Ann Surg Oncol (2024) 31:3495–3501

https://doi.org/10.1245/s10434-024-14935-4

ORIGINAL ARTICLE – TRANSLATIONAL RESEARCH

BRAF V600E Mutation Lacks Association with Poorer Clinical

Prognosis in Papillary Thyroid Carcinoma
Hon‑Fan Lai, MD1,2, Jen‑Fan Hang, MD2,3,4, Po‑Chung Kuo, MD1,2, Chin‑Sung Kuo, MD, PhD2,5,
San‑Fan Yao, MD2,6, Jui‑Yu Chen, MD, PhD1,2,7, and Chen‑Hsen Lee, MD1,2

1
Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; 2School
of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC; 3Department of Pathology and Laboratory
Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; 4Institute of Clinical Medicine, National Yang Ming
Chiao Tung University, Taipei, Taiwan, ROC; 5Division of Endocrinology and Metabolism, Department of Medicine,
Taipei Veterans General Hospital, Taipei, Taiwan, ROC; 6Department of Nuclear Medicine, Taipei Veterans General
Hospital, Taipei, Taiwan, ROC; 7Institute of Biology and Anatomy, National Defense Medical Center, Taipei,
Taiwan, ROC

ABSTRACT whereas there was no significant association with age, sex,

Background. Previous literatures showed wide range of lymph node metastasis, extrathyroidal extension, and multi-
prevalence of BRAF V600E in papillary thyroid carcinoma centricity. Kaplan–Meier curve showed similar disease-free
(PTC). The correlation of BRAF V600E mutation with survival rate between the two groups.
aggressive tumor characteristics and poor prognosis is con- Conclusions. Negative BRAF V600E tumors show more
troversial. The present study was designed to evaluate the aggressive behavior with a higher risk of developing distant
association between BRAF V600E mutation with clinico- metastasis in patients with PTC. The usefulness of BRAF in
pathological factors and tumor recurrence. predicting the prognosis of PTC remains questionable. Fur-
Patients and Methods. We performed a retrospective chart ther molecular analysis should be conducted for contribution
review of 672 patients who underwent thyroid surgery for to aggressive tumor phenotype.
PTC during 2013 and 2018. The prevalence of the BRAF
V600E mutation was studied. Its correlation with clinico- Keywords BRAF V600E mutation · Papillary thyroid
pathologic characteristics and aggressive features, including carcinoma · Thyroid cancer · Genetic analysis · Prognosis
macroscopic extrathyroidal extension, lymph node metas-
tasis, and distant metastasis, were analyzed with Fisher’s
exact test. Papillary thyroid carcinoma (PTC) represents the vast
Results. A total of 672 patients who underwent surgi- majority of thyroid malignant neoplasm, accounting for
cal treatment for PTC were included in this study with a 84–90% of all thyroid cancers.1,2 The behavior of PTC
mean age of 49.7 (± 13.2) years; 76.8% of the patients were is relatively indolent in that the 10-year survival rate can
detected with BRAF V600E mutation. Mean tumor size was reach more than 90% after adequate treatment. Neverthe-
1.30 (± 1.07) cm. A significant association was demonstrated less, postoperative recurrence or metastasis were observed
between negative BRAF V600E and larger primary tumor in which 10–20% of cancer recurrence rate was estimated
size, distant metastasis, and advanced staging (p < 0.05), over 10-year follow-up.3,4 Previous studies have investigated
the traditional histopathological risk factors, including sex,
age, tumor size, extrathyroidal extension, and lymph node
© Society of Surgical Oncology 2024
metastasis, for predicting the risk of disease recurrence and
First Received: 8 August 2023
mortality of PTC. On the basis of these factors, a three-tiered
Accepted: 31 December 2023
Published online: 1 February 2024 categorical risk stratification was established by the Ameri-
can Thyroid Association (ATA) for thyroid cancer treatment
J.-Y. Chen, MD, PhD guideline in 2009.5
e-mail: chenjy@vghtpe.gov.tw

Vol.:(0123456789)
3496 H.-F. Lai et al.

