Hashimoto Thyroiditis

Slide 1 · Hashimoto thyroiditis

Autoimmune injury · Morphology · Clinicopathologic correlation

A source-grounded thyroid pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain the breakdown of thyroid self-tolerance and the principal effector mechanisms.

Recognize the characteristic gross, microscopic and cytologic findings.

Link progressive follicular loss to the thyroid-function trajectory.

Distinguish Hashimoto thyroiditis from other common thyroiditides and Graves disease.

Slide 3 · Definition: Chronic autoimmune thyroid injury

Hashimoto thyroiditis is immune-mediated destruction of the thyroid gland.

Follicular epithelial loss accumulates over time, causing progressive thyroid failure.

Lymphoplasmacytic inflammation, oncocytic metaplasia and variable fibrosis form the morphologic signature.

Slide 4 · Where Hashimoto fits in hypothyroidism

Primary hypothyroidism

Intrinsic thyroid injury

Autoimmune thyroiditis

Hashimoto disease

Hashimoto disease is a major autoimmune cause of primary hypothyroidism in iodine-sufficient settings.

Slide 5 · Why iodine sufficiency changes the differential

Context

Important thyroid failure mechanism

Iodine-sufficient areas

Autoimmune hypothyroidism, mostly Hashimoto thyroiditis

Iodine-deficient areas

Deficient substrate for thyroid-hormone synthesis

After gland ablation

Loss of thyroid tissue from surgery or irradiation

Cause of hypothyroidism depends on population and clinical context.

Slide 6 · Age distribution and clinical setting

Most prevalent in adults aged 45–65 years.

Occurs across ages; Adult predominance does not exclude pediatric disease.

Many patients come to attention because of a painless goiter and evolving thyroid dysfunction.

Slide 7 · Marked female predominance

Sex distribution

A female-to-male ratio of approximately 10:1–20:1.

Interpretation

Female predominance supports epidemiologic suspicion but is not diagnostic.

Practice point

A male patient with compatible morphology may still have Hashimoto thyroiditis.

Slide 8 · Pediatric Hashimoto thyroiditis

Hashimoto thyroiditis occurs in children as well as adults.

It is an important cause of nonendemic goiter during childhood.

The underlying process remains autoimmune damage of thyroid parenchyma.

Slide 9 · Historical descriptor: Struma lymphomatosa

Hashimoto described goitrous thyroid glands with prominent lymphocytic infiltration in 1912.

“Struma lymphomatosa” reflects the dense lymphoid reaction, not a diagnosis of lymphoma.

Modern interpretation integrates this morphology with autoimmune follicular destruction.

Slide 10 · Initiating abnormality: Lost self-tolerance

Tolerance to thyroid antigens fails

Immune response targets thyrocytes

Follicular damage accumulates

Thyroid reserve declines

The precise initiating events remain unresolved.

Slide 11 · Two autoantigen targets

Thyroid peroxidase (TPO)

Thyroid enzyme frequently recognized by circulating autoantibodies.

Thyroglobulin (Tg)

Thyroid follicular protein also targeted by circulating autoantibodies.

Important distinction

Antibody presence demonstrates autoimmunity; It does not establish how much injury antibodies cause.

Slide 12 · Autoantibodies: Evidence versus mechanism

Established observation

Unresolved mechanism

Anti-TPO and anti-Tg often detectable

Antibodies may participate in injury—or result from injured tissue

Autoimmune thyroid disease established by integrated findings

Direct antibody cytotoxicity is not proved by seropositivity

Useful etiologic evidence

Cannot replace functional and morphologic assessment

Do not equate an antibody marker with a proven pathogenic effector.

Slide 13 · Genetic susceptibility is polygenic

Hashimoto thyroiditis has a strong genetic component.

Associated polymorphisms affect genes involved in immune regulation.

CTLA4, PTPN22 and IL2RA as examples.

Association with susceptibility does not imply a single-gene deterministic disease.

Slide 14 · CTLA4: An immune-regulatory association

CTLA4

Encodes cytotoxic T-lymphocyte–associated antigen 4.

Relevance

Part of the machinery regulating T-cell responses.

Clinical interpretation

Susceptibility association; Not a standalone diagnostic test.

Slide 15 · PTPN22: T-cell response regulation

PTPN22

Encodes protein tyrosine phosphatase non-receptor type 22.

