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The Laryngoscope
VC 2014 The American Laryngological,
Rhinological and Otological Society, Inc.
BRAF V600E Does Not Predict Aggressive Features of Pediatric
Papillary Thyroid Carcinoma
Daniel J. Givens, MD; Luke O. Buchmann, MD; Archana M. Agarwal, MD; Johannes F. Grimmer, MD;
Jason P. Hunt, MD
Objectives/Hypothesis: This study aimed to review the prevalence of the BRAF V600E mutation in pediatric papillary
thyroid carcinoma (PTC) and any possible association with aggressive tumor behavior.
Study Design: A retrospective chart review and post hoc BRAF V600E mutational analysis of archived tumor tissue.
Methods: Patients 0 to 18 years old who underwent surgery for PTC from 1999 to 2012 were selected for a retrospec-
tive chart review to assess for aggressive disease characteristics. Microdissection was performed on archived tumor tissue,
which was analyzed for the BRAF V600E mutation by pyrosequencing.
Results: Archived tumor specimens were available for 19/27 pediatric patients who fit the inclusion criteria. Ages
ranged from 2.8 to 18 years (median, 13.7 years). Thirteen patients (68.4%) had central neck metastases, eight (42.1%) had
lateral neck metastases, and five (26.3%) had pulmonary metastases. The BRAF V600E mutation was present in seven
patients (36.8%). There were 11 patients with classic PTC, seven with a follicular variant of PTC, and one with an oncocytic
variant. Seven (63.6%) with classical PTC were BRAF V600E positive. All histologic variants were wild type. PTC histology
significantly correlated with the BRAF mutation (P 5.013). The BRAF mutation was associated with a lower metastases, age
at diagnosis, completeness of resection, invasion, and size of the tumor score, which trended toward significance (P 5.087).
Presence of lymphatic or pulmonary metastases, tumor size, overall age, lymphovascular invasion, or extrathyroidal extension
were not associated with BRAF V600E. Our results are combined with existing studies for a combined incidence of 28.4%.
Conclusions: BRAF V600E mutations may be more prevalent than previously thought in pediatric patients with PTC,
but do not correlate with aggressive disease characteristics.
Key Words: Papillary thyroid cancer, pediatric, BRAF V600E mutation.
Level of Evidence: 4.
Laryngoscope, 124:E389–E393, 2014
INTRODUCTION
Thyroid cancers comprise 0.5% to 3% of all child-
hood malignancies,1 and papillary thyroid cancer (PTC)
is the predominant histologic subtype.2 Children often
present at a more advanced disease stage than adults;
35% to 83% present with cervical lymphatic disease and
9% to 30% with pulmonary metastases.2 Potentially,
tumor markers could help identify patients at higher
risk for more aggressive disease and serve as a treat-
ment target, or could be used as a diagnostic adjunct to
help identify malignant disease on fine-needle aspiration
(FNA) biopsy.
B-type RAF kinase (BRAF) is a member of a family
of serine-threonine kinases that regulates intracellular
growth signals. 3 The T1799A/V600E mutation leads to
500-fold higher activation of this signaling pathway in
vitro than the wild-type protein.4 In vivo, the mutation
is thought to constitutively activate the pathway, leading
to malignant transformation. 3,5 BRAF V600E is the
most common gene mutation in PTC, with a prevalence
of 29% to 83% in adult PTC.6 Two recent meta-analyses
estimated its prevalence in classical PTC at 45% and
50.9% and found a significant association with several
aggressive disease characteristics.7,8 BRAF mutations
are not found in benign adenomas or follicular carcino-
mas, making it a highly specific marker for PTC.9
To our knowledge, only five series have examined
the frequency of BRAF in non–radiation-associated pedi-
atric PTC; these series have shown a 0% to 37% preva-
lence of BRAF mutations.7,10–13 Two of these studies
examined the relationship between BRAF status and
aggressive tumor behavior, and did not find a positive
correlation.11,14 The overall prevalence of the BRAF
mutation in the pediatric literature is variable, and cor-
relation with aggressive tumor characteristics remains
unclear. We aimed to review the prevalence of this
tumor marker in our pediatric population, and to
From the Division of Otolaryngology, Head & Neck Surgery (D .J.G .,
L.O.B., J.F.G., J.P.H.) and the Department of Pathology (A.M. A.), The Univer-
sity of Utah, Salt Lake City, Utah, U.S.A.
Editor’s Note: This Manuscript was accepted for publication
February 24, 2014.
Presented as a poster at the Triological Society Annual Meeting at
the Combined Otolaryngology Spring Meeting, Orlando, Florida, U.S.A.,
April 10–14, 2013.
This work was performed at The University of Utah Hospital,
Huntsman Cancer Hospital, Primary Children’s Medical Center, Salt
Lake City, Utah.
The authors have no funding, financial relationships, or conflicts
of interest to disclose.
Send correspondence to Luke Buchmann, MD, The University of
Utah Division of Otolaryngology, Head & Neck Surgery, 30 N. 1900 E.,
Rm. 3c120, Salt Lake City, UT 84132.
E-mail:
DOI: 10.1002/lary.24668
Laryngoscope 124: September 2014 Givens et al.: BRAF V600E and Pediatric Thyroid Carcinoma
Reprinted by permission of Laryngoscope. 2014; 124(9):E389-E393.
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