POLE, MMR, and MSI Testing in Endometrial Cancer: Proceedings of the ISGyP Companion Society Session at the USCAP 2020 Annual Meeting

Abstract

Subclassification of endometrial carcinoma (EC) based on morphologic features alone has been shown to have suboptimal reproducibility, both in regard to biopsy versus hysterectomy findings, as well as interobserver agreement. This restricts the role of morphologic classification of EC as a tool for risk prediction and therefore treatment planning. A diagnostic algorithm based on The Cancer Genome Atlas (TCGA) classification of EC holds promise for improving accuracy in risk prediction. This classifies EC into 4 groups: those harbouring mutations in the exonuclease domain of DNA polymerase epsilon, POLE (POLEmut), those showing a mismatch repair defect, those showing mutations in TP53 (p53abn) and a heterogenous group showing none of these 3 abnormalities (currently termed no specific molecular profile). These groups can be accurately and reproducibly diagnosed on biopsy samples using a limited panel of tests, namely immunohistochemistry for mismatch repair proteins and p53, and testing for POLE exonuclease domain pathogenic variants. In this article we briefly review the biology, testing and interpretation of POLE and mismatch repair defects in EC.

Reporting Subclonal Immunohistochemical Staining of Mismatch Repair Proteins in Endometrial Carcinoma in the Times of Ever-Changing Guidelines

“…This manner of reporting in turn triggers the appropriate clinical follow-up and additional testing for identification of patients with Lynch syndrome. In the times of ever-changing guidelines, our results support recommended terminology for reporting of MMR protein IHC, including subclonal cases discussed by Casey and Singh 17 in their review paper published very recently (January 2021) in the International Journal of Gynecological Pathology as the Proceedings of the International Society of Gynecological Pathologists companion society session of the United States and Canadian Academy of Pathology 2020 meeting. In this publication, 17 reporting of isolated subclonal staining of MMR proteins in endometrial carcinomas was recommended because the subclonal staining may be associated with Lynch syndrome germline mutations.…”

“…In the times of ever-changing guidelines, our results support recommended terminology for reporting of MMR protein IHC, including subclonal cases discussed by Casey and Singh 17 in their review paper published very recently (January 2021) in the International Journal of Gynecological Pathology as the Proceedings of the International Society of Gynecological Pathologists companion society session of the United States and Canadian Academy of Pathology 2020 meeting. In this publication, 17 reporting of isolated subclonal staining of MMR proteins in endometrial carcinomas was recommended because the subclonal staining may be associated with Lynch syndrome germline mutations. The 4 cases of isolated subclonal staining (group 2) reported as a complete loss of MMR protein staining all demonstrated patterns 2 and 3 of subclonal staining of MLH1/PMS2 (Figure 2).…”

“…4,6,7,9,11,13 Variable immunohistochemical staining patterns of MMR proteins have emerged through the use of universal screening practices for newly diagnosed endometrial carcinomas. 10,12,[14][15][16] Documented patterns of IHC staining include uniform or complete loss of nuclear staining of tumor cells and heterogenous or subclonal loss of MMR protein expression, although reporting of subclonal staining was not recommended 10,12,14 until the January 2021 publication by Casey and Singh 17 in the Proceedings of the International Society of Gynecologic Pathology companion society session at the United States and Canadian Academy of Pathology 2020 annual meeting. The current reporting guideline issued by the College of American Pathologists 18 considers the presence of any positive nuclear staining, albeit weak or focal, as intact MMR protein expression, thus excluding tumors with subclonal immunohistochemical staining.…”

FDA-Approved and Emerging Next Generation Predictive Biomarkers for Immune Checkpoint Inhibitors in Cancer Patients

“…Although MSI-H can be present in almost all solid tumor types, its prevalence is widely variable across the different tumor types. MSI testing should be performed using IHC, PCR, or NGS method for the tumor types with high frequency of MSI, generally belonging to the spectrum of Lynch syndrome, including colorectal cancer ( 31 ), endometrial cancer ( 32 ), gastric cancer ( 33 ), ovarian cancer ( 34 ), and small Intestinal cancer ( 35 ). For other tumor types that do not belong to the spectrum of Lynch syndrome with low prevalence of MSI or no MSI data available on the reliability of IHC and the PCR method, such as NSCLC, breast cancer, melanoma, and kidney cancer, NGS-MSI should be considered because the NGS method can scan all types of MSI and also couple analyses of MSI with TMB.…”

α-Fetoprotein-Producing Endometrial Carcinoma Is Associated With Fetal Gut-Like and/or Hepatoid Morphology, Lymphovascular Infiltration, TP53 Abnormalities, and Poor Prognosis: Five Cases and Literature Review

“…D2-40 and CD31 IHC were used to aid in the identification of vascular invasion. Immunostaining for p53 ( 35 ) and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) ( 36 ) were interpreted according to previous reports. HER2 immunostaining was scored according to a previous study (NCT01367002) ( 37 ).…”