von Hippel-Lindau Disease

von Hippel-Lindau Diseasevon Hippel-Lindau Disease
VICKI COUCH, MS; NORALANE M. LINDOR, MD; PAMELA S. KARNES, MD; AND VIRGINIA V. MICHELS, MD
An autosomal dominant tumor predisposition syndrome, von Hippel-Lindau disease (VHL) is characterized by the presence of benign and malignant tumors. Hallmark le­ sions include retinal angiomas, hemangioblastomas of the cerebellum and spinal cord, and renal cell carcinomas. Affected persons may also have angiomatous or cystic lesions of the kidneys, pancreas, and epididymis, as well as adrenal pheochromocytomas. In this article, we discuss the clinical features and diagnostic criteria for this clinically underdiagnosed condition. An update on recent findings regarding the molecular genetics of VHL is provided, in­ cluding a discussion of the evolving understanding of geno-
Benign and malignant tumors in multiple organ systems are the characteristic findings in patients with von
Hippel-Lindau disease (VHL), a hereditary multisystemic disorder. Hallmark features of the condition include devel­ opment of retinal angiomas, hemangioblastomas of the cerebellum and spinal cord, and renal cell carcinomas (RCCs). Additionally, this condition can cause angioma­ tous or cystic lesions in the kidneys, pancreas, and epididy­ mis as well as adrenal pheochromocytomas. I
Since the mid-1800s, ophthalmologists have reported retinal angiomas associated with blindness and occasion­ ally with similar cerebellar lesions.' In 1904, German oph­ thalmologist Eugen von Hippel first recognized the heredi­ tary component of retinal angiomas.' In 1927, Arvid Lindau, a Swedish pathologist, was the first to report a connection between retinal angiomas and hemangiomas of the cerebellum." Subsequently, numerous clinical reports have described families with retinal angiomas, central ner­ vous system (CNS) hemangioblastomas, renal tumors and cysts, epididymal cystadenomas, pancreatic cysts and tu­ mors, and pheochromocytomas, confirming the association of these Iesions.? However, it was not until 1964 that Melman and Rosen' coined the term von Hippel-Lindau disease in their classic review of the subject.
von Hippel-Lindau disease is seen in all ethnic groups, and both sexes are affected equally. Epidemiological stud-
From the Department of Medical Genetics, Mayo Clinic Rochester, Rochester, Minn.
Address reprint requests and correspondence to Vicki Couch, MS, Department of Medical Genetics, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905.
Mayo Clin Proc. 2000;75:265-272 265
type-phenotype correlations. Understanding the molecu­ lar and functional aspects of this condition will lead to the development of strategies for the management and treat­ ment of inherited and sporadic VHL-associated tumors.
Mayo Clin Proc. 2000;75:265-272
CNS =central nervous system; CT =computed tomography; MRI = magnetic resonance imaging; mRNA = messenger RNA; pVHL =VHL protein; RCC =renal cell carcinoma; VEGF = vascular endothelial growth factor; VHL = von Hippel-Lindau disease
ies suggest that the birth incidence in eastern England is I in 36,000,6 and the prevalence in southwestern Ger­ many is 1 in 39,000 persons.' Penetrance is estimated at 80% to 90% by the time a person is 65 years old, and expression is highly variable." The age at diagnosis ranges from infancy to the seventh decade of life or later, depending on the expression of the condition within the family and whether and which type of asymptomatic le­ sions are sought. Although VHL is considered rare, the condition is likely underdiagnosed." The goal of this review is to familiarize the practicing physician with this impor­ tant, yet underrecognized, syndrome that predisposes to cancer.
CLINICAL FEATURES There are several characteristic features of VHL but no single unique pathognomonic finding. Thus, multidisci­ plinary involvement in the diagnosis and management of this condition is crucial, and many investigators have stressed the importance of interdisciplinary exchange of information.P-'?
CNS Hemangioblastomas Central nervous system hemangioblastomas are most
frequently found in the cerebellum and then the spine and the brain stem, I I Supratentorial hemangioblastomas can occur, although they are rare. Central nervous system in­ volvement is reported in 21% to 72% of VHL patienrs.v" In VHL, the tumors are often multiple, and the mean age of VHL patients at diagnosis of cerebellar hemangio­ blastomas is considerably younger than that of patients with sporadic cases. The primary age range of VHL pa-
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266 von Hippel-Lindau Disease
tients who present with CNS lesions is 25 to 40 years, although CNS lesions can occur in children.v"-"
The hemangioblastomas seen in VHL are benign, but they may produce symptoms depending on their size, site, and number. Symptoms are due to local disruption of neu­ rologic function or increased intracranial pressure, some­ times compounded by hydrocephalus. Spinal cord lesions may cause syringomyelia." Surgical resection of CNS hemangioblastomas often provides excellent results. How­ ever, the development of multiple tumors is still a major problem, and CNS involvement is an important cause of morbidity and mortality in patients with VHL. 14
,15
Symptoms of CNS hemangioblastomas can include headache, nausea, vertigo, and broad-based gait. Signs such as papilledema, ataxia, slurred speech, and nystagmus may occur." Detection of CNS hemangioblastomas has improved substantially with the use of modem imaging techniques and preventive screening of VHL patients to identify presymptomatic or asymptomatic tumors. The cur­ rent preferred method for detection of CNS lesions in VHL is gadolinium-enhanced magnetic resonance imaging (MRI) , for both intracranial and intraspinal tumors.l-" More studies are needed to confirm whether presymp­ tomatic CNS screening for and treatment of identified le­ sions in patients who have VHL or are at risk for VHL actually improves quality of life or extends survival.
