2015 HSC Section 1 Book of Articles

Reprinted by permission of Laryngoscope. 2014; 124(9):E389-E393.

The Laryngoscope V C 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 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.,

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

Rm. 3c120, Salt Lake City, UT 84132. E-mail: luke.buchmann@hsc.utah.edu

DOI: 10.1002/lary.24668

Givens et al.: BRAF V600E and Pediatric Thyroid Carcinoma

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