Relevance

Immune regulation contributes to autoimmune susceptibility.

Clinical interpretation

Genetic predisposition is distinct from an established initiating trigger.

Slide 16 · IL2RA: Regulatory immune pathways

IL2RA

Encodes the interleukin-2 receptor α chain.

Relevance

Another immune-response regulator implicated by susceptibility polymorphisms.

Clinical interpretation

Interpret as a risk association rather than direct proof of thyrocyte injury.

Slide 17 · The initiating event remains uncertain

Proposed possibility

Evidence level in Robbins

Regulatory T-cell abnormality

Suggested, not established as a universal trigger

Exposure of sequestered thyroid antigens

Proposed, not a demonstrated initiating sequence

Immune-regulation gene variants

Supported susceptibility association; do not infer determinism

Keep proposed initiation mechanisms separate from established tissue injury.

Slide 18 · Immune injury has several effector routes

Common initiating context

Breakdown of self-tolerance allows autoreactive immune responses to thyroid antigens.

Direct cytotoxic route

CD8⁺ T cells can destroy follicular epithelial cells.

Inflammatory cytokine route

CD4⁺ Th1 signals recruit and activate macrophages; Routes converge on follicular injury.

Slide 19 · CD8⁺ cytotoxic lymphocytes

Cytotoxic CD8⁺ T cells can directly damage thyroid follicular epithelial cells.

Repeated killing reduces the population of functioning thyrocytes.

This contributes to the depletion of thyroid follicles seen microscopically.

Slide 20 · CD4⁺ Th1 immune activation

CD4⁺ Th1-cell activation

Inflammatory cytokine release

Local immune-cell recruitment

Follicular damage

CD4⁺ T-cell activity amplifies local inflammatory injury rather than simply forming an inert infiltrate.

Slide 21 · Interferon-γ and macrophage recruitment

Th1 cells produce inflammatory cytokines, including interferon-γ.

These signals recruit and activate macrophages within the thyroid.

Local cytokine-associated injury contributes to destruction of follicles.

Slide 22 · What is uncertain about antibody-mediated damage?

Hypothesized route

Critical interpretation

Antibody-dependent cellular cytotoxicity

Historically proposed; pathogenic importance uncertain

Complement-dependent damage

Possible, but not established as the dominant cause

Anti-TPO / anti-Tg seropositivity

Robust autoimmune association without proven causality for each antibody

Robbins explicitly cautions that antibodies may be cause or consequence of injury.

Slide 23 · Injury evolves into tissue remodeling

Autoimmune activity

Lymphocytic inflammation develops

Follicular loss

Thyrocytes are progressively depleted

Remodeling

Parenchyma is replaced by inflammation and fibrosis

Slide 24 · Integrative pathogenesis schematic

Immune dysregulation

Genetic susceptibility and lost tolerance

Cell-mediated injury

CD8⁺ killing and CD4⁺ / Th1 inflammation

Morphology

Atrophy, lymphoid aggregates, oncocytic change

Function

Declining thyroid reserve and primary hypothyroidism

Slide 25 · Gross morphology: Enlargement without invasion

The gland is usually diffusely enlarged and remains sharply separated from adjacent structures.

Gross cut surface is characteristically pale, yellow-tan and firm.

A somewhat nodular cut appearance may be present, even without a discrete neoplasm.

Slide 26 · Interpreting the gross cut surface

Diffuse increase in size

Often reflects chronic inflammatory enlargement.

Pale, firm texture

Consistent with inflammatory remodeling and variable fibrosis.

Well-defined gland edge

Classic fibrosis remains within the gland rather than invading adjacent neck structures.

Slide 27 · Macroscopic differential: Localized enlargement

Hashimoto enlargement is usually symmetric and diffuse.

In some patients, the enlargement is sufficiently localized to simulate a thyroid neoplasm.

Apparent nodularity therefore requires clinicopathologic correlation; The label “Hashimoto” alone is insufficient.

Slide 28 · Microscopy: Three linked compartments

Follicular compartment

Residual follicles alongside inflammation

Immune compartment

Lymphoid aggregates with germinal centers

Stromal compartment

Variable connective-tissue increase

Schematic architecture — not a histologic specimen

Slide 29 · Lymphoplasmacytic infiltration

Extensive mononuclear inflammation replaces portions of thyroid parenchyma.

