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Ipf or non ipf interstitial lung diseases
1.
2. IPF or Non-IPF Interstitial Lung
Diseases
By
Gamal Rabie Agmy , MD , FCCP
Professor of Chest Diseases ,Assiut University
3.
4. What is the Pulmonary
Interstitium?
• Interstitial compartment is
the portion of the lung
sandwiched between the
epithelial and endothelial
basement membrane
• Expansion of the interstitial
compartment by
inflammation with or without
fibrosis
– Necrosis
– Hyperplasia
– Collapse of basement
membrane
– Inflammatory cells
5.
6. The Lung Interstitium
The interstitium of the lung is not normally visible radiographically; it becomes visible only when disease (e.g., edema,
fibrosis, tumor) increases its volume and attenuation.
The interstitial space is defined as continuum of loose
connective tissue throughout the lung composed of three
subdivisions:
(i) the bronchovascular (axial), surrounding the bronchi,
arteries, and veins from the lung root to the level of the
respiratory bronchiole
(ii) the parenchymal (acinar), situated between the alveolar
and capillary basement membranes
(iii) the subpleural, situated beneath the pleura, as well as in
the interlobular septae.
8. The terminal bronchiole in the center
divides into respiratory bronchioles with
acini that contain alveoli.
Lymphatics and veins run within the
interlobular septa
Centrilobular area in blue (left)
and perilymphatic area in yellow
(right)
22. Practical issues
• Clinical setting with regular meetings
of key specialists
• Not all IIP cases are classifiable:
„non-classifiable interstitial
pneumonias‟ (8th category)
• NSIP is an area of important
uncertainty (NSIP ~ provisional
category)
> 50% of inter-observer variation between pathologists
and radiologists relate to the diagnosis of NSIP
Nicholson AG, Thorax 2004; 59:500-5 // Aziz ZA, Thorax 2004; 59:506-11
26. Roles of Clinicians,
Radiologists and Pathologists
•History
•Exposure
•Drugs
•Symptoms & Signs
Clinicians
(Pulmonologists)
Radiologists
•Should know, identify
and report patternspecific features
•Systemic
Diseases (CVD)
•Age
Pathologists
•Should know, identify
and report patternspecific features
27. Diagnostic Process in DPLD
History, physical examination,
chest radiograph, lung function tests
Not IIP
Possible IIP
e.g. assoc. collagen vascular disease,
environmental, drug-related, etc.
HRCT
33. HRCT
Confident CT
diagnosis of IPF with
consistent clinical
features
Atypical clinical
or CT features
for IPF
TBBx or
BAL?
Features diagnostic
of another
DPLD e.g. HX
If non-diagnostic
Suspected
other DPLD
TBBx, BAL or
other relevant
test
Surgical lung biopsy
UIP
NSIP
RB
DIP DAD
OP
LIP
non-IIP
confirmed
34. IPF without surgical biopsy
(ATS/ERS Statement 2000)
Major Criteria (all
required)
Minor criteria (3 of 4
required)
• exclusion of known causes • age > 50 yr
of ILD
• insidious onset of otherwise
• abnormal PFT including
unexplained dsypnea on
restriction and impaired
exertion
gas exchange
• duration of illness > 3
• bibasilar reticular
months
abnormalities with minimal
ground glass on HRCT
• bibasilar inspiratory crackles
• TBB or BAL showing no
(velcro-type)
features to support an
alternate diagnosis
36. HRCT Criteria of IPF
1-reticular abnormality and/or traction
bronchiectasis with basal and peripheral
predominance
2-honeycombing with basal and peripheral
predominance
3-atypical features are absent
–
–
–
–
Micronodules are not present
peribronchovascular nodules are not present
consolidation is not present
ground glass attenuation, if present, is less extensive
than reticular opacity
– mediastinal adenopathy, if present, is not extensive
enough to be visible on chest X-ray
Definite IPF: all 3 are met
Probable IPF: 1 and 3 are met
37. Accuracy of Clinical & Radiological
Diagnosis of IPF
• 59 patients with surgical biopsies
• clinical diagnosis or radiological diagnosis
• clinical diagnosis of IPF
- 97% specific
- 62% sensitive
• HRCT diagnosis of IPF
- 90% specific
- 79% sensitive
Raghu et al, 1999
42. Role of BAL in IPF
• BAL may reveal alternative specific
diagnoses: malignancy, infections,
eosinophilic pneumonia, histiocytosis X,
alveolar proteinosis
• Increase in neutrophils +/eosinophils (in 90%)
suggests a fibrosing
process:
IPF, collagen/vascular
disease, asbestosis
• A lone increase in
lymphocytes is uncommon,
exclude: sarcoidosis, EAA,
BOOP, NSIP, LIP
43. HRCT
Confident CT
diagnosis of IPF with
consistent clinical
features
Atypical clinical
or CT features
for IPF
TBBx or
BAL?
