High-Grade Follicular Cell-Derived Non-Anaplastic Thyroid Carcinoma and Anaplastic Thyroid Carcinoma

Although uncommon, high-grade follicular cell-derived non-anaplastic thyroid carcinoma and anaplastic thyroid carcinoma (ATC) represent the most aggressive and disproportionately lethal end of the thyroid cancer spectrum, making accurate recognition particularly important. High-grade follicular cell-derived thyroid carcinoma bridges the gap both from a molecular and clinical perspective between well differentiated thyroid carcinomas and ATC. This family of tumors has significantly evolved and is currently subdivided into poorly differentiated thyroid carcinoma and the more recently recognized high-grade differentiated thyroid carcinoma, of which high-grade papillary thyroid carcinoma is the most common subtype. ATC, on the other hand, is the prototypical aggressive thyroid cancer type that has been recognized for over a century and a half. However, ATC can still pose a significant diagnostic challenge because of the broad differential diagnosis with many entities that need to be considered before rendering an ATC diagnosis. Moreover, the diagnosis is often further complicated by limited tissue sampling. Biomarker testing for ATC is now of critical importance in the modern era of targeted therapy and checkpoint inhibitor therapy. This review addresses fundamental concepts and pragmatic issues that pathologists encounter when evaluating these aggressive tumor types in a narrative question-and-answer format.