The infiltrate contains small lymphocytes and plasma cells.

Lymphoid aggregates may organize into follicle-like structures with germinal centers.

Slide 30 · Germinal centers within the thyroid

Lymphoid follicles

Organized collections of small lymphocytes

Germinal centers

Paler reactive central zones

Context

Surrounded by altered thyroid follicles

Schematic architecture — not a histologic specimen

Slide 31 · Why organized lymphoid follicles matter

Morphologic clue

Prominent germinal centers support a sustained autoimmune inflammatory process.

Site matters

These structures are within thyroid tissue; They are not native thyroid follicles.

Interpretation

Assess in the company of epithelial atrophy, oncocytic change and fibrosis.

Slide 32 · Progressive thyroid follicular atrophy

Small follicles

Loss of epithelium diminishes functioning units

Parenchymal replacement

Inflammation occupies previously follicular space

Consequence

Functional reserve falls progressively

Schematic architecture — not a histologic specimen

Slide 33 · Follicular loss explains functional decline

Epithelial destruction

Fewer intact functional follicles

Reduced thyroid hormone output

Compensatory TSH increase

The structure–function link explains the usual gradual evolution to primary hypothyroidism.

Slide 34 · Oncocytic metaplasia of follicular epithelium

Residual lining

Abundant granular eosinophilic cytoplasm

Older term

Hürthle-cell change

Interpretation

Metaplastic response to chronic injury

Schematic architecture — not a histologic specimen

Slide 35 · Recognizing oncocytes

Residual follicles are often lined by cells with abundant eosinophilic, granular cytoplasm.

These cells are termed oncocytes; The older term is Hürthle cells.

Robbins interprets the change as metaplasia in response to chronic epithelial injury.

Slide 36 · Oncocytic change is not synonymous with cancer

Observation

Interpretation

Oncocytes in inflamed residual follicles

Expected in Hashimoto thyroiditis

Abundant granular eosinophilic cytoplasm

Epithelial phenotype, not an independent malignancy criterion

Focal thyroid enlargement with oncocytes

Correlate with tissue architecture and clinical features

Cytomorphology must be interpreted in its inflammatory context.

Slide 37 · Interstitial fibrosis: The tissue boundary

Stromal remodeling

Variable intrathyroidal collagen deposition

Peripheral border

Classic disease remains gland-confined

Comparison

Riedel fibrosis extends beyond gland

Schematic architecture — not a histologic specimen

Slide 38 · Fibrosis in Hashimoto versus Riedel

Classic Hashimoto thyroiditis

Riedel thyroiditis

Fibrosis may be abundant inside the thyroid

Dense fibrosis includes adjacent neck structures

Gland remains well demarcated

Hard, fixed mass may simulate carcinoma

Prominent lymphoid inflammation and oncocytes

Extensive invasive fibrosclerosis is dominant

The peripheral extent of fibrosis is a major distinguishing principle.

Slide 39 · Fine-needle aspirate: A characteristic pairing

Epithelial population

Oncocytes with granular eosinophilic cytoplasm.

Inflammatory population

Heterogeneous lymphocytes accompanying the oncocytes.

Interpretation

The combination is characteristic of Hashimoto thyroiditis in an appropriate clinical setting.

Slide 40 · Cytologic interpretation requires context

Oncocytes are not sufficient alone to classify a lesion as Hashimoto thyroiditis.

Mixed lymphocytes reinforce the chronic thyroiditis pattern.

Localized enlargement can raise the suspicion of neoplasia, so interpretation is integrated rather than isolated.

Slide 41 · The classic clinical presentation

Painless thyroid enlargement is a common mode of presentation.

The gland is generally diffusely and symmetrically enlarged.

Some degree of thyroid hypofunction may already be present at first assessment.

Slide 42 · A gradual course is typical

Autoimmune injury

Inflammation begins before reserve is exhausted

Compensation

TSH responds as hormone synthesis becomes limited

Overt failure

Thyroid hormone levels decline as tissue loss progresses

Slide 43 · Hashitoxicosis: Release, not stimulation

Follicle disruption

Preformed hormone escapes

Transient thyrotoxicosis

Later hypofunction may develop

Transient thyrotoxicosis can precede the more characteristic hypothyroid phase.

