Which cancer is most associated with hypercalcemia due to PTHrP production (alternative phrasing)?

• A. Small cell carcinoma
• B. Squamous cell carcinoma
• C. Adenocarcinoma
• D. Merkel cell carcinoma

Answer: (B)

Hypercalcemia of malignancy caused by PTH-related peptide (PTHrP) is a humoral paraneoplastic syndrome where a tumor secretes PTHrP that acts like PTH, raising calcium by increasing bone resorption and renal calcium reabsorption. The classic producers of PTHrP are squamous cell carcinomas, especially in the lung, making this the typical source of this specific hypercalcemia mechanism.

Small cell carcinoma tends to secrete ectopic hormones such as ACTH or ADH rather than PTHrP. Adenocarcinoma can cause hypercalcemia through various mechanisms but is not the textbook source of PTHrP-driven hypercalcemia. Merkel cell carcinoma is a cutaneous neuroendocrine tumor not commonly associated with PTHrP-mediated hypercalcemia. Thus, squamous cell carcinoma best fits the pattern of hypercalcemia from PTHrP production.