to 84 percent of patients, and typically occur in the cerebellum, spinal cord, or retina [1,2,22]. Patients with VHL-associated hemangioblastomas tend to be younger than those with sporadic hemangioblastomas with a mean age at diagnosis in one series of 29 years, and a range of 9 to 78 years of age [1]. While sporadic hemangioblastomas usually are solitary and generally do not recur after surgery, lesions in patients with VHL disease tend to be infratentorial and multiple [23]. In a detailed analysis of 160 patients with VHL disease and hemangioblastoma, 655 discrete tumors were identified, of which 51 percent were in the spinal cord, 38 percent in the cerebellum, 10 percent in the brainstem, and 2 percent supratentorial [22].

In a cohort of 188 consecutive patients presenting with a seemingly sporadic hemangioblastoma, no family history of VHL, and no other evidence of the disease, VHL germline pathogenic variants were present in 5 percent of cases [24]. Of those who tested negative, 5 percent developed a VHL-related lesion in the ensuing years, which may result from being mosaic for a VHL pathogenic variant. (See 'Patients with somatic mosaicism' below.)

Thus, we recommend that all patients with either a retinal or central nervous system (CNS) hemangioblastoma be tested for VHL germline pathogenic variants, even in the case of a single lesion, given the high sensitivity and specificity of the testing. Where access to genetic investigations is limited, it would be reasonable to focus testing on patients with lesions presenting under the age of 50 years since the likelihood of identifying a germline VHL pathogenic variant is inversely correlated with the age of the patient.

Because CNS hemangioblastomas often initially develop in the second decade, routine screening with magnetic resonance imaging (MRI) of the brain and spinal cord is recommended in patients with VHL disease starting at age 11 years [25]. (See 'Surveillance protocols' below.)

Management

General approach — Patients with VHL are at risk for CNS hemangioblastomas in deep and critical locations within the brainstem, cerebellum, and spinal cord. They are at risk for slow, asymptomatic progression as well as for sudden deterioration due to hemorrhage or cyst expansion. Some patients present with a symptomatic hemangioblastoma as the first sign of VHL disease, while others are diagnosed later through surveillance imaging or development of new neurologic symptoms. (See "Hemangioblastoma", section on 'Treatment'.)

Because patients frequently develop multiple lesions, therapeutic efforts should focus on avoiding treatment-related morbidity by minimizing the frequency of surgical interventions. Although surgery can usually successfully remove lesions in the spinal cord, brainstem, and cerebellum, intervention is reserved until lesions become symptomatic or they display accelerated growth [22,23,26,27]. Patients who demonstrate progression by CNS imaging should be followed at more frequent intervals for evidence of clinical symptoms.

Surveillance and risk of progression — For patients with imaging evidence of one or more hemangioblastomas who are asymptomatic and/or have indolent tumor growth, we suggest surveillance with serial imaging rather than surgical or medical therapy. Surveillance imaging with MRI can be obtained for these patients either annually or more frequently as appropriate [13].Surveillance allows the deferral of therapy and its associated toxicity until the development of more compelling disease progression, such as tumor-related symptoms or accelerated growth.

Belzutifan, a hypoxia-inducible factor-2alpha (HIF-2alpha) inhibitor, is a reasonable alternative to surveillance for patients with tumors that could become symptomatic if allowed to progress, or for those who wish to delay or defer future surgery. Small, asymptomatic tumors should not be preemptively treated with radiation therapy (RT) [28]. (See 'Symptomatic or progressive disease' below.)

CNS hemangioblastomas can remain dormant for unpredictable periods of time or can present with accelerated growth [22,29]. There are no definitive clinical (eg, age, sex, location), radiographic, or specific molecular markers (ie, underlying pathogenic variants) that can predict the natural history of a given lesion. Therefore, regular follow-up with imaging and observation of clinical signs and symptoms is necessary. (See 'Surveillance protocols' below.)

A review of 225 patients with 1921 CNS hemangioblastomas demonstrated that 51 percent of lesions did not grow. In the remaining 49 percent of hemangioblastomas, 72 percent grew in a saltatory (stepwise), 6 percent in a linear, and 22 percent in an exponential fashion [30]. Partial germline deletions and male sex were associated with increased tumor burden. The unpredictable nature of hemangioblastoma growth emphasizes the need for ongoing surveillance in these patients.

Symptomatic or progressive disease — For patients with VHL and symptomatic and/or progressively enlarging CNS hemangioblastomas, options for therapy include surgery, radiation therapy, and systemic agents (eg, belzutifan). VHL-associated hemangioblastomas are best managed in a multidisciplinary fashion with input from neurosurgeons, interventional neuroradiologists, radiation oncologists, and neurooncologists with expertise in central nervous system malignancies. (See "Hemangioblastoma", section on 'Treatment'.)

While surgery and radiation therapy have traditionally been first-line therapies for progressive CNS disease, our approach is evolving with the development of effective systemic therapies with CNS activity (eg, belzutifan).

Indications for surgery — Surgery is typically required for patients with hemangioblastomas that are causing significant neurologic symptoms or are threatening compromise due to mass effect or hemorrhage. Surgical management of hemangioblastomas is discussed separately. (See "Hemangioblastoma", section on 'Surgery'.)

Patients with enlarging, operable tumors who do not have an immediate risk for decline are good candidates for belzutifan in an effort to delay or avoid surgery. (See 'Belzutifan' below.)

Belzutifan — For most patients with symptomatic or rapidly enlarging CNS hemangioblastomas that are unresectable or pose a high risk of postoperative deficits, we suggest a trial of systemic therapy with the HIF-2alpha inhibitor, belzutifan, rather than initial RT or an attempt at high-risk surgical debulking. Belzutifan is also appropriate in patients with recurrent/refractory tumors after surgery or RT.

The management of toxicities associated with belzutifan are discussed separately. (See 'Belzutifan' above.)

Belzutifan has shown evidence of effective and durable responses in the CNS. A phase II study (Study 004) of 61 patients with systemic therapy-naïve VHL-associated renal cell carcinoma (RCC) included a subset of 50 patients with measurable CNS hemangioblastoma [15,16]. At median follow-up of 22 months, among this subset, objective responses were seen in 15 patients (30 percent), including three complete (six percent) and 12 partial responses (24 percent) [16]. The median time to response was three months, and approximately three-quarters of patients (73 percent) experienced durable responses lasting one year or longer.

Based on these data, the US Food and Drug Administration (FDA) granted regulatory approval to belzutifan in adult patients with VHL disease who require therapy for associated CNS hemangioblastoma and do not require immediate surgery [15]. Belzutifan also has regulatory approval from the FDA for VHL-associated RCC and pancreatic neuroendocrine tumors. (See 'Renal cell carcinomas' above and 'Pancreatic tumors' below.)

Radiation therapy — Stereotactic radiosurgery (SRS) and conventional fractionated RT play a selective role in treating recurrent/refractory lesions that are not readily accessible by surgery and/or have failed belzutifan [31,32].

