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Confident Pathological Diagnosis of Interstitial Lung Diseases

~Differential Diagnosis between Idiopathic Interstitial Pneumonias and Chronic Hypersensitivity

Pneumonitis and Connective Tissue Diseases~

Tamiko Takemura,MD, PhD.Department of Pathology, Japanese Red Cross Medical Center, Tokyo, Japan

The 1578th Chest Conference/3rd Biennial Clnical-Radiologic-Pathologic Correlation

Secondary lobule of Miller

ILS, interlobular septum

Perilobular fibrosis

centriacinar

Vein and lymphatic vessels in the interlobular septum(ILS)

RB

RB

RB

BrBr

ILS

ILS

ILS

RB

Secondary lobule of Reid

●acinus, beneath the terminal bronchiole (Reid)Reid’ lobule composed of 3~5 acini ( 8 mm)

●Miller ‘s secondary lobule contain 1~3 lobules of Reid(Reid L. The pathology of Emphysema

1967)

Centriacinar

(RB and alveoli）

終末細気管支

Intralobular membranous bronchiole

centrilobular

PleuraInterlobular septumInterlobular veinInterlobular bronchus, Pulmonary artery

Above mentioned structureIntralobular vein/venuleMembranous bronchioleTerminal bronchiole/PA

perilobular

periacinar

Pulmonary lobule and acinus (Matsumoto, 1977)

PV

PA

Br

PV

PA

acinus

RB

Centriacinar

acinus

perillobular

岡田慶夫. （図説. 肺のリンパ系と肺癌. 金芳堂. 1989 p 13）

precap

Post cap

Distribution of Intrapulmonary lymphatic vessels (Okada)

Subpleural lymphatics pleura

Intralobular venule

Capillarynetwork

Periarteriallymphatic

Interlobular septum

Lymphatics along ILS and vein

Interlobularlymphatics

RB

TB

Lymphaticsalong bronchus

Interlobular vein

Bronchus

PA

Pathological basis of interstitial pneumonia

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RB

Back-to back alveoli

細血管は背中合わせ肺胞の稜の部分に存在

Lung parenchyma is composed of alveolar duct, alveolar sac, alveoli and air

AD

AD

AD

Interstitial pneumonia is usually defined as diffuse lung disease involving mainly alveolar septa with inflammatory cell infiltration and fibrosis.Ⅰ型

Ⅱ型

cellular~ fibrosingNSIP

normal

Basset F:Am J Pathol 1986; 122: 443-461

Intraluminal fibrosis

Basement membrane

Collagen fiber

Elastic fiber

Fibroblast/myofibrobalst

Type Ⅰpneumocyte

Type Ⅱpneumocyte

Regenerative epithelium

macrophage

Collagen globule

Intra-alveolar polypoid fibrosis (Masson body）

Alcian blue-PAS

Mural incorporation fibrosis of f0brosing NSIP

Obliterative fibrosis

DAD organizing ; proliferation of fibroblast and myofobrobalsts in the alveolar walls and alveolar lumina with ill-definedborder.

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UIP is the basic pathological pattern of interstitial pneumonia

UIP pattern according to 2002 statement and 2011 guideline (AJRCCM 2002;165: 277-304, 2011; 183: 788-824)

1. Marked fibrosis with architecture distortion with or without

honeycombing in predominantly subpleural and paraseptal

distribution

2. Patchy involvement of fibrosis alternating normal alveoli

3. Presence of fibroblastic foci

4. Absence of features against diagnosis of UIP suggesting an

alternative diagnosis

① Hyaline membrane, ② Organizing pneumonia, ③ Granuloma

④Marked interstitial inflammatory cell infiltrate away from

honeycombing

⑤ Predominant airway centered fibrosis

⑥ Other features suggestive of an alternate diagnosis (sarcoidosis,

Lagerhans’ cell histiocytosis, asbetosis etc)

