BRAF V600E mutation: Differential impact on central lymph node metastasis by tumor size in papillary thyroid carcinoma

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1 ORIGINAL ARTICLE BRAF V600E mutation: Differential impact on central lymph node metastasis by tumor size in papillary thyroid carcinoma Seo Ki Kim, MD, 1 Jun Ho Lee, MD, 2 Jung-Woo Woo, MD, 1 Inhye Park, MD, 1 Jun-Ho Choe, MD, PhD, 1 Jung-Han Kim, MD, PhD, 1 Jee Soo Kim, MD, PhD 1 * 1 Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, 2 Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea. Accepted 3 July 2015 Published online 13 August 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The necessity of prophylactic central neck dissection is one of debating issues in the treatment of papillary thyroid carcinoma (PTC). In a previous study, the predictive value of BRAF mutation for lymph node metastasis was only significant in 0.5 to 1.0 cm PTC. Thus, we assess the predictive value of BRAF mutation for central lymph node metastasis according to tumor size. Methods. Medical records of 3107 patients with PTC who underwent thyroidectomy with central neck dissection were retrospectively reviewed. Results. BRAF mutation was a predictor for central lymph node metastasis in 2.0 to 4.0 cm PTC (odds ratio [OR] ; p 5.002). Although BRAF mutation was associated with central lymph node metastasis in 0.5 to 1.0 cm PTC in univariate analysis (OR ; p 5.047), this significance was not observed in multivariate analysis (OR ; p 5.163). BRAF mutation was not associated with central lymph node metastasis in other tumor sizes. Conclusion. Prophylactic central neck dissection could be considered in 2.0 to 4.0 cm PTC with positive BRAF mutation. VC 2015 Wiley Periodicals, Inc. Head Neck 38: E1203 E1209, 2016 KEY WORDS: papillary thyroid carcinoma, central lymph node metastasis, BRAF mutation, central neck dissection, tumor size INTRODUCTION Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. 1,2 Although the 10-year overall survival rate is over 90%, PTC is commonly associated with morbidities from metastasis or recurrence. 3,4 Cervical lymph node metastases are common in PTC, occurring in approximately 20% to 90% of cases, 5,6 whereas micrometastases are even more common, observed in nearly 90% of examined nodes. 7 Moreover, nodal metastases are known to have significant correlation with the persistence and recurrence of PTC, 3,8 and a large population-based study demonstrated increased mortality rate in patients with regional lymph node metastasis. 9 metastasis and central neck dissection are currently key issues in the treatment of PTC. 10,11 Considerable numbers of patients with PTC with clinically uninvolved central lymph node metastasis were eventually found to have central lymph node metastasis at the time of surgery or in the pathology specimens Thus, some studies have emphasized the necessity of prophylactic central neck dissection in patients with clinically uninvolved central lymph node metastasis However, other studies of prophylactic central neck dissection demonstrated higher *Corresponding author: J. S. Kim, Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul , South Korea. jskim0126@skku.edu morbidity, primarily recurrent laryngeal nerve injury, and transient hypoparathyroidism, with no reduction in recurrence. 18,19 Primary tumor size and extrathyroidal extension were also reported to be strong indicators of central lymph node metastasis Thus, prophylactic central neck dissection is generally considered in T3 and T4 PTC, which includes patients with tumors larger than 4 cm or extrathyroidal extension. 24 However, several previous studies demonstrated high frequency of subclinical central lymph node metastasis in papillary thyroid microcarcinoma, which is PTC <1 cm in size. 13,20,25 Because there are no definite indicators for central lymph node metastasis in patients with T1 and T2 PTC, additional novel indicators are required for determining the necessity of prophylactic central neck dissection. BRAF V600E mutation (hereafter referred to as BRAF mutation ), the most potent activator of the mitogenactivated protein kinase pathway, plays a central role in the regulation of cell growth, division, and proliferation. 26 BRAF mutation has now been reported in numerous types of human cancer with various frequencies, and has been frequently detected in thyroid cancers. 27 The BRAF mutation is found predominantly in PTC, particularly in conventional and tall cell variants, as well as some forms of anaplastic/ poorly differentiated thyroid carcinoma. 27 The prevalence of BRAF mutation in PTC ranged from 29% to 83% in different studies, whereas the rate of 73% to 86% was reported in Korea, a BRAF mutation-prevalent area. 27,28 Numerous studies have demonstrated association of BRAF mutation HEAD & NECK DOI /HED APRIL 2016 E1203

