CARCINOSARCOMAS (MALIGNANT MIXED MULLERIAN TUMORS) OF THE FEMALE GENITAL-TRACT - COMPARATIVE MOLECULAR ANALYSIS OF EPITHELIAL AND MESENCHYMAL COMPONENTS

Female genital tract carcinosarcomas (FGTCS) are biphasic neoplasms co mposed of an admixture of malignant epithelial and mesenchymal element s. Histogenesis of FGTCS centers on two theories: (1) simultaneous for mation of independent tumors (bi-clonal theory), (2) multidirectional differentiation of a single neoplasm (monoclonal theory). In an attemp t to resolve this histogenetic controversy, we determined the presence , specific genotype, and timing of p53 mutational change in each compo nent of FGTCS using a topographic genotyping (TG) approach, We selecte d 43 FGTCS from the files of Magee-Womens Hospital, Pittsburgh, and in itially immunostained them for p53 protein, Strong p53 immunopositivit y was detected in 35 (82%) of 43 tumors. Subsequently, topographic gen otyping (TG) was performed on a subset of nine immunopositive tumors w ith sufficiently distinct malignant components to enable effective sam pling, All nine tumors showed point mutations in p53 exons 5 through 8 . In each case, the identical point mutational genotype was present in both components. Furthermore, in all nine cases mutations were presen t with loss of the wild-type allele. P53 gene mutation is a frequent e vent in progression of FGTCS. Of importance, both p53 mutation and all elic loss occur before the differentiation into separate epithelial an d mesenchymal malignant components. These molecular findings strongly support monoclonal, multidirectional histogenesis of FGTCS. Copyright (C) 1998 by W.B. Saunders Company.