Tumor infiltrating lymphocytes (TILs) in endometrioid and clear cell ovarian carcinoma: Characterization, association with mismatch repair system deficiency and endometriosis, and prognostic implications.
Authors: Gallego Alejandro , Berjon Alberto , Mendiola Marta , Diez Jesus , Castelo Beatriz , Hernandez Alicia , Hardisson David , Feliu Batlle Jaime , Garcia Maria Jose , Redondo Andrés 
Published: June 2021

e17549 Background: In contrast to high-grade serous ovarian cancer, relationship between tumor infiltrating lymphocytes (TILs) with endometrioid (EC) and clear cell ovarian carcinomas (CC) are less known. However, these tumors are thought to arise from a transformed endometriosis, a disease with a marked inflammatory response, and are also more related to Lynch syndrome. The characterization of TILs in these tumors could lead to stratify patients according to their prognosis and to identify candidates for immumotherapy in case of relapse. Methods: We conducted a retrospective observational study of 121 patients with EC and CC, diagnosed and treated in La Paz University Hospital, from November 1992 until December 2013. An expert pathologist reviewed the histopathological diagnosis, using the immunohistochemical algorithm with WT1, p53, Napsin A and progesterone receptor, and the presence of endometriosis. Clinicopathological data, genetic testing and personal and familial background were collected. Tissue-microarrays (TMAs) were used to analyze CD8+, CD4+ and CD3+ intra-epithelial TILs, according to the score designed by the Ovarian Tumor Tissue Analysis Consortium, peritumoral and endometriosis lymphocytes, ARID1A, MLH1, PMS2, MSH2 and MSH6. Software SPSS18 version was used for descriptive and statistical analysis. Results: Mean age was 54.3 years, and the median follow-up 10.02 years. 48.8% were CC and 51.2% EC, of which, 55.9% were well-differentiated, 32.2% moderately and 11.9% poorly. 58.8% of patients were diagnosed in early stages and 41.2% in advanced ones. 9.1% had family history of ovarian, colorectal or endometrial cancer and 16.5% of breast cancer. 37.2% of patients had a relapse (median progression-free survival of 31 months) and 41.6% died (32.6% related to the tumor). 55.4% of the patients had endometriosis (53.2% were EC and 57.6% CC). 8.2% had lost of MLH1, PMS2, MSH2 or MSH6 and 42% lost ARID1A expression. Moderate or high levels of CD3+, CD8+ and CD4+ TILs were seen in the 57.9%, 53.7% and 1.1%, respectively. There was no relationship between TILs and the lost of MLH1, PMS2, MSH2 and MSH6. Moderate or higher levels of CD3+ TILs were related with better overall survival (OS) only in early stages (p = 0.045). Increased CD8+ TILs in EC patients were associated with a trend towards an improved OS in comparison with those patients with lower or negative CD8+ TILs. Moderate o higher levels of CD8+ TILs were also associated, without statistical significance, with the presence of endometriosis and ARID1A. Conclusions: In our study CD3+ TILs correlated to a better OS, but only in early stages of CC and EC. CD8+ TILs were also associated with a tendency to better OS in EC. We did not find statistically significant association between TILs and Mismatch Repair System deficiency, ARID1A or endometriosis.