World J Surg DOI 10.1007/s00268-011-1383-1
BRAFV600E Mutation is Associated with Tumor Aggressiveness in Papillary Thyroid Cancer Su-jin Kim • Kyu Eun Lee • Jun Pyo Myong • Jeong-hwan Park • Yoon Kyung Jeon • Hye Sook Min • So Yeon Park • Kyeong Cheon Jung Do Hoon Koo • Yeo-Kyu Youn
•
Ó Socie´te´ Internationale de Chirurgie 2011
Abstract Background The BRAFV600E mutation is the most common genetic alteration found in papillary thyroid cancer (PTC). Recent studies show that this mutation occurs more frequently in patients with PTC showing aggressive clinicopathologic features. The aim of the present study was to evaluate the prevalence of the BRAFV600E mutation in tumor samples and its association with high-risk clinicopathologic features prospectively. Patients and methods From February 2009 to January 2010, 547 PTC patients who underwent surgery in Seoul National University Hospital were enrolled in the study.
S. Kim Department of Surgery, Haeundae Paik Hospital, Inje University College of Medicine, 1435 Jwa-dong, Haeundae-gu, Busan 612-030, Korea e-mail:
[email protected] K. E. Lee Y.-K. Youn (&) Department of Surgery, Seoul National University College of Medicine and Hospital, Seoul, Korea e-mail:
[email protected] K. E. Lee Y.-K. Youn Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea J. P. Myong Graduate School of Medicine, The Catholic University of Korea, Seoul, Korea J. Park Y. K. Jeon H. S. Min S. Y. Park K. C. Jung Department of Pathology, Seoul National University College of Medicine, Seoul, Korea D. H. Koo Department of Surgery, Seoul National University Boramae Medical Center, Seoul, Korea
Polymerase chain reaction was used to amplify exon 15 of the BRAF gene from paraffin-embedded thyroid tumor specimens, followed by direct sequencing to detect the BRAFV600E mutation. Both univariate and multivariate analyses were performed to analyze associations between the BRAFV600E mutation and clinicopathologic features. Results The BRAFV600E mutation was found in 381/547 (69.7%) patients with primary PTC. The BRAFV600E mutation was significantly associated with age (C45 years), tumor size ([1 cm), extrathyroidal extension, and cervical lymph node metastases (P \ 0.05). Multiple logistic regression showed that it was significantly associated with gender (OR = 1.834; 95% CI 1.021–3.463), tumor size (OR = 1.972; 95% CI 1.250–3.103), and extra-thyroidal extension (OR = 2.428; 95% CI 1.484–3.992), but not with age, multifocality, lymph node metastases, and advanced disease stage. The proportion of BRAFV600E mutation was significantly associated with the number of high-risk factors of tumor recurrence (P \ 0.001). Conclusions The BRAFV600E mutation was associated with high-risk clinicopathologic characteristics in patients with PTC. The BRAFV600E mutation may be a potential prognostic factor in PTC patients.
Introduction The B-type Raf kinase (BRAF) mutation is the most common genetic alteration in papillary thyroid cancer (PTC) [1]. Of the three forms of Raf kinase, BRAF is the most potent activator of the mitogen-activated protein kinase (MAPK) pathway [2], which plays a major role in the regulation of cell growth, division, and proliferation [3, 4]. The T1779A point mutation in BRAF exon 15, resulting in a V600E amino acid substitution, is the most common and represents more than 90% of all the mutations found in the BRAF gene [2].
