Thyroid Pathology
Pathology · Endocrine · lean revision notes
Thyroid Pathology
The thyroid is one of the highest-yield organs in NEET PG pathology — a single gland that delivers questions on autoimmune thyroiditis, hyperthyroidism, and four morphologically distinct carcinomas. Master the histology buzzwords (Orphan Annie nuclei, psammoma bodies, Hürthle cells, amyloid) and the antibody profiles, and you secure several near-guaranteed marks.
Overview & approach
Thyroid disease is conveniently split into goitre/inflammation, functional disorders (hyper-/hypothyroidism), and neoplasms (benign vs malignant). Many entities straddle these — Graves disease is both an autoimmune and a hyperfunctional state, and Hashimoto thyroiditis can present as a goitre, hypothyroidism, and a lymphoma risk factor. Anchor your reasoning on three pillars: clinical function, antibody profile, and histology.
High-yield: When a stem gives a histology buzzword, jump straight to the diagnosis — Orphan Annie eye nuclei + psammoma bodies = papillary carcinoma; Hürthle cells + germinal centres = Hashimoto; amyloid stroma = medullary carcinoma.
Thyroiditis
Classification
| Type | Etiology | Key feature | Function |
|---|---|---|---|
| Hashimoto (chronic lymphocytic) | Autoimmune (anti-TPO, anti-Tg) | Hürthle cells, germinal centres | Hypothyroid |
| Subacute granulomatous (de Quervain) | Post-viral (Coxsackie, mumps) | Granulomas, painful gland, ↑ESR | Transient hyper → hypo → euthyroid |
| Subacute lymphocytic (painless/postpartum) | Autoimmune | Lymphocytic infiltrate, no Hürthle/fibrosis | Transient hyper → hypo |
| Riedel thyroiditis | IgG4-related fibrosis | Rock-hard, fibrosis extending beyond capsule | Hypothyroid; mimics carcinoma |
| Acute (suppurative) | Bacterial (Staph, Strep) | Neutrophilic abscess | Usually euthyroid |
Hashimoto thyroiditis
The commonest cause of hypothyroidism in iodine-sufficient areas, classically a middle-aged woman with painless diffuse goitre. Autoimmune destruction is CD8 T-cell mediated plus antibody-dependent cytotoxicity.
Histology: extensive mononuclear infiltrate with germinal (lymphoid) follicles, atrophic thyroid follicles lined by Hürthle (Askanazy) cells — large eosinophilic granular cytoplasm packed with mitochondria.
Antibodies: Anti-thyroid peroxidase (anti-TPO/anti-microsomal) is most sensitive and characteristic; anti-thyroglobulin also positive.
High-yield: Hashimoto is the strongest risk factor for primary thyroid lymphoma (B-cell, MALT type) and is also associated with papillary carcinoma. New rapid enlargement in a known Hashimoto patient = suspect lymphoma.
High-yield: Anti-TPO antibody is the single most useful serological marker of Hashimoto thyroiditis.
de Quervain (subacute granulomatous) thyroiditis
Follows a viral URTI; painful, tender gland with neck pain radiating to jaw/ear, fever, and a markedly raised ESR. Early release of preformed hormone causes transient thyrotoxicosis with low radioiodine uptake (distinguishes it from Graves). Histology shows granulomatous inflammation around damaged colloid with multinucleate giant cells. Self-limiting; treat with NSAIDs/paracetamol, steroids if severe.
Riedel thyroiditis
Part of the IgG4-related disease spectrum. Dense fibrosis replaces the gland and extends into adjacent strap muscles, producing a fixed, stony-hard mass that mimics anaplastic carcinoma. May coexist with retroperitoneal fibrosis and sclerosing cholangitis.
Graves disease
The commonest cause of endogenous hyperthyroidism. Autoimmune; an IgG anti-TSH-receptor antibody (TSI — thyroid-stimulating immunoglobulin) binds and chronically activates the TSH receptor.
