Thyroid Neoplasms

Overview

Most primary tumours=follicular epithelium origin; few=C-cells. COMMONEST benign=FOLLICULAR ADENOMA. Malignant=less common overall; CARCINOMA dominant (lymphoma/sarcoma rare).

Follicular adenoma

COMMONEST benign thyroid tumour, adult women. Solitary nodule(~1% population) — must distinguish from NODULAR GOITRE dominant nodule + THYROID CARCINOMA. Mostly “cold nodule,” rarely mild hyperthyroid “hot nodule.” RARELY/NEVER malignant.

Morphology — 4 GROSS features distinguish from nodular goitre nodule: SOLITARY, COMPLETE encapsulation, distinct architecture inside/outside capsule, compression of surrounding parenchyma. Small(≤3cm), spherical; grey-white to red-brown, less colloidal, ±fibrous scarring/calcification/haemorrhage/cysts.

6 growth patterns (may coexist):

1. MICROFOLLICULAR(foetal) — small follicles, little/no colloid, loose stroma
2. NORMOFOLLICULAR(simple) — resembles normal thyroid
3. MACROFOLLICULAR(colloid) — large colloid-distended follicles
4. TRABECULAR(embryonal) — solid/trabecular, occasional abortive follicles
5. HÜRTHLE CELL(oxyphilic) — uncommon, large oxyphilic cells, minimal stroma, NO follicles
6. ATYPICAL adenoma — malignancy-suggestive features(pleomorphism/mitoses/atypia) but NO capsular/vascular invasion (= differentiator from follicular carcinoma)

Thyroid cancer — overview

~95% = carcinomas. Lymphoma(<5%)=mostly from autoimmune thyroiditis. Sarcoma=extremely rare. ~20% of metastatic-malignancy deaths have thyroid mets(melanoma>RCC>bronchogenic CA commonest sources). FEMALE preponderance(~2x), like most thyroid disease.

4 major types: PAPILLARY, FOLLICULAR, MEDULLARY, ANAPLASTIC.

Etiopathogenesis:

1. EXTERNAL RADIATION — SINGLE MOST important factor (childhood thymic/skin irradiation, atomic bomb survivors, nuclear accident vicinity). Esp. children/young adults→↑PAPILLARY risk later
2. Iodine excess+TSH — supplementation in endemic regions→↑papillary incidence. Many well-diff cancers express TSH receptors→respond to T4 suppression
3. Genetics — familial clustering esp. medullary. By type:
   • PAPILLARY: RET overexpression(chr10q, ~20%) — renders receptor susceptible to promoters like radiation; NTRK1 rearrangement(chr1q, 5-10%)
   • FOLLICULAR: RAS mutations(HRAS/NRAS/KRAS) ~50%; PAX-8/PPARγ-1 fusion(adenoma+carcinoma)
   • MEDULLARY: RET point mutation(familial MEN2+sporadic)
   • ANAPLASTIC: dedifferentiation of papillary/follicular, OR p53 mutation, OR β-catenin mutation

Papillary carcinoma — MOST COMMON (75-85%)

All ages(↑with age), ~3x females. Slow-growing, asymptomatic solitary nodule. Nodal spread COMMON, distant RARE. “LATERAL ABERRANT THYROID” = cervical node thyroid tissue = usually occult primary metastasis.

Morphology: Gross=microscopic-10cm, poorly delineated, grey-white/hard/scar-like, ±cystic(“papillary cystadenocarcinoma”). Micro:

1. PAPILLARY pattern — fibrovascular stalk+single cell layer, ±follicles
2. GROUND-GLASS/optically-clear NUCLEI (KEY identifying feature — highest clinical payoff given best prognosis)
3. Invasion — capsular+intrathyroidal lymphatic; vascular RARE
4. PSAMMOMA BODIES — concentric calcified spherules, ~half of cases

Prognosis: EXCELLENT, 10yr survival 80-95% (pure or mixed pattern).

Follicular carcinoma — 2nd commonest (10-20%)

Middle-old age, F:M 2.5:1. POSITIVE correlation with endemic goitre(unlike papillary); radiation role unclear. Solitary/irregular nodular. Slow(faster than papillary). Nodal spread RARE, DISTANT haematogenous(lung/bone) COMMON — sometimes presenting feature (OPPOSITE metastatic pattern from papillary — drives different surveillance strategy).

Morphology: Gross=solitary adenoma-like or overt irregular; grey-white ±haemorrhage/necrosis/cysts. Micro:

1. Follicular pattern — variable sizes, ±trabecular/solid, hyperchromatic nuclei, ±clear/Hürthle variants. LACKS papillae/ground-glass nuclei/psammoma bodies(vs papillary)
2. VASCULAR INVASION+direct extension = SIGNIFICANT diagnostic feature; lymphatic RARE

Prognosis: INTERMEDIATE, 10yr survival 50-70%.

