Abstract
Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.
Highlights
Dedifferentiated endometrial carcinoma (DDEC) is a rare and more aggressive type of endometrioid carcinoma than high grade endometrioid carcinoma [1,2,3]
Previous studies have suggested that DDEC is associated with a deficiency of mismatch repair (MMR) proteins (MLH1, postmeiotic segregation increased 2 (PMS2), MLH2, and mutS protein homolog 6 (MSH6)) [5]
DDEC is generally associated with 58% MMR deficiency and is more frequent than endometrial carcinoma [5]
Summary
Dedifferentiated endometrial carcinoma (DDEC) is a rare and more aggressive type of endometrioid carcinoma than high grade endometrioid carcinoma [1,2,3]. Clinical trials of immune checkpoint inhibitors for MMR-deficient tumors have been studied in many carcinomas including colorectal cancer and melanoma [12]. As a biomarker for the effectiveness of immune checkpoint inhibitors, PD-L1 expression on IHC, cytotoxic T lymphocyte (CD8+ T cell), and neo antigen (mutation burden rich) are shown in existing reports [12,13,14,15]. It has been suggested that immune checkpoint inhibitors may be effective when there is a high infiltration of CD8+ T cells into the tumor [16,17,18]. We investigated the relationship between the expression of PD-L1 protein and CD8+ T cell tumor-infiltration and MMR deficiency in DDEC
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