In recent decades, extensive research has explored molec- (TNM) staging system recommended by the 8th edition of
ular analysis as a diagnostic tool of thyroid cancer. PTC har- the American Joint Committee on Cancer (AJCC).
bors a number of genetic alterations involving the mitogen-
activated protein kinase (MAPK) pathway, including B-type BRAF Testing
Raf kinase (BRAF) mutation, RAS mutation, and RET/PTC
rearrangement. BRAF substitution mutation at codon 600 Polymerase reaction chain (PCR) and direct Sanger
(p.Val600Glu) resulting from T to A transversion in exon 15 sequencing for BRAF exon 15 was performed at our insti-
at nucleotide 1799 (c.T1799A) is the most frequent, com- tution before 2015 as previously described.17 A validated
posing 98% of BRAF mutations in PTC.6,7 Wide range of immunohistochemical assay using VE1 antibody (Spring
prevalence of BRAF V600E mutation was observed in about Bioscience, Pleasanton, CA, USA) on Leica Bond-Max
27.3–87.1% of all PTC.8 Previous studies have demonstrated autostainer (Leica Microsystems GmbH, Wetzlar, Ger-
that BRAF V600E mutation was associated with high-risk many) was applied at our institution after 2015 as previ-
clinicopathological features.9–11 However, other literatures ously described.17
showed conflicting evidence and no significant correlation
was found.12–15 In the latest 2015 ATA guidelines, it was Statistical Analysis
modified to a dynamic risk stratification system and BRAF
V600E mutation was incorporated in the context of other Statistical analyses were computed using Statistical Prod-
standard clinicopathological risk factors. Nevertheless, uct and Service Solutions (SPSS) version 24.0 (IBM Corp.,
BRAF mutational evaluation was not routinely recommended Armonk, NY). Results were reported as median (range) and
due to its unclear clinical implications.16 mean (standard deviation, SD). All categorical variables
Considering the controversial results of previous litera- were summarized as numbers and percentages and were
ture, further studies are needed to verify the role of BRAF compared using Fisher’s exact test. Disease-free survival
V600E mutation in risk stratification. In this study, we evalu- was estimated by the Kaplan–Meier method and the differ-
ated the prevalence and clinical relevance of BRAF V600E ence was evaluated using the log-rank test. Cox proportional
on patients surgically treated for PTC at a single institution. hazard model was applied to identify independent prognostic
factors for disease-free survival. All tests were two-sided,
and a p-value < 0.05 was considered statistically significant.
MATERIALS AND METHODS
RESULTS
Patients
Patient Demographics
This study was approved by the Institutional Review
Board (IRB) of the Taipei Veterans General Hospital (IRB- A total of 672 patients were included in this study, includ-
TPEVGH no. 2023-03-00AC). From November 2013 to ing 173 men (25.7%) and 499 women (74.3%). Among them,
April 2018, medical charts of patients who were surgically 516 patients (76.8%) were detected with BRAF V600E muta-
treated for PTC at Taipei Veterans General Hospital were tion. The mean age at diagnosis was 49.7 (± 13.2) years
retrospectively reviewed. Central compartment neck dissec- (median 50 years, range 11–87 years). The mean tumor size
tion was conducted when preoperative sonogram or intraop- was 1.30 (± 1.07) cm (median 1.00 cm, range 0.1–11.0 cm).
erative findings showed suspicious nodes. Modified radical Overall distant metastasis rate was 2.4% at presentation. The
neck dissection was performed with preoperative cytological median follow-up time was 70 months and recurrence rate
proof of lymph node metastasis. Patients’ baseline demo- was 8.2%. Table 1 presents the clinicopathological charac-
graphics and clinical features, BRAF status, and pathologi- teristics of the 672 patients in this cohort.
cal findings were reviewed. Status of distant metastasis was
established at presentation, including preoperative computer Correlation Between BRAF V600E Status
tomography (CT) scan, pathological report of the surgery and Clinicopathological Features
for distant metastasis before thyroidectomy, and whole body
scan with 131-radioiodine after thyroidectomy. Among 16 Various clinicopathological features were compared
patients who exhibited distant metastasis at presentation, 5 between patients with BRAF V600E mutation and those
patients had bone metastasis, while 6 had metastases in the without mutation. The results are presented in Table 1. No
lungs. In total, 3 patients underwent metastasectomy before statistical difference was noted between two groups for age
thyroid surgery and 13 patients had undergone radioactive and sex. Regarding extrathyroidal extension, multicentric-
iodine (RAI) therapy (≥ 100 mCi) after total thyroidectomy. ity, and positive surgical margin, the two groups showed
Tumors were staged according to the tumor, node, metastasis similar results. Classical PTC was significantly associated
BRAF V600E Mutation Lacks Association … 3497

