Thyroid pathology explain

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Thyroid Pathology - Complete Overview

Source: Robbins, Cotran & Kumar Pathologic Basis of Disease

Anatomy & Normal Physiology

The thyroid gland consists of two lateral lobes connected by a thin isthmus, anterior to the larynx. It develops embryologically from pharyngeal epithelium descending from the foramen cecum at the base of the tongue - explaining ectopic thyroid tissue (lingual thyroid) seen occasionally. The gland is divided by fibrous septa into lobules, each containing 20-40 colloid-filled follicles lined by cuboidal to low columnar epithelium.

The diagram below shows the hypothalamic-pituitary-thyroid axis:

Hormone synthesis: TSH from the anterior pituitary binds the TSH receptor on follicular cells → activates Gs protein → raises cAMP → stimulates thyroid hormone synthesis. Follicular cells convert thyroglobulin into T4 (thyroxine) and T3 (triiodothyronine). In the periphery, T4 is deiodinated to T3, which binds thyroid hormone nuclear receptors with 10-fold greater affinity. Net effect: increased basal metabolic rate, carbohydrate/lipid catabolism, protein synthesis, and critical fetal brain development.

The gland also contains C cells (parafollicular cells) that secrete calcitonin, promoting calcium absorption into bone and inhibiting osteoclasts.

Classification of Thyroid Diseases

Hyperthyroidism (thyrotoxicosis)
Hypothyroidism
Thyroiditis
Goiter
Tumors (adenoma, carcinoma)

1. HYPERTHYROIDISM (Thyrotoxicosis)

A hypermetabolic state caused by elevated free T3/T4.

Major causes (in order of frequency):

Graves disease (~85% of cases)
Hyperfunctional multinodular goiter
Hyperfunctional thyroid adenoma
Iodine-induced hyperthyroidism
Subacute thyroiditis (transient release, not true hyperfunction)
TSH-secreting pituitary tumor (rare)

Clinical features:

Skin: warm, soft, flushed (vasodilation), heat intolerance, increased sweating
Cardiovascular: tachycardia, palpitations, cardiomegaly, atrial fibrillation (especially in elderly), congestive heart failure
Metabolic: weight loss despite increased appetite, muscle wasting
Neuromuscular: anxiety, irritability, fine tremor, hyperreflexia
GI: increased bowel motility, diarrhea
Eyes: exophthalmos (specific to Graves disease - see below)
Reproductive: oligomenorrhea, infertility

Graves Disease

The most common cause of hyperthyroidism. It is an autoimmune disorder caused by thyroid-stimulating immunoglobulins (TSI) - IgG antibodies that bind and activate the TSH receptor, mimicking TSH and causing unregulated thyroid hormone production.

Pathogenesis: Loss of T-regulatory cell tolerance → T helper cells sensitized to thyroid antigens → B cells produce anti-TSH receptor antibodies (TSI/TRAb).

Morphology:

Diffusely enlarged gland (2-3x normal)
Microscopically: tall, columnar follicular epithelium with papillary infoldings, reduced colloid with scalloped ("moth-eaten") edges
Lymphocytic infiltrates with germinal centers

Unique features of Graves (not seen in other causes):

Ophthalmopathy: exophthalmos due to inflammatory cell infiltration and glycosaminoglycan deposition in the retro-orbital space and extraocular muscles
Dermopathy (pretibial myxedema): skin thickening due to glycosaminoglycan accumulation - despite the name, this is a feature of Graves hyperthyroidism, not hypothyroidism

2. HYPOTHYROIDISM

Defined as deficiency of thyroid hormone.

