Case Report: Metastatic Duodenal Neuroendocrine Tumor: A Rare Cause of Humoral Hypercalcemia of Malignancy

<ns3:p>Background Humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome commonly associated with solid organ malignancies like squamous cell carcinomas of the lung, head &amp; neck, as well as breast, ovarian, renal, and bladder carcinomas and hematological malignancies like Non-Hodgkins Lymphoma (NHL). However, its occurrence in neuroendocrine tumors (NETs) is rare, with the majority of reported cases linked to pancreatic NETs. Here, we describe an extremely rare case of a metastatic duodenal NET presenting with severe hypercalcemia due to the secretion of Parathyroid Hormone-related Protein (PTHrP). This case features an exceptionally high PTHrP level, placing it among the most severe reported cases of NET-associated HHM. Case Presentation A 70-year-old male with known metastatic duodenal NET (grade 2, Ki67 index: 18.2%) presented with unresponsiveness. Despite previous distal gastrectomy with D1 duodenal resection, Octreotide Long-Acting Release (LAR), Everolimus, and four cycles of Peptide Receptor Radionuclide Therapy (PRRT), disease progression was evident on Gallium- 68 DOTANOC PET/CT scan. Laboratory evaluation revealed severe hypercalcemia (corrected calcium: 14.06 mg/dL) with suppressed iPTH levels (Intact Parathyroid Hormone) and markedly elevated PTHrP levels of 252 pmol/L (Parathyroid Hormone related Peptide), thereby confirming HHM. Multiple myeloma and osteolytic bone metastasis were excluded by appropriate testing. Despite aggressive management with intravenous fluids, calcitonin, ibandronate, and multiple hemodialysis sessions, the patient succumbed to hypoxic brain injury. Discussion HHM is rarely seen in neuroendocrine tumors (NETs) and is most commonly associated with pancreatic NETs; we report a rare case of metastatic duodenal NET causing severe hypercalcemia due to excessive PTHrP production. With a remarkably elevated PTHrP level, this case is among the most severe documented cases of NET-associated HHM. The relationship between tumor grade and PTHrP production, along with the refractory nature of the hypercalcemia despite standard interventions, highlights the complex pathophysiology of this condition.</ns3:p>