von Hippel-Lindau disease

UpToDate: 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 VHL gene abnormality is present in about 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 about 26 years [1]. The spectrum of VHL-associated tumors includes:

  • Hemangioblastomas of the brain (cerebellum) and spine
  • 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

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 carry a missense mutation in the VHL gene.

Type 1 — Patients in kindreds with type 1 disease have a substantially lower risk of developing pheochromocytomas, although they are at high risk for the other VHL-associated lesions.

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 renal cell carcinoma (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 for affected individuals, 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.

The molecular pathogenesis of VHL disease is discussed elsewhere. A «two-hit» model appears to apply to this disorder. Affected patients have a germline mutation 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 mutation or deletion of the second allele, or through hypermethylation of its promoter.

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 at a very young age, and screening for other lesions starting slightly later.

Hemangioblastomas

Clinical manifestations 

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.

Hemangioblastomas are the most common lesions associated with VHL disease, affecting 60 to 84% of patients and typically occur in the cerebellum or spinal cord [1,2,7]. 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 tend to be infratentorial and multiple [8]. In a detailed analysis of 160 patients with VHL and hemangioblastoma, 655 discrete tumors were identified, of which 51% were in the spinal cord, 38% in the cerebellum, 10% in the brainstem, and 2% supratentorial [7].

We recommend that all patients with either a retinal or CNS hemangioblastoma be tested for VHL germline mutations, even in the case of a single lesion. Where access to genetic investigations is limited, it would be reasonable to focus testing on patients with solitary lesions presenting under the age of 50 years since the likelihood of identifying a germline VHL mutation is inversely correlated with the age of the patient.

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 mutations were present in 5% of cases [9]. Of those who tested negative, 5% developed a VHL-related lesion in the ensuing years, which may result from being mosaic for a VHL mutation.

Because 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 after the age of 10.

Management 

Hemangioblastomas can remain dormant for unpredictable periods of time or can present with accelerated growth [7,10]. Currently there are no definitive clinical (eg, age, gender, location), radiographic, or specific molecular markers (ie, underlying mutations) that can predict the natural history of a given lesion, and regular follow-up with imaging and observation of clinical signs and symptoms is necessary. A review of 225 patients with 1921 central nervous system hemangioblastomas demonstrated that 51% of lesions did not grow. In the remaining 49% of hemangioblastomas, 72% grew in a saltatory, 6% in a linear, and 22% in an exponential fashion [11]. 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.

Therapeutic efforts should focus on avoiding treatment-related morbidity by minimizing the frequency of surgical interventions because of the frequent development of multiple lesions. Small asymptomatic lesions can be followed with careful surveillance. Although surgery usually can successfully remove lesions in the spinal cord, brainstem, and cerebellum, intervention is reserved until lesions become symptomatic or they display accelerated growth [7,8,12,13]. Patients who demonstrate progression by neural imaging should be followed at more frequent intervals for evidence of clinical symptoms.

Stereotactic radiosurgery (SRS) and conventional fractionated radiation therapy (RT) may play a role in treating lesions that are not readily accessible by surgery [14]. There are no 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 [14]. On the basis of these findings, prophylactic treatment of asymptomatic hemangioblastomas with SRS is not recommended, and surgery is still considered the standard of care when feasible.

At this time, no effective systemic therapy has been validated for hemangioblastomas. A prospective clinical trial with sunitinib, an antiangiogenic agent, failed to demonstrate response in hemangioblastomas [15]. Preclinical data suggested that fibroblast growth factor receptor (FGFR) inhibitors may provide some value in the management of hemangioblastomas. Based on these findings, a case report of response to the antiangiogenic agent pazopanib, which possesses modest FGFR blocking activity, was reported [16]. Further work needs to be done to define the value of specific antiangiogenic agents for hemangioblastomas.

Outcomes with different therapeutic approaches for the management of hemangioblastoma are discussed elsewhere.

Retinal capillary hemangioblastomas

Retinal capillary hemangioblastomas (RCH) 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 [17]. 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% of VHL patients by age 60 years; they are often multifocal and bilateral. Compared with patients with sporadic retinal angiomas, 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, 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 [18].

