Which cancer type is most commonly associated with PTHrP-mediated hypercalcemia?

• A. Adenocarcinoma of breast
• B. Small cell lung carcinoma
• C. Osteosarcoma
• D. Squamous cell carcinoma

Answer: (D)

PTHrP-mediated hypercalcemia is a type of humoral hypercalcemia of malignancy, where the tumor secretes parathyroid hormone–related peptide that acts like PTH on bone and kidney. This drives increased bone resorption and enhanced renal calcium reabsorption, raising serum calcium while endogenous PTH falls due to feedback. The classic tumors that produce PTHrP are squamous cell carcinomas, especially squamous cell carcinoma of the lung (and some head and neck squamous cancers). While other cancers can cause hypercalcemia through different mechanisms (for example, bone metastases with local osteolysis in breast cancer), the PTHrP-humoral mechanism most characteristically points to squamous cell carcinoma. Therefore, squamous cell carcinoma is the cancer type most commonly associated with PTHrP-mediated hypercalcemia.