{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T07:03:22Z","timestamp":1790492602444,"version":"4.1.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Parathyroid carcinoma (PC) is an extremely rare malignant tumor with an incidence of about 6 new cases per 10 million inhabitants per year. While several papers have been published on treatments and outcomes of PC patients with loco-regional disease, little is known about the prognosis, treatment strategies, and prognostic factors of patients with distant metastasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>We performed a systematic review and a pooled analysis of histopathologically confirmed PC cases published in literature using the following keywords: \u201cmetastasis\u2013metastatic\u2013secondary nodes\u201d AND \u201cparathyroid carcinoma\u201d. Original case reports and case series reporting metastatic parathyroid carcinoma were included. Data from 58 articles were extracted in a piloted form by five reviewers on a shared database.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seventy-nine patients with metastatic PC were identified between 1898 and 2018. Ten (13%) patients had synchronous metastases, while metachronous metastases occurred in 43 (54%) patients. The remaining 26 patients developed metastatic disease concomitantly to local recurrence. Primary hyperparathyroidism guided the diagnosis of metastatic recurrence in 58 (73%) patients. Surgery was the main primary approach adopted, as it was performed in 43 (54%) patients. Twenty (25%) patients underwent systemic antineoplastic therapy, consisting of chemotherapy, immunotherapy, tyrosine kinase inhibitors, and hexestrol therapy. Bone resorption inhibitors had a limited efficacy in the long-term control of hypercalcemia. After a median follow-up of 37.5 months, 43 (55%) patients died, 22 (51%) due to the consequences of uncontrolled PHPT. The median overall survival was 36 months (range: 1\u2013252). Surgery was associated with a better OS (HR 0.48, 95% CI 0.26\u20130.88), whereas bone metastases represented a negative prognostic factor (HR 2.7, 95% CI 1.4\u20135.2).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Metastatic PC has a relatively poor prognosis. The main goals of treatment are to counteract tumor growth and control hypercalcemia. Surgery of metastases is the best approach to achieve rapid control of PHPT and longer survival. Target therapies and immunotherapy deserve to be extensively tested in metastatic PC and strategies to better control hypercalcemia should be implemented.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2022.997009","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T05:12:27Z","timestamp":1664169147000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":36,"title":["Treatment and outcome of metastatic parathyroid carcinoma: A systematic review and pooled analysis of published cases"],"prefix":"10.3389","volume":"12","author":[{"given":"Andrea","family":"Alberti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Smussi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Zamparini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Turla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Laini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Marchiselli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Grisanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Bossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Berruti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19990801)86:3<538::AID-CNCR25>3.0.CO;2-K","article-title":"Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985-1995: A national cancer data base report","volume":"86","author":"Hundahl","year":"1999","journal-title":"Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1007\/s40618-016-0447-3","article-title":"Update on parathyroid carcinoma","volume":"39","author":"Cetani","year":"2016","journal-title":"J Endocrinol Invest"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-010-1003-6","article-title":"Clinical presentation, staging and long-term evolution of parathyroid cancer","volume":"17","author":"Talat","year":"2010","journal-title":"Ann Surg Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2018.11.002","article-title":"Parathyroid carcinoma","volume":"32","author":"Salcuni","year":"2018","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B5","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1016\/j.clon.2010.04.007","article-title":"Parathyroid carcinoma","volume":"22","author":"Givi","year":"2010","journal-title":"Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2012.08.009","article-title":"Parathyroid carcinoma: challenges in diagnosis and treatment","volume":"26","author":"Mohebati","year":"2012","journal-title":"Hematol Oncol Clin North Am"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.suronc.2014.03.005","article-title":"Parathyroid carcinoma.","volume":"23","author":"Al-Kurd","year":"2014","journal-title":"Surg Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/BF01665308","article-title":"Diagnosis and treatment of patients with parathyroid carcinoma: An update and review","volume":"15","author":"Obara","year":"1991","journal-title":"World J