Management of von Hippel-Lindau disease

INTRODUCTION — Von Hippel-Lindau (VHL) disease is an inherited, autosomal-dominant syndrome that occurs due to germline pathogenic variants in the VHL gene. VHL disease is characterized by a variety of benign and malignant tumors, which include central nervous system hemangioblastoma, clear cell renal cell carcinomas, and pheochromocytoma, among other tumors (table 1).

The management of tumors associated with VHL disease is discussed here. The molecular biology and pathogenesis, and the clinical presentation, diagnosis, and surveillance of VHL disease are discussed separately.

●(See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)

●(See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease".)

●(See "Gene test interpretation: VHL".)

ASSOCIATED TUMORS — Patients with VHL disease can present with a specific group of benign and malignant tumors. Specific treatment approaches are based on tumor type.

●Clear cell renal cell carcinomas – (See 'Renal cell carcinoma' below.)

●Central nervous system hemangioblastomas – (See 'CNS hemangioblastoma' below.)

●Retinal capillary hemangioblastomas (retinal angiomas) – (See 'Retinal capillary hemangioblastoma' below.)

●Pheochromocytomas – (See 'Pheochromocytoma' below.)

●Pancreatic cysts and serous cystadenomas; pancreatic neuroendocrine neoplasms – (See 'Pancreatic abnormalities' below.)

●Endolymphatic sac tumors of the middle ear – (See 'Endolymphatic sac tumors of the middle ear' below.)

●Papillary cystadenomas of the epididymis and broad ligament – (See 'Papillary cystadenomas of the epididymis and broad ligament' below.)

The management of patients with VHL disease requires a multidisciplinary approach involving expertise in the treatment of the disease as well as its associated social, genetic, and psychosocial issues. Patients should ideally be treated at a center of excellence in the management of VHL disease. (See 'Additional resources' below.)

RENAL CELL CARCINOMA — The clinical presentation of clear cell renal cell carcinoma (RCC) in VHL disease is discussed separately. (See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease", section on 'Renal cell carcinomas'.)

The management of patients with VHL disease and clear cell RCC is evolving. Patients with VHL disease and kidney masses should seek multidisciplinary care from clinicians familiar with VHL management guidelines [1], 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. (See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease", section on 'Genetic counseling'.)

Our approach to the management of these patients is outlined below.

Locoregional tumors <3 cm

Rapidly progressive tumors — For patients with VHL disease and solid locoregional kidney tumors <3 cm with accelerated tumor growth, we suggest belzutifan (algorithm 1). Although there are no formal criteria, some experts define accelerated tumor growth as greater than 5 mm per year. In these patients, belzutifan is effective, has durable responses, and may be used to potentially postpone or avoid future surgical interventions.

Belzutifan — 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 – For patients who develop anemia on belzutifan (hemoglobin <10), we offer the use of erythropoiesis-stimulating agents (ESAs) to maintain a target goal hemoglobin of ≥10. ESAs are highly effective in treating anemia and can reduce the need for red blood cell transfusion in our clinical experience. We avoid red blood cell transfusion (when possible) and offer dose reduction of belzutifan if ESAs are not effective in maintaining hemoglobin levels.

This approach diverges from the US Food and Drug Administration (FDA) label, which does not recommend the use of ESAs with belzutifan due to limited safety data [2,3]. The indications for ESAs in the treatment of anemia in patients with cancer are discussed separately. (See "Role of ESAs in adults with non-hematologic cancers".)

●Management of hypoxia – Oxygen saturation should be monitored before initiating and during therapy.

•For patients with hypoxia (eg, pulse oximeter <88 percent or partial pressure of oxygen [PaO₂] <55 mmHg) during exercise, we hold belzutifan until hypoxia resolves, then resume at the same dose or offer a dose reduction to 80 mg daily, depending on the severity of the hypoxia. (See "Long-term supplemental oxygen therapy", section on 'Prescribing oxygen'.)

•For those with hypoxia at rest, we hold belzutifan until hypoxia has resolved and either resume at a reduced dose or discontinue, depending on the severity of the hypoxia.

•For patients with life-threatening hypoxia or recurrent symptomatic hypoxia, belzutifan should be permanently discontinued.

