What Lies behind Paraneoplastic Hypercalcemia Secondary to Well-Differentiated Neuroendocrine Neoplasms? A Systematic Review of the Literature

Abstract

Background: Neuroendocrine neoplasms (NEN) originate from neuroendocrine cells ubiquitously spread throughout the body. Hypercalcemia associated with cancer is the most common life-threatening metabolic disorder in patients with advanced stage cancer. Paraneoplastic hypercalcemia is more commonly associated with hematological malignancies, renal and breast carcinomas, and squamous cell carcinomas, but it has also been described in patients with well-differentiated NEN, where it often remains undiagnosed. Among its causes, systemic secretion of parathyroid hormone-related protein (PTHrP) and ectopic production of 1,25-dihydroxyvitamin D and parathyroid hormone (PTH) may be considered paraneoplastic causes of hypercalcemia. In order to clarify the diagnostic work up of paraneoplastic hypercalcemia in patients with NEN, we perform a systematic review, which is lacking in the literature. Methods: We performed a data search using MEDLINE and SCOPUS including papers from 1961 to 2021. We selected articles on paraneoplastic hypercalcemia associated with well-differentiated NEN. Results: The search led to the selection of 78 publications for a total of 114 patients. Pooled data showed that the most frequent primary tumor site associated with paraneoplastic hypercalcemia was pancreatic NEN, followed by Pheochromocytoma. In most cases, paraneoplastic hypercalcemia was caused by PTHrP production and secretion. In more than two thirds of cases, paraneoplastic hypercalcemia was present at the time of NEN diagnosis and, in metachronous cases, was related to local recurrence, distant metastasis development, or tumor progression. In most patients, a combination of therapeutic approaches was employed, and reduction of the tumor burden was essential to control the paraneoplastic syndrome. Discussion: The onset of hypercalcemia associated with cancer in patients with well-differentiated NEN represents a major clinical challenge. The complex clinical and therapeutical management of paraneoplastic hypercalcemia implies the need for a multidisciplinary approach, aimed at controlling the clinical syndrome and tumor growth.

Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, MEN1 Gene-Related Tumors, and Insulin Resistance

“…An inter-connection between the pancreas and hypercalcemia might involve the presence of paraneoplastic (humoral) syndrome in pancreatic NETs, either functioning (such as gastrinomas or insulinomas) or not [ 165 ]. Generally, hypercalcemia of malignancy represents the most common paraneoplastic syndrome, and it accompanies one-third of all cancers, but typically, NETs are less frequently associated with this particular endocrine complication [ 166 ].…”

Severe hypercalcemia due to metastatic pancreatic neuroendocrine tumor: a case report

“…Paraneoplastic hypercalcemia due to NET rarely occurs and usually presents in patients with end stage disease [ 5 ]. NET can lead to paraneoplastic hypercalcemia through three mechanisms; the most common is PTHrP secretion (85%), the second one is PTH production (11.3%), and the least common one is overproduction of calcitriol (3.8%) [ 13 ].…”

“…Moreover, hypercalcemia was often associated with distant metastases, except in 10.5%, where there were just local lymph node metastasis or no metastasis. It seems that it differs for pheochromocytoma, in which the tumor burden at the onset of diagnosis or during progression of the disease determines the hormone secretion capacity by the tumor [ 13 ]. Paraneoplastic hypercalcemia usually presents with severe manifestation as an emergency of oncology [ 5 ].…”

“…Paraneoplastic hypercalcemia usually presents with severe manifestation as an emergency of oncology [ 5 ]. However, NET paraneoplastic hypercalcemia, similar to primary hyperparathyroidism, usually has moderate symptoms [ 13 ].…”

“…Although it is unusual, in patients who present with hypercalcemia due to NET, it would be better to consider ectopic production of PTH whenever high PTH levels are present with no parathyroid-related cause. It is worth recognizing, because it could prevent unnecessary parathyroidectomy or neck exploration [ 13 ].…”