My study notes for all pathologists

1. FLASHPATH
H A Z E M A L I

2. HYPERSENSITIVITY
PNEUMONITIS
(EXTRINSIC ALLERGIC
ALVEOLITIS)
H A Z E M A L I

3. CLINICAL
HP/EAA is one of the “chronic interstitial lung diseases” that show
“restrictive pulmonary functions”
Obstructive airway disease Restrictive airway disease
General features (Reduced lung AIRFLOW)
Increase in resistance to
airflow due to obstruction at
any level
(Reduced lung VOLUME)
Reduced expansion of lung
parenchyma
Total lung capacity (TLC) Normal / Increased Reduced
Forced Expiratory Volume in
one second (FEV1)
Markedly reduced Normal / slightly reduced

4. CLINICAL
• HP is an immunologically-induced inflammation of lung parenchyma
in response to inhalation of organic antigens
• Higher prevalence in farmers, animal breeders, and agricultural
industries
• Mainly affect Adults (50 – 60 years)
• 95% of HP cases occur in nonsmokers
– Smoking is related to lower prevalence but worse prognosis
• Treatment: Avoid antigen + / - Corticosteroids

5. CLINICAL
Acute HP Subacute HP Chronic HP
Symptoms Dyspnea, cough, fatigue, low grade fever
Onset Rapid
(within hours after
exposure)
Gradual
Duration Resolve within 24 –
48 hours
Last for Days -
weeks
Last for Months -
years
Antigen Exposure following single
heavy exposure
Recurrent episodes following continued or
intermittent exposure to low dose
Acute Exacerbations -------- May be seen on heavy exposure
Treatment Remove Antigen
+
Supportive
Treatment
Avoid Antigen
+
Steroids
Usually irreversible
 lung transplant

6. CLINICAL
Radiological studies (HRCT) of HP
• Bilateral, more evident in upper lobes
• Centrilobular nodularity
• Ground glass opacities
• Chronic disease shows reticular fibrosis
– May progress to honeycomb change
• Usually central, but may be peripheral

7. CLINICAL
• HP is mainly diagnosed based on:
– History of exposure to antigen
– Clinical presentations and pulmonary function tests
– Recurrence of symptoms following suspected antigen re-exposure
– Radiological findings
– Positive serum antibodies against suspected antigen
• Biopsy is mainly done to suggest the diagnosis when it was not
suspected clinically, to rule out infection or to evaluate cases with
atypical presentation.
– Even if the biopsy suggests hypersensitivity pneumonitis, the final
diagnosis must be made clinically

8. PATHOGENESIS
Suspected Antigens
• Microorganisms (bacteria, fungi, and non-tuberculous mycobacteria)
– Maple bark strippers lung: by fungal spores
– Farmers lung: by spores of thermophilic actinomycetes (in hay)
– Air conditioner lung: by thermophilic bacteria
– Hot tub lung: by non-tuberculous mycobacterium

9. PATHOGENESIS
Suspected Antigens
• Animal proteins (serum, excreta, feces)
– Pigeon breeders lung / bird fancier's disease: by proteins from serum and
feathers
• Organic material (hay, grain, sugar cane, cheese, bark, cork)
• Byssinosis (cotton, linen and hemp fibers)
– Textile workers lung

10. PATHOGENESIS
HP is an abnormal hyper-reactivity to the causative antigens,
mainly by a combination of:
• Immune complex-mediated (type III) hypersensitivity
– Detection of antibodies against causative antigens in the serum
– Precipitation of immunoglobulins and complements at damaged tissues
can be detected by immunofluorescence
• T-cell–mediated, delayed (type IV) hypersensitivity
– Granulomas formation
In contrast to asthma, extrinsic allergic alveolitis (or HP) leads to pathologic changes
that primarily involve the alveolar walls, not the bronchi

11. MICROSCOPY
Acute HP (rarely biopsied)
• Features of acute injury:
– Neutrophils fill alveoli and respiratory bronchioles
– Intra-alveolar fibrin deposition may be present
• The reaction is mainly Bronchiolocenteric

12. MICROSCOPY
Subacute HP (triad)
1. Interstitial inflammation:
– Distribution:
• Patchy (focal)
– Pattern:
• Mainly Peri-bronchiolar (Bronchiolo-centric)
• Also extends to surrounding alveolar septa
– Cellular infiltrate:
• Mainly Lympho-plasmacytic
• scattered neutrophils and eosinophils may be seen
• Occasional lymphoid follicles may be seen