Medullary carcinoma — from C-CELLS, ~5%

Equal M:F. 3 distinguishing features: familial occurrence, calcitonin/peptide secretion, amyloid stroma.

1. FAMILIAL — mostly sporadic, ~10% familial(RET point mutation, chr10q). Familial: pheochromocytoma+parathyroid adenoma(MEN2A) OR pheochromocytoma+mucosal neuromas(MEN2B) — DIAGNOSIS PROMPTS BROADER GENETIC WORKUP, not just thyroid management. Sporadic=older(5th-6th decade), unilateral. Familial=younger(2nd-3rd decade), bilateral/multicentric
2. Secretes CALCITONIN(hypocalcaemic)+prostaglandins/histaminase/somatostatin/VIP/ACTH→carcinoid syndrome/Cushing’s/diarrhoea
3. AMYLOID STROMA — Congo red+, from altered calcitonin prohormone

Morphology: Gross=unilateral solitary(sporadic) or bilateral/multicentric(familial); firm, grey-white/yellow-brown. Micro:

1. ORGANOID pattern — nests+fibrovascular septa (like other neuroendocrine tumours), uniform C-cell characteristics
2. Amyloid stroma — calcitonin immunostain+, ±irregular calcification WITHOUT psammoma-body-style lamination
3. C-CELL HYPERPLASIA = precursor in FAMILIAL only (not sporadic)

Slow-growing, nodal spread occurs, distant infrequent. Prognosis: familial > sporadic. 10yr survival 60-70%.

Anaplastic (undifferentiated) carcinoma

<5% but ONE OF MOST MALIGNANT human tumours. Old age(7th-8th decade), F:M 1.5:1. Widely aggressive, rapid — dyspnoea/dysphagia/hoarseness from adjacent invasion + rapidly-growing neck mass. Mets to nodes+lungs.

Morphology: Gross=large, irregular, invades strap muscles; white firm, ±necrosis/haemorrhage. Micro=too poorly differentiated for other categories, ±residual papillary/follicular areas. 3 cell types(variant named by predominant type):

1. SMALL CELL — packed, hyperchromatic, mitoses. Resembles LYMPHOMA
2. SPINDLE CELL — sarcoma-resembling, ±osteosarcoma/chondrosarcoma/rhabdomyosarcoma areas
3. GIANT CELL — highly anaplastic, atypical mitoses, bizarre/lobed nuclei

Prognosis: DISMAL, 5yr survival <10%, median survival ~2 MONTHS.

Comparison table

Clinical relevance

Regional-vs-distant metastasis pattern = single most useful discriminator (papillary=nodal not distant; follicular=OPPOSITE) — drives different surveillance strategies for the 2 commonest types. Ground-glass nuclei+psammoma bodies = highest-payoff histologic ID (commonest type + best prognosis). Medullary’s MEN2A/2B link = diagnosis prompts BROADER genetic workup (pheochromocytoma+parathyroid/mucosal neuroma screening), not just local management. Anaplastic’s dismal 2-month median survival despite only 5% frequency = starkest illustration that differentiation status determines outcome more than almost anything else — contrast directly against papillary’s 80-95% survival.

Overview

Most primary thyroid tumours arise from follicular epithelium; a few from parafollicular C-cells. The commonest benign tumour is follicular adenoma; malignant tumours are less common overall, with carcinoma the dominant malignant type (lymphomas and sarcomas are rare).

Follicular Adenoma

The commonest benign thyroid tumour, more frequent in adult women. Presents clinically as a solitary nodule (found in ~1% of the population) — must be distinguished from the other two causes of a clinically apparent solitary thyroid nodule: a dominant nodule of nodular goitre and thyroid carcinoma. Most adenomas cause no clinical problem and behave as a “cold nodule”; rarely they cause mild hyperthyroidism and appear as a “hot nodule” on RAIU. Rarely, if ever, becomes malignant.

Morphology — four gross features distinguish it from a nodular-goitre nodule: solitary, complete encapsulation, clearly distinct architecture inside vs outside the capsule, and compression of surrounding parenchyma. Usually small (≤3 cm), spherical; cut surface grey-white to red-brown, less colloidal than surrounding tissue, ± degenerative fibrous scarring, calcification, haemorrhage, cyst formation.

Histologic growth patterns (more than one may coexist in a single tumour):

1. Microfollicular (foetal) — small follicles, little/no colloid, abundant loose stroma.
2. Normofollicular (simple) — closely packed follicles resembling normal thyroid.
3. Macrofollicular (colloid) — large, variably-sized, colloid-distended follicles.
4. Trabecular (embryonal) — closely packed solid/trabecular epithelial pattern, occasional abortive follicles, resembling embryonal thyroid.
5. Hürthle cell (oxyphilic) — uncommon; solid trabeculae of large cells with abundant granular oxyphilic cytoplasm, vesicular nuclei, minimal stroma, no follicle formation.
6. Atypical adenoma — pronounced cellular proliferation with malignancy-suggestive features (pleomorphism, increased mitoses, nuclear atypia) but no capsular/vascular invasion — the feature distinguishing it from follicular carcinoma.

