Christian A. Koch, MD, FACP, FACE, Professor of Medicine, Director,
Division of Endocrinology, University of Mississippi, Jackson, MS
McClellan M. Walther, MD, Urologic Oncology Branch, National Cancer
Institute, National Institutes of Health, Bethesda, MD
W. Marston Linehan, MD, Chief, Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
Updated: December 30, 2008
TO OBTAIN A COMPLETE DOWNLOAD OF THIS CHAPTER IN PDF OR WORD FORMAT, CLICK HERE
Key words:VHL, pheochromocytoma, tumor formation, second hit, hemangioblastoma, renal cancer
Von Hippel-Lindau disease is an autosomal dominant, hereditary cancer syndrome with a prevalence of approximately 1/36,000 livebirths per year (1-3). Germline mutations in a tumor suppressor gene, the VHL gene, put affected individuals at risk for developing a variety of tumors, including hemangioblastomas of the retina (often referred to as retinal angiomas) and of the central nervous system, clear cell renal cancer, pheochromocytoma, pancreatic neuroendocrine tumors, endolymphatic sac tumors, and papillary cystadenomas of the epididymis (males) or broad ligament (females). In addition, patients with VHL syndrome can develop visceral cysts, mainly affecting the pancreas and kidneys (4,5).
A clinical classification system divides individuals who are affected by VHL disease into two groups (6, 7): those predominantly without pheochromocytoma classified as VHL type 1, and those predominantly with pheochromocytoma classified as VHL type 2. VHL type 2 is further subdivided into type 2A (with renal cancer) and type 2B (without renal cancer).
Cerebellar and spinal hemangioblastomas (in approximately 65% of patients)
Retinal angiomas (approx. 60%)
Bilateral, multifocal clear-cell renal carcinomas (approx. 45%)
Bilateral, multifocal renal cysts (approx. 45%)
Bilateral, multifocal pheochromocytomas (approx. 26%)
Epididymal cystadenomas (approx. 26%)
Pancreatic cysts and microcystic adenomas (up to 75%), pancreatic neuroendocrine tumors (17%)
Endolymphatic sac tumors (approx. 10%)
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 (1,8,9). VHL-associated hemangioblastomas occur on average 15 years earlier than sporadic ones (10). 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 (11). By analyzing postmortem CNS tissues from patients with well-established diagnosis of VHL disease, studies conducted by Vortmeyer et al. (12)helped better understand the histogenetic origin of hemangioblastomas. Exclusive activation of hypoxia-inducible factor 2 alpha (HIF2alpha) occurs in small mesenchymal tumors and in the mesenchymal component of large tumors. Activation of HIF1alpha is observed in epitheloid lesions. These findings suggest that central nervous system lesions in patients with VHL disease develop as a protracted process of hemangioblastic proliferation and differentiation (13).
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. VHL-associated ocular lesions comprise retinal and optic nerve hemangioblastomas and belong to VHL types 1, 2A, and 2B (Fig. 1A-D, Ref. 14) (14).
Figure 1A.Fundoscopic photograph showing a typical hemangioblastoma in the peripheral retina of a patient with von Hippel-Lindau disease.
Figure 1B.Fundoscopic photograph illustrating a hemangioblastoma in the optic nerve head of a patient with von Hippel-Lindau syndrome.
Figure 1C. Macroscopic photograph showing multiple retinal hemangioblastomas in the eye of a patient with von Hippel-Lindau disease.
Figure 1D.Microphotograph showing small clusters of tumorlet like cells in a von Hippel-Lindau associated optic nerve head hemangioblastoma (hematoxylin & eosin, x400), all images from Chan CC et al., Retina 2007, Ref. 14.