Classic triad: hyperthyroidism with diffuse goitre + ophthalmopathy (exophthalmos) + pretibial myxoedema (dermopathy). Thyroid acropachy (clubbing) is a fourth, rarer sign.
Pathophysiology of eye signs: TSH-R antibodies stimulate orbital fibroblasts → glycosaminoglycan deposition + T-cell infiltration of extraocular muscles → proptosis, periorbital oedema, diplopia.
Histology: diffuse hypertrophy and hyperplasia — tall columnar follicular cells crowded into papillary infoldings, and "scalloped" colloid (peripheral reabsorption vacuoles) at the cell-colloid interface.
| Feature | Graves | Toxic multinodular goitre | de Quervain |
|---|---|---|---|
| Goitre | Diffuse | Nodular | Tender, firm |
| RAIU | Diffusely ↑ | Patchy ("hot" nodules) | ↓ (suppressed) |
| Antibody | TSI / anti-TSH-R | None specific | None |
| Eye/skin signs | Yes | No | No |
High-yield: Anti-TSH-receptor antibody (TSI) is pathognomonic of Graves. Radioiodine uptake is diffusely increased in Graves but low in subacute thyroiditis and factitious thyrotoxicosis.
Thyroid storm: life-threatening decompensation, often triggered by surgery/infection. Treat (sequence matters): β-blocker (propranolol) → propylthiouracil/carbimazole → iodine (Lugol's) given ≥1 hr after antithyroid drug → hydrocortisone.
Goitre & nodules
A goitre is thyroid enlargement. Diffuse non-toxic (simple/colloid) goitre results from iodine deficiency, goitrogens, or dyshormonogenesis, with compensatory TSH-driven hyperplasia, later evolving into multinodular goitre with areas of haemorrhage, fibrosis, calcification, and cystic change. Autonomous "hot" nodules can give toxic multinodular goitre (Plummer disease).
Approach to a solitary thyroid nodule (NEET-favourite flow): Clinical + TSH → if TSH low: radionuclide scan (hot nodule → rarely malignant) → if TSH normal/high: USG + FNAC → Bethesda category guides surgery.
High-yield: Features favouring malignancy in a nodule: solitary, cold on scan, young/elderly, male, fixed/hard, rapid growth, cervical lymphadenopathy, hoarseness, prior head-neck irradiation, microcalcifications on USG.
Bethesda system for FNAC reporting (cytology investigation of choice):
| Category | Interpretation | Malignancy risk |
|---|---|---|
| I | Non-diagnostic | — (repeat) |
| II | Benign | <3% |
| III | AUS/FLUS | ~10–30% |
| IV | Follicular neoplasm | 25–40% |
| V | Suspicious for malignancy | 50–75% |
| VI | Malignant | ~99% |
High-yield: FNAC cannot distinguish follicular adenoma from follicular carcinoma (Bethesda IV) — the difference is capsular/vascular invasion, seen only on histology after surgery.
Thyroid neoplasms
Follicular adenoma
Benign, solitary, well-encapsulated nodule of follicular cells; cold on scan. Key learning point: a complete intact capsule with no invasion distinguishes it from follicular carcinoma.
Papillary thyroid carcinoma (PTC)
Most common thyroid malignancy (~80%) and the one most associated with radiation exposure. Excellent prognosis; spreads via lymphatics to cervical nodes.
Diagnostic nuclear features (cytology > architecture):
- "Orphan Annie eye" nuclei — optically clear/empty, ground-glass nuclei
- Nuclear grooves and intranuclear cytoplasmic pseudoinclusions
- Psammoma bodies — concentric lamellated calcifications (represent infarcted papillae tips)
High-yield: Diagnosis of PTC rests on nuclear features, not papillae — even a purely follicular-patterned tumour with Orphan Annie nuclei is PTC (follicular variant). Psammoma bodies are a perennial NEET PG favourite and are highly suggestive of papillary carcinoma in the thyroid.
