Immunophenotypic Panel for Comprehensive Characterization of Aggressive Thyroid Carcinomas

Aggressive thyroid carcinomas-anaplastic (ATC) and poorly differentiated (PDTC)-are rare but highly lethal malignant entities. Their immunophenotypical characterization is still incomplete, and no standardized diagnostic algorithms have been used. Our study retrospectively analyzes 40 thyroidectomy cases as follows: 12 ATC and 28 PDTC from 2014 to 2024 by evaluating clinical data, histopathological aspects, molecular analysis for presence of BRAFV600E and TERTC228/250T mutations, as well as immunohistochemical expression of BRAF_V600E, total BRAF, K-RAS, TERT, PAX-8, TTF-1, P53, and Ki-67. BRAF_V600E was present in 70% of cases, with higher prevalence in ATC. Total BRAF correlated positively with K-RAS and TERT and negatively with BRAF_V600E. TERT abnormal expression was highly prevalent in over 90% of cases, while loss of TTF-1 and PAX-8 is associated with anaplastic transformation. Ki-67 proliferative index had significantly higher values in ATC, thus supporting its role as a marker for aggressiveness. On univariate analysis, higher Ki-67 indices and lymph node invasion are independent predictor factors for the presence of metastases. However, on multivariate analysis, they both lose significance. Upon multivariate analysis, loss of TTF-1 and tumor necrosis were significant predictors for anaplastic histotype. Specific BRAF_V600E immunohistochemistry may be a good screening tool for the BRAF_V600E mutation. Molecularly, there is a relatively frequent association of the BRAFV600E mutation and TERTC228, mainly in the PDTC subgroup. Patterns of marker expression suggest that BRAF or RAF activation with subsequent loss of TTF-1 or PAX-8, TERT upregulation, and TP53 alteration are frequent occurrences in aggressive thyroid carcinomas. The association between TTF-1 loss and anaplastic transformation, presence of necrosis alongside BRAF_V600E, underlines their diagnostic potential in subclassifying aggressive thyroid carcinomas.