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Although in the majority of patients PTC shows an indolent course and favorable prognosis [5], in some PTC can spread, recur after initial treatment, and cause death [6]. The clinical outcome may be affected by high-risk clinicopathologic characteristics such as older age at diagnosis, male gender, large tumor size, the presence of extrathyroidal extension, lymph node and distant metastases, and an advanced disease stage [7–9]. Many investigators have studied the association between the BRAFV600E mutation and various clinicopathologic features and clinical outcome, but the relationship between the BRAFV600E mutation and clinicopathologic features is still controversial. Several studies show a significant association between the BRAFV600E mutation and the highrisk clinicopathologic characteristics of PTC, and even with recurrence [10–14]. In contrast, some studies failed to find a significant association between the BRAFV600E mutation and high-risk clinicopathologic characteristics [15–17]. The prevalence of the BRAFV600E mutation is highly variable, ranging from 29 to 83% in PTC [18]. Also, the prevalence of the BRAFV600E mutation in PTC is much higher (52–83%) in Korea than in other countries (30–49%) [19]. This discrepancy is thought to be due to the lack of any prospective studies reducing the selection bias, small numbers in the study populations, the lack of multivariate analysis in most studies, and the heterogeneous histological subtypes within PTC. The aim of the present study was to evaluate the prevalence of the BRAFV600E mutation in patients diagnosed with PTC and to analyze the association between high-risk clinicopathologic characteristics and the BRAFV600E mutation in a large Korean population of PTC patients.
mutation and evaluated its association with various clinicopathologic features of primary PTC. Data regarding age at diagnosis, gender, tumor size, multifocality, extrathyroidal extension, lymph node and distant metastases, TNM stage, and family history were available for all enrolled patients (Table 1). Clinicopathologic characteristics of patients with PTC A total of 547 patients (471 females and 76 males; mean age: 46.3 ± 11.5 years; range 13–81 years) were enrolled. The mean tumor size was 0.8 ± 0.6 cm (range 0.1–5.0 cm), and micro-PTC (B1 cm in diameter) was found in 404 (73.9%) patients. There were 536 (98.0%) patients with Table 1 Clinicopathologic characteristics of the study population (n = 547) Characteristics
Number (%)
Age at diagnosis, years Mean ± SD
46.3 ± 11.5
Range
13–81
C45
312 (57.0)
\45
235 (43.0)
Gender Male Female
76 (14.0) 471 (86.1)
Tumor size, cma Mean ± SD
0.8 ± 0.6
Range
0.1–5.0
B1 cm
404 (73.9)
[1 cm
143 (26.1)
Histology
Patients and methods
Conventional papillary thyroid cancer
536 (98.0)
Follicular variant of papillary thyroid cancer
11 (2.0)
Multifocality
Patients The BRAFV600E mutation was prospectively analyzed in patients diagnosed with PTC after February 2009. A total of 547 patients who underwent thyroidectomy for primary PTC at Seoul National University Hospital (Seoul, Korea) between February 2009 and January 2010 were enrolled in the study. During this period, 769 patients were diagnosed with thyroid cancer. Of these, 709 (92.2%) patients were diagnosed with PTC and 60 (7.8%) were diagnosed with other cancers (52 with follicular thyroid cancer, 4 with medullary thyroid cancer, and 4 with other cancers). Of the PTC patients, 136 (17.7%) refused to enroll, and 26 (3.4%) patients diagnosed with a recurrence of PTC were excluded. We routinely performed central node dissection in all patients diagnosed with PTC by frozen section of thyroid tumor. We analyzed the prevalence of the BRAFV600E
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180 (32.9)
