On thyroid biopsy, a tumor shows cells with ground-glass ('Orphan Annie eye') nuclei, nuclear grooves, pseudoinclusions, and psammoma bodies. The characteristic molecular alteration in this tumor type and its associated hereditary syndrome are:

• A PAX8-PPARγ translocation in follicular thyroid carcinoma
• B PTEN germline mutation in Cowden syndrome causing follicular thyroid carcinoma
• C RET/PTC rearrangement (sporadic) or RET germline mutation (familial MEN2A/B — but MTC, not PTC); BRAF V600E is the most common somatic mutation in papillary thyroid carcinoma ✓
• D TP53 mutation causing anaplastic transformation of differentiated thyroid carcinoma

Explanation

The described features are classic for papillary thyroid carcinoma (PTC). The most common somatic mutation in sporadic PTC is BRAF V600E (~60%), which constitutively activates the MAPK pathway. RET/PTC rearrangements occur in ~20% of sporadic and most radiation-induced PTCs. Germline RET mutations cause MEN2A/B-associated medullary thyroid carcinoma, not PTC. PAX8-PPARγ is characteristic of follicular thyroid carcinoma. PTEN mutation in Cowden also predisposes to follicular carcinoma. TP53 loss is a late event in anaplastic transformation.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.