Granulomatous Diseases

Slide 1 · Granulomatous Diseases

Sarcoidosis and hypersensitivity pneumonitis

Mechanisms • morphology • clinicopathologic diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Describe immune-mediated granuloma formation in pulmonary disease.

Recognize characteristic morphology and organ distribution in sarcoidosis.

Relate inhaled-antigen exposure to hypersensitivity pneumonitis.

Compare granulomatous patterns, clinical manifestations and outcomes.

Apply source-supported diagnostic reasoning to short clinical cases.

Slide 3 · Two different granulomatous disorders

Sarcoidosis

Multisystem granulomatous condition of unknown cause

Often involves lung and thoracic nodes

Well-formed nonnecrotizing granulomas

Hypersensitivity pneumonitis

Immune reaction to inhaled antigenic material

Predominantly interstitial / bronchiolocentric injury

Often poorly formed nonnecrotizing granulomas

Slide 4 · A nonnecrotizing granuloma: Cellular architecture

Original schematic — not a histologic specimen

Tightly clustered epithelioid macrophages

Activated macrophages form the core of the lesion.

Multinucleated giant cells

May occur centrally; Not essential for diagnosis.

Peripheral lymphocytes surround the core.

Slide 5 · What granuloma morphology does—and does not—prove

Epithelioid macrophage aggregates reflect a sustained cellular immune response.

Giant cells may be present within granulomas.

Absence of necrosis is an important morphologic descriptor, not an etiologic diagnosis.

Clinical exposure, organ distribution and competing causes remain essential.

Slide 6 · Nonnecrotizing granulomas are not specific to sarcoidosis

Possible cause

Clinical discriminator

Interpretive caution

Sarcoidosis

Typical systemic / pulmonary pattern

Diagnosis of exclusion

Mycobacterial disease

Infectious context

May have nonnecrotizing lesions

Fungal infection

Infectious exposure or risk

Organisms must be considered

Beryllium-associated disease

Occupational exposure

May mimic sarcoidosis

Slide 7 · Sarcoidosis: Defining features

Multisystem granulomatous disease with no established causative agent.

Lung parenchyma and hilar lymph nodes are most frequently affected.

Ocular, cutaneous and other systemic lesions are common patterns.

Well-formed nonnecrotizing granulomas are the histopathologic hallmark.

Slide 8 · Sarcoidosis: Where disease is found

Pulmonary or bilateral hilar nodal involvement occurs in about 90% of cases.

Eye and skin manifestations are next in clinical frequency.

Lymph nodes, spleen, liver and bone marrow may harbor granulomas.

Heart, central nervous system and endocrine tissues may also be affected.

Slide 9 · Sarcoidosis: Epidemiologic context

Often presents in adults younger than 40 years; Any age can be affected.

Overall frequency is higher among females description.

Prevalence and patterns of organ involvement differ across populations.

Epidemiology raises or lowers suspicion but does not establish diagnosis.

Slide 10 · Sarcoidosis: Proposed immune pathogenesis

Genetic predisposition

Unidentified antigenic stimulus

CD4⁺ T-cell activation

Macrophage recruitment / activation

Granuloma formation

Causal antigen is unproven; This is an evidence-based working model.

Slide 11 · Pulmonary CD4⁺ T-cell enrichment

Sarcoid lungs accumulate CD4⁺ T cells in alveolar and interstitial spaces.

Textbook CD4:CD8 ratios in the local infiltrate range from 5:1 to 15:1.

The enrichment implicates helper T-cell responses in granuloma formation.

These observations do not by themselves identify an etiologic antigen.

Slide 12 · Oligoclonal T-cell expansion: Evidence of antigen drive

Rearrangement analyses show expansion of selected T-cell clones.

Oligoclonality is consistent with antigen-driven proliferation.

The responsible antigen has not been established.

Interpret immune clonality as a mechanistic clue, not proof of one trigger.

Slide 13 · Th1 cytokines connect T cells to macrophages

Pulmonary CD4⁺ Th1 cells

IL-2 production

T-cell expansion

IFN-γ release

Macrophage activation

Distinct cytokine effects are illustrated in a simplified teaching sequence.

Slide 14 · Chemokines and TNF amplify the granuloma

Activated macrophages release TNF in the local pulmonary environment.

IL-8 and macrophage inflammatory protein-1α facilitate leukocyte recruitment.

Incoming T cells and monocytes enlarge and sustain granulomatous foci.