In a study of 890 patients with VHL, 335 patients had a retinal capillary hemangioblastoma in at least one eye. Lesions were detected unilaterally in 42% and bilaterally in 58% of affected patients. No correlation was detected between the age, gender, or laterality of involvement. Of involved eyes, 87% had tumors that could be individually visualized; of these, tumors were commonly found in the peripheral retina (85%) only, and less commonly in the juxtapapillary area (15%). The tumor count in the periphery averaged 2.5+/-1.8 per eye, with 25% of eyes having more than one quadrant of retinal involvement [19]. An assessment of the genotype-phenotype relationship in retinal capillary hemangioblastoma suggested that 15% of individuals with complete deletions of VHL protein had hemangioblastoma development versus an overall prevalence in the patient population of 37%. 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 hemangioblastomas, any patient presenting with a retinal capillary hemangioblastoma (particularly if prior to age 40) should have a complete evaluation for the presence of VHL.

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 ophthalmic surveillance in the pediatric population.

The treatment of retinal capillary hemangioblastoma requires that the benefits of treatment be balanced against potential treatment-related complications. Whether the smallest lesions can be carefully observed without specific treatment until there is any evidence of growth or symptoms is controversial [20]. 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.

Laser photocoagulation and cryotherapy are effective in over 70% of cases, generally with a single treatment, and are the preferred methods of treatment [20]. 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 [21].

Investigational approaches have focused on interfering with angiogenesis. The experimental vascular endothelial growth factor (VEGF) receptor inhibitor semaxinib (SU5416) was reported to successfully reduce peritumoral edema and improve vision in six patients with VHL, although the drug did not reduce the actual tumor size itself [22-25]. This agent is not commercially available.

In a study assessing impact of sunitinib on VHL-related lesions, the very small number of individuals with retinal lesions did not show signs of improvement [15]. In a small study of five patients, the VEGF-binding monoclonal antibody ranibizumab produced only a minimal effect in one of five patients [26]. These investigational approaches may be useful to reduce the symptoms generated from hemangioblastomas of the optic nerve that are difficult to treat. Further studies need to be performed to better understand the biology of the hemangioblastoma cell of origin and its endothelium and to develop more effective systemic therapies.

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 [27,28].

The diagnosis of RCC is rare in VHL disease prior to age 20 but occurs with increasing frequency thereafter; thus screening is initiated in adolescence [1,2,29]. The mean age at onset in one large series was 44 years and it was estimated that 69% of patients surviving to age 60 would develop RCC [1]. The incidence of RCC is lower in patients who carry missense mutations in the VHL gene in which pheochromocytoma is prominent [4].

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 [30]. Histopathologic changes in the renal parenchyma are widespread and are not limited to renal cysts [31]. 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 mutation (54 out of 64 treated, 10 out of 64 active surveillance) over a mean follow-up of 55 months [32]. In this series, the mean growth rate of 96 tumors was 4.4 mm/year (SD 3.2, median 4.1 mm/year), 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.

Treatment 

The therapeutic approach to RCC in patients with VHL has shifted from radical nephrectomy to nephron-sparing approaches (observation for small lesions, partial nephrectomy, cryotherapy, radiofrequency ablation), with the goal of preserving as much renal parenchyma as possible [29,33-35]. Patients diagnosed with VHL should be aware of these recommendations and should seek care from a urologist familiar with VHL guidelines if a renal mass is discovered.

Several factors have contributed to this change:

  • Improved imaging modalities (eg, computed tomography [CT], magnetic resonance imaging [MRI], and ultrasound), combined with regular surveillance programs, have led to the identification of more RCCs at an early stage.
  • Solid renal tumors <3 cm in diameter generally have a low metastatic potential and can be safely monitored as long as they remain stable. In one study, for example, serial imaging studies were performed in 96 patients with VHL syndrome and small renal tumors [34]. Surgery was performed in 52 when a tumor reached a threshold size of 3 cm in diameter. Only two patients required nephrectomy, and none developed metastatic disease at a median follow-up of 60 months. In the other 44 patients, this size threshold was not used as an indication for immediate surgery. In this group, 12 patients required nephrectomy, and 11 developed metastatic disease with a median follow-up of 66 months.
  • 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 renal parenchyma and avoid dialysis [35]. The rationale and results with partial nephrectomy for patients with RCC are discussed separately.
  • Other nephron-sparing approaches, particularly cryoablation and radiofrequency ablation, may permit the eradication of multiple small tumors while minimizing damage to the normal kidney.

