Individuals affected with a germline mutation in the VHL gene can develop CNS hemangioblastomas in childhood, although the mean age at diagnosis is 29 years (1,7). VHL-associated hemangioblastomas occur on average 15 years earlier than sporadic ones (8). Depending on the size and location of the tumor, symptoms include signs of increased intracranial pressure such as headache and nausea, as well as vertigo, ataxia, dysmetria, nystagmus, and slurred speech. A spinal hemangioblastoma may lead to focal neurologic deficits such as weakness and paresthesias. Diagnosis is established by an magnetic resonance imaging scan of the head and spine. Hemangioblastomas, usually slow growing and asymptomatic tumors, are associated with a risk of bleeding. Surgical removal of the tumor may be curative. However, in VHL disease, tumors including hemangioblastomas often are multifocal, i.e. they may occur at other locations. The natural history of these lesions has recently been reported and will help in determining optimal timing of screening for individual patients and for evaluating the timing and results of treatment (9). By analyzing postmortem CNS tissues from patients with well-established diagnosis of VHL disease, studies conducted by Vortmeyer et al. (10) helped better understand the histogenetic origin of hemangioblastomas.

In many patients with VHL syndrome, these eye lesions are the first manifestation. Retinal angiomas are not malignant, but can lead to retinal detachment, blindness, cataracts, and (secondary) glaucoma. The mean age at diagnosis is 25 years but these tumors also can occur in infants. Therefore, at risk individuals should undergo a careful ophthalmologic evaluation in regular periods, starting at the age of 1 year. Once detected, retinal angiomas are often treated by laser therapy or cryotherapy (1,4,11).

Patients with VHL syndrome can develop renal cysts but also renal cancer (12-17). The mean age at diagnosis is 37 years. Detection methods include computed tomography and ultrasound (18-20). Solid cancer lesions may contain cystic parts, making it difficult to distinguish benign from malignant renal lesions by imaging in the absence of clear-cut metastases. treatment should be directed at removing these lesions, whenever possible by parenchymal-sparing surgery to maintain renal function as long as possible and to avoid dialysis (13,21). Usually, these renal tumors enlarge slowly (< 0.5 cm/year) (22,23). The risk of metastatic disease is related to tumor size. In general, surgery is recommended when solid renal lesions exceed 3 cm in size (standard in the U.S.) or 5 cm (standard in Europe) (13,15,23,24).

As mentioned in the chapter by Dr. Pacak (www.endotext.com, “Pheochromocytoma”), pheochromocytomas usually are sporadic but in approximately 10% of patients can occur in a familial syndrome such as VHL syndrome. Pheochromocytomas occur in patients with VHL disease type 2 (Fig.1). In a series of 246 patients with VHL syndrome, 64 patients were found to have a pheochromocytoma (25). In one third, these tumors were “nonfunctional” and did not cause symptoms of catecholamine excess such as hypertension. The mean age at diagnosis was 29 years with a range from age 6 to age 54. Bilateral tumors in this group were found in 39% of patients. In contrast to other familial pheochromocytoma syndromes such as multiple endocrine neoplasia type 2 (MEN 2) and neurofibromatosis type 1 (NF 1), extraadrenal pheochromocytomas occur in patients with VHL syndrome in up to 30% (25-28). Malignant pheochromocytomas (defined as the presence of chromaffin tissue at locations where such tissue should not be present, i.e. lungs, liver, bone, lymph nodes) are uncommon in VHL syndrome and MEN 2 (25,26,29-31). Unfortunately, there are no markers yet that can reliably distinguish a benign from a malignant pheochromocytoma (32). The detection of a pheochromocytoma in patients with VHL syndrome is particularly important, given the possible need for surgical interventions for other tumors such as CNS hemangioblastomas. Just like in any patient with undetected pheochromocytoma, surgery and other factors can lead to life-threatening hypertensive attacks. Screening for pheochromocytoma in at risk patients should include measurement of urinary catecholamines and fractionated metanephrines, as well as of plasma metanephrines (33-35). This should be started already in childhood at the age of 6 years (36). More than 70% of pheochromocytomas presenting in children are due to VHL disease. The diagnosis can further be established by abdominal computed tomography and/or magnetic resonance imaging (37). In addition, every patient with confirmed pheochromocytoma by biochemical findings and an adrenal mass on imaging, should undergo 131I-MIBG scanning to search for extraadrenal or metastatic lesions, before adrenal sparing adrenalectomy is performed. Importantly, (isolated) pheochromocytoma can be the presenting manifestation of VHL syndrome (38,39). The biochemical tumor profile can help distinguish VHL-associated pheochromocytoma from MEN 2-related pheochromocytoma, the latter also occurring in the isolated form, i.e. before medullary thyroid carcinoma (40). Genetic profiling by performing mutation analysis for the VHL, RET, and SDHD/SDHB genes, appears to be mandatory for all patients presenting with apparently sporadic pheochromocytoma, since up to 24% have germline mutations in the aforementioned genes (41). Treatment of nonmetastatic adrenal pheochromocytoma consists of adrenal sparing (partial) adrenalectomy, either uni- or bilateral, depending on whether one or both adrenal glands are affected (42-45). Partial adrenalectomy is mainly indicated for pheochromocytomas less than 3 cm in size (42,43). Whether nonfunctional pheochromocytomas (clinically only remarkable as adrenal masses on imaging with fractionated urinary metanephrines less than three times normal) require treatment/surgery, if they are smaller than 5 cm, remains unclear. Important aspects are how fast such tumors grow, if and when they cause symptoms, and if and when (at what size) they metastasize.

