Background/Objectives: Ovarian adnexal masses present diagnostic challenges due to their heterogeneous etiologies. Accurately differentiating these conditions is critical for timely and effective clinical intervention. This study evaluated circulating molecules and serum-induced apoptosis as complementary tools to conventional diagnostic methods (CA125, HE4, and the ROMA index) for distinguishing benign masses from malignant masses. Methods: A cohort of 136 participants (9 healthy controls, 87 women with benign ovarian adnexal masses and 40 with malignant ovarian adnexal masses) was analyzed. The induction of apoptosis in Jurkat cells by patient serum was assessed using flow cytometry. Serum concentrations of sFas/CD95, HE4, CA125, and additional molecules were measured by ELISA and LEGENDplex™. Clinical, ultrasonographic, and histopathological data were correlated with tumor malignancy. To improve diagnostic performance beyond individual biomarkers, we developed two multiparametric classifiers that integrate the dominant parameters identified through group divergence analysis and ROC evaluation across multiple clinical comparisons. Results: Malignant tumors were associated with older age (51.45 ± 8.35 years, p = 0.0002), postmenopausal status (61.1%, p = 0.0013), and larger tumor size (>10 cm). Ultrasonographic features of complexity were observed exclusively in malignant masses. Functional assays revealed reduced apoptosis in Jurkat cells exposed to malignant sera, suggesting tumor-mediated immune evasion. Although higher sFas levels were observed in tumors, no significant differences were identified between the groups. Among the circulating biomarkers, CA125, HE4, MRP8/14, OPN, and SAA levels were significantly higher in malignant tumors than in benign tumors and controls. Conclusions: The evaluation of CA125, HE4, MRP8/14, and apoptosis (Classifier 1) and, more prominently, the measurement of additional molecules: OPN, SAA, IL-6, IL-8, and IGFBP-4 (Classifier 2), systematically outperformed the ROMA. Both achieved superior specificity and balanced accuracy (Youden’s J index) across all clinical comparisons by capturing the biological diversity of malignancies.

Human papillomaviruses of the beta genus (beta-HPV) are ubiquitous components of the cutaneous virome, persistently colonizing the skin of immunocompetent individuals from early infancy. Unlike their alpha counterparts, which drive mucosal carcinogenesis through viral integration and sustained oncoprotein expression, beta-HPVs employ transient, cofactor-dependent mechanisms that operate primarily at the initiation stages of keratinocyte carcinogenesis, a paradigm known as the hit-and-run model. Although their association with cutaneous squamous cell carcinoma is well supported, particularly in immunocompromised individuals, beta-HPV genotypes are being increasingly detected in patients with cervical, head and neck, anal, vulvar, and colorectal carcinomas. This raises the question of whether beta-HPVs play a broader oncogenic role. This review examines the clinical significance of beta-HPV across anatomical sites and evaluates existing and next-generation preventive strategies. Collectively, the evidence suggests that beta-HPVs may act as clinically relevant viral cofactors, although whether their detection at these sites is incidental or causal remains unclear.