A 42-year-old woman undergoes thyroidectomy for a 3 cm thyroid mass. Histology shows follicular-patterned cells with nuclear features including nuclear enlargement, oval nuclei, nuclear membrane irregularities ('nuclear grooves'), nuclear clearing ('Orphan Annie eyes'), and nuclear pseudo-inclusions. There is no capsular or vascular invasion. Molecular testing shows BRAF V600E mutation. What is the correct WHO (2022) diagnosis, and how does BRAF V600E alter clinical management compared to RAS-mutated follicular-patterned thyroid tumors?

• A Follicular thyroid carcinoma (FTC) — BRAF V600E is the defining mutation of follicular carcinoma; the absence of invasion is a criterion for minimally invasive FTC; managed with total thyroidectomy plus radioiodine ablation
• B Papillary thyroid carcinoma (PTC) with follicular variant — nuclear features of PTC (grooves, inclusions, clearing) define PTC regardless of architecture; BRAF V600E mutation confirms this; unlike RAS-mutated tumors (which are often NIFTP/low-risk), BRAF V600E-mutant PTC has higher rates of extrathyroidal extension, lymph node metastasis, and recurrence, justifying more aggressive surgical and RAI management ✓
• C Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) — since there is no invasion, and BRAF V600E can occur in NIFTP
• D Poorly differentiated thyroid carcinoma — BRAF V600E with a follicular growth pattern defines the Turin criteria for poorly differentiated carcinoma

Explanation

Nuclear features (Orphan Annie-eye nuclei, nuclear grooves, pseudo-inclusions) define the papillary thyroid carcinoma lineage regardless of architecture; a fully encapsulated follicular-patterned tumor with PTC nuclear features and no invasion would be classified as the follicular variant of PTC. Importantly, per WHO 2022, BRAF V600E mutation excludes NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) — NIFTP definition requires RAS-like mutations and absence of BRAF V600E/high-risk molecular alterations. BRAF V600E activates MAPK signaling more potently than RAS mutations, is associated with extrathyroidal extension, lymph node metastasis, and BRAF V600E also causes radioiodine resistance by downregulating NIS expression, influencing RAI-131 management decisions.

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

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Written and medically reviewed by the StethoPrep medical team.