Retinal Angiomas Retinal angiomas (hemangioblastomas) are present in
more than one half of all patients with VHL.9,18,19 These benign tumors are often multiple, bilateral, and recurrent. If untreated, they may cause retinal detachment and hemor­ rhage, leading to blindness. Most angiomas are found in the second and third decades of life, with a mean age at diagno­ sis of 25 years.v" However, age at onset is variable; these tumors can be found in infants, or they may not be present until the eighth decade of life or later."
Often, there are no clinical symptoms until serious dam­ age occurs due to hemorrhage, retinal detachment, or other complications. Detection of these lesions is by ophthalmo­ scopic examination, with the classic finding being a red­ dish spherical tumor of variable size with a dilated feeding artery and a draining vein.22,23 Microangiomas with no di­ lated or tortuous feeder vessels precede the tumors. Most small lesions are peripheral and difficult to detect. 10 Regu­ lar ophthalmologic examinations, often including tonom­ etry, fluorescein angioscopy, and indirect ophthalmoscopy, are an essential component of the preventive screening that should be performed for all patients with VHL. IO,13,2 1
Treatment of small lesions is by laser coagulation and cryotherapy, usually with few complications." Thus far, the pathogenesis of retinal detachment in VHL is poorly
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understood. It often occurs with no warning symptoms, and there may be no identifiable precipitating factor. Treatment of detachment is difficult and often unsuccessful. 10 This is a compelling reason for regular ophthalmologic screening and early intervention for retinal lesions in VHL. Many clinicians recommend initiation of annual ophthalmologic screening at an early age (6 years or younger) to ensure that vision can be preserved.P:"
Renal Lesions The renal lesions in VHL include both cysts and carci­
nomas.":" Renal cysts are present in 50% to 70% of pa­ tients, and, while they are frequently bilateral and multiple, they rarely cause pronounced renal impairment.v-" Occa­ sionally, innumerable cysts are present, as occurs in auto­ somal dominant polycystic kidney disease." Unlike the sequelae in autosomal dominant polycystic kidney disease, multiple cysts in VHL infrequently lead to chronic renal decompensation or renal hypertension."
The predominant histological finding of an RCC in patients with VHL is a clear cell carcinoma.P'-'? The life­ time risk for RCC is greater than 70%, and RCC causes death in 15% to 50% of VHL patients."?" When an RCC is identified as a result of symptoms, 30% to 50% of VHL patients with renal lesions already have metastases to the lymph nodes, liver, lungs, or bones.>" These metastatic lesions respond poorly to chemotherapy and radiation. 10
Thus, the strategy for managing patients with VHL or those at risk for VHL is careful annual surveillance with com­ puted tomography (CT), ultrasonography, or both. If only asymptomatic cysts are identified, continued surveillance is sufficient. When solid lesions are detected, treatment is parenchymal-sparing surgery when possible.P'" Because the lesions are often bilateral, partial nephrectomy or tumor enucleation, when possible, may avoid or delay the need for dialysis or transplantation. Microscopically, kidneys from patients with VHL may contain numerous small neo­ plasms, and the development of primary tumors is almost inevitable." Patients must be informed of the need for ongoing surveillance and the likelihood of repeated renal surgery. The goal of renal surgery in patients with VHL is to prolong renal function while decreasing the risk of metastasis.
