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This study aimed to determine the frequency and clinicopathological features of DHGTC within a cohort of advanced follicular cell-derived thyroid carcinomas (AdvTC) and compare them to non-high-grade DFCDTC (non-HGDTC) and poorly differentiated thyroid carcinoma (PDTC).\u00a0A retrospective analysis was conducted on 138 patients with AdvTC who underwent total thyroidectomy followed by radioactive iodine therapy (131I).\u00a0DHGTC was identified in 15.9% of the cases (22\/138), showing a higher prevalence in this selected cohort of AdvTC compared to other studies. Compared to non-HGDTC, DHGTC was significantly associated with adverse clinicopathological features, including age ranges\u2009\u2264\u200918 and\u2009\u2265\u200955\u00a0years, presence of distant and synchronous metastasis, larger tumor size (&gt;\u20092\u00a0cm), tall-cell subtype of papillary thyroid carcinoma, higher mitotic index (\u2265\u20095\/2 mm<jats:sup>2<\/jats:sup>), tumor necrosis, angioinvasion, higher AJCC 8th edition pT stage (pT3\/T4), and more frequent administration of additional therapies, such as tyrosine kinase inhibitors. In comparison to PDTC, DHGTC displayed lower median tumor size, less frequent tumor necrosis, and a higher mitotic count. Independent prognostic factors for worse DSS in the entire cohort were age\u2009\u2265\u200955\u00a0years (HR\u2009=\u200919.625, <jats:italic>p<\/jats:italic>\u2009=\u20090.005) and male sex (HR\u2009=\u20097.441, <jats:italic>p<\/jats:italic>\u2009=\u20090.029). DHGTC cases consistently demonstrated worse clinical outcomes compared to non-HGDTC, including lower survival rates and higher persistence of disease at the end of follow-up.\u00a0Our results validate the inclusion of DHGTC as a distinct high-grade subgroup within follicular cell-derived thyroid carcinomas, as proposed by the 5th WHO classification. DHGTC exhibits aggressive clinicopathological features and poor outcomes, supporting its relevance in clinical risk stratification and therapeutic decision-making.<\/jats:p>","DOI":"10.1007\/s00428-025-04109-2","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:02:08Z","timestamp":1746144128000},"page":"1305-1315","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Comparative analysis of follicular cell- derived thyroid carcinoma: assessing the impact of high-grade features in an advanced disease cohort"],"prefix":"10.1007","volume":"486","author":[{"given":"Mariana","family":"Caldeira","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3736-1323","authenticated-orcid":false,"given":"Sule","family":"Canberk","sequence":"additional","affiliation":[]},{"given":"Sofia","family":"Macedo","sequence":"additional","affiliation":[]},{"given":"Miguel","family":"Melo","sequence":"additional","affiliation":[]},{"given":"Valdemar","family":"M\u00e1ximo","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Soares","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"4109_CR1","doi-asserted-by":"publisher","first-page":"e389708","DOI":"10.1200\/EDBK_389708","volume":"43","author":"SA Salgado","year":"2023","unstructured":"Salgado SA, Kaye ER, Sargi Z, Chung CH, Papaleontiou M (2023) Management of Advanced Thyroid Cancer: Overview, Advances, and Opportunities. 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