Maha Salama

Moesin and Ezrin as New Promising Markers for Early Detection of Endometrial Carcinoma: An Immunohistochemical Study

the aim of this study is to evaluate immunohistochemically the expression of ezrin, and moesin, in endometrial lesion cases in order to detect EC at early stages which will have an important implication on the patients' outcome. 100 stored, formalin-fixed, paraffin-embedded tissue blocks of endometrial curettage obtained due to abnormal uterine bleeding or postmenopausal bleeding were collected. Each paraffin block was re-cut by rotatory microtome at 4 μm thickness then mounted on a glass slide and stained by hematoxylin and eosin for routine histopathological examination and on charged slides for immunohistochemistry using an automated staining system (Dako autostainer link 48) with antibodies against Moesin and Ezrin. Cytoplasmic staining was evaluated for both Moesin and Ezrin based on the intensity and extent of staining and scored for each sample. Both Moesin and Ezrin were significantly higher in atypical endometrial hyperplasia compared to benign hyperplasia and significantly higher in endometrial carcinoma compared to atypical hyperplasia. Moesin also significantly correlated with higher tumor grades while Ezrin was significantly higher in postmenopausal women denoting their role in tumor progression and poor prognosis. Both Moesin and Ezrin could be potentially used as predictive markers for endometrial carcinoma screening programmes as well as indicators for cancer progression.

PD-L1 Immunohistochemical Expression in Endometrial Carcinoma: Egyptian Cross-Sectional Study

Endometrial carcinoma (EC) is the most common cancer of the female genital tract. According to the recently evolved strategies of cancer immunotherapy, immune checkpoints inhibitors are one of the most crucial strategies. Programmed Death Ligand 1 (PD-L1) is an important immune checkpoint regulator. PD-L1 antibodies have shown efficacy in clinical trials of some malignancies. Some of these antibodies have been approved for clinical usage by the Food and Drug Administration (FDA). This retrospective study included a total of 100 ECs, collected from archived, formalin-fixed, paraffin-embedded tissue blocks of hysterectomy specimens of Egyptian females. The samples were immunohistochemically analyzed for PD-L1 expression (in both tumor cells; TCs and tumor infiltrating leucocytes; TILs) by a semiquantitative score (0 to 4), with cutoff points of (0: <1% of the cells, 1: 1% to 4%, 2: 5% to 9%, 3: 10% to 49%, and 4: ≥ 50%). Membranous staining only was considered positive. PD-L1 was highly expressed in ECs (67% TCs+ and 61% TILs+), with statistically significant relationships with age, lympho-vascular space invasion (LVSI) and TILs score (P = 0.006, 0.016 and <0.005 respectively).  However, no statistically significant relationships were detected between PD-L1 expression and the following parameters: histological type, histological grade, pathological stage (pT) or FIGO stage, myometrial, cervical, adnexal/serosal, parametrial involvements and nodal metastasis, as well as ESMO risk stratification system. Moreover, statistically significant relationships were achieved when correlating TILs score with tumor grade and LVSI (P = 0.034 and 0.012 respectively). Also, comparing endometrial hyperplasia (EH) PD-L1 and TCs PDL1 median scores achieved statistically significant relationship (P = 0.001). Our results concluded that PD-L1 expression was greater in both TCs and TILs in a subgroup of patients that have advanced age, LVSI and are TILs-rich, identifying them as potential candidates for anti-PD-1/PD-L1 immunotherapy.

Immunohistochemical Expression of Programmed Death Ligand 1(PDL1) in Endometrial Carcinoma and Its Relation to CD4 and CD8 Positive Immune Cells

Endometrial cancer (EC) is the most common cancer of the female genital tract. Egypt showed a significant increase in incidence lately of which 25% were premenopausal. Advanced or recurrent disease are mostly unresectable and the traditional adjuvant therapy give modest results with devastating side effects. Late discoveries of immune checkpoint inhibitors have produced promising results. Programmed cell death 1 (PD1) is an immune inhibiting receptor on surface of lymphocytes, which plays critical roles in maintaining immunological self-tolerance. There are two ligands for this receptor, PDL1 and PDL2. PD-L1 is expressed on tumor cells; attaches to PD1, allowing tumor cells to escape from the host immune response. Its prognostic significance in various tumors is controversial and its significance in ECs has just begun to be investigated. Therefore, we investigated the relationship between PDL1 expression and different clinicopathologic parameters in EC cases and its correlation with CD4 and CD8 immune cells, in order to identify the predictive biomarkers for the outcome by immune therapy. Hundred, paraffin tissue blocks of EC cases were collected and stained with antibodies against PDL1,CD4 and CD8. PDL1 was positive in 67% of cases in tumor cells and in 61% of cases in immune cells. CD4 and CD8 were expressed in 79% of cases. Statistically significant correlations were observed between PDL1 expression and patients mean age, LVSI, TILS score and CD4+/CD8+ expression. Those variables can stratify candidates who can benefit most from immunotherapy, or can be chosen for further high cost molecular investigations application.

Expression of Programmed Death-1 Ligands (PD-L1 and PD-L2) in Endometrial Carcinoma: Immunohistochemical Study

On basis of knowledge about the relationship between the immunity and cancer; cancer immunotherapies were introduced. Immune checkpoint regulators rank among the most crucial of those tactics. Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2) are 2 ligands of Programmed Death-1 (PD-1); an immune checkpoint regulator. PD-L1 and PD-L2 antibodies have been effective in treating a variety of malignancies in clinical trials. Few of these antibodies have been approved for clinical use by the Food and Drug Administration (FDA). The purpose of this study was to assess the immunohistochemical expression of PD-L1 and PD-L2 by tumor cells (TC) and tumoral stroma immune cells (IC) in endometrial carcinoma (EC) and their association with the tumor's clinico-pathologic characteristics. For 62 EC cases, PD-L1 and PD-L2 immunohistochemical expression was examined in the TC and IC. Positive TC PD-L1 (25.8% of cases) was linked to high stromal tumor infiltrating lymphocytes (TILs) and high tumor grade. High TC PD-L2 (33.9% cases) was associated with non-endometrioid types, high tumor grade, and high FIGO stage. Positive IC PD-L1 (51.6% of cases) was correlated to non-endometrioid types, high tumor grade, high FIGO stage and high stromal TILs. High IC PD-L2 expression (14.5% of cases) was associated with lympho-vascular space invasion. Both PD-L1 and PD-L2 expression in both TC and IC were found to be directly correlated. Crucially, some of the PD-L1 negative cases had significant expression of PD-L2. Our results supported PD-L1 & PD-L2 expression in EC, particularly in high grade, high FIGO stage, non-endometrioid and TILs rich tumors, highlighting such cases as candidates for anti- PD-1 therapy. Furthermore, the identification of PD-L2 positive PD-L1 negative cases may indicate the combination of PD-L1 and PD-L2 testing to nominate cases that may benefit from the PD-1 pathway targeting therapies.