●Patients (or those with partners) who may become pregnant – Patients (or those with partners) who may become pregnant should use effective contraception during and at least one week after the last belzutifan dose, as this agent is a teratogen and can cause fetal harm. Belzutifan may also render some hormonal contraceptives ineffective.

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 [4], 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) [4].

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 immediate surgery [2].

Slowly progressive tumors — For patients with VHL disease and solid locoregional kidney tumors <3 cm that are slowly progressive (≤5 mm per year), we suggest initial surveillance rather than immediate surgery or medical therapy due to the low metastatic potential of these tumors (algorithm 1). Belzutifan is an acceptable alternative to surveillance for those who desire a more aggressive management strategy to potentially postpone or avoid future surgical interventions. (See 'Belzutifan' above.)

Tumors under surveillance 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 [1].

Solid kidney 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 observational study, serial imaging studies were performed in 96 patients with VHL disease and small kidney tumors [5]. 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".)

Locoregional tumors ≥3 cm

Nephron-sparing approaches — For patients with VHL disease and locoregional RCC ≥3 cm, we suggest a nephron-sparing approach rather than radical nephrectomy, as this approach preserves kidney parenchyma and reduces the risk of chronic kidney disease (CKD) (algorithm 1). Of the available nephron-sparing approaches, we suggest partial nephrectomy in patients with good performance status and minimal comorbidities. Radiofrequency ablation and cryotherapy are alternatives to surgery for select populations, such as patients who need to preserve kidney parenchyma (eg, solitary kidney, bilateral and/or multiple tumors, recurrent tumors), patients with CKD, older patients, or patients with significant comorbidities.

Young patients with VHL disease may experience bilateral kidney tumors, recurrent tumors and require multiple interventions throughout their lifetime. As a result, the management of locoregional RCC in 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 long-term risk of chronic kidney function impairment [5-10]. Improved imaging modalities (eg, computed tomography [CT], MRI, and ultrasound) combined with regular surveillance programs have led to the identification of more early-stage RCCs. The use of nephron-sparing approaches to treat VHL disease-associated locoregional RCC is also based on data from patients with sporadic early-stage locoregional RCCs, including from randomized trials [11-13]. These data demonstrate similar oncologic outcomes for nephron-preserving surgery compared with radical nephrectomy, with lower risk of chronic kidney function impairment. Further details are discussed separately. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)

As an example, in one observational study, 65 patients with VHL disease were treated with either radical nephrectomy (16 patients) or nephron-sparing surgery (49 patients) [7]. Nephron-sparing surgery was associated with higher 10-year cancer-specific survival compared with radical nephrectomy (81 versus 36 percent), despite a high local recurrence rate (51 percent). Long-term kidney function was preserved in all but one patient treated with partial nephrectomy (mean preoperative versus postoperative serum creatinine of 1 versus 1.6 mg/dL). In contrast, among the 15 patients who developed end-stage kidney disease, more than one-half (8 patients) were treated with bilateral radical nephrectomy. Subsequent observational studies evaluating partial nephrectomy in patients with VHL disease have also confirmed excellent long-term survival outcomes [9] and avoidance of dialysis [8].

There are no randomized trials comparing the various nephron-sparing approaches in VHL disease. We prefer initial treatment with partial nephrectomy in patients with good performance status and minimal comorbidities. Repeat partial nephrectomies (to preserve kidney parenchyma and avoid dialysis) may also be feasible in carefully selected patients [8]. However, radiofrequency ablation and cryoablation also permit the eradication of multiple small tumors while minimizing damage to the normal kidney [10]. These approaches are appropriate alternatives to surgery in patients who need to preserve kidney parenchyma (eg, solitary kidney, bilateral and/or multiple tumors, recurrent tumors), patients with CKD, older patients, or patients with significant comorbidities. Further details are discussed separately. (See "Radiofrequency ablation, cryoablation, and other ablative techniques for renal cell carcinoma", section on 'Indications'.)

Continued close surveillance is required after treatment of RCC in patients with VHL disease. New kidney tumors are detected in approximately 30 percent of patients by 5 years and 85 percent by 10 years. The risk of metastatic disease appears to be low if the patient is carefully monitored. However, in one report of 21 such patients, 2 developed metastatic disease at a median follow-up of 29 months [6]. (See "Surveillance for metastatic disease after definitive treatment for renal cell carcinoma".)

