A 40-year-old woman with a 2 cm thyroid nodule undergoes FNA cytology showing nuclear grooves, nuclear inclusions (pseudo-inclusions), overlapping nuclei, and powdery chromatin with pale nuclear clearing. Molecular testing reveals a BRAF V600E mutation. According to the WHO 2022 classification of thyroid tumors, what is the most appropriate histological diagnosis after surgical resection, and why does BRAF V600E alone not establish the diagnosis of malignancy on FNA?

• A Follicular variant of papillary thyroid carcinoma (FVPTC) — BRAF V600E is pathognomonic for malignancy and the FNA is diagnostic; no resection needed if cytology is Bethesda VI
• B Hurthle cell carcinoma — BRAF V600E is the driving mutation in oxyphilic thyroid tumors, and nuclear inclusions confirm oncocytic differentiation
• C Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) — a low-risk neoplasm with PTC nuclear features but follicular architecture and NO invasive growth; BRAF V600E is exceedingly rare in NIFTP and its presence essentially excludes NIFTP, mandating reclassification as infiltrative/invasive PTC ✓
• D Medullary thyroid carcinoma — nuclear inclusions with pale chromatin are characteristic of parafollicular C-cell tumors and the BRAF mutation is a secondary event

Explanation

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) — introduced in WHO 2022 with updated criteria — is a low-risk neoplasm with follicular (not papillary) architecture and PTC-type nuclear features (grooves, overlapping, clearing), but without infiltrative growth, capsular invasion, vascular invasion, or papillary architecture. NIFTP carries near-zero risk of metastasis after complete excision. BRAF V600E mutation, however, is essentially incompatible with NIFTP — it is found in <1% of NIFTP and essentially defines a tumor as infiltrative/invasive PTC (conventional or follicular variant). On FNA, nuclear features alone (Bethesda V/VI cytology) cannot distinguish NIFTP from invasive FVPTC; architectural assessment (invasiveness) requires histological evaluation of the whole specimen. Hence BRAF V600E on molecular cytology would reclassify the FNA toward malignancy, and surgical resection with complete histological assessment is mandatory.

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

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Written and medically reviewed by the StethoPrep medical team.