World J Surg (2012) 36:310–317
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
Published online: 22 December 2011
Ó Société Internationale de Chirurgie 2011
Abstract
Background The BRAFV600E mutation is the most com-
mon genetic alteration found in papillary thyroid cancer
(PTC). Recent studies show that this mutation occurs more
frequently in patients with PTC showing aggressive clini-
copathologic 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 clinico-
pathologic 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: su.jin.kim.md@gmail.com
K. E. Lee  Y.-K. Youn (&)
Department of Surgery, Seoul National University College
of Medicine and Hospital, Seoul, Korea
e-mail: ykyoun@plaza.snu.ac.kr
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
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•
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].
World J Surg (2012) 36:310–317 311

Although in the majority of patients PTC shows an mutation and evaluated its association with various clini-
indolent course and favorable prognosis [5], in some PTC copathologic features of primary PTC. Data regarding age
can spread, recur after initial treatment, and cause death at diagnosis, gender, tumor size, multifocality, extrathy-
[6]. The clinical outcome may be affected by high-risk roidal extension, lymph node and distant metastases, TNM
clinicopathologic characteristics such as older age at stage, and family history were available for all enrolled
diagnosis, male gender, large tumor size, the presence of patients (Table 1).
extrathyroidal extension, lymph node and distant metasta-
ses, and an advanced disease stage [7–9]. Clinicopathologic characteristics of patients with PTC
Many investigators have studied the association between
the BRAFV600E mutation and various clinicopathologic A total of 547 patients (471 females and 76 males; mean
features and clinical outcome, but the relationship between age: 46.3 ± 11.5 years; range 13–81 years) were enrolled.
the BRAFV600E mutation and clinicopathologic features is The mean tumor size was 0.8 ± 0.6 cm (range 0.1–5.0 cm),
still controversial. Several studies show a significant and micro-PTC (B1 cm in diameter) was found in 404
association between the BRAFV600E mutation and the high- (73.9%) patients. There were 536 (98.0%) patients with
risk clinicopathologic characteristics of PTC, and even
with recurrence [10–14]. In contrast, some studies failed to Table 1 Clinicopathologic characteristics of the study population
find a significant association between the BRAFV600E (n = 547)
mutation and high-risk clinicopathologic characteristics Characteristics Number (%)
[15–17]. The prevalence of the BRAFV600E mutation is
highly variable, ranging from 29 to 83% in PTC [18]. Also, Age at diagnosis, years
the prevalence of the BRAFV600E mutation in PTC is much Mean ± SD 46.3 ± 11.5
higher (52–83%) in Korea than in other countries Range 13–81
(30–49%) [19]. This discrepancy is thought to be due to the C45 312 (57.0)
lack of any prospective studies reducing the selection bias, \45 235 (43.0)
small numbers in the study populations, the lack of mul- Gender
tivariate analysis in most studies, and the heterogeneous Male 76 (14.0)
histological subtypes within PTC. Female 471 (86.1)
The aim of the present study was to evaluate the prev- Tumor size, cma
alence of the BRAFV600E mutation in patients diagnosed Mean ± SD 0.8 ± 0.6
with PTC and to analyze the association between high-risk Range 0.1–5.0
clinicopathologic characteristics and the BRAFV600E B1 cm 404 (73.9)
mutation in a large Korean population of PTC patients. [1 cm 143 (26.1)
Histology
Conventional papillary thyroid cancer 536 (98.0)
Patients and methods Follicular variant of papillary thyroid cancer 11 (2.0)
Multifocality 180 (32.9)
Patients Extrathyroidal extension 306 (56.8)
Lymph node metastasis 175 (32.0)
The BRAFV600E mutation was prospectively analyzed in Central node metastasis 165 (30.2)
patients diagnosed with PTC after February 2009. A total Lateral node metastasis 44 (8.4)
of 547 patients who underwent thyroidectomy for primary
Distant metastasis 1 (0.2)
PTC at Seoul National University Hospital (Seoul, Korea)
TNM stage
between February 2009 and January 2010 were enrolled in
I 356 (65.1)
the study. During this period, 769 patients were diagnosed
II 0 (0.0)
with thyroid cancer. Of these, 709 (92.2%) patients were
III 167 (30.5)
diagnosed with PTC and 60 (7.8%) were diagnosed with
IV 24 (4.4)
other cancers (52 with follicular thyroid cancer, 4 with
Extent of thyroidectomy
medullary thyroid cancer, and 4 with other cancers). Of the
Total thyroidectomy 518 (94.7)
PTC patients, 136 (17.7%) refused to enroll, and 26 (3.4%)
Less than total thyroidectomy 29 (5.3)
patients diagnosed with a recurrence of PTC were exclu- b
Family history of differentiated thyroid cancer 44 (8.0)
ded. We routinely performed central node dissection in all
a
patients diagnosed with PTC by frozen section of thyroid Largest tumor diameter
tumor. We analyzed the prevalence of the BRAFV600E 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 fifty-
six (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 near-
total thyroidectomy. There were 44 (8.0%) cases of PTC in
which there was a documented family history of differen-
tiated 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 paraffin-
embedded sections of primary tumors obtained after
thyroidectomy. Areas of tumor were identified on hema-
toxylin 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: for-
ward, 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 Ter-
minator (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
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World J Surg (2012) 36:310–317
independent sample Student’s t-test was used for continu-
ous variables. A P value of \0.05 was regarded as sig-
nificant. 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 prev-
alence 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], extra-
thyroidal 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 asso-
ciated with the BRAFV600E mutation. However, the
BRAFV600E mutation was not significantly associated with
gender, multifocality, or TNM stage. Nor was there a sig-
nificant association between the BRAFV600E mutation and
a family history of differentiated thyroid cancer in a first-
degree 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 recur-
rence (P for trend \0.001; Table 4).
Univariate analysis also showed that the BRAFV600E
mutation was significantly associated with age (C45 years),
World J Surg (2012) 36:310–317 313