Continued close surveillance is required after treatment of RCC in VHL patients. New renal tumors are detected in approximately 30% of patients by five years and 85% 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 [29].

Renal transplantation has been used in VHL patients who required bilateral nephrectomy for RCC or developed end-stage renal 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 receiving renal transplants and 32 matched transplant recipients without the disorder [36]. At an average follow-up of four years, no differences were observed between the two groups in graft and patient survival or renal function.

Systemic therapy options are being studied in patients with VHL and RCC. With the advent of molecularly targeted therapy that can decrease the size of RCC lesions, it may be possible to decrease frequency of surgical intervention through chronic or intermittent use of currently available agents. A clinical trial assessing sunitinib in 15 VHL patients showed a 33% partial response rate [15]. An ongoing clinical trial is testing pazopanib in the same patient population (NCT01436227).

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, neurofibromatosis type 1, and mutations of the succinate dehydrogenase (SDH) subunits B, D, and C. The different familial syndromes manifesting pheochromocytomas are discussed in detail elsewhere.

A significant proportion of patients with seemingly sporadic pheochromocytoma have an underlying cancer susceptibility syndrome, including VHL. This issue was addressed in a review of 271 patients with apparently sporadic pheochromocytoma (no other tumors or family history of the disease) from population-based registries in Germany and Poland [37]. All were tested for germline mutations in VHL and three other genes (Ret, SDHB, SDHD) that have been implicated in familial pheochromocytoma. A germline VHL mutation was identified in 30 patients overall (11%) and in 42% 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 mutation since both parents tested negative.

All patients with pheochromocytoma should have a genetic evaluation to identify the underlying syndrome (found in 40% of patients) so that the proper surveillance is initiated for other tumors for which the patient is at risk. The presence of pheochromocytomas is used to define types 2A-C VHL disease.

Pheochromocytomas in VHL disease tend to be seen in younger patients, are often multiple, may be extraadrenal, and are less likely to be associated with symptoms or biochemical evidence of catecholamine production compared with those occurring in patients without VHL [38-40]. Pediatric cases are not infrequent [41,42].

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 [40]. Of these, 12% originated outside the adrenal gland and 35% of patients were asymptomatic, without hypertension or evidence of increased catecholamine production.
  • In the Mayo Clinic experience, 20 of 109 patients with VHL disease (18%) had a pheochromocytoma at a median age of 30 years, including three originating outside the adrenal gland [39]. 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.

The possibility of an occult pheochromocytoma needs to be considered whenever a patient with VHL type 2 disease requires surgery because of the risk of sympathetic overactivity and severe hypertension.

Diagnosis 

Pheochromocytomas can be detected with radiographic imaging, via urine metanephrine/normetanephrine testing, and with plasma metanephrine/normetanephrine testing. Conventional imaging may not be sufficient because of the potential for extraadrenal lesions, referred to as paragangliomas. Studies with 18F-DOPA PET provide some context and suggest that 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 (7 out of 7), as did computed tomography (CT) scan. On the other hand [(123/131)I]-MIBG scintigraphy failed to detect 4 of the 7 lesions [43].
  • These data were confirmed in an independent study of 48 patients with hereditary and nonhereditary cases [44].
  • In a prospective study assessing adrenal imaging of 52 patients with VHL, 390 lesions were identified by CT (n = 139), magnetic resonance imaging (MRI) (n = 117), 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% of patients and 4.4% of lesions [45].
  • 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. Metastatic disease was detected by 18F-FDG PET in three patients in whom it was not detected by CT scan and suggested non-neoplastic disease in an additional three patients.

Measurement of plasma metanephrines and normetanephrines provides important diagnostic information.

In a study of patients with VHL and multiple endocrine neoplasia type 2 (MEN-2), measurements of plasma normetanephrines and metanephrines provided a sensitivity of 97%, and specificity of 96% [46]. VHL patients almost exclusively produced normetanephrines (indicating norepinephrine production), so a high normetanephrine to metanephrine ratio is expected in patients with VHL.

Management 

The recommended surveillance testing for pheochromocytoma in patients with VHL disease is discussed below.

Treatment of choice for symptomatic pheochromocytomas is surgical removal after appropriate alpha-adrenoreceptor blockade and other supportive measures, if needed [47]. 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.