Slide 44 · Destructive versus stimulatory thyrotoxicosis

Hashitoxicosis

Graves disease

Leakage from injured follicles

TSH-receptor antibody stimulation

Transient phase may precede failure

Sustained hormone overproduction

Autoimmune destruction of gland

Diffuse epithelial hypertrophy / hyperplasia

An elevated thyroid-hormone level does not automatically imply increased synthesis.

Slide 45 · Primary thyroid feedback during failure

Thyroid follicle loss

T₄ and T₃ output falls

Anterior pituitary response

TSH secretion increases

Primary hypothyroidism: Low thyroid output with compensatory TSH elevation

Directional physiology only; Hormone concentrations vary with stage.

Slide 46 · Laboratory pattern evolves with disease stage

Stage or physiology

Expected direction of markers

Progressive primary thyroid failure

TSH increases as feedback weakens

Established hypothyroidism

T₄ and T₃ decline; TSH becomes elevated

Transient destructive thyrotoxicosis

Released thyroid hormone may temporarily rise

These are directional patterns, not diagnostic cutoffs or substitute reference intervals.

Slide 47 · Autoimmune disorders may coexist

Endocrine

Type 1 diabetes; Autoimmune adrenalitis.

Nonendocrine

Systemic lupus erythematosus; Myasthenia gravis; Sjögren syndrome.

Implication

The thyroid disorder may be one manifestation of broader immune dysregulation.

Slide 48 · Endocrine comorbidity: Diagnostic context

Type 1 diabetes and autoimmune adrenalitis are specifically associated conditions.

Autoimmune hypothyroidism may occur in the setting of autoimmune polyendocrine syndromes.

An existing autoimmune disease increases clinical suspicion but does not by itself establish thyroiditis.

Slide 49 · Nonendocrine autoimmune comorbidity

Systemic lupus erythematosus, myasthenia gravis and Sjögren syndrome are recognized associations.

Coexistence supports an autoimmune tendency across tissue systems.

The thyroid diagnosis still requires direct clinical, functional or pathologic evidence.

Slide 50 · Rare lymphoma association

Hashimoto thyroiditis confers an increased risk of extranodal marginal zone B-cell lymphoma in the thyroid.

The complication is rare, despite chronic lymphoid infiltration being common.

Distinguish reactive thyroid-associated lymphoid tissue from true lymphoma when morphology raises concern.

Slide 51 · Thyroid epithelial cancer: Preserve uncertainty

Established in Robbins

Not firmly established

Increased risk of thyroid extranodal marginal zone B-cell lymphoma

Causal predisposition to thyroid epithelial carcinoma

Coexistence of autoimmunity and thyroid lesions can occur

Whether papillary carcinoma risk is increased remains controversial

Do not treat a disputed epithelial cancer link as settled.

Slide 52 · Clinicopathologic diagnostic synthesis

Presentation

Painless diffuse goiter or evolving dysfunction

Immune evidence

Anti-TPO and/or anti-Tg antibodies

Microscopy

Lymphoid germinal centers, oncocytes and atrophy

Function

Progressive primary hypothyroidism; Sometimes hashitoxicosis

Slide 53 · Serology: What the test establishes

Anti-TPO / anti-Tg finding

Interpretation

Present

Evidence of autoimmune response to thyroid antigens

Absent or unavailable

Assess the total clinical and pathologic picture

High antibody result

Not a direct quantitative measure of tissue destruction

These autoantibodies in the great majority, not in every patient.

Slide 54 · Differential: Hashimoto versus painless thyroiditis

Hashimoto

Painless (silent) thyroiditis

Gradually progressive hypothyroidism is typical

Often transient thyrotoxicosis followed by recovery

Oncocytic metaplasia and fibrosis prominent

Oncocytic change and fibrosis not prominent

Painless goiter possible

Painless goiter common; postpartum cases recognized

Both may display lymphocytic infiltration and germinal centers.

Slide 55 · Differential: Hashimoto versus subacute thyroiditis

Hashimoto

Subacute granulomatous (de Quervain)

Usually painless

Painful thyroid is characteristic

Lymphoid infiltrates, oncocytes, follicular atrophy

Granulomatous inflammation with giant cells and colloid

Usually progressive thyroid failure

Often transient, self-limited thyroiditis

Pain and tissue reaction pattern strongly shift the differential.

