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.

Background and Objectives: Hereditary cancer predisposition is associated with pathogenic germline variants in numerous genes. Identification of inherited cancer susceptibility enables personalized screening, preventive interventions, and targeted therapies. It also facilitates cascade testing of relatives who may be at increased risk and benefit from tailored clinical management. We describe the first results of hereditary cancer patient identification, selection, and genetic testing at the University Hospital of Split. Materials and Methods: Next-generation sequencing and hereditary cancer gene panel analysis were performed in individuals who met the National Comprehensive Cancer Network clinical criteria for genetic testing at the University Hospital of Split between May 2025 and July 2026. A comprehensive cancer gene panel covering 101 genes was used. Results: A total of 297 individuals underwent genetic testing, including 268 (90.24%) females and 29 (9.76%) males. Of these, 138 (46.46%) were unaffected individuals who met testing criteria based on a family history of cancer. Among individuals with a personal history of malignancy, breast cancer was the most common diagnosis, occurring in 130 patients (43.77%). Pathogenic or likely pathogenic (P/LP) variants, as well as risk variants, were identified in 80 individuals (26.94%), including seven individuals carrying two P/LP variants. Variants were detected in 29 different genes, most frequently BRCA1 (n = 14), BRCA2 (n = 11), CHEK2 (n = 9) and PALB2 (n = 7). The detected variant types included frameshift (n = 30), missense (n = 22), nonsense (n = 21), splice-site variants (n = 4), start loss variants (n = 4), large deletions (n = 4), and in-frame deletions (n = 2). Conclusions: To our knowledge, this is the first study to report the results of panel germline testing for hereditary cancer syndromes in a Croatian population. These findings provide initial epidemiological data on the spectrum and distribution of P/LP variants. The relatively high detection rate may reflect the recent implementation of genetic testing and the careful selection of individuals with a strong clinical suspicion of hereditary cancer predisposition.