PD-L1 Expression in Complex Atypia Hyperplasia and Early Stage Endometrial Cancer

Project no. 28485 · Status: Kapanmış (Yayın bekleniyor) · 2023

Summary

Endometrial cancer is the most common gynecological malignancy. Every year, 142 thousand women are diagnosed with endometrial cancer in the world and 42 thousand women die due to endometrial cancer. It is the fourth most common cancer in women in the United States, after breast, lung, and colorectal cancers. The mean age of patients at diagnosis is 63 years, and 90% of cases occur in women older than 50 years. Only 20% of patients with endometrial cancer are diagnosed before menopause, and 4% of patients are under the age of 40. However, in the last 10 years, the incidence of endometrial cancer in young women has increased dramatically as a result of early-onset obesity.Since the childbearing age of women is higher today than in the past, more than 70% of patients diagnosed with endometrial cancer under the age of 40 are nulliparous at the time of diagnosis. This situation brings the fertility-preserving treatment approaches to the fore. When considering a conservative approach, the clinical and pathological features of the tumor should be considered in order to select the appropriate medical intervention. A conservative management approach may be considered in the following patients: patients under 40 years of age (relative indication), patients aiming to preserve fertility and planning to conceive as soon as possible after remission, without any contraindications for medical treatment and histological diagnosis of Grade 1 endometrioid type and hormone receptor Patients with positivity, tumor diameter <2 cm, stage IA without myometrial and adnexal involvement, negative lymph-vascular space invasion (LVSI) and immunohistochemically progesterone receptor positivity in endometrial biopsy. These patients are considered the “low-risk” population.Standard treatment for grade 1 endometrial cancer; bilateral salpingo-oophorectomy with hysterectomy, additionally, lymph node dissection and pelvic washing, if necessary. These treatment methods can be combined with adjuvant chemotherapy or radiotherapy treatments if necessary. Although this is a highly effective approach and has a 5-year survival rate of 93%, it results in a permanent loss of fertility that is often unacceptable for young women who want to preserve their fertility. For this reason, fertility-preserving medical approach comes to the fore in patients who want pregnancy. The basis of this approach is oral progestin therapy and hysteroscopic resection (alone or in combination). Progestins used in treatment; medroxyprogesterone acetate and megestrol acetate. Although there is currently no consensus on the optimal dose or duration of treatment, studies have reported that 62-75% of patients respond well to progestogen therapy. Other treatment modalities are levonorgestrel-releasing intrauterine device, GnRH analogues, aromatase inhibitors, and hysteroscopic resection. These other methods can be used in combination with progestin therapy. A key feature for tumor cell survival and progression is its escape from the body's immune system. Therapies that reverse the blocked interaction of immune system components with tumor cells are an innovative and promising therapeutic approach in cancer treatment. One of the most important immune checkpoints is receptor programmed cell death-1 (PD-1), which is expressed, inter alia, on activated T lymphocytes. This receptor interacts with programmed cell death ligand-1 (PD-L1), which is frequently expressed in cancer cells. PD-1 (programmed cell death protein-1) is a transmembrane glycoprotein in the immunoglobulin superfamily. It acts as an immune inhibitory receptor specifically expressed on cytotoxic T cells. PD-1 has two different ligands, PD-L1 (CD274) and PD-L2 (CD273). Generally, PD-L1 is expressed on the surface of various cells of the immune system, such as T- and B-cells and macrophages, while PD-L2 is expressed in previously activated macrophages and dendritic cells. PD-1 and PD-L1 are immune checkpoint antibodies and drugs developed as immune checkpoint inhibitors are used in the treatment of many tumors. In recent studies, it has been reported that immune checkpoint inhibitors are also used in the treatment of cervical and endometrial cancer. In the literature; Although there are many studies on the use of PD-1 and PD-L1 inhibitors in the treatment of patients with melanoma, breast cancer, lung cancer, and colorectal cancer, there are limited studies on PD-1 and PD-L1 expressions in patients with endometrial cancer and evaluating the relationship with the clinical course. With this study, it is aimed to obtain more data on the subject and contribute to the literature.PD-L1 expression will be examined in the hysterectomy material of patients who were pathologically diagnosed with complex atypia hyperplasia and early stage endometrial cancer (stage 1a) in the Department of Obstetrics and Gynecology at Ege University Medical Faculty Hospital. Eighty patients who underwent surgery in Ege University Gynecological Oncology Department will be included in the study. The hysterectomy materials of these 80 cases will be examined. 20 of these cases will have complex atypia hyperplasia, 20 stage 1a grade 1 tumors, 20 stage 1a grade 2 tumors, and 20 stage 1a grade 3 tumors. After examining the tumor sections of the cases, appropriate paraffin blocks will be removed. Sections taken from paraffin blocks will be stained immunohistochemically with PD-L1 marker. Clinical and pathological data of the cases will be extracted from patient files and pathology reports retrospectively. Immunohistochemical staining results and clinical data will be compared. Slides of each case containing tumor sections in our archive will be re-evaluated. After selecting the appropriate slides, which are thought to represent the tumor best, the PDL1 (22c3, 1/80 dilution, DAKO) antibody will be studied immunohistochemically on 4 micron thick sections prepared from formalin-fixed paraffin blocks of the appropriate preparations. This application will be done by following the instructions of the manufacturers in the Ventana Benchmark XP (Benchmark XT; Ventana Medical Systems, Roche Diagnostics) fully automatic immunohistochemistry stainer after the paraffin sections are dewaxed in xylene and gradually rehydrated with a series of graded alcohols. Immunohistochemically, PDL1 (22c3) applied slides were stained under light microscopy (Axio imager A2, Zeiss, Germany); tumor proportion score (TPS) and Combined positive score (CPS). TPS is the score to be obtained by multiplying the number of tumor cells stained positively with PDL-1 by 100 after dividing by the total number of tumor cells. CPS is the score obtained by multiplying the total number of cells (tumor cells, lymphocytes, macrophages) stained with PDL-1 by 100 after dividing by the total number of tumor cells. TPS <1% negative, 1-14% positive, 50% or more staining will be considered strong positive. CPS <1% negative, 1-19% positive, 20% or more staining will be considered strong positive.

View details