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

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

tall-cell variantsPTC Variant % Positive for BRAF

V600EConventional 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 may have utility in

advanced or aggressive tumors

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

Other emerging molecular markers• PAX8/PPAR gamma fusion

– 35% of follicular carcinomas• RAS mutations

– 10% of papillary thyroid carcinoma• Possible role in prognosis

– 45% of follicular carcinoma• RET/PTC gene re-arrangements

– Many types of fusion– 20% of papillary thyroid carcinoma– 35% of follicular carcinoma

• RET mutations– Sporadic– Germ-line

• Familial form of medullary thyroid carcinoma• Potential role for targeted therapies

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.– Potential role of therapy selection

• Advanced/aggressive tumors• Other emerging molecular markers with

diagnostic, prognostic, and therapeutic significance

Selected Resources

Nikiforov YE. Thyroid carcinoma: molecular pathways and therapeutic targets. Mod Pathol. 2008 May;21 Suppl 2:S37-43.

Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013 Mar;13(3):184-99

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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