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The 1578th Chest Conference/

3rd Biennial Clnical-Radiologic-Pathologic Secondary lobule of Miller
Correlation
ILS, interlobular
septum
ILS RB

Confident Pathological Diagnosis of RB

RB
Interstitial Lung Diseases ILS Perilobular fibrosis
~Differential Diagnosis between Idiopathic
Interstitial Pneumonias and Chronic Hypersensitivity RB

Pneumonitis and Connective Tissue Diseases~ ILS

centriacinar

Br
Tamiko Takemura,MD, PhD. Br

Department of Pathology, Japanese Red Cross

Medical Center, Tokyo, Japan

Vein and lymphatic vessels in the interlobular septum(ILS)

Secondary lobule of Reid Pulmonary lobule and acinus (Matsumoto, 1977)

perilobular Br
Intralobular membranous RB
bronchiole Pleura

centrilobular Interlobular septum PA

Interlobular vein
Interlobular bronchus,
Pulmonary artery Centriacinar
periacinar
Above mentioned structure
Intralobular vein/venule
Membranous bronchiole
Terminal bronchiole/PA perillobular

PV
Centriacinar
acinus, beneath the terminal bronchiole
(Reid)
(RB and alveoli
Reid lobule composed of 3~5 acini ( 8 mm)
acinus
PA
Miller s secondary lobule contain 1~3
acinus
PV
(Reid L. The pathology of Emphysema lobules of Reid
1967)

Distribution of Intrapulmonary lymphatic vessels (Okada)

Subpleural lymphatics pleura

RB precap
Intralobular venule
Pathological basis of interstitial
TB Capillary
network
Post
cap
pneumonia
Interlobular
Periarterial septum
lymphatic
Lymphatics
along Lymphatics along
bronchus ILS and vein

Interlobular
Interlobular vein
lymphatics
Bronchus
. . .
PA . 1989 p 13

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Back-to back alveoli Interstitial pneumonia is usually defined as diffuse lung disease involving

RB mainly alveolar septa with inflammatory cell infiltration and fibrosis.

AD
normal

AD

AD
Lung parenchyma is cellular~ fibrosing
composed of alveolar duct, NSIP
alveolar sac, alveoli and air

Intraluminal fibrosis Intra-alveolar polypoid fibrosis (Masson body

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

Basement membrane
Collagen fiber
Collagen globule
Elastic fiber
Fibroblast/myofibrobalst

Type pneumocyte
Type pneumocyte
Regenerative
epithelium
macrophage

Obliterative fibrosis

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

Mural incorporation fibrosis of f0brosing NSIP

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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
UIP is the basic pathological pattern 2. Patchy involvement of fibrosis alternating normal alveoli
of interstitial pneumonia 3. Presence of fibroblastic foci
4. Absence of features against diagnosis of UIP suggesting an
alternative diagnosis
Hyaline membrane, Organizing pneumonia, Granuloma
Marked interstitial inflammatory cell infiltrate away from
honeycombing
Predominant airway centered fibrosis
Other features suggestive of an alternate diagnosis (sarcoidosis,
Lagerhans cell histiocytosis, asbetosis etc)

UIP
S10

MB MB TB

A MB

Early phase of UIP Perilobular, periacinar fibrosis

Interlobular vein and artery running along Interlobular septum
65
the perilobular area
63 Intralobular bronchiole running along the Interacinar septum
2001.5.17 Courtesy of Drs. Ogura and Itoh periacinal region
H.O

UIP in early phaseperilobular fibrosis FF

FF

RB A

ILS

v
MB
A

Marked fibrosis at the pleuro-

septal junction (wedge-shaped)
v
ILS
Hyperplasia of smooth
V muscle in the fibrosis

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IPF/UIP UIP Fibrosis along the pleura, interlobular septa, and intralobular
Upper lobe image of the same case vein

V
RB V

A
MB

Perilobular area

485 Fine nodular lesion arising from the pleura

(Reid)
Reconstruction of the arrangement of the connective pleura
tissue septa at the tip of the lingula

Minor septum
Honeycombing
Major septum
Connection between pleurae Broncho-vascular
bundle
Larger septum
Connection bewwen ILS
and bronchus) Minor septum
connection between
pleura and bronchus

L. Reid. The connective tissue septa in the adult human pleura

lung. (Thorax 1959; 14: 138-145)

Autopsy lung of IPF/UIP

Histology of honeycombing

MB

alveolar tip)

Histologically, collapsed alveoli, dilated alveolar ducts

in the cyst wall with smooth muscle hyperplasia.
3~5 mm-sizd Bronchiolar epithelium lining the cystic spaces
concav-convex (bronchiolization)
pleural surface

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Microscopic honeycombing
Alveolar structure is simplified and dilated by periacinar
fibrosis with atelectasis, developing to the clustered cystic
V V
lesions. The dilated bronchioles connect to these cystic
ILS
V lesions.

