{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:45:39Z","timestamp":1789544739879,"version":"build-2803163510"},"reference-count":110,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T00:00:00Z","timestamp":1663718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerial research project","award":["PRIN2017Z3N3YC"],"award-info":[{"award-number":["PRIN2017Z3N3YC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/jpm12101553","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T01:47:06Z","timestamp":1663811226000},"page":"1553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["What Lies behind Paraneoplastic Hypercalcemia Secondary to Well-Differentiated Neuroendocrine Neoplasms? A Systematic Review of the Literature"],"prefix":"10.3390","volume":"12","author":[{"given":"Elisa","family":"Giannetta","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3850-627X","authenticated-orcid":false,"given":"Franz","family":"Sesti","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3768-5803","authenticated-orcid":false,"given":"Roberta","family":"Modica","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University \u201cFederico II\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika Maria","family":"Grossrubatscher","sequence":"additional","affiliation":[{"name":"Endocrine Unit, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9278-8939","authenticated-orcid":false,"given":"Alberto","family":"Ragni","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolic Diseases Unit, SS. Antonio e Biagio e Cesare Arrigo Hospital, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Zanata","sequence":"additional","affiliation":[{"name":"Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Colao","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University \u201cFederico II\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9324-3946","authenticated-orcid":false,"given":"Antongiulio","family":"Faggiano","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant\u2019Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1200\/JCO.2007.15.4377","article-title":"One hundred years after \u201ccarcinoid\u201d: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States","volume":"26","author":"Yao","year":"2008","journal-title":"J. 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