Comparative analysis of follicular cell- derived thyroid carcinoma: assessing the impact of high-grade features in an advanced disease cohort

The 5th edition of the WHO Classification of Tumors of Endocrine Organs introduced the term Differentiated High-Grade Thyroid Carcinoma (DHGTC) to identify cases of differentiated follicular cell-derived thyroid carcinomas (DFCDTC) with a worse prognosis. 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). A retrospective analysis was conducted on 138 patients with AdvTC who underwent total thyroidectomy followed by radioactive iodine therapy (131I). DHGTC 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 ≤ 18 and ≥ 55 years, presence of distant and synchronous metastasis, larger tumor size (> 2 cm), tall-cell subtype of papillary thyroid carcinoma, higher mitotic index (≥ 5/2 mm²), 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 ≥ 55 years (HR = 19.625, p = 0.005) and male sex (HR = 7.441, p = 0.029). 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. Our 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.