Background
Thyroid carcinoma is the most common endocrine malignancy and its prevalence is increasing. Recent extensive use of thyroid ultrasound has led to the increased detection of non-palpable thyroid nodules. Papillary thyroid carcinoma (PTC) is the most common type of endocrine malignancy followed by follicular thyroid carcinoma. The prevalence of PTC is rapidly increasing and currently accounts for >95% of all thyroid carcinomas in Korea [
1]. Papillary thyroid microcarcinoma (PTMC), a form of PTC, is defined by the World Health Organization as a tumor measuring 1 cm or less in its greatest dimension. Based on the high incidence of PTMC in autopsy studies, its prognosis is generally favorable and sometimes it is truly indolent and non-progressive [
2]. However, it has been reported that PTMC may have a metastatic potential similar to that of their clinically detectable counterparts [
3‐
5]. Thus, estimate of prognosis as well as detection of PTMC has become an important issue.
The BRAF
V600E mutation, which accounts for about 60–80% of PTCs, has been identifiedas a promising prognostic marker for risk stratification of PTC patients in Korea [
4]. However, uncertainties still exist due to the discordance of studies. Some studies show a significant relationship between the BRAF
V600E mutation and the high-risk clinicopathologic characteristics of PTC [
4,
6]. However, other studies have failed to find a significant association between the BRAF
V600E mutation and high-risk clinicopathologic characteristics [
5,
7]. With regards to PTMC, studies show no significant correlation [
7]. Nevertheless, considering its nature, further study of the characteristics of PTMC through BRAF
V600E mutational status analysis is needed. We investigated the prevalence of the BRAF
V600E mutation andanalyzed the relationship between the BRAF
V600E mutation and clinicopathologic factors in PTMC.
Results
All included patients had PTMC confirmed on the surgical specimen. Of 101 patients, BRAF
V600E mutation in PTMC was observed in 72 patients, indicating a prevalence of 71.3%. The number of patients aged ≥45 years were 76[mutant: 56 (77.8%), wild: 20(69.0%)] and showed no statistical significance. The female sex was dominant in PTMC patients (89.1%); however, there was no statistical significance with BRAF
V600E mutation. There were 31 patients with multifocality [mutant: 22(30.6%), wild: 9(31.0%)], 53 patients with extrathyroidal extension [mutant: 37(51.4%), wild: 16(55.2%)], and 22 patients with combined Hashimoto’s thyroiditis [mutant: 14(19.4%), wild: 8(27.6%)]. These three factors were not significantly related. There were 48 T1a patients [mutant: 36(50.0%), wild: 12(41.4%)], 52 T3 patients [mutant: 35(48.6%), wild: 17(58.6%)], and 1 T4a patient [mutant: 1(1.4%), wild: 0(0%)]. There were 18 patients with nodal metastasis; among these, 11 were N1a [mutant: 8 (11.1%), wild: 3 (10.3%)] and 7 were N1b [mutant: 3 (4.2%), wild: 4 (13.8%)]. The T and N staging were not significantly related to BRAF
v600Emutation (Table
1). Distant metastasis to the lung was found in one patient with wild type and it was not significantly relevant with BRAF
v600E.
Table 1
Relationship between the BRAF
V600E
mutation and clinicopathologic factors in papillary thyroid microcarcinoma
Age | | | | 0.862 | 0.353 |
<45 years | 25(24.8) | 16(22.2) | 9(31.0) | | |
≥45 years | 76(75.2) | 56(77.8) | 20(69.0) | | |
Gender | | | | 0.669 | 0.413 |
Female | 90(89.1) | 63(87.5) | 27(93.1) | | |
Male | 11(10.9) | 9(12.5) | 2(6.9) | | |
Multifocality | | | | 0.002 | 0.962 |
No | 70(69.3) | 50(69.4) | 20(69.0) | | |
Yes | 31(30.7) | 22(30.6) | 9(31.0) | | |
Extrathyroidal extension | | | | 0.119 | 0.73 |
No | 48(47.5) | 35(48.6) | 13(44.8) | | |
Yes | 53(52.5) | 37(51.4) | 16(55.2) | | |
Hashimoto thyroiditis | | | | 0.804 | 0.37 |
Not combined | 79(78.2) | 58(80.6) | 21(72.4) | | |
Combined | 22(21.8) | 14(19.4) | 8(27.6) | | |
T staging | | | | 1.128 | 0.569 |
T1a | 48(47.5) | 36(50.0) | 12(41.4) | | |
T3 | 52(51.5) | 35(48.6) | 17(58.6) | | |
T4a | 1(1.0) | 1(1.4) | 0(0) | | |
Nodal metastasis | | | | 2.973 | 0.226 |
N0 | 83(82.2) | 61(84.7) | 22(75.9) | | |
N1a | 11(10.9) | 8(11.1) | 3(10.3) | | |
N1b | 7(6.9) | 3(4.2) | 4(13.8) | | |
Distant metastasis | | | | 2.508 | 0.113 |
No | 100(99.0) | 72(100.0) | 28(96.6) | | |
Yes | 1(1.0) | 0(0.0) | 1(3.4) | | |
In summary, as shown in Tables
1 and
2, there were no statistically significant correlationswith regards to age, gender, multifocality, extrathyroidal extension, presence of Hashimoto thyroiditis, and lymph node metastasis between the BRAF
V600E mutant and wild-type groups.