Extrathyroidal extension
306 (56.8)
Lymph node metastasis
175 (32.0)
Central node metastasis
165 (30.2)
Lateral node metastasis
44 (8.4)
Distant metastasis TNM stage
1 (0.2)
I
356 (65.1)
II
0 (0.0)
III
167 (30.5)
IV
24 (4.4)
Extent of thyroidectomy Total thyroidectomy
518 (94.7)
Less than total thyroidectomy Family history of differentiated thyroid cancer
29 (5.3) b
44 (8.0)
a
Largest tumor diameter
b
Family history of differentiated thyroid cancer in the first degree
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conventional PTC and 11 (2.0%) with follicular variant PTC. Multifocality, extrathyroidal extension, and lymph node metastasis were present in 180 (32.9%), 306 (56.8%), and 175 (32.0%) patients, respectively. Three hundred fiftysix (65.1%) patients had stage I disease, 167 (30.5%) had stage III disease, and 24 (4.4%) had stage IV disease. Of these 547 patients, 518 (94.7%) underwent total, or neartotal thyroidectomy. There were 44 (8.0%) cases of PTC in which there was a documented family history of differentiated thyroid cancer in a first-degree family member. Pathology staging was defined according to the Tumor, Lymph Node, Metastasis (TNM) classification system of the International Union Against Cancer and the American Joint Committee on Cancer. All diagnoses were confirmed by permanent histological examination, and the study was approved by the institutional review board of Seoul National University Hospital. DNA isolation and BRAFV600E mutation analysis We performed BRAFV600E mutation analysis on paraffinembedded sections of primary tumors obtained after thyroidectomy. Areas of tumor were identified on hematoxylin and eosin (H&E) stained slides, marked by pathologists and microdissected using a fine needle from 10-lm-thick unstained sections. In patients with multifocal lesions (32.9%), the largest tumor lesion was examined for the BRAFV600E mutation. Genomic DNA was isolated by incubation with extraction buffer [1 M Tris-HCl, pH 7.4; 0.5 M ethylenediaminetetraacetic acid (EDTA), pH 8.0, 5% Tween 20] and proteinase K at 60°C for 12–15 h, followed by standard phenol-chloroform extraction and ethanol precipitation. The BRAF exon 15, which contains the most common BRAF mutation, a T1799A transversion (BRAFV600E), was amplified by polymerase chain reaction (PCR) with genomic DNA. The primers and PCR conditions were as follows: forward, 50 -GCTTGCTCTGATAGGAAAATGAG-30 ; reverse 50 -GTAACTCAGCAGCATCTCAGG-30 ; denaturation at 94°C for 10 min, followed by 35 cycles of 94°C for 1 min, 60°C for 1 min, 72°C for 1 min, and a final extension step at 72°C for 10 min. After purification of the PCR products with the QIAGEN-QIAquick PCR purification kit (QIAGEN, Hilden, Germany), direct DNA bidirectional sequencing was done with an ABI 3130XL Genetic Analyzer BigDye Terminator (Applied Biosystems, Foster City, CA). Sequence data were analyzed manually by two independent pathologists. Statistical analysis Statistical analyses were performed with SPSS software (version 17.0; SPSS Inc., Chicago, IL). The v2 and Fisher’s exact tests were used for categorical variables and an
independent sample Student’s t-test was used for continuous variables. A P value of \0.05 was regarded as significant. Univariate and multivariate analyses were performed to determine the association between BRAFV600E mutation status and clinicopathologic characteristics. We estimated the P for trend to estimate a trend of the prevalence of positive BRAFV600E mutation for the tumor size and number of risk factors for tumor recurrence.