2 KIM ET AL. with aggressive clinicopathological characteristics of PTC, such as advanced stage, extrathyroidal extension, lymph node metastasis, and tumor recurrence However, others failed to observe such associations Interestingly, a study carried out on 71 patients with PTC found that the predictive value of BRAF mutation for lymph node metastasis was only significant in the group with tumor sizes of 0.5 to 1.0 cm. 20 Thus, the controversies regarding the association of BRAF mutation and lymph node metastasis may be due to the inclusion of various sample sizes and lack of consideration of the tumor size of PTC. In this study, we hypothesized that in PTC the predictive value of BRAF mutation for central lymph node metastasis might be dependent on tumor size. MATERIALS AND METHODS Patient selection This study was approved by the institutional review board at Samsung Medical Center. The medical records of 3107 patients surgically proven to have PTC who had been treated at the Thyroid Cancer Center of Samsung Medical Center between January 2008 and December 2012 were retrospectively reviewed. All patients in this study underwent lobectomy or total thyroidectomy with ipsilateral or comprehensive central neck dissection. Following a previous study 20 and American Joint Committee on Cancer staging, 35 the 3107 patients with PTC were separated into groups according to tumor size for analysis, as follows: <0.5 cm; 0.5 to 1.0 cm; 1.0 to 2.0 cm; 2.0 to 4.0 cm; and >4.0 cm. Patients with the following conditions were excluded from this study: a history of previous head and neck surgery, including thyroidectomy because of various cervical area diseases; the presence of distant metastasis of thyroid malignancy; family history of endocrine cancer; a history of neck irradiation in childhood or adolescence; and mixed type thyroid cancer. Surgical protocols Following the American Thyroid Association management guidelines, 24 total thyroidectomy was performed when primary tumor size was >1 cm, multifocality, bilaterality, extrathyroidal extension, or abnormal lymphadenopathy was detected during the preoperative or intraoperative examination. Central neck dissection was defined as a level VI dissection, including pretracheal and paratracheal nodes, the precricoid (Delphian) node, the perithyroidal nodes, and the lymph node along the recurrent laryngeal nerves. 36 Ipsilateral central neck dissection was performed in all lobectomy cases, whereas bilateral central neck dissection was carried out in all cases of total thyroidectomy. Histological examination of surgical specimens Surgical specimens were microscopically examined by 2 or more experienced pathologists for assessment of the following histopathological factors: the cell type of the main lesion; primary tumor size (measured as the longest diameter of the largest lesion); location; multifocality; extrathyroidal extension; lymphovascular invasion; margin involvement; the underlying condition of the thyroid (such as the presence of chronic lymphocytic thyroiditis); and lymph node metastasis. Multifocality was defined as more than 2 lesions of PTC in 1 lobe, regardless of the presence of tumor bilaterality. BRAF mutation analysis BRAF mutation analysis was performed at the Molecular Diagnostics Laboratory of Samsung Medical Center. DNA samples for analysis were extracted from preoperative fineneedle aspiration biopsy (FNAB) specimens or postoperative surgical specimens using QIAamp DNA minikits (QIAGEN, Chatsworth, CA). Three distinct molecular methods were used for molecular analysis of the BRAF mutation. Direct sequencing was performed after conventional polymerase chain reaction (PCR) using an ABI PRISM 3100 sequencer with BigDye Terminator cycle sequencing ready reaction kits (Applied Biosystems, Foster City, CA). Dual priming oligonucleotide-based allele-specific PCR was performed using the Seeplex BRAF ACE detection system (Seegene, Seoul, Korea), after which the amplified products were analyzed using the ScreenTape system (Lab901, Edinburgh, Scotland, UK). Mutant enrichment with 3 0 -modified oligonucleotides-based real-time PCR was