Surg"},{"key":"B9","article-title":"Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia","volume":"101","author":"Levin","year":"1987","journal-title":"Surgery"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/350512a0","article-title":"A novel cyclin encoded by a bcl1-linked candidate oncogene","volume":"350","author":"Motokura","year":"1991","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1186\/s12957-015-0672-9","article-title":"A nonfunctioning parathyroid carcinoma misdiagnosed as a follicular thyroid nodule","volume":"13","author":"Cetani","year":"2015","journal-title":"World J Surg Onc"},{"key":"B12","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1200\/JOP.19.00540","article-title":"Contemporary evaluation and management of parathyroid carcinoma","volume":"17","author":"Fingeret","year":"2021","journal-title":"JCO Oncol Pract"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-1571","article-title":"Parathyroid carcinoma: A 43-year outcome and survival analysis","volume":"96","author":"Harari","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2014.00064","article-title":"Targeting PI3K\/Akt\/mTOR signaling in cancer","volume":"4","author":"Porta","year":"2014","journal-title":"Front Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2018-0334","article-title":"Genomic profiling of parathyroid carcinoma reveals genomic alterations suggesting benefit from therapy","volume":"24","author":"Kang","year":"2019","journal-title":"Oncologist"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92061","article-title":"Genomic profiling reveals mutational landscape in parathyroid carcinomas","volume":"2","author":"Pandya","year":"2017","journal-title":"JCI Insight"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33166","article-title":"The genomic profile of parathyroid carcinoma based on whole-genome sequencing","volume":"147","author":"Hu","year":"2020","journal-title":"Int J Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-014-3530-z","article-title":"Oncologic resection achieving R0 margins improves disease-free survival in parathyroid cancer","volume":"21","author":"Schulte","year":"2014","journal-title":"Ann Surg Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/hed.20049","article-title":"Parathyroid carcinoma: A 22-year experience","volume":"26","author":"Busaidy","year":"2004","journal-title":"Head Neck"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjsurg.2010.09.025","article-title":"Incidence and prognosis of parathyroid gland carcinoma: A population-based study in the Netherlands estimating the preoperative diagnosis","volume":"202","author":"Schaapveld","year":"2011","journal-title":"Am J Surg"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2014.08.069","article-title":"Parathyroid carcinoma in more than 1,000 patients: A population-level analysis","volume":"156","author":"Sadler","year":"2014","journal-title":"Surgery"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2014.05.014","article-title":"Prognostic factors and staging systems in parathyroid cancer: a multicenter cohort study","volume":"156","author":"Villar-del-Moral","year":"2014","journal-title":"Surgery"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22599","article-title":"Trends in the incidence and treatment of parathyroid cancer in the united states","volume":"109","author":"Lee","year":"2007","journal-title":"Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s11864-011-0171-3","article-title":"Parathyroid carcinoma: Update and guidelines for management","volume":"13","author":"Wei","year":"2012","journal-title":"Curr Treat Options Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.5306\/wjco.v2.i10.348","article-title":"FDG-PET\/CT and parathyroid carcinoma: Review of literature and illustrative case series","volume":"2","author":"Evangelista","year":"2011","journal-title":"World J Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1097\/RLU.0000000000001652","article-title":"18F-fluorocholine, 18F-FDG, and 18F-fluoroethyl tyrosine PET\/CT in parathyroid cancer","volume":"42","author":"Hatzl","year":"2017","journal-title":"Clin Nucl Med"},{"key":"B27","first-page":"383","article-title":"Metastasizing carcinoma of the parathyroid gland with osteitis fibrosa cystica and extensive calcinosis","volume":"27","author":"Ellis","year":"1951","journal-title":"Am J Pathol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-196611000-00021","article-title":"Metastatic parathyroid carcinoma and hormonal chemotherapy. Case report and response to hexestrol","volume":"164","author":"Goepfert","year":"1966","journal-title":"Ann Surg"},{"key":"B29","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1001\/archinte.1984.00350140229032","article-title":"Successful combination chemotherapy for metastatic parathyroid carcinoma","volume":"144","author":"Bukowski","year":"1984","journal-title":"Arch Intern Med"},{"key":"B30","article-title":"Parathyroid carcinoma: biochemical and pathologic response to DTIC","volume":"96","author":"Calandra","year":"1984","journal-title":"Surgery"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3949\/ccjm.60.4.331","article-title":"Parathyroid carcinoma: 50-year experience at the Cleveland clinic