Table 2 Comparison of the

Variable BRAFV600E mutation P value
BRAFV600E mutation and
clinicopathologic characteristics Positive (n = 381) Negative (n = 166)
in PTCs
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%)
Gender 0.0575
Male 60 (15.8%) 16 (9.6%)
Female 321 (84.3%) 150 (90.4%)
Tumor size, cma
Mean ± SD 0.8 ± 0.5 0.6 ± 0.5 0.0004
B1 cm 267 (70.1%) 137 (82.5%) 0.0023
[1 cm 114 (29.9%) 29 (17.5%)
Histology 0.0095
Conventional papillary 378 (99.2%) 158 (95.2%)
thyroid cancer
Follicular variant of papillary 3 (0.8%) 8 (4.8%)
thyroid caner
Multifocality 0.9409
Yes 125 (32.8%) 55 (33.1%)
No 256 (67.2%) 111 (66.9%)
Extrathyroidal extension \0.0001
Yes 241 (64.1%) 65 (39.9%)
No 135 (35.9%) 98 (60.1%)
Lymph node metastasis 0.0268
Yes 133 (34.9%) 42 (25.3%)
No 248 (65.1%) 124 (74.7%)
Central node metastasis 0.0249
Yes 126 (33.1%) 39 (23.5%)
No 255 (66.9%) 127 (76.5%)
Lateral node metastasis 0.0672
Yes 36 (9.4%) 8 (4.8%)
No 345 (90.6%) 158 (95.2%)
TNM stage 0.5031
I 243 (63.8%) 113 (68.1%)
II 0 (0.0%) 0 (0.0%)
III 119 (31.2%) 48 (28.9%)
IV 19 (5.0%) 5 (3.0%)
a
Largest tumor diameter Family history of differentiated thyroid cancerb 0.8249
b
Family history of Yes 30 (7.9%) 14 (8.4%)
differentiated thyroid cancer in No 351 (92.1%) 152 (91.6%)
the first degree

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 signifi-
cant 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 extra-
thyroidal extension (OR = 2.428; 95% CI 1.484–3.992),
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