There are limited randomized prospective studies that compare the long-term efficacy and safety of SRS with conventional RT for hemangioblastomas. In a prospective observational study performed at the National Institutes of Health, diminishing tumor control over time was observed in lesions treated with SRS [31].

Further details on the use of RT in patients with hemangioblastoma are discussed separately. (See "Hemangioblastoma", section on 'Radiation therapy'.)

Antiangiogenic agents — Antiangiogenic agents such as pazopanib and sunitinib are less preferred options, as they have limited efficacy in these neoplasms. (See "Hemangioblastoma", section on 'Antiangiogenic therapy'.)

●Pazopanib – Pazopanib does provide clinical benefit in individuals with CNS hemangioblastomas, but should be used with caution. Preclinical and observational data suggested that pazopanib, which possesses modest inhibition of fibroblast growth factor receptors (FGFRs), may provide some value in the management of hemangioblastomas [33]. In a phase II trial of 31 patients with VHL disease, pazopanib demonstrated a partial response in 4 percent of those with hemangioblastomas and stabilization of disease in the majority of patients, but resulted in CNS bleeding in two patients [20].

●Sunitinib – A prospective clinical trial with sunitinib, an antiangiogenic agent, failed to demonstrate response in hemangioblastomas, although this class of agents is active in RCCs [21].

RETINAL CAPILLARY HEMANGIOBLASTOMAS

Clinical presentation — Retinal capillary hemangioblastomas are typically found either in the peripheral retina and/or the juxtapapillary region. Visual loss from retinal capillary hemangioblastomas is generally caused by exudation from the tumor, causing retinal edema or by tractional effects, in which glial proliferation on the surface of the tumor induces retinal striae and distortion [34]. In addition, retinal capillary hemangioblastomas can hemorrhage, leading to retinal detachment, glaucoma, and loss of vision.

Retinal capillary hemangioblastomas are found in up to 70 percent of VHL patients by age 60 years; they are often multifocal and bilateral. Compared with patients with sporadic retinal hemangioblastomas, patients with VHL are much younger and more likely to have multiple lesions. In one series of 31 patients with VHL and 37 patients without VHL disease, the VHL patients were younger (18 versus 36 years of age, respectively), had an average of four tumors, and were more likely to develop new tumors than those without the disease [35].

In a study of 890 patients with VHL disease, 335 patients had a retinal capillary hemangioblastoma in at least one eye. Lesions were detected unilaterally in 42 percent and bilaterally in 58 percent of affected patients. No correlation was detected between the age, gender, or laterality of involvement. Of involved eyes, 87 percent had tumors that could be individually visualized; of these, tumors were commonly found in the peripheral retina (85 percent) only, and less commonly in the juxtapapillary area (15 percent). The tumor count in the periphery averaged 2.5+/-1.8 per eye, with 25 percent of eyes having more than one quadrant of retinal involvement [36]. An assessment of the genotype-phenotype relationship in retinal capillary hemangioblastoma suggested that 15 percent of individuals with variants that result in complete loss of VHL protein had hemangioblastoma development versus an overall prevalence in the patient population of 37 percent. The risk of vision loss was found to increase with age although tumor number did not increase significantly as a function of age.

As is the case with seemingly sporadic central nervous system (CNS) hemangioblastomas, any patient presenting with a retinal capillary hemangioblastoma (particularly if prior to age 40) should undergo germline genetic testing for pathogenic variants in the VHL gene. (See 'Clinical presentation' above.)

Routine surveillance for retinal capillary hemangioblastoma is recommended for patients with VHL disease because of its high frequency. The frequent onset of such lesions during childhood makes it important to initiate ophthalmologic surveillance in the pediatric population upon making the diagnosis, and it is one of the reasons that genetic testing for VHL pathogenic variants in young children is recommended. (See 'Surveillance protocols' below.)

Management — The treatment of retinal capillary hemangioblastoma requires that the benefits of treatment be balanced against potential treatment-related complications. Data are controversial for whether small lesions can be carefully observed without specific treatment until there is any evidence of growth or symptoms [37]. Some groups recommend that retinal capillary hemangioblastoma be treated immediately upon detection (in order to prevent growth and complications) whereas others wait for some change in size before initiating treatment. For those who initiate treatment, we suggest laser photocoagulation rather than other therapies. Other alternative options include photodynamic therapy or radiation therapy (RT; particularly for salvage therapy). Systemic therapy with belzutifan is an acceptable option for patients who are ineligible for local therapy due to tumor proximity to the optic nerve or multiple progressive lesions. Clinical trials are encouraged, where available.

●Local therapies – Laser photocoagulation is effective in over 70 percent of cases, generally with a single treatment, and is the preferred method of treatment [37]. An exception is that hemangioblastomas of the optic nerve should not be treated with these methods because of the deleterious side effects on the normal retina. Photodynamic therapy can also be considered as an option in the treatment of retinal capillary hemangioblastoma, although limited data exist on its efficacy. External beam RT may have a role for salvage therapy if other modalities have failed [38].

●Belzutifan – Belzutifan, a hypoxia-inducible factor-2alpha (HIF-2alpha) inhibitor, is an option for patients with retinal capillary hemangioblastomas that are close to the optic nerve or those with multiple progressive hemangioblastomas; such patients are typically ineligible for local therapies. In a phase II study, belzutifan improved disease in all 16 eyes (100 percent) in 12 patients with evaluable retinal hemangioblastomas [16].

The management of toxicities associated with belzutifan is discussed separately. (See 'Belzutifan' above.)

●Investigational therapies (antiangiogenic agents) – Further investigational studies are needed to better understand the biology of the hemangioblastoma cell of origin and its endothelium, as well as to develop active systemic therapies. Several vascular endothelial growth factor (VEGF) receptor inhibitors which interfere with angiogenesis, such as sunitinib, pazopanib, bevacizumab, and ranibizumab, have demonstrated limited efficacy in retinal hemangioblastoma [20,21,39,40]. (See "Hemangioblastoma", section on 'Antiangiogenic therapy'.)

PHEOCHROMOCYTOMAS

Clinical features — Pheochromocytomas are seen both sporadically and in association with a number of genetic syndromes, including VHL disease, multiple endocrine neoplasia type 2, pathogenic variants of the succinate dehydrogenase (SDH) subunits A, B, D, and C, neurofibromatosis type 1, and other rare conditions. The different familial syndromes manifesting pheochromocytomas are discussed in detail elsewhere. (See "Pheochromocytoma in genetic disorders".)

All patients with pheochromocytoma should have a genetic evaluation to identify the underlying syndrome so that proper surveillance can be initiated for other tumors for which the patient is at risk. Given the increasing number of genes associated with these tumors, genetic testing generally relies on a multigene next-generation sequencing (NGS) panel for making the appropriate genetic diagnosis. The presence of pheochromocytoma is used to define types 2A-C VHL disease.