13. MICROSCOPY
Subacute HP (triad)
2. Granulomas
– Bronchiolo-centric
– Non-caseating
– Loose (poorly-formed) aggregation of
epithelioid histiocytes
– And/Or Single interstitial multinucleated giant cells
– Giant cells may contain:
• Cholesterol clefts
• Schaumann bodies
• Asteroid bodies

14. MICROSCOPY
Subacute HP (triad)
3. Features of healing (organization):
– Bronchiolo-centric
– Either:
• Intra-luminal (BOOP-like plugs)
• Interstitial fibroblastic foci
– Loose, edematous (granulation tissue-like)
– Contain Fibroblasts + inflammatory cells

15. MICROSCOPY
Chronic HP similar to subacute
EXCEPT:
• Less interstitial inflammation
• Less granulomas
• More Fibrosis +/- Honeycomb change (especially in upper lobes)
– BOOP-like plugs and interstitial fibroblastic foci are markedly decreased and
focally distributed

16. MICROSCOPY
Fibrosis in Chronic HP may take several patterns
1. Peribronchiolar
– Patchy “spatially heterogeneous” || Uniform “temporally homogenous”
– May occlude bronchiole (intra-luminal foamy macrophages at distal airways)
– May progress to honeycomb change (affect lobule center > periphery)
2. NSIP-like:
– Homogeneous linear pattern
– Preserved architecture (no honeycomb change)
3. UIP-like:
– Patchy “Mainly distal acinar (subpleural)” || fibroblastic foci “temporally heterogeneous
– More obvious honeycomb change (affect lobule periphery > center)

17. MICROSCOPY
Honeycomb changes
• Loss of normal lung architecture with cystic changes:
– Markedly thickened “fibrotic” walls
• May show smooth muscle hyperplasia
– Filled with mucus
– Lined by bronchiolar epithelium (metaplasia)
• Columnar, ciliated
The honeycombed spaces represent dilated respiratory
bronchioles, alveolar ducts and alveoli due to:
• Loss of the surrounding alveoli
• Increased traction on their walls by fibrosis
– Traction bronchiolectasis

18. MICROSCOPY
Other associated lesions / complications (chronic HP):
• Traction bronchiectasis may be seen
– Due to peri-bronchial fibrosis
• Pulmonary hypertension
• RB or DIP-like areas (focal pattern)
• Acute exacerbation on top of chronic HP
– Features of acute damage:
• Neutrophils fill alveoli and respiratory bronchioles
• Intra-alveolar fibrin deposition may be present

19. CYTOLOGY
Bronchoalveolar lavage:
• Increased total cell count
• Increased lymphocyte percentage
– ≥ 30% for nonsmokers or exsmokers
– ≥ 20% for current smokers
• CD4 / CD8 ratios usually decreased in HP
– In sarcoidosis the ratio is increased

20. SPECIAL STUDIES
Clinical tests:
• Positive Inhalation challenge
– Antigen exposure after a period of avoidance provokes symptoms of HP
Serological tests
• Positive Antibodies against suspected antigens
• Increased serum KL-6
– High-molecular weight glycoprotein
– Secreted by type 2 pneumonocytes
– Increased in interstitial lung diseases

21. SPECIAL STUDIES
Microbiological tests
• Culture and sensitivity tests
• Special stains:
– Ziehl-Neelsen stain  mycobacteria
– PAS and GMS stains  fungi

22. SPECIAL STUDIES
Special stains:
• Movat’s Pentachrome stain
– Asses the stage of the disease
• (degree of fibrosis/fibroblastic foci)
– Stain fibroblastic proliferation “blue-green“
– Stain dense collagen “yellow“
Movat’s Pentachrome also stains:
• Elastic laminae “ black “
• Smooth muscle fibers “ dull red “
• Fibrinoid necrosis “ bright red “

23. SPECIAL STUDIES
Special stains:
• Verhoeff’s Van Gieson “Elastic stain”
– Asses the lung architecture (preservation of elastic tissue)
– Stain elastic fibers “black”
– Stain collagen “red”
– Stain other tissue elements “yellow”
Verhoerff’s Van Gieson is also used in:
• Confirm invasion of elastic fibers in the visceral pleura
• For lung cancer staging
• Differentiate arteries from veins
• Evaluate vascular elastic tissue in vascular diseases

