-2 :: Case - 2482 :: - Epididymal cystadenomas, von Hippel-Lindau disease
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Additional Discussion:
Epididymal cystadenomas (ECA) are uncommon tumors that, even as sporadic lesions, are associated with a somatic mutation in the VHL gene on chromosome 3. In Von-Hippel Lindau disease (VHL) patients, there is a germ-line mutation in the VHL gene, affecting every cell in the patient's body. The presence of bilateral epididymal lesions suggests a germline systemic mutation, rather than a local somatic mutation. Of course, the additional findings of the lesions in the kidney and pancreas provide further evidence of the systemic disease - Von Hippel Lindau disease.

VHL was originally described as the familial association of multiple vascular "angiomas" of the retina (von Hippel disease) with hemangioblastomas (the Lindau tumor). However, it was shortly recognized that these patients had a more complex systemic disease with lesions affecting the solid abdominal organs (kidney and pancreas) with cysts and both benign and malignant neoplasms. Unlike the "classic" phakomatoses, VHL is not associated with cutaneous findings. VHL is autosomal dominant, without racial or sexual predilection. The responsible gene has been identified on chromosome 3p, and the prevalence is estimated at about 1/35,000 to 1/50,000 people in the United States.

The study group at the NIH has suggested subclassifying VHL into 3 subtypes. The most frequent is Type I, VHL without pheochromocytoma. These patients have the "classic" features of renal and pancreatic cysts, and a high risk for developing renal cell carcinoma (RCC).
Type II is VHL with pheochromocytoma, and it is further divided into IIA and IIB. Type IIA has pancreatic islet cell tumors (typically without cysts) and IIB has both Renal and Pancreatic disease.

This patient has evidence of previous adrenal surgery, and has both pancreatic and renal cysts. So this is Type IIB.

More than half of these patients will develop or present with retinal angiomas. These are actually hemangioblastomas of the retina, and cause retinal hemorrhage and detachment. Two-thirds or more of VHL patients will have hemangioblastomas, usually infratentorial, with the cerebellum by far the most common site. Although the hemangioblastoma is a benign nonglial neoplasm, it is hypervascular, and may recur if incompletely resected. In addition, patients with VHL are prone to develop multiple hemangioblastomas, that may be present simultaneously or may appear as metachronous (asynchronous) lesions.

As this patient illustrates, the epididymis may develop benign cystadenomas. The presence of multiple lesions should always suggest a systemic disease. Systemic diseases may be congenital (maldevelopmental and genetic), inflammatory (infectious, autoimmune, etc.), toxic, metabolic, and dissemination of a neoplasm (metastasis). Hematogenous dissemination of neoplasms and infection may create multiple and often bilateral lesions, but they are usually located in asymmetric and somewhat random patterns. However, toxic, metabolic and genetic lesions may show anatomic distributions of lesions that may be bilateral and can be strikingly symmetric.

In the differential diagnosis of this case, the presence of bilateral masses of the scrotum could have been inflammatory or infectious. However, the localization of these masses with anatomic symmetry within the epididymis, might suggest consideration of a syndrome. In addition, the morphology of the masses as heterogeneously solid and cystic also suggests the specific diagnosis of a cystadenoma. These two clues fit together well if the patient has von Hippel-Lindau disease.

SUGGESTED READINGS:

Binkovitz, L.A., Johnson, C.D., and Stephens, D.H. "Islet Cell Tumors in von Hippel-Lindau Disease: Increased Prevalence and Relationship to the Multiple Endocrine Neoplasias.". AJR 1990;155:501-505.


Choyke, P.L., Glenn, G.M., Walther, M.M., Zbar, B., Weiss, G.H., Alexander, R.B., and Hayes, W.S. "The Natural History of Renal Lesions in von Hippel-Lindau Disease: A Serial CT Study in 28 Patients.". AJR 1992;159:1229-1234.


Choyke, P.L., Glenn, G.M., Walther, M.M., Patronas, N.J., Linehan, W.M., and Zbar, B. von Hippel-Lindau Disease: Genetic, Clinical, and Imaging Features. Radiology 1995194:629-642.


Ho, V.B., Smirniotopoulos, J.G., Murphy, F.M., and Rushing, E.J. Radiologic-pathologic correlation: hemangioblastoma. AJNR Am J Neuroradiol 1992;13(5):1343-1352.