Results Prevalence of the BRAFV600E mutation in PTC Tumor samples from 547 patients with histologically confirmed primary PTC were analyzed for the BRAFV600E mutation. The BRAFV600E mutation was detected in 69.7% (381/547) of primary PTCs by direct DNA sequencing of the PCR-amplified exon 15. BRAFV600E mutation status and clinicopathologic characteristics of primary PTC Comparison between the BRAFV600E mutation status and the clinicopathologic characteristics of PTC patients revealed that age [C45 years; 205/381 (53.8%) vs. 107/166 (64.5%), P = 0.0207], tumor size [[1 cm; 114/381 (29.9%) vs. 29/166 cases (17.5%), P = 0.0023], extrathyroidal extension [241/381 (64.1%) vs. 65/166 (39.9%), P \ 0.0001], and cervical lymph node metastases [133/381 (34.9%) vs. 42/166 (25.3%), P = 0.0268] were all associated with the BRAFV600E mutation. However, the BRAFV600E mutation was not significantly associated with gender, multifocality, or TNM stage. Nor was there a significant association between the BRAFV600E mutation and a family history of differentiated thyroid cancer in a firstdegree family member (P = 0.8249; Table 2). To evaluate associations between the BRAFV600E mutation and tumor size, we assessed tumor size in 0.5 cm increments. Table 3 shows that the BRAFV600E mutation occurs at a significantly higher proportion as PTC tumor size increases (P for trend \0.001). Age at diagnosis, male gender, tumor size, extrathyroidal extension, and lymph node metastasis are known to be high risk factors for tumor recurrence [36–38]. We found a significant association between a number of high risk factors in PTC patients and the BRAFV600E mutation (P for trend \0.001; Table 4). Statistically significant increases in odds ratio from lowest and highest 1.967, 3.277, 3.898, 7.000, and 9.798 according to the numbers of risk factors for tumor recurrence (P for trend \0.001; Table 4). Univariate analysis also showed that the BRAFV600E mutation was significantly associated with age (C45 years),
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World J Surg Table 2 Comparison of the BRAFV600E mutation and clinicopathologic characteristics in PTCs
Variable
BRAFV600E mutation
P value
Positive (n = 381)
Negative (n = 166)
Age, years Mean ± SD
44.8 ± 10.7
45.5 ± 10.5
0.2068
C45 years
205 (53.8%)
107 (64.5%)
0.0207
\45 years
176 (46.2%)
59 (35.5%)
Male
60 (15.8%)
16 (9.6%)
Female
321 (84.3%)
150 (90.4%)
Mean ± SD
0.8 ± 0.5
0.6 ± 0.5
0.0004
B1 cm
267 (70.1%)
137 (82.5%)
0.0023
[1 cm Histology
114 (29.9%)
29 (17.5%)
Conventional papillary thyroid cancer
378 (99.2%)
158 (95.2%)
Follicular variant of papillary thyroid caner
3 (0.8%)
8 (4.8%)
Gender
0.0575
Tumor size, cma
0.0095
Multifocality
0.9409
Yes
125 (32.8%)
55 (33.1%)
No
256 (67.2%)
111 (66.9%)
241 (64.1%)
65 (39.9%)
135 (35.9%)
98 (60.1%)
Yes
133 (34.9%)
42 (25.3%)
No
248 (65.1%)
124 (74.7%)
Yes
126 (33.1%)
39 (23.5%)
No
255 (66.9%)
127 (76.5%)
Yes
36 (9.4%)
8 (4.8%)
No
345 (90.6%)
158 (95.2%)
I
243 (63.8%)
113 (68.1%)
II
0 (0.0%)
0 (0.0%)
III
119 (31.2%)
48 (28.9%)
Extrathyroidal extension Yes No
\0.0001
Lymph node metastasis
0.0268
Central node metastasis
0.0249
Lateral node metastasis
0.0672
TNM stage
a
Largest tumor diameter
b
Family history of differentiated thyroid cancer in the first degree
IV 19 (5.0%) Family history of differentiated thyroid cancerb
5 (3.0%) 0.8249
Yes
30 (7.9%)
14 (8.4%)
No
351 (92.1%)
152 (91.6%)
size of tumor ([1 cm), extra-thyroidal extension, and lymph node metastasis, but not with male gender, multifocality, or advanced disease stage (III and IV). Multiple logistic regression analysis adjusting all variables showed a significant association between BRAFV600E mutation and male gender (OR = 1.834; 95% CI 1.021–3.463), size of tumor ([1 cm; OR = 1.972; 95% CI 1.250–3.103), and extrathyroidal extension (OR = 2.428; 95% CI 1.484–3.992),
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0.5031
but not with age, multifocality, lymph node metastasis, and advanced disease stage (Table 5).