Primary causes:

Category	Examples
Autoimmune	Hashimoto thyroiditis (most common in iodine-sufficient areas)
Iatrogenic	Surgery, radioiodine ablation, external radiation
Drug-induced	Lithium, amiodarone, methimazole, propylthiouracil
Iodine deficiency	Endemic (still common worldwide)
Congenital	PAX8, FOXE1 mutations; biosynthetic defects

Secondary ("central") hypothyroidism:

Pituitary failure (low TSH)
Hypothalamic failure (low TRH) - rare

Clinical features (adults - myxedema):

Generalized slowing of metabolic processes
Cold intolerance, weight gain, fatigue, lethargy
Constipation, dry coarse skin, hair loss
Periorbital puffiness, macroglossia, hoarse voice
Bradycardia, diastolic hypertension
Hyponatremia, hyperlipidemia
Myxedematous coma (life-threatening) in severe untreated cases

Congenital hypothyroidism (cretinism):

Due to iodine deficiency in endemic areas or genetic defects
Severe intellectual disability, short stature, coarse facial features, umbilical hernia
Now rare due to iodine supplementation and neonatal screening

3. THYROIDITIS

Hashimoto Thyroiditis

The most common cause of hypothyroidism in iodine-sufficient areas. Primarily affects middle-aged women.

Pathogenesis: T cell-mediated autoimmune destruction of follicular epithelium. Both CD8+ cytotoxic T cells (direct killing) and CD4+ T helper cells (inducing apoptosis via Fas-FasL) contribute. Anti-TPO (antithyroid peroxidase) and anti-thyroglobulin antibodies are present but are markers rather than primary effectors.

Morphology:

Symmetric thyroid enlargement
Dense lymphocytic infiltration with germinal centers
Oxyphilic (Hurthle/Askanazy) change - follicular cells acquire abundant granular eosinophilic cytoplasm
Follicle destruction and atrophy

Clinical features:

Painless thyroid enlargement - may mimic neoplasm
Gradual hypothyroidism (TSH rises as T4/T3 fall)
Initial transient thyrotoxicosis possible ("hashitoxicosis")
Associated autoimmune diseases: type 1 DM, adrenal autoimmunity, SLE, Sjogren, myasthenia gravis
Increased risk of extranodal marginal zone B-cell lymphoma (rare) and possibly papillary carcinoma

Subacute Granulomatous Thyroiditis (de Quervain Thyroiditis)

Triggered by viral infection (coxsackievirus, mumps, SARS-CoV-2, adenovirus). Peak age 40-50 years, F:M ~4:1.

Morphology: Disrupted follicles with foreign-body giant cells engulfing colloid → granulomas; replaced by fibrosis.

Clinical course (4 phases):

Thyrotoxic phase: Release of stored hormone → mild hyperthyroidism, neck pain, fever, elevated ESR
Euthyroid phase
Hypothyroid phase: Transient, as follicles are depleted
Recovery: Most return to normal thyroid function

Chronic Lymphocytic (Painless/Silent) Thyroiditis

Presumed autoimmune. Common in the postpartum period (up to 5% of women - "postpartum thyroiditis"). Anti-TPO antibodies present. Similar triphasic course to subacute, but without pain or granulomas. Up to 30% develop permanent hypothyroidism.

Riedel Thyroiditis

Rare; dense fibrous replacement of thyroid parenchyma, extending into surrounding structures. Associated with IgG4-related disease. Can mimic malignancy clinically.

4. GOITER

Enlargement of the thyroid, reflecting compensatory response to impaired hormone synthesis.

Diffuse Nontoxic (Simple) Goiter

Caused by iodine deficiency or goitrogens → low T4 → elevated TSH → gland hyperplasia.

Multinodular Goiter (MNG)

Results from repeated cycles of hyperplasia and involution → asymmetric growth → nodule formation. Microscopically: nodules of varying size, some colloid-rich, some with hemorrhage, cysts, or calcification.