TABLE 1  Clinicopathological Total, n (%) Positive, n (%) Negative, n (%) p-value

features of patients undergoing
thyroid surgery for papillary Total 672 516 (76.8) 156 (23.2)
thyroid carcinoma based on
Age, year 49.7 (± 13.2) [11–87] 0.572
BRAF V600E status
< 55 419 (62.4) 325 (63.0) 94 (60.3)
≥ 55 253 (37.6) 191 (37.0) 62 (39.7)
Sex 0.754
Male 173 (25.7) 131 (25.4) 42 (26.9)
Female 499 (74.3) 385 (74.6) 114 (73.1)
Subtype < 0.001
Classic 603 (89.7) 480 (93.0) 123 (78.8)
Tall cell 30 (4.5) 29 (5.6) 1 (0.6)
Follicular 34 (5.1) 7 (1.4) 27 (17.3)
Diffusing sclerosing 2 (0.3) 0 (0) 2 (1.3)
Cribriform-morular 3 (0.4) 0 (0) 3 (1.9)
Primary tumor size, cm 0.020
Mean (SD) 1.30 (± 1.07) [0.1–11.0] 1.232 (0.940) 1.513 (1.407)
Lymph node involvement 0.433
Negative 283 (42.1) 222 (43.0) 61 (39.1)
Positive 215 (32.0) 175 (33.9) 40 (25.6)
Extrathyroidal extension 0.571
Negative 536 (79.8) 414 (80.2) 122 (78.2)
Positive 136 (20.2) 102 (19.8) 34 (21.8)
Multicentricity 0.465
Negative 366 (54.5) 277 (53.7) 89 (57.1)
Positive 306 (45.5) 239 (46.3) 67 (42.9)
Surgical margin 0.627
Negative 666 512 (99.2) 154 (98.7)
Positive 6 4 (0.8) 2 (1.3)
Distant metastasis < 0.001
Negative 656 (97.6) 511 (99.0) 145 (92.9)
Positive 16 (2.4) 5 (1.0) 11 (7.1)
Stage 0.016
I + II 651 (96.9) 508 (98.4) 148 (94.9)
III + IV 21 (3.1) 8 (1.6) 8 (5.1)

Bold values indicate statistical significance with p < 0.05

with BRAF V600E mutation whereas follicular variant was undergone RAI therapy after total thyroidectomy. Therefore,
correlated to BRAF-negative tumors (p < 0.001). No signifi- 659 patients (672 patients excluding 13) were enrolled in
cant difference of lymph node metastasis was found between this analysis. With a median follow-up period of 70 months,
the two groups. Negative BRAF V600E tumors were sig- negative BRAF V600E group showed slightly decreased dis-
nificantly larger than the positive group (1.513 cm versus ease-free survival but no significant difference was found
1.232 cm, respectively, p = 0.020). Negative BRAF V600E (p = 0.924) (Fig. 1). We further assessed various risk fac-
patients exhibited more advanced stage (p = 0.016) and more tors affecting disease-free survival. In univariate analysis
distant metastasis (p < 0.001). as presented in Table 2, male sex, extrathyroidal extension,
tumor multicentricity, large tumor size, distant metastasis,
Risk Factors Affecting Recurrence positive surgical margin, and advanced staging were sig-
nificantly correlated with recurrent disease. Multivariate
We investigated whether BRAF V600E mutation affected regression analysis controlling the above factors demon-
disease-free survival. In our cohort, 16 patients exhibited strated that extrathyroidal extension (HR 1.933, 95% CI
distant metastasis at presentation, and 3 of them underwent 1.081–3.456, p = 0.026), tumor multicentricity (HR 3.317,
metastasectomy before thyroid surgery and 13 patients had 95% CI 1.802–6.105 p < 0.001), large tumor size (HR 1.426,
3498 H.-F. Lai et al.