H.O

2001.5.17

63

UIP （小葉辺縁性病変）

65

Courtesy of Drs. Ogura and Itoh

Early phase of UIP ：Perilobular, periacinar fibrosis

●Interlobular vein and artery running along the perilobular area●Intralobular bronchiole running along the periacinal region

MB MB TB

MB

Interlobular septum

Interacinar septum

S10

A

UIP in early phase：perilobular fibrosis → FF

MB

V

ILS

A

Ｖ

ILS

v

RB A

FF

v

Hyperplasia of smooth muscle in the fibrosis

Marked fibrosis at the pleuro-septal junction (wedge-shaped)

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485

IPF/UIP

Fine nodular lesion arising from the pleura

Upper lobe image of the same case

RB

MBA

Fibrosis along the pleura, interlobular septa, and intralobularvein

UIP

V

V

V

V

Perilobular area

舌区先端の小葉間隔壁の模式図 (Reid)

L. Reid. The connective tissue septa in the adult humanlung. (Thorax 1959; 14: 138-145)

pleura

Broncho-vascular bundle

pleura

Minor septum

Larger septum

Major septum

（Connection bewwen ILS and bronchus)

（connection between pleura and bronchus）

Reconstruction of the arrangement of the connective tissue septa at the tip of the lingula

Minor septum

Connection between pleurae

Honeycombing

Autopsy lung of IPF/UIP

3~5 mm-sizdconcav-convex pleural surface

Histologically, collapsed alveoli, dilated alveolar ducts

in the cyst wall with smooth muscle hyperplasia.

Bronchiolar epithelium lining the cystic spaces

(bronchiolization)

Histology of honeycombing

（→alveolar tip)

MB

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V

PVV

V

br

A

PA

ILS

A

V

MB

Pleural indentation at the interlobular septa wherealveoli are collapsed.

Microscopic honeycombing

Alveolar structure is simplified and dilated by periacinarfibrosis with atelectasis, developing to the clustered cystic

lesions. The dilated bronchioles connect to these cystic lesions.

v v

A

TB

Histopathological criteria for UIP pattern (2011)

UIP pattern

(All four criteria)

Probable UIP pattern

Possible UIP pattern (All three

criteria)

Not UIP pattern

(Any of the 6 criteria)

●Evidence of marked

f ibrosis/architectural distortion, ±honeycombing in a predominantly subpleural/paraseptaldistribution

●Presence of patchy involvement of lung parenchyma by fibrosis

●Presence of fibroblastic foci

●Absence of features against diagnosis of UIP suggesting an alternate diagnosis (see fourth column)

●Evidence of marked fibrosis/architectural distortion, ±honeycombing

●Absence of either patchy involvement orfibroblastic foci, but not both

●Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (see fourth column)

or

● Honeycomb changes

only

●Patchy or diffuse involvement of lung parenchyma by fibrosis, with or without interstitial inflammation

●Absence of other criteria for UIP (see UIP pattern column)

●Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (see fourth column)

●Hyaline membranes

●Organizing pneumonia

●Granuloma

●Marked interstitial inflammatory cell infiltrate away from honeycombing

●Predominant airway centered changes

●Other features suggestive of an alternate diagnosis

（Raghu G et al. AJRCCM, 183: 788-824, 2011）

HRCT Surgical lung biopsyPattern (when performed)

Diagnosis IPF?

UIP UIPProbable UIPPossible UIPNonclassifiable fibrosis

Not UIP

Yes

No

Possible UIP UIPProbable UIP

Possible UIPNonclassifiable fibrosis

Not UIP

Yes

Probable

No

Inconsistent with UIP

UIPProbable UIP

Possible UIPNon-classifiable fibrosisNot UIP

Possible

No

Combination of HRCT and surgical lung biopsy for the diagnosis of IPF

Key features for the pathologist in the 2011 evidence-based guidelines for IPF (Larsen & Colby : Arch Pathol Lab Med 2012; 136: 1234-41)

1. Surgical lung biopsy is no longer necessary for diagnosis of IPF; HRCT is acceptable instead

2. MDD is integral to the diagnosis and management of IPF

3. Pathologists should attempt to assign levels of confidence to the histologic diagnosis of UIP, but these levels are not validated and should be more conceptual than practical.

