Thyroid Pathology

Dr. Mulenga B
2024
Introduction to the Thyroid Gland
 Location: Situated in the neck, adjacent to the larynx.

 Structure: Comprised of hormone-producing follicular epithelial cells

organized into follicles.
Thyroid

Location Normal Histology

Thyroid Hormones Overview
 Primary Hormones: Thyroxine (T4) and Triiodothyronine (T3).

 Role in Metabolism: Regulate the body’s metabolic rate, affecting

carbohydrate and lipid catabolism and protein synthesis.
Thyroid Hormone Synthesis, storage and
release
 Initiation: Triggered by Thyroid-Stimulating Hormone (TSH) from the
pituitary gland.
 TSH Action: Binds to G-protein-coupled receptors on thyroid follicular
cells, initiating synthesis and release of T4 and T3.
 Colloid as Storage Site: Thyroid hormones are stored in the glandular
lumen as colloid, bound to proteins like thyroglobulin.
 Hormone Release: Upon stimulation, T4 and T3 are released into the
bloodstream.
Circulation, Conversion and Activation of
Thyroid Hormones
 Binding Proteins: They circulate in blood bound to plasma proteins,
aiding in their transport.
 Peripheral Conversion: Most circulating T4 is converted to the more
active form, T3, in peripheral tissues.
 T3 Functionality: T3 enters cells and binds to nuclear thyroid
hormone receptors.
Mechanism of Action
 Receptor Binding: T3 binds to nuclear receptors, initiating
transcription of target genes.
 Metabolic Effects: Results in increased basal metabolic rate,
carbohydrate and lipid catabolism, and protein synthesis.
Effects of Thyroid Hormones on Metabolism
 Carbohydrates and Lipids: Enhanced catabolism to provide energy.

 Proteins: Increased synthesis for cellular growth and repair.

Clinical Significance of Thyroid Hormones
 Importance in Physiology: Essential for growth, development, and
energy metabolism.
 Thyroid Dysfunction: Impacts overall metabolic rate and can lead to
disorders such as hyperthyroidism and hypothyroidism.
Clinical Syndromes of Thyroid
Dysfunction
Introduction to Thyroid Dysfunction
 Thyroid dysfunction is divided into:
o Hyperthyroidism (thyrotoxicosis): Increased production of thyroid hormones,
leading to heightened metabolic activity.
o Primary or secondary

o Hypothyroidism: Decreased production of thyroid hormones, resulting in

lowered metabolic activity.
o Primary or Secondary
Definition of Hyperthyroidism
 Hyperthyroidism: Increased activity of the thyroid gland, leading to
excess T3 and T4 production.
 Thyrotoxicosis: Clinical syndrome caused by elevated thyroid
hormone levels, regardless of origin.

• Hyperthyroidism usually refers to thyroid gland abnormalities.

Common Causes of Hyperthyroidism
1. Graves Disease: An autoimmune disorder causing diffuse thyroid
hyperplasia (~85% of hyperthyroidism cases).

2. Hyperfunctioning Multinodular Goiter: So-called “toxic” goiter.

3. Hyperfunctioning Adenoma: Toxic adenoma that secretes excess

thyroid hormones.
Clinical Manifestations of Hyperthyroidism
 Systemic: Warm skin, heat intolerance, sweating, weight loss.

 Gastrointestinal: Increased motility leading to malabsorption, diarrhea.

 Cardiac: Tachycardia, palpitations.

 Neuromuscular: Tremors, irritability, muscle weakness (thyroid

myopathy).
 Ocular: Staring gaze, lid lag; proptosis in Graves disease.
Thyroid Storm
 Definition: Acute, severe exacerbation of hyperthyroid symptoms,
often triggered by stress (e.g., infection, surgery).
 Mechanism: Elevated catecholamines synergize with thyroid
hormones, causing life-threatening manifestations.
 Management: Emergency treatment to stabilize hormone levels and
manage symptoms.
Diagnosis of Hyperthyroidism
 TSH Levels: Primary screening test; typically low in hyperthyroidism.

 T4 Levels: Typically elevated.

 Radioactive Iodine Uptake: Assists in identifying underlying causes.

Definition of Hypothyroidism
 Hypothyroidism: Clinical syndrome resulting from insufficient thyroid
hormones.
 Main causes:
1. Dietary iodine deficiency (common in lower-income regions).