carried out using Real-Q BRAF V600E detection kits (BioSewoom, Seoul, Korea), after which the amplified products were analyzed by BigDye Terminator Cycle Sequencing Kits version 3.1 (Applied Biosystems). The DNA sequences obtained from each of the methods were compared with the normal BRAF gene exon 15 in the GenBank Database using sequence assembly software (Gene Codes, Ann Arbor, MI). When a thyroid nodule was evaluated using two or more molecular methods with discordant results, the positive result was chosen for analysis. Statistical analysis Statistical analysis was performed using SPSS software version 21.0 (Chicago, IL). Statistically significant differences were defined as those with p values of <.05. Categorical variables were presented as the number of cases, percentage (%), and odds ratio (OR), and the chi-square test or Fisher s exact test for categorical variables was used for the univariate analysis. The Kaplan Meier method and log-rank test were adopted for analysis of the time-dependent variables. Multivariate analysis was carried out on the variables that achieved p values <.05 in the univariate analysis. RESULTS Baseline characteristics of patients with papillary thyroid carcinoma according to BRAF mutation status Among the total of 3107 patients with PTC enrolled, 508 (16.4%) showed tumor sizes <0.5 cm, 1546 (49.6%) had tumor sizes of 0.5 to 1.0 cm, 793 (25.5%) displayed tumor sizes of 1.0 to 2.0 cm, 232 (7.5%) showed tumor sizes of 2.0 to 4.0 cm, and 28 (0.9%) had tumor sizes >4.0 cm. BRAF mutation was detected in 2530 patients (81.4%), with significantly higher frequency in those with male sex (OR ; p 5.001), multifocality (OR ; p 5.021), and central lymph node metastasis (OR ; p <.001). However, BRAF mutation was significantly less frequent in the patients with PTC with chronic lymphocytic thyroiditis (OR ; p <.001). E1204 HEAD & NECK DOI /HED APRIL 2016

3 CENTRAL LYMPH NODE METASTASIS AND BRAF TABLE 1. Baseline characteristics of patients with papillary thyroid carcinoma according to BRAF mutation status. BRAF mutation no. (%) Negative Positive OR (95% CI) p value Total no. 577 (18.6) 2530 (81.4) Tumor size <0.5 cm 130 (22.5) 378 (14.9) cm 264 (45.8) 1282 (50.7) cm 126 (21.8) 667 (26.4) cm 44 (7.6) 188 (7.4) >4.0 cm 13 (2.3) 15 (0.6) NA.086 Age <45 y 269 (46.6) 1114 (44.0) ( ).259 Men 88 (15.3) 548 (21.7) ( ).001 Multifocality 112 (19.4) 605 (23.9) ( ).021 Extrathyroidal extension 230 (39.9) 1300 (51.4) ( ) <.001 metastasis 207 (35.9) 1111 (43.9) ( ) <.001 Chronic lymphocytic thyroiditis 208 (36.0) 620 (24.5) ( ) <.001 A significant association with age <45 years was not observed (OR ; p 5.259; Table 1). with tumor sizes <0.5 cm Of the 508 patients with PTC with tumor sizes <0.5 cm, central lymph node metastasis was found in 100 (19.7%). Male sex (OR ; p 5.002) was only significantly associated with central lymph node metastasis in univariate analysis. However, there was no significant association of central lymph node metastasis with age <45 years (OR ; p 5.606), BRAF mutation (OR ; p 5.359), multifocality (OR ; p 5.159), extrathyroidal extension (OR ; p 5.114), or chronic lymphocytic thyroiditis (OR ; p 5.880; Table 2). with tumor sizes of 0.5 to 1.0 cm Of the 1546 patients with PTC with tumor sizes of 0.5 to 1.0 cm, central lymph node metastasis was observed in 557 (36.0%). From the multivariate analysis, age <45 years (OR ; p <.001), male sex (OR ; p <.001), multifocality (OR ; p <.001), and extrathyroidal extension (OR ; p <.001) were all found to be independent predictors for high prevalence of central lymph node metastasis. However, although BRAF mutation was significantly associated with central lymph node metastasis in the univariate analysis (OR ; p 5.047), this significance did not carry over to the multivariate analysis (OR ; p 5.163). In addition, chronic lymphocytic thyroiditis (OR ; p 5.441) was not significantly associated with central lymph node metastasis in the patients with PTC with tumor sizes of 0.5 to 1.0 cm (Table 3). with tumor sizes of 1.0 to 2.0 cm Of the 793 patients with PTC with tumor sizes of 1.0 to 2.0 cm, central lymph node metastasis was seen in 469 (59.1%). From the multivariate analysis, age <45 years (OR ; p <.001), male sex (OR ; p 5.001), multifocality (OR ; p 5.023), and extrathyroidal extension (OR ; p <.001) were all demonstrated to be independent predictors for high prevalence of central lymph node metastasis. However, significant associations TABLE 2. Association between clinicopathological characteristics and central <0.5 cm. Total no. 408 (80.3) 100 (19.7) Age <45 y 172 (42.2) 45 (45.0) ( ).606 NA NA Men 54 (13.2) 26 (26.0) ( ).002 NA NA BRAF 300 (73.5) 78 (78.0) ( ).359 NA NA Multifocality 62 (15.2) 21 (21.0) ( ).159 NA NA Extrathyroidal extension 88 (21.6) 29 (29.0) ( ).114 NA NA Chronic lymphocytic thyroiditis 95 (23.3) 24 (24.0) ( ).880 NA NA HEAD & NECK DOI /HED APRIL 2016 E1205