Neumann, H. Basic criteria for clinical diagnosis and genetic counseling in von Hippel-Lindau Syndrome. VASA 198716:220-226


Tibbs Jr., R.E., Bowles Jr., A.P., Raila, F.A., Fratkin, J.D., and Hutchins, J.B. Should Endolymphatic Sac Tumors Be Considered Part of the Von Hippel-Lindau Complex? Pathology Case Report. Neurosurg 1997;40(4):848-855.

Discussion Author: MS-4 USU Teaching File

Von Hippel-Lindau Syndrome (VHL) is an autosomal dominant disorder (with incomplete penetrance) caused by deletions or mutations in a tumor suppressor gene mapped to chromosome 3p25. This is a relatively rare disease with an estimated prevalence of 1 in 45,000 (approx 6,000-7,000 pts in USA). It is characterized clinically by vascular tumors, including retinal and CNS hemangioblastomas (cerebellar, spinal, and brainstem), cystic lesions of the kidneys, liver, and pancreas. Clear cell renal cell carcinoma occurs in up to 70% of patients with VHL and is a frequent cause of death. Additionally, some families possess a VHL pattern that includes pheochromocytoma. Patients with VHL may also develop endolymphatic sac tumors. Table 1 summarizes a classification scheme for different family patterns proposed by the NCI.

Clinically, the patient with VHL will develop different manifestations of the disease at different ages. The mean age of diagnosis of retinal hemangioblastoma is 25 years (range 1-67 yrs), of cerebellar hemangioblastoma is 30 years (range 11-78 yrs), and of renal cell carcinoma 37 years (range 16-67 years). Symptoms of cerebellar hemangioblastoma may include headache, vomiting, wide-based gait, slurred speech, nystagmus, labile hypertension, positional vertigo, and dysmetric. Erythrocytosis occurs in 5-20% of patients due to erythropoietin generated by hemangioblastomas. Retinal hemangioblastomas are usually asymptomatic if they are in a peripheral location, but if they are centrally located or become large, they can cause profound blindness. Complications include macular edema, glaucoma, and cataract. Renal lesions are asymptomatic and are detected by imaging studies. Endolymphatic sac tumors may cause tinnitus or deafness. In particularly involved cases, pancreatic replacement by cystic lesions may result in IDDM. Up to 50% of patients show only one manifestation of the syndrome.
Diagnosis on clinical grounds requires either a positive family history and the finding of a single retinal or cerebellar hemangioblastoma, pheochromocytoma, or RCC. Pancreatic cysts have been argued to be adequate by some researchers. Renal or epididymal cysts are to common in the general population to make the diagnosis. In the abscence of a family history, two or more retinal or cerebellar hemangioblastomas or one hemangioblastoma plus one visceral tumor must be present to justify the diagnosis. The diagnosis can be confirmed by genetic testing. Screening of family members is imperative.

The VHL gene encodes a protein that inhibits transcription elongation and functions as a tumor suppressor molecule. Loss of the protein allows the unregulated growth of vascular tumors in multiple tissues.

Historically, studies of the natual history of VHL have shown a life expectancy of less than 50 years, with death frequently due to complications of cerebellar hemangioblastoma (47.7%) or metastatic clear cell renal cell carcinoma (32%). This is not believed to represent current expectations, and is expected to be improved because of earlier diagnoses and development of surveillance protocols.

Current recommendations for the surveillance of patients with VHL is summarized in Table 2.

A brief historical note: in 1904, yon Hippel (a German ophthalmologist) first recognized the familial nature of retinal hemangioblastomas. It was not until 1926 that Arvid Lindau (a Swedish ophthalmologist) observed that cerebellar and retinal hemangioblastomas are part of a larger "angiomatous lesion of the CNS", and that the condition was heritable.

Table 1: National Cancer Institute VHL Classification Scheme
I. VHL without pheochromocytomas (most common)
IIA. VHL with pheochromocytomas, retinal and CNS mangioblastoma, and islet cell tumor of pancreas. No pancreatic or renal cysts, milder clinical course.
IIB. VHL with pheochromocytomas, retinal and CNS hemangioblastomas, renal cancers, and
pancreatic involvement.

Table 2: Recommendations for monitoring patients with VHL and family members

Age (yrs) Recommendation
0-2   Annual physical and ophthalmologic examination
2   Urinary catecholamines every 1-2 years
11   Biannual MRI of brain and spine, annual ultrasound of abdomen; if renal cysts or tumor
   present, CT scans every 6 months
20   Change annual abdominal ultrasound examination to annual CT scan
60   If no evidence of VHL, change MRI of brain and spine to every 3-5 years, change CT scan of abdomen to every other year

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