Thyroid Cancer — Overview

~95% of primary thyroid cancers are carcinomas; primary lymphomas (<5%) mostly evolve from autoimmune (lymphocytic) thyroiditis; sarcomas are extremely rare. ~20% of patients dying with metastasising malignancy have thyroid metastatic deposits — most commonly from malignant melanoma, renal cell carcinoma, bronchogenic carcinoma. Like most thyroid disease, carcinoma has a female preponderance (roughly 2× more common in women).

Four major morphologic types with distinct clinical behaviour: papillary, follicular, medullary, anaplastic (undifferentiated) carcinoma.

Etiopathogenesis:

1. External radiation — the single most important environmental risk factor, especially after high-dose exposure years earlier: evidence from thymic/skin-disorder childhood irradiation, Japanese atomic bomb survivors, and nuclear-accident-vicinity populations. Radiation exposure in children/young adults particularly raises later papillary carcinoma risk.
2. Iodine excess and TSH — dietary iodine supplementation in endemic-goitre regions has raised papillary cancer incidence; many well-differentiated cancers express TSH receptors and respond to T4-mediated TSH suppression.
3. Genetic basis — familial clustering, especially in medullary carcinoma. Distinct mutations by histologic type:
   • Papillary: RET gene overexpression (chromosome 10q, ~20% of cases) — renders the tyrosine kinase receptor susceptible to tumour-promoting factors like radiation; NTRK1 gene rearrangement (chromosome 1q, 5–10% of cases).
   • Follicular: RAS family mutations (HRAS, NRAS, KRAS) in ~50% of cases; PAX-8/PPARγ-1 fusion-translocation in a proportion of both follicular adenomas and carcinomas.
   • Medullary: RET-protooncogene point mutation, in both familial (MEN2) and sporadic cases.
   • Anaplastic: arises from dedifferentiation of papillary/follicular carcinoma, or from p53 inactivating mutation, or β-catenin pathway mutation.

Papillary Thyroid Carcinoma

The most common thyroid carcinoma type (75–85%). Occurs at all ages including children/young adults, incidence rising with age; ~3× more common in females.

Slow-growing, typically an asymptomatic solitary nodule. Regional lymph node involvement is common; distant metastases are rare. Some cases first present with cervical lymphadenopathy. “Lateral aberrant thyroid” — thyroid tissue found in a lateral cervical node — usually represents well-differentiated metastasis from an occult primary.

Morphology: Gross — microscopic foci to 10 cm nodules, generally poorly delineated; grey-white, hard, scar-like cut surface; sometimes cystic with papillae projecting in (“papillary cystadenocarcinoma”). Micro:

1. Papillary pattern — fibrovascular-stalk papillae covered by a single tumour cell layer, often admixed with follicles.
2. Tumour cells — characteristic ground-glass/optically-clear nuclei (dispersed chromatin) with clear/oxyphilic cytoplasm; may also form follicles and solid sheets.
3. Invasion — capsular and intrathyroidal lymphatic invasion; blood vessel invasion is rare.
4. Psammoma bodies — small, concentric, calcified spherules in the stroma, seen in ~half of cases.

Prognosis: excellent — 10-year survival 80–95%, regardless of pure papillary vs mixed papillary-follicular pattern.

Follicular Thyroid Carcinoma

The second commonest type (10–20%). Middle-to-old age, female preponderance (2.5:1). Unlike papillary carcinoma, has a positive correlation with endemic goitre; role of external radiation is unclear.

Presents as a solitary nodule or irregular firm nodular enlargement; slow-growing (though faster than papillary). Regional node metastases are rare, but distant haematogenous metastases (lungs, bones) are common — sometimes the presenting feature.

Morphology: Gross — solitary adenoma-like circumscribed nodule, or overt irregular cancerous enlargement; grey-white cut surface with haemorrhage/necrosis/cysts, ± adjacent structure extension. Micro:

1. Follicular pattern — variable follicle sizes, ± trabecular/solid pattern; hyperchromatic nuclei; clear/oxyphilic (Hürthle) variants exist. Lacks papillae, ground-glass nuclei, and psammoma bodies — the features distinguishing it from papillary carcinoma.
2. Vascular invasion and direct extension — significant diagnostic features (into the capsule); lymphatic invasion is rare.

Prognosis: intermediate between papillary and anaplastic — 10-year survival 50–70%.