Slide 56 · Differential: Hashimoto versus Graves

Hashimoto

Graves disease

Autoimmune follicular destruction

TSH-receptor stimulation is the principal mechanism

Atrophic follicles and oncocytic change

Tall, crowded hyperplastic epithelium

Hypothyroidism dominates later course

Hyperthyroidism dominates usual presentation

Lymphoid infiltrates can be present in both: Their existence alone does not discriminate.

Slide 57 · Thyroiditis differential: A morphology map

Hashimoto

Painless · oncocytes · intrathyroidal fibrosis

Silent thyroiditis

Painless · transient · minimal oncocytes / fibrosis

De Quervain

Painful · giant-cell reaction to colloid

Riedel

Hard fixed gland · fibrosis beyond thyroid

Slide 58 · Case 1: Painless goiter and rising TSH

Clinical vignette

A 52-year-old woman presents with a gradually enlarging, painless thyroid gland.

Serum TSH has increased over serial testing and thyroid hormone output is declining.

What unifying disease process and microscopic triad should be considered?

Use the mechanism and tissue pattern to answer; Discussion follows.

Slide 59 · Case 1: Mechanistic resolution

Immune phase

Lost tolerance to thyroid antigens

Tissue phase

T-cell / cytokine injury and follicular atrophy

Functional phase

Declining T₄ / T₃ and compensatory TSH rise

Pattern

Painless goitrous chronic autoimmune thyroiditis

Slide 60 · Case 2: Initial thyrotoxicosis

Clinical vignette

A patient with autoimmune thyroiditis develops transient clinical thyrotoxicosis.

The gland subsequently shows declining functional reserve.

Does the initial hormone excess prove a Graves-type stimulatory mechanism?

Use the mechanism and tissue pattern to answer; Discussion follows.

Slide 61 · Case 2: Distinguish the mechanism

Destructive release

Active synthesis

Follicular rupture liberates stored hormones

TSH receptor stimulation increases ongoing production

May be transient before thyroid failure

Sustained stimulation is typical of Graves disease

Underlying morphology: injury / atrophy

Underlying morphology: hyperplasia

Mechanism, not the isolated word “thyrotoxicosis,” determines the differential.

Slide 62 · Case 3: Hard thyroid and fibrosis

Clinical vignette

A firm thyroid enlargement is investigated for possible neoplasia.

Histology shows extensive lymphoplasmacytic inflammation and fibrosis.

Which anatomic observation best helps distinguish classic Hashimoto from Riedel thyroiditis?

Use the mechanism and tissue pattern to answer; Discussion follows.

Slide 63 · Case 3: The importance of boundaries

Intrathyroidal fibrosis

Extrathyroidal fibrosis

Compatible with classic Hashimoto

Suggests Riedel-type invasive fibrosclerosis

Thyroid border remains discernible

Contiguous surrounding neck tissue becomes involved

Evaluate oncocytes and germinal centers

Hard fixed mass may resemble a carcinoma

The gross-anatomic pattern is an etiologically useful morphologic sign.

Slide 64 · Four high-yield diagnostic anchors

Mechanism

Autoimmune loss of thyrocytes.

Morphology

Germinal centers, atrophy, oncocytes, variable fibrosis.

Functional evolution

Often gradual primary hypothyroidism; Possible hashitoxicosis.

Complication

Rare extranodal marginal zone B-cell lymphoma.

Slide 65 · Common interpretation errors

Calling thyroid autoantibodies proven causes of follicular injury; Their role remains uncertain.

Mistaking a transient destructive hormone leak for sustained synthesis-driven hyperthyroidism.

Interpreting oncocytes alone as evidence of a thyroid epithelial neoplasm.

Overstating papillary carcinoma risk when the literature remains controversial.

Slide 66 · Essential reading and image provenance

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. 2026. Chapter 24, pp. 980–985.

Hashimoto thyroiditis: textbook pp. 982–983; pathogenesis Fig. 24.10 and morphology Fig. 24.11.

Thyroiditis key concepts and the Graves disease comparison: pp. 983–985.

All explanatory tissue illustrations in this lecture are original editable schematics; no photomicrographs are reproduced.