Figure 1. VHL-associated pheochromocytoma. Round, small neuroendocrine cells with prominent clear and amphophilic cytoplasm (modified from Koch et al., Endocrine Pathology 2002, ref. 24)

These are benign tumors that can occur bilateral (46). These typically 2 cm large lesions are found in the globus major of the epididymis and can involve the spermatic cord, leading to infertility. Surgery is rarely required in these mostly asymptomatic tumors.

Between 35 and 75% of patients with VHL syndrome have benign cysts and microcystic (serous) adenomas of the pancreas (47-50). According to the radiological literature, up to 17% of VHL patients have pancreatic neuroendocrine tumors by computed tomography (49,51). The mean age at diagnosis is 35 years. Pancreatic cysts in VHL patients can occur at the age of 15 years and are most often asymptomatic. Depending on size and location, symptoms can be caused by biliary obstruction and/or pancreatic insufficiency. Treatment in these circumstances consists of placing biliary stents and/or replacing pancreatic enzymes. Hormonally functional neuroendocrine pancreatic tumors are rare (49,53). Importantly, these tumors can metastasize with an increased risk for lesions exceeding 3 cm (51,52). Surgical resection is required for growing tumors or those that cause symptoms. The benefit of surgery for asymptomatic pancreatic neuroendocrine tumors needs to be determined.

This tumor of the inner ear lies between the dura of the posterior fossa at the end of the endolymphatic sac canal and the intraosseous portion of the endolymphatic duct/sac, the vestibular aqueduct (18,54,55), Fig. 2.. Although metastases from endolymphatic sac tumors have not yet been reported, these tumors can invade locally. Symptoms include hearing loss, tinnitus, and/or facial paresis (56, 57). Patients affected by a VHL germline mutation should be evaluated by a good history, physical examination, audiologic evaluation and high-resolution CT and MRI through the inner ear (58). Whether early surgical intervention can preserve hearing needs to be determined. On the other hand, in patients with bilateral endolymphatic sac tumors resulting in deafness, hearing can be restored by cochlear implants.

Figure 2. Radiologic, morphologic, and immunohistochemical features of ELSTs (Ref. 55, Glasker et al., Cancer Res 2005)

The VHL gene was isolated in 1993 and is located at chromosome 3p25/26 (59, 60).. Almost all individuals with the clinical diagnosis VHL disease have a germline mutation in the VHL gene. Approximately 20% of VHL patients demonstrate deletion of the VHL locus at the maternal or paternal allele (61,62). The VHL gene consists of 3 exons encoding a mRNA of 4.5 kb. The VHL protein comprises 213 amino acid residues with a molecular weight of approximately 28 kDa. pVHL interacts with a transcriptional elongation complex. When bound to elongin B and elongin C, pVHL also interacts with Cul2, a member of the cullin family. In a multimeric complex, pVHL polyubiquitinates hypoxia-induced factor alpha (HIFalpha) subunits. This then may lead to degradation of proteins in the 26S Proteasome. Tumor cells that lack pVHL accumulate HIF, leading to an overproduction of the products of HIF target genes such as vascular endothelial growth factor and transforming growth factor alpha (63). This phenomenon may explain why VHL-associated neoplasms are very vascularized. At the molecular level, VHL disease follows Knudson’s two-hit model based on a recessive mutation, i.e. in most patients, the first hit is represented in the VHL germline mutation and the second hit in the deletion of the remaining wild-type VHL allele. Interestingly, almost all VHL germline mutations that occur in VHL patients with pheochromocytoma, are missense mutations (for instance, in codon 167). The “second hit” in VHL-associated pheochromocytomas could be demonstrated as loss of heterozygosity at 3p25/26 in 91% of tumors (64-66). Whether inactivation of the VHL wild-type allele is sufficient for the formation of tumor, remains to be elucidated. Biallelic inactivation of VHL in the germline leads to embryonic lethality, as demonstrated in the mouse (67). On the other hand, renal cysts in VHL patients show loss of the remaining wild-type VHL allele, as do renal cancer lesions, underscoring that an inactivation of the VHL wild-type allele appears necessary but not sufficient for tumor formation (12, 55). Similarly, in patients with a germline mutation in RET, such a mutation, although here in an oncogene, may not be sufficient to lead to tumor formation (68,69). Although VHL is ubiquitously expressed, somatic VHL mutations are rare in human cancer except for clear cell renal carcinoma (4,70-73). The majority of sporadic clear cell renal carcinomas are found to have mutations of the VHL gene. Indications for VHL germline mutation screening are: a) patients with one or more VHL-associated tumor (for instance, pheochromocytoma), especially when younger than age 50, and b). relatives of patients with VHL disease.