V
PV
v v

PA
A
MB
br
TB
Pleural indentation at the
A
interlobular septa where A
alveoli are collapsed.

Histopathological criteria for UIP pattern (2011) Combination of HRCT and surgical lung biopsy for the
UIP pattern Probable UIP Possible UIP Not UIP pattern diagnosis of IPF
(All four criteria) pattern pattern (All three (Any of the 6 HRCT Surgical lung biopsy Diagnosis IPF?
criteria) criteria) Pattern (when performed)
Evidence of Evidence of marked Patchy or diffuse Hyaline membranes
marked fibrosis/architectural involvement of lung UIP UIP
Organizing
f ibrosis/architectural distortion, parenchyma by pneumonia Probable UIP Yes
distortion, honeycombing fibrosis, with or Possible UIP
Granuloma
honeycombing in a without interstitial
Marked interstitial Nonclassifiable fibrosis
predominantly Absence of either inflammation
inflammatory cell Not UIP No
subpleural patchy involvement or Absence of other
infiltrate away from
/paraseptal fibroblastic foci, but criteria for UIP (see honeycombing Possible UIP UIP Yes
distribution not both UIP pattern column)
Predominant airway Probable UIP
Presence of patchy Absence of features
centered changes Possible UIP Probable
involvement of lung against a diagnosis of Absence of features
against a diagnosis of Other features
parenchyma by UIP suggesting an Nonclassifiable fibrosis
fibrosis UIP suggesting an suggestive of an
alternate diagnosis
alternate diagnosis alternate diagnosis
Presence of (see fourth column)
(see fourth column) Not UIP No
fibroblastic foci or
Absence of features Honeycomb changes UIP Possible
against diagnosis of only Inconsistent with Probable UIP
UIP suggesting an Possible UIP No
alternate diagnosis UIP
(see fourth column) Non-classifiable fibrosis
Not UIP
Raghu G et al. AJRCCM, 183: 788-824, 2011

Key features for the pathologist in the 2011 evidence- Summary of Update classification of IIPs
based guidelines for IPF
(Larsen & Colby : Arch Pathol Lab Med 2012; 136: 1234-41) 1. Idiopathic NSIP is accepted.
2. RB-ILD is clinico-radiologically diagnosed without surgical biopsy.
1. Surgical lung biopsy is no longer necessary for diagnosis of IPF; CPFE is recognized.
HRCT is acceptable instead
3. The behavior of IPF is acknowledged to be heterogeneousstable,
2. MDD is integral to the diagnosis and management of IPF rapid progression, steady, acute exacerbation)
3. Pathologists should attempt to assign levels of confidence to the 4. Acute exacerbation occurs in chronic fibrosing IP (IPF, NSIP)
histologic diagnosis of UIP, but these levels are not validated 5. Unclassifiable IIPs are recognized, often because of multiple mixed
and should be more conceptual than practical. patterns of lung injury.
4. Acute exacerbation of IPF is an accepted phenomenon, and 6. Clinical algorithm is necessary for classifying and managing IIP
acute lung injury superimposed on a patchy fibrotic UIP-like cases, especially when no biopsy is available.
background. 7. Pleuroparenchymal fibroelastosis (PPFE) is recognized as a specific
5. Exclusionary histologic features for diagnosis of UIP are rare entity.
imprecise, and there are no guideline that specifically define 8. Molecular and genetic studies are necessary to diagnose and predict
how they should be applied. prognosis.

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Revised ATS/ERS classification of IIPs: Multidisciplinary

diagnoses (Travis, et al. AJRCCM 2013; 733-48)
Major idiopathic interstitial pneumonias
Idiopathic pulmonary fibrosis Fibrosing IP Important differential diagnosis
Idiopathic nonspecific interstitial pneumonia
Respiratory bronchiolitis-interstitial lung disease Smoking-
related IP
IIPs vs CHP and CTD
Desquamative interstitial pneumonia
Cryptogenic organizing pneumonia Acute/subacute IP focusing on UIP pattern
Acute interstitial pneumonia
Rare idiopathic interstitial pneumonias
Idiopathic lymphoid interstitial pneumonia
Idiopathic pleuroparencymal fibroelastosis
Unclassifiable idiopathic interstitial pneumonias

Clinical phenotype of CHP Histologic diagnosis of CHP required presence of a bronchiolocentric

(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 subsequent
diagnosis of CHP. (Morell. Lancet Resp Med 2013 1; 685-94, 2013)
These data suggest many cases of CHP are managed as IPF.
chronic 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 interstitialpneumonia (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 %)