24. DIFFERENTIAL DIAGNOSIS
Other interstitial lung diseases
• Usual interstitial pneumonia (one of the HP patterns)
– Affects lower lobes > upper lobes
– Affect periphery “subpleural” > Peri-bronchiolar
– No granulomas / giant cells
– No history of Exposure
• Nonspecific interstitial pneumonia
– Diffuse, uniform interstitial fibrosis (NO honeycomb changes)
– Diffuse interstitial inflammation (especially cellular phase)
– No granulomas / giant cells
– No history of Exposure

25. DIFFERENTIAL DIAGNOSIS
Other interstitial lung diseases
• Lymphoid interstitial pneumonia
– Extensive diffuse interstitial chronic inflammation
– Affect Alveolar septa > peri-bronchiolar tissue (widened septa by inflammatory
infiltrate)
– No BOOP-like areas or fibroblastic foci
– Very rare granulomas / giant cells
– Minimal to mild interstitial fibrosis
– No history of Exposure

26. DIFFERENTIAL DIAGNOSIS
Other interstitial lung diseases
(Smoking-related)
• Desquamative interstitial pneumonia
– Diffuse intra-alveolar macrophages
– Mild – moderate interstitial fibrosis (with temporal uniformity)
– No granulomas / giant cells
– No history of Exposure
• Respiratory bronchiolitis-related interstitial lung disease
– Patchy, bronchiolo-centric intraluminal macrophages
– Mild – moderate interstitial fibrosis (with temporal uniformity)
– No granulomas / giant cells
– No history of Exposure

27. DIFFERENTIAL DIAGNOSIS
Clinical
Diagnosis
Histologic
Pattern
Duration of Illness
Radiological findings
HRCT
Prognosis
Interstitial
pulmonary
fibrosis
Usual interstitial
pneumonia
Chronic
> 12 months
• Subpleural & bibasal
predominance
• Honeycombing
• Reticular opacities
• Ground-glass opacities
• Traction bronchiectasis
5-year survival: 20%
Nonspecific
interstitial
pneumonia
Nonspecific
interstitial
pneumonia
Subacute – chronic
Months - years
• Bilateral, symmetrical & basal
• Ground-glass opacities
• Reticular opacities
• Lower lobe volume loss
• Rare honeycombing
• Cellular NSIP
10-year survival: more
than 90%
• Fibrotic NSIP
5-year survival: 90%
10-year survival: 35%
Cryptogenic
organizing
pneumonia
Organizing
pneumonia
Subacute
< 3 months
Subpleural, peribronchial patchy
consolidation / nodularity
5-year survival >95%

28. DIFFERENTIAL DIAGNOSIS
Clinical
Diagnosis
Histologic
Pattern
Duration of Illness
Radiological findings
HRCT
Prognosis
Acute
respiratory
distress
syndrome
Diffuse alveolar
damage
Acute
1 – 2 weeks
• Diffuse pulmonary infiltrate
• Ground-glass opacities
40%-60%
mortality rate in
< 6 months
Desquamative
interstitial
pneumonia
Desquamative
interstitial
pneumonia
Subacute
Weeks - months
• Subpleural predominance
• Ground-glass opacities
• Reticular opacities
• Thin-walled cysts
• Rare honeycombing
5-year survival:
more than 95%
Respiratory
bronchiolitis–
associated
interstitial lung
disease
Respiratory
bronchiolitis
Subacute
Weeks - months
• Diffuse bronchial wall thickening
• Centrilobular nodules
• Patchy ground-glass opacity
No deaths
reported

29. DIFFERENTIAL DIAGNOSIS
Connective tissue disease-associated
• Common associated patterns: NSIP and LIP
• Less common: UIP (especially with Rheumatoid arthritis)
• Think about connective tissue diseases if:
– More Interstitial chronic inflammation
• Prominent plasma cells differentiation
• Lymphoid aggregates with germinal center
– Less fibrosis / honeycomb changes
– Extensive pleuritic
– Dense perivascular collagen
• Also positive specific antibodies

30. DIFFERENTIAL DIAGNOSIS
Other restrictive lung diseases
 Chest Wall / Pleura
• Neuromuscular diseases (e.g. poliomyelitis)
• Severe obesity
• Pleural diseases
• Kyphoscoliosis

31. DIFFERENTIAL DIAGNOSIS
G e n e r a l C a t e g o r i e s of G r a n u l o m a s
Classic
(Non-
necrotizing)
Necrotizing
Caseating Necrobiotic Suppurative
Non-classic

