BRAF genetic heterogeneity in papillary thyroid carcinoma and its metastasis

Intratumoral heterogeneity is widely recognized as an important determinant of a cancer's initial response and its subsequent resistance to targeted therapy. BRAF V600E mutation, common in papillary thyroid carcinoma (PTC), is helpful in fine needle aspiration diagnosis of thyroid nodules and is being evaluated for targeted therapies. This study was designed to assess the presence of BRAF mutation heterogeneity within primary PTCs and between paired primary and metastatic lesions. Genetic heterogeneity was evaluated in 47 PTCs (38 differentiated papillary thyroid carcinomas and 9 poorly differentiated PTCs with anaplastic areas). The differentiated papillary thyroid carcinomas included 16 cases with regional lymph node metastases at thyroidectomy and 9 cases with recurrent metastases to regional lymph nodes more than 5 years post thyroidectomy. Genetic heterogeneity of BRAF was studied by comparing the mutation status in different samples of tumor as follows: (a) 2 separate areas (each >1.5 cm in diameter) within the primary tumor, (b) a more than 1.5 cm area of primary carcinoma and a second 5 mm area simulating a fine needle aspiration sample from a different portion of the primary tumor, (c) primary carcinoma and its lymph node metastasis at thyroidectomy, (d) primary carcinoma and the recurrent metastasis, and (e) differentiated and anaplastic areas in the primary carcinoma. BRAF mutation status was concordant in 95.2% of the 62 paired samples. Discordant BRAF status was detected in only 4.8% of the pairs studied and most frequently involved cases with recurrent metastasis thus suggesting a need for additional testing of these lesions before instituting therapy.