Features diagnostic
of another
DPLD e.g. HX
If non-diagnostic
Suspected
other DPLD
TBBx, BAL or
other relevant
test
Surgical lung biopsy
UIP
NSIP
RB
DIP DAD
OP
LIP
non-IIP
confirmed
44. When do we need surgical biopsy in
idiopathic interstitial pneumonias?
• IPF-like CT pattern and age > 50 yrs: no
• COP with characteristic
clinical/CT/BAL/TBLB features: no
• RBILD/DIP?
• Other IIP entities: yes
45. Surgical Lung Biopsy – special risk
in IPF
• 60 pat with UIP (46 idiopathic, 14
associated with collagen/vasc dis) from
Mayo Clinic 1986 - 1995
• 10/60 (=17%) died within 30 days after
surgical biopsy
3/16 (19%) after VATS
7/44 (16%) after thoracotomy and
biopsy
• All 10 who died had IPF, 5 of these were
biopsied for accelerated progress
Utz et al, ERJ 2001; 17: 175
46. Mortality and Risk factors for
Surgical Lung Biopsy in IIP
• 200 pat. with IIP (140 IPF, 46 NSIP, 14
COP), retrospective study
• 4.3% died within 30 days after surgical
biopsy,
no difference between VATS or OLB
no difference between IPF and other
IIPs
• Biopsy at time of acute exacerbation:
mortality 29% vs 3%
• DLCO<50%: mortality 11% vs 1.4%
Park JH et al, Eur J Cardiothorac Surg 2007
47. Key histopathological features
- UIP Pattern
• Dense fibrosis and
honeycombing
• Fibroblastic foci prominent
• Patchy, heterogeneous
pattern
• Subpleural, paraseptel
distribution
53. How to make the diagnosis of an IIP
entity?
• Not by histology alone!
• To define a disease as idiopathic, all known
associated conditions and causes have to be
excluded.
• This cannot be done by the pathologist – none
of the histologic patterns are specific for the
idiopathic entities but also seen in associated
conditions.
• The final diagnosis can only be made in a
clinical/radiologic/pathologic synopsis.
54. Controversy and Confusion with
the term UIP
• Clinicians have used the name of the
histological patterns for the clinical diagnosis
• Radiologists use the term UIP for the HR-CT
pattern
• What is UIP? - A histological (or CT/or BAL)
pattern, not a clinical diagnosis
• Is UIP the same as IPF? -- No!
(Histological UIP pattern can be seen in other ILDs)
• Why not call IPF “idiopathic UIP“?
56. Prognosis of
Fibrotic Interstitial Pneumonia
IIP vs CVD-IP
(n = 362; IIP 269, CVD 93)
Idiopathic UIP vs CVD-UIP v
Idiopathic NSIP vs CVD-NS
Park JH, et al. AJRCCM 2007; 175: 705
57. Clinical conditions associated
with NSIP pattern
• No detectable cause (idiopathic NSIP)
• Collagen vascular disease
• Hypersensitivity pneumonitis
• Drug-induced pneumonitis
• Infection
• Immunodeficiency including HIV
infection
58. Chronic bird fancier‘s lung: histopathological and clinical correlation
Ohtani et al 2005
• BOOP
• NSIP, cellular
2
5
recurrent episodes,
good outcome
• NSIP, fibrotic
• UIP-like
8
11
insidious onset,
unfavorable outcome
Total
n = 26
59. Controversy
• Do NSIP and DIP reflect early stages of
the IPF/UIP patients ?
• Majority of researchers believe now that
these three histologic patterns also
reflect three different entities
61. Controversies with RBILD/DIP
• Should RBILD be included in the IIP„s?
100% are cigarette smokers, so a
disease of known aetiology!
• DIP is not exclusively seen in smokers,
15% are nonsmokers
Ryu et al. Chest 2005,127:178
62. Is histopathology still the gold
standard for diagnosis?
Problems:
• Sampling error
• Interoberserver variation between
histopathologists
67. Interobserver variation
between histopathologists
In a recent study, 133 biopsies were
assessed by 10 experienced specialist
histopathologists
The interobserver agreement was barely
clinically