Clinical meaning
Hypercalcemia of malignancy (HCM) occurs through three main mechanisms: (1) Humoral hypercalcemia of malignancy (HHM, 80%): tumor secretion of PTHrP (parathyroid hormone-related peptide), which activates PTH/PTHrP receptors on osteoblasts, stimulating RANKL expression and osteoclast-mediated bone resorption, while also increasing renal calcium reabsorption — most common with squamous cell carcinomas (lung, head/neck), renal cell carcinoma, and breast cancer. (2) Local osteolytic hypercalcemia (20%): direct bone destruction by metastases releasing calcium — breast cancer, multiple myeloma, lymphoma; myeloma produces osteoclast-activating factors (RANKL, MIP-1α, IL-6). (3) Calcitriol-mediated (1%): lymphoma cells express 1-alpha-hydroxylase, converting 25-OH vitamin D to active 1,25-(OH)2 vitamin D (calcitriol), which increases intestinal calcium absorption. HCM is a poor prognostic indicator — median survival after diagnosis is 1-3 months for most solid tumors.
Diagnosis & workup
Diagnostics & workup: - Corrected calcium = measured calcium + 0.8 × (4.0 - albumin) — always correct for albumin; ionized calcium is more accurate but less available - PTHrP level: elevated in HHM (> 2.0 pmol/L); PTH should be suppressed (< 20 pg/mL) — if PTH is elevated, consider concurrent primary hyperparathyroidism - PTH (intact): SUPPRESSED in malignant hypercalcemia (negative feedback from high calcium); ELEVATED in primary hyperparathyroidism - Calcitriol (1,25-OH-D): elevated in lymphoma-mediated hypercalcemia - Calcium level classification: mild 10.5-12.0 mg/dL, moderate 12.0-14.0, severe > 14.0 mg/dL (symptoms correlate poorly with level — rate of rise matters more than absolute value) - BMP: renal function (pre-renal AKI from dehydration common), electrolytes (hypokalemia, hypomagnesemia from polyuria) - ECG: shortened QT interval (QTc < 360 ms), widened T waves, Osborn waves (severe); bradycardia, heart block at very high levels - Staging workup: CT chest/abdomen/pelvis, bone scan or PET-CT for extent of disease