Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis

Abstract

Many endometrial adenocarcinomas, particularly those of endometrioid type, express estrogen receptors (ERs), progesterone receptors (PRs), and vimentin. This typical immunophenotype is frequently considered a standard against which others are compared when immunohistochemistry is used for differential diagnosis. We tested large numbers of endometrial cancers, enriched for high-grade tumors, to determine whether this reported immunophenotype was valid and whether expression differences between types of endometrial carcinoma could be exploited for diagnostic purposes. Immunohistochemical stains were performed on the following types of endometrial cancers using established methodology: International Federation of Gynecology and Obstetrics (FIGO) grades 1 and 2 endometrioid-42; FIGO grade 3 endometrioid-40; serous-24; clear cell-11; carcinosarcoma-9. In total, 92% of serous carcinomas expressed p16 strongly compared to weak-tomoderate expression of p16 in 7-67% of other tumors (FIGO grades 1 and 2 carcinoma and carcinosarcoma, respectively). A total of 84% of FIGO grades 1 and 2 carcinomas expressed ER compared to 9-54% of other tumors (clear cell and serous carcinomas respectively); 83% of FIGO grades 1 and 2 expressed PR compared to 11-54% of other carcinomas (carcinosarcoma and serous carcinoma, respectively). Most carcinomas were negative for monoclonal carcinoembryonic antigen (mCEA), and those that were positive showed mostly only focal membrane expression. Vimentin was expressed in nearly every tumor. Most tumors were diffusely vimentin positive, but a large range of expression patterns, from focal to diffuse and from weak to strong, was noted. Only 70% of FIGO grades 1 and 2 endometrioid carcinomas and 26% of grade 3 endometrioid carcinomas possessed the reportedly characteristic endometrial cancer immunophenotype p16 (À), ER ( þ ), PR ( þ ), mCEA (À), and vimentin ( þ ). Endometrial cancers demonstrate substantial immunophenotypic diversity that remained apparent even within groups of similar histologic subtype and grade. ER, PR, and p16 expression was more illustrative of tumor type and degree of differentiation than they were of endometrial origin. In contrast, the vimentin-positive/CEA-negative phenotype remained the most constant among all endometrial cancers.

p53 overexpression in morphologically ambiguous endometrial carcinomas correlates with adverse clinical outcomes

“…Strong and diffuse staining for p16 has been shown to correlate with serous morphology. [43][44][45] Some studies have suggested that p16 is a more robust marker of serous differentiation than p53, 43 although other studies have reported an expression gradient, with increasing levels of p16 staining from low-to high-grade endometrioid carcinoma, clear cell carcinoma and, finally, serous carcinoma, 45 suggesting that additional work is necessary to define relevant diagnostic cutoffs. We are aware of only one study that reports an association between p16 expression and aggressive clinical behavior specifically.…”

“…We are aware of only one study that reports an association between p16 expression and aggressive clinical behavior specifically. 46 Loss of PTEN staining (or presence of PTEN mutation) has been associated with endometrioid histology and favorable clinical outcomes, 1,45,47,48 but antibodies against PTEN are notoriously difficult to work with. 49 Some studies have shown that a combination of markers including p53, p16, PTEN and PR may be superior to p53 alone in discriminating uterine serous versus endometrioid carcinoma.…”

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

“…The alternative interpretation, which seems to have been adopted by other investigators, is that the expression (or 'overexpression') of p16 in endometrial carcinoma is abnormal, analogous to the situation in cervix. [47][48][49][50][51] A very wide range in p16 immunoreactivity (7-83%) has been reported in endometrial cancer, and this may be partly explained by differences in case selection, technical factors and varied definitions of 'positive' staining. It has been noted earlier that, when present, p16 immunoreactivity in endometrial carcinoma is typically focal and this may be helpful in distinguishing primary endometrial from endocervical adenocarcinomas.…”

Endometrial Intraepithelial Neoplasia

“…The mechanism of this overexpression, however, is probably different from that described in viral-related malignancies, since HPV DNA in situ hybridization has been negative in all studied cases (Chiesa-Vottero, Malpica et al 2007). ESC, it is rather linked to the inactivation of RB gene through dysregulation of the p16INK4a/cyclin D-CDK/pRb-E2F pathway (Reid-Nicholson, Iyengar et al 2006). Reid-Nicholson et al, (Reid-Nicholson, Iyengar et al 2006) reported that p16 overexpression was detected in 92% (22 of 24) of ESC cases, compared with 7% (3 of 42) FIGO grade 1and 2 EEC, and 25% (10 of 40) of FIGO grade 3 EEC cases.…”