FIG. 1  Kaplen–Meier curve p=0.924

for the disease-free survival of BRAF
1.0
patients with surgically treated BRAF V600E positive positive
papillary thyroid carcinoma negative
based on BRAF V600E mutation BRAF V600E negative
positive-censored
negative-censored
0.8

Disease-free Survival
0.6

0.4

0.2

0.0

0 20 40 60 80 100 120
Time (month)

TABLE 2  Univariate analysis for disease-free survival in patients TABLE 3  Multivariate Cox regression analysis for prognostic
with surgically treated PTC parameters associated with disease-free survival in patients with sur-
gically treated PTC
Prognostic factor Univariate analysis
Prognostic factor Multivariate analysis
Hazard ratio (95% CI) p-Value
Hazard ratio (95% CI) p-Value
BRAF V600E 0.968 (0.494–1.897) 0.924
Histology subgroup 0.734 (0.419–1.287) 0.281 BRAF V600E 0.870 (0.426–1.777) 0.702
Lymph node metastasis 1.333 (0.954–1.863) 0.092 Extrathyroidal extension 2.407 (1.296–4.471) 0.005
Extrathyroidal extension 3.780 (2.155–6.630) < 0.001 Tumor multicentricity 4.097 (2.072–8.102) < 0.001
Tumor multicentricity 3.981 (2.076–7.635) < 0.001 Tumor size 2.946 (1.607–5.400) < 0.001
Tumor size 4.207 (2.379–7.438) < 0.001 Male sex 1.608 (0.879–2.940) 0.123
Age 1.001 (0.560–1.789) 0.998 Distant metastasis 16.753 (2.179–128.809) 0.007
Male sex 1.799 (1.007–3.216) 0.047 Positive surgical margin 3.301 (0.723–15.070) 0.123
Distant metastasis 12.774 (3.090–52.806) < 0.001 AJCC stages III–IV 1.558 (0.421–5.767) 0.507
Positive surgical margin 10.073 (2.430–41.758) 0.001 Bold values indicate statistical significance with p < 0.05
AJCC stages III–IV 8.105 (3.203–20.512) < 0.001

male sex portend poorer prognosis. Regarding pathological

95% CI 1.207–1.684, p < 0.001), and distant metastasis at aspect, patients with large tumor size, lymph node metasta-
presentation (HR 16.753, 95% CI 2.179–128.809, p = 0.007) ses, extrathyroidal extension, extensive microscopic vascular
were independent predictors of recurrence (Table 3). invasion, and gross invasion into major neck structures dem-
onstrate high risks of recurrence.19,20 Recent developments
DISCUSSION in molecular analyses help improve our understanding on
the tumorigenesis of thyroid cancer. BRAF V600E mutation,
PTC is the most common form of thyroid cancer. Its which accounts for the majority of PTC, has been identified
tumor behavior is relatively inert and shows a more favora- as a prognostic indicator.9–11
ble outcome with almost 100% survival rate over a 5-year Wide range of positive BRAF prevalence was previously
course. However, up to 20% of patients experience relapse reported, accounting for 27.3–87.1% of all PTC. 8 In the
after initial treatment and require aggressive management.18 cohort analyzed from The Cancer Genome Atlas (TCGA), it
This raises concern about the identification of high-risk was observed that 59.7% of patients with PTC had a positive
groups for tumor recurrence and distant metastasis. Several BRAF V600E mutation.21 In our study, a higher proportion
conventional clinicopathological factors were well estab- of patients, specifically 76.8%, exhibited this mutation. Our
lished. Patient characteristics including advanced age and findings align with previous studies conducted by Rashid
BRAF V600E Mutation Lacks Association … 3499