In one evaluation of 271 patients with apparently sporadic pheochromocytoma (no other tumors or family history of the disease) from population-based registries in Germany and Poland, all were tested for germline pathogenic variants in VHL and three of the other genes (RET, SDHB, SDHD) that have been implicated in familial pheochromocytoma [41]. A germline VHL pathogenic variant was identified in 30 patients overall (11 percent) and in 42 percent of those who presented at age 18 or younger. A positive family history had been established at last follow-up in 12 of the 30 patients and at least four others had a de novo germline VHL pathogenic variant since both parents tested negative. (See "Clinical presentation and diagnosis of pheochromocytoma".)

Pheochromocytomas in VHL disease tend to be seen in younger patients, are often multiple, may be extra-adrenal, and are less likely to be associated with symptoms or biochemical evidence of catecholamine production compared with those occurring in patients without VHL [42-46]. Pediatric cases of pheochromocytomas are not infrequent [47,48].

Two large series illustrate the clinical characteristics of pheochromocytomas in patients with VHL disease:

●In a report from the National Institutes of Health of 64 patients with VHL disease and pheochromocytomas, a total of 106 tumors were identified [44]. Of these, 12 percent originated outside the adrenal gland and 35 percent of patients were asymptomatic, without hypertension or evidence of increased catecholamine production.

●Experience reported by the Mayo Clinic found that 20 of 109 patients with VHL disease (18 percent) had a pheochromocytoma at a median age of 30 years, including three originating outside the adrenal gland [43]. Detailed analysis of these patients failed to reveal evidence of catecholamine production in one-third.

Tumors that produce catecholamines may be associated with the typical clinical signs and symptoms of pheochromocytomas, including hypertension, diaphoresis, tachycardia, and apparent mood changes. Patients with VHL disease and catecholamine production due to pheochromocytoma almost exclusively produce normetanephrines (indicating norepinephrine production) [49]. (See 'Diagnosis' below.)

The possibility of an occult pheochromocytoma needs to be considered whenever a patient with VHL disease requires surgery because of the potential risk of anesthetic complications, including sympathetic overactivity and severe hypertension.

Diagnosis — In addition to the surveillance described below, pheochromocytomas can be detected with radiographic imaging, plasma metanephrine/normetanephrine testing, and, less commonly, urine metanephrine/normetanephrine testing. (See 'Surveillance protocols' below.)

Conventional imaging may not be sufficient because of the potential for extra-adrenal lesions, referred to as paragangliomas. Studies with 18-F-dihydroxy-phenyl-alanine (18F-DOPA) positron emission tomography (PET) provide some context and suggest that iobenguane (also known as metaiodobenzylguanidine [MIBG]) scanning is not effective at detecting pheochromocytomas in patients with VHL:

●A pilot study of 18F-DOPA PET in seven patients with VHL indicated a high detection rate (seven out of seven), as did computed tomography (CT) scan. On the other hand [(123/131)I]-MIBG scintigraphy failed to detect four of the seven lesions [50].

●These data were confirmed in an independent study of 48 patients with hereditary and nonhereditary cases [51].

●In a prospective study assessing adrenal imaging of 52 patients with VHL disease, 390 lesions were identified by CT (n = 139), magnetic resonance imaging (MRI; n = 117), 18F-fluorodeoxyglucose (18F-FDG) PET (n = 94), and 18F-DOPA PET (n = 40). 18F-DOPA PET identified 20 pancreatic and 20 extrapancreatic tumors, including lesions in the adrenal gland (n = 11), kidney (n = 3), liver (n = 4), lung (n = 1), and cervical paraganglioma (n = 1). These tumor sites were not seen by conventional imaging studies in 9.6 percent of patients and 4.4 percent of lesions [52].

●In a prospective study of 197 patients with VHL-associated pancreatic lesions, clinical and imaging characteristics were analyzed to study the associations between 18F-FDG PET uptake, tumor growth, and the development of metastatic disease [53]. PET imaging detected metastatic disease in three patients in whom it was not detected by CT scan and suggested nonneoplastic disease in three more patients.

Measurement of plasma metanephrines and normetanephrines provides important diagnostic information. In a study of patients with VHL disease and multiple endocrine neoplasia type 2 (MEN-2), measurements of plasma normetanephrines and metanephrines provided a sensitivity of 97 percent and a specificity of 96 percent [49]. A high normetanephrine-to-metanephrine ratio is expected because patients with VHL disease almost exclusively produce normetanephrines (indicating norepinephrine production).

Management — The treatment of choice for symptomatic pheochromocytomas is surgical removal after appropriate alpha-adrenergic blockade and other supportive measures, if needed [54].

It is critical to follow established protocols to suppress catecholamine production in the preoperative period, and follow patients carefully perioperatively and postoperatively for several weeks to ensure that endocrine and cardiovascular function has not been compromised by prolonged overproduction of catecholamines. Additional information on the pharmacologic management of patients with pheochromocytoma prior to surgery is discussed elsewhere. (See "Treatment of pheochromocytoma in adults" and "Pheochromocytoma and paraganglioma in children".)

ENDOLYMPHATIC SAC TUMORS OF THE MIDDLE EAR

Manifestations — Papillary cystadenomas of the endolymphatic sac are highly vascular lesions arising within the posterior portion of the temporal bone [55]. Common clinical manifestations include hearing loss, tinnitus, vertigo, and less often, facial muscle weakness [55-58].

Three mechanisms have been described to account for the hearing loss and other symptoms associated with endolymphatic sac tumors (ELSTs) [58].

●Tumors can invade the otic capsule, resulting in destruction of the membranous labyrinth and disruption of endolymphatic flow.

●Sudden, irreversible hearing loss may be due to intralabyrinthine hemorrhage.

●Gradual onset of hearing loss, tinnitus, and vertigo can be caused by blockage of endolymphatic sac resorption of fluid (hydrops).

Although these tumors also occur sporadically, they arise at a younger age in VHL patients, in whom they are often bilateral. In one series, for example, bilateral tumors were present in 28 percent of the patients with VHL versus 1 percent in the patients without VHL disease [57]. In two other reports in VHL patients, 5 of 34 tumors (15 percent) were bilateral [55,56].

ELSTs are common in patients with VHL disease, within an incidence of approximately 15 percent on detailed evaluation [55-57,59-61].

Diagnosis — ELSTs may be difficult to detect with a single modality. Patients with VHL disease should be questioned annually about any auditory or vestibular symptoms with routine audiology performed for surveillance. Any patient with abnormalities in auditory tests should be screened for the presence of these tumors by computed tomography (CT) of the skull base or magnetic resonance imaging (MRI) with fine cuts of the temporal bones (table 2) [55]. A one-time screening MRI of the internal auditory canal can also be obtained in adolescence (table 2). These lesions can be very difficult to see radiographically. Whether surgery is indicated for patients with an asymptomatic tumor is controversial [58], and additional studies are required to assess the risk of acute hearing loss in such patients.

