Specialty Guide · Path-iQ Global Pathology Review
Thyroid pathology encompasses the interpretation of fine needle aspiration cytology (reported by the Bethesda System), follicular-patterned lesion diagnosis, the recognition of papillary nuclear features, and the histological classification of thyroid malignancies from the indolent well-differentiated papillary carcinoma to the uniformly lethal anaplastic carcinoma. The 2023 Bethesda System (3rd edition) and 2022 WHO Classification of Endocrine and Neuroendocrine Tumours have introduced important reclassifications, notably the expanded use of NIFTP.
The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) provides a six-tier framework for thyroid FNA cytology that links cytological category to malignancy risk and clinical management. The 2023 3rd edition updated malignancy risk estimates to reflect reduced risk in most categories following widespread NIFTP recognition (NIFTP is non-malignant and should not be counted in malignancy rate calculations).
| Category | Name | Malignancy Risk (if NIFTP = benign) | Usual Management |
|---|---|---|---|
| I | Non-diagnostic / Unsatisfactory | 5–10% | Repeat FNA with ultrasound guidance; if persistently non-diagnostic → consider surgical excision |
| II | Benign | 0–3% | Clinical and radiological follow-up; repeat FNA if nodule grows or changes |
| III | Atypia of Undetermined Significance (AUS) / Follicular Lesion of Undetermined Significance (FLUS) | 10–30% | Molecular testing (ThyroSeq v3, Afirma GSC, ThyGenX/ThyraMIR); repeat FNA; or diagnostic lobectomy |
| IV | Follicular Neoplasm / Suspicious for Follicular Neoplasm (SFN) | 25–40% | Molecular testing or diagnostic lobectomy; BRAF/RAS testing may guide surgical extent |
| V | Suspicious for Malignancy | 50–75% | Near-total thyroidectomy or lobectomy depending on molecular/clinical risk; BRAF V600E in this category → near-total thyroidectomy |
| VI | Malignant | 97–99% | Near-total thyroidectomy; RAI ablation in intermediate/high-risk PTC; targeted therapy (dabrafenib+trametinib for BRAF V600E ATC; selpercatinib for RET-mutated MTC) |
NIFTP (Nikiforov et al., 2016) replaced the prior diagnosis of "non-invasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC)." It recognises that tumours with follicular architecture, papillary nuclear features, complete fibrous encapsulation, and no invasion have a near-zero recurrence risk and should not be called carcinoma. NIFTP is a borderline neoplasm, not a malignancy.
Diagnostic criteria for NIFTP (all must be met):
On FNA, NIFTP is most often categorised Bethesda III (AUS) or IV (follicular neoplasm) — it cannot be reliably distinguished from invasive FVPTC on cytology. This drives molecular testing use in the indeterminate FNA categories.
| Tumour | Frequency | Histology | Key Molecular Feature | Prognosis |
|---|---|---|---|---|
| Papillary thyroid carcinoma (PTC) — classical variant | ~85% of thyroid malignancies | Papillary and/or follicular architecture; papillary nuclear features (enlargement, grooving, pseudo-inclusions, chromatin clearing); psammoma bodies; fibrous stroma | BRAF V600E (~60%); RET/PTC rearrangements (~10–15%); NTRK fusions; TERT promoter mutations in high-risk PTC | Excellent — 10-year survival >95% for low-risk; TERT promoter + BRAF V600E = high-risk co-mutation with worse prognosis |
| PTC — follicular variant (FVPTC, invasive) | ~20% of PTC | Predominantly follicular architecture with papillary nuclear features; invasion (capsular or vascular) distinguishes from NIFTP | RAS mutations (~40%); BRAF V600E less common than classical PTC; PAX8-PPARγ fusions (some) | Excellent for encapsulated invasive; widely invasive FVPTC behaves like follicular carcinoma |
| PTC — tall cell variant | ~5–10% of PTC | Cells 2–3× taller than wide; abundant eosinophilic cytoplasm; prominent papillary architecture; requires ≥30% tall cells; often extrathyroidal extension | BRAF V600E in >90%; TERT promoter co-mutations more common; more aggressive behaviour | Worse than classical PTC; higher recurrence; BRAF inhibitor therapy (dabrafenib+trametinib) for radioiodine-refractory |
| Follicular thyroid carcinoma (FTC) | ~10% of thyroid malignancies | Follicular architecture; NO papillary nuclear features; capsular invasion (minimally invasive) and/or vascular invasion (widely invasive) — invasion determines malignancy | RAS mutations (~40–50%); PAX8-PPARγ fusions (~30%); TERT promoter mutations in widely invasive; no BRAF V600E | Minimally invasive (capsular only): excellent (>95% survival); angioinvasive (>4 vascular foci): poor; Hürthle cell carcinoma subtype = less RAI-avid, worse prognosis |