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 [48]. Common clinical manifestations include hearing loss, tinnitus, vertigo, and less often, facial muscle weakness [48-51].

Three mechanisms have been described to account for the hearing loss and other symptoms associated with endolymphatic sac tumors (ELSTs) [51].

  • 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% of the patients with VHL versus 1% in the patients without VHL [50]. In two other reports in VHL patients, 5 of 34 tumors (15%) were bilateral [48,49].

ELSTs have been associated with mutations in the VHL gene and with other manifestations of VHL disease [49,50,52-54]. In two studies that included a total of 250 patients with VHL disease, detailed evaluation revealed ELSTs in 34 (14%) [48,49].

Diagnosis 

ELSTs may be difficult to detect with a single modality. Patients with VHL 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 [48]. These lesions can be very difficult to see radiographically. Whether surgery is indicated for patients with an asymptomatic tumor is controversial [51], 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 [55,56]. 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, endolymphatic sac tumors were suspected based on audiovestibular symptoms, audiometry, and MRI in 34, 30, and 12.5% of subjects, respectively. In total, more than 90% of radiologically diagnosed ELSTs were associated with abnormal audiometric findings [57].

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 ELST is primarily surgical; if the lesions can be completely excised, surgery is curative [58-60]. Stereotactic radiosurgery may have a role for recurrent disease [61].

Cochlear implants may be an option for patients with hearing loss due to bilateral ELSTs [62].

Pancreatic tumors

Pancreatic abnormalities are common in patients with VHL disease. In a multi-institutional study of 158 consecutive patients from 94 affected families, 77% had lesions in the pancreas, including cysts (70%), serous cystadenomas (9%), and neuroendocrine tumors (9%) [63]. In another series of 633 patients with VHL disease, neuroendocrine tumors were identified in 108 (17%) [64].

Simple pancreatic cysts and serous cystadenomas may be asymptomatic even when the radiologic presentation is dramatic. However, such lesions can cause epigastric pain and discomfort [65,66]. 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 VHL patients who have pancreatic cysts. Mucinous cysts of the pancreas are not seen in association with VHL disease, and VHL patients do not have an increased risk of pancreatic adenocarcinoma.

Neuroendocrine tumors of the pancreas can metastasize to the liver and may produce symptoms due to secreted peptides (eg, diarrhea with vasoactive intestinal peptide and hypoglycemic episodes with insulin) [63]. In one series of 108 patients with neuroendocrine tumors, nine (8%) had metastatic disease [64].

However, most of these tumors are asymptomatic 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 [63,67]. As a result, many of these lesions are diagnosed incidentally during surveillance for renal lesions [64].

Management of pancreatic neuroendocrine tumors is surgical. Resection is generally reserved for lesions greater than 3 cm in diameter in the body or tail of the pancreas, or 2 cm in diameter in the head of the pancreas [64,68]. Smaller asymptomatic lesions may be monitored with imaging at yearly intervals. In a study of 108 VHL patients with pancreatic neuroendocrine tumors, tumors <3 cm, with a doubling time >500 days, and mutations in VHL gene exons 1 or 2 had a minimal risk for metastasis, suggesting that such patients could be managed with observation [64].

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) [69]. 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. On the other hand, bilateral papillary cystadenomas are almost pathognomonic of VHL disease [2,70]. 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 [70].

Papillary cystadenomas in the broad ligament in women are also asymptomatic in most patients, and thus the true incidence of these lesions is unknown [71,72]. Symptoms that have been reported include pain, dyspareunia, and menorrhagia; treatment is symptomatic.

VHL mutations 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 [27,54,73-77]. As noted above, two hits appear to be required in VHL disease in both the hereditary and sporadic tumors. The hits can result from inherited mutations, somatic mutations followed by loss of heterozygosity, or loss of gene expression caused by promoter hypermethylation.

The following observations illustrate the frequency with which this occurs:

  • Somatic mutations of the VHL gene and/or allelic deletion may be present in as many as 50% of sporadic hemangioblastomas.
  • Abnormalities of the VHL gene are also found in 50 to 60% of patients with sporadic RCC, suggesting that the VHL gene has a role in pathogenesis in this setting as well.
  • VHL abnormalities in apparently sporadic pheochromocytoma are observed less commonly (4% of benign lesions and in 17% of malignant tumors in a series of 72 patients) [75]. However, some of these patients actually have germline mutations and, therefore, VHL disease [37].