Pheochromocytomas Approximately 20% of all pheochromocytomas are due
to VHL.37 The pheochromocytomas seen in VHL differ from those in sporadic cases since they occur in younger patients and are often bilateral, multiple, and extra-adrenal. Metastasis is infrequent. 32,38,39 A pheochromocytoma may be the only symptom of VHL in an affected person. 37
Pheochromocytomas are seen in 7% to 20% of families
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Mayo Clin Proc, March 2000, Vol7S
with VHL.9,19 There is dramatic clustering of pheochromo­ cytomas in a subset of families with VHL (as is discussed in the section on diagnostic criteria). However, it is still unclear whether the correlation between specific VHL genotypes and particular phenotypic expression of the disorder will be absolute. It may be tempting to use details of a patient's genotype to determine whether to pursue screening for pheochromocytomas (or possibly for other manifestations of VHL), but this approach is premature. For example, evidence shows that modifier genes may influence the expression of the phenotype of VHL.14Addi­ tional research is needed for a complete definition of the specificity and sensitivity of the relationship between particular VHL mutations and the predicted disease spec­ trum before such genotype-specific screening strategies can be endorsed. Thus, while a family history of pheo­ chromocytomas in affected relatives is clearly an indica­ tion for careful surveillance," all persons diagnosed with or at risk for VHL should be screened regularly for a pheochromocytoma.
Pheochromocytomas among patients with VHL may cause intermittent or sustained hypertension, episodic sweating, palpitations, and headaches. Pheochromocy­ tomas are diagnosed by biochemical tests, which demon­ strate elevated urine levels of catecholamines (epinephrine, norepinephrine, and metanephrine), in combination with imaging studies (ultrasonography, CT, or MRI).40,41 Often, pheochromocytomas in VHL remain asymptomatic, and findings on biochemical tests and MRI may be unremark­ able." The behavior of pheochromocytomas in VHL is un­ predictable, and previously inactive pheochromocytomas may suddenly become life threatening. This situation can be especially risky if an unsuspected pheochromocytoma is present in a patient with VHL who has a cerebellar hemangioblastoma, is undergoing surgery for another VHL-associated lesion, or is pregnant.":" Screening for pheochromocytomas before surgery consists of 24-hour urine metanephrine and catecholamine determinations. If the patient is normotensive and asymptomatic, results ob­ tained within the past 6 months are acceptable; however, if the patient is hypertensive or symptomatic, current studies are necessary.
Symptomatic pheochromocytomas must be removed surgically. When there are bilateral lesions, adrenal-spar­ ing surgery may be considered to preserve some function­ ing adrenal tissue." As with nephron-sparing surgery in patients with VHL, this necessitates ongoing surveillance for recurrent pheochromocytomas. If pheochromocytomas must be removed, it is important to attempt to localize extra-adrenal pheochromocytomas that may be present and to recognize the potential for life-threatening complica­ tions during surgery because manipulation can cause a
von Hippel-Lindau Disease 267
sudden elevation in circulating catecholamines, leading to hypertension and arrhythmia during surgery."
Pancreatic Lesions Pancreatic lesions are common in VHL and are most
often limited to cystS.25,44 These lesions are diagnosed in patients at the mean age of 41 years, although they can be diagnosed from the second through the sixth decade of Iife." The cysts are often multiple and are present throughout the body of the pancreas. They are frequently asymptomatic, but complications can occur because of space-occupying effects. If biliary obstruction occurs, it is managed by placement of biliary stents. Pancreatic exo­ crine insufficiency may develop and is managed by en­ zyme replacement. 13 Imaging techniques such as CT or MRI may provide more accurate detection of small lesions and solid lesions than ultrasound scanning.w" but over a lifetime a combination of imaging techniques is suggested to balance cost and radiation exposure.
Pancreatic islet cell tumors (which can secrete insulin) can occur in VHL. This process is apparently independent of the pancreatic cyst formation, and the tumors are of neural origin." Like the renal, CNS, and retinal lesions in VHL, pancreatic islet cell tumors are substantially vascu­ lar. Most of these lesions grow slowly and are asymp­ tomatic, although they can be malignant, Computed to­ mography or MRI is used to diagnose islet cell tumors, and lesions that are growing are excised surgically.
Epididymal Lesions Epididymal lesions are found in 10% to 60% of male
patients with VHL.2,16 Papillary cystadenomas of the epi­ didymis may be unilateral or bilateral. These lesions are benign and, if bilateral, may present as infertility." An analogous lesion may occur in women with VHL, present­ ing as papillary cystadenoma of the broad ligament."
Endolymphatic Sac Tumors Endolymphatic sac tumors were only recently recog­
nized as a manifestation of VHL.50 An estimated 10% of VHL patients have these slow-growing, low-grade papil­ lary adenocarcinomas. These tumors are frequently bilat­ eral and can invade locally, an outcome associated with hearing loss. Patients with VHL who experience symptoms such as hearing loss, vertigo, or tinnitus should undergo CT or MRI of the internal auditory canal. Whether surgical intervention will help preserve hearing is still unknown."
