Prognostic Value of Morphological Characteristics and Immune Microenvironment in High-Grade Serous Cancer (HGSC)

Background/Objectives: High-grade serous ovarian carcinoma (HGSC) is the most aggressive subtype of epithelial ovarian cancer and is characterized by marked heterogeneity of the tumor immune microenvironment. SET morphology has been associated with homologous recombination deficiency and BRCA1/2 mutations; however, its relationship with the immune microenvironment and progression-free survival (PFS) remains insufficiently understood. This study investigated the association between SET morphology, immune microenvironment characteristics, and PFS in patients with advanced-stage HGSC. Methods: A retrospective cohort of 305 patients with FIGO stage III-IV HGSC treated with primary surgery between 1996 and 2021 was analyzed. Histopathological assessment included evaluation of SET morphology, stromal and intraepithelial tumor-infiltrating lymphocytes (sTILs and itTILs), tumor immune phenotype, and lymphoid aggregates. Immunohistochemical analyses included CD8 and PD-L1 expression. Associations between SET morphology and immune parameters were evaluated using χ² and logistic regression analyses. PFS was assessed using Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards regression. Results: SET morphology was significantly associated with higher sTIL and itTIL levels, increased stromal and intraepithelial CD8⁺ T-cell infiltration, higher PD-L1 TPS and CPS, more frequent primary and secondary lymphoid aggregates, and a predominance of the inflamed immune phenotype (all p < 0.05). Despite these features of an immune-active tumor microenvironment, SET morphology, CD8⁺ T-cell density, PD-L1 expression, lymphoid aggregates, and immune phenotype were not independently associated with prolonged PFS. In contrast, age remained an independent prognostic factor, with patients older than 55 years having a 50% higher risk of disease progression than younger patients (HR = 1.5, 95% CI: 1.1-2.1; p = 0.012). Higher intraepithelial TIL levels (>10%) were independently associated with improved PFS (HR = 2.1, 95% CI: 1.0-4.4; p = 0.045). Conclusions: SET morphology identifies an immune-active subtype of HGSC characterized by increased immune infiltration and PD-L1 expression but does not independently predict prolonged PFS. The dissociation between immune cell abundance and clinical outcome suggests that immune cell functionality, rather than immune infiltration alone, may determine prognosis. Routine histopathological assessment of SET morphology may facilitate biological characterization of HGSC and provide a practical surrogate marker for future biomarker-driven studies evaluating immunotherapy and targeted treatment strategies.