Diagnosis

Genetic testing 

Although clinical criteria were originally developed for the diagnosis of VHL primarily based upon the finding of more than one VHL-associated tumor, detection of a germline mutation in the VHL gene now is typically used to establish the diagnosis, particularly in patients with a single manifestation of the condition [2].

Genetic testing, which is typically performed on peripheral blood lymphocytes, involves DNA sequencing and dosage analysis using MLPA or Southern blot analysis of the VHL gene. The sensitivity and specificity of these methods are nearly 100% [78]. Germline mutations in the VHL gene can be inherited or arise de novo. The latter occurs in about 20% of kindreds. Rare patients may have the clinical features of VHL without a detectable mutation due to mosaicism for the VHL mutation.

Patients suspected of having VHL disease should be referred to specialized centers for evaluation, genetic counseling, and definitive diagnosis, even if there is no family history of VHL disease. Approved VHL Clinical Care Centers are listed at the VHL Alliance. These centers have been approved for standards of care that were developed by the VHL Alliance’s Medical Advisory Board.

Comprehensive genetic testing of the VHL gene should be based on the presence of one or more characteristic lesions. The specific criteria used at the Massachusetts General Hospital VHL Clinic are summarized in the table (table 2). Testing for a specific familial VHL mutation should then be performed for at-risk relatives based upon having a blood relative with an established diagnosis of VHL.

Somatic mosaicism 

In a patient with somatic mosaicism, a mutation occurs during embryonic development after fertilization; in these circumstances, some cells will be normal while others carry the mutation. In contrast to finding germline mutations, diagnostic difficulties are more likely [79,80]. Although an individual with somatic mosaicism may present with classic VHL disease, the mutation may not be detectable in the peripheral blood because the hematologic stem cells do not carry the mutation.

Thus, the possibility of mosaicism should be considered in patients presenting with VHL-associated tumors and a negative VHL genetic test based upon peripheral blood. The disease manifestations in such patients are dependent upon when the de novo mutation event occurred in embryogenesis. The earlier the new mutation occurred, the more tissue types are likely to be affected.

Genetic counseling 

Patients should be referred for appropriate genetic counseling in conjunction with testing for VHL mutations. VHL disease is inherited in an autosomal dominant fashion, and affected individuals have a 50% probability of transmitting the VHL mutation to each offspring.

Among patients with somatic mosaicism, the risk to offspring depends upon whether or not the germ tissue carries the mutation, although that cannot be determined clinically. Thus, patients with documented mosaicism should be counseled that their risk of having an affected child may be as high as 50% and the affected child will inherit the mutation in 100% of their cells and potentially have more severe manifestations of the disease. Testing of multiple tumors from the same patient with mosaicism can sometimes provide information on the causative mutation but should be interpreted by an experienced geneticist or genetic counselor.

The diagnosis of VHL in a child of unaffected parents can be very alarming, and the concept of de novo mutations should be carefully explained. In particular, parents should be reassured and potential guilt alleviated by explaining that the mutation is unlikely to be the result of any action that occurred immediately prior to or during the pregnancy.

Pregnancy and VHL

Prospective parents planning or carrying a pregnancy at risk for VHL face different options for learning the carrier status of the fetus. The couple may choose not to know until after the child is born. Alternatively, a couple may choose prenatal diagnosis, utilizing a sample obtained by amniocentesis or chorionic villus sampling. Some couples that choose prenatal diagnosis wish to know the carrier status prior to birth in order to prepare, while others may elect to terminate a pregnancy if the fetus is affected. If prenatal genetic testing is not performed, then all at-risk children should be tested for the VHL mutation found in the affected parent in order to determine whether or not the VHL surveillance regimen is required.

Prospective parents should also be provided with information about reproductive technologies that greatly lower their risk of having a child with VHL, such as sperm or oocyte donation (depending on which parent is affected), and preimplantation genetic diagnosis. Preimplantation genetic diagnosis involves testing embryos fertilized in vitro for the familial VHL mutation, usually on a single cell of a blastocyst, and selecting unaffected embryos for implantation [81]. The various reproductive options available to prospective parents require thoughtful discussion and genetic counseling.

