By Cary J. Buresh, M.D.
Von Hippel-Lindau disease is a genetic disorder characterized by the development of tumors associated with inactivating germline mutations in the von Hippel-Lindau tumor suppressor gene (VHL).
Among these, hemangioblastoma of either central nervous system (CNS) or retina, and renal cell carcinoma are among the most well-known.
Recently, reports of reactivity in normal tissues and in tumors with a rabbit polyclonal antibody to the VHL protein (pVHL) have become available. In normal tissues, pancreatic ductal epithelium, acini, and islets are positive. Gallbladder epithelium and bile ducts (but not hepatocytes) are positive. Both proximal and distal renal tubules typically show strong cytoplasmic/membranous staining, and glomeruli are negative.
With this antibody, nearly all renal epithelial neoplasms are positive, including both primary and metastatic (conventional) clear cell renal cell carcinomas, papillary renal cell carcinomas, chromophobe renal cell carcinomas, and oncocytomas. pVHL also stains over 90% of clear cell carcinomas of the ovary and uterus, and reportedly , about 25% of hepatocellular carcinomas and ampullary adenocarcinomas are positive, and ~20% of cholangiocarcinomas express pVHL.
Although benign pancreatic epithelium stains with pVHL, pancreatic adenocarcinomas have been consistently negative. Also, although the number of tumors examined has been small, most other non-renal carcinomas have been negative. Interestingly, 14 cases of CNS hemangioblastoma in one study were pVHLnegative.
According to the third reference cited below, in which the authors investigated expression of pVHL in salivary gland and salivary gland tumors, reactivity with pVHL was seen in normal salivary gland ducts, as well as in 24 of 24 Warthin tumors, 3 of 3 oncocytomas, 5 of 22 mucoepidermoid carcinomas, and 4 of 4 benign mixed tumors (duct epithelial cells). No staining was seen in adenoid cystic carcinoma, acinar cell carcinoma, or salivary duct carcinoma.
In summary, pVHL can be a useful antibody for detection of metastatic renal cell carcinoma, and may be useful in recognizing clear cell carcinoma in endometrium or ovary. Other uses for this antibody may subsequently discovered, and there is little doubt that we will see more about pVHL in the future surgical pathology literature. pVHL is now available in the ProPath Immunohistochemistry Laboratory.
1. Lin F, et al. Immunohistochemical Detection of the von Hippel- Lindau Gene Product (pVHL) in Human Tissues and Tumors. A Useful Marker for Metastatic Renal Cell Carcinoma and Clear Cell Carcinoma of the Ovary and Uterus. American Journal of Clinical Pathology 129(4):592-605, 2008.
2. Lin F, et al. Diagnostic Utility of S100P and von Hippel-Lindau Gene Product (pVHL) in Pancreatic Adenocarcinoma – With Implication of Their Roles in Early Tumorigenesis. The American Journal of Surgical Pathology 32(1):78-91, 2008.
3. Liu H, et al. Loss of or Reduced Expression of the von Hippel- Lindau Gene Product (pVHL) in Malignant Salivary Epithelial Neoplasms – With an Implication of Its Role in Tumorigenesis. Modern Pathology 21(S1):238A, 2008 (abstract #1089).
Date of last revision: December 2008.