Radiologic findings include retrolabyrinthine location, intratumoral calcification on CT scan, hyperintense focal signals on T1-weighted (noncontrast-enhanced) MRI, and a heterogeneous signal on T2-weighted MRI scan [62,63]. Visualization of these lesions requires dedicated images, and ELSTs will often be missed on brain MRI scans ordered for surveillance of cerebellar hemangioblastoma.

In a prospective 40-patient study, ELSTs were suspected based on audiovestibular symptoms, audiometry, and MRI in 34, 30, and 12.5 percent of subjects, respectively. More than 90 percent of radiologically diagnosed ELSTs were associated with abnormal audiometric findings [64].

Management — Management of ELSTs needs to consider the presence and severity of symptoms, their generally slow growth rate, and the potential complications associated with surgery. Treatment of ELSTs is primarily surgical; if the lesions can be completely excised, surgery is curative [65-67]. Stereotactic radiosurgery may have a role for recurrent disease [68].

Cochlear implants may be an option for patients with hearing loss due to bilateral ELSTs [69]. (See "Hearing amplification in adults", section on 'Cochlear implants'.)

PANCREATIC TUMORS

Types of pancreatic abnormalities — Pancreatic abnormalities are common in patients with VHL disease. Observational studies suggest that pancreatic lesions can be identified in up to 77 percent of adolescents and adults [70]. The most frequently encountered lesions are:

●Pancreatic cysts (70 percent)

●Serous cystadenomas (9 percent)

●Neuroendocrine neoplasms (9 to 17 percent) [70,71].

Pancreatic cysts and serous cystadenomas — Simple pancreatic cysts and serous cystadenomas may be asymptomatic even when the radiologic presentation is dramatic. However, lesions that cause epigastric pain and discomfort [72,73] or biliary obstruction can occur and should be evaluated and treated appropriately [74]. (See "Pancreatic cystic neoplasms: Clinical manifestations, diagnosis, and management", section on 'Management'.)

Pancreatitis and pancreatic failure are exceedingly rare complications, although some degree of exocrine pancreatic dysfunction has been reported. Asking about change in stool characteristics and digestive patterns should be part of a comprehensive review of systems with patients with VHL disease and pancreatic cysts. (See "Exocrine pancreatic insufficiency".)

Mucinous cysts of the pancreas are not seen in association with VHL disease. Patients with VHL disease also do not have an increased risk of pancreatic adenocarcinoma. (See "Classification of pancreatic cysts".)

Neuroendocrine neoplasms — Neuroendocrine neoplasms of the pancreas are often multifocal. While the majority are well differentiated (grade 1 or 2) neuroendocrine tumors (G1 or G2 pancreatic neuroendocrine tumors [pNETs]) [75,76], high-grade well-differentiated (ie, pNET, G3) and high-grade poorly differentiated tumors (neuroendocrine carcinomas [NEC]) have been described (table 3) [77,78].

pNETs may be benign or malignant (as indicated by the presence of metastases to local nodes and/or liver). In one series of 108 patients with neuroendocrine tumors, nine (8 percent) had metastatic disease [71]. However, it is not possible to gauge clinical behavior on the basis of histologic appearance. pNETs that are most likely to metastasize are those that are >3 cm in diameter, have a rapid tumor doubling time (<500 days), and those with VHL missense and/or exon 3 pathogenic or likely pathogenic variants [71,75,76,79]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'.)

Most of these neoplasms are nonfunctional and grow slowly for prolonged periods without producing symptoms of peptide overproduction. In two combined series, none of 25 patients had symptoms related to peptide hormone secretion [70,80]. However, there are reported cases of functional syndromes due to secreted peptides (eg, diarrhea from vasoactive intestinal peptide and hypoglycemic episodes from insulin) [70]. Patients with confirmed functional VHL-associated pNETs can be monitored using tumor-specific pancreatic polypeptide levels to assess disease burden [74]. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Functioning tumors'.)

As a result of all of these issues, many of these lesions are diagnosed incidentally during routine VHL surveillance for renal lesions [71]. (See 'Surveillance protocols' below.)

Management

Pancreatic solid lesions and pNETs

Role of surgery — Management of pNETs is primarily surgical, although the criteria for surgical resection differ from those of patients with sporadic pNETs. Patients with VHL-associated pNETS who are being treated surgically should receive preoperative imaging, typically with a Gallium GA-68 DOTATATE PET-CT, although other imaging options are available [74]. Further details on the preoperative evaluation of pNETs are discussed separately. (See "Surgical resection of sporadic pancreatic neuroendocrine tumors".)

We suggest surgical resection rather than other interventions or systemic therapy for patients with potentially resectable lesions greater than 3 cm in diameter in the body or tail of the pancreas, or greater than 2 cm in diameter in the head of the pancreas. We suggest belzutifan rather than other systemic therapies if surgery is not feasible or the tumor is considered unresectable.

Nonoperative approaches (eg, surveillance, belzutifan) are appropriate for small primary lesions (≤3 cm), incorporating other clinical factors such as the type and location of the VHL pathogenic variant and rate of tumor growth (algorithm 2) [71,75,79]. (See 'Role of surveillance and belzutifan' below.)

Data support risk stratification of pNETs <2 to 3 cm according to both size [71,76] and the results of VHL genotyping [75,81]. In one prospective observational study, 175 patients with VHL and solid pancreatic lesions consistent with a pNET (median of two pNETs per patient) were managed according to the above surgical criteria. Among the entire study population, 156 patients also underwent VHL gene sequencing. At median follow-up of 53 months, the following results were noted:

●Patients with a greatest tumor diameter <1.2 cm (n = 83) had a 100 percent negative predictive value for developing metastases and requiring surgical intervention during follow-up.

●Patients with a tumor diameter >3 cm (n = 12) had a high risk of developing metastatic disease (on multivariable analysis, hazard ratio [HR] 8.6, 95% CI 1.7-43.2).

●Among the 80 patients with tumors ≥1.2 cm and ≤3 cm, only those with a VHL missense pathogenic variant developed metastases over time (five versus zero for patients with other types of pathogenic variants). Surgical intervention was required more frequently among patients with a missense VHL pathogenic variant compared to other types of molecular alterations (40 versus 16 percent) and those with an exon 3 (as compared with exon 1 or 2) pathogenic variant (on multivariate analysis HR 8.8, 95% CI 1.2-66.3).

Earlier studies emphasized the prognostic influence of tumor growth rate [71,79].

Surgical principles are similar to those of sporadic pNET, although given tumor multifocality and the potential for future pancreatic resections, pancreas-preserving surgery is emphasized. Long-term outcomes of resected VHL-associated pNET appear to be generally better than those of sporadic pNET [76,82]. (See "Surgical resection of sporadic pancreatic neuroendocrine tumors", section on 'Extent of resection'.)

Role of surveillance and belzutifan — For patients with pNET ≤3 cm and indolent tumor growth, we suggest surveillance with serial imaging rather than resection (algorithm 2). Initial therapy with the hypoxia-inducible factor-2alpha (HIF-2alpha) inhibitor belzutifan is an alternative to surveillance for patients with lesions that exhibit rapid tumor growth (ie, accelerated doubling time <500 days) or those with a resectable tumor who wish to delay or defer future surgical interventions, as this targeted therapy has effective and durable responses in this patient population.

