29/08/57 1 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 1578 th Chest Conference/ 3 rd 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 Br Br 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 Pleura Interlobular septum Interlobular vein Interlobular bronchus, Pulmonary artery Above mentioned structure Intralobular vein/venule Membranous bronchiole Terminal 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 Capillary network Periarterial lymphatic Interlobular septum Lymphatics along ILS and vein Interlobular lymphatics RB TB Lymphatics along bronchus Interlobular vein Bronchus PA Pathological basis of interstitial pneumonia
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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
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)
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)
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
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
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
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