Discussion The purpose of this prospective study was to analyze the prevalence of the BRAFV600E mutation in a large PTC
World J Surg Table 3 The association between BRAFV600E mutation and tumor size BRAFV600E mutation Positive (n, %)
Negative (n, %)
P for trend \0.001
Tumor size, cm 0.1–0.5
66 (52.0)
61 (48.0)
0.6–1.0 1.1–1.5
201 (72.6) 58 (77.3)
76 (27.4) 17 (22.7)
1.6–2.0
32 (80.0)
8 (20.0)
[2 cm
24 (85.7)
4 (14.3)
Table 5 Univariate and multivariate analysis of BRAFV600E mutation and clinicopathologic features in PTC Variables
Univariate Odds ratio (95% CI)
Multivariate Odds ratio (95% CI)
Age Continuous variable
0.990 (0.974–1.006)
\45 years C45 years
1 0.642 (0.439–0.933)
1 0.759 (0.442–1.302)
Female
1
1
Male
1.752 (0.999–3.239)
1.834 (1.021–3.463)
Gender
Size of tumor Table 4 Association of BRAFV600E mutation with high-risk clinicopathologic features BRAFV600E mutation Positive
Negative
Odds ratio
95% CI
P for trend \0.0001
No. of risk factors 0
10 (41.7%)
14 (58.3%)
1
1
59 (58.4%)
42 (41.6%)
1.967
0.803–4.971
2
103 (70.1%)
44 (29.9%)
3.277
1.364–8.148
3
142 (73.6%)
51 (26.4%)
3.898
1.642–9.575
4
55 (83.3%)
11 (16.7%)
7.000
2.534–20.504
5
7 (87.5%)
1 (12.5%)
9.798
1.426–198.653
0–1
69 (55.2%)
56 (44.8%)
1
2?
307 (74.2%)
107 (25.2%)
2.329
1.535–3.529
Previously known risk factors of recurrence: age (C45 years), male gender, tumor size ([1 cm), extrathyroidal extension, lymph node metastasis, and distant metastasis
patient population in Korea, and to evaluate any association between this mutation and high-risk clinicopathologic features. The prevalence of the BRAFV600E mutation in primary PTC patients who underwent thyroidectomy in our study was 69.7% (381/547). Xing [20] and Lee et al. [19] have reviewed studies of the association between the BRAFV600E mutation and clinicopathologic characteristics. In a review of 12 studies with a total of 1,168 patients, Lee et al. [19] reported that the BRAFV600E mutation was detected in 49% (570/1,168). Recent studies report a varying prevalence of the mutation in PTC, ranging from 29 to 83% [18]. A review of Korean studies with large sample sizes reveals a high prevalence of the BRAFV600E mutation, ranging from 58 to 83% [10, 21–24], but a lower prevalence in Western countries (49% [14]; 42.8% [25]; 48.5% [26]; 37.3% [27]; 31% [28]), and Saudi Arabia (51.7%) [29], Taiwan (47%) [30], and Japan (23.8%; 38.4%) [12, 17]. The reason for this is unclear, but we suppose that geographic or genetic factors may account for these differences.
Continuous variable
2.017 (1.292–3.230)
B1 cm
1
1
[1 cm
2.075 (1.339–3.204)
1.972 (1.250–3.103)
No
1
1
Yes
2.692 (1.849–3.940)
2.428 (1.484–3.992)
No
1
1
Yes
0.985 (0.671–1.457)
0.891 (0.592–1.348)
Extrathyroidal extension
Multifocality
Lymph node metastasis No 1 Yes
1.583 (1.059–2.400)
1 1.168 (0.738–1.867)
TNM stage I
1
1
III and IV
1.184 (0.806–1.752)
0.810 (0.426–1.413)
In China, Guan et al. [31] reported that the BRAFV600E mutation was found in 69% of PTC cases in high iodine intake areas and 53% in normal iodine intake areas (P \ 0.0001), and the authors suggest that high iodine intake may be a significant risk factor for the BRAFV600E mutation in thyroid tissues. Frasca et al. [32] studied 323 PTC cases in Sicily and found a strong independent association between PTC and environmental factors. Also, the authors found a significant association between the BRAFV600E mutation and residency in eastern Sicily compared with western Sicily (45.9% vs. 22.7%, respectively; P \ 0.001). Koreans eat an iodine-rich diet, which would explain the high prevalence of the BRAFV600E mutation in thyroid cancer patients. Further study will be needed to evaluate the association between BRAFV600E mutation and iodine intake in the Korean population. Also, the proportion of patients with a family history of differentiated thyroid cancer in a first-degree relative was somewhat higher (8.0%) than in other studies [33]. Genetic differences may influence the prevalence of BRAFV600E in prevalent Korean populations compared with other racial groups. Further studies will be needed to identify the