Ineligible for surgery or other nephron-sparing approaches — 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 [14]. 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 [15,16]. The management of these patients is the same as those with sporadic advanced and metastatic clear cell RCC, which is discussed separately. (See "Systemic therapy for advanced and metastatic clear cell renal carcinoma" and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)

CNS HEMANGIOBLASTOMA — The clinical presentation of central nervous system (CNS) hemangioblastoma in VHL disease is discussed separately. (See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease", section on 'CNS hemangioblastomas'.)

General approach — Patients with VHL disease are at risk for CNS hemangioblastomas in deep and critical locations within the brainstem, cerebellum, and spinal cord [17,18]. 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 [17-22]. 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 [1]. 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) [23]. (See 'Symptomatic or progressive disease' below.)

CNS hemangioblastomas can remain dormant for unpredictable periods of time or can present with accelerated growth [19,24]. 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 "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease", section on 'Surveillance for associated tumors'.)

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 [17]. 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 disease and symptomatic and/or progressively enlarging CNS hemangioblastomas, options for therapy include surgery, RT, and systemic agents (eg, belzutifan). VHL-associated hemangioblastomas are best managed in a multidisciplinary fashion with input from neurosurgeons, interventional neuroradiologists, radiation oncologists, and neuro-oncologists with expertise in CNS malignancies. (See "Hemangioblastoma", section on 'Treatment'.)

While surgery and RT 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 (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 is 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 [4]. At median follow-up of 22 months, among this subset, objective responses were seen in 15 patients (30 percent), including 3 complete (6 percent) and 12 partial responses (24 percent) [4]. 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 granted regulatory approval to belzutifan in adult patients with VHL disease who require therapy for associated CNS hemangioblastoma and do not require immediate surgery [2].

Radiation therapy — Stereotactic radiosurgery (SRS) and conventional fractionated RT may play a role in treating recurrent/refractory lesions that are not readily accessible by surgery and/or have progressed on belzutifan, although data are limited for this approach [25,26].

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 [25].

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 provides clinical benefit in individuals with CNS hemangioblastomas but should be used with caution. Preclinical and observational data suggest that pazopanib, which possesses modest inhibition of fibroblast growth factor receptors, may provide some value in the management of hemangioblastomas [27]. 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 [15].

●Sunitinib – A prospective clinical trial with sunitinib failed to demonstrate response in hemangioblastomas, although this class of agents is active in RCCs [16].

RETINAL CAPILLARY HEMANGIOBLASTOMA — The clinical presentation of retinal capillary hemangioblastoma in VHL disease is discussed separately. (See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease", section on 'Retinal capillary hemangioblastomas'.)

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 [28].

Some groups recommend that retinal capillary hemangioblastomas be treated immediately upon detection (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 [28]. 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 hemangioblastomas, although limited data exist on its efficacy. External beam RT may have a role in salvage therapy if other modalities have failed [29].

●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 [4].

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 that interfere with angiogenesis (eg, such as sunitinib, pazopanib, bevacizumab, and ranibizumab) have demonstrated limited efficacy in retinal hemangioblastoma [15,16,30,31]. Other studies have also evaluated VEGF inhibitors in combination with platelet-derived growth factor inhibitors [32]. (See "Hemangioblastoma", section on 'Antiangiogenic therapy'.)

PHEOCHROMOCYTOMA — The clinical presentation of pheochromocytoma in VHL disease is discussed separately. (See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease", section on 'Pheochromocytoma'.)

In patients with VHL disease, pheochromocytomas are surgically removed after appropriate alpha- and beta-adrenergic blockade and other (as needed) supportive measures [33]. It is critical to suppress catecholamine production in the preoperative period and follow patients carefully peri- and postoperatively for several weeks to ensure that endocrine and cardiovascular function has not been compromised by prolonged overproduction of catecholamines.

Further details on the management of pheochromocytoma in adults and children are discussed separately. (See "Treatment of pheochromocytoma in adults" and "Pheochromocytoma and paraganglioma in children".)

PANCREATIC ABNORMALITIES

Pancreatic cystic lesions — The clinical presentation of pancreatic cysts and serous cystadenomas in VHL disease is discussed separately. (See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease", section on 'Pancreatic cysts and serous cystadenomas'.)

Asymptomatic pancreatic cysts and serous cystadenomas in VHL disease are simply observed since they do not have malignant potential.