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Table 3 The association between BRAFV600E mutation and tumor Table 5 Univariate and multivariate analysis of BRAFV600E muta-
size tion and clinicopathologic features in PTC
BRAFV600E mutation P for Variables Univariate Multivariate
trend Odds ratio (95% CI) Odds ratio (95% CI)
Positive (n, %) Negative (n, %)
Age
Tumor size, cm \0.001
Continuous variable 0.990 (0.974–1.006)
0.1–0.5 66 (52.0) 61 (48.0)
\45 years 1 1
0.6–1.0 201 (72.6) 76 (27.4)
C45 years 0.642 (0.439–0.933) 0.759 (0.442–1.302)
1.1–1.5 58 (77.3) 17 (22.7)
Gender
1.6–2.0 32 (80.0) 8 (20.0)
Female 1 1
[2 cm 24 (85.7) 4 (14.3)
Male 1.752 (0.999–3.239) 1.834 (1.021–3.463)
Size of tumor
Continuous variable 2.017 (1.292–3.230)
Table 4 Association of BRAFV600E mutation with high-risk clini- B1 cm 1 1
copathologic features
[1 cm 2.075 (1.339–3.204) 1.972 (1.250–3.103)
BRAFV600E mutation Odds 95% P for Extrathyroidal extension
ratio CI trend
Positive Negative No 1 1
Yes 2.692 (1.849–3.940) 2.428 (1.484–3.992)
No. of risk factors \0.0001
Multifocality
0 10 (41.7%) 14 (58.3%) 1
No 1 1
1 59 (58.4%) 42 (41.6%) 1.967 0.803–4.971
Yes 0.985 (0.671–1.457) 0.891 (0.592–1.348)
2 103 (70.1%) 44 (29.9%) 3.277 1.364–8.148
Lymph node metastasis
3 142 (73.6%) 51 (26.4%) 3.898 1.642–9.575
No 1 1
4 55 (83.3%) 11 (16.7%) 7.000 2.534–20.504
Yes 1.583 (1.059–2.400) 1.168 (0.738–1.867)
5 7 (87.5%) 1 (12.5%) 9.798 1.426–198.653
TNM stage
0–1 69 (55.2%) 56 (44.8%) 1
I 1 1
2? 307 (74.2%) 107 (25.2%) 2.329 1.535–3.529
III and IV 1.184 (0.806–1.752) 0.810 (0.426–1.413)
Previously known risk factors of recurrence: age (C45 years), male gen-
der, tumor size ([1 cm), extrathyroidal extension, lymph node metastasis,
and distant metastasis
In China, Guan et al. [31] reported that the BRAFV600E
mutation was found in 69% of PTC cases in high iodine
patient population in Korea, and to evaluate any associa- intake areas and 53% in normal iodine intake areas
tion between this mutation and high-risk clinicopathologic (P \ 0.0001), and the authors suggest that high iodine
features. The prevalence of the BRAFV600E mutation in intake may be a significant risk factor for the BRAFV600E
primary PTC patients who underwent thyroidectomy in our mutation in thyroid tissues. Frasca et al. [32] studied 323
study was 69.7% (381/547). Xing [20] and Lee et al. [19] PTC cases in Sicily and found a strong independent asso-
have reviewed studies of the association between the ciation between PTC and environmental factors. Also, the
BRAFV600E mutation and clinicopathologic characteristics. authors found a significant association between the
In a review of 12 studies with a total of 1,168 patients, Lee BRAFV600E mutation and residency in eastern Sicily
et al. [19] reported that the BRAFV600E mutation was compared with western Sicily (45.9% vs. 22.7%, respec-
detected in 49% (570/1,168). Recent studies report a tively; P \ 0.001). Koreans eat an iodine-rich diet, which
varying prevalence of the mutation in PTC, ranging from would explain the high prevalence of the BRAFV600E
29 to 83% [18]. A review of Korean studies with large mutation in thyroid cancer patients. Further study will be
sample sizes reveals a high prevalence of the BRAFV600E needed to evaluate the association between BRAFV600E
mutation, ranging from 58 to 83% [10, 21–24], but a lower mutation and iodine intake in the Korean population. Also,
prevalence in Western countries (49% [14]; 42.8% [25]; the proportion of patients with a family history of differ-
48.5% [26]; 37.3% [27]; 31% [28]), and Saudi Arabia entiated thyroid cancer in a first-degree relative was
(51.7%) [29], Taiwan (47%) [30], and Japan (23.8%; somewhat higher (8.0%) than in other studies [33]. Genetic
38.4%) [12, 17]. The reason for this is unclear, but we differences may influence the prevalence of BRAFV600E in
suppose that geographic or genetic factors may account for prevalent Korean populations compared with other racial
these differences. groups. Further studies will be needed to identify the

