BRAF mutation is associated with a specific cell type with features suggestive of senescence in ovarian serous borderline (atypical proliferative) tumors.

Abstract

Serous borderline tumor also known as atypical proliferative serous tumor (APST) is the precursor of ovarian low-grade serous carcinoma (LGSC). In this study, we correlated the morphologic and immunohistochemical phenotypes of 71 APSTs and 18 LGSCs with the mutational status of KRAS and BRAF, the most common molecular genetic changes in these neoplasms. A subset of cells characterized by abundant eosinophilic cytoplasm (EC), discrete cell borders, and bland nuclei was identified in all (100%) 25 BRAF-mutated APSTs but in only 5 (10%) of 46 APSTs without BRAF mutations (P<0.0001). Among the 18 LGSCs, EC cells were found in only 2, and both contained BRAF mutations. The EC cells were present admixed with cuboidal and columnar cells lining the papillae and appeared to be budding from the surface, resulting in individual cells and clusters of detached cells "floating" above the papillae. Immunohistochemistry showed that the EC cells always expressed p16, a senescence-associated marker, and had a significantly lower Ki-67 labeling index than adjacent cuboidal and columnar cells (P=0.02). In vitro studies supported the interpretation that these cells were undergoing senescence, as the same morphologic features could be reproduced in cultured epithelial cells by ectopic expression of BRAF(V600E). Senescence was further established by markers such as SA-β-gal staining, expression of p16 and p21, and reduction in DNA synthesis. In conclusion, this study sheds light on the pathogenesis of this unique group of ovarian tumors by showing that BRAF mutation is associated with cellular senescence and the presence of a specific cell type characterized by abundant EC. This "oncogene-induced senescence" phenotype may represent a mechanism that impedes progression of APSTs to LGSC.