2. Autoimmune thyroid disease (e.g., Hashimoto thyroiditis).

3. Congenital defects.

4. Iatrogenic causes (e.g., post-surgical or post-radiation damage).

Clinical Manifestations of Hypothyroidism
 Symptoms vary by age:
o Infancy and Early Childhood (Cretinism): Intellectual disability, short stature,
coarse facial features.
o Older Children & Adults (Myxedema): Fatigue, apathy, sluggishness, cold
intolerance, non-pitting edema, coarse skin, and hair.
Cretinism
 Definition: Hypothyroidism in infancy or early childhood, often due
to iodine deficiency or genetic abnormalities such at trisomy 21.
 Characteristics: Impaired skeletal and nervous system development,
intellectual disability, short stature, coarse facial features.
 Prevalence: Endemic in iodine-deficient areas (e.g., Himalayas,
Andes).
Myxedema
 Definition: Adult hypothyroidism with characteristic clinical
presentation.
 Symptoms:
o Reduced basal metabolic rate, fatigue, and apathy.

o Cool skin, bradycardia, and reduced cardiac output.

o Accumulation of extracellular matrix proteins, leading to non-pitting edema,

enlarged tongue, and coarse skin.
Diagnosis of Hypothyroidism
 TSH Levels: Primary screening tool; often elevated in hypothyroidism.

 T4 Levels: Typically reduced.

 Additional Tests: Thyroid antibodies (e.g., anti-TPO) to confirm

autoimmune etiology (e.g., Hashimoto thyroiditis).
Summary
 Thyroid dysfunction presents as hyperthyroidism or hypothyroidism,
each with distinct causes, clinical manifestations, and diagnostic
markers.
 Hyperthyroidism: Elevated T3/T4, low TSH, symptomatic of an
overactive thyroid.
 Hypothyroidism: Low T3/T4, high TSH, resulting in reduced
metabolism and characteristic myxedema in adults.
Discussion and Questions
 What are the primary causes of hyperthyroidism and
hypothyroidism?
 Clinical significance of TSH and T4 levels in diagnosis.
Autoimmune Thyroid Diseases
Introduction to Autoimmune Thyroid Diseases
 Autoimmune thyroid diseases (AITD) are among the most common
autoimmune disorders.
 Two Major Types:
o Hashimoto's Thyroiditis: Leads to hypothyroidism.

o Graves' Disease: Leads to hyperthyroidism.

 Both result from immune reactions targeting thyroid antigens but

have distinct mechanisms and outcomes.
Hashimoto's Thyroiditis Overview
 Also Known As: Chronic lymphocytic thyroiditis

 Predominant Effect: Destructive inflammation leading to

hypothyroidism
 Pathogenesis: Primarily T-cell mediated, with antibodies present but
not directly pathogenic
 Prevalence: Common in middle-aged women, with a female-to-male
ratio of 10:1 to 20:1
Pathogenesis of Hashimoto's Thyroiditis
 Genetic Predisposition: Evidence of high concordance in identical
twins and associations with immune-regulatory gene
polymorphisms.
 Immune Mechanism:
o CD8+ cytotoxic T cells directly destroy thyroid epithelial cells.

o CD4+ T cells release cytokines, causing inflammation and damage to follicles.

o Autoantibodies against thyroid antigens (e.g., thyroglobulin, TSH receptor)

are detectable.
Morphology of Hashimoto's Thyroiditis
 Thyroid Gland Appearance:
o Diffuse enlargement of the gland.

o Dense mononuclear cell infiltrates: Lymphocytes, plasma cells, and germinal

centers.
o Follicular atrophy with some cells undergoing Hurthle cell transformation (large,
eosinophilic).

 Histological Hallmarks: Atrophic follicles, germinal centers, Hurthle

cells.
Morphology of Hashimoto's Thyroiditis

Gross appearance Microscopy

Clinical Features of Hashimoto's Thyroiditis
 Common Symptoms:
o Painless, diffuse enlargement of the thyroid (goiter).

o Gradual progression to hypothyroidism.

 Transient Hyperthyroidism:
o Early in the disease, injured follicular cells may release stored hormones, causing a
temporary hyperthyroid phase.