Table 2
Summary of logistic regression for variables predicting the BRAF
V600E
mutation in PTMC
Age (1 = <45, 0 = ≥45*) | −0.541 | 0.535 | 1.024 | 1 | 0.312 | 0.582 | 0.204 | 1.661 |
Gender (1 = female, 0 = male*) | −0.673 | 0.854 | 0.621 | 1 | 0.431 | 0.510 | 0.096 | 2.720 |
Multifocality (1 = no, 0 = yes*) | −0.007 | 0.512 | 0.000 | 1 | 0.989 | 0.993 | 0.364 | 2.707 |
Extrathyroidal extension (1 = no, 0 = yes*) | 0.101 | 0.485 | 0.044 | 1 | 0.835 | 1.106 | 0.428 | 2.860 |
Hashimoto thyroiditis (1 = not combined, 0 = combined*) | 0.481 | 0.532 | 0.817 | 1 | 0.366 | 1.617 | 0.570 | 4.586 |
Nodal metastasis (Ib) | - | - | 2.636 | 2 | 0.268 | - | - | - |
Nodal metastasis (1 = N0, 0 = NIb*) | 1.384 | .855 | 2.622 | 1 | 0.105 | 3.992 | 0.747 | 21.325 |
Nodal metastasis (1 = NIa, 0 = NIb*) | 1.303 | 1.053 | 1.530 | 1 | 0.216 | 3.680 | 0.467 | 29.005 |
Constant | −0.015 | 1.230 | 0.000 | 1 | 0.991 | 0.986 | - | - |
Discussion
PTMC belongs to the low-risk well-differentiated PTC group of carcinomas, which are probably of little clinical significance and do not affect patient survival. However, PTMC may be associated with lymph node metastases at presentation and/or loco-regional recurrence during follow-up [
8]. Xing et al. investigated the relationship between BRAF
V600E mutation and PTC-related mortality in 1,849 patients. The overall mortality was 5.3% vs. 1.1% (mutant vs. wild,
P < 0.001). They showed the BRAF
V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC [
9]. In their study, it is uncertain that the BRAF
V600E mutation is correlated with poor prognostic factors in PTMC. In the currentstudy, we investigated the incidence of BRAF
V600E mutation and the clinicopathologic relationship between mutant and wild-type groupsofPTMC patients.
BRAF mutations are the most common genetic alterations in PTC. Thesemutations activate the RAS/RAF/mitogen-activated protein kinase pathway and result in the malignant transformation of cells. 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 [
10]. In Korea, the BRAF
V600E mutation has been reported to be present in about 60–80% of PTC, which is higher than what is reported in other countries [
4‐
7,
10]. In this study, the BRAF
V600E mutation was observed in 72 PTMC patients (71.3%). Guan et al. reported that the BRAF
V600E mutation was found in 69% of PTC cases in high iodine intake areas and 53% in normal iodine intake areas (
P < 0.0001) [
11]. The authors think that Koreans eat iodine-rich diet, which increases the prevalence of the BRAF
V600E mutation in PTC. Further study is needed to evaluate the association between BRAF
V600E mutation and the iodine-rich diet in the Korean population.
In our study, we did not find a significant relationship between BRAFV600E mutation and clinicopathologic characteristics such as older age, gender, Hashimoto thyroiditis, T staging, nodal metastasis, multifocality, extrathyroidal extension, and distant metastasis. Based on these results, it seems that the BRAFV600E mutation is not related to the prognostic factors for PTMC thatdetermine the invasiveness of the tumors.
Several studies have shown an association between the BRAF
V600E mutation and prognostic factors in PTC. Kebebewet al. reported the BRAF
V600E mutation was associated with older age (
P = 0.0381) [
6]. However, Kim et al.[
4] and Lee et al. [
12] revealed that age was not associated with the BRAF
V600E mutation. In our study, the prevalence of mutation in patients aged ≥ 45 years was higher than in wild-type patients (77.8% vs. 69%,
P = 0.353). However, there was no significant association in patients with old age. Kim et al. [
4] and Xu et al. [
13] showed the BRAF
V600E mutation was associated with male gender. We found a higherprevalence of mutation in the male gender (12.5% vs. 6.9%,
P = 0.413), althoughthis is not statistically significant due to the small number of male patients. Further, other reports showed no association between the BRAF
V600E mutation and male gender [
5‐
7,
12]. Lim et al. reported that the BRAF
V600E mutation was associated with extrathyroidal extension and multifocality [
14]. Kim et al. showed no significant relationship between the BRAF
V600E mutation and extrathyroidal extension and multifocality [
7]. Our results also showed no relationships (
P >0.05). However, in the study by Park et al.
, multifocality was associated with the BRAF
V600E mutation [
12]. Lim et al. reported a significant association between the BRAF
V600E mutation and Hashimoto thyroiditis [
14]. In this study, we could not find these significant associations. Several studies have reported that lymph node metastasis was significantly higher in patients withthe BRAF
V600E mutation [
4,
6,
12,
14]. In our result, lymph node metastasis had no significant association with the BRAF
V600E mutation (15.3% vs. 24.1%,
P = 0.226). Ahn et al. [
5] and Kim et al. [
7] also found that the lymph node metastasis did not differ significantly between patients with and without the BRAF
V600E mutation.
Against expectations, nodal metastasis and distant metastasis showed a slight negative association with BRAFv600E mutation. This result seems to be due to the small sample size andshort follow-up period time. Therefore, oncologic outcomes such as recurrence, metastasis, and survival rate could not be observed. Further, the higher incidence of BRAFV600E mutation in Korea may have had an effect on the study results. Future studies with larger patient groups are needed to evaluate the oncologic outcomes.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JCH organized all of the study. HSP, MKK, DKL, KDL, HSL, SWK and ENL participated in the study design and revised the manuscript. SYC drafted and wrote this manuscript. All authors read and approved the final manuscript.