Molecular: BRAF V600E and RET/PTC rearrangements.
High-yield: Diagnosis is made on FNAC because the nuclear changes are cytological — PTC is the one major thyroid cancer reliably diagnosed by FNAC (follicular cannot be).
Follicular thyroid carcinoma (FTC)
Second commonest; commoner in iodine-deficient areas. Spreads haematogenously (lung, bone), not via lymphatics.
Diagnosis = capsular and/or vascular invasion on histology — uniform follicles, lacking PTC nuclear features. Minimally invasive (capsular only) vs widely invasive subtypes. RAS mutation and PAX8-PPARγ translocation typical.
High-yield: Follicular carcinoma metastasises to bone and lung by blood. Functioning bony metastases can take up radioiodine — basis for I-131 therapy and whole-body scanning.
Medullary thyroid carcinoma (MTC)
Arises from parafollicular C cells (neuroendocrine, neural-crest origin) → secretes calcitonin.
Histology: nests of polygonal/spindle cells in an amyloid stroma (amyloid = deposited calcitonin; Congo red positive, apple-green birefringence). Calcitonin is the tumour marker; CEA also rises.
Associations: ~70–80% sporadic; the rest familial as part of MEN 2A (MTC + phaeochromocytoma + parathyroid hyperplasia) and MEN 2B (MTC + phaeo + mucosal neuromas + marfanoid habitus). Driven by RET proto-oncogene germline mutations.
High-yield: Before thyroidectomy for MTC/MEN 2, rule out phaeochromocytoma first (measure metanephrines) — operating on an undiagnosed phaeo can precipitate fatal hypertensive crisis. MEN 2B carries the most aggressive MTC and warrants prophylactic thyroidectomy in infancy.
Anaplastic (undifferentiated) carcinoma
Rare but most aggressive/lethal thyroid cancer; elderly patients with a rapidly enlarging hard neck mass, hoarseness, dysphagia, stridor. Histology: highly pleomorphic, giant and spindle cells, brisk mitoses. Often arises from dedifferentiation of pre-existing well-differentiated carcinoma; p53 mutations common. Median survival is only months.
Comparison of thyroid carcinomas
| Feature | Papillary | Follicular | Medullary | Anaplastic |
|---|---|---|---|---|
| Cell of origin | Follicular | Follicular | C cells | Follicular |
| Frequency | ~80% | ~10% | ~5% | <5% |
| Spread | Lymphatic | Haematogenous | Both | Aggressive local + distant |
| Marker | Thyroglobulin | Thyroglobulin | Calcitonin/CEA | — |
| Buzzword | Orphan Annie nuclei, psammoma bodies | Capsular/vascular invasion | Amyloid stroma | Pleomorphic giant cells |
| Genetics | BRAF, RET/PTC | RAS, PAX8-PPARγ | RET (MEN 2) | TP53 |
| Prognosis | Excellent | Good | Intermediate | Dismal |
Diagnosis & investigations — quick map
- Function: TSH (best screening test) → free T4/T3.
- Autoimmune: anti-TPO (Hashimoto), TSI/anti-TSH-R (Graves).
- Anatomy/nodule: USG (microcalcifications, taller-than-wide, hypoechoic = suspicious) → FNAC (Bethesda) is the investigation of choice for a nodule.
- Function of a nodule: radionuclide (Tc-99m / I-123) scan — cold nodule needs FNAC.
- Tumour markers (follow-up): thyroglobulin after total thyroidectomy for differentiated cancers; calcitonin/CEA for MTC.
Management — drug & treatment of choice (pathology-relevant)
- Hypothyroidism (Hashimoto): lifelong levothyroxine.
- Graves: carbimazole/methimazole; propylthiouracil preferred in first trimester pregnancy and thyroid storm; definitive = radioiodine or surgery; propranolol for symptomatic control.