4 KIM ET AL. TABLE 3. Association between clinicopathological characteristics and central from 0.5 to 1.0 cm. Total no. 989 (64.0) 557 (36.0) Age <45 y 403 (40.7) 276 (49.6) ( ) ( ) <.001 Men 171 (17.3) 138 (24.8) ( ) < ( ) <.001 BRAF 806 (81.5) 476 (85.5) ( ) ( ).163 Multifocality 180 (18.2) 181 (32.5) ( ) < ( ) <.001 Extrathyroidal extension 394 (39.8) 297 (53.3) ( ) < ( ) <.001 Chronic lymphocytic thyroiditis 270 (27.3) 142 (25.5) ( ).441 NA NA of BRAF mutation (OR ; p 5.275) and chronic lymphocytic thyroiditis (OR ; p 5.079) with central lymph node metastasis were not observed (Table 4). BRAF mutation is an independent indicator of central with tumor sizes of 2.0 to 4.0 cm Of the 232 patients with PTC with tumor sizes of 2.0 to 4.0 cm, central lymph node metastasis was seen in 173 (74.6%). From the multivariate analysis, age <45 years (OR ; p <.001), BRAF mutation (OR ; p 5.002), and extrathyroidal extension (OR ; p 5.047) were all found to be independent predictors for high prevalence of central lymph node metastasis. However, male sex (OR ; p 5.724), multifocality (OR ; p 5.481), and chronic lymphocytic thyroiditis (OR ; p 5.665) were not significantly associated (Table 5). with tumor sizes >4.0 cm Of the 29 patients with PTC with tumor sizes >4.0 cm, central lymph node metastasis was seen in 19 (67.9%). The univariate analysis in this group revealed no significant associations of age <45 years (OR ; p 5.097), male sex (OR ; p ), BRAF mutation (OR ; p ), multifocality (OR ; p ), extrathyroidal extension (OR ; p ), and chronic lymphocytic thyroiditis (OR ; p 5.062) with central lymph node metastasis (Table 6). DISCUSSION The purpose of this study was to investigate whether the predictive value of BRAF mutation for determining central lymph node metastasis might be dependent on the tumor size of PTC. There are still controversies in the predictive value of BRAF mutation for lymph node metastasis. Based on the results of a previous study, 20 we hypothesized that the controversies on the association between BRAF mutation and lymph node metastasis may be due to the various sample sizes examined, and the lack of stratification according to tumor size. As seen in Table 1, the prevalence of BRAF mutation in the patients with PTC was 81.4% (2530 of 3107 patients), which reflects the high prevalence of BRAF mutation in Korea. 28,37 BRAF mutation displayed significant associations with aggressive clinicopathological characteristics, including multifocality (OR ; p 5.021), extrathyroidal extension (OR ; p <.001), and central lymph node metastasis (OR ; p <.001). This result is in agreement with the observations of previous reports. 38 Particularly, chronic lymphocytic thyroiditis was significantly associated with low prevalence of BRAF mutation (OR ; p <.001). Some investigators have reported that PTC with coexistence of chronic lymphocytic thyroiditis was less associated with extrathyroidal extension, advanced stage, lymph node metastasis, and recurrence. 39,40 TABLE 4. Association between clinicopathological characteristics and central from 1.0 to 2.0 cm. Total no. 324 (40.9) 469 (59.1) Age <45 y 117 (36.1) 220 (46.9) ( ) ( ) <.001 Men 59 (18.2) 127 (27.1) ( ) ( ).001 BRAF 267 (82.4) 400 (85.3) ( ).275 NA NA Multifocality 71 (21.9) 141 (30.1) ( ) ( ).023 Extrathyroidal extension 186 (57.4) 345 (73.6) ( ) < ( ) <.001 Chronic lymphocytic thyroiditis 105 (32.4) 125 (26.7) ( ).079 NA NA E1206 HEAD & NECK DOI /HED APRIL 2016

