A 58-year-old man with squamous cell carcinoma of the lung develops hypercalcemia unrelated to bone metastasis. Immunohistochemistry of the tumor reveals cytoplasmic staining for a peptide that shares structural homology with the mid-region of parathyroid hormone. Which molecular mechanism best explains the hypercalcemia?
- A Ectopic 1-alpha-hydroxylase activity converting 25-OH vitamin D to calcitriol
- B Osteoclast-activating factor release from bone marrow infiltration
- C Tumor secretion of PTHrP activating PTH/PTHrP receptor (PTH1R) on osteoclasts and renal tubules ✓
- D Prostaglandin E2-mediated increase in osteoclastic bone resorption
Correct answer: C. Tumor secretion of PTHrP activating PTH/PTHrP receptor (PTH1R) on osteoclasts and renal tubules
Explanation
Humoral hypercalcemia of malignancy (HHM) in squamous cell lung carcinoma is classically mediated by PTHrP (parathyroid hormone-related protein), which shares N-terminal homology with PTH and binds the same PTH1R receptor, driving osteoclastic resorption and increased renal calcium reabsorption. Ectopic 1-alpha-hydroxylase is the mechanism in lymphoma-associated hypercalcemia. OAF-mediated hypercalcemia is the mechanism in multiple myeloma. PGE2 is a historical, less-clinically-dominant mechanism.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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