SUN-931 Characterization of an Ovarian Steroid Cell Tumor in a VHL Patient

Most ovarian steroid cell tumors arise sporadically. However, they can also be observed as a rare manifestation of von Hippel Lindau disease. Here, we present a clinical, pathological and molecular characterization of a steroid cell tumor in a VHL patient. A 14 year old girl with molecularly confirmed diagnosis of VHL developed hirsutism and amenorrhea. Initial clinical hormonal evaluation was notable for elevated 17-OHP of 406ng/dl, androstenedione 275ng/dl, and testosterone 102ng/dl. In order to exclude congenital adrenal hyperplasia as a common cause of hirsutism in adolescents, ACTH stimulation was performed, but no increase in 17-OHP was observed. Anti Muellerian hormone, inhibin (INH) A and INH B were normal. Imaging revealed a bilobed 6cm left adnexal mass. The mass was resected en bloc via a left oophorectomy. Pathological evaluation showed multinodular steroid cell tumor with clear cytoplasm and delicate vascular meshwork. Immunoprofiling demonstrated positivity for inhibin and calretinin; while renal cell carcinoma markers were negative. All laboratory values normalized post-surgery. In addition to clinical measurements pre- and post-surgery, steroid profiles were evaluated by LC-MS/MS. Quantitative RT-PCR analysis showed robust tumor expression of enzymes facilitating the production of androgens, but not estrogens. Further preliminary analysis by exome sequencing confirmed the known germline pathogenic variant in VHL, but no additional obvious somatic driver mutations were identified. Interestingly, the NGS analysis of different specimens from the same tumor revealed multiple different single base pair variants in the VHL gene as a second hit. In summary, hirsutism in VHL patients should raise the suspicion for unusual ovarian tumors. In contrary to the usual theory of a monoclonal expansion after loss of the wt VHL allele, this tumor appeared to be oligoclonal as evidenced by different somatic VHL mutations. This could be either explained by initial parallel occurrence of several clones or that the VHL second hit is not an initial event, but the mutation instead supports tumor expansion following initial steps of tumorigenesis.