Emerging Concepts in the Diagnosis and Work-up of Thyroid Cancer

1. Emerging Concepts in the Diagnosis and Work-up of Thyroid Cancer Short Presentation in Emerging Concepts (SPEC)

2. Thyroid Nodules • Found in 4-7% of U.S. adults • Approximately 5% are malignant. • Fine needle aspiration (FNA) mainstay of diagnosis • Bethesda system: • Six diagnostic categories • Correlate with risk of malignancy and recommended clinical management

3. Bethesda Diagnostic Categories(2009)

4. Papillary thyroid carcinoma (PTC) • Approximately 85% of thyroid cancers • Often (50-60%) harbor mutations in BRAF gene • Point mutation at codon 600 results in substitution of glutamate for valine (V600E) • Most common mutation in PTC • Mutation found more often in conventional and tall-cell variants

5. BRAF V600E mutation leads to constitutive activation of the mitogen activated protein kinase (MAPK) signaling pathway

6. Atypia of Undetermined Significance • 10-15% of fine needle aspirations (FNAs) • 5-15% risk of malignancy • Often referred for diagnostic thyroidectomy • Low but defined risk of complications

7. BRAF in diagnosis of PTC • BRAF V600E is VERY SPECIFIC (99.8%) for PTC. • BRAF mutation is very strong evidence of PTC • BRAF V600E is NOT SENSITIVE for PTC (49.5%) • Failure to detect a BRAF mutation does NOT rule out PTC. • Niche for BRAFtesting in cases with indeterminate cytology? • BRAFtesting can increase the ability of FNA biopsy to reach a diagnosis.

8. Studies evaluating BRAF in thyroid FNAs

9. BRAF and PTC prognosis • Numerous studies have found that PTC with mutated BRAF have more aggressive features • Extrathyroidal extension, regional metastasis, etc. • Even applies to small lesions (less than 1.0 cm) • However, excellent prognosis in general for PTC • Over 95% 10-year survival rate • Targeted therapy against BRAF unlikely to markedly improve survival

10. BRAF testing • Predominantly occurs via PCR • Assay should have the ability to detect the mutation in the background of normal cells seen in the cytology • Can be performed on: • Residual cytology sample in preservative solution after cytological examination • Formalin fixed paraffin embedded tissue blocks and slides

11. Conclusions • BRAF testing can aid in diagnosing papillary thyroid carcinoma from cytology samples • Particularly useful with indeterminate cytology • Identifies PTC with more aggressive features. • May help identify patients needing surgery. • No current role in therapy selection • Full prognostic significance still unknown

12. Selected Resources Melck AL, Yip L, Carty SE. The utility of BRAF testing in the management of papillary thyroid cancer. Oncologist. 2010;15:1285-1293. Nikiforova MN, Kimura ET, Gandhi M, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 2003;88:5399-5404

13. Additional Free Resource for CAP Members NOTE:  please remove this page before presenting. CAP Member Exclusive: CAP Pathology Resource Guides Focused on a specific hot-topic technology, these comprehensive guides highlights current resources, select journal articles, as well as CAP and non-CAP educational opportunities. And don’t miss the “Insights From Early Adopters” section in each guide to gain perspective from pioneering colleagues. AVAILABLE NOW: • Molecular Pathology (single gene test, small panel) • Genomic Analysis (large panel, exome, genome) Learn more: go to cap.org and type Pathology Resource Guides in the “search” field located at the top of your screen. “An outstanding overview of basic materials, including the technology and links to a number of individuals and centers that can assist.” “Extremely well done, of high practical and educational value.”