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-

Although histologic definition of follicular thyroid lesions is readily available, application of the diagnostic criteria and personal experience may lead to disagreement among pathologists. To investigate interobserver variation in assessment of encapsulated follicular lesions, eight pathologists (four American and four Japanese) reviewed the same hematoxylin and eosin-stained slide of each of 21 cases of thyroid lesions showing encapsulation and follicular growth pattern. In 10% of the cases, there was complete agreement. At least seven pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76% of the cases. American and Japanese pathologists agreed among themselves in 33% and 52% of cases, respectively. The frequency of diagnosis of adenomatous goiter among Japanese pathologists (31%) was considerably higher than that among American pathologists (6%). In contrast, the frequency of diagnosis (25%) of papillary carcinoma among American pathologists was considerably higher than that (4%) among Japanese pathologists. Our analysis revealed three main factors affecting observer variation: 1) interpretation of the significance of microfollicles intimately related to capillaries within the tumor capsule, 2) evaluation of what constituted the type of nuclear clearing indicative of papillary carcinoma, and 3) absence of clear morphologic criteria for separation of adenomatous goiter and follicular adenoma. To reduce observer variation of encapsulated follicular lesions, it will be necessary to provide more explicit criteria for diagnosis.