Once detected, retinal angiomas are often treated by laser therapy or cryotherapy (1,4,15). Recently, systemic or intravitreal injection of anti-VEGF (vascular endothelial growth factor) medications had been tried with various success. In spite of intravenous administration for 7 months, SU5416, a VEGF receptor inhibitor, did not reduce the size of VHL retinal hemangioblastoma (16,17). Wong et al. (18,19) reported that 335 patients of 890 with VHL disease (37%) had ocular involvement with the lowest prevalence (14%) among patients with complete deletions of VHL. Chew et al. 2005 (20) found that approximately 8% of the eyes of VHL patients had poor visual acuity of 20/200 or worse with approx. 8% of these eyes requiring enucleation.
Patients with VHL syndrome can develop renal cysts but also renal cancer (21-26). The mean age at diagnosis is 37 years. Detection methods include computed tomography and ultrasound (27-29). Since 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 (22,30). Usually, these renal tumors enlarge slowly (< 0.5 cm/year) (31,32). 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) (22,24,32,33).
After nephron-sparing surgery in patients with VHL disease and renal tumors, some authors reported a local recurrence rate of approx. 50% with a mean time to recurrence of 53 months (range 10 to 115), and a tumor growth rate of 0.34 cm per year (range 0.1 to 1.08) (34). Although the gold standard for treating small renal tumors are open and laparoscopic partial nephrectomy, alternative therapies including cryotherapy and radiofrequency ablation are presently utilized (35). This can impact the outcome of a precise pathological diagnosis, although some authors reported that the pathologic diagnosis following the first-freeze-thaw cycle of cryotherapy was accurate in approx. 91% of cases when comparing the pretreatment biopsy (36).
As mentioned in chapter 34 by Dr. Pacak (www.endotext.com, “Pheochromocytoma”), pheochromocytomas usually are sporadic but in more than 20% of patients can occur in a familial syndrome such as VHL syndrome. Pheochromocytomas predominantly occur in patients with VHL disease type 2 (Fig.2, Ref. 37).
Figure 2 A and B.
VHL-associated pheochromocytoma. Round, small neuroendocrine cells with prominent clear and amphophilic cytoplasm (modified from Koch et al., Endocrine Pathology 2002, ref. 37)
In a series of 246 patients with VHL syndrome, 64 patients (26%) were found to have a pheochromocytoma (38). In one third, these tumors were “nonfunctional” and did not cause symptoms of catecholamine excess such as hypertension. Patients (without VHL disease) with biochemically silent abdominal paragangliomas have recently been reported to have germline mutations in the SDHB gene (39). The mean age at diagnosis of patients reported by Walther et al. (38) was 29 years with a range from age 6 to age 54. Bilateral pheochromocytomas 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% (38, 40, 41, 42). The reason for this phenomenon is not clear but may be related to cooperative tumor suppression (Koch and Pacak, in preparation).
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 (37, 38, 40, 43-45). Unfortunately, there are no markers yet that can reliably distinguish a benign from a malignant pheochromocytoma, although germline mutations in the SDHB gene appear to be of prognostic value (44-46). 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 free metanephrines (47-49). This should be started already in childhood at the age of 6 years (50). Approximately 40% of pheochromocytomas in children have an underlying hereditary cause with germline mutations in either the SDHx genes, RET proto-oncogene, VHL gene, or neurofibromatosis type 1 gene (51). 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 (52). In addition, every patient with VHL disease and confirmed pheochromocytoma by biochemical findings and an adrenal mass on imaging, should undergo 123I-MIBG scanning to search for extraadrenal or metastatic lesions, before adrenal sparing adrenalectomy is performed (53). Importantly, (isolated) pheochromocytoma can be the presenting manifestation of VHL syndrome (54,55). 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 (56). Genetic profiling by performing mutation analysis for the VHL, RET, and SDHD/SDHB/(SDHC) genes, appears to be mandatory for all patients presenting with apparently sporadic pheochromocytoma, since up to 24% have germline mutations in the aforementioned genes (57). 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 (58-61). Partial adrenalectomy is mainly indicated for pheochromocytomas less than 3 cm in size (58,59). Inasmuch nonfunctional pheochromocytomas (clinically only remarkable as adrenal masses on imaging with fractionated urinary metanephrines and/or plasma free metanephrines less than three times normal) require treatment/surgery, if they are smaller than 5 cm, remains unclear. Important aspects in this context are the questions how fast such tumors grow, if and when they cause symptoms, and if and when (at what size) they metastasize. The likelikhood for malignancy amongst hereditary pheochromocytoma syndromes seems to be in descending order when having a germline mutation in the following genes: SDHB, NF1, VHL, RET (62, 63). Therapy with sunitinib, a tyrosine kinase inhibitor of vascular endothelial growth factor, platelet derived growth factor, RET, c-KIT, and FLT-3 receptor, may be promising, when looking at a 21% tumor shrinkage (pelvic malignant pheochromocytoma) and reduction of plasma normetanephrine and chromogranin A after 6 months of therapy (64).