The text associates elevated bronchoalveolar TNF with disease activity.

Slide 15 · Sarcoidosis: Local immunity versus systemic tests

Local pulmonary response

CD4⁺ helper T-cell accumulation

Increased Th1-related cytokine activity

Epithelioid granuloma formation

Systemic immune abnormalities

Anergy to common skin-test antigens

Polyclonal hypergammaglobulinemia

Complex rather than globally increased immunity

Slide 16 · Genetic susceptibility is contributory, not deterministic

Familial and population clustering suggests heritable susceptibility.

Associations with HLA genotypes are described in the source.

Environmental or antigenic contributions remain unidentified.

No single HLA pattern establishes or excludes sarcoidosis.

Slide 17 · Sarcoid granulomas: The central histologic lesion

Compact epithelioid macrophages form well-demarcated aggregates.

Multinucleated giant cells may occur in the lesion.

Central necrosis is unusual.

Lymphocytes surround lesions variably; Chronic lesions become fibrotic.

Slide 18 · Sarcoid granuloma: Activity and remodeling

Active lesion

Coherent clusters of epithelioid histiocytes

Potential giant cells

Limited or absent central necrosis

Chronic lesion

Fibrous rims may encircle granulomas

Progressive hyalinization may replace cellular lesion

Late fibrotic change may impair function

Slide 19 · Giant-cell inclusions: Schaumann and asteroid bodies

Schaumann bodies are laminated concretions containing calcium and proteins.

Asteroid bodies are stellate inclusions found in giant cells.

Both are described in sarcoid granulomas.

Neither inclusion is pathognomonic; Other granulomatous diseases can show them.

Slide 20 · Granuloma remodeling and functional decline

Persistent granulomas

Formation of fibrous rims

Hyaline fibrous scars

Accumulating interstitial fibrosis

Fibrosis is a possible chronic outcome, not an inevitable consequence of each granuloma.

Slide 21 · Pulmonary sarcoidosis: Gross appearance

Grossly visible lung changes may be absent despite histologic granulomas.

Advanced lesions may coalesce into firm nodules.

Textbook describes occasional 1–2 cm noncaseating, noncavitated consolidations.

Disease stage alters the balance between inflammatory nodules and fibrosis.

Slide 22 · Sarcoidosis: Pulmonary compartment relationships

Lymphatic routes

Granuloma deposition

Potential consequences

Around bronchi

Around blood vessels

Pleura; Alveoli also possible

Well-formed granulomas

Bronchial submucosal lesions

Fibrosis / hyalinization

Airway biopsy yield

Restricted gas exchange

Late fibrotic remodeling

Slide 23 · Why bronchoscopic sampling may be informative

Bronchial submucosal granulomas occur frequently in pulmonary sarcoidosis.

Endobronchial tissue can therefore demonstrate a diagnostic pattern.

A tissue pattern must still be interpreted after exclusion of mimics.

Sampling should be directed by the available tissue and clinical pattern.

Slide 24 · Hilar and mediastinal lymph nodes

Lymph-node involvement is present in almost all described cases.

Hilar and mediastinal nodes are particularly prominent sites.

Nodes are enlarged and discrete; Some undergo calcification.

Nodal findings help explain the common radiographic presentation.

Slide 25 · Spleen: Common microscopic, less common gross disease

Granulomas can affect splenic tissue even without clinical enlargement.

The source reports splenic involvement in about 75% of cases.

Overt splenomegaly is described in approximately 20%.

Coalescent granulomas occasionally produce visible splenic nodules.

Slide 26 · Liver: Portal-predominant granulomas

Hepatic involvement occurs somewhat less often than splenic involvement.

Tissue typically contains scattered granulomas.

Granulomas predominate in portal triads rather than lobules.

Clinical enlargement may occur, but histologic involvement can be subtle.

Slide 27 · Bone marrow and skeletal manifestations

Marrow involvement is described in roughly one-fifth of cases.

Phalangeal bones of hands and feet may show discrete resorption foci.

Radiographs may demonstrate a reticulated marrow-cavity pattern.

Bone remodeling can produce expansion or periosteal new bone formation.

Slide 28 · Cutaneous sarcoidosis: Varied appearances

Granulomatous skin lesions

Subcutaneous nodules

Raised erythematous plaques

Flat erythematous, scaling lesions

Other cutaneous presentations

Mucosal lesions can occur

Shin nodules may represent erythema nodosum

Clinical appearances are not uniform

Slide 29 · Erythema nodosum: Inflammatory skin manifestation

Typically presents with painful erythematous nodules on the shins.