et al. in East Asian countries, such as China, South Korea, BRAF V600E mutation harbors some high-risk features,
and Japan, which reported high rates of BRAF mutations including larger tumor size and advanced staging. To better
ranging from 70.6% to 75.5%.22 Our data are consistent with understand this discrepancy, it is important to consider the
this Asian series and other Taiwanese studies,23,24 indicat- inclusion of benign follicular neoplasm that was mistakenly
ing a geographical heterogeneity that could be influenced categorized as PTC prior to the implementation of the 2017
by genetic and dietary factors, contributing to the variation WHO classification. This misclassification could potentially
in mutation rates between Eastern and Western countries. contribute to the lower incidence of BRAF mutations and
Previous literatures in Asian countries have proposed high inaccurately portray the strong association between BRAF
iodine intake as a risk factor for the development in BRAF mutation and aggressive features.
mutation.25 Moreover, radiation exposure has been found In an analysis of 2948 patients with PTC, Yan et al. found
to be correlated to BRAF mutation in Japan.26 Nonetheless, BRAF V600E mutation was not associated with distant
iodine intake in Taiwan remains borderline adequate and no metastasis and disease persistence or recurrence.33 Henke
major radiation exposure event was recorded in Taiwanese et al. reported lack of relationship between the mutation
history.27 Increased occurrence of the BRAF V600E muta- and disease recurrence or disease-specific mortality. 34 A
tion in Taiwanese population cannot be ascribed to nutri- meta-analysis conducted by Vuong et al. showed that BRAF
tional or environmental factors. V600E mutation was not significantly associated with an
From a pathological perspective, the overdiagnosis of increased risk for distant metastasis.35 Although our patients
benign lesions as the follicular variant of PTC leads to a with mutated BRAF V600E consist of more high-risk his-
lower incidence of BRAF mutations in the Western world.28 tological subtype such as tall cell variant, BRAF V600E
It is worth noting that the follicular variant of PTC is com- status is not predictive of long-term outcome in PTC. No
monly associated with RAS driver mutations, which were significant association with disease recurrence was found.
found to occur relatively frequently in the TCGA cohort.21 Our results further suggest that negative BRAF V600E muta-
In contrast, Asian countries demonstrate a lower occurrence tions correlate with spread to distant sites. In addition, we
of RAS-mutated follicular variant PTCs.29 The 2017 WHO analyzed the correlation between clinicopathological fea-
classification introduced significant changes by reclassifying tures and disease-free survival. In multivariate analysis for
most noninvasive encapsulated follicular variant of PTC as increased risk of recurrence, larger tumor size, extrathyroi-
noninvasive follicular thyroid neoplasm with papillary-like dal extension, tumor multicentricity, and distant metasta-
nuclear features (NIFTP).30 By excluding these RAS-like sis at presentation were the strongest predictors. Most of
tumors from the diagnosis of PTC, the proportion of BRAF- the features are well established and included in the AJCC
positive tumors increased. Hang et al. reported a notable staging system and the risk stratification system in ATA
shift in the incidence of BRAF V600E mutation from 78.8 guideline.5 Nevertheless, BRAF V600E mutation lost sig-
to 86.8% following the implementation of the 2017 WHO nificance as an indicator of recurrent disease in our cohort.
classification.31 If these benign lesions that exhibit low The findings may justify that presence of BRAF V600E
BRAF mutation rates are mistakenly included in a study, it mutation does not always predict aggressive characteristics
might create a misleading conclusion of a strong correlation and poor prognosis. The incorporation of BRAF mutation
between BRAF mutations and aggressive behavior. status in management algorithm of centers with high BRAF
Early in 2003, Nikiforova et al. discovered the association prevalence is contentious. Further analysis of the correlation
of BRAF V600E mutation with older age, classic papillary between BRAF mutation and aggressive behavior should be
carcinoma or tall cell variant histology, extrathyroidal exten- conducted for clarification.
sion, and more frequent presentation at advanced stages.32 Our study yielded intriguing findings regarding the
In the following years, other studies demonstrated correla- negative BRAF V600E mutation group, which exhibited a
tion of BRAF V600E mutation with larger tumor size, lymph more aggressive tumor behavior compared with patients
node metastasis, and adjacent structures invasion. The BRAF with mutated BRAF V600E. Notably, this group displayed a
mutation frequency was relatively low, ranging from 33.2 to higher incidence of distant metastasis and advanced staging.
45.7% in these studies.9–11 However, other literatures showed Among the patients with distant metastasis, five individuals
contradictory findings, with no statistically significant cor- experienced bone metastasis, while six had metastases in
relation observed between BRAF V600E mutation and tumor the lungs. These findings raise important questions about
aggressiveness. Notably, a higher BRAF mutation frequency exploring alternative molecular pathways and their impact
with 70–76.5% was documented in these cohorts.13–15 The on the aggressiveness of negative BRAF V600E PTC.
result of the present study was consistent with the latter liter- In a cohort conducted by Lee et al., consisting of 525
atures. BRAF V600E mutation was not associated with older consecutive PTC cases, 12 out of 60 BRAF V600E negative
age, sex, extrathyroidal extension, multicentricity, or lymph cases demonstrated NTRK1/3 rearrangement.36 Furthermore,
node metastasis. Our study further showed that negative a recent study identified driver gene fusions as a prominent
3500 H.-F. Lai et al.