VHL related lesions may demonstrate accelerated growth in some women during pregnancy. Particular care needs to be taken during follow-up of these individuals, especially if they have a prior history of pheochromocytomas, CNS lesions, or retinal lesions [82,83]. All women with pheochromocytomas need to have these surgically removed before attempting to become pregnant. Growth or development of pheochromocytomas can have catastrophic consequences during pregnancy and delivery, so plasma metanephrine testing during early and late pregnancy is warranted.

Women with existing retinal, brain, and spinal cord lesions may be at increased risk for tumor growth during pregnancy [83,84]. Eyes should be checked regularly throughout the pregnancy, and noncontrast magnetic resonance imaging (MRI) may be considered in the fourth month to follow up on CNS lesions. Delivery via cesarian section should be considered to lower the probability of developing increased intracranial pressure.

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 VHL disease, 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 has focused primarily on hemangioblastomas (including retinal capillary hemangioblastomas), renal cell carcinomas (RCCs), and pheochromocytomas, the three manifestations most often resulting in severe disability or death. Surveillance recommendations need to be adapted to the individual patient, taking into account the presence of previously diagnosed asymptomatic disease and disease manifestations in other members of the family. However, there is variability within families, and patients should understand that they may develop manifestations of VHL that were not seen in their affected relatives.

There is some controversy concerning the optimal frequency for various imaging and screening procedures, which attempts to balance the risks and costs versus the potential for a delayed diagnosis. The following summarizes recommendations made by the VHL Alliance in conjunction with their medical advisory board.

Ages 1 to 4

Annually

  • 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 mutation.
  • Pediatrician to look for signs of neurological disturbance, nystagmus, strabismus, white pupil, and abnormalities in blood pressure, vision, or hearing.

Ages 5 to 15

Annually

  • Physical examination and neurological assessment by pediatrician informed about VHL, with particular attention to blood pressure, lying and standing, hearing issues, neurological disturbance, nystagmus, strabismus, white pupil, and other signs which might indicate a referral to a retinal specialist.
  • Eye/retinal examination with indirect ophthalmoscopy by ophthalmologist informed about VHL, using a dilated exam.
  • Test for plasma metanephrines or urinary metanephrines using 24-hour urine test.
  • Abdominal ultrasonography annually from eight years or earlier if indicated. Abdominal magnetic resonance imaging (MRI) or functional imaging scan only if biochemical abnormalities found.

Every 2 to 3 years

  • Complete audiology assessment by an audiologist. Annually if any hearing loss, tinnitus, or vertigo is found.
  • In the case of repeated ear infections, MRI with contrast of the internal auditory canal using thin slices, to check for a possible endolymphatic sac tumor (ELST).

Ages 16 and beyond

Annually

  • Eye/retinal examination with indirect ophthalmoscopy by ophthalmologist informed about VHL, using a dilated exam.
  • Quality ultrasound, and at least every other year MRI scan of abdomen with and without contrast to assess kidneys, pancreas, adrenals, but notduring pregnancy.
  • Physical examination by clinician informed about VHL.
  • Test for plasma metanephrines, or urinary metanephrines using 24-hour urine test.

Every 2 years

  • MRI with contrast of brain and cervical spine, with thin cuts through the posterior fossa, and attention to inner ear/petrous temporal bone to rule out both ELST and hemangioblastomas of neuraxis.
  • Audiology assessment by an audiologist.

During pregnancy 

A review of VHL progression during pregnancy at one VHL center in the Netherlands demonstrated that there appeared to be accelerated growth of cerebellar hemangioblastoma in the two years around pregnancy [83], although this was not observed in a second series [84]. In addition, there were a number of VHL-related pregnancy complications which suggest that women with VHL who are pregnant should have close follow-up.

  • Regular retinal checkup to anticipate potentially more rapid progression of lesions.
  • Test for pheochromcytoma in early, mid, and again late pregnancy to ensure that there is no active pheochromcytoma during pregnancy or, especially, labor and delivery.
  • During the fourth month of pregnancy, MRI – without contrast – to check on any known lesions of the brain and spine. If known retinal, brain, or spinal lesions, consider C-section [85].

Summary and recommendations

von Hippel-Lindau (VHL) disease is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors. The spectrum of VHL-associated tumors includes hemangioblastomas (including retinal hemangioblastomas), clear cell renal cell carcinomas (RCCs), pheochromocytomas, endolymphatic sac tumors (ELSTs) of the middle ear, serous cystadenomas and neuroendocrine tumors of the pancreas, and papillary cystadenomas of the epididymis and broad ligament.