 Risk of Complications:
o Increased risk of B-cell lymphoma in the affected thyroid.
Graves' Disease Overview
 Primary Feature: Excessive stimulation of thyroid cells leading to
hyperthyroidism
 Pathogenesis: Caused by autoantibodies stimulating the TSH
receptor
 Demographics: Primarily affects women aged 20–40, with higher
prevalence in females
Pathogenesis of Graves' Disease
 Mechanism:
o Autoantibodies, especially against the TSH receptor, mimic TSH effects.

o Continuous stimulation of thyroid cells due to lack of feedback control on

these autoantibodies.

 Key Feature: Unregulated, excessive production of thyroid hormones.

 Exophthalmos (proptosis): Immune-mediated inflammation in retro-

orbital space due to T-cell infiltration.
Morphology of Graves' Disease
 Thyroid Gland Changes:
o Diffuse hypertrophy and hyperplasia of follicular cells.

o Follicular cells appear columnar and are arranged in papillary folds.

o Lymphoid infiltrates present, though less prominent than in Hashimoto's.

 Ophthalmopathy:
o Edema and accumulation of extracellular matrix in retro-orbital tissues.

o T-cell infiltration around the eye.

Light Microscopic appearance of thyroid in
Grave’s disease
Clinical Features of Graves' Disease
 Symptoms of Hyperthyroidism:
o Weight loss, increased metabolism, heat intolerance, palpitations.

o Exophthalmos (bulging eyes), specific to Graves' disease.

 Other Physical Findings:

o Thyroid bruit due to increased blood flow.

o Pretibial myxedema (localized thickening of skin, less common).

Grave’s disease symptoms Grave’s exopthalmopathy
Comparison of Hashimoto's Thyroiditis and
Graves' Disease
Feature Hashimoto's Thyroiditis Graves' Disease

Primary Mechanism T-cell-mediated destruction Autoantibody-mediated stimulation

Thyroid Function Hypothyroidism Hyperthyroidism

Thyroid Gland Enlarged, dense lymphocytic infiltrates Enlarged, hypertrophic follicles

Unique Symptoms Increased risk of B-cell lymphoma Exophthalmos, pretibial myxedema

Diagnosis and Management
 Hashimoto's Thyroiditis:
o Lab: Elevated TSH, low T3/T4, presence of anti-thyroid antibodies (anti-TPO).

o Treatment: Thyroid hormone replacement.

 Graves' Disease:
o Lab: Suppressed TSH, elevated T3/T4, TSH receptor antibodies.

o Treatment: Antithyroid drugs, radioactive iodine, surgery (in some cases).

Questions and Discussion
o How does Graves disease differ from Hashimoto thyroiditis in terms
of thyroid function and pathology?
Other Forms of Inflammatory
Thyroid Disease
Overview
 Overview of less common types of thyroiditis

 Key forms discussed:

o Subacute Granulomatous Thyroiditis (de Quervain)

o Subacute Lymphocytic Thyroiditis

o Riedel Thyroiditis
Subacute Granulomatous Thyroiditis (de
Quervain)
 Definition: A self-limiting thyroiditis, potentially viral in origin

 Demographics: Common in ages 30–50, predominantly affecting

women
 Clinical Presentation:
o Acute onset with neck pain, fever, and thyroid enlargement

o May cause transient hyperthyroidism

 Prognosis: Typically resolves in 6–8 weeks

Histopathology of Subacute Granulomatous
Thyroiditis
 Microscopic Features:
o Disrupted thyroid follicles

o Presence of inflammatory infiltrates

 Diagnostic Imaging: (Reference Supplementary Fig. 16.3 if available

for visuals)
 Key Note: This form of thyroiditis is transient and self-limiting
Subacute Lymphocytic Thyroiditis
 Definition: Often follows pregnancy and may have autoimmune etiology

 Demographics: Primarily seen in women

 Clinical Presentation:
o Painless neck mass

o Symptoms of hyperthyroidism

o Initial phase of thyrotoxicosis, followed by return to euthyroid state within months

Histopathology of Subacute Lymphocytic
Thyroiditis
 Microscopic Features:
o Lymphocytic infiltrates with germinal centers in the thyroid gland

o Absence of prominent Hurthle cell change (distinct from Hashimoto

thyroiditis)

