Serous precursor lesions in the distal fallopian tube.

CS18-02

Background: Epithelial ovarian carcinoma (EOC) is thought to arise from the simple epithelial lining of the ovarian surface, which exhibits both mesenchymal and epithelial features and can convert to either phenotype in response to different stimuli. However, the major subtypes of EOCs are differentiated and morphologically resemble specialized epithelia of the reproductive tract. Thus, EOC differentiation is more specialized than that of the ovarian surface epithelium (OSE), the presumed tissue of origin. These observations have led to models of pathogenesis invoking metaplasia from the uncommitted mesothelial OSE to the more committed phenotype of the Mullerian epithelium as an intermediate step in the development of EOCs. While these models likely represent key steps in the pathogenesis of certain subtypes of ovarian cancer, very few serous carcinomas, the most common and aggressive type of EOC, have been documented to arise directly from the ovarian surface in women with or without a known familial predisposition (BRCA-1 or -2 mutation positive; 'BRCA+'). Recent studies from our group suggest that the fallopian tube - principally the distal portion - is a prime site of origin for serous carcinomas in both BRCA+ and sporadic (non-familial) tubal carcinomas. However, until now, a precursor lesion to this neoplasm has not been described. This study describes the identification of a distinct biological entity, termed the "p53 signature", in benign-appearing fallopian tube mucosa that exhibits properties consistent with a precursor lesion to ovarian serous carcinomas. In addition, a novel ex-vivo culture system of primary fallopian tube epithelium is described that faithfully recapitulates fallopian tube morphology and immunophenotype and is being used to characterize the biological response of this specialized epithelium to genotoxic stress. Methods: Fallopian tubes from women with BRCA mutations (n=28) and controls (n=65) were examined using the SEE-FIM protocol (Sectioning and Extensively Examining the FIMbria) and immunostaining for p53. p53 signatures were identified and correlated with age, location, cell type, p53 mutation status, proliferation, and markers of the DNA damage checkpoint response. Results: Twenty-eight and forty percent of tubes from BRCA+ women and controls, respectively, contained p53 signatures. p53 signatures were associated with a slightly higher mean age, fimbria versus proximal tube, benign appearing secretory tubal epithelial cells and a low proliferation index. A high percentage of these signatures contained p53 mutations previously linked to ovarian cancer. Interestingly, the p53 signatures exhibited evidence of DNA damage as measured by immuno-positive staining for gamma-H2AX. H2AX is a unique histone that gets phosphorylated by the ATM kinase in response to genotoxic stress. Conclusions: This study shows that a proportion of normal fallopian tubes of adult women - irrespective of ovarian cancer risk - harbor discrete epithelial alterations that are morphologically, histochemically, and genetically unique. This entity, termed the "p53 signature", shares several attributes with serous carcinomas of the genital tract. Most important are the secretory phenotype, p53 immunostaining, p53 mutations, and evidence of DNA damage. Whether p53 signatures precede serous carcinoma cannot be determined from this study. However, the strong similarity between p53 signatures and in situ and invasive carcinomas indicates that they share a common pathogenesis.