Review ArticlesAdvances in Thyroid Pathology: High Grade Follicular Cell-derived Thyroid Carcinoma and Anaplastic Thyroid CarcinomaXu, Bin MD, PhD; Ghossein, Ronald A. MD Author Information Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY No competing financial interests exist for all contributory authors. Research reported in this publication was supported in part by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no funding or conflicts of interest to disclose. Reprints: Ronald A. Ghossein, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (e-mail: [email protected]). All figures can be viewed online in color at www.anatomicpathology.com. Advances In Anatomic Pathology 30(1):p 3-10, January 2023. | DOI: 10.1097/PAP.0000000000000380 Buy Metrics Abstract In the upcoming World Health Organization fifth edition classification of endocrine tumors, there were several major changes related to high grade follicular-derived thyroid carcinoma (HGFCTC) and anaplastic thyroid carcinoma (ATC) based on emerging evidence about the diagnostic criteria clinical behavior, prognostic factors, and molecular signatures of these tumors. In this review, we aim to summarize the major evolutions of HGFCTC and ATC. HGFCTC is a nonanaplastic carcinoma with high grade features (High mitotic count, tumor necrosis). It is subdivided into poorly differentiated thyroid carcinoma diagnosed using the Turin proposal and differentiated high grade thyroid carcinoma. The latter is defined by the presence of the cytoarchitectutal features of well-differentiated thyroid carcinoma (eg, papillae) but harbors elevated mitotic activity and/or tumor necrosis. Poorly differentiated thyroid carcinoma is predominantly RAS-driven and associated with RAI avidity and high propensity for distant metastasis, whereas differentiated high grade thyroid carcinoma is mostly BRAFV600E-driven. ATC may show a wide range of histologic features. Carcinoma of pure squamous phenotype is associated with a high frequency of BRAF V600E mutations and is now considered as a subtype of ATC. There is a stepwise molecular progression from well-differentiated carcinoma to HGFCTC to ATC manifested by 1) early and persistent driver alteration in the MAPK pathway, particularly BRAF V600E and RAS mutations, and 2) gain of secondary aggressive molecular signatures (such as TERT promoter and TP53 mutations) when tumors progress from well-differentiated to high grade to anaplastic carcinoma. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.