High-Grade Follicular Cell-Derived Non-Anaplastic Thyroid Carcinoma: Correlating Extent of Invasion and Mutation Profile with Oncologic Outcome

Background: The 2022 World Health Organization classification introduced the term high-grade follicular cell-derived nonanaplastic thyroid carcinoma (HGFCTC) to define invasive/infiltrative nonanaplastic thyroid carcinoma with high-grade features, including poorly differentiated thyroid carcinoma and high-grade differentiated thyroid carcinoma. Our objectives were to compare clinicopathological characteristics, oncologic outcomes, and mutation profiles among HGFCTC subgroups to better inform prognostication and treatment. Methods: In this single-center, retrospective cohort study of 252 patients who had surgery for HGFCTC from 1986 to 2020, we categorized HGFCTC and its related entity, "encapsulated noninvasive neoplasms of follicular cells with high-grade features," into five subgroups: (A) encapsulated noninvasive, (B) encapsulated with capsular invasion only (minimally invasive), (C) encapsulated angioinvasive with focal vascular invasion (VI), (D) encapsulated angioinvasive with extensive VI, and (E) infiltrative tumors. Next-generation sequencing with Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets was available for 117/252 patients to investigate differences in mutation profiles. Results: The cohort comprised 50% infiltrative, 33% encapsulated angioinvasive, and 18% encapsulated noninvasive/minimally invasive tumors. No patients with encapsulated noninvasive or minimally invasive disease had regional or distant metastases at presentation. Patients with infiltrative tumors were significantly more likely to present with T3/T4 disease (71%), regional metastases (55%), and distant metastases (25%) (p ≤ 0.003). Five-year disease-specific survival was poorer in patients with infiltrative disease (67.7%), compared to encapsulated angioinvasive focal VI (90.4%), encapsulated angioinvasive extensive VI (88.1%), and encapsulated noninvasive/minimally invasive (100%) (p = 0.0002) subgroups. Common mutations were TERT (42%), BRAF^V600E (29%), NRAS (27%), EIF1AX (11%), and TP53 (9%). Pathways altered included RTK/RAS/RAF/MAPK (69%), PI3K/AKT/MTOR (14%), histone methyltransferases (9%), and SWI/SNF chromatin remodeling complex (8%). Subgroup analysis showed the infiltrative subgroup was mainly BRAF^V600E-driven, and the encapsulated angioinvasive and minimally invasive subgroups were NRAS-driven. Encapsulated noninvasive tumors had a different mutation profile, with DICER1 as the main driver mutation. Conclusions: HGFCTC comprises different subgroups with different clinical behaviors determined by the extent of vascular invasion and degree of infiltration. Excellent recurrence and survival outcomes occur in encapsulated noninvasive and minimally invasive tumors compared to infiltrative tumors. Infiltrative tumors are largely "BRAF-like," whereas encapsulated angioinvasive tumors are "RAS-like." Encapsulated noninvasive tumors have a particularly unique molecular profile consisting of DICER1 mutations and a lack of BRAF^V600E mutations.