These are benign tumors that can occur bilaterally (65). Most often, 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. Tumor development appears to occur in two sequential steps: maldevelopment of VHL-deficient mesonephric cells with subsequent neoplastic papillary proliferation (66).
Between 35 and 75% of patients with VHL syndrome have benign cysts and microcystic (serous) adenomas of the pancreas (67-70). According to the radiological literature, up to 17% of VHL patients have pancreatic neuroendocrine tumors by computed tomography (69, 71, 72). Of 633 patients with VHL disease, 108 (17%) had pancreatic endocrine neoplasms and 9 of these patients (8%) had metastatic disease from the pancreatic neuroendocrine tumor (73). If the pancreatic tumor exceeded 3 cm in size (n = 25) in this study, metastases were more likely to develop than in patients with tumors less than 3 cm. 78% of patients with metastases (7/9) had exon 3 germline mutations in the VHL gene and an average tumor doubling time of 337 days. These data may help in selecting patients for operative resection and suggest that a nonsurgical approach may be acceptable if patients have tumors less than 3 cm in size, slow tumor doubling time and no mutation in exon 3 of the VHL gene. The mean age at diagnosis for patients with pancreatic endocrine tumors 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 (69, 74). Importantly, these tumors can metastasize with an increased risk for lesions exceeding 3 cm, as stated above (71,72,74). In a recent study, the mortality rate for pancreatic endocrine tumors has been reported to be 6% with somatostatin receptor scintigraphy being positive in 60% of cases and with malignant tumors in up to 58% of cases without correlation with the VHL genotype (75). Surgical resection is required for growing tumors or such that cause symptoms. The role/benefit of surgery for asymptomatic pancreatic neuroendocrine tumors needs to be determined.
This tumor type in the inner ear lies between the dura of the posterior fossa at the end of the endolymphatic sac canal and arise from endolymphatic epithelium within the intraosseous portion of the endolymphatic duct/sac, the vestibular aqueduct (27,76-78) Fig. 3, Ref. 77 and Fig. 4, Ref. 78.
Figure 3.Radiologic, morphologic, and immunohistochemical features of ELSTs (from Ref. 77, Glasker et al., Cancer Res 2005)
Figure4A.Schematic illustration detailing the anatomy of the endolymphatic system and its relationship to surrounding petrous bone structure. The endolymphatic sac and duct are part of the membranous labyrinth of the inner ear. The endolymphatic duct is connected to the membranous labyrinth of the inner ear by the saccular and utricular ducts. The saccular and utricular ducts form the sinus of the endolymphatic duct. The sinus of the endolymphatic duct tapers and becomes the isthmus of the endolymphatic duct as it enters the bony vestibular aqueduct. The isthmus of the endolymphatic duct connects to the intraosseous portion (within the vestibular aqueduct) of the endolymphatic sac. Endolymphatic sac tumors arise from the endolymphatic epithelium of the endolymphatic duct and sac with the vestibular aqueduct (osseous portion, striped area). Distally, the extraosseous portion of the endolymphatic sac begins as the sac exits the aperture of the vestibular aqueduct. The extraosseous portion of the sac resides between the leaves of the posterior fossa dura mater on the posterior wall of the petrous ridge. (from Lonser RR et al., J Neurosurgery 2008, Ref. 78)