Chronic bird-
FF
related HP
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)

UIP in cHP
Radiological features Histopathological features S2

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 bronchovascular
FF v
bundle with rare fibroblast foci
Individual interstitial giant cells, some with
cholesterol clefts
RB
Honeycomb cyst (lower and upper lobes)
Extensive peribronchiolar metaplasia
Bridging fibrosis across lobules

Alcian blue Bridging fibrosis

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Bridging fibrosis Comparison of incidence of pathological features between chronic

linear connection of fibrosis between
centrilobular to perilobular area, HP with UIP-like pattern and IPF/UIP
and centrilobular to centrilobular Pathological features Chronic HP (n=22) IPF/UIP (n=13) P value

Bridging fibrosis is seen in 70% of cHP Bronchiolitis 22 (100 %) 6 (46.2 %) 0.0003

cases. Perilobular fibrosis 22 (100 %) 13 (100 %) 1.0000
Centrilobular fibrosis 22 (100 %) 6 (46.2 %) 0.0003
RB~Subpleural (41 %) RB
Bridging fibrosis 18 (81.8 %) 4 (30.8 %) 0.0042
RB~Interlobular septum (82 %)
Organizing 18 (81.8 %) 3 (23.1 %) 0.0006
RB~RB (65 %) pneumonia
Fibroblastic foci 22 (100 %) 13 (100 %) 1.0000
Honeycombing 13 (59.1 %) 10 (76.9 %) 1.0000
Granuloma 14 (63.6 %) 0 0.0002
RB
Giant cell 15 (68.2 %) 0 <0.0001
Isolated cyst with 3 (13.6 %) 0 0.2790
RB collagen deposition
ILS
RB Lymphocytic 19 (86.4 %) 4 (30.8 %) 0.0022
v alveolitis
ILS
RB
Lymphoid follicle Histopathology
(Takemura 17 (77.3 %) 61: 1026-35)
2012: 5 (38.5 %) 0.0268

Patterns of fibrosis of CHP Autopsy cases of chronic bird fanciers disease

Abundant exposure Small amount exposure
Centrilobular (centrilacinar) fibrosis
Insult to the respiratory bronchiole Alveolar duct Intralumial and
peribronchiolar fibrosis obliteration, centriacinar(centrilobular)fibrosis

Perilobular (periacinar) fibrosis UIP pattern

Diffusion of antigens to the peripheral alveoli Macrophage and
lymphatic clearance Perilobular accumulation, inflammation and
fibrosis

Bridging fibrosis

Connection between centrilobulra(centriacinar) and perilobular

/periacinar fibrosis, or centriacinar to centriacinar

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

Comparison of Microscopic Features between

CHP and IPF/UIP in autopsy cases Histopathological features of CHP autopsy lungs
CHP (n=16) IPF/UIP (n=11)
UIP f- CLF* Bridging Atelectat Cyst with
patter NSIP fibrosis* ic collagen
UIP-like area Fibroblastic foci 2 0 deposit *
absent n patter fibrosis
6 9
n
2 0
present BFL Insidious
Lymphoid follicle 14 11 11 4 11 7 4 9
n=12 DAD 7
absent
Recurren 1 1 1 1 0 0
present t
F-NSIP like area absent 3 7
present 9 4 SHP Insidious 2 2 2 1 2 1
n=4
CLF absent 0 3
present 16 8 * Recurren 2 2 2 0 0 1
p<0.03 t
DAD 2
Bridging fibrosis absent 8 10 CLF; centrilobular fibrosis
present 8 1 * * CLF, bridging fibrosis, and cyst with membranous collagen deposit
p<0.03 significantly present in CHP compared with IPF/UIP (p<0.03)
Atelectasis(Akashi ,Takemura absent
Am J Clin Pathol10 5
2009; 131:405-415)
present 6 6

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

CHP IPF/UIP vs CTD/UIP

Bronchiole
Pulmonary artery
Fibrosis

Usual interstitial pneumonia-pattern fibrosis in

RA 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)

UIP in rheumatic disease

Radiological features Histopathological features

Reticular opacities with lobular Fibrosis

more haphazard and more airway-
distortion centerd
Honeycomb cysts uncommon and fewer Nodular inflammatory(lymphoid)
than infiltration, often with germinal centers
UIP in IPF NSIP-like alveolar septal fibrosis
Traction bronchioloectasis common
RA 60s M Airway-associated abnormalities Follicular bronchiolitis common
Arthralgia, Pleural effusion, sometimes Bronchiolar remodeling common
Anti CCP Ab 753.9U/ml , (peribronchiolar metaplasia)
Honeycombing, UIP pattern RF 43.4 IU/ml Pleural inflammation and fibrosis common
Perilobular fibrosis
Occasional fibroblast foci (always fewer
Lymphoid follicles with than UIP in IPF)
germinal center