5 CENTRAL LYMPH NODE METASTASIS AND BRAF TABLE 5. Association between clinicopathological characteristics and central from 2.0 to 4.0 cm. Total no. 59 (25.4) 173 (74.6) Age <45 y 19 (32.2) 112 (64.7) ( ) < ( ) <.001 Men 12 (20.3) 39 (22.5) ( ).724 NA NA BRAF 41 (69.5) 147 (85.0) ( ) ( ).002 Multifocality 12 (20.3) 43 (24.9) ( ).481 NA NA Extrathyroidal extension 37 (62.7) 131 (75.7) ( ) ( ).047 Chronic lymphocytic thyroiditis 14 (23.7) 46 (26.6) ( ).665 NA NA We hypothesize that there may be an unrevealed relationship between BRAF mutation and chronic lymphocytic thyroiditis, thus, further investigation will be required to provide support for this hypothesis. As can be seen in Figure 1, BRAF mutation was found to be an independent predictor for central lymph node metastasis only in the patients with PTC with tumor sizes of 2.0 to 4.0 cm (OR ; p 5.002). Therefore, we suggest that the predictive value of BRAF mutation for central lymph node metastasis in PTC is related to the tumor size. As mentioned above, we expect that the controversies surrounding the proposed association between BRAF mutation and lymph node metastasis 29 34,38,41 44 may be due to lack of consideration of the tumor size in previous studies. Furthermore, controversies also remain regarding the necessity of prophylactic central neck dissection in patients with PTC. 10 Generally, it is considered that prophylactic central neck dissection should be performed in patients with T3 and T4 PTC, which are defined as those with extrathyroidal extension or tumors larger than 4 cm. 24 However, no definite indicator for central lymph node metastasis in patients with T1 and T2 PTC has been identified, despite their considerable prevalence of central lymph node metastasis. 13,20,25 Therefore, in spite of the general recommended guidelines for prophylactic central neck dissection, we performed ipsilateral central neck dissection in all lobectomy cases, and bilateral central neck dissection in all total thyroidectomy cases. Because BRAF mutation was a strong indicator for central lymph node metastasis in patients with PTC with tumor sizes of 2.0 to 4.0 cm, regardless of the presence of extrathyroidal extension, we strongly recommend BRAF mutation analysis in patients with PTC with tumor sizes of 2.0 to 4.0 cm for prediction of central lymph node metastasis. Furthermore, clinicians should consider prophylactic central neck dissection in patients with PTC with tumor sizes of 2.0 to 4.0 cm who test positive for BRAF mutation, particularly when associated with other independent predictors such as age <45 years and extrathyroidal extension (Table 5). As can be seen in Tables 3 to 5, extrathyroidal extension was an independent predictor for central lymph node metastasis in patients with PTC with tumor sizes of 1.0 to 4.0 cm. The predictive value of extrathyroidal extension for central lymph node metastasis was already proven in previous studies. 22,25 This result supported that the consideration of prophylactic central neck dissection in patients with T3 and T4 PTC. 24 However, extrathyroidal extension was not an independent predictor for central lymph node metastasis in patients with PTC with tumor sizes <0.5 cm (Table 2). This result could be explained by the relatively low prevalence of central lymph node metastasis (19.7%; 100 of 508) and extrathyroidal extension (23.0%; 117 of 508) in this small tumor size (< 0.5 cm) group. As can be seen in Table 6, all the clinicopathological characteristics, even including BRAF mutation and extrathyroidal extension, showed no significant relationship with central lymph node metastasis in patients with PTC with tumor sizes >4.0 cm. This result could be explained by the small sample size of patients with PTC within this group, which included only 28 patients. Further investigations might be helpful for determining the TABLE 6. Association between clinicopathological characteristics and central from >4.0 cm. Total no. 9 (32.1) 19 (67.9) Age <45 y 4 (44.4) 15 (78.9) ( ).097 NA NA Men 3 (33.3) 7 (36.8) ( ) NA NA BRAF 5 (55.6) 10 (52.6) ( ) NA NA Multifocality 2 (22.2) 4 (21.1) ( ) NA NA Extrathyroidal extension 7 (77.8) 16 (84.2) ( ) NA NA Chronic lymphocytic thyroiditis 0 (0.0) 7 (36.8) ( ).062 NA NA HEAD & NECK DOI /HED APRIL 2016 E1207

6 KIM ET AL. FIGURE 1. Association between tumor size and predictive value of BRAF mutation for central lymph node metastasis. OR, odds ratio; CI, confidence interval. predictors of central lymph node metastasis in patients with PTC with tumor size >4.0 cm, however, we have already performed prophylactic central neck dissection in this tumor size group according to the recommendation of American Thyroid Association management guidelines. 