Hypercalcemia Secondary to Gastrointestinal Stromal Tumors: Parathyroid Hormone-related Protein Independent Mechanism?

Objective: Hypercalcemia is a common paraneoplastic manifestation of many malignancies like breast, ovarian, and squamous-cell cancers of head and neck; however, there have been only a few case reports of hypercalcemia associated with gastrointestinal stromal tumors (GISTs). We report a case of GIST presenting with hypercalcemia without any osseous metastasis and provide a literature review regarding the mechanisms of hypercalcemia and therapeutic strategies.

Methods: We present a report of case and a review of the relevant literature.

Results: A 52-year-old woman with history of localized breast cancer in remission and a pelvic 13 × 12 cm GIST with peritoneal, liver, and lung metastases presented with hypercalcemia of 14.3 mg/dL (8.5-10.5 mg/dL). Parathyroid hormone-related protein (PTHrP) was undetectable, intact parathyroid hormone (PTH) was appropriately low at 1 pg/mL (10-65 pg/mL), and 1,25 dihydroxy vitamin D (1,25 OH2 vit D) was elevated at 131 pg/mL (18-78 pg/mL) with normal renal function. Calcium responded transiently to tyrosine kinase inhibitor therapy and bisphosphonates but within a year, she expired due to tumor progression.

Conclusion: GIST is a rare cause of hypercalcemia. In addition to PTHrP expression, direct tumor production of 1,25(OH)2 vit D or 1-α hydroxylase enzyme resulting in activation of 25-hydroxy vitamin D may be an alternative mechanism in GIST-related hypercalcemia. Therapy with tyrosine kinase inhibitors and bisphosphonates is recommended, though prognosis is poor. Further investigations are needed to characterize the etiology and management of hypercalcemia in these patients.