DIAGNOSTIC CRITERIA Minimal diagnostic criteria for patients with a known fam­ ily history of VHL include the presence of a single retinal or cerebellar hemangioblastoma, RCC, or pheochromo-
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268 von Hippel-Lindau Disease
cytoma.' Multiple pancreatic cysts may indicate that an at-risk person inherited the mutation since these lesions are otherwise uncommon. However, because renal and epididymal cysts occur with some frequency in the gen­ eral population, the presence of these lesions may not be reliable evidence that an at-risk person carries a VHL mutation." The number of renal cysts and age at detection must be considered because such cysts are extremely un­ common in children and young adults, especially if they are multiple.
In an isolated case, the clinical diagnosis of VHL can be made in a person who has 2 or more retinal or CNS hemangioblastomas or a single hemangioblastoma and a characteristic visceral tumor." De novo mutations tend to be underrecognized compared with mutations in a fa­ milial setting. A diagnosis of VHL should be considered in any patient with a retinal or CNS hemangioblastoma, especially if onset is at an early age and there are famil­ ial, early-onset, or bilateral clear cell RCC; familial or bi­ lateral pheochromocytoma; and bilateral endolymphatic sac tumors."
There is a fairly clear distinction between VHL families with greater or lesser likelihood of developing pheo­ chromocytomas (as discussed further in the section on genotype-phenotype correlations). Investigators have pro­ posed that VHL without pheochromocytoma be classified as type 1 while that with pheochromocytoma be classified as type 2.52 Type 2 has been further divided into type 2A, VHL with pheochromocytomas but without RCC, and type 2B, VHL with pheochromocytomas and RCC.53
CLINICAL GENETIC TESTING Genetic testing (which is described subsequently in more detail) can also be used to determine whether a person carries a pathological mutation in the VHL gene. Deleteri­ ous mutations in the VHL gene can be identified in 80% or more of families with VHL.54 In a VHL family in which a mutation has previously been identified in an affected per­ son, at-risk relatives can be tested to determine whether they carry the same mutation. With this approach, family members with a 50% risk of having inherited a mutation but found not to have the specific mutation known to be present in an affected family member can be reassured that they do not need to follow the screening recommendations, which are appropriate for those who do have the mutation; thus, they are spared the expense and inconvenience of repeated medical testing.'?
In a person who has no known family history of VHL but has a personal clinical history that is suspicious for this disorder, a gene test may be able to confirm whether there is a known deleterious mutation in the gene for VHL. Clearly, such a person would benefit from full VHL screen-
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ing recommendations, even in the absence of a known family history of the disorder. Such persons may have VHL due to a new mutation not previously present in their fam­ ily, and each of their offspring would have a 50% risk of inheriting the mutation. Alternatively, other relatives of a person with an apparently sporadic case of VHL may also carry the VHL gene mutation and not yet manifest clini­ cally recognized symptoms. In this situation, relatives such as parents, siblings, and children would be at risk for mani­ festations of the disorder. Mutation analysis can be offered to family members of a person who appears to have a sporadic case of VHL, and for whom a mutation in the gene for VHL has been identified, to determine whether they are currently asymptomatic gene carriers who would benefit from VHL screening recommendations.
In discussing the option of predictive mutation analysis for at-risk persons when a mutation has been identified in an affected family member, reviewing potential risks and benefits of obtaining such information is important. In other inherited cancer predisposition conditions, a concern is that predictive mutation testing may result in possible employment or insurance discrimination for a person who is found to carry a predisposing mutation. This concern may be most germane in the setting of cancer predisposi­ tion syndromes for which there is no evidence of benefit from early screening of currently asymptomatic gene carri­ ers. However, in VHL, there is a direct benefit from appro­ priateearly screening, beginning in childhood.v"
MOLECULAR GENETICS Identification and Localization of the VHL Gene
Evidence from clinical and molecular epidemiological data suggests that VHL is due to inactivation of a tumor suppressor gene." Tumor suppressor genes inhibit tumor cell development, and their loss or inactivation predisposes to cancer. Carriers of mutations in a tumor suppressor gene inherit a germline mutation in 1 allele of the gene, and tumors develop if a somatic mutation occurs in the homolo­ gous normal allele. 16 While the germline mutation is inher­ ited in an autosomal dominant fashion with a 50% risk of the mutant allele being transmitted to each child, the actual mechanism of tumor development in a specific cell is re­ cessive because tumors occur only when both copies of the tumor suppressor gene are inactivated. This "2-hit" hypoth­ esis for the origin of cancer was proposed by Knudson" in 1971 to explain the observation that some types of cancer, such as retinoblastoma, occur in both sporadic and heredi­ tary forms. Inherited cases of retinoblastoma tend to in­ volve bilateral, multifocal tumors and are typically diag­ nosed at an earlier age than sporadic cases, in which the tumors are usually unilateral. Tumor suppressor genes have regulatory roles in cell proliferation and differentiation as
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Mayo elin Proc, March 2000, Vol7S
well as other basic cellular functions and have been found to have…