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factors that determine the levels of the BRAFV600E mutation in various geographic and racial groups. In the present study, the prevalence of the BRAFV600E mutation was somewhat different from the prevalence reported in studies by Kim et al. (83%) [10], Kim et al. (73%) [21], Kim et al. (81%) [23], Jo et al. (63.4%) [34], and Lee et al. (58%) [22], who analyzed the BRAFV600E mutation in tumor samples obtained after thyroidectomy by direct DNA sequencing (Table 6). The reason for this difference is unclear, but we thought that the prevalence of the BRAFV600E mutation calculated in our study was more precise than the prevalence reported in other studies. We performed a prospective BRAFV600E mutation analysis in all patients diagnosed with PTC after February 2009, using permanent sections obtained after thyroidectomy according to the protocol established by the Endocrine Surgery of Seoul National University Hospital. The present study, the largest research effort analyzing the association between the BRAFV600E mutation and clinicopathologic features in a single institution to date in Korea, shows that the BRAFV600E mutation is associated with high-risk clinicopathologic features, in agreement with the majority of recent studies. The proportion of BRAFV600E mutation significantly increases among patients with previously known high-risk factors for tumor recurrence, such as older age, male gender, large tumor size ([1 cm), extrathyroidal extension, and lymph node and distant metastases (Table 4). However, multiple logistic regression analysis showed that the BRAFV600E mutation was closely associated with gender, tumor size, and extrathyroidal extension, but not with age at diagnosis, lymph node metastasis, or advanced disease stage. Many other studies have found that the BRAFV600E mutation is most commonly associated with extrathyroidal extension, lymph node metastasis, and advanced disease stage [20]. In comparison, we only found a significant association between the BRAFV600E mutation and extrathyroidal extension (OR = 2.428; 95% CI 1.484–3.992).
Table 6 Prevalence of the BRAFV600E mutation in Korean studies Study
Year
No. of cases
BRAFV600E mutation No.
Proportion (%)
Kim et al. [10]
2004
70
58
82.9
Kim et al. [23]
2005
79
64
81.0
Kim et al. [21]
2006
203
149
73.4
Jo et al. [34]
2006
161
102
63.4
Lee et al. [22]
2006
100
58
58.0
Present study
2010
Total
123
547
381
69.7
1,160
812
70.0
Lymph node metastasis (OR = 1.168; 95% CI 0.738–1.867) and advanced disease stage (OR = 0.810; 95% CI 0.426–1.413) were not significantly associated with this mutation according to multiple logistic regression analysis after adjusting for various clinicopathologic parameters. Although we identified an association between the BRAFV600E mutation and lymph node metastasis by univariate analysis, this association was not shown by multivariate analysis. Also, we found a somewhat higher rate of BRAF mutation in advanced stage PTC [138/191 (72.3%) versus 243/356 (68.3%)] in this study. Although several studies show an association between the BRAFV600E mutation and older age [11, 26, 28, 35–37], this was not the case in the meta-analysis undertaken by Lee et al. [19]. Also, our study revealed that, although age (as a continuous variable) was not associated with the BRAFV600E mutation, age C45 years was negatively associated with the mutation (OR = 0.642, 95% CI 0.439–0.933) in univariate analysis. Lupi et al. [25] also analyzed the association between age (C45 years) and the BRAFV600E mutation. They found that the prevalence of this mutation in patients younger than 45 years was somewhat higher [44.4% (108/204) vs. 40.6% (99/244)], but that there was no significant association with age C45 years. However, multivariate analysis adjusting for various clinicopathologic parameters showed that age C45 years was not associated with the BRAFV600E mutation (OR = 0.759, 95% CI 0.442–1.302). This study also showed that the BRAFV600E mutation was associated with male gender (OR = 1.834, 95% CI 1.021–3.463) in multivariate analysis. This is consistent with the results of Kim et al. [21] and Xu et al. [38], but not with those of Ito et al. [17], Kebebew et al. [26], Lupi et al. [25], or Elisei et al. [27]. Park et al. [24] reported that the prevalence of the BRAFV600E mutation in multifocal PTC was 86.9%, but many studies (including our own) do not show this