Tubal Origin of “Ovarian” Low-Grade Serous Carcinoma: A Gene Expression Profile Study

Abstract

Objective. Ovarian low-grade serous carcinomas are thought to evolve in a stepwise fashion from ovarian epithelial inclusions, serous cystadenomas, and serous borderline tumors. Our previous study with clinicopathological approach showed that the majority ovarian epithelial inclusions are derived from the fallopian tubal epithelia rather than from ovarian surface epithelia. This study was designed to gain further insight into the cellular origin of ovarian low-grade serous carcinomas by differential gene expression profiling studies. Methods. Gene expression profiles were studied in 43 samples including 11 ovarian low-grade serous carcinomas, 7 serous borderline tumors, 6 serous cystadenomas, 6 ovarian epithelial inclusions, 7 fallopian tubal epithelia, and 6 ovarian surface epithelia. Comprehensive analyses with hierarchical clustering, Rank-sum analysis and Pearson correlation tests were performed. Final validation was done on selected genes and corresponding proteins. Results. The gene expression profiles distinguished ovarian low-grade serous carcinomas from ovarian surface epithelia, but not from fallopian tubal epithelia cells. Hierarchical clustering analysis showed ovarian serous tumors and ovarian epithelial inclusions were clustered closely in a branch, but separated from ovarian surface epithelia. The results were further validated by selected proteins of OVGP1, WT-1, and FOM3, which were highly expressed in the samples of the fallopian tube, ovarian epithelial inclusions, and ovarian serous tumors, but not in ovarian surface epithelia. The reverse was true for the protein expression patterns of ARX and FNC1. Conclusions. This study provides evidence in a molecular level that ovarian low-grade serous carcinomas likely originate from the fallopian tube rather than from ovarian surface epithelia. Similar gene expression profiles among fallopian tube, ovarian epithelial inclusions, and serous tumors further support that ovarian low-grade serous carcinomas develop in a stepwise fashion. Such findings may have a significant implication for “ovarian” cancer-prevention strategies.

Low-Grade Serous Carcinoma of the Ovary: The Current Status

“…However, there has been controversy around the cells of origin of LGSC. Some investigators have suggested the fallopian tube as the origin of LGSC [ 14 , 16 , 17 ]. It is postulated that most epithelial inclusion glands are tubal in origin rather than ovarian due to invagination of the ovarian surface epithelium with metaplasia.…”

Importance of serous intraepithelial ovarian tubal carcinomas in the occurrence of "high-grade" serous carcinomas and / or peritoneal serous carcinomas of unknown primary origin.

“…У свою чергу, тип ІІ, що відповідно має за аналог "high-grade" серозну карциному, характеризується високим рівнем генетичної нестабільності із 81 20/ Том XXV / 1 залученням мутації ТР53. Вірогідно мають місце й різні шляхи канцерогенезу цих двох типів серозних карцином яєчників [3,13,18].…”

“…85 20/ Том XXV / 1 Епітеліальні пухлини видалених фаллопієвих труб гістологічно були серозними тубулярними інтраепітеліальними карциномами (in situ) або "high-grade" серозними інвазивними карциномами. І головне, вони мали ідентичні до "highgrade" серозної карциноми яєчників мутацію ТР53, аберантну експресію протеїну р53, високу проліферативну активність та значну геномну нестабільність [5,10,18].…”

“…У таких випадках яєчниковий поверхневий епітелій або епітелій кортикальних інклюзивних кіст (КІК) може бути вірогідним джерелом раку. КІК мають бути вислані плоскими, подібними до поверхневого мезотеліуму яєчників клітинами, але більшість з них мають клітини гістологічно та імуногістохімічно подібні до трубного епітелію, що можливо імплантувався туди з труби під час овуляції [5,15,18].…”

Are histomorphologic changes in the fimbrial ends more to blame for primary epithelial ovarian carcinomas than initially thought?

“…In contrast to HGSCs, it was assumed that, LGSCs arose from ovarian epithelial inclusions, serous cystadenoma or adenofibroma, and then progressed to serous borderline tumors and invasive carcinoma [9][10][11][12][13]. However, a few recent studies explored some histomorphological changes in the FEs of fallopian tubes, and concluded that secretory cells in fallopian tubes could be the source of LGSCs [14][15][16].…”