The underlying tissue reaction is septal panniculitis.

It is a clinical manifestation associated with sarcoidosis.

Do not equate erythema nodosum itself with a diagnostic sarcoid granuloma.

Slide 30 · Ocular involvement can threaten sight

Ocular sarcoidosis frequently presents as iritis or iridocyclitis.

Inflammation may be unilateral or bilateral.

Complications described include corneal opacity and glaucoma.

Untreated or progressive ocular involvement can result in visual loss.

Slide 31 · Lacrimal and salivary gland involvement

Inflammation of lacrimal glands can diminish tear production.

Dry eyes are described as part of a sicca presentation.

Parotid and other major salivary glands can be affected.

Ocular and glandular involvement can coexist in multisystem disease.

Slide 32 · Muscle, heart and nervous system

Muscle granulomas can be asymptomatic; Weakness or myalgia may prompt investigation.

Cardiac granulomas are uncommon but clinically consequential.

Central nervous system involvement is described in a minority of cases.

Pituitary and other endocrine involvement can occur.

Slide 33 · How pulmonary sarcoidosis presents

Bilateral hilar lymphadenopathy may be found incidentally.

Insidious dyspnea and cough often prompt evaluation.

Chest pain and hemoptysis are also described.

An apparently localized pulmonary syndrome may coexist with systemic lesions.

Slide 34 · Constitutional manifestations and multisystem clues

Fever, fatigue, weight loss and anorexia can precede diagnosis.

Night sweats are among the reported presenting symptoms.

Peripheral adenopathy, skin changes or ocular symptoms may dominate.

The wide spectrum follows from variable organ distribution.

Slide 35 · Sarcoidosis may follow several time courses

Initial manifestation

Active granulomatous phase

Spontaneous or therapy-associated remission

Residual fibrosis or recurrence

The last two possibilities are alternatives; The diagram should not be read as an inevitable linear pathway.

Slide 36 · Sarcoidosis: Long-term clinical trajectories

65%–70%

Recovery with minimal or no residual disease

≈20%

Residual pulmonary or visual impairment

10%–15%

Severe cases; Some deaths from pulmonary, cardiac or CNS disease

Slide 37 · Sarcoidosis: Why the diagnosis remains exclusionary

Nonnecrotizing granulomas support but do not uniquely identify sarcoidosis.

Mycobacterial and fungal infections can share the granulomatous pattern.

Beryllium-associated granulomatous disease is another recognized mimic.

A convincing diagnosis requires compatible morphology and clinical evaluation.

Slide 38 · Sarcoidosis: Interpret the tissue in context

Observation

Supports

Does not establish

Well-formed granulomas

Granulomatous inflammation

Unique sarcoid etiology

Absent central necrosis

Nonnecrotizing morphology

Exclusion of infection

Thoracic adenopathy

Compatible organ pattern

Sarcoidosis without differential

Systemic skin/eye signs

Broader organ correlation

An antigen or molecular cause

Slide 39 · Case 1: Bilateral hilar lymphadenopathy

A young adult has bilateral hilar lymph-node enlargement and a biopsy showing sharply formed nonnecrotizing granulomas. The patient also reports recurrent painful eye inflammation.

Interpretation tasks

Which diagnosis is most strongly suggested?

Why is the biopsy finding not sufficient on its own?

Slide 40 · Case 1 interpretation

The combination strongly suggests sarcoidosis.

Pulmonary / hilar nodal disease with ocular inflammation fits the textbook pattern.

Well-formed nonnecrotizing granulomas are supportive.

Infection and relevant exposure-related granulomatous mimics must be considered.

Slide 41 · Hypersensitivity pneumonitis: Defining mechanism

Immune-mediated interstitial lung disease from inhaled antigenic material.

Exposure is often intense, repeated or prolonged.

Primary site of injury is the alveolar wall and related small airways.

The alternate term is extrinsic allergic alveolitis.

Slide 42 · HP: Exposure source and antigen type

Biologic antigens

Spores of thermophilic bacteria

Fungal material and microbial products

Animal-derived proteins

Common exposure environments

Warm or damp agricultural material

Bird handling or bird-housing sites

Contaminated humidifier / air-conditioning water

Slide 43 · Farmer’s lung: A biologically plausible exposure

Warm, moist harvested hay can support thermophilic actinomycetes.

