BRAF Mutation in Papillary Thyroid Carcinoma in a Japanese Population: Its Lack of Correlation with High-Risk Clinicopathological Features and Disease-Free Survival of Patients

Abstract

Abstract. Recent studies have demonstrated that BRAF V600E mutation is a common event in papillary thyroid carcinoma and a majority of these lesions have shown a direct relationship between BRAF V600E mutation and aggressive characteristics, including a worse patient prognosis. However, there are no studies from Japan regarding this issue in a large series with adequate postoperative follow-up periods. We investigated BRAF V600E mutation in 631 patients with papillary carcinoma having median follow-up periods of 83 months. The prevalence of BRAF V600E mutation was 38.4%, and the rate was higher in carcinoma larger than 1.0 cm but did not successively increase with tumor size. Furthermore, the prevalence did not significantly increase in cases demonstrating high-risk biological features such as clinically apparent lymph node metastasis, massive extrathyroid extension, advanced age, distant metastasis at surgery, and advanced Stage. The disease-free survival of patients with BRAF V600E mutation did not differ from that of those without BRAF V600E mutation. These findings indicate that, although BRAF V600E mutation may play some roles in local carcinoma development, there is no evidence that BRAF V600E mutation significantly reflects the aggressive characteristics and poor prognosis of patients with papillary carcinoma in Japan.Key words: BRAF mutation, Papillary carcinoma, Thyroid, Prognosis (Endocrine Journal 56: 89-97, 2009) PAPILLARY carcinoma of the thyroid is the most common malignancy arising from thyroid follicular cells. Although papillary carcinoma frequently metastasizes to the regional lymph node, it generally shows an indolent character and grows slowly. However, cases displaying certain characteristics are progressive, show a dire prognosis and are considered highrisk. There are several classification systems evaluating the progression of thyroid carcinoma and among these, the UICC/AJCC TNM staging system is the most widely adopted [1]. It consists of three components; T factor, tumor size and extrathyroid extension; N factor, lymph node metastasis; M factor, distant metastasis. Then, each case is staged based on the TNM classification and patient age. This system is evaluated on preoperative imaging studies (TNM and Stage) and also on postoperative pathological examination (pTNM and pStage). We previously demon-

Pre-operative role of BRAF in the guidance of the surgical approach and prognosis of differentiated thyroid carcinoma

“…The most prevalent subgroup of classical and follicular variants of PTC showed no association of BRAF mutation with poor prognostic factors or poor outcome. Our findings corroborated recent studies (20,21,22,23) and also discarded the association of p.V600E with higher frequency of cervical LN and distant metastases (13,24,25,26). In order to justify the lack of association, it has also been proposed that it is not the intratumoral presence of BRAF mutation that determines prognosis but the higher frequency of mutant BRAF alleles, identified in an innovatory analysis of pyrosequencing technique, that favors more frequent recurrence (27).…”

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

“…The prognostic value of the BRAF V600E mutation in PTC patients has been an object of extensive studies. While many studies report an association of BRAF V600E mutation with a more aggressive behavior (13,16,17,20,22), others, including the present series, failed to document such association (14,18,19,21). These apparently conflicting results have to be reevaluated in light of a recent study (38) demonstrating that clonal occurrence of BRAF mutation is a rare event in PTC and that more frequently this mutation affects only a subpopulation of cells.…”

“…The V600E mutation constitutively activates BRAF kinase, leading to prolonged stimulation of the MAPK pathway, which ultimately leads to uncontrolled cell proliferation and faulty apoptosis (8,9,12). The majority of studies have associated BRAF V600E mutation with a more aggressive PTC behavior, whereas a few studies failed to reproduce this finding (13,14,15,16,17,18,19,20,21,22). Still, its value as a prognostic marker remains incompletely established and other players might be implicated, justifying the search for additional molecular markers.…”

Braf Mutation Correlates with Recurrent Papillary Thyroid Carcinoma in Chinese Patients

“…The lack of any associations between BRAF mutation and advanced clinicopathologic features 28 reported that high iodine intake is a significant risk factor for BRAF mutation, and a meta-analysis showed that a high prevalence of the BRAF V600E mutation tended to have a smaller meta-risk of extrathyroidal invasion and lymph node metastasis 7 . Second, a significant number of our patients underwent subtotal thyroidectomy or lobectomy, which might lead to an underestimation of aggressive pathologic characteristics 21,29 . Consistent with an earlier study 7 , BRAF mutation was confirmed as an independent predictor of recurrence in our cohort at 3 years of follow-up.…”

“…In contrast to BRAF mutation, RET/PTC rearrangement has been associated with better prognosis 15 . Yet despite those findings, controversy remains [16][17][18][19][20][21] . In addition, questions about the clinical significance of these mutations in the management of microptc are ongoing 22 .…”