24 As can be seen in Tables 2 to 6, the prevalence of central lymph node metastasis was 19.7% (100 of 508) in the group of PTC cases with tumor size <0.5 cm, 36.0% (557 of 1546) in the 0.5 to 1.0 cm group, 59.1% (469 of 793) in the 1.0 to 2.0 cm group, 74.6% (173 of 232) in the 2.0 to 4.0 cm group, and 67.9% (19 of 28) in the >4.0 cm group. This tendency of general increase in the prevalence of central lymph node metastasis with increase of tumor size reflects that tumor size is an independent predictor for central lymph node metastasis in PTC As shown in multivariate analysis of Tables 3 and 4, age <45 years, male sex, and multifocality were independent predictors for central lymph node metastasis in the patients with PTC with tumor sizes of 0.5 to 2.0 cm, regardless of the presence of extrathyroidal extension. From the results of previous studies, 20 22,25,45 these clinicopathological characteristics are well known indicators of central lymph node metastasis in patients with PTC. Thus, clinicians should undertake careful preoperative evaluation of clinicopathological characteristics, and even consider prophylactic central neck dissection in patients with PTC with tumor sizes of 0.5 to 2.0 cm who meet the clinicopathological characteristics of age <45 years, male sex, and multifocality in the preoperative status. Particularly, a review article by Sancho et al 46 suggests that larger tumors (T3, T4), patients aged 45 years and older or 15 years and younger, male patients, patients with bilateral or multifocal tumors, and patients with known involved lateral lymph nodes could all be candidates for routine unilateral level VI dissection. This result is inconsistent with our result. However, there is no level 1 evidence from randomized controlled trials and the sample size of our study, more than 3000 patients with PTC, is larger than any other studies referred in the review article by Sancho et al. Moreover, there were studies whose results were consistent with our study demonstrated age <45 years to be an independent risk factor for central lymph node metastasis. 21,47 Therefore, further investigations will be required to make clear the controversy on the relationship between age and central lymph node metastasis. This study had several limitations. First, the results may not be applicable to other races or countries because of the high prevalence of BRAF mutation in our study (82.7%), which could be explained by the geographic bias toward a BRAF-prevalent area. 28,37,42 Second, because only patients with PTC were enrolled, this study cannot be applied to other types of thyroid cancers, such as medullary thyroid carcinoma, anaplastic thyroid carcinoma, and follicular thyroid carcinoma. Third, as only surgically proven data were included in the analysis, the selection might be biased toward high-risk patients. Following the management guidelines for thyroid cancer, 24,48 total thyroidectomy was performed when the primary tumor size was >1 cm, or when multifocality, bilaterality, extrathyroidal extension, or abnormal lymphadenopathy were detected during the preoperative or intraoperative evaluations. Because prophylactic central neck dissection was performed in almost all patients, central lymph node metastasis might be overemphasized. Fourth, 3 distinct types of molecular methods and 2 distinct types of specimens were used for the BRAF mutation analysis. BRAF mutation analysis was not performed as a routine preoperative examination at our clinic, and the molecular methods used for analysis have changed over the years. This might have created discrepancies in the results of BRAF mutation testing. Although BRAF mutation analysis was performed with both FNAB specimens and surgical specimens, numerous studies have demonstrated that preoperative BRAF mutation analysis can be performed readily and reliably using FNAB specimens. 49,50 Finally, because this study was not randomized and was conducted retrospectively, the patient data might not have been fully collected. In conclusion, the predictive value of BRAF mutation for central lymph node metastasis in PTC was found to be related to the tumor size. BRAF mutation was an independent indicator for central lymph node metastasis in patients with PTC with tumor sizes of 2.0 to 4.0 cm, but not in groups with other tumor sizes. Therefore, prophylactic central neck dissection could be considered in patients with PTC with tumor sizes of 2.0 to 4.0 cm and BRAF mutation, particularly when associated with age <45 years and extrathyroidal extension. REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, CA Cancer J Clin 2013;63: Ahn HY, Park YJ. Incidence and clinical characteristics of thyroid cancer in Korea. Korean J Med 2009;77: Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97: Kouvaraki MA, Shapiro SE, Fornage BD, et al. 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