4. Acute exacerbation of IPF is an accepted phenomenon, and acute lung injury superimposed on a patchy fibrotic UIP-like background.

5. “Exclusionary” histologic features for diagnosis of UIP are imprecise, and there are no guideline that specifically define how they should be applied.

Summary of Update classification of IIPs

1. Idiopathic NSIP is accepted.

2. RB-ILD is clinico-radiologically diagnosed without surgical biopsy.

CPFE is recognized.

3. The behavior of IPF is acknowledged to be heterogeneous（stable, rapid progression, steady, acute exacerbation)

4. Acute exacerbation occurs in chronic fibrosing IP (IPF, NSIP)

5. Unclassifiable IIPs are recognized, often because of multiple mixed patterns of lung injury.

6. Clinical algorithm is necessary for classifying and managing IIP cases, especially when no biopsy is available.

7. Pleuroparenchymal fibroelastosis (PPFE) is recognized as a specific rare entity.

8. Molecular and genetic studies are necessary to diagnose and predict prognosis.

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Revised ATS/ERS classification of IIPs: Multidisciplinary diagnoses (Travis, et al. AJRCCM 2013; 733-48)

Major idiopathic interstitial pneumoniasIdiopathic pulmonary fibrosisIdiopathic nonspecific interstitial pneumoniaRespiratory bronchiolitis-interstitial lung diseaseDesquamative interstitial pneumoniaCryptogenic organizing pneumoniaAcute interstitial pneumonia

Rare idiopathic interstitial pneumoniasIdiopathic lymphoid interstitial pneumoniaIdiopathic pleuroparencymal fibroelastosis

Unclassifiable idiopathic interstitial pneumonias

Fibrosing IP

Acute/subacute IP

Smoking-related IP

Important differential diagnosis

IIPs vs CHP and CTD

focusing on UIP pattern

Clinical phenotype of CHP(Yoshizawa, Y. J Allergy Clin Immunol 1999; 103: 315-320)

• Recurrent type; pulmonary fibrosis after repeated acute episodes

• Insidious onset ;chronic disease without acute episodes

＊It is difficult to differentiate insidious-onset chronic HP from IPF.

* Up to 30 % of subjects with histologic HP have no identifiable antigen. (Travis et al. AJRCCM 2013; 188: 733-748)

*43 % of patients with IPF according to 2011 guideline had a subsequentdiagnosis of CHP. (Morell. Lancet Resp Med 2013 1; 685-94, 2013)

These data suggest many cases of CHP are managed as IPF.

Histologic diagnosis of CHP required presence of a bronchiolocentricchronic interstitial pneumonias and/or chronic bronchiolitis and poorly formed nonnecrotizing granulomatous inflammation confined to peribronchiolar interstitium. (Trahan et al. 2008; Chest 134; 126-132)

(31 specimens from 15 patients with clinical diagnosis of HP)

●1) Bronchiolocentric chronic interstitial pneumonia (83 %)

2) Interstitial pneumonia with a peripheral/subpleural and /or patchwork distribution (16%)

3) Fibroblastic foci (associated with honeycomb 13 %,

unrelated to OP or honeycomb 26 %)

4) Honeycomb change (16 %)

● 5) Lymphoid hyperplasia (79 %)

● 6) Chronic bronchiolitis (96 %)

7) Peribronchiolar fibrosis with bronchiolar metaplasia (54 %)

● 8) Isolated multinucleated giant cells (71 %)

● 9) Poorly-formed granulomas within peribronchiolar interstitium (58 %)

10) Organizing pneumonia (42 %)

Usual interstitial pneumonia-pattern fibrosis in surgical lung biopsies. Clinical, radiological and histopathological clues to aetiology. (Smith M, Dalurzo M, Panse P et al. J Clin Pathol 2013; 66: 896-903)

