VON HIPPEL-LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects.

PURPOSE: To provide an update summarizing the biologic pathways governing von Hippel-Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations. METHODS: A PubMed search of the English language literature was reviewed using the following search terms: von Hippel-Lindau, von Hippel-Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review. RESULTS: von Hippel-Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs. CONCLUSION: The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.

Abdominal visceral lesions in von Hippel-Lindau disease: incidence and clinical behavior of pancreatic and adrenal lesions at a single center.

INTRODUCTION: Von Hippel-Lindau disease (VHL) is a dominantly inherited multi-system syndrome. Although pheochromocytoma is the hallmark endocrine neoplasm, pancreatic lesions occur frequently, and their management can be complex. This report describes 26 patients from a single institution with pancreatic or adrenal lesions (or both) in the background of VHL. METHODS: We reviewed records for all patients treated for adrenal (type 2 VHL) or pancreatic manifestations of VHL at our institution from 1990 to 2004. RESULTS: Forty patients with VHL were identified from 24 pedigrees; 26 (65%) had adrenal or pancreatic involvement (or both). Seven patients had isolated pheochromocytomas, 16 had isolated pancreatic lesions, and 3 had both. Of the 10 patients with pheochromocytomas, 4 had bilateral adrenal involvement. All but three pheochromocytomas were diagnosed in patients aged 40 years or younger. Of the 19 patients with pancreatic lesions, 8 had cystic lesions, 8 had neuroendocrine tumors, and 3 had both. Of 11 patients with neuroendocrine tumors, 4 had metastases (3 hepatic, 1 nodal). No patient with cystic pancreatic lesions developed carcinoma. CONCLUSIONS: VHL should be familiar to the endocrine surgeon because of the high incidence (65% in our series) of visceral endocrine lesions (pancreas 40%, adrenal gland 18%, both 7%). As seen in other hereditary endocrinopathy syndromes, pheochromocytomas are frequently bilateral; therefore,close follow-up of the contralateral gland in young patients with a unilateral lesion is critical. Cystic lesions of the pancreas may be closely monitored, whereas neuroendocrine tumors should be removed because of the risk of metastasis. Pancreatic pathology is not uncommon in VHL patients with pheochromocytoma and should be sought during the preoperative assessment.