Genetic alterations in papillary thyroid cancer: clinicopathological correlations and diagnostic implications

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, encompassing distinct histological variants and a wide spectrum of clinical behaviors. Advances in molecular diagnostics have identified key genetic alterations - particularly BRAFV600E, RAS mutations, RET/PTC fusions, and TERT promoter mutations - that are strongly linked to tumor aggressiveness and prognosis. This study aimed to determine the prevalence of these alterations and evaluate their clinicopathological significance in a Saudi Arabian patient cohort.

A retrospective analysis was conducted on 114 formalin-fixed paraffin-embedded (FFPE) PTC samples diagnosed between 2019 and 2023. Targeted next-generation sequencing (NGS) was used to detect BRAF, NRAS, KRAS, HRAS, RET/PTC fusions, and TERT promoter mutations. Immunohistochemistry (IHC) for BRAFV600E, TTF-1, CK19, HBME-1, and galectin-3 was performed using automated staining systems. Associations between genetic alterations and clinicopathological parameters - including tumor size, histological subtype, lymph node metastasis, and extrathyroidal extension - were analyzed statistically.

BRAFV600E mutations were identified in 39.5% of cases and were significantly associated with larger tumor size (P = 0.01), extrathyroidal extension (P = 0.04), and lymph node metastasis (P = 0.03). RET/PTC fusions were detected in 15.8% of patients, predominantly younger individuals, and correlated with multifocal tumors and lymphovascular invasion. RAS mutations (19.3%) were more frequent in the follicular variant but showed no significant association with adverse features. TERT promoter mutations were present in 10.5% of cases, significantly correlating with older age and advanced tumor stage. IHC profiles demonstrated strong concordance with molecular findings.

In this Middle Eastern cohort of PTC patients, BRAFV600E and TERT promoter mutations were significantly associated with aggressive clinicopathological features, while RET/PTC fusions and RAS mutations demonstrated distinct demographic and histological distributions. The integration of NGS and IHC enhanced diagnostic accuracy and supports personalized risk stratification in PTC management.