Despite limited data, we also suggest belzutifan over other systemic therapies for localized tumors >3 cm if surgery is not feasible (ie, because of multiple primary surgeries or multiple comorbidities) or if the tumor is otherwise unresectable.

Belzutifan has not been directly compared to other systemic therapies used for locally advanced or metastatic well-differentiated pNETs, and its use in this population requires further investigation. Further details on choices for systemic therapy for patients with non-VHL-associated advanced pNETs are discussed separately. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'General approach to the patient'.)

A phase II study (Study 004) of 61 patients with systemic therapy-naïve VHL-associated renal cell carcinoma (RCC) included a subset of 22 patients with measurable pNETs [15,16]. At median follow-up of 22 months, among this subset, objective responses were seen in 20 patients (91 percent), including 3 complete (14 percent) and 17 partial responses (77 percent) [16]. The median time to response was approximately 8 months, and no cases of progressive disease were reported. There were no data provided on histologic differentiation or mitotic rate, VHL genotype, or prior therapies for those with pNET.

Based on these data, the US Food and Drug Administration (FDA) granted regulatory approval to belzutifan in adult patients with VHL disease who require therapy for VHL-associated pNET and do not require immediate surgery [15]. Belzutifan also has regulatory approval from the FDA for VHL-associated RCC and central nervous system (CNS) hemangioblastomas. (See 'Renal cell carcinomas' above and 'Hemangioblastomas' above.)

The management of toxicities associated with belzutifan are discussed separately. (See 'Belzutifan' above.)

PAPILLARY CYSTADENOMAS OF THE EPIDIDYMIS AND BROAD LIGAMENT — Papillary cystadenomas occur in both the epididymis in men and the broad ligament in women (also known as adnexal papillary tumors of probable mesonephric origin) [83]. Bilateral papillary cystadenomas are almost pathognomonic of VHL disease [2,84]. In contrast, single epididymal cysts are common in the general population and should not raise suspicion for VHL disease in the absence of other VHL-related findings.

In one series of 56 patients with VHL who were screened with both ultrasound and physical examination, 30 had epididymal abnormalities, two-thirds of which were bilateral. Papillary cystadenomas are benign and generally asymptomatic, and no treatment is required [84]. (See "Nonacute scrotal conditions in adults".)

Papillary cystadenomas in the broad ligament in women are also asymptomatic in most patients, and thus the true incidence of these lesions is unknown [85,86]. Symptoms that have been reported include pain, dyspareunia, and menorrhagia; treatment is symptomatic.

VHL SOMATIC PATHOGENIC VARIANTS IN SPORADIC TUMORS — Sporadic renal cell carcinomas (RCCs), pheochromocytomas, endolymphatic sac tumors (ELSTs), and hemangioblastomas frequently have acquired somatic (as opposed to germline) abnormalities involving the VHL gene, supporting a role for the VHL gene in tumorigenesis in sporadic cases [7,61,87-91]. As noted above, two hits or loss of function events appear to be required in VHL disease in both the hereditary and sporadic tumors. The hits can result from a combination of inherited or somatic pathogenic variants followed by loss of heterozygosity, or loss of gene expression caused by promoter hypermethylation. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)

The following observations illustrate the frequency with which this occurs:

●Somatic pathogenic variants of the VHL gene and/or allelic deletion may be present in as many as 50 percent of sporadic hemangioblastomas. (See "Hemangioblastoma", section on 'Molecular biology'.)

●Abnormalities of the VHL gene are also found in 50 to 60 percent of patients with sporadic RCC, suggesting that the VHL gene has a role in pathogenesis in this setting as well. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Von Hippel-Lindau gene'.)

●VHL gene abnormalities in apparently sporadic pheochromocytoma are observed less commonly (in 4 percent of benign lesions and in 17 percent of malignant tumors in a series of 72 patients) [89]. However, some of these patients actually have germline pathogenic variants and, therefore, VHL disease [41]. (See 'Pheochromocytomas' above.)

DIAGNOSIS

Genetic testing — The diagnosis of VHL disease is typically established through detection of a germline pathogenic (typically loss of function) variant in the VHL gene. This is most commonly seen in patients who undergo genetic testing after being diagnosed with a single manifestation of VHL disease, or those who are tested because they have a close relative diagnosed with VHL disease [2,92]. The diagnosis of VHL disease can also occur when genetic testing is performed for another reason and unexpectedly reveals a secondary pathogenic variant in VHL. Rarely, in patients who do not have access to genetic testing, the diagnosis of VHL disease can be based on clinical criteria (eg, those with one VHL-associated lesion and a family history of VHL, or those with multiple VHL-associated lesions).

Patients suspected of having VHL disease should be referred to specialized centers for evaluation, genetic counseling, and definitive diagnosis through genetic testing, even if there is no family history of VHL disease. Approved VHL Clinical Care Centers are listed at the VHL Alliance website [13]. These centers have been approved for standards of care that were developed by the VHL Alliance's medical advisory board. The VHL Alliance also provides recommendations for ongoing surveillance of patients diagnosed with VHL disease (table 2). (See 'Genetic counseling' below and 'Surveillance protocols' below.)

How to perform and interpret genetic testing — Genetic testing is typically performed on isolated DNA from a fresh blood sample, which is obtained primarily from lymphocytes. Many laboratories can also perform this testing from DNA isolated from saliva or buccal samples. Most DNA diagnostic laboratories rely on next-generation sequencing (NGS) techniques, whether assessing a single gene or panel of hereditary cancer genes. Deletions (either intragenic or whole gene) are assessed using read-depth from NGS data [93] or confirmed directly using a targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA) [94]. Many patients now undergo genetic testing using larger multi-gene panels by NGS analysis that include the VHL gene as one of the cancer susceptibility genes under study, including those cancer patients undergoing paired tumor/normal sequencing [95].

A molecular diagnosis of VHL disease is based on the identification of a pathogenic or likely pathogenic variant in the VHL gene based on the American College of Medical Genetics and Genomics (ACMG) classification scheme [96]. Pathogenic variants in the VHL gene can be inherited or arise de novo. The frequency of de novo pathogenic variants has been reported to be as high as 20 percent of VHL patients in less contemporary studies [97]. Rare patients may have the clinical features of VHL without a detectable pathogenic variant from analysis of a blood sample due to mosaicism for the VHL pathogenic variant. (See 'Patients with somatic mosaicism' below.)

It can be particularly challenging to have a patient with a single VHL-associated tumor and a variant of uncertain significance (VUS) in the VHL gene. Many clinicians will use their own judgment to decide whether to pursue VHL surveillance in that setting. The Clinical Genome Resource (ClinGen) has launched a VHL Variant Classification Expert Panel to try to further improve evaluation of germline variants in VHL and reduce the number of VUS results [98,99].

