Markers of Lymphocytic-Macrophagal Infiltration and Their Association With the Receptor Phenotype and Proliferative Activity of Tumor Tissue in Various Molecular-Biological Types of Endometrial Cancer

Abstract

Background and Aims: The last years were characterized by a shift from the former subdivision of endometrial cancer (EC) into two main types [1, 2] to modern molecular biological classifications of this disease [3-5]. The purpose of this investigation was an attempt to compare such prognostic indicators for EC as features of lymphocytic [6] and macrophage infiltration of tumor tissue with markers of its hormonal sensitivity (receptor phenotype) and the proliferation index Ki-67 [7], taking into account the molecular biological type of the disease. Materials and Methods: The study involved material from untreated patients with endometrial cancer (a total of 219 people). The average age of patients was close to 55-60 years. Using classification of Talhouk et al. [5] allowed to perform a search for POLE mutations, evaluate by IHC the expression of the oncoprotein p53 and MMR (mismatch-repair) proteins /MLH1, MSH2, MSH6 and PMS2/, and also identify the type of disease without a characteristic molecular profile (WCMP). The IHC method was also used to study the rate of estrogen (ER) and progesterone (PR) receptors, Ki-67 proliferative activity index, as well as the severity of macrophage-lymphocytic tissue infiltration of EC based on the analysis of the macrophage (CD68) and lymphocytic cells (cytotoxic CD8 and regulatory FoxP3) markers using reagents from Ventana and Dako. Statistical assessment of the relationships of the studied indicators was carried out by the Spearman rank correlation coefficient. Results: FoxP3 (in contrast to CD8 and CD68) positively and significantly correlates (ρ varies from 0.2895 to 0.3477) more often with ER, but not with PR. Ki-67 index in EC tissue positively and reliably correlates with FoxP3 both in the MMR-D and WCMP groups and in the combined cohort of EC patients. In the latter case, a similar relationship with Ki-67 extends to other studied markers of lymphocytic-macrophage infiltration, namely CD8 and CD68 (ρ 0,1746-0,3294). Only in the entire group of EC patients there is a positive rank correlation (0.4119!) between ER and PR expression. Conclusions: In patients with certain types of EC the connection between the estrogenic signal and PR induction is lost; it is especially noticeable in the MMR-D group, as exemplified by the negative correlation (-0.2951) of FoxP3 and PR expression. Taken together with existing data this indicates an important role of the endocrine component for differentiating separate groups of patients with EC, that may also be of practical importance.