Dust generated during handling carries antigenic microbial material.

An exposed, sensitized person may develop recurrent pulmonary symptoms.

An occupational history can link episodes to the relevant environment.

Slide 44 · Bird fancier’s lung: An animal-protein exposure

Bird-related serum, excreta and feathers contain triggering proteins.

Pigeon breeding is the named textbook example.

Domestic pet-bird exposure may be missed without direct questioning.

The diagnosis turns on a plausible exposure–illness relationship.

Slide 45 · Humidifier and air-conditioner lung

Heated water reservoirs can support thermophilic microorganisms.

Aerosolized biologic material provides an inhalational exposure.

The source lists humidifier and air-conditioning systems as exposure settings.

Indoor water systems deserve attention when workplace causes are absent.

Slide 46 · Exposure history is central in suspected HP

Ask specifically about farming, hay and damp agricultural storage.

Ask about domestic birds, pigeon breeding and bird-related activities.

Enquire about humidifiers, water reservoirs and mold-prone environments.

Relate symptoms to repeated contact, duration and removal from exposure.

Slide 47 · Hypersensitivity pneumonitis: Immune response

Inhaled antigen

Sensitization / abnormal reactivity

Cellular and antibody responses

Alveolar / bronchiolar inflammation

Granulomas ± fibrosis

The source supports humoral and cell-mediated immune evidence; The diagram is a synthesis, not a single obligatory pathway.

Slide 48 · HP: Immune evidence from lavage

Acute bronchoalveolar lavage may show elevated proinflammatory chemokines.

The source names IL-8 and macrophage inflammatory protein-1α (CCL3).

Both CD4⁺ and CD8⁺ lymphocytes increase in lavage specimens.

The immune profile differs from a purely bronchodilator-responsive airway disorder.

Slide 49 · HP: Antibodies and complement

Antibodies directed at an implicated exposure antigen are common.

Immunoglobulin and complement deposits may be found in vessel walls.

These observations support a humoral immune component.

Circulating antigen-specific antibodies alone should not be treated as proof of clinical disease.

Slide 50 · HP: Why granulomas suggest cellular immunity

Nonnecrotizing granulomas are reported in approximately two-thirds of patients.

The morphology supports a T-cell–mediated component of tissue injury.

The source explicitly implicates type IV hypersensitivity mechanisms.

Granulomas must be interpreted alongside interstitial and bronchiolar changes.

Slide 51 · HP: Acute injury pattern

Morphology depends on time since antigenic challenge.

Acute alveolar injury dominates in the first hours or days.

Inflammatory responses can accompany fever and new respiratory symptoms.

A single biopsy cannot be interpreted without phase and exposure context.

Slide 52 · HP: Subacute interstitial pneumonitis

Inflammation prominently affects bronchioles and adjacent interstitium.

Lymphocytes, plasma cells and macrophages dominate the infiltrate.

Eosinophils are uncommon in this pattern.

Nonnecrotizing granulomas may accompany the cellular interstitial process.

Slide 53 · HP: Characteristic bronchiolocentric injury

Tissue injury tends to center on bronchioles and nearby lung.

Peribronchiolar metaplasia may involve alveolar ducts and respiratory bronchioles.

Granulomas are often loosely organized rather than densely formed.

This arrangement helps distinguish HP from perilymphatic sarcoidosis.

Slide 54 · HP: Chronic fibrotic remodeling

Persistent disease may produce interstitial fibrosis and fibroblastic foci.

Honeycombing and obliterative bronchiolitis can coexist with granulomas.

Fibrosis may overlap with organizing pneumonia or other interstitial patterns.

In advanced disease, nonspecific or UIP-like fibrosis can obscure the cause.

Slide 55 · HP: Exposure and progression

Continued antigen exposure

Repeated interstitial inflammation

Airway-centered tissue injury

Variable chronic fibrotic change

Recognizing the exposure early allows preventive antigen removal.

Slide 56 · Acute HP: Characteristic timing

Symptoms typically develop 4–6 hours after antigenic dust exposure.

Fever, cough, dyspnea and leukocytosis are described.

Attacks can last from 12 hours to several days.

Re-exposure can reproduce the syndrome.

Slide 57 · HP: Respiratory physiology and imaging

The acute phase may produce a restrictive ventilatory disorder.

Chest radiography may show micronodular interstitial infiltrates.

