MON-833 - Ectopic PTH-Mediated Hypercalcemia in A High-Grade Gallbladder Neuroendocrine Carcinoma

Background: Gallbladder neuroendocrine tumors (GB-NETs) are exceptionally uncommon, representing approximately 0.04–0.5% of all NETs. High-grade GB-NETs, classified as neuroendocrine carcinomas (NEC), frequently metastasize to the liver. These tumors arise from neuroendocrine cells capable of hormone secretion, however ectopic production of parathyroid hormone (PTH) is exceedingly rare. We describe a case of severe hypercalcemia caused by ectopic PTH secretion from a GB-NEC.

Clinical

Case: A 66-year-old woman with hypothyroidism, CKD3, and hypertension presented after a fall and several days of confusion. Laboratory evaluation revealed severe hypercalcemia (17.4 mg/dL) with markedly elevated PTH (368 pg/mL) and normal 25-hydroxyvitamin D. She was treated with IV fluids, calcitonin, and zoledronic acid with clinical improvement. Neck ultrasound showed no parathyroid enlargement. Four-dimensional CT revealed a 5-mm ill-defined focus inferior to the left thyroid lobe, but Tc-99m sestamibi imaging was non-localizing. Urgent subtotal parathyroidectomy was performed; all four glands appeared hyperplastic, yet intraoperative PTH levels remained persistently elevated (745 → 609 pg/mL), raising concern for an ectopic source.

CT abdomen and pelvis identified a 5.1-cm gallbladder mass with multiple hepatic lesions. Two days later, the patient experienced cardiac arrest and died. Autopsy showed two gallbladder masses with extensive liver metastases and left adrenal cortical involvement. Histopathology confirmed high-grade NEC. Immunohistochemical stains of the tumor cells were positive for chromogranin and synaptophysin staining, consistent with metastatic NEC, but negative for PTH staining. Despite the absence of PTH staining, her clinical course strongly supported ectopic PTH secretion causing profound hypercalcemia.

Conclusion: This case demonstrates an exceptionally rare etiology of severe hypercalcemia due to ectopic PTH secretion from a high-grade GB-NEC, confirmed on autopsy. It highlights the diagnostic challenge of unexplained PTH-dependent hypercalcemia when parathyroid imaging is inconclusive and underscores the importance of considering ectopic PTH production when PTH levels are massively elevated and remain elevated after parathyroidectomy. Importantly, negative PTH immunohistochemical staining does not exclude ectopic PTH secretion, particularly in high-grade NEC, where rapid hormone secretion, lack of storage granules, and low intracellular peptide concentrations may result in false-negative staining. Isolated case reports document ectopic intact PTH secretion from neuroendocrine and non-neuroendocrine tumors from head/neck, endometrium and liver. To our knowledge, this represents the first reported case of a GB-NEC producing PTH, expanding the differential diagnosis for PTH-mediated hypercalcemia in malignant disease.

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