Mechanisms, Management and Prognosis of Paraneoplastic Hypercalcemia in Penile Squamous Cell Carcinoma: A Structured Review

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.