Hypercalcemia in metastatic pancreatic neuroendocrine tumor: a case report of ectopic 1,25 hydroxyvitamin D production by tumor cells and tumor-associated macrophages.

Background: Hypercalcemia associated with neuroendocrine tumors (NETs) is typically attributed to increased circulating parathyroid hormone-related protein (PTHrP). However, several cases have now been reported in which hypercalcemia is linked to increased serum 1,25-dihydroxyvitamin D [1,25(OH)2D]. Until now, the source of this ectopic 1,25(OH)2D production had not been localized. Case Description: A 53-year-old Caucasian woman presented with hypercalcemia secondary to a metastatic grade 2 distal pancreatic NET, accompanied by a 4.6-fold increase in serum 1,25(OH)2D. Her hypercalcemia responded to high dose prednisolone and normalized after staged resection of her primary tumor and hepatic metastases. 1,25(OH)2D levels also normalized with reduction in tumor load. Immunofluorescence of both primary tumor and a hepatic metastasis showed positive expression of 1-alpha hydroxylase, the enzyme that converts 25-hydroxyvitamin D (25OHD) into 1,25(OH)2D, in tumor cells. High expression was also observed in tumor-associated macrophages (TAMs). Conclusions: Conversion of 25OHD into 1,25(OH)2D by 1-alpha hydroxylase represents a lesser-known NET-associated hypercalcemia. This is the first case to localize 1-alpha hydroxylase expression in NETs, and also to report its expression in TAMs. Given that this form of hypercalcemia is responsive to glucocorticoid therapy, measurement of serum 1,25(OH)2D should be considered in patients with NET presenting with hypercalcemia. Furthermore, these findings highlight a potential role for TAMs in ectopic hormone production and suggest they may serve as therapeutic targets in 1,25(OH)2D-mediated malignancy-associated hypercalcemia.