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

Introduction: 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 BRAF V600E, 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.

Materials and methods: 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 BRAF V600E, 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.

Results: BRAF V600E 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.

Conclusions: In this Middle Eastern cohort of PTC patients, BRAF V600E 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.