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factors that determine the levels of the BRAFV600E muta- Lymph node metastasis (OR = 1.168; 95% CI 0.738–1.867)
tion in various geographic and racial groups. and advanced disease stage (OR = 0.810; 95% CI
In the present study, the prevalence of the BRAFV600E 0.426–1.413) were not significantly associated with this
mutation was somewhat different from the prevalence mutation according to multiple logistic regression analysis
reported in studies by Kim et al. (83%) [10], Kim et al. after adjusting for various clinicopathologic parameters.
(73%) [21], Kim et al. (81%) [23], Jo et al. (63.4%) [34], Although we identified an association between the
and Lee et al. (58%) [22], who analyzed the BRAFV600E BRAFV600E mutation and lymph node metastasis by uni-
mutation in tumor samples obtained after thyroidectomy by variate analysis, this association was not shown by multi-
direct DNA sequencing (Table 6). The reason for this variate analysis. Also, we found a somewhat higher rate of
difference is unclear, but we thought that the prevalence of BRAF mutation in advanced stage PTC [138/191 (72.3%)
the BRAFV600E mutation calculated in our study was more versus 243/356 (68.3%)] in this study.
precise than the prevalence reported in other studies. We Although several studies show an association between
performed a prospective BRAFV600E mutation analysis in the BRAFV600E mutation and older age [11, 26, 28, 35–37],
all patients diagnosed with PTC after February 2009, using this was not the case in the meta-analysis undertaken by
permanent sections obtained after thyroidectomy according Lee et al. [19]. Also, our study revealed that, although age
to the protocol established by the Endocrine Surgery of (as a continuous variable) was not associated with the
Seoul National University Hospital. The present study, the BRAFV600E mutation, age C45 years was negatively
largest research effort analyzing the association between associated with the mutation (OR = 0.642, 95% CI
the BRAFV600E mutation and clinicopathologic features in 0.439–0.933) in univariate analysis. Lupi et al. [25] also
a single institution to date in Korea, shows that the analyzed the association between age (C45 years) and the
BRAFV600E mutation is associated with high-risk clinico- BRAFV600E mutation. They found that the prevalence of
pathologic features, in agreement with the majority of this mutation in patients younger than 45 years was
recent studies. The proportion of BRAFV600E mutation somewhat higher [44.4% (108/204) vs. 40.6% (99/244)],
significantly increases among patients with previously but that there was no significant association with age
known high-risk factors for tumor recurrence, such as older C45 years. However, multivariate analysis adjusting for
age, male gender, large tumor size ([1 cm), extrathyroidal various clinicopathologic parameters showed that age
extension, and lymph node and distant metastases C45 years was not associated with the BRAFV600E muta-
(Table 4). However, multiple logistic regression analysis tion (OR = 0.759, 95% CI 0.442–1.302).
showed that the BRAFV600E mutation was closely associ- This study also showed that the BRAFV600E mutation
ated with gender, tumor size, and extrathyroidal extension, was associated with male gender (OR = 1.834, 95% CI
but not with age at diagnosis, lymph node metastasis, or 1.021–3.463) in multivariate analysis. This is consistent
advanced disease stage. with the results of Kim et al. [21] and Xu et al. [38], but not
Many other studies have found that the BRAFV600E with those of Ito et al. [17], Kebebew et al. [26], Lupi et al.
mutation is most commonly associated with extrathyroidal [25], or Elisei et al. [27]. Park et al. [24] reported that the
extension, lymph node metastasis, and advanced disease prevalence of the BRAFV600E mutation in multifocal PTC
stage [20]. In comparison, we only found a significant was 86.9%, but many studies (including our own) do not
association between the BRAFV600E mutation and extra- show this level of prevalence [25, 26, 39]. Xing et al. [14]
thyroidal extension (OR = 2.428; 95% CI 1.484–3.992). 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).
Table 6 Prevalence of the BRAFV600E mutation in Korean studies Our results show that the proportion of BRAFV600E muta-
tion increased significantly with tumor size (P for trend
Study Year No. of BRAFV600E mutation
cases \0.001; Table 3).
No. Proportion (%) Interestingly, in our study, we found that the proportion
Kim et al. [10] 2004 70 58 82.9 of the BRAFV600E mutation was significantly higher (P for
Kim et al. [23] 2005 79 64 81.0 trend\0.0001) in those patients having a number of known
Kim et al. [21] 2006 203 149 73.4
high-risk factors for tumor recurrence (Table 4). It is pre-
Jo et al. [34] 2006 161 102 63.4
sumed that the BRAFV600E mutation in PTC could have
Lee et al. [22] 2006 100 58 58.0
potential prognostic value.
Although the present study is prospective and large, and
Present study 2010 547 381 69.7
although we used multiple logistic regression analysis to
Total 1,160 812 70.0
account for confounding factors, it has some inherent

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limitations. First, we could not analyze the clinical out-
come 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 long-
term 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 prog-
nosis 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 aggressive-
ness 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 popu-
lation. 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 pro-
phylactic 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 statisti-
cally significant difference in patients who underwent
central node dissection with the BRAFV600E mutation and
without it (P = 0.8520).
123
World J Surg (2012) 36:310–317
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. There-
fore, the BRAFV600E mutation may be a potential prog-
nostic 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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