Figure 4B.Serial imaging and histological findings in a 38-year-old patient with VHL disease that demonstrate the development of a left-sided ELST within the vestibular aqueduct. The patient presented in the year 2000 with acute onset of left-sided tinnitus. A: Axial, T1-weighted, enhanced MR imaging did not demonstrate evidence of an ELST. In 2002, the patient presented with worsening tinnitus and acute left-sided hearing loss. B: Axial, T1-weighted, enhanced MR imaging at that time demonstrated an enhancing tumor (arrow)within the proximal vestibular aqueduct. C: Corresponding axial, unenhanced CT imaging demonstrated tumor-associated erosion in the vestibular aqueduct (arrowhead).Consistent with imaging findings, a small ELST was identified within the vestibular aqueduct. D: Hematoxylin and eosin staining demonstrates a papillary-cystic ELST. Original magnification × 20. (from Lonser RR et al., J Neurosurgery 2008, Ref. 78)
These tumors can invade locally but metastases from endolymphatic sac tumors have rarely been reported (79). Symptoms include hearing loss, tinnitus, vertigo, and/or facial paresis (80,81). Patients affected by a VHLgermline mutation should be evaluated by a good history, physical examination, audiologic evaluation and high-resolution CT and MRI through the inner ear (82). 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.
The VHL gene was isolated in 1993 and is located at chromosome 3p25/26 (83,84). 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 VHLlocus at the maternal or paternal allele (85,86). 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, and Rbx1 (ROC1). 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 or undergo hypoxia accumulate HIF, leading to an overproduction of the products of HIF target genes (that are involved in adaptation to hypoxia) such as vascular endothelial growth factor/VEGF, erythropoietin, and transforming growth factor/TGF alpha (87-89). This phenomenon may explain why VHL-associated neoplasms are very vascularized. HIF consists of an unstable alpha-subunit (HIF-1alpha) and a stable beta-subunit (HIF-1beta). In renal cell carcinomas, HIF-responsive gene products including VEGF, PDGF B, TGFalpha and TGFbeta, etc. play a role, possibly explaining why these solid cancers do respond to agents (for instance, sunitinib and sorafenib) that inhibit VEGF or its receptor (90,91) Fig. 5, Ref. 91.
Figure 5.Potential cancer drug targets linked to pVHL and HIF. pVHL inhibits the heterodimeric transcription factor HIF by targeting it for proteasomal degradation. HIF protein levels are also sensitive to changes in histone deacetylase (HDAC), heat shock protein 90 (HSP90), and mTOR activities. HIF transcriptionally activates > 100 genes including many suspected or known to play roles in tumorigenesis (solid arrows). Sorafenib and sunitinib inhibit signaling by the VEGF receptor KDR and platelet-derived growth factor receptor (PDGFR). (from Kaelin WG. Clin Cancer Res 2007;13:680s-684s, Ref. 91)
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 VHLallele. Interestingly, almost all VHLgermline 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 (92-94). Whether inactivation of the VHL wild-type allele is sufficient for the formation of tumor, remains to be elucidated. Biallelic inactivation of VHLin the germline leads to embryonic lethality, as demonstrated in the mouse (95). On the other hand, renal cysts in VHL patients show loss of the remaining wild-type VHLallele, as do renal cancer lesions, underscoring that an inactivation of the VHL wild-type allele appears necessary but not sufficient for tumor formation (21,77). Similarly, in patients with a germline mutation in the RET proto-oncogene, such a mutation, although here in an oncogene (and not in a “tumor suppressor gene”), may not be sufficient to lead to tumor formation (96,97, 98).
Although VHL is ubiquitously expressed, somatic VHLmutations are rare in human cancer except for clear cell renal carcinoma (4,99-103). The majority of sporadic clear cell renal carcinomas are found to have mutations of the VHL gene. Of note, one should be aware of the phenomenon “mosaicism” which may help prevent misclassifying probands as having de novo VHL mutations before performing mutation screening of both parents with techniques that allow detection of somatic mosaicism (104).
Indications for VHLgermline mutation screening are given in 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.