Background/Objectives: Penile squamous cell carcinoma (PSCC) is a rare malignancy with a potential major impact on survival. Prognostic assessment remains challenging, particularly in underrepresented eastern European populations, where region-specific evidence is lacking. This paper aimed to identify independent predictors of overall survival in surgically treated patients with PSCC from a Romanian high-volume tertiary center. Methods: This retrospective cohort study analyzed 60 patients who were surgically treated for PSCC between October 2020 and December 2024. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent prognostic factors. Results: The mean patient age was 62 ± 12 years. T-stage distribution showed 30% pT1, 35% pT2, 31.67% pT3, and 3.33% pT4, with 55% of patients presenting with nodal metastases. Univariate analyses demonstrated significant associations between lymphovascular invasion (p < 0.001), perineural invasion (p = 0.022), and positive surgical margins (p = 0.030) and risk of death. Multivariate analysis identified three independent prognostic factors: absence of histologically documented urethral invasion (HR 0.32; p = 0.027), T3–T4 disease (HR 8.26; p = 0.005 vs. T1), and N3 stage (HR 3.53; p = 0.030 vs. N0–N1). Patients without urethral invasion demonstrated significantly longer median overall survival (63 months vs. 11 months). The final three-variable prognostic model demonstrated good discrimination (C-index 0.78), providing a potential practical risk stratification tool. Conclusions: Urethral invasion, advanced T-stage, and N3 disease independently predict poor survival in surgically treated PSCC. The identification of urethral invasion as an independent prognostic factor warrants consideration in clinical practice. This is the first study of a Romanian cohort to provide critical data for risk-adapted treatment strategies in underrepresented eastern European populations.

Background and Objectives: Paraneoplastic hypercalcemia represents a rare but clinically significant complication of penile squamous cell carcinoma (PSCC), with limited evidence available. This systematic review aimed to comprehensively evaluate the pathophysiological mechanisms, clinical presentation, therapeutic strategies and prognostic outcomes of tumor-induced hypercalcemia in PSCC. Methods: A comprehensive literature search was conducted across PubMed/MEDLINE and Scopus databases from inception to December 2024. Cases were included if they documented histopathologically confirmed PSCC with biochemically verified hypercalcemia and objective evidence of paraneoplastic etiology. Data extraction encompassed tumor characteristics, hypercalcemia severity, mechanistic classification, therapeutic interventions and survival outcomes. Analysis followed PRISMA 2020 guidelines adapted for descriptive synthesis. Results: Twelve published cases spanning six decades (1965-2024) met inclusion criteria. The median age at presentation was 56 years, with 91.6% of patients presenting with advanced disease. Severe hypercalcemia (≥14 mg/dL) occurred in 66.7% of cases, with a median calcium level of 15.45 mg/dL. Three distinct pathophysiological mechanisms were identified: PTHrP-mediated humoral hypercalcemia, bone metastasis-associated hypercalcemia and tumor burden-mediated hypercalcemia. Despite biochemical correction, median overall survival was 9 weeks following hypercalcemia diagnosis. Conclusions: Paraneoplastic hypercalcemia in PSCC represents a rare metabolic emergency. While aggressive management can achieve biochemical correction, the occurrence of hypercalcemia uniformly indicates advanced tumor biology with limited survival benefit. Early recognition and prompt multidisciplinary intervention remain essential for symptomatic relief and quality of life preservation. Future prospective studies are needed to better characterize optimal management strategies and refine prognostic models.

Background and Objectives: Paraneoplastic hypercalcemia represents a rare but clinically significant complication of penile squamous cell carcinoma (PSCC); however, limited information is available for this condition. Therefore, this systematically conducted narrative review aimed to comprehensively evaluate the pathophysiological mechanisms, clinical presentation, therapeutic strategies and prognostic outcomes of tumor-induced hypercalcemia in PSCC. Methods: A comprehensive literature search was conducted across PubMed/MEDLINE and Scopus databases from their inception to December 2024. Cases were included if they documented histopathologically confirmed PSCC with biochemically verified hypercalcemia and objective evidence of paraneoplastic etiology. Data extraction included tumor characteristics, severity of hypercalcemia, mechanistic classification, therapeutic interventions and survival outcomes. The search methodology followed PRISMA 2020 guidelines adapted for narrative synthesis. Given the absence of comparative studies for this rare condition, all study types were eligible for inclusion, resulting in an evidence base that consisted exclusively of case reports and case series. Results: Twelve published cases spanning six decades (1965–2024) met the inclusion criteria. The median age at presentation was 56 years, with 91.6% of patients presenting with advanced disease. Severe hypercalcemia (≥14 mg/dL) occurred in 66.7% of cases, with a median calcium level of 15.45 mg/dL. Two established pathophysiological mechanisms were identified: PTHrP-mediated humoral hypercalcemia and bone metastasis-associated hypercalcemia. By contrast, three cases with unmeasured PTHrP levels had an undetermined mechanism. Despite biochemical correction, median overall survival was 9 weeks following diagnosis of hypercalcemia. Conclusions: Paraneoplastic hypercalcemia in PSCC represents a rare metabolic emergency. While aggressive management can achieve biochemical correction, the occurrence of hypercalcemia uniformly indicates advanced tumor biology with limited survival benefit. Early recognition and prompt multidisciplinary intervention remain essential for symptomatic relief and preserving quality of life. Reporting future cases and collaborating with international registries will be necessary to improve understanding of this rare paraneoplastic entity.