Humoral hypercalcemia of malignancy caused by parathyroid hormone-related peptide-secreting neuroendocrine tumors: Report of six cases

We report the clinical characteristics and management of six patients with metastatic gastroenteropancreatic neuroendocrine tumor (NET) presenting with severe hypercalcemia due to elevation of parathyroid hormone-related protein (PTHrP). All patients had histological confirmation of NET, five well-differentiated and one poorly differentiated. In 5 patients, hypercalcemia developed after years after the initial diagnosis of NET. One patient presented with concomitant elevation of PTHrP and intact parathyroid hormone (PTH) in the setting of multiple endocrine neoplasia 1 (MEN1). In all the other cases, PTH levels were low or undetectable. Management of malignant hypercalcemia due to PTHrP-producing NET is challenging, and optimal therapy depends on the extent of metastatic disease and the grade of malignancy. Aggressive tumor cytoreduction in addition to the systemic treatment modalities is frequently used to control disease progression and endocrine symptoms. To our knowledge, this is the largest series to date of hypercalcemia mediated by PTHrP-secreting NET.