Radiological features Histopathological features

●Reticular pattern with traction bronchiectasis●Ground-glass opacities, common●Mid and upper lung zones commonly affected in a bronchovascular distribution with resulting micronodules●Non-basilar distribution common●Mosaic attenuation●Irregular bronchovascular bundles●Subpkleural honeycomb cysts, not always basilar

●Patchy fibrosis along the bronchovascularbundle with rare fibroblast foci●Individual interstitial giant cells, some with cholesterol clefts●Honeycomb cyst (lower and upper lobes)●Extensive peribronchiolar metaplasia●Bridging fibrosis across lobules

UIP in cHP

S2

FF v

RB

Bridging fibrosis

FF

Alcian blue

Chronic bird-related HP

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Bridging fibrosislinear connection of fibrosis between centrilobular to perilobular area,

and centrilobular to centrilobular

① RB~Subpleural (41 %)

② RB~Interlobular septum (82 %)

③ RB~RB (65 %)

①

② ③

RB

ILS

v

RB

RB

RB

RBILS

Bridging fibrosis is seen in 70% of cHPcases.

Comparison of incidence of pathological features between chronic HP with UIP-like pattern and IPF/UIP

Pathological features Chronic HP (n=22) IPF/UIP (n=13) P value

Bronchiolitis 22 (100 %) 6 (46.2 %) 0.0003

Perilobular fibrosis 22 (100 %) 13 (100 %) 1.0000

Centrilobular fibrosis 22 (100 %) 6 (46.2 %) 0.0003

Bridging fibrosis 18 (81.8 %) 4 (30.8 %) 0.0042

Organizing pneumonia

18 (81.8 %) 3 (23.1 %) 0.0006

Fibroblastic foci 22 (100 %) 13 (100 %) 1.0000

Honeycombing 13 (59.1 %) 10 (76.9 %) 1.0000

Granuloma 14 (63.6 %) 0 0.0002

Giant cell 15 (68.2 %) 0 <0.0001

Isolated cyst with collagen deposition

3 (13.6 %) 0 0.2790

Lymphocytic alveolitis

19 (86.4 %) 4 (30.8 %) 0.0022

Lymphoid follicle 17 (77.3 %) 5 (38.5 %) 0.0268(Takemura Histopathology 2012: 61: 1026-35)

Patterns of fibrosis of CHP

Perilobular (periacinar) fibrosis UIP pattern

Centrilobular (centrilacinar) fibrosis

Bridging fibrosis

Insult to the respiratory bronchiole ～Alveolar duct → Intralumial and peribronchiolar fibrosis → obliteration, centriacinar(centrilobular)fibrosis

Diffusion of antigens to the peripheral alveoli → Macrophage and

lymphatic clearance → Perilobular accumulation, inflammation and

fibrosis

Connection between centrilobulra(centriacinar) and perilobular

/periacinar fibrosis, or centriacinar to centriacinar

Autopsy cases of chronic bird fancier’s disease

The patient had fed 300 chickens The patient had contact to birds in the park

Abundant exposure Small amount exposure

Comparison of Microscopic Features betweenCHP and IPF/UIP in autopsy cases

CHP (n=16) IPF/UIP (n=11)

UIP-like area Fibroblastic foci absent

present

Lymphoid follicle absent

present

2

6

2

14

0

9

0

11

F-NSIP like area absent

present

3

9

7

4

CLF absent

present

0

16

3

8 * p<0.03

Bridging fibrosis absent

present

8

8

10

1 * p<0.03

Atelectasis absent

present

10

6

5

6(Akashi ,Takemura Am J Clin Pathol 2009; 131:405-415)

