Integrating Molecular Testing in the Diagnosis and Management of Children with Thyroid Lesions

Pediatr Dev Pathol. 2016 Mar-Apr;19(2):94-100. doi: 10.2350/15-05-1638-OA.1. Epub 2015 Sep 14.

Abstract

Thyroid nodules occur in 1-2% of children, and identifying which nodules are malignant is often challenging. Cytologic evaluation facilitates the diagnosis of thyroid lesions (TLs), but in 10-40% of cases the interpretation is indeterminate. Patients with indeterminate diagnoses are often treated with hemithyroidectomy followed by completion thyroidectomy, if cancer is found in the initial specimen. Exposing patients to multiple surgeries increases costs and morbidity. The American Thyroid Association states that a combination of molecular markers is likely to optimize the management of patients with indeterminate cytology. However, few studies have addressed the molecular alterations present in pediatric TL. Twenty-seven thyroid carcinomas from patients 10 to 19 years of age were tested for alterations common in adult TL, including BRAF V600E mutation, RET fusions, and TERT promoter mutations. Mutation-negative cases were subsequently analyzed with a next-generation sequencing (NGS) mutation panel to search for additional targets. Histologic diagnoses included 12 classic papillary thyroid carcinomas (PTCs), 13 follicular variant PTCs, 1 medullary thyroid carcinoma, and 1 follicular carcinoma. Fourteen cases showed lymph node involvement, and 13 cases demonstrated lymphovascular invasion. The BRAF V600E mutation was detected in 10/27 cases, and RET fusions were detected in 6/27 cases. No TERT promoter mutations were identified in any of the cases. The NGS panel revealed additional RET and CTNNB1 pathogenic missense mutations. Our results demonstrate that molecular abnormalities are common in pediatric TLs and suggest that incorporation of molecular testing will be helpful in optimizing patient management.

Keywords: BRAF; RET- PTC; TERT; papillary thyroid carcinoma; pediatric thyroid carcinoma; thyroid carcinoma.

MeSH terms

  • Adolescent
  • Age Factors
  • Biomarkers, Tumor / genetics*
  • Biopsy
  • Carcinoma / genetics*
  • Carcinoma / secondary
  • Carcinoma / therapy
  • Child
  • DNA Mutational Analysis
  • Female
  • Gene Fusion*
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lymphatic Metastasis
  • Male
  • Molecular Diagnostic Techniques*
  • Mutation*
  • Neoplasm Invasiveness
  • Phenotype
  • Predictive Value of Tests
  • Prognosis
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-ret / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Factors
  • Telomerase / genetics
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / therapy
  • Thyroid Nodule / genetics*
  • Thyroid Nodule / pathology
  • Thyroid Nodule / therapy
  • Young Adult
  • beta Catenin

Substances

  • Biomarkers, Tumor
  • CTNNB1 protein, human
  • beta Catenin
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • TERT protein, human
  • Telomerase