 Clinical Course:
o Typically, the condition is self-resolving with restoration of normal thyroid
function
Riedel Thyroiditis
 Definition: Chronic fibrosing thyroiditis leading to replacement of the thyroid
gland with dense fibrosis
 Characteristics:
o Presents as a firm, hard mass in the neck

o May be part of a systemic condition called IgG4-related disease

 IgG4-Related Disease:
o Associated with fibrosis in multiple organs

o Elevated serum IgG4 levels, though the pathogenic role is unclear

Histopathology of Riedel Thyroiditis
 Microscopic Features:
o Extensive fibrosis replacing normal thyroid tissue

o Involvement can extend to nearby neck structures, complicating resection

 Clinical Implications:
o Often requires differential diagnosis from malignancy due to mass-like
presentation
Summary
 Subacute Granulomatous Thyroiditis: Acute, viral-associated, self-
limiting
 Subacute Lymphocytic Thyroiditis: Autoimmune, postpartum, self-
resolving thyrotoxicosis
 Riedel Thyroiditis: Rare, fibrosing, associated with IgG4-related
systemic disease
Discussion Questions
1. How do you differentiate between Hashimoto thyroiditis and
subacute lymphocytic thyroiditis histologically?
Goiter
Definition of Goiter
 Goiter: Enlargement of the thyroid gland.

 Cause: Impaired synthesis of thyroid hormone, leading to increased

TSH and follicular epithelial cell hyperplasia.
Pathogenesis of Goiter
 Key Mechanism: Defective synthesis of T3 and T4 due to various
factors.
 Negative Feedback Failure: Sustained TSH production drives the
proliferation of thyroid follicular cells.
 Types of Goiter:
o Endemic

o Sporadic
Endemic Goiter
 Cause: Dietary iodine deficiency.

 Prevalence: Found in regions with insufficient dietary iodine.

 Current Trends: Decrease in incidence due to iodine

supplementation.
Sporadic Goiter
 Most Common in: Women, particularly during puberty and early
adulthood.
 Possible Causes:
o Dietary factors (e.g., high calcium intake, cruciferous vegetables like cabbage
and cauliflower)
o Inherited defects in thyroid hormone synthesis enzymes.
Clinical Features of Goiter
 Typical Presentation: Neck mass.

 Complications from Enlargement:

o Airway obstruction

o Dysphagia (difficulty swallowing)

o Vascular compromise

• Multinodular Goiters: Usually silent but may cause thyrotoxicosis in

some cases.
Toxic Multinodular Goiter
 Definition: Development of autonomous nodules that produce
thyroid hormones independent of TSH.
 Distinguishing Features: Lacks the ophthalmopathy and dermopathy
associated with Graves' disease.
 Prevalence: ~10% of multinodular goiters over 10 years.
Risk of Malignancy in Goiter
 General Risk: Low (<5%) but increases with sudden changes in size or
symptoms of compression (e.g., hoarseness).
Morphology of Goiter
 Initial Stage – Diffuse Goiter:
o TSH-induced proliferation results in a diffusely enlarged gland.

 Progression – Multinodular Goiter:

 Cycles of proliferation and involution lead to an irregular, enlarged gland
Morphology of Goiter

Clinically appearance Light Microscopy

Summary and Key Points
 Goiter Types: Endemic vs. Sporadic

 Clinical Impact: Ranges from asymptomatic to compressive

symptoms and potential for thyrotoxicosis.
 Morphological Changes: Diffuse goiter can evolve into multinodular
goiter over time.
Discussion Questions
 What factors lead to the development of a multinodular goiter?

 Why is iodine deficiency linked to goiter formation?

 How can goiter be distinguished clinically from other thyroid

pathologies?
Tumors of the Thyroid Gland
Overview of Thyroid Nodules
 Key Points:
o Majority are benign (adenomas or dominant goiter nodules).

o Only about 1% of thyroid nodules are carcinomas.

o Diagnostic importance of distinguishing benign from malignant.

o Diagnostic tools: Fine-needle aspiration (FNA) and pathologic study of biopsy.

Indicators of Malignancy in Thyroid Nodules
 Clinical Characteristics Increasing Malignancy Probability:
o Solitary nodule.

o Patient age <20 or >70 years.

o History of radiation exposure.

o Cold nodule on radioactive iodine imaging.

o Ultrasonographic evidence of extrathyroidal extension or enlarged cervical

lymph nodes.
Thyroid Adenomas
 Definition:
o Benign, usually solitary tumors from follicular epithelium.

o Mostly nonfunctional; a minority cause hyperthyroidism (toxic adenomas).