- de Quervain: NSAIDs/paracetamol ± steroids; β-blocker for symptoms.
- Differentiated carcinoma (PTC/FTC): total thyroidectomy ± radioactive iodine ablation, then TSH-suppressive levothyroxine; thyroglobulin monitoring.
- MTC: total thyroidectomy + central node dissection (does not take up radioiodine — C cells don't trap iodine).
- Anaplastic: palliative; airway protection; chemoradiation, generally incurable.
Complications & key differentials
- Hashimoto → hypothyroidism, MALT lymphoma, papillary carcinoma.
- Graves → thyroid storm, atrial fibrillation, osteoporosis, sight-threatening ophthalmopathy.
- Carcinoma → recurrent laryngeal nerve palsy (hoarseness), tracheal compression, distant metastasis; post-thyroidectomy hypoparathyroidism (hypocalcaemia) and RLN injury.
Key differential — the firm/hard neck mass: Riedel thyroiditis vs anaplastic carcinoma vs lymphoma. Age, rapidity, and biopsy distinguish them.
Lymphocytic-infiltrate differential: Hashimoto (Hürthle cells + germinal centres) vs painless thyroiditis (lymphocytes but no Hürthle cells/fibrosis).
Mnemonics & eponyms
- Psammoma bodies & Papillae → Papillary carcinoma (lots of Ps).
- Orphan Annie eye nuclei → empty, "orphaned" of chromatin → PTC.
- MEN 2 = "MTC + Pheo +" → 2A adds Parathyroid; 2B adds mucosal neuromas/Marfanoid (no parathyroid).
- Hürthle = Askanazy cells (eponym pair).
- de Quervain → painful, post-viral, Quietens with NSAIDs.
- Plummer disease = toxic multinodular goitre.
Recently asked / exam angle
- Psammoma bodies location: thyroid (PTC), ovary (serous), meningioma, mesothelioma, papillary RCC — "PSaMMoma."
- Histology image of Orphan Annie nuclei / nuclear grooves → identify PTC; "follicular variant of PTC diagnosed on nuclear features."
- Amyloid in thyroid stroma → medullary carcinoma; marker = calcitonin; Congo red apple-green birefringence.
- Capsular/vascular invasion as the sole criterion separating follicular adenoma from carcinoma — FNAC cannot tell them apart.
- Anti-TPO = Hashimoto; anti-TSH-R/TSI = Graves; low RAIU in subacute/factitious thyrotoxicosis vs high in Graves.
- MEN 2 association of MTC with RET mutation; rule out phaeochromocytoma before surgery.
- Most common thyroid cancer = papillary; most aggressive = anaplastic; spreads by blood = follicular.
- Hashimoto as risk factor for thyroid lymphoma.
Rapid revision
- Anti-TPO = Hashimoto; anti-TSH-receptor (TSI) = Graves.
- Hürthle/Askanazy cells + germinal centres = Hashimoto.
- Orphan Annie nuclei + psammoma bodies + nuclear grooves = papillary carcinoma.
- Papillary cancer diagnosed on nuclear features and reliably on FNAC; spreads via lymphatics.
- Follicular carcinoma = capsular/vascular invasion; spreads by blood to bone/lung.
- FNAC cannot separate follicular adenoma from carcinoma (Bethesda IV).
- Medullary carcinoma = C cells, amyloid stroma, calcitonin, RET/MEN 2.
- Rule out phaeochromocytoma before thyroidectomy in MEN 2.
- Anaplastic carcinoma = elderly, rapidly enlarging, pleomorphic giant cells, dismal prognosis.
- Graves: diffuse goitre + exophthalmos + pretibial myxoedema; RAIU diffusely high.
- de Quervain = painful gland, post-viral, raised ESR, low RAIU, giant-cell granulomas.
- Riedel thyroiditis = IgG4 stony-hard fibrosis; psammoma = PSaMMoma (Papillary, Serous ovary, Meningioma, Mesothelioma).