Tubal Origin of 'Ovarian' Low-grade Serous Carcinoma

Jie Li; Nisreen Abushahin; Shujie Pang; Li Xiang; Setsuko K Chambers; Oluwole Fadare; Beihua Kong; Wenxin Zheng

Disclosures

Mod Pathol. 2011;24(11):1488-1499. 

In This Article

Abstract and Introduction

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+/tubulin− secretory cells and PAX8−/tubulin+ ciliated cells with a proliferative index of ~3%. The vast majority of ovarian surface epithelia displayed a mesothelial phenotype (calretinin+/PAX8−/tubulin−) and low proliferative index (0% (12 per 1000)), although 4% of cases also displayed foci with tubal phenotype (calretinin−/PAX8+/tubulin+). 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.

Introduction

Until recently, the incessant ovulation theory put forward by Fathalla[1] in 1971 has been the most widely accepted theory of ovarian carcinogenesis. According to this theory, constant ovulation-induced damage and repair of the ovarian surface epithelium eventually results in its malignant transformation to ovarian epithelial cancers.[2] However, several morphologic, epidemiologic, and molecular observations have gradually accumulated over the ensuing decades such that, at present time, the ovarian surface epithelium is not considered to be the cell of origin of ovarian epithelial cancers by most investigators. The reasons include different histologic and immunophenotypes between ovarian surface epithelium and ovarian epithelial cancers, the pathologic properties of ovarian epithelial cancers showing striking similarities to Mullerian epithelia,[3] and the presence of precancerous lesions of ovarian high-grade serous carcinomas in tubal fimbria but not in the ovary or on ovarian surface.[4–9] All these findings, as well as other factors, have led to an increased recognition in recent years that the fallopian tube is the likely source of most pelvic high-grade serous carcinomas.[6,10]

Recent molecular studies have suggested that ovarian epithelial cancers can be divided into two broad groups.[11] In this model, high-grade serous carcinoma, which constitute the majority of pelvic carcinomas, are classified as type II. Type II cancers commonly show genetic instability, TP53 mutations, and are usually not found in association with precursor lesions within the ovary.[12] The 'ovarian' serous carcinomas that are putatively derived from distal fallopian tube are predominantly high grade.[13–16] In contrast, the less common low-grade serous carcinoma is classified as a type I cancer in this model. Low-grade serous carcinoma displays more genetic stability, shows specific mutations in genes such as BRAF and KRAS, and seems to evolve in a stepwise fashion from ovarian epithelial inclusions, benign cystadenomas, and borderline tumors.[11] Accordingly, in many current models of pelvic serous carcinogenesis, the majority of pelvic high-grade serous carcinomas originate from the endosalpinx, whereas most low-grade serous carcinomas originate in the ovary from ovarian epithelial inclusions. The cell of origin of 'ovarian' low-grade serous carcinoma is therefore best evaluated by analyzing the earliest putative precursor, the ovarian epithelial inclusions.

In the current study, a detailed comparative morphologic and immunophenotypic evaluation of low-grade serous carcinoma and its putative precursors was performed in order to gain some insights into the origins of the cancer (fallopian tube versus ovary).

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