For large discrete cystic lesions that cause symptoms due to mass effect, treatment options include decompression via cyst drainage or marsupialization [34]. (See "Approach to walled-off pancreatic fluid collections in adults", section on 'Our approach to drainage'.)

More invasive interventions, such as surgery, may be necessary for cysts that cause biliary or enteric obstruction or in those where the diagnosis of a benign cystic lesion is uncertain [34].

The use of belzutifan remains investigational for nonmalignant pancreatic cystic lesions in VHL disease. Belzutifan reduced the size of pancreatic cystic lesions in a phase II study (Study 004) of 61 patients with systemic therapy-naïve VHL-associated renal cell carcinoma (RCC) [4]. All 61 patients also had pancreatic lesions, a majority of which were cystic (64 percent). At median follow-up of 22 months, the objective and complete response rates were 77 and 10 percent, respectively.

Pancreatic solid lesions and pNETs

Role of surgery — Management of pancreatic neuroendocrine tumors (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 positron emission tomography-CT, although other imaging options are available [34]. 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 >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 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) [35-37]. (See 'Role of surveillance and belzutifan' below.)

Data support risk stratification of pNETs <2 to 3 cm according to both size [35,38] and the results of VHL genotyping [36,39]. In one prospective observational study, 175 patients with VHL disease 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 (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 (5 versus 0 for patients with other types of pathogenic variants). Surgical intervention was required more frequently among patients with a missense VHL pathogenic variant compared with other types of molecular alterations (40 versus 16 percent) and those with an exon 3 (as compared with exon 1 or 2) pathogenic variant (HR 8.8, 95% CI 1.2-66.3).

Earlier studies emphasized the prognostic influence of tumor growth rate [35,37].

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 pNETs appear to be generally better than those of sporadic pNETs [38,40]. (See "Surgical resection of sporadic pancreatic neuroendocrine tumors", section on 'Extent of resection'.)

Role of surveillance and belzutifan — For patients with pNETs ≤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 with 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 "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors", section on 'General approach to the patient'.)

A phase II study (Study 004) of 61 patients with systemic therapy-naïve VHL-associated RCC included a subset of 22 patients with measurable pNETs [4,41]. 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) [4]. The median time to response was approximately eight 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 granted regulatory approval to belzutifan in adult patients with VHL disease who require therapy for VHL-associated pNETs and do not require immediate surgery [2].

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

ENDOLYMPHATIC SAC TUMORS OF THE MIDDLE EAR — The clinical presentation of endolymphatic sac tumors (ELSTs) of the middle ear in VHL disease is discussed separately. (See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease", section on 'Endolymphatic sac tumors of the middle ear'.)

Patients with ELSTs are treated based on the presence and severity of tumor-related symptoms.

●Asymptomatic disease – For most patients with asymptomatic ELSTs, we suggest surgical excision, which can prevent hearing loss or other associated vestibular symptoms [42]. However, observation is still a reasonable alternative, as some studies suggest that hearing loss is a potential complication of surgery [43]; further data are necessary to assess this risk.

●Symptomatic disease – Patients with symptomatic ELSTs are treated with surgery, which is curative if the lesion is completely excised [43-45].

Patients with recurrent disease may be treated with stereotactic radiosurgery [46]. Cochlear implants may be an option for patients with hearing loss due to bilateral ELSTs [47]. (See "Hearing amplification in adults", section on 'Cochlear implants'.)

PAPILLARY CYSTADENOMAS OF THE EPIDIDYMIS AND BROAD LIGAMENT — The clinical presentation of papillary cystadenoma of the epididymis (in males) or broad ligament (in females) with VHL disease is discussed separately. (See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease", section on 'Papillary cystadenomas'.)

Papillary cystadenomas are benign lesions. Patients with these conditions who are asymptomatic do not require treatment and can be observed [48]. Patients with mild pain or dyspareunia and female patients with mild menorrhagia can be offered supportive care. Surgery is reserved for the rare patient who is severely symptomatic or at risk for infertility due to these lesions [49]. (See "Nonacute scrotal conditions in adults", section on 'Epididymal cyst/spermatocele'.)

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 various languages as a download 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: Cancer of the kidney and ureters" and "Society guideline links: Primary brain tumors" and "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors" and "Society guideline links: Pheochromocytoma and paraganglioma".)