Pulmonary dysfunction follows alveolar-wall and interstitial involvement.

Findings must be integrated with exposure rather than interpreted alone.

Slide 58 · Chronic HP: Clinical consequences

Ongoing exposure can produce progressive fibrosis.

Dyspnea and cyanosis may emerge with advanced interstitial disease.

Chronic presentations resemble other fibrotic interstitial lung diseases.

Loss of a classic granulomatous pattern complicates etiologic recognition.

Slide 59 · Why early recognition of HP matters

Antigen removal may prevent progression to serious chronic fibrosis.

Exposures may be hidden in domestic, occupational or indoor environments.

Clinical recurrence after contact is a useful contextual clue.

Separating exposure-driven HP from sarcoidosis changes prevention strategy.

Slide 60 · Granuloma distribution in lung: Anatomic clues

Sarcoidosis

Hypersensitivity pneumonitis

Predominantly perilymphatic / peribronchovascular

Bronchiolocentric inflammation and granulomas

Slide 61 · Sarcoidosis versus hypersensitivity pneumonitis

Feature

Sarcoidosis

Hypersensitivity pneumonitis

Principal context

Multisystem, cause unknown

Exposure-related interstitial disease

Granulomas

Often well-formed

Often poorly formed

Lung distribution

Perilymphatic

Bronchiolocentric

Extra clues

Thoracic nodes, eye, skin

Bird, hay, humidifier exposure

Clinical trajectory

Remissions or progression

Recurrent exposure-related episodes or fibrosis

Slide 62 · Case 2: Fever after agricultural dust exposure

A person working with damp stored hay experiences episodes of fever, cough and breathlessness several hours after handling it. Examination during one episode suggests an interstitial restrictive disorder.

Interpretation tasks

What exposure-associated diagnosis is suggested?

Which tissue compartments are expected to show inflammation?

Slide 63 · Case 2 interpretation

An acute presentation of hypersensitivity pneumonitis is suggested.

Damp hay can harbor thermophilic actinomycetes capable of provoking HP.

The 4–6-hour delay and recurrence after exposure are compatible features.

Pathology, when sampled, may show alveolar-wall inflammation and bronchiolocentric changes.

Slide 64 · Case 3: A granuloma is not a final diagnosis

Lung tissue shows a nonnecrotizing granuloma. No clinical exposure history, imaging distribution or systemic examination has been supplied.

Interpretation tasks

Can the specimen alone establish sarcoidosis?

Which two major categories of alternative causes require consideration?

Slide 65 · Case 3 interpretation

No: Granuloma morphology alone is insufficiently specific.

Infectious granulomatous disease must be considered.

Occupational beryllium-associated disease is another named mimic.

Exposure context and distribution must precede a confident etiologic diagnosis.

Slide 66 · Interpretive clues: A comparative diagnostic grid

Observation

Favors consideration of

Limitation

Well-formed granuloma, hilar nodes

Sarcoidosis

May overlap infection / berylliosis

Exposure-related recurrent fever

Hypersensitivity pneumonitis

History requires correlation

Bronchiolocentric mixed inflammation

Hypersensitivity pneumonitis

Not uniquely diagnostic

Nonnecrotizing granuloma alone

Multiple causes

No etiologic specificity

Slide 67 · Common diagnostic reasoning errors

Calling every nonnecrotizing granuloma “sarcoidosis.”

Failing to ask specifically about birds, damp hay and indoor water systems.

Ignoring distribution: Perilymphatic versus bronchiolocentric patterns.

Assuming advanced fibrosis must retain the classic initiating morphology.

Slide 68 · Five integrated pathology conclusions

Sarcoidosis is systemic, commonly thoracic, and a diagnosis of exclusion.

Local Th1-associated T-cell and macrophage activity underlies its granulomas.

Organ-specific disease produces pulmonary, ocular, cutaneous and systemic signs.

HP links inhaled biologic antigen exposure to interstitial / bronchiolar injury.

Granuloma quality, distribution and exposure history guide differentiation.

Slide 69 · Primary reading and source limitations

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026).

Chapter 15, The Lung: “Granulomatous Diseases,” pp. 634–636.

Scope: Sarcoidosis; Hypersensitivity Pneumonitis, with contiguous text on p. 637.

The supplied Markdown interleaves columns; unrelated asbestosis text was excluded.

Original chapter PDF and embedded textbook figures were not provided.