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Ovarian endometrioid and clear cell carcinomas (molecular pathology)

Wednesday 10 September 2014

After serous carcinoma, endometrioid and clear cell carcinomas are the most frequent types of EOC accounting for approximately 15-20% of EOC in Western countries.

PI3K/PTEN signaling pathway

Based on genome-wide mutational analysis, the most common molecular genetic changes in clear cell carcinoma are a somatic inactivating mutation of ARID1A, a tumor suppressor gene detected in about 50% of cases, an activating mutation of PIK3CA in about 50% of tumors and deletion of PTEN, a tumor suppressor gene involved in the PI3K/PTEN signaling pathway, in about 20%, supporting the role of an aberrant PI3K/PTEN pathway in the development of clear cell carcinoma.

In addition, SNP array analysis has identified frequent amplification of the ZNF217 (zinc finger protein 217) locus and deletion of the CDKN2A/2B locus in clear cell carcinomas, suggesting that the pathways involving these two genes are also important in their development.

Like clear cell carcinoma, mutations that deregulate PI3K/PTEN signaling are common in low-grade endometrioid carcinoma and, in fact, mutation of the tumor suppressor gene PTEN, which occurs rarely in other types of EOC, has been reported in approximately 20% of ovarian low-grade endometrioid carcinomas.

Another mechanism by which activation of PI3K signaling occurs is through activating mutations of PIK3CA, which has been detected in 20% of low-grade endometrioid carcinomas.

Wnt/b-catenin signaling pathway

The Wnt/b-catenin signaling pathway, which is involved in the regulation of several important cellular processes including proliferation, motility and survival, is deregulated in up to 40% of ovarian endometrioid carcinomas, usually on the basis of activating mutations of CTNNB1, the gene that encodes β-catenin.

Notably, mutation of CTNNB1 has been associated with squamous differentiation, low tumor grade and a favorable outcome, features that characterize low-grade endometrioid carcinoma (47-50).


Although low-grade endometrioid carcinomas are easily recognized, the distinction of high-grade endometrioid carcinoma from HGSC can be very difficult.

Some pathologists even question the existence of high-grade endometrioid carcinoma regarding it as a variant of HGSC whereas others classify high-grade endometrioid carcinoma as “mixed high-grade endometrioid carcinoma and HGSC” or as “HGSC with features of endometrioid carcinoma”.

It is therefore of interest that in a study of ovarian endometrioid carcinomas of all grades, low-grade endometrioid carcinomas were characterized by mutations that deregulate the canonical Wnt/β-catenin and PI3K/PTEN signaling pathways and lacked TP53 mutations whereas high-grade endometrioid carcinomas lacked Wnt/β catenin or PI3K/PTEN signaling pathway defects and frequently harbored TP53 mutations.

A few high-grade endometrioid carcinomas did, in addition, to TP53 mutation, display molecular changes found in the low-grade endometrioid carcinomas suggesting that some low-grade endometrioid carcinoma may progress to high-grade carcinoma.

The findings parallel those seen in the serous tumors, namely that generally low- and high-grade tumors develop independently but that rarely progression of a low-grade to a high-grade tumor occurs.

The similar high frequency of TP53 mutations in the high-grade endometrioid carcinoma as in HGSC suggests that both develop in a similar fashion, via TP53 mutation, and that most high-grade endometrioid carcinoma is closely related or is a variant of HGSC.

Morphologic studies over the past two to three decades have repeatedly shown an association of endometrioid and clear cell carcinoma with endometriosis and early molecular genetic studies demonstrated LOH in the same chromosomal regions in endometrioid carcinoma and adjacent endometriosis confirming a clonal relationship between endometriosis and endometrioid carcinoma.

In addition, a recent study reported mutation of ARID1A in atypical endometriosis adjacent to clear cell carcinoma but not in distant sites of endometriosis further linking endometriosis to clear cell carcinoma and thereby providing further evidence that endometriosis is the likely precursor of endometrioid and clear cell carcinoma.

Although both clear cell and endometrioid carcinomas are derived from endometriosis and share some molecular genetic features, such as mutation of ARID1A and deletion of PTEN, they clearly adopt different molecular programs for their development, as is evident by their distinctly different morphologic phenotype and clinical behavior.

For example, canonical Wnt signaling pathway defects and microsatellite instability, which occur frequently in low-grade endometrioid carcinoma have only rarely been detected in clear cell carcinoma.

Also it has been recently demonstrated that unlike all the other types of EOC, clear cell carcinoma has significantly longer telomeres and this finding correlates with poor outcome.

Finally, morphologic studies have linked the "endocervical-type mucinous borderline tumor", also referred to as “atypical proliferative seromucinous tumor”, to endometriosis in about a third of cases.


- Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Kurman RJ, Shih IeM. Hum Pathol. 2011 Jul;42(7):918-31. doi : 10.1016/j.humpath.2011.03.003 PMID: 21683865 (Free)