Tubal origin of ‘ovarian’ low-grade serous carcinoma

Abstract

Ovarian low-grade serous carcinomas are thought to evolve in a stepwise fashion from ovarian epithelial inclusions, cystadenomas, and borderline tumors. The current study was designed to gain insight into the origins of low-grade serous carcinomas (tubal versus ovarian) by comparatively evaluating the morphologic (secretory and ciliated cell distribution) and immunophenotypic (using antibodies to PAX8, tubulin, calretinin, and Ki67) attributes of its putative precursor lesions, the normal tubal epithelium, and the overt malignancy. A total of 226 adnexal tissues from 178 patients were studied, including 98 adnexae removed for non-neoplastic indications, 48 serous cystadenomas, 42 serous borderline tumors, and 38 low-grade serous carcinomas. Normal distal tubal epithelium comprised an admixture of PAX8 þ /tubulinÀ secretory cells and PAX8À/ tubulin þ ciliated cells with a proliferative index of B3%. The vast majority of ovarian surface epithelia displayed a mesothelial phenotype (calretinin þ /PAX8À/tubulinÀ) and low proliferative index (0% (12 per 1000)), although 4% of cases also displayed foci with tubal phenotype (calretininÀ/PAX8 þ /tubulin þ ). In contrast, most (78%) of the ovarian epithelial inclusions displayed a tubal phenotype and had a significantly higher proliferative index (1%) than ovarian surface epithelium, indicating that in most cases, the ovarian surface epithelium and ovarian epithelial inclusions are of different lineages. There was a progressive decrease in the population of ciliated cells, as evidenced by increasing secretory/ciliated cell ratio, from ovarian epithelial inclusions/cystadenomas to borderline tumors to low-grade serous carcinoma, indicating that the latter is a clonal expansion of secretory cells. Overall, the findings make a strong argument that the ovarian epithelial inclusions with a tubal phenotype is likely derived from fallopian tube through an intraovarian endosalpingiosis rather than through Mullerian metaplasia from ovarian surface epithelium. Genetic and molecular studies are needed to further confirm this finding as tubal origination of ovarian serous cancers will have a significant impact on ovarian cancer prevention and management.

Facts about Endosalpingiosis

“…The alternative theory, based on numerous observations and laboratory investigations, is tubal-cell origin [1] [6] [14]. In support of the theory is the intense proliferation of tubal cells, which presents as cell tufting or papillae with narrow stalks at the base; or sometimes as piles of cells with poor adhesion [6].…”

“…A body of evidence show that endosalpingiosis is the precursor of serous tumors, especially low-grade serous carcinoma [1] [4] (reviewed in [5] [6]). Li and associates [1] claim that 78% of the ovarian inclusions are of tubal-cell origin.…”

“…The tubal epithelium consists of ciliated, unciliated columnar and intercalated cells. Some lymphocytes, shown by some studies as T cells [1] [2], are scattered just above the basement membrane. Though growing ectopically endosalpingiosis keeps the morphologic features of tubal epithelium.…”

“…Immunohistochemisty can be applied to determine the cell origin of the inclusions. PAX-8 and calretinin are the most useful markers [1] [6]. Tubulin can show cilia on the apical surface of the epithelium [1] [6].…”

“…When lining cells of endosalpingiosis undergo degeneration or inclusions are filled with secretions, they become flat and cilia are hardly seen. Unciliated cells are regarded as secretory cells, which are observed to expand in cell proliferation or with age [1] [4] (reviewed in [5] [6]). Immunohistochemisty can be applied to determine the cell origin of the inclusions.…”