A 58-year-old man with a 35 pack-year smoking history develops hypercalcemia, weight loss, and a 3.5 cm hilar mass. Biopsy shows large polygonal cells with abundant pink cytoplasm, intercellular bridges, and keratin pearls. Which paraneoplastic mechanism best explains his hypercalcemia?

• A Ectopic PTH secretion by tumor cells
• B Calcitriol overproduction via CYP27B1 upregulation
• C Osteolytic skeletal metastases releasing stored calcium
• D PTHrP secretion causing humoral hypercalcemia of malignancy ✓

Explanation

Squamous cell carcinoma of the lung is the classic tumor associated with humoral hypercalcemia of malignancy (HHM), mediated by PTHrP (parathyroid hormone-related protein) secreted by the tumor. PTHrP binds PTH receptors on kidney and bone, raising serum calcium without elevating true PTH. True ectopic PTH secretion is exceedingly rare; calcitriol-mediated hypercalcemia is more characteristic of lymphomas; osteolytic metastases from breast/lung can cause hypercalcemia but the dominant mechanism in SCC lung is PTHrP.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.