Emerging Concepts in the
Diagnosis and Work-up of
Thyroid Cancer
Short Presentation in Emerging Concepts
(SPEC)
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
Bethesda Diagnostic Categories
(2009)
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 tallcell variants
PTC Variant
% Positive for BRAF
V600E
Conventional PTC
60%
Tall-cell PTC
77%
Follicular variant PTC
12%
BRAF
V600E mutation leads to constitutive activation of the
mitogen activated protein kinase (MAPK) signaling pathway
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
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 BRAF testing in cases with
indeterminate cytology?
• BRAF testing can increase the ability of FNA
biopsy to reach a diagnosis.
Studies evaluating BRAF in thyroid
FNAs
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
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
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
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
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