Severe hypercalcemia as the initial presentation of renal cell carcinoma: a diagnostic case report.

Renal cell carcinoma (RCC) represents 90% of renal malignancies with rising global incidence. While the classic triad includes hematuria, flank pain, and palpable masses, paraneoplastic hypercalcemia occurs in 17% of cases and indicates aggressive disease behavior. This case documents severe hypercalcemia as the initial manifestation of metastatic RCC. A 64-year-old male presented with malaise, bloating, and weight loss. Laboratory evaluation revealed severe hypercalcemia (15.1 mg/dL), suppressed parathyroid hormone (4.2 pg/mL), and elevated parathyroid hormone-related peptide (83 pg/mL). Imaging identified a 5.5 × 5.0 × 5.3 cm left renal mass with metastases to lungs, brain, and possibly bone. Biopsy confirmed metastatic clear-cell RCC. Management comprised aggressive hydration, zoledronic acid, combined immunotherapy (pembrolizumab/lenvatinib), and palliative radiation for cerebral lesions. This case illustrates PTHrP-mediated humoral hypercalcemia of malignancy in metastatic RCC. The pathophysiology differs from alternative mechanisms such as calcitriol-mediated hypercalcemia or cytokine-driven osteoclast activation. Diagnostic markers demonstrated a classic humoral pattern with PTHrP elevation (83 pg/mL) and PTH suppression (4.2 pg/mL). The multimodal imaging protocol effectively delineated primary tumor dimensions, vascular invasion, and metastatic burden. Treatment efficacy was objectively measured through serial calcium levels and documented radiographic regression of primary and metastatic lesions. This aligns with recent data on combination immunotherapy (anti-PD-1) with tyrosine kinase inhibition in advanced RCC, supporting current therapeutic paradigms for PTHrP-mediated hypercalcemia in metastatic disease. Prompt recognition of paraneoplastic hypercalcemia in RCC facilitates timely intervention. This case demonstrates the value of comprehensive diagnostic evaluation and multidisciplinary management combining supportive care with targeted immunotherapy. Further prospective studies are needed to optimize therapeutic strategies for patients presenting with metabolic derangements suggestive of underlying malignancy.