Comparison of pathologic scores between Connective tissue disease-associated interstitial lung

CVD-UIP and IPF/UIP disease. A call for clarification (Lung-dominant CTD)
(Fischer A, e t al. Chest 2010; 138: 251-156)
Category CVD-UIP IPF/UIP (n=61) P value
(n=39) 1. Interstitial pneumonia(NSIP, UIP, LIP, OP, DAD) as determined by SLB or
Fibroblastic foci 1.56 0.74 2.01 0.81 0.007 HRCT and
2. Not definite connective disease and
Germinal centers 1.04 1.07 0.33 0.61 < 0.001 3. No identifiable alternative etiology for IP and
4. Any one of the following autoantibodies ot at least two of the
Total inflammation 2.10 0.69 1.74 0.66 0.010 histopathology features:
Honeycomb (size) 1.71 1.09 2.20 1.09 0.034 Autoantibodies
ANA(>1:x320), RF(>60 IU/ml), Nucleolar ANA, anti-CCP,
Plasma cells 1.72 0.68 1.43 0.71 0.044 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
Organizing 0.33 0.53 0.38 0.60 NS
Pathological features
pneumonia
a) Lymphoid aggregates with germinal centers
Intraalveolar M 0.76 0.54 0.85 0.45 NS b) Extensive pleuritis
c) Prominent plasmacytic infiltration
Pleural fibrosis, % of 4 (10.5) 7 (11.5) NS
affected cases
d) Dense perivascular collagen
(Song JW Chest 2009; 136: 23-30)

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Histopathological features of Lung dominant-CTD
Extensive pleuritis
Prominent plasmacytic infiltration
60s Male
ANA 640 x, RAPA 1280 x
UIP pattern with lymphoid follicles
upper lobe
Pleuroparenchymal fibroelastosis (PPFE)
Pleural thickening with collagen
Parenchymal fibrosis
(intraalveolar collagen deposition)
Parenchymal elastosis (subpleural
elastosis)
High frequency of pneumothorax
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Autoimmune-featured interstitial lung disease
A distinct Entity (Vij, Chest 2011; 140: 1292-99)
Patients with ILD may have features of an autoimmune
disorder that do not meet the diagnostic criteria fro CTD.
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 %,
Lymphoid follicle with germinal center
Patients with AIF-ILD and IPF had similar survival, worse than those with
CTD-ILD.
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.
Dense perivascular collagen
No apparent CTD, 4 years after biopsy
Idiopathic Pleuoparenchymal Fibroelastosis
(PPFE)
Amitani s disease; idiopathic pulmonary upper lobe
fibrosis (1992)
Frankel; Idiopathic pleuroparenchymal fibroelastosis
(2004)
Fibroblastic foci at the edge of elastofibrosis Intra-alveolar fibrosis with marked
elastosis.
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Clinical settings of PPFE

Idiopathic
Bone marrow transplantation
Drugs(chemotherapy) Rare histologic patterns of IP
Radiation
Graft-vs-host disease
Tuberculosis
Mycobacteriosis (MAC)
Ankylosing spondylitis
Pulmonary Langerhans cell histiocytosis
Sarcoidosis
Chronic hypersensitivity pneumonitis
Pneumoconiosis(silicosis, asbestosis)
Rheumatoid arthritis
Neuromuscular disorders

1. Acute fibrinous organizing pneumonia 2. Bronchiolocentric patterns of interstitial pneumonia

may be associated with environmental and occupational exposures

(1) Intra-alveolar fibrin (2) OP (3) Patchy distribution Chronic bird-related HP Hard metal lung disease; Fibrosis
confined to the respiratory bronchiole
This is a case of RA.
AFOP can be seen in CTD, HP, and drug-induced lung disease.

Coexisting patterns UIP+ f-NSIP

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)
Insmokers, 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.

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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 2(b) new entity

Cystic lesion beneath the terminal
bronchiole, destructive alveoli,
Mucostasis, fibroblastic foci
(smoking related IP)

Fibroblastic focus (

Rt.S4

Rt.S9

2(b) unusual variant of recognized entity

C-NSIP background + acute lung injury
Summary

1. Pathological diagnosis should be made in

reference to the clinical relevance and course,
and HRCT findings in each case.
CK
2. The diagnosis and management of the IIPs
require clinical-radiologic-pathologic correlations
with a multidisciplinary discussion.
Epithelial shedding, fibrinous exudate
Macrophage and mononuclear cell
infiltration
Ill-defined border between
alveolar septum and lumina

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