Mutational Analysis in Pediatric Thyroid Cancer and Correlations with Age, Ethnicity, and Clinical Presentation

Abstract

Background: Well-differentiated thyroid cancer (WDTC) incidence in pediatrics is rising, most being papillary thyroid carcinoma (PTC). The objective of the study was to assess the prevalence of different mutations in pediatric WDTC and correlate the genotype with the clinical phenotype.Methods: This is a single-center retrospective study. Thyroid tissue blocks from 42 consecutive pediatric WDTC patients who underwent thyroidectomy between 2001 and 2013 were analyzed at Quest Diagnostics for BRAFV600E, RAS mutations (N,K,H), and RET/PTC and PAX8/PPARγ rearrangements, using validated molecular methods. Thyroid carcinomas included PTC, follicular thyroid carcinoma (FTC), and follicular variant of PTC (FVPTC).Results: Thirty-nine samples (29 females) were genotyped. The mean age at diagnosis was 14.7 years (range 7.9–18.4 years), and most were Hispanic (56.4%) or Caucasian (35.9%). The mean follow-up period was 2.9 years. Mutations were noted in 21/39 (53.8%), with both BRAFV600E (n = 9), and RET/PTC (n = 6) detected only in PTC. Mutations were detected in 2/5 FTC (PAX8/PPARγ and NRAS) and 3/6 FVPTC cases (PAX8/PPARγ). Of 28 PTC patients, 57.1% had mutations: 32.1% with BRAFV600E, 21.4% with RET/PTC, and 3.6% with NRAS. Of patients with BRAFV600E, 77.8% were Hispanic and 88.9% were >15 years, while all RET/PTC-positive patients were ≤15 years (p = 0.003). Tumor size, lymph node involvement, and distant metastasis at diagnosis (or soon after 131I ablation) did not vary significantly based on the mutation.Conclusions: BRAFV600E was the most common mutation, especially in older and Hispanic adolescents. A larger, ethnically diverse pediatric cohort followed long term will enable the genotypic variability, clinical presentation, and response to therapy to be better assessed.

AGK‐BRAF is associated with distant metastasis and younger age in pediatric papillary thyroid carcinoma

“…On the other hand, some of the most common genetic alterations of adult PTC are rare or absent in pediatric PTC, supporting the hypothesis that biological features of PTC may differ by patient age . For instance, BRAF V600E mutation represents the most prevalent event in PTC reported in adults (23–63%) but the prevalence is lower (3–48%) in pediatric PTC patients in most studies . BRAF fusion has rarely been reported in adult PTC, whereas it has been described in radiation‐exposed pediatric PTC .…”

“…Despite the vast number of studies conducted in adults, there is limited information regarding the prevalence and clinical significance of BRAF V600E in pediatric PTC. 13,14,20,22,[28][29][30][31][32][33][34][35]45,46 In fact, a significantly lower percentage of the pediatric cases (≤18 years old) had BRAF V600E mutation ( Table 2), suggesting that other less common or noncanonical mutation in BRAF gene could serve as surrogates for the BRAF V600E canonical mutation or even that BRAF is not essential for development pediatric PTC and diverse pathogenic mechanisms may be involved.…”

“…12,14,[22][23][24][25][26] For instance, BRAF V600E mutation represents the most prevalent event in PTC reported in adults (23-63%) but the prevalence is lower (3-48%) in pediatric PTC patients in most studies. 12,14,[27][28][29][30][31][32][33][34][35] BRAF fusion has rarely been reported in adult PTC, whereas it has been described in radiation-exposed pediatric PTC. 13,[36][37][38] The most prevalent BRAF fusions reported in radiation-exposed pediatric PTC are AKAP9-BRAF and AGK-BRAF.…”

miRNA expression can classify pediatric thyroid lesions and increases the diagnostic yield of mutation testing

“…Molecular testing to complement the cytopathological evaluation of indeterminate thyroid nodules is widely accepted for adult patients but remain limited in the pediatric population. We and others have previously shown that testing for oncogenic gene alterations can identify thyroid malignancy in children and adolescents with a very low false‐positive rate in benign tumors 6,13‐16 . The present study is the first to evaluate miRNA biomarkers in a set of representative benign and malignant lesions commonly found in the pediatric population.…”

Papillary Thyroid Carcinoma: A Malignant Tumor with Increased Antioxidant Defense Capacity

“…The most important aim in the clinical evaluation of patients with thyroid nodules is to discriminate thyroid cancer from benign nodules. Although this objective can be achieved with conventional diagnostic techniques including ultrasonography and fine needle aspiration biopsy (FNAB), in most patients, these diagnostic procedures cannot always provide reliable preoperative diagnosis (Nikita et al 2016). Various studies have examined the molecular pathology of PTC while striving to provide reliable and informative diagnostic and prognostic biomarkers.…”