A 42-year-old woman has a 1.8 cm thyroid nodule. Fine-needle aspiration is classified as Bethesda VI (malignant). Histology post-thyroidectomy shows follicular architecture with ground-glass ('Orphan Annie eye') nuclei, nuclear grooves, and nuclear pseudoinclusions, without vascular or capsular invasion. Molecular testing of this tumor would most likely reveal:

• A RAS point mutation (NRAS Q61R)
• B PAX8-PPARG fusion
• C RET/PTC rearrangement (RET-NCOA4 fusion)
• D BRAF V600E point mutation ✓

Explanation

The described morphology — follicular architecture with ground-glass/Orphan Annie eye nuclei, nuclear grooves, and pseudoinclusions, without invasion — represents noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), formerly classified as the encapsulated follicular variant of papillary thyroid carcinoma. BRAF V600E is strongly associated with classical papillary thyroid carcinoma and, importantly, is virtually absent from NIFTP/encapsulated follicular variant; its detection would exclude NIFTP and diagnose conventional PTC. However, the described features in a malignant FNA (Bethesda VI suggesting unequivocal malignant features such as frank papillary architecture or psammoma bodies on FNA) and the nuclear features described are most consistent with classical PTC where BRAF V600E is present in ~60%. RAS mutations are characteristic of NIFTP and follicular carcinoma; RET/PTC fusions occur in ~20% of classical PTC.

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

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Written and medically reviewed by the StethoPrep medical team.