Emerging Concepts in the
Diagnosis and Work-up of
Thyroid Cancer
APMG Pathologist, MD FCAP
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
tall-cell 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
Questions?
• Contact pathologist with questions or
to request testing on a patient:
APMG Pathologist, MD FCAP
tlpath@domain.com
(888) 555-1212