VHL DEFICIENCY IN THE FEMALE GENITAL TRACT

Charles J Bechert, M.D.¹, SB Shively, Ph.D.², S Gläsker, Ph.D.³, N Yuldasheva, M.D.⁴, A Vortmeyer, M.D.⁵

¹Department of Pathology, UTMB; ²National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch, Bethesda, MD; ³Neurochirurgische Universitätsklinik, Albert-Ludwigs Universität, Freiburg, Germany; ⁴National Cancer Institute, Surgical Oncology Branch, Bethesda, MD; ⁵Yale, School of Medicine, Department of Pathology, New Haven, CT

Background: von Hippel-Lindau (VHL) disease is an autosomal dominant neoplasia syndrome that results from a germline mutation in the VHL tumor suppressor gene (3p26-p25). Affected individuals are at risk for developing various tumors, benign and malignant, most notably renal cell carcinoma (clear cell type). Broad ligament cystadenomas, are known by a number of names including adnexal papillary cystadenoma of probable mesonephric origin (APMO) and clear cell papillary cystadenoma. When clear cell features are present, there is the diagnostic challenge of ruling out metastatic renal cell carcinoma. These lesions have also been misdiagnosed as serous borderline (atypical proliferative) tumors. Most of these lesions are silent and have gone unrecognized in women with VHL disease. Design: Tumor and precursor cells from two VHL patients were microdissected and subjected to loss of heterozygosity (LOH) analysis. Control samples were obtained from the matched normal tissue on the same histological slide. The samples were analyzed for LOH with the microsatellite markers D3S1038 and D3S1110 flanking the VHL gene on chromosome 3p25. Additionally, the expression of hypoxia-inducible factors (HIF 1) and (HIF 2) was investigated by immunohistochemistry. Results: We established that broad ligament papillary cystadenomas are deficient at VHL gene locus (3p26-p25). PCR based LOH analysis of micro-dissected tumor cells, revealed a loss of the wildtype copy of the VHL gene. Adjacent normal tissue micro-dissected from the same slide did not reveal LOH (negative control). As expected for VHL deficient cells, neoplastic epithelium expressed HIF 1 and HIF 2 as well as HIF downstream targets CAIX and GLUT-1. Conclusion: Papillary cystadenomas of the broad ligament are true neoplasms that arise secondary to inactivation of the wild-type copy of the VHL gene. The lesions form in remnant mesonephric duct tissue and share virtually identical morphology with that of VHL-deficient epididymal cystadenoma; they are the female counterpart to the male epididymal cystadenomas. Furthermore, diagnosis of papillary cystadenomas of the broad ligament should prove a useful addition to clinical criteria for determining which patients require screening workups for detection von Hippel Lindau disease. Supported by NIH intramural research funds and UTMB Department of Pathology.