FINAL DIAGNOSIS: HEMANGIOBLASTOMA.
Following the diagnosis on a morphologic basis, it was found that the patient had a family history of Von Hippel-Lindau disease (VHL) with an affected parent having a retinal hemangioma, CNS hemangioblastoma and a renal tumor. In addition, the patient had undergone surgery for a retinal hemangioma in the past.
An important differential is metastatic renal cell carcinoma, particularly because of the association of renal cell carcinoma and hemangioblastoma in VHL. Renal cell carcinoma would be immunopositive for cytokeratin and epithelial membrane antigen.
Von Hippel Lindau disease
The hereditary component of retinal angiomas was first recognized in 1904 by an ophthalmologist Eugen von Hippel and it was in 1927 that Lindau first reported a connection between retinal and cerebellar angiomas. It was in 1964 that Melmon and Rosen coined the term Von Hippel-Lindau disease (VHL).
VHL is an autosomal dominant tumor predisposition syndrome with an incidence of 1: 31000 to 1:36000 live births. It is seen in all ethnic groups and affects both sexes equally. It is 80-90% penetrant with a highly variable expression. It is characterized by the occurrence of multiple retinal, cerebellar and spinal cord hemagioblastomas and is variably associated with renal cell carcinoma (RCC) and pheochromocytoma. In addition multiple renal and pancreatic cysts, cyst adenomas of the epidydimis and broad ligament and endolymphatic sac tumors may also develop.
VHL syndrome is clinically sub classified into types 1 and 2. Type 2 is further sub classified as 2a, 2b and 2c. Type 1 is not associated with pheochromocytoma. Type 2 is associated with pheochromocytoma, with a low risk of RCC and pancreatic tumors in 2a and a high risk of the same in 2b. Type 2c is characterized by isolated pheochromocytoma.
Retinal angiomas are often the earliest manifestation of and are present in more than 50% of all VHL patients. The tumors are often multiple, bilateral and recurrent. They may cause hemorrhage and retinal detachment leading to blindness.
VHL accounts for approximately 30% of CNS hemagioblastomas and CNS involvement is reported in 20-70% of VHL patients. In VHL, CNS hemagioblastomas are most frequently found in the cerebellum, followed by the spinal cord and then the brain stem. An important feature is that in VHL the tumors are often multiple and the affected patients are younger. Patients with a cerebellar hemangioblastoma may present with headache, nausea, broad based gait, ataxia, slurred speech, nystagmus or papilledema. On post contrast injection MRI they are seen as brightly enhancing sharply delimited mural nodules projecting into a cyst. They have a reddish brown-yellow coloration reflective of their rich vasculature and lipid content.
The neoplastic cell in hemangioblastomas is the "stromal cell" that has a pale finely vacuolated to foamy cytoplasm rich in neutral fats.
Spinal cord hemagioblastomas account for ~1.5-2% of all spinal cord tumors. They occur in 15-40% of VHL patients and upto 80% of spinal cord hemagioblastomas are associated with VHL disease. Therefore the occurrence of a spinal hemangioblastoma warrants excluding Von Hippel Lindau disease. Spinal cord lesions may cause syringomyelia.
The lifetime risk for renal cell carcinoma (RCC) in VHL disease is greater than 70%, it occurs at a mean age of 33-37 years and causes death in 15-50% of VHL patients. 30-50% of patients with renal lesions have metastases to the lymph nodes, liver, lungs or bones. Mutations in the 3p region are also seen in sporadic renal cell carcinomas of the clear cell type.
20% of all pheochromocytomas are due to VHL disease and they are seen in 7-20% of families with VHL. Compared to sporadic cases, the pheochromocytomas seen in VHL are often bilateral, multiple and extra adrenal.
VHL protein product
The vhl protein has no known homology to other known proteins and while it's exact function is unknown, a role in oxygen dependent angiogenesis, fibronectin matrix assembly, cytoskeleton organization, cell cycle control and cellular differentiation have all been proposed. Inactivation of pVHL leads to an expression of a hypoxia-inducible factor (HIF) and up regulation of its targets such as vascular endothelial growth factor (VEGF), erythropoietin, and transforming growth factor-beta and alpha (TGF- and TGF- ). Diagnostic criteria
Diagnosis is based on three elements- hemangioma ( retinal or CNS), visceral lesions and a family history of VHL. If a family history is present only one hemangioma (retinal or CNS) or one visceral lesion is required to make a diagnosis. With a negative family history, two or more hemangiomas (retinal or CNS) or one hemangioma and a visceral lesion is required to make a diagnosis of VHL.
The patient presented meets the criteria for VHL with a positive family history and multiple hemangiomas.
VHL is associated with inactivation of a gatekeeper tumor suppressor gene-vhl. The VHL gene(vhl) has been mapped to the 3p25-26 region. It is composed of three exons that encode for a 25 KD, 213 amino acid protein (pVHL).
More than 300 germline mutations have been identified in familial VHL and these occur throughout the coding region. While the germline mutation is inherited in an autosomal dominant fashion, tumors occur when the second normal allele is inactivated.
Deletions, frame shift, nonsense or splice mutations leading to a truncated protein are seen in 73-96% of cases with a Type 1 phenotype, while missense mutations leading to an amino acid substitution are associated with a type 2 phenotype in 70-98% of cases. VHL gene mutations are also common in sporadic hemangioblastomas and renal cell carcinomas.
In patients with a family history close surveillance by physical examination, CT scan or MRI with inclusion of the spinal cord, blood pressure monitoring and catecholamine metabolite screening is advocated to allow for early intervention. Gene therapy by reintroduction of wild type vhl is a possibility in the future.
Contributed by Uma Krishnamurti MD, PhD, Amin Kassam MD, William Welch MD and Clayton Wiley MD, PhD