Histopathological features of CHP autopsy lungs

UIP pattern

f-NSIP

pattern

CLF* Bridging fibrosis*

Atelectaticfibrosis

Cyst with collagen

deposit *

BFL

n=12

Insidious 11DAD 7

4 11 7 4 9

Recurrent

1 1 1 1 0 0

SHP

n=4

Insidious 2 2 2 1 2 1

Recurrent

2DAD 2

2 2 0 0 1

CLF; centrilobular fibrosis* CLF, bridging fibrosis, and cyst with membranous collagen deposit significantly present in CHP compared with IPF/UIP (p<0.03)

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Three dimensional reconstruction ofcentrilobular and bridging fibrosis of CHPvs IPF/UIP

BronchiolePulmonary arteryFibrosis

CHP

IPF/UIP

IPF/UIP vs CTD/UIP

RA

RA 60’s M Arthralgia,Anti CCP Ab 753.9U/ml , RF 43.4 IU/ml

Honeycombing,Perilobular fibrosisLymphoid follicles with germinal center

UIP pattern

Usual interstitial pneumonia-pattern fibrosis in surgical lung biopsies. Clinical, radiological and histopathological clues to aetiology. (Smith M, Dalurzo M, Panse P et al. J Clin Pathol 2013; 66: 896-903)

Radiological features Histopathological features

●Reticular opacities with lobular distortion●Honeycomb cysts uncommon and fewer than

UIP in IPF●Traction bronchioloectasis●Airway-associated abnormalities●Pleural effusion, sometimes

●Fibrosis more haphazard and more airway-centerd●Nodular inflammatory(lymphoid) infiltration, often with germinal centers●NSIP-like alveolar septal fibrosis

common● Follicular bronchiolitis common● Bronchiolar remodeling common (peribronchiolar metaplasia)● Pleural inflammation and fibrosis common●Occasional fibroblast foci (always fewer than UIP in IPF)

UIP in rheumatic disease

Comparison of pathologic scores betweenCVD-UIP and IPF/UIP

Category CVD-UIP (n=39)

IPF/UIP (n=61) P value

Fibroblastic foci 1.56 ± 0.74 2.01 ± 0.81 0.007

Germinal centers 1.04 ± 1.07 0.33± 0.61 < 0.001

Total inflammation 2.10 ± 0.69 1.74 ± 0.66 0.010

Honeycomb (size) 1.71 ± 1.09 2.20 ± 1.09 0.034

Plasma cells 1.72± 0.68 1.43± 0.71 0.044

Organizing pneumonia

0.33 ± 0.53 0.38 ± 0.60 NS

Intraalveolar Mφ 0.76 ± 0.54 0.85 ± 0.45 NS

Pleural fibrosis, % of

affected cases

4 (10.5) 7 (11.5) NS

(Song JW Chest 2009; 136: 23-30)

Connective tissue disease-associated interstitial lung disease. A call for clarification (Lung-dominant CTD)

(Fischer A, e t al. Chest 2010; 138: 251-156)

1. Interstitial pneumonia(NSIP, UIP, LIP, OP, DAD) as determined by SLB or HRCT and2. Not definite connective disease and3. No identifiable alternative etiology for IP and 4. Any one of the following autoantibodies ot at least two of the

histopathology features:Autoantibodies

ANA(>1:x320), RF(>60 IU/ml), Nucleolar ANA, anti-CCP,

anti-Scl-70,anti-Ro, anti-LA, anti-dsDNA, anti-Smith,anti- RNP, anti- t RNA synthetase(Jo-1, PL-7, PL-12, EJ) anti-PM-Scl, anti-centromere

Pathological features a) Lymphoid aggregates with germinal centersb) Extensive pleuritisc) Prominent plasmacytic infiltrationd) Dense perivascular collagen

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Histopathological features of Lung dominant-CTD

Lymphoid follicle with germinal centerExtensive pleuritis

Prominent plasmacytic infiltrationDense perivascular collagen

Autoimmune-featured interstitial lung disease A distinct Entity (Vij, Chest 2011; 140: 1292-99)

Comparison between AIF-ILD(63 cases), IPF(58 cases), and known CTD-ILD(37 cases):

62 % of patients with AIF-ILD had UIP on CT

Lung Bx; UIP 81 %, NSIP 6 %,

Patients with AIF-ILD and IPF had similar survival, worse than those with CTD-ILD.