level of prevalence [25, 26, 39]. Xing et al. [14] reported that the BRAFV600E mutation was associated with a somewhat smaller tumor size, but Frasca et al. [32] found that the BRAFV600E mutation in 323 PTC patients was strongly associated with a larger tumor size (P = 0.0048). Our results show that the proportion of BRAFV600E mutation increased significantly with tumor size (P for trend \0.001; Table 3). Interestingly, in our study, we found that the proportion of the BRAFV600E mutation was significantly higher (P for trend\0.0001) in those patients having a number of known high-risk factors for tumor recurrence (Table 4). It is presumed that the BRAFV600E mutation in PTC could have potential prognostic value. Although the present study is prospective and large, and although we used multiple logistic regression analysis to account for confounding factors, it has some inherent
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limitations. First, we could not analyze the clinical outcome such as recurrence, metastasis, and cancer-related mortality relative to the BRAFV600E mutation because we started BRAFV600E mutation analysis in PTC patients in Feburary 2009. However, we might analyze the role of the BRAFV600E mutation in PTC patients with the longterm clinical outcome in the future based on the results of the present study. Second, the reason for the discrepancy between Korea and other countries in clinicopathologic features of PTC remains unknown. The proportion of micro-PTC was higher (73.9%) in the present study, and the mean tumor size was smaller than that in other studies [25, 26]. It is presumed that incidentalomas have increased owing to the widespread use of ultrasonography (US) in health surveillance and US-guided fine-needle aspiration biopsy [40, 41], as well as other imaging modalities, such as fluorodeoxyglucose positron emission tomography (FDG-PET), computed tomography (CT), and magnetic resonance imaging (MRI), which are used for thyroid examination for other purposes [39]. The prognosis for micro-PTC is thought to be favorable in most cases [42]. Park et al. reported that the rate of recurrent or persistent disease did not differ between patients with micro-PTC and PTC ([1 cm) (corrected P = 0.112) and the prevalence of BRAFV600E mutation was similar in patients with micro-PTC and PTC ([1 cm) (65.6% vs. 67.2%) in the Korean population [43]. The precise reason for high prevalence of BRAFV600E mutation in micro-PTC patients in Korea is unclear. Future studies will be needed to evaluate factors associated with the tumor aggressiveness in Korean patients with PTC in comparison with patients from other countries who have PTC. Furthemore, a screening protocol for thyroid cancer is needed based on long-term results, such as recurrence, metastasis, and cancer-related mortality from PTC in the Korean population. In addition, we could not find stage II patients in the present study. Stages I, III, and IV are represented in 356 (65.1%), 167 (30.5%), and 24 (4.4%) patients, respectively. It is suggested that the high incidence of stage III and the absence of stage II are a result of prophylactic central node dissection. In our institution, we routinely performed central node dissection in patients diagnosed with PTC in frozen section of thyroid tumor to prevent local recurrence and reoperation of the central neck. We confirmed PTC by frozen section of thyroid tumor in 500/547 (91.4%) patients. We performed central node dissection in 355/381 (93.2%) patients with the BRAFV600E mutation and 155/166 (93.4%) patients without the BRAFV600E mutation. There was no statistically significant difference in patients who underwent central node dissection with the BRAFV600E mutation and without it (P = 0.8520).
Conclusions The BRAFV600E mutation is associated with high-risk clinicopathologic characteristics in patients with PTC, and the proportion of this mutation is significantly related to a number of high-risk factors for tumor recurrence. Therefore, the BRAFV600E mutation may be a potential prognostic indicator for PTC patients. Future studies will be needed to demonstrate a potential role for the BRAFV600E mutation as an indicator of poor prognosis.
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