Medullary Thyroid Carcinoma

Derived from parafollicular (C) cells; ~5% of thyroid carcinomas; equal male/female incidence. Three distinguishing features: familial occurrence, calcitonin/peptide secretion, amyloid stroma.

1. Familial occurrence — most cases sporadic, but ~10% familial with RET-protooncogene point mutation (chromosome 10q). Familial form associates with pheochromocytoma + parathyroid adenoma (MEN 2A) or pheochromocytoma + multiple mucosal neuromas (MEN 2B). Sporadic cases: middle/old age (5th–6th decades), usually unilateral. Familial cases: younger (2nd–3rd decades), usually bilateral/multicentric.
2. Calcitonin/peptide secretion — hypocalcaemic hormone calcitonin, plus prostaglandins, histaminase, somatostatin, VIP, ACTH — producing clinical syndromes (carcinoid syndrome, Cushing’s syndrome, diarrhoea).
3. Amyloid stroma — Congo red-positive amyloid representing stored/altered calcitonin prohormone from neoplastic C-cells.

Most present as a solitary nodule; sometimes an enlarged cervical node is the first sign.

Morphology: Gross — unilateral solitary nodule (sporadic) or bilateral/multicentric (familial); firm-to-hard, grey-white to yellow-brown, ± haemorrhage/necrosis. Micro:

1. Organoid pattern — nests of tumour cells separated by fibrovascular septa (like other neuroendocrine tumours — carcinoid, islet cell tumour, paraganglioma); alternative patterns include sheets, ribbons, pseudopapillae, small follicles; uniform cells with C-cell characteristics, occasionally spindle-shaped.
2. Amyloid stroma — from altered calcitonin (calcitonin immunostain-demonstrable); similar staining to systemic amyloidosis; ± irregular calcification (without the regular lamination of psammoma bodies).
3. C-cell hyperplasia — a precursor lesion in familial cases (not sporadic).

Slow-growing; regional node metastases occur, distant metastases are infrequent. Prognosis better in familial than sporadic form: overall 10-year survival 60–70%.

Anaplastic (Undifferentiated) Carcinoma

<5% of thyroid cancers, but one of the most malignant human tumours. Old age (7th–8th decades), slight female preponderance (1.5:1). Widely aggressive, rapidly growing — presents with extensive adjacent soft tissue/trachea/oesophagus invasion (dyspnoea, dysphagia, hoarseness) alongside a rapidly-growing neck mass. Metastasises to regional nodes and distant organs (lungs).

Morphology: Gross — large, irregular, invades adjacent strap muscles/structures; white, firm cut surface with necrosis/haemorrhage. Micro: too poorly differentiated for other categorisation, though better-differentiated areas may show residual papillary/follicular components. Three cell types, in varying proportions, each defining a variant when predominant:

1. Small cell carcinoma — closely packed small cells, hyperchromatic nuclei, numerous mitoses; closely resembles lymphoma.
2. Spindle cell carcinoma — sarcoma-resembling spindle cells; some show obvious sarcomatous elements (osteosarcoma, chondrosarcoma, rhabdomyosarcoma areas).
3. Giant cell carcinoma — highly anaplastic giant cells, numerous atypical mitoses, bizarre/lobed nuclei, some spindled.

Prognosis: dismal — 5-year survival <10%, median survival ~2 months after diagnosis.

Comparison of Thyroid Carcinoma Types

Clinical Relevance

• The regional-vs-distant metastasis pattern is the single most clinically useful discriminator among the differentiated carcinomas: papillary spreads to nodes but rarely distantly, while follicular does the reverse (rare nodal spread, common haematogenous spread to lung/bone) — this drives completely different surveillance strategies for the two most common thyroid cancers.
• Ground-glass nuclei and psammoma bodies are worth prioritising as the two histologic findings that most reliably identify papillary carcinoma, given it’s both the commonest type and the one with by far the best prognosis (80–95% ten-year survival) — recognising it correctly has the highest clinical payoff.
• Medullary carcinoma’s MEN 2A/2B associations make it the type most directly tied to a broader genetic workup obligation — a diagnosis of medullary carcinoma should prompt screening for pheochromocytoma and parathyroid/mucosal-neuroma involvement, not just local thyroid management.
• Anaplastic carcinoma’s dismal prognosis (median survival ~2 months) despite representing only ~5% of thyroid cancers is a stark illustration of how differentiation status, more than almost any other single factor, determines thyroid cancer outcome — worth contrasting directly against papillary carcinoma’s near-90% survival to make the point vivid.

• Four-way comparison table of papillary/follicular/medullary/anaplastic carcinoma by frequency, metastatic pattern, and 10-year survival
• Papillary carcinoma’s ground-glass nuclei and psammoma bodies shown as labelled histology diagrams
• MEN 2A vs MEN 2B component diagram, both built around medullary thyroid carcinoma + pheochromocytoma

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