Patients with ILD may have features of an autoimmune disorder that do not meet the diagnostic criteria fro CTD.

Frequency and implication of autoimmune serologies in IPF (Moua T.Mayo Clin Proc 2014; 89: 319-326)

29 % of patients with biopsy-confirmed IPF have positive serologic tests.No survival difference was observed between cases with or without autoantibodies.

60’s MaleANA 640 x, RAPA 1280 x No apparent CTD, 4 years after biopsy

UIP pattern with lymphoid follicles

Idiopathic Pleuoparenchymal Fibroelastosis(PPFE)

Amitani’ s disease; idiopathic pulmonary upper –lobe fibrosis (1992)Frankel; Idiopathic pleuroparenchymal fibroelastosis(2004)

upper lobePleuroparenchymal fibroelastosis (PPFE)

●Pleural thickening with collagen●Parenchymal fibrosis (intraalveolar collagen deposition)

●Parenchymal elastosis (subpleuralelastosis)

High frequency of pneumothorax

Fibroblastic foci at the edge of elastofibrosis Intra-alveolar fibrosis with marked elastosis.

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Clinical settings of PPFE

IdiopathicBone marrow transplantationDrugs(chemotherapy)RadiationGraft-vs-host disease

TuberculosisMycobacteriosis (MAC)Ankylosing spondylitisPulmonary Langerhans cell histiocytosisSarcoidosisChronic hypersensitivity pneumonitisPneumoconiosis(silicosis, asbestosis)Rheumatoid arthritis Neuromuscular disorders

Rare histologic patterns of IP

1. Acute fibrinous organizing pneumonia

This is a case of RA. AFOP can be seen in CTD, HP, and drug-induced lung disease.

(1) Intra-alveolar fibrin (2) OP (3) Patchy distribution

2. Bronchiolocentric patterns of interstitial pneumoniamay be associated with environmental and occupational exposures

Chronic bird-related HP Hard metal lung disease; Fibrosis confined to the respiratory bronchiole

Coexisting patterns

Multiple pathologic and /or HRCT patterns may be found in the same patient.

● Different patterns my be seen in a single biopsy or in biopsies from multiple sites, or when pathologic and HRCT patterns differ. (e.g.UIP-NSIP, discordant UIP)

● In smokers, multiple features may coexist, i.e.,

PLCH, RB, DIP, pulmonary fibrosis (UIP, NSIP), and emphysema.

●CPFE is an example of coexisting patterns (UIP, NSIP and

emphysema)

● When coexisting patterns occur, MDD may determine the clinical significance of individual patterns.

UIP+ f-NSIP

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UIP+centrilobular cystic lesion and mucostasis (smoking-related change) Unclassifiable IIPs

1) Inadequate clinical, radiologic or pathologic data

2) Major discordance between clinical, radiologic, or pathologic findings in the following situations

a. previous therapy resulting in substantial alteration of radiologic or histologic findings. (e.g., DIP→ f-NSIP)

b. new entity, or unusual variant of recognized entity

c. multiple HRCT findings and pathologic patterns with IIP.

2(a) DIP steroid → f-NSIP

Fibroblastic focus (→）

Rt.S4

Rt.S9

2(b) new entity

Cystic lesion beneath the terminal bronchiole, destructive alveoli,Mucostasis, fibroblastic foci

(smoking related IP)

2(b) unusual variant of recognized entity C-NSIP background + acute lung injury

CK

Ill-defined border between alveolar septum and lumina

Epithelial shedding, fibrinous exudateMacrophage and mononuclear cell infiltration

1. Pathological diagnosis should be made in reference to the clinical relevance and course, and HRCT findings in each case.

2. The diagnosis and management of the IIPs require clinical-radiologic-pathologic correlations with a multidisciplinary discussion.

Summary