{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:17:59Z","timestamp":1788866279372,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T00:00:00Z","timestamp":1636070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Multiple Endocrine Neoplasia 2 (MEN2) is a hereditary cancer syndrome for developing medullary thyroid cancer (MTC) due to germline mutations of RET gene. Subjects harboring a germline RET mutation without any clinical signs of MTC are defined as gene carriers (GCs), for whom guidelines propose a prophylactic thyroid surgery. We evaluate if active surveillance of GCs, pursuing early thyroid surgery, can be safely proposed and if it allows safely delaying thyroid surgery in children until adolescence\/adulthood. We prospectively followed 189 GCs with moderate or high risk germline RET mutation. Surgery was planned in case of: elevated basal calcitonin (bCT) and\/or stimulated CT (sCT); surgery preference of subjects (or parents, if subject less than 18 years old); other reasons for thyroid surgery. Accordingly, at RET screening, we sub-grouped GCs in subjects who promptly were submitted to thyroid surgery (Group A, n = 67) and who were not (Group B, n = 122). Group B was further sub-grouped in subjects who were submitted to surgery during their active surveillance (Group B1, n = 22) and who are still in follow-up (Group B2, n = 100). Group A subjects presented significantly more advanced age, bCT and sCT compared to Group B. Mutation RETV804M was the most common variant in both groups but it was significantly less frequent in Group A than B. Analyzing age, bCT, sCT and genetic landscape, Group B1 subjects differed from Group B2 only for sCT at last evaluation. Group A subjects presented more frequently MTC foci than Group B1. Moreover, Group A MTCs presented more aggressive features (size, T and N) than Group B1. Accordingly, at the end of follow-up, all Group B1 subjects presented clinical remission, while 6 and 12 Group A MTC patients had structural and biochemical persistent disease, respectively. Thank to active surveillance, only 13\/63 subjects younger than 18 years at RET screening have been operated on during childhood and\/or adolescence. In Group B1, three patients, while actively surveilled, had the possibility to reach the age of 18 (or older) and two patients the age of 15, before being submitted to thyroid surgery. In Group B2, 12 patients become older than 18 years and 17 older than 15 years. In conclusion, we demonstrated that an active surveillance pursuing an early thyroid surgery could be safely recommended in GCs. This patient-centered approach permits postponing thyroid surgery in children until their adolescence\/adulthood. At the same time, we confirmed that genetic screening allows finding hidden MTC cases that otherwise would be diagnosed much later.<\/jats:p>","DOI":"10.3390\/cancers13215554","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T10:33:09Z","timestamp":1636108389000},"page":"5554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Active Surveillance in RET Gene Carriers Belonging to Families with Multiple Endocrine Neoplasia"],"prefix":"10.3390","volume":"13","author":[{"given":"Alessandro","family":"Prete","sequence":"first","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4263-4717","authenticated-orcid":false,"given":"Antonio","family":"Matrone","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Gambale","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Bottici","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Cappagli","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Romei","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liborio","family":"Torregrossa","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Valerio","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Minaldi","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Campopiano","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredana","family":"Lorusso","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Agate","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Molinaro","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7683-152X","authenticated-orcid":false,"given":"David","family":"Viola","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Ramone","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Mul\u00e8","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Ciampi","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1657-5020","authenticated-orcid":false,"given":"Fulvio","family":"Basolo","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5333-9257","authenticated-orcid":false,"given":"Rossella","family":"Elisei","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1210\/js.2018-00178","article-title":"Update on Multiple Endocrine Neoplasia Type 2: Focus on 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