Special populations

Patients with characteristic VHL lesions — Comprehensive genetic testing of the VHL gene is recommended for individuals with the presence of one or more characteristic lesions including hemangioblastomas of the brain, spine, or retina; endolymphatic sac tumors; epididymal cystadenomas; pheochromocytoma (often as part of a larger paraganglioma/pheochromocytoma hereditary panel); multiple pancreatic cystadenomas; and clear cell RCC diagnosed at age 40 or younger. There is also a large variety of hereditary cancer panels, many of which include the VHL gene. Thus, individuals might be diagnosed with a pathogenic variant in VHL due to other combinations of tumor diagnoses and family history (eg, those with a diagnosis of clear cell RCC over the age of 40 and a family history of kidney cancer).

At-risk relatives — For at-risk relatives (eg, any individual with a family history of VHL where prior genetic testing has been performed), testing should be obtained for the pathogenic VHL variant identified in the affected relative. This approach is often called "known familial pathogenic variant" testing. However, laboratories often use automated sequencing platforms may re-evaluate the entire VHL gene for each family member.

Patients with secondary pathogenic variants — There is increasing clinical use of whole exome sequencing for the diagnosis of Mendelian disorders [100,101]. As a result, the ACMG published recommendations for the reporting of secondary (previously referred to as "incidental") findings of pathogenic or likely pathogenic variants. The VHL gene is included in this list that are thought to be medically actionable, even if the original indication for testing was unrelated to a cancer diagnosis [102,103]. Data suggest that a majority (over 90 percent) of patients undergoing this testing request to have the results of secondary pathogenic variants reported to them [104]. Thus, certain individuals (particularly young children) may be diagnosed with presymptomatic VHL disease using such whole exome sequencing testing, prior to developing any features of the disorder. (See "Molecular biology and pathogenesis of von Hippel-Lindau disease", section on 'Pathogenic variants and clinical manifestations of disease'.)

Patients with somatic mosaicism — In a patient with somatic mosaicism, a pathogenic variant occurs during embryonic development after fertilization; in these circumstances, some cells will be normal while others carry the pathogenic variant. In contrast to detecting germline pathogenic variants, diagnostic difficulties are more likely as the clinical presentation depends on the proportion of cells that carry this mosaic VHL pathogenic variant [105,106]. Although an individual with somatic mosaicism may present with classic VHL disease, the disease-associated variant may not be detectable in the peripheral blood because the hematologic stem cells do not carry the pathogenic variant. In this scenario, the individual carries three VHL alleles, one "normal" allele inherited from each parent, and a third allele that contains the pathogenic variant (which may occur on either parental chromosome (figure 2)).

Thus, the possibility of mosaicism should be considered in patients presenting with VHL-associated tumors and a negative VHL genetic test using peripheral blood cells. The disease manifestations in such patients are dependent upon when the de novo pathogenic variant event occurred in embryogenesis. The earlier the new pathogenic variant occurred, the more tissue types are likely to be affected. The use of NGS technologies for VHL pathogenic variant analysis provides increased sensitivity to detect VHL variants that exist at very low levels in the blood sample compared with older Sanger sequencing methods [107]. Additional testing approaches for mosaicism can include genetic analyses of skin fibroblasts or buccal mucosal cells. Testing of multiple tumors from the same patient with mosaicism can sometimes provide information on the causative pathogenic variant shared across tumors, but it should be interpreted by an experienced geneticist or genetic counselor.

Genetic counseling — Patients should be referred for appropriate genetic advice in conjunction with genetic testing for VHL pathogenic variants [92]. VHL disease is inherited in an autosomal dominant fashion, and affected individuals have a 50 percent probability of transmitting the disease-associated VHL variant to each offspring. Given the variable age of tumor onset, most individuals with VHL live into adulthood and have children, often before the diagnosis is made. Therefore, it is not unusual to see multigenerational VHL pedigrees with many affected individuals, each having slightly different patterns of tumor diagnoses and variable age of onset.

Among the rare patients with somatic mosaicism, the risk to offspring depends upon whether or not the germline tissue carries the pathogenic variant, although that generally is not determined clinically. Thus, patients with documented mosaicism should be counseled that their risk of having an affected child may be as high as 50 percent and that any affected child will inherit the pathogenic variant in 100 percent of their cells and will potentially have more severe manifestations of the disease than the mosaic parent.

The diagnosis of VHL in a child of unaffected parents can be very alarming, and the concept of de novo pathogenic variants or variable expressivity (eg, where the parent may not yet have been diagnosed with a VHL-associated tumor) should be carefully explained. One should never assume that healthy parents are negative for the VHL variant without direct genetic testing. Parents should be reassured and potential guilt alleviated by explaining that a de novo pathogenic variant is unlikely to be the result of any action that occurred immediately prior to or during the pregnancy.

There is increasing awareness of the concern of parents as to when to provide information about the diagnosis to children with a positive VHL genetic test. In general, it is best for this information to be conveyed in multiple settings as the child's maturity increases, and parents may benefit from the support of a medical professional in initiating these discussions [92]. The VHL Alliance provides resources that help explain the disease to children, parents, and other health care professionals [13].

PREGNANCY AND VHL

Assessment of fetal VHL genetic status — Prospective parents planning or carrying a pregnancy at risk for VHL disease have multiple options for learning the VHL pathogenic variant status of the fetus.

Prenatal diagnosis — A couple may choose prenatal diagnosis after pregnancy is initiated, utilizing a sample obtained by amniocentesis or chorionic villus sampling. Some couples that choose prenatal diagnosis wish to know the VHL status prior to birth in order to prepare, while others may elect to terminate a pregnancy if the fetus is affected.

Prospective parents should also be provided with information about reproductive technologies that greatly lower their risk of having a child with VHL disease, such as sperm or oocyte donation (depending on which parent is affected), and preimplantation genetic diagnosis. The latter involves testing embryos fertilized in vitro for the familial VHL pathogenic variant, usually on a single cell of a blastocyst, and selecting unaffected embryos for implantation [108]. In one study, 6.5 percent of couples with an affected individual chose to pursue prenatal diagnosis [109]. The various reproductive options available to prospective parents require thoughtful discussion and genetic counseling. (See "Preimplantation genetic testing".)

Postnatal diagnosis — The couple may choose not to know their child's VHL genetic status until after the child is born. If prenatal genetic testing is not performed, then all at-risk children should be tested in infancy for the VHL pathogenic variant found in the affected parent in order to determine whether or not the VHL disease surveillance regimen is required. In such children diagnosed with VHL, surveillance should be initiated promptly.

Surveillance prior to and during pregnancy — Women with VHL who are pregnant should have close surveillance for associated lesions, due to the risk of VHL-related pregnancy complications. Whether VHL-related lesions demonstrate new or accelerated growth during pregnancy is controversial [110-112]. Nevertheless, for women known to have VHL, it is recommended to have complete VHL surveillance performed to assess for such lesions prior to attempted conception and on an as needed basis during pregnancy (table 2). The VHL Alliance also provides recommendations for the care of VHL patients prior to and during pregnancy [13]. (See 'Surveillance protocols' below.)

