Manifestările locale ale imunității celulare în carcinomul mamar la pacienții cu diabet zaharat de tip 2: Teză de doctor în științe medicale: 311.02 – Anatomie patologică

Abstract

Thesis structure: Introduction, 6 chapters, general conclusions, practical recommendations, bibliography with 330 titles, 16 annexes, 110 pages of core text. The results were published in 40 scientific papers. Keywords: breast cancer, hormonal profile, HER2, Ki67, type 2 diabetes mellitus (T2DM), local immunity, T lymphocytes, macrophages, angiogenesis. The purpose of the study: A complex evaluation of invasive ductal breast carcinoma (NST) associated with T2DM, through the lens of the tumor’s molecular profile and local cellular immune status, compared to non-diabetic patients. Research methodology: A retrospective, comparative study on a batch of 102 specimens: 72 patients with breast cancer (43 without diabetes and 29 with T2DM) and a control group of 30 cases (unaffected breast tissue). Classical histological (HE) and immunohistochemical methods were used (a panel of 11 antibodies: ER, PR, HER2, Ki67, CD3, CD4, CD8, CD34, CD45, CD56, CD68). Results obtained: Morphological analysis demonstrated that T2DM-associated tumors exhibit more aggressive characteristics, showing larger sizes and more advanced pathological stages compared to the non-diabetic group. It was established that diabetes mellitus is not merely a comorbidity but an active factor that remodels the tumor microenvironment. The evaluation of immune status revealed significant changes induced by T2DM. In the tumors of diabetic patients, a decrease in the density of cytotoxic T lymphocytes (CD8+ ) and macrophages (CD68+ ) was observed in the intratumoral area compared to the peritumoral stroma. Conversely, the peritumoral stroma in diabetics is characterized by a more intense infiltration of NK cells (CD56+ ) and increased vascular density (CD34+ ), suggesting a compensatory adaptation. Unlike non-diabetic patients, where intratumoral vascularization correlates positively with aggressiveness, in diabetics, it correlates negatively with histological grade and Ki67, indicating paradoxical or inefficient angiogenesis. From a molecular perspective, T2DM-associated tumors are predominantly hormone-dependent (ER/PR positive), and the Luminal B/HER2- subtype is the most frequent. Although diabetes does not alter the global distribution of molecular subtypes, it modulates the relationships between markers: a strong positive correlation was highlighted between HER2 and Ki67 in diabetics, suggesting more aggressive behavior of HER2-positive tumors in a context of altered metabolism. Conclusions: Metabolic disturbances in T2DM profoundly influence the interaction between tumor and host, favoring a modified local immune profile that may contribute to neoplastic progression and necessitates a personalized therapeutic approach.