SUMMARY AND RECOMMENDATIONS

●Definition – Von Hippel-Lindau (VHL) disease is an inherited, autosomal-dominant syndrome that occurs due to germline pathogenic variants in the VHL gene. VHL disease is characterized by a variety of benign and malignant tumors, which include central nervous system (CNS) hemangioblastomas, clear cell renal cell carcinomas (RCCs), and pheochromocytomas, among other tumors (table 1). (See "Clinical presentation, diagnosis, and surveillance of von Hippel-Lindau disease".)

●Management by tumor type – For patients with VHL disease, specific treatment approaches are based on tumor type. The management of patients with VHL disease requires a multidisciplinary approach. (See 'Associated tumors' above and 'Additional resources' above.)

●Clear cell RCCs – The management of locoregional clear cell RCC is as follows (algorithm 1) (see 'Renal cell carcinoma' above):

•Tumors <3 cm – For patients with solid kidney tumors <3 cm and accelerated tumor growth (>5 mm per year), we suggest belzutifan, a hypoxia-inducible factor-2alpha (HIF-2alpha) inhibitor (Grade 2C). (See 'Rapidly progressive tumors' above.)

For patients with tumors <3 cm that are slowly progressive (≤5 mm per year), we suggest initial surveillance rather than immediate surgery or medical therapy (Grade 2C) due to the low metastatic potential of these tumors. Belzutifan is an acceptable alternative to surveillance for those who desire a more aggressive management strategy to potentially postpone or avoid future surgical interventions. (See 'Slowly progressive tumors' above.)

•Tumors ≥3 cm – For patients with a diagnosis of RCC ≥3 cm, we suggest a nephron-sparing approach rather than radical nephrectomy (Grade 2C), as this approach preserves kidney parenchyma and reduces the risk of chronic kidney disease (CKD). Of the available nephron-sparing approaches, we suggest partial nephrectomy in patients with good performance status and minimal comorbidities (Grade 2C). Radiofrequency ablation and cryotherapy are alternatives to surgery for select populations, such as patients who need to preserve kidney parenchyma (eg, solitary kidney, bilateral and/or multiple tumors, recurrent tumors), patients with CKD, older patients, or patients with significant comorbidities. (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".)

For patients who are not candidates for further surgery or other nephron-sparing approaches, we offer systemic therapy with belzutifan. (See 'Ineligible for surgery or other nephron-sparing approaches' above.)

●Central nervous system hemangioblastomas – The management of CNS hemangioblastomas is as follows (see 'CNS hemangioblastoma' above):

•Asymptomatic and/or indolent disease – 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). Belzutifan 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.)

•Symptomatic or rapidly growing disease – 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 'Symptomatic or progressive disease' above and '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 belzutifan rather than initial radiation therapy (RT) or an attempt at high-risk surgical debulking (Grade 2C). (See 'Belzutifan' above.)

●Retinal capillary hemangioblastoma – 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 hemangioblastoma' above.)

●Pheochromocytoma – Pheochromocytomas are surgically removed after appropriate alpha- and beta-adrenergic blockade and other supportive measures, if needed. The management of pheochromocytoma is discussed separately. (See "Treatment of pheochromocytoma in adults" and "Pheochromocytoma and paraganglioma in children".)

●Pancreatic solid lesions and neuroendocrine neoplasms – The management of pancreatic solid lesions and neuroendocrine neoplasms is as follows (algorithm 2):

•Tumors ≤3 cm (body or tail) or ≤2 cm (head) of the 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 >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). (See 'Role of surgery' above.)

•Unresectable disease – For those with unresectable disease, we suggest belzutifan over other systemic therapies (Grade 2C). (See 'Role of surveillance and belzutifan' above.)

●Endolymphatic sac tumors (ELST) of the middle ear – For most patients with asymptomatic ELSTs, we suggest surgical excision (Grade 2C), which can prevent hearing loss or other associated vestibular symptoms; however, observation is an appropriate alternative since hearing loss is a potential complication of surgery. (See 'Endolymphatic sac tumors of the middle ear' above.)

Patients with symptomatic ELSTs are treated with surgery, which is curative if the lesion is completely excised. Cochlear implants may be an option for patients with hearing loss due to bilateral ELSTs.