foundation","volume":"60","author":"Hakaim","year":"1993","journal-title":"Cleve Clin J Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.5507\/bp.2015.001","article-title":"Brain metastases of parathyroid carcinoma: Review of the literature and a case report","volume":"159","author":"Studentova","year":"2015","journal-title":"BioMed Pap Med Fac Univ Palacky Olomouc Czech Repub"},{"key":"B33","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.ejso.2004.06.014","article-title":"One stage treatment of parathyroid cancer","volume":"31","author":"Kirkby-Bott","year":"2005","journal-title":"Eur J Surg Oncol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1001\/jama.1961.03040450020004","article-title":"Carcinoma of the parathyroid glands: Report of 10 cases with endocrine function","volume":"178","author":"Barnes","year":"1961","journal-title":"JAMA"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1097\/00000478-198309000-00004","article-title":"Immunoperoxidase study of uncommon parathyroid tumors report of two cases of nonfunctioning parathyroid carcinoma and one intrathyroid parathyroid tumor-producing amyloid","volume":"7","author":"Ordo\u00f1ez","year":"1983","journal-title":"Am J Surg Pathol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1001\/archinte.1984.00350210219049","article-title":"Chemotherapy for metastatic parathyroid carcinoma","volume":"144","author":"Chahinian","year":"1984","journal-title":"Arch Intern Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.11138\/gchir\/2013.34.5.170","article-title":"Parathyroid carcinoma: Case report","volume":"34","author":"Sturniolo","year":"2013","journal-title":"G Chir"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2020-235293","article-title":"Microsatellite instability driven metastatic parathyroid carcinoma managed with the anti-PD1 immunotherapy, pembrolizumab","volume":"13","author":"Park","year":"2020","journal-title":"BMJ Case Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1530\/EDM-16-0113","article-title":"Diagnosis and treatment challenges of parathyroid carcinoma in a 27-year-old woman with multiple lung metastases","volume":"2017","author":"Rozhinskaya","year":"2017","journal-title":"Endocrinol Diabetes Metab Case Rep"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-019-02136-z","article-title":"Long-term remission of disseminated parathyroid cancer following immunotherapy","volume":"67","author":"Sarquis","year":"2020","journal-title":"Endocrine"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00731","article-title":"The clinicopathological spectrum of parathyroid carcinoma","volume":"10","author":"Akirov","year":"2019","journal-title":"Front Endocrinol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.K09E-283","article-title":"First Japanese patient treated with parathyroid hormone peptide immunization for refractory hypercalcemia caused by metastatic parathyroid carcinoma","volume":"57","author":"Horie","year":"2010","journal-title":"Endocr J"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-031911","article-title":"Hormonal and biochemical normalization and tumor shrinkage induced by anti-parathyroid hormone immunotherapy in a patient with metastatic parathyroid carcinoma","volume":"89","author":"Betea","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.794988","article-title":"Denosumab for the treatment of hypercalcemia in a patient with parathyroid carcinoma: A case report","volume":"12","author":"Roukain","year":"2022","journal-title":"Front Endocrinol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-0585","article-title":"Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma","volume":"92","author":"Silverberg","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1007\/s00774-016-0797-0","article-title":"Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism","volume":"35","author":"Takeuchi","year":"2017","journal-title":"J Bone Miner Metab"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-031825","article-title":"The effect of octreotide on parathyroid carcinoma","volume":"89","author":"Denney","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-19-0026","article-title":"Morbidity and mortality of bone metastases in advanced adrenocortical carcinoma: a multicenter retrospective study","volume":"180","author":"Berruti","year":"2019","journal-title":"Eur J Endocrinol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdn424","article-title":"Prognostic factors in 1,038 women with metastatic breast cancer","volume":"19","author":"Largillier","year":"2008","journal-title":"Ann Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)06469-1","article-title":"Control of hypercalcaemia of parathyroid carcinoma by immunisation","volume":"353","author":"Bradwell","year":"1999","journal-title":"Lancet"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.997009\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T05:12:32Z","timestamp":1664169152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.997009\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,26]]},"references-count":50,"alternative-id":["10.3389\/fonc.2022.997009"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.997009","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,26]]},"article-number":"997009"}}