Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Sep 21;12(10):1553.
doi: 10.3390/jpm12101553.

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

Elisa Giannetta  1 , Franz Sesti  1 , Roberta Modica  2 , Erika Maria Grossrubatscher  3 , Alberto Ragni  4 , Isabella Zanata  5 , Annamaria Colao  2 , Antongiulio Faggiano  6
Affiliations
Review

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

Elisa Giannetta et al. J Pers Med. .

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.

Keywords: 1,25-dihydroxyvitamin D; NEN; NET; PTH; PTHrP; hypercalcemia; hyperparathyroidism.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of the literature search for the systematic review study. From: Liberati A, Altman DG, Tetzlaff J, Mulrow C, et al. (2009) The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration. PLoS Med 6(7): e1000100. doi:10.1371/journal.pmed.1000100.
See this image and copyright information in PMC

References

    1. Yao J.C., Hassan M., Phan A., Dagohoy C., Leary C., Mares J.E., Evans D.B. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J. Clin. Oncol. 2008;26:3063–3072. doi: 10.1200/JCO.2007.15.4377. - DOI - PubMed
    1. Zamponi V., La Salvia A., Tarsitano M.G., Mikovic N., Rinzivillo M., Panzuto F., Giannetta E., Faggiano A., Mazzilli R. Effect of Neuroendocrine Neoplasm Treatment on Human Reproductive Health and Sexual Function. J. Clin. Med. 2022;11:3983. doi: 10.3390/jcm11143983. - DOI - PMC - PubMed
    1. Modica R., Scandurra C., Maldonato N.M., Dolce P., Dipietrangelo G.G., Centello R., Di Vito V., Giannetta E., Isidori A.M., Lenzi A., et al. Health-related quality of life in patients with neuroendocrine neoplasms: A two-wave longitudinal study. J. Endocrinol. Investig. 2022:1–8. doi: 10.1007/s40618-022-01872-w. - DOI - PMC - PubMed
    1. Scandurra C., Modica R., Maldonato N.M., Dolce P., Dipietrangelo G.G., Centello R., Di Vito V., Bottiglieri F., de Cicco F., Giannetta E., et al. Quality of Life in Patients with Neuroendocrine Neoplasms: The Role of Severity, Clinical Heterogeneity, and Resilience. J. Clin. Endocrinol. Metab. 2021;106:e316–e327. doi: 10.1210/clinem/dgaa760. - DOI - PubMed
    1. Gaudenzi G., Dicitore A., Carra S., Saronni D., Pozza C., Giannetta E., Persani L., Vitale G. MANAGEMENT of ENDOCRINE DISEASE: Precision medicine in neuroendocrine neoplasms: An update on current management and future perspectives. Eur. J. Endocrinol. 2019;181:R1–R10. doi: 10.1530/EJE-19-0021. - DOI - PubMed