32. DIFFERENTIAL DIAGNOSIS
1. Classic (non-necrotizing):
• Round aggregate of histiocytes
– Abundant cytoplasm (epithelioid)
– Indistinct cell borders (syncytial growth)
• Giant cells are usually (but not always) present
• Examples:
– Foreign body or particles (suture, beryllium)
– Sarcoidosis
– Infection (some cases are non-necrotizing)
– Autoimmune (Crohn’s, hypersensitivity pneumonitis, primary biliary cirrhosis)
– Drug reactions
– Chronic granulomatous disease (rare)
Better to called it granulomatous
inflammation (rather than granuloma) if
syncytial aggregates of
histiocytes/giant cells are in sheets
(rather than in a discreet nodule)

33. DIFFERENTIAL DIAGNOSIS
2. Caseating granuloma:
• Caseating:
– Cheese-like appearance
– Macroscopic term only
• Necrotizing:
– Microscopic counterpart to “caseating”
• Examples:
– Infection (TB, fungus)
– Sarcoidosis (minimal necrosis is allowed)
– Necrobiotic granulomas (see later)

34. DIFFERENTIAL DIAGNOSIS
3. Suppurative granuloma:
• Granulomas with central collections of neutrophils
• Also called “ stellate microabscesses “
• Examples:
– Cat scratch disease (Bartonella henselae)
– Lymphogranuloma venereum (Chlamydia trachomatis)
– Tularemia
– Yersinia
• You should rule out Mycobacteria, Fungi at first

35. DIFFERENTIAL DIAGNOSIS
4. Necrobiotic granuloma:
• Granulomas with central nuclear (karyorrhectic) debris
– Resulted from degenerated neutrophils and/or degenerated collagen
– Appear as Blue-red granular necrosis
– In dermatopathology cases, it may appear bluish “degenerated” collagen, without
prominence of nuclear debris
• Macrophages at the periphery have elongated
nuclei that are palisaded (parallel to each other)
– Called “ palisading granulomas “

36. DIFFERENTIAL DIAGNOSIS
4. Necrobiotic granuloma:
• Examples:
– Rheumatoid nodule
– Post-transurethral resection granuloma (prostate, bladder)
– Wegener’s granulomatosis
– Granuloma annulare (central mucin)
– Necrobiosis lipoidica (shins; cake-like horizontal layers)
Granulomaannulare
Necrobiosislipoidica

37. DIFFERENTIAL DIAGNOSIS
5. Non-classic granulomas:
• Either a “misnomer”
– E.g. clinical term of “nodule/mass”, applied by non-pathologists
• Or Not strictly follow the “classic definition” of granulomas
– E.g. lesions where histiocytes are present but are not prominent
• Examples:
– Plasma cell granuloma (lung) = Inflammatory myofibroblastic tumor
– Eosinophilic granuloma (lung) = Langerhans cell histiocytosis
– Pulmonary hyalinizing granuloma = sclerosing lesion analogous to sclerosing mediastinitis
– Pyogenic granuloma = Lobular capillary hemangioma
– Lethal midline granuloma = NK/T lymphoma nasal type

38. DIFFERENTIAL DIAGNOSIS
Other Granulomatous Lung Diseases
• Infectious diseases (e.g. TB, fungi)  organisms detected by special stains
• Foreign bodies (e.g. Beryllium, talc, aluminum)  clinical history
• Sarcoidosis  clinical history, well formed granulomas distributed along lymphatic pathways
“bronchovascular bundles and pleura”, milder interstitial inflammation than HP
• Granulomatous reaction to 1ry / metastatic tumors (e.g. lymphomas, lung cancer,
seminoma)  clinical history
• Drug reactions  clinical history
• Wegener's granulomatosis  poorly formed granulomas, vasculitis, necrosis, c-ANCA
Note that other causes of lung granulomas do NOT show Intraluminal BOOP-like areas or UIP-like
or NSIP-like fibrosis

39. DIFFERENTIAL DIAGNOSIS
Also
• Follicular Bronchiolitis
– No BOOP-like areas or fibroblastic foci
– No granulomas / giant cells
– No interstitial fibrosis
– No history of Exposure

40. DIFFERENTIAL DIAGNOSIS
Honeycomb changes Emphysema
Wall Thick (fibrotic) Thin
Lining Bronchiolar epithelium Alveolar lining
Contents Mucus Air
location Mainly lower lobes Mainly upper lobes
AQUIRED CYSTIC LUNG DISEASES

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H A Z E M A L I