Pheochromocytoma — It is particularly important to evaluate for any evidence of pheochromocytoma prior to conception. The growth or development of pheochromocytomas can have catastrophic consequences during pregnancy and delivery, such as the release of metanephrines due to pressure on the tumor during labor and subsequent blood pressure instability [110,111]. All women with pheochromocytomas, including those with VHL disease, need to have them surgically removed before attempting to become pregnant. If preconception VHL screening is not performed, then plasma metanephrines and normetanephrines are generally tested in the first trimester and then early in the third trimester of pregnancy.

Further details on the management of pheochromocytoma in pregnancy and in adults are discussed separately. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Pheochromocytoma in pregnancy' and "Treatment of pheochromocytoma in adults".)

Other VHL lesions — Women with existing retinal, brain, and spinal cord lesions may be at increased risk for tumor growth during pregnancy [111,113]. In such patients, retinal exams should be performed regularly throughout the pregnancy. Additionally, noncontrast magnetic resonance imaging (MRI) of the brain are performed in the fourth month of pregnancy to follow up on central nervous system (CNS) lesions. Delivery via cesarean section should be considered to lower the probability of developing increased intracranial pressure.

A review of VHL progression during pregnancy at one VHL center in the Netherlands demonstrated accelerated growth of cerebellar hemangioblastoma in the two years around pregnancy [111], although this was not observed in a second series [113].

SURVEILLANCE PROTOCOLS — Morbidity and mortality in patients with VHL disease have decreased substantially due to an improved understanding of the natural history of the serious clinical manifestations of the disorder, better imaging techniques, and improvements in therapy. Surveillance is important not only to detect new lesions at an early stage, but also to monitor small asymptomatic lesions for evidence of progression.

Surveillance protocols focus on hemangioblastomas (including retinal capillary hemangioblastomas), renal cell carcinomas (RCCs), pheochromocytomas and audiology given the increased risk of endolymphatic sac tumors (ELST) in patients with VHL. Surveillance recommendations may need to be adapted to the individual patient, taking into account the patient’s current or prior tumor diagnoses. However, all individuals with VHL, even if currently asymptomatic, should understand that they may develop manifestations of VHL disease and will benefit from following surveillance guidelines.

Several organizations provide updated surveillance guidelines that account for contemporary imaging and laboratory diagnostic methods. An international panel of clinicians who care for children with VHL was convened in 2016 as part of the American Association for Cancer Research (AACR) Childhood Cancer Predisposition Workshop. The panel reviewed both the American and European VHL regimens and published surveillance recommendations that incorporated increased intensity of and earlier initiation of screening [114]. These guidelines were subsequently assessed by a consensus panel formed by the VHL Alliance, consisting of clinicians covering all fields of expertise involved in the management of VHL disease and representatives from the AACR workshop. The following summarizes those recommendations from the VHL Alliance consensus panel (table 2) [13].

Ages 0 to 4

●Every 6 to 12 months

•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist skilled in diagnosis and management of retinal disease, especially for children known to carry the VHL pathogenic variant from infancy

●Annually

•From age 1 year – History and physical examination by a clinician informed about VHL disease

•From age 2 years – Blood pressure and pulse measurements

Ages 5 to 10

●Every 6 to 12 months

•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist informed about VHL, using a dilated exam

●Annually

•History and physical examination by a clinician informed about VHL disease

•Blood pressure and pulse measurements

•Assessment of plasma metanephrines, or urinary metanephrines using 24-hour urine testing

Age 11 and beyond

●Every 6 to 12 months

•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist informed about VHL, using a dilated exam

●Annually

•History and physical examination by a clinician informed about VHL disease

•Assessment of plasma metanephrines or urinary metanephrines using 24-hour urine testing

●Every 2 years

•Magnetic resonance imaging (MRI) with and without contrast of brain, cervical, thoracic, and lumbar spine

•Audiogram performed by an audiologist

Ages 15 and beyond

●Every 6 to 12 months

•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist informed about VHL, using a dilated exam

●Annually

•History and physical examination by a clinician informed about VHL disease

•Assessment of plasma metanephrines or urinary metanephrines using 24-hour urine testing

●Every 2 years

•MRI with and without contrast of brain, cervical, thoracic, and lumbar spine

-A one-time MRI of the brain with thin cuts through inner ear/petrous temporal bones (internal auditory canal) to rule out ELST of the middle ear

•MRI abdomen with and without contrast

•Audiogram performed by an audiologist

Beginning age 30

●Decrease frequency of eye exam to annually. All other testing remains the same.

Beginning age 65

●Annually

•Eye/retinal examination with indirect ophthalmoscopy by an ophthalmologist informed about VHL, using a dilated exam.

•History and physical examination by a clinician informed about VHL disease.

•Assessment of plasma metanephrines or urinary metanephrines using 24-hour urine testing.

•Stop surveillance MRI imaging for areas that have not shown any disease manifestations. For areas that have active disease, continue imaging at a frequency that allows follow-up and management of lesions in question.

ADDITIONAL RESOURCES — Summary information concerning VHL disease may be useful for counseling patients and affected families. The following organization can provide such information:

VHL Alliance

2001 Beacon Street, Suite 208

Boston, MA 02135

Telephone: 617-277-5667

Toll free number in the United States and Canada: 800-767-4VHL

FAX: 858-712-8712

www.vhl.org

The VHL Handbook is available in eight languages as a download on the web [email protected] or through the VHL Alliance office. The handbook is a reference guide for patients and their health care teams.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

●Von Hippel-Lindau (VHL) disease – VHL disease is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors (table 1). (See 'Introduction' above.)

●VHL-associated tumors – For patients with VHL disease, the primary goal of management is the early diagnosis and treatment of VHL-associated tumors that otherwise might cause severe disability or death (table 2). The spectrum of such tumors includes the following:

•Clear cell renal cell carcinomas (RCCs) (see 'Renal cell carcinomas' above)

•Hemangioblastomas (including retinal hemangioblastomas) (see 'Hemangioblastomas' above and 'Retinal capillary hemangioblastomas' above)

•Pheochromocytomas (see 'Pheochromocytomas' above)

•Endolymphatic sac tumors (ELSTs) of the middle ear (see 'Endolymphatic sac tumors of the middle ear' above)

•Serous cystadenomas and neuroendocrine tumors of the pancreas (see 'Pancreatic tumors' above)

•Papillary cystadenomas of the epididymis and broad ligament (see 'Papillary cystadenomas of the epididymis and broad ligament' above)

●Clear cell RCCs – Clear cell RCCs occur in approximately 70 percent of VHL patients who survive to 60 years of age. Surveillance imaging of the kidneys with magnetic resonance imaging (MRI) should be initiated in early adolescence (table 2). (See 'Renal cell carcinomas' above.)

