The recent prevalence of ultrasound-guided fine-needle aspiration biopsy has resulted in a marked increase in the number of patients with papillary microcarcinoma (maximum diameter,

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-

We previously demonstrated that (1) most papillary microcarcinomas can be followed without surgical treatment and (2) when surgery is performed, patients with lateral lymph node metastasis detected on preoperative ultrasonography (US) are more likely to develop recurrence. In this study, we further investigated the application of these strategies. To date, we have observed 211 patients (average follow-up 47.9 months). In more than 70% of these patients the tumor size did not increase during the follow-up period. There were no clinicopathologic features linked to tumor enlargement except in tumors > or = 7 mm, which tended to enlarge in patients followed for 4 years. To evaluate not only whether observation can continue but also how to dissect the lymph nodes optimally at surgery, US diagnosis for lateral node metastasis is essential because the presence of US-diagnosed lateral metastasis is an even stronger predictive marker for recurrence than the presence of pathologically confirmed node metastasis. The positive predictive value (PPV) was 80.6% for US but reached 100% if fine-needle aspiration biopsy (FNAB) of nodes or FNAB-thyroglobulin measurement is added. Furthermore, carcinomas occupying the upper region of the thyroid more frequently showed US-diagnosed and pathologically confirmed lateral metastasis, and those measuring > or = 7 mm were more likely to show pathologically confirmed lateral metastasis. These findings suggest that, for papillary microcarcinoma: (1) US-diagnosed lateral metastasis is a strong marker predicting a worse relapse-free survival; (2) FNAB of nodes and FNAB-thyroglobulin measurement are useful tools for evaluating lymph node metastasis; and (3) careful US evaluation for lateral metastasis is necessary in patients with a tumor measuring > or = 7 mm or that is located in the upper region of the thyroid both during observation and preoperatively.

These findings suggest that (1) upgrading of T category for tumors with massive extension is appropriate, whereas that for tumors with only minimal extension is not, and (2) careful surgical treatment and postoperative follow-up are required for tumors with massive extension to posterior organs other than the recurrent laryngeal nerve.

The long-term clinical outcome of the PTC patients who had been treated by lobectomy without RAI ablation was excellent. Based on the above results, we concluded that lobectomy is a valid alternative to total thyroidectomy for the treatment of PTC patients who are younger than aged 45 years, whose tumor diameter is 40 mm or less, and who do not have clinical lymph node metastasis or extrathyroidal invasion.