Are the uterine serous carcinomas underdiagnosed? Histomorphologic and immunohistochemical correlates and clinical follow up in high-grade endometrial carcinomas initially diagnosed as high-grade endometrioid carcinoma

Abstract

Histologic subclassification of high-grade endometrial carcinomas can sometimes be a diagnostic challenge when based on histomorphology alone. Here we utilized immunohistochemical markers to determine the immunophenotype in histologically ambiguous high-grade endometrial carcinomas that were initially diagnosed as pure or mixed high-grade endometrioid carcinoma, aiming to determine the utility of selected immunohistochemical panel in accurate classification of these distinct tumor types, while correlating these findings with the clinical outcome. A total of 43 high-grade endometrial carcinoma cases initially classified as pure high-grade endometrioid carcinoma (n=32), mixed high-grade endometrioid carcinoma/serous carcinoma (n=9) and mixed high-grade endometrioid carcinoma/clear cell carcinoma (n=2) were retrospectively stained with a panel of immunostains, including antibodies for p53, p16, estrogen receptor, and mammaglobin. Clinical follow-up data were obtained, and stage-to-stage disease outcomes were compared for different tumor types. Based on aberrant staining for p53 and p16, 17/43 (40%) of the high-grade endometrial carcinoma cases initially diagnosed as high-grade endometrioid carcinoma were re-classified as serous carcinoma. All 17 cases showed negative staining for mammaglobin, while estrogen receptor was positive in only 6 (35%) cases. The remaining 26 cases of high-grade endometrioid carcinoma showed wild-type staining for p53 in 25 (96%) cases, patchy staining for p16 in 20 (77%) cases, and were positive for mammaglobin and estrogen receptor in 8 (31%) and 19 (73%) cases, respectively, thus the initial diagnosis of high-grade endometrioid carcinoma was confirmed in these cases. In addition, the patients with re-classified serous carcinoma had advanced clinical stages at diagnosis and poorer overall survival on clinical follow-up compared to that of the remaining 26 high-grade endometrioid carcinoma cases. These results indicate that selected immunohistochemical panel, including p53, p16, and mammaglobin can be helpful in reaching accurate diagnosis in cases of histomorphologically ambiguous endometrial carcinomas, and can assist in providing guidance for appropriate therapeutic options for the patients.

Endometrial Tumor Classification by Histomorphology and Biomarkers in the Nurses’ Health Study

“…The application of biomarkers (i.e., immunohistochemical staining) assists pathologists in rendering more accurate diagnoses. A recent study found that up to 40% of cases initially diagnosed as high-grade endometrial endometrioid adenocarcinomas may be reclassified as uterine serous carcinomas based on a panel of four immunostains (p53, p16, estrogen receptor (ER), and mammaglobin) [ 10 ]. Immunostains in routine practice, however, are often not pursued due to a pathologist's degree of morphologic certainty or the possibility of ambiguous results.…”

Low Expression of miR-375 and miR-190b Differentiates Grade 3 Patients with Endometrial Cancer

“…Assignment to the appropriate grade is based on the percentage of solid non-squamous, non-morular tumor cells during histopathological evaluation, with grade 3 assigned to cases with over 50% of the tumor cells. However, this assignment is affected by the inter-observer variability, especially in high-grade EC, when the diagnosis is based on histomorphology alone [5,6]. The availability of molecular methods encourages to support EC diagnosis with genomic and transcriptomic data.…”

A 4-gene signature predicts prognosis of uterine serous carcinoma

“…Unlike EEC, USC tends to develop in elderly women, with low body weight and arises in the background of atrophic endometrium (4). Microscopically, USC typically forms complex papillary structure with almost high-grade polymorphic nuclei in contrast to glandular/cribriform pattern with mild to moderate atypical nuclei in EEC (5,6). 80-90% of USC tumors harbor TP53 mutation while retaining wildtype PTEN but losing ER/PR expression (5)(6)(7)(8).…”

“…Microscopically, USC typically forms complex papillary structure with almost high-grade polymorphic nuclei in contrast to glandular/cribriform pattern with mild to moderate atypical nuclei in EEC (5,6). 80-90% of USC tumors harbor TP53 mutation while retaining wildtype PTEN but losing ER/PR expression (5)(6)(7)(8). USC accounts for almost 10% of endometrial cancers but is disproportionately responsible for poor outcomes, contributing up to 40% cancer-related deaths from endometrial cancer (4).…”