In patients with VHL disease, the management of locoregional RCC is as follows (algorithm 1):

•Tumors <3 cm – For patients with solid renal tumors <3 cm who are asymptomatic, we suggest initial surveillance rather than immediate surgery or medical therapy (Grade 2C), due to the low metastatic potential of these tumors. However, for such patients with accelerated tumor growth (>5 millimeters per year) or those who wish to potentially postpone or avoid future surgical interventions, we offer belzutifan as an alternative to surveillance. (See 'Locoregional tumors <3 cm' above and 'Belzutifan' above.)

•Tumors ≥3 cm – For patients with a diagnosis of RCC ≥3 cm, we recommend a nephron-sparing approach rather than radical nephrectomy (Grade 1B), based on data in patients with and without VHL disease. While data suggest similar survival outcomes, nephron-sparing approaches preserve kidney parenchyma and reduce the risk of chronic kidney dysfunction, which is preferable for patients with VHL disease who are at risk for bilateral and recurrent tumors. (See 'Locoregional tumors ≥3 cm' above and "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy' and "Radiofrequency ablation, cryoablation, and other ablative techniques for renal cell carcinoma".)

●Central nervous system hemangioblastomas – Central nervous system (CNS) hemangioblastomas are the most common lesions in patients with VHL disease and tend to be multiple and infratentorial. Annual retinal examinations should be initiated beginning in infancy to diagnose and treat retinal hemangioblastomas at an early enough stage to preserve vision. Starting at the age of 11 years, surveillance imaging of the brain and spinal cord with magnetic resonance imaging (MRI) every other year is indicated to identify lesions as they develop and minimize disease-related complications (table 2). (See 'Hemangioblastomas' above and 'Surveillance protocols' above.)

In patients with VHL disease, the management of CNS hemangioblastomas is as follows:

•For patients with imaging evidence of one or more hemangioblastomas who are asymptomatic and/or have indolent tumor growth, we suggest surveillance with serial imaging rather than surgery or medical therapy (Grade 2C). However, belzutifan, a hypoxia-inducible factor-2alpha (HIF-2alpha) inhibitor, is a reasonable alternative to surveillance for patients with tumors that could become symptomatic if allowed to progress or for those who wish to delay or defer future surgery. (See 'Surveillance and risk of progression' above.)

•Surgery is typically required for patients with hemangioblastomas that are causing significant neurologic symptoms or are threatening compromise due to mass effect or hemorrhage. (See 'Indications for surgery' above.)

•For most patients with symptomatic or rapidly enlarging CNS hemangioblastomas that are unresectable or pose a high risk of postoperative deficits, we suggest a trial of systemic therapy with the HIF-2alpha inhibitor, belzutifan, rather than initial radiation therapy (RT) or an attempt at high-risk surgical debulking (Grade 2C). (See 'Belzutifan' above.)

•For patients with retinal hemangioblastoma who initiate treatment, we suggest laser photocoagulation rather than other therapies (Grade 2C). Alternative options include photodynamic therapy or RT (particularly for salvage therapy). Belzutifan is an acceptable option for patients who are ineligible for local therapy due to tumor proximity to the optic nerve or multiple progressive lesions. (See 'Retinal capillary hemangioblastomas' above and 'Management' above.)

●Pheochromocytomas – Pheochromocytomas tend to be seen in younger patients, are often multiple or extra-adrenal, and although symptoms can be present, are less likely to be associated with symptoms or biochemical evidence of catecholamine production compared with those occurring in patients without VHL disease who are primarily diagnosed based on the presence of symptoms. Annual assessment of plasma metanephrines should begin with young children. Surveillance imaging of the abdomen for pheochromocytomas should be initiated in early adolescence (table 2). (See 'Pheochromocytomas' above.)

●Endolymphatic sac tumors of the middle ear – ELSTs are slowly growing lesions that can cause significant hearing loss and may be bilateral. Baseline audiometry should begin in early childhood, and appropriate imaging should be carried out based on symptoms (table 2). Retesting and appropriate imaging are indicated if there are symptoms of ringing, tinnitus, pain, or change in auditory acuity. (See 'Endolymphatic sac tumors of the middle ear' above.)

●Pancreatic tumors – Patients with VHL may present with pancreatic abnormalities such as simple cysts, serous cystadenomas and neuroendocrine neoplasms (algorithm 2). Patients with VHL do not have an increased risk of pancreatic adenocarcinoma. Surveillance imaging of the abdomen for pancreatic tumors should be initiated in early adolescence (table 2) (See 'Pancreatic tumors' above.)

•Tumors ≤3 cm (body or tail) or ≤2 cm (head) of pancreas – For patients with primary lesions ≤3 cm in the body or tail of the pancreas, or ≤2 cm in the head of the pancreas, we suggest surveillance with serial imaging rather than resection (Grade 2C). Belzutifan is an alternative to surveillance for patients with lesions that exhibit rapid tumor growth or those with resectable disease who wish to delay or defer future surgical interventions. (See 'Role of surveillance and belzutifan' above.)

•Tumors >3 cm (body or tail) or >2 cm (head) of the pancreas – For patients with potentially resectable pancreatic neuroendocrine tumors (pNETs) >3 cm in diameter in the body or tail of the pancreas, or >2 cm in diameter in the head of the pancreas, we suggest surgical resection rather than other interventions or systemic therapy (Grade 2C). For those with unresectable disease, we suggest belzutifan over other systemic therapies (Grade 2C). (See 'Role of surgery' above.)

●Diagnosis – The diagnosis of VHL disease is typically established through detection of a germline pathogenic (typically loss of function) variant in the VHL gene, most commonly in patients who undergo genetic testing after being diagnosed with a single manifestation of VHL disease, or those who are tested because they have a close relative diagnosed with VHL disease. (See 'Diagnosis' above.)

With the increasing use of next-generation sequencing (NGS) test methods, hereditary cancer panels, and tumor sequencing in the care of cancer patients, there is an increase in the diagnosis of VHL disease in patients with the apparently sporadic forms of VHL-associated tumors, as well as, more rarely, from secondary findings in patients undergoing whole exome or genome sequencing for other indications. Changes in ascertainment, for example as a secondary finding, may result in a decrease in the estimate of VHL tumor risks since most knowledge is based on individuals presenting with symptomatic disease and their close relatives. (See 'Genetic testing' above.)

●Prospective parents – Prospective parents planning or carrying a pregnancy at risk for VHL disease should be offered genetic counseling, provided with information about reproductive technologies that lower their risk of having a child with VHL, and be counseled on the multiple options for learning the VHL pathogenic variant status of the fetus. (See 'Genetic counseling' above and 'Assessment of fetal VHL genetic status' above.)

●Pregnancy and VHL – Women with VHL disease who plan to or who become pregnant need a much higher level of surveillance than usual, with particular attention to evaluating and treating pheochromocytomas prior to pregnancy. (See 'Surveillance prior to and during pregnancy' above.)