Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)
Von Hippel-Lindau (VHL) disease was the first heritable RCC to be discovered. Its characterization in the early twentieth century led to subsequent breakthroughs applicable to even the sporadic form of the disease, where over 90% of cases are found to harbor the similar genetic alterations . Determination of the responsible gene by the NCI began with the observation that there was a consistent loss of chromosome 3p in affected individuals , but it was not until sometime later that the researchers localized the locus to 3p25.1 . With an autosomal dominant pattern of inheritance, VHL has a high degree of penetrance. The VHL gene functions as a classic tumor suppressor  and requires a “second hit” for loss of the wild-type allele. The VHL gene encodes for a protein, VHL, that modulates the activities of hypoxic-induced factor (HIF), most notably HIF-1α and HIF-2α. When VHL is either absent or nonfunctional, the HIFs are stabilized even under normoxic conditions, resulting in unchecked shift toward a pseudo-hypoxic state with upregulation of anaerobic metabolism, angiogenesis, and carcinogenesis.
Fig. 8.1. Coronal T2-weighted MRI image of a VHL patient in whom the pancreas was completely replaced with cysts
The clinical manifestations of VHL include hemangioblastomas (of the retina, brain, and spinal cord), pheochromocytomas, pancreatic cysts or neuroendocrine tumors (Fig. 8.1), cystadenomas of the epididymis or broad ligament, and bilateral, multifocal kidney cysts or tumors . While renal cysts in non-syndromic patients are predominantly benign, individuals with VHL tend to have cysts lined with malignant cells, and there may be other microscopic foci of RCC . An estimated 70% of affected individuals develop RCC by the age of 60. Not only do these people present with multiple lesions, their age of onset was also noted to be an estimated 25 years earlier than sporadic RCC .
VHL has also been divided into several subtypes based on the presence of pheochromocytoma, RCC, and type of genetic mutation. Type 1 VHL typically presents with RCC but low risk for pheochromocytomas, and its genetic alterations are germline deletions or truncating mutations. Type 2 VHL carries a low risk for RCC but the presence of pheochromocytoma is a characteristic; this type or subtype of VHL has underlying missense mutation of the affected gene [14, 15]. While useful to help understand which patients have the highest risk of each condition, clinically overlap has been observed.
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