Endometrial Carcinoma and Associated Secondary Neoplasia: The Role of Clinical Features, Pathology, and Comorbidities in a University-Affiliated Clinical Center from Western Romania

<i>Background and Objectives</i>: Multiple primary malignancies involving endometrial carcinoma (EC) present complex diagnostic and management challenges. This study aimed to identify clinical, pathological, and demographic patterns among patients with EC and a second primary tumor and assess the role of comorbidities in tumor behavior. <i>Materials and Methods</i>: We retrospectively analyzed 35 women diagnosed with EC and a second malignancy between 2017 and 2024. We evaluated clinical variables, tumor characteristics, and comorbidities. Statistical analysis included chi-square tests, Mann-Whitney U tests, Kruskal-Wallis tests, Spearman correlations, and logistic regression. Multiple testing correction was applied using the Benjamini-Hochberg method. <i>Results</i>: Endometrioid EC was the most prevalent subtype (80%), most frequently associated with breast (28.5%) and colorectal cancers (11.4%). Obesity (45.7%), hypertension (62.9%), and diabetes (22.9%) were common. While univariate analysis suggested associations between comorbidities and tumor features (e.g., obesity and tumor type, ρ = 0.30, <i>p</i> = 0.08), no correlation remained significant after adjustment. Logistic regression identified age (OR = 0.88, CI: 0.79-0.98, <i>p</i> = 0.022) and obesity (OR = 0.11, CI: 0.01-0.83, <i>p</i> = 0.033) as independent predictors of non-endometrioid histology. <i>Conclusions</i>: These findings suggest that age and obesity may influence histological differentiation in EC with multiple primaries. This study suggest that age and obesity may play a role in the histological differentiation of EC in patients with multiple primary tumors. The small cohort size (<i>n</i> = 35) limits the statistical power and generalizability of the results; therefore, they should be regarded as exploratory and hypothesis-generating, warranting validation in larger prospective studies.