feature in the majority of patients with negative BRAF PTC, 5. Cooper DS, Doherty GM, Haugen BR, et al. American thyroid
with RET fusions being the most frequent finding, followed association guidelines taskforce. Management guidelines for
patients with thyroid nodules and differentiated thyroid cancer.
by NTRK fusions.31 A meta-analysis further supported these Thyroid. 2006;16(2):109–42.
findings by demonstrating a strong association between the 6. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene
presence of TERT promoter mutation, RAS mutations, and in human cancer. Nature. 2002;417(6892):949–54.
RET/PTC rearrangements and a significantly increased risk 7. Moretti S, Macchiarulo A, De Falco V, et al. Biochemical and
molecular characterization of the novel BRAF(V599Ins) muta-
for distant metastasis. Surprisingly, BRAF mutations showed tion detected in a classic papillary thyroid carcinoma. Oncogene.
no correlation with distant metastasis.35 2006;25(30):4235–40.
These insights emphasize the importance of conducting 8. Li C, Lee KC, Schneider EB, Zeiger MA. BRAF V600E mutation
additional genetic analyses in BRAF-negative patients to and its association with clinicopathological features of papil-
lary thyroid cancer: a meta-analysis. J Clin Endocrinol Metab.
identify potential molecular markers that may contribute to 2012;97(12):4559–70.
the poor prognosis of PTC. By exploring these alternative 9. Tufano RP, Teixeira GV, Bishop J, Carson KA, Xing M. BRAF
pathways, we can gain a deeper understanding of the under- mutation in papillary thyroid cancer and its value in tailoring ini-
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2012;91(5):274–86.
negative cases. 10. Xing M, Alzahrani AS, Carson KA, et al. Association between
The present study has some limitations. There is a selec- BRAF V600E mutation and mortality in patients with papillary
tion bias at our institution due to PCR sequencing not being thyroid cancer. JAMA. 2013;309:1493–501.
a routine service, but on the basis of physician’s preference, 11. Elisei R, Viola D, Torregrossa L, et al. The BRAF(V600E) muta-
tion is an independent, poor prognostic factor for the outcome of
before August 2015. This results in selection bias. Moreo- patients with low-risk intrathyroid papillary thyroid carcinoma:
ver, only BRAF V600E mutation was tested for this study single-institution results from a large cohort study. J Clin Endo-
but other mutations were not controlled. Lastly, it is ret- crinol Metab. 2012;97(12):4390–8.
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Head Neck Surg. 2013;139(11):1164–70.
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DISCLOSURES The authors declare that the research was con- Thyroid Association Guidelines Task Force on thyroid nodules
ducted in the absence of any commercial or financial relationships and differentiated thyroid cancer. Thyroid. 2016;26(1):1–133.
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