The primary goal of management for patients with VHL diagnosis is the early diagnosis and treatment of tumors that otherwise might cause severe disability or death:

  • The diagnosis of VHL disease is based upon the detection of a germline mutation in the VHL gene and rarely by multiple VHL-associated tumors in the absence of a germline mutation.
  • 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 or early childhood to diagnose and treat retinal angiomas at an early enough stage to preserve vision. Every other year, imaging of the brain and spinal cord with magnetic resonance imaging (MRI) starting after the age of 15 years is indicated to establish the diagnosis and minimize disease-related complications.
  • Clear cell RCCs occur in approximately 70% of VHL patients who survive to 60 years of age. Annual imaging of the kidneys with MRI or computed tomography (CT) is indicated to establish the diagnosis. For patients in whom an RCC is diagnosed, we recommend a nephron-sparing approach to remove lesions that are 3 cm or larger whenever possible (Grade 1B).
  • Pheochromocytomas tend to be seen in younger patients, are often multiple or extraadrenal, and are less likely to be associated with symptoms or biochemical evidence of catecholamine production compared with those occurring in patients without VHL. Annual assessment of plasma metanephrines should begin with young children. Annual imaging of the abdomen for pheochromocytomas and pancreatic tumors should be initiated during adolescence.
  • ELSTs are slowly-growing lesions that can cause significant hearing loss and may be bilateral. Baseline ear, nose, and throat examination including audiometry should be carried out in adolescents. Retesting and appropriate imaging are indicated if there are symptoms of ringing, tinnitus, pain, or change of auditory acuity.

Prospective parents planning or carrying a pregnancy at risk for VHL should be offered genetic counseling and should also be provided with information about reproductive technologies that lower their risk of having a child with VHL. Additionally, women who plan to or become pregnant may need a much higher level of surveillance than usual.

Clinical manifestations of von Hippel-Lindau disease

Ages at diagnosis Most common ages at dx Frequency in patients CNS
CNS
Retinal hemangioblastomas 0-68 yrs 12-25 yrs 25-60%
Endolymphatic sac tumors 12-46 yrs 24-35 yrs 10-25%
Cerebellar hemangioblastomas 9-78 yrs 18-25 yrs 44-72%
Brainstem hemangioblastomas 12-36 yrs 24-35 yrs 10-25%
Spinal cord hemangioblastomas 12-66 yrs 24-35 yrs 13-50%
Viscera
Renal cell carcinoma or cysts 16-67 yrs 25-50 yrs 25-60%
Pheochromocytomas* 4-58 yrs 12-25 yrs 10-20%
Pancreatic tumor or cyst 5-70 yrs 24-35 yrs 35-70%
Epididymal cystadenomas 17-43 yrs 14-40 yrs 25-60% of males*
Adnexal papillary cystadenoma of mesonephric origin (broad ligament cystadenoma) 16-64 yrs 16-46 yrs Estimated 10% of females

* Includes the 20% of lesions that occur outside the adrenal gland, also called paragangliomas.
• Frequency of pheochromocytoma varies widely depending on genotype.

 

Criteria for referral to Massachusetts General Hospital VHL clinic

 

  • Any blood relative of an individual diagnosed with VHL disease
  • Any individual with TWO VHL-associated lesions:
    • Hemangioblastoma
    • Clear cell renal carcinoma
    • Pheochromocytoma
    • Endolymphatic sac tumor
    • Epididymal or adnexal papillary cystadenoma
    • Pancreatic serous cystadenomas
    • Pancreatic neuroendocrine tumors
  • Any individual with ONE or more of the following:
    • CNS hemangioblastoma
    • Pheochromocytoma or paraganglioma
    • Endolymphatic sac tumor
    • Epididymal papillary cystadenoma
  • Any individual with:
    • Clear cell renal carcinoma diagnosed at age <40 years
    • Bilateral and/or multiple clear cell RCCs
    • >1 Pancreatic serous cystadenoma
    • >1 Pancreatic neuroendocrine tumor
    • Multiple pancreatic cysts + any VHL associated lesion

VHL: von Hippel-Lindau.

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