 Pathogenesis:
o Approximately 50% have gain-of-function mutations in TSH receptor pathway.

o Some exhibit mutations in RAS or similar genes, shared with follicular thyroid
carcinomas.
Morphology of Thyroid Adenomas
 Characteristics:
o Solitary lesion composed of colloid-filled follicles.

o Uniform epithelial cells surrounded by a capsule.

o Occasional cellular atypia, but malignancy requires capsular invasion.

o Follicular adenomas are generally not carcinoma precursors.

Gross appearance of thyroid adenoma
Light microscopy of thyroid adenoma
Clinical Features of Thyroid Adenomas
 Presentation:
o Painless nodule, often detected during routine physical examination.

o Toxic adenomas produce thyroid hormones, causing hyperthyroidism.

• Diagnosis: Radioactive iodine scanning; “cold” nodules (non-

functional) vs. “hot” nodules (toxic adenomas).
Overview of Thyroid Carcinomas
 Types of Thyroid Carcinomas:
o Papillary carcinoma (85% of cases).

o Follicular carcinoma.

o Medullary carcinoma.

o Anaplastic carcinoma.

 Key Differences:
 Pathogenesis, morphologic features, and clinical course vary by type.
Papillary Thyroid Carcinoma
 Epidemiology and Risk Factors:
o Most common thyroid carcinoma, often seen after neck radiation exposure.

o Involves MAP-kinase pathway activation (RET rearrangements or BRAF mutations).

 Morphology:
o Branching papillae with clear, "Orphan Annie" nuclei features.

o Psammoma bodies (calcified structures) often present.

 Clinical Presentation:
 Neck masses or metastatic cervical lymph nodes.
Morphology

Papillae structures Nuclear features

Follicular Thyroid Carcinoma
 Epidemiology and Risk Factors:
o Second most common thyroid carcinoma.

o More common in areas with iodine deficiency.

 Pathogenesis:
o RAS mutations and PAX8-PPARγ translocations are common.

 Morphology:
o Encapsulated tumor with follicular structure.

o Key distinction: capsular or vascular invasion differentiates it from benign adenomas.

 Clinical Presentation:
o
Morphology of Follicular Thyroid Carcinoma

Capsular invasion Light microscopy view

Medullary Thyroid Carcinoma
 Definition and Pathogenesis:
o Arises from parafollicular (C) cells producing calcitonin.

o Commonly associated with RET mutations, especially in familial cases (MEN 2A/2B).

 Morphology:
o Amyloid deposits (calcitonin-derived).

 Clinical Features:
 Neck mass, possible paraneoplastic syndrome (e.g., diarrhea).
Morphology of Medullary Thyroid
Carcinoma
Anaplastic Thyroid Carcinoma
 Overview:
o Rare but highly aggressive.

o Typically affects older adults.

 Pathogenesis and Morphology:

o Loss of differentiation markers.

o Tumor often infiltrates surrounding tissues.

 Clinical Course:
 Poor prognosis with rapid growth and local invasion.
Diagnostic Approaches in Thyroid Tumors
 Primary Diagnostic Tools:
o Fine-needle aspiration (FNA) biopsy.

o Radioactive iodine uptake studies.

o Ultrasonography for structural assessment.

 Evaluation Criteria:
o Features such as capsular invasion (for follicular neoplasms).

o Nuclear features and calcifications (papillary carcinoma).

Treatment Options and Prognosis
 General Treatment Approaches:
o Surgery (total or partial thyroidectomy).

o Radioactive iodine therapy (especially for papillary and follicular carcinomas).

o Targeted therapy for medullary carcinoma (RET inhibitors).

 Prognosis:
 Papillary carcinoma has a favorable prognosis; anaplastic carcinoma has poor
outcomes.
Summary and Key Takeaways
 Benign vs. Malignant Distinction:
o Importance of distinguishing for management.

 Characteristics of Major Thyroid Tumors:

o Key features of adenomas and carcinomas.

 Diagnostic and Treatment Implications:

o Approach based on clinical and morphological criteria.
END