| Poorly differentiated thyroid carcinoma (PDTC) | ~2–3% | Turin criteria: solid/trabecular/insular growth + at least one of: convoluted nuclei, ≥3 mitoses/10HPF, coagulative necrosis; intermediate between DTC and ATC | RAS, BRAF, TERT promoter, TP53 mutations; loses HBME-1 and TTF-1 expression variably | Intermediate — 5-year survival ~50–70%; RAI-refractory; sorafenib/lenvatinib for systemic disease |
| Anaplastic thyroid carcinoma (ATC) | ~1–2% | Completely dedifferentiated; spindle cells, giant cells, epithelioid cells; necrosis; high mitotic rate; extensive extrathyroidal invasion; loses all thyroid markers | BRAF V600E (~25–45%); TERT promoter (>70%); TP53 (>70%); PIK3CA, PTEN, ATM mutations; ALK fusions (rare, targetable) | Lethal — median survival 3–6 months; dabrafenib+trametinib (BRAF V600E-mutated ATC): partial responses in ~70%, median PFS ~6 months; pembrolizumab combinations under investigation |
| Medullary thyroid carcinoma (MTC) | ~5% | C-cell origin; nests or sheets of polygonal to spindle cells; abundant granular cytoplasm; amyloid stroma (Congo red positive); neuroendocrine morphology | RET mutation: germline (MEN2A, MEN2B, FMTC — ~25% of MTC); somatic RET M918T (~40%); RAS mutations in RET-negative sporadic MTC | Depends on stage and RET mutation type; MEN2B (RET M918T): most aggressive; 10-year survival ~75% overall; selpercatinib, pralsetinib (RET kinase inhibitors) for advanced/metastatic |
| Marker | PTC | FTC / Hürthle | PDTC | ATC | MTC | Use |
|---|---|---|---|---|---|---|
| TTF-1 (NKX2-1) | + | + | +/− | − (usually) | + | Confirms thyroid origin; lost in ATC |
| Thyroglobulin (Tg) | + | + | +/− | − | − | Most specific for follicular cell origin; lost in ATC and MTC; used for serum monitoring post-thyroidectomy |
| PAX8 | + | + | +/− | +/− | + | Broad thyroid/renal/Müllerian marker; more sensitive than Tg in poorly differentiated tumours |
| Calcitonin | − | − | − | − | +++ (strong, diffuse) | Diagnostic for MTC; serum calcitonin elevated clinically; amyloid in stroma = Congo red birefringence |
| CEA | − | − | − | − | + (in most MTC) | Combined calcitonin + CEA IHC panel for MTC; serum CEA used for MTC surveillance |
| HBME-1 | + (apical/luminal membranous) | + (in carcinoma) | +/− | − | − | Helps distinguish carcinoma from adenoma in follicular lesions; not fully specific |
| CK19 | +++ (diffuse strong) | +/− | +/− | +/− | − | Supports PTC diagnosis; combined with HBME-1 and galectin-3 in "PTC marker panel" |
| Galectin-3 | + | + (carcinoma > adenoma) | + | + | − | Malignancy marker in thyroid; part of PTC/FTC panel; not specific alone |
| BRAF VE1 (IHC for BRAF V600E) | +++ in V600E-mutated PTC | − (BRAF V600E rare in FTC) | +/− | + (in BRAF V600E-mutated ATC) | − | Clone VE1; very high sensitivity/specificity for BRAF V600E; guides targeted therapy eligibility for ATC; positive result should be confirmed with molecular testing for treatment decisions |
| Ki-67 | Low (usually <5%) | Low–moderate | 5–30% | High (>30%, often >70%) | Low–moderate | Proliferation index; helps grade between DTC, PDTC, and ATC in equivocal cases |
For cytologically indeterminate thyroid nodules (Bethesda III and IV), two commercially available molecular tests are widely used in the US:
Creator of the NIFTP concept and co-developer of ThyroSeq molecular testing. World's foremost authority on thyroid molecular diagnostics, BRAF/RAS testing in thyroid FNA, and radiation-induced thyroid carcinoma. Lead investigator in NIFTP multi-institutional validation studies.
Doyen of American thyroid pathology; author of the definitive textbook Surgical Pathology of the Thyroid (Saunders). Decades of contributions to papillary carcinoma histological classification, Hashimoto's thyroiditis pathology, and thyroid tumour nomenclature debates.
Co-editor of WHO Classification of Endocrine and Neuroendocrine Tumours (5th edition, 2022). International authority on thyroid, pituitary, adrenal, and parathyroid tumour pathology. Pioneer in the molecular classification of neuroendocrine tumours across multiple organ systems.
Co-editor of WHO Endocrine Tumours 2022; expert on thyroid tumour classification, C-cell lesions, parathyroid pathology, and pituitary tumour transcription factor-based classification. Contributor to NIFTP validation and endocrine tumour WHO nomenclature reform.
Leading thyroid oncologist and collaborator with thyroid pathologists on targeted therapy trial design; investigator in RET inhibitor trials (selpercatinib LIBRETTO-531 for MTC) and BRAF-targeted therapy in ATC. Pathology-oncology integration model for thyroid cancer treatment.
One of the most influential surgical pathologists of the 20th century; author of Rosai and Ackerman's Surgical Pathology. His thyroid pathology contributions — particularly on papillary carcinoma nuclear features and hyalinising trabecular tumour classification — remain foundational references.