Clear cell and endometrioid carcinomas: are their differences attributable to distinct cells of origin?

Abstract

Endometrial epithelium is the presumed tissue of origin for both eutopic and endometriosis-derived clear cell and endometrioid carcinomas. We had previously hypothesized that the morphological, biological and clinical differences between these carcinomas are due to histotype-specific mutations. Although some mutations and genomic landscape features are more likely to be found in one of these histotypes, we were not able to identify a single class of mutations that was exclusively present in one histotype and not the other. This lack of genomic differences led us to an alternative hypothesis that these cancers could arise from distinct cells of origin within endometrial tissue, and that it is the cellular context that accounts for their differences. In a proteomic screen, we identified cystathionine γ-lyase (CTH) as a marker for clear cell carcinoma, as it is expressed at high levels in clear cell carcinomas of the ovary and endometrium. In the current study, we analysed normal Müllerian tissues, and found that CTH is expressed in ciliated cells of endometrium (both eutopic endometrium and endometriosis) and fallopian tubes. We then demonstrated that other ciliated cell markers are expressed in clear cell carcinomas, whereas endometrial secretory cell markers are expressed in endometrioid carcinomas. The same differential staining of secretory and ciliated cells was demonstrable in a three-dimensional organoid culture system, in which stem cells were stimulated to differentiate into an admixture of secretory and ciliated cells. These data suggest that endometrioid carcinomas are derived from cells of the secretory cell lineage, whereas clear cell carcinomas are derived from, or have similarities to, cells of the ciliated cell lineage. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Distinct molecular pathways in ovarian endometrioid adenocarcinoma with concurrent endometriosis

“…While some high‐grade serous ovarian cancers are thought to arise from the malignant transformation of fimbria of the fallopian tube with subsequent early metastasis to the ovary, others may arise from the ovary itself . OEA is thought to arise from secretory epithelial cells that are frequently found in eutopic endometrium and ectopic endometriomas . Further, the cell of origin may predict aggressive disease.…”

“…Further, the cell of origin may predict aggressive disease. For example, high‐grade OEA without endometriosis may develop from the secretory epithelial cells of the eutopic endometrium and already have a metastatic phenotype by the time it is discovered . On the other hand, OEA with concurrent endometriosis may develop from secretory epithelial of endometriomas and represent a nonmetastatic phenotype .…”

“…Most ovarian cancers arise from cells that are not normally found in the ovary . For example, ovarian endometrioid adenocarcinoma (OEA) is thought to arise from secretory epithelial cells of the eutopic endometrium or endometriosis. Endometriosis is a hormonally responsive, pathologic growth of endometrium outside the uterus (i.e.…”

“…Previous reports have identified a limited number of oncogenes or tumor suppressors that may be involved in the pathogenesis of OEA . Mutations alone cannot explain the clinical and phenotypic differences, and thus, the endometriotic tumor microenvironment may play a significant role in the pathogenesis of OEA . However, specific molecular contributions of the endometriotic tumor microenvironment to OEA remain poorly understood.…”

Unraveling endometriosis-associated ovarian carcinomas using integrative proteomics

“…It is important to note that 10 of the 40 concordant genes were significantly upregulated in our data (FDR = 0.05, S0 = 1) with many of them being known markers of CC including napsin A (NAPSA), annexin 4 (ANXA4) and hepatocyte nuclear factor 1-beta (HNF1B). Furthermore, cystathionine gamma-lyase (CTH) and interleukin-6 receptor subunit beta (IL6RB) – markers that have been associated with CC ( Cochrane et al , 2017; Hughes et al , 2016; Yanaihara et al , 2016) – were found to be elevated in CC compared to EMT samples. CTH was found to be significantly elevated in CC compared to EMT (p=0.01) while IL6RB was undetectable in all EMT samples but expressed in 4/6 of the CC samples.…”