Nontoxic MNG: Most common; euthyroid or hypothyroid
Toxic MNG (Plummer disease): One or more autonomous hyperfunctioning nodules (often due to activating TSH receptor mutations) → hyperthyroidism without ophthalmopathy

5. THYROID TUMORS

Thyroid Adenoma

Benign follicular neoplasm, encapsulated
Most are nonfunctioning ("cold" nodule on scan); rarely autonomous ("hot" / toxic)
Morphology: uniform follicular cells, intact capsule - NO capsular or vascular invasion
Fine-needle aspiration (FNA) cannot reliably distinguish follicular adenoma from follicular carcinoma

Malignant Tumors

Feature	Papillary Ca	Follicular Ca	Medullary Ca	Anaplastic Ca
Frequency	~85%	5-15%	5%	<5%
Origin	Follicular cells	Follicular cells	C cells	Follicular cells
Key molecular alteration	BRAF V600E, RET/PTC fusions	RAS mutations, PAX8-PPARG fusion	RET mutations (MEN2)	TP53, TERT promoter
Spread	Lymphatic (early)	Hematogenous	Lymphatic + hematogenous	Local invasion
Prognosis	Excellent (>95% 10-yr survival)	Good (minimally invasive) to poor (widely invasive)	Intermediate	Very poor (months)
Radioiodine responsive	Yes	Yes	No	No

Papillary Thyroid Carcinoma (PTC)

Most common thyroid malignancy. Can occur at any age; strongly associated with prior radiation exposure (especially childhood).

Molecular: BRAF V600E mutation (~60%), RET/PTC gene rearrangements.

Morphology:

Papillary fronds with fibrovascular cores
Characteristic nuclear features (pathognomonic):
- Optically clear ("Orphan Annie eye") nuclei
- Nuclear grooves and intranuclear pseudoinclusions
Psammoma bodies (laminated calcifications) - highly specific
Sclerotic stroma

Behavior:

Lymphatic spread to regional nodes is common but does not significantly worsen prognosis
5-20% local/regional recurrence; 10-15% distant metastases
Prognosis worsened by: age >55, extrathyroidal extension, distant metastases

Follicular Thyroid Carcinoma (FTC)

More common in iodine-deficient areas. Peak age 40-60 years.

Key diagnostic criterion: Capsular and/or vascular invasion on histology - cannot be diagnosed on FNA alone.

Morphology:

Uniform follicular cells forming follicles with colloid (resembles normal thyroid)
Oncocytic (Hurthle cell) variant: cells with abundant eosinophilic granular cytoplasm
No Orphan Annie nuclei, no psammoma bodies

Behavior: Spreads hematogenously (lung, bone, liver) rather than to lymph nodes.

Medullary Thyroid Carcinoma (MTC)

Arises from C cells (parafollicular cells) → secretes calcitonin (useful tumor marker).

Sporadic (70%): Usually unilateral, presents in adults
Familial (30%): Associated with MEN2A and MEN2B syndromes, RET proto-oncogene mutations (germline); often bilateral and multicentric
Morphology: polygonal to spindle cells in nests/sheets, amyloid deposits in stroma (derived from procalcitonin)
Lab: elevated serum calcitonin; CEA also elevated
Genetic testing for RET mutations is mandatory in all patients

Anaplastic (Undifferentiated) Thyroid Carcinoma

Highly aggressive. Usually in elderly patients, often arising from a pre-existing differentiated thyroid carcinoma (with TP53 or TERT promoter mutations driving dedifferentiation).

Rapid growth, infiltrates and compresses trachea/esophagus
Morphology: bizarre pleomorphic giant cells, spindle cells, wide necrosis
Mean survival: 6 months; does not take up radioiodine

Summary Table: Key Distinguishing Features

Condition	Key Lab Findings	Key Histology	Unique Clinical Feature
Graves disease	Low TSH, high T3/T4, +TRAb/TSI	Tall columnar cells, scalloped colloid	Exophthalmos, pretibial myxedema
Hashimoto	High TSH, low T4, +anti-TPO	Oxyphilic change, germinal centers	Most common hypothyroidism
De Quervain	Low TSH (early), high ESR	Granulomas, giant cells	Painful, post-viral
Papillary Ca	Normal or low TSH	Orphan Annie nuclei, psammoma bodies	Best prognosis; radiation-linked
Follicular Ca	-	Capsular/vascular invasion (no FNA diagnosis)	Hematogenous spread
Medullary Ca	High calcitonin	Amyloid stroma	RET mutation; MEN2
Anaplastic Ca	-	Bizarre giant cells, necrosis	Worst prognosis

Source: Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 24 - Endocrine Pathology

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