Dissecting Anaplastic Thyroid Carcinoma: A Comprehensive Clinical, Histologic, Immunophenotypic, and Molecular Study of 360 Cases

Abstract

Background: Anaplastic thyroid carcinoma (ATC) is nearly always fatal. Large studies on ATC are exceedingly rare. We aimed to study the clinical, genotypic, and histologic characteristics of ATC in the largest retrospective cohort of ATC to date. Methods: Three hundred sixty patients with ATC from two tertiary centers were studied. Molecular testing was performed in 126 cases including 107 using next-generation sequencing. Results: The median patients' age was 68 years. Differentiated thyroid carcinoma (DTC) was present in 208 cases (58%), the most common being papillary carcinoma (n = 150). The 1-, 2-, 3-, and 5-year overall survival (OS) was 36%, 17%, 13%, and 11%, respectively. On univariate analysis, age, resectability, chemotherapy, radiotherapy, margin status, encapsulation, gross residual disease, gross extrathyroidal extension, percentage, and size of ATC in the primary tumor predicted OS (p < 0.05). Age, resectability, chemotherapy, and gross residual disease were independent prognostic factors in the entire cohort, while gross residual disease was the only independent predictor of OS in patients who had resection of their tumor. BRAF, RAS, TERT promoter, TP53, PIK3CA, E1F1AX, and PTEN mutations were detected in 45%, 24%, 75%, 63%, 18%, 14%, and 14% of ATC, respectively. Concomitant BRAF/RAS and TERT mutations were associated with worse outcome than mutation in only one of the genes. BRAF-mutated and RAS-mutated ATCs had similar frequency of nodal and distant metastasis. Twelve cases were pure squamous cell carcinoma, 60% of which carried BRAF^V600E mutation and showed a similar OS to other ATCs. Conclusions: (i) Gross residual disease remains the most crucial indicator of outcome in ATC. (ii) Encapsulation, margin status, percentage, and size of ATC in the primary were prognostically relevant. (iii) Pure thyroid squamous cell carcinoma may be considered as ATC given a BRAF^V600E genotype and similar outcome. (iv) In contrast to DTC, BRAF-mutated and RAS-mutated ATCs have similar metastatic spread. (v) Concomitant mutations of BRAF or RAS with TERT confer a worse prognosis.

Keywords: BRAF; RAS; TERT; anaplastic thyroid carcinoma; prognosis; undifferentiated thyroid carcinoma.

FIG. 1.

Histologic features of ATC. ATC may show spindle (A), pleomorphic (B), epithelioid (C), squamous (D), rhabdoid (E), osteoclast giant cell-rich (F) features. Inset in (D) PAX8 immunohistochemistry is positive in the anaplastic squamous cell carcinoma component. Inset in (E) BRAF^V600E immunostain is positive in the rhabdoid ATC cells. (G–I) Immunoprofile of the osteoclast cell-rich ATC (F). (G) PAX8, (H) TTF-1, and (I) BRAF^V600E. The papillary thyroid carcinoma component (right) is positive for PAX8, TTF-1, and BRAF^V600E. The ATC component (left) is focally and weakly positive for PAX8 and TTF-1, whereas diffusely positive for BRAF^V600E. Note that BRAF immunostain is negative in osteoclast giant cells, suggesting that they are reactive rather than neoplastic in nature. (J–L) Unusual features of ATC, showing myxoid stroma (J), osteosarcomatous differentiation (K), and chondrosarcomatous differentiation (L). ATC, anaplastic thyroid carcinoma.

FIG. 2.

Molecular profile of ATC. (A) Oncoprint of 102 ATCs that are sequenced using MSK-IMPACT next-generation sequencing panel. (B) TERT promoter mutation is associated with worse overall survival in ATC (log-rank test, p = 0.016). (C) Prognostic significance of BRAF, RAS, and TERT promoter mutations in ATC: ATC carrying both BRAF/RAS and TERT promoter mutations is associated with significantly shorter overall survival compared with those without either mutations (wild type), BRAF/RAS mutation alone, or TERT promoter mutation alone (log-rank pairwise comparison, p < 0.05). MMR, mismatch repair.

FIG. 3.

Kaplan–Meier plots of overall survival. OCGCR, osteoclast giant cell rich.