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BRAF^V600E Mutation and Outcome of Patients with Papillary Thyroid Carcinoma: A 15-Year Median Follow-Up Study

Departments of Endocrinology and Metabolism (R.E., D.V., A.B., C.R., A.P.), and of Surgery (P.M., C.U., C.L., R.G., F.B.), University Hospital of Pisa, 56100 Pisa, Italy; and AMBISEN Center (A.P.), High Technology Center for the Study of the Environmental Damage of the Endocrine and Nervous Systems, University of Pisa, 56124 Pisa, Italy

Address all correspondence and requests for reprints to: R. Elisei, M.D., Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. E-mail: relisei{at}endoc.med.unipi.it.

Background: The BRAF^V600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAF^V600E mutation as a poor prognostic factor has been controversially reported in series with short-term follow-ups. In this study we verified the prognostic value of the BRAF^V600E mutation in PTC patients with a long-term follow-up.

Methods: We studied 102 PTC patients with a median follow-up of 15 yr. The BRAF^V600E mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence/absence of the BRAF^V600E mutation, clinicopathological features, and outcome of PTC patients were evaluated.

Results: The BRAF^V600E mutation was found in 38 of 102 (37.3%) PTC patients, and was significantly more frequent in patients older than 60 yr (P = 0.02), in advanced stages (P = 0.03), and in cases with vascular invasion (P = 0.02). At univariate analysis the worst outcome for PTC patients was significantly correlated with clinicopathological features (i.e. age, tumor size, extrathyroid extension, lymph node and distant metastases, advanced stage, vascular endothelial growth factor expression, and vascular invasion) and the BRAF^V600E mutation (P < 0.002). However, at multivariate analysis only the BRAF^V600E mutation showed an independent correlation with the worst outcome (P = 0.03). Moreover, the survival curves of PTC patients showed a lower percentage of survivors in the BRAF^V600E-mutated group (P = 0.015).

Conclusions: In this study the BRAF^V600E mutation correlated with the worst outcome for PTC patients, who were not only at a higher risk not to be cured but also for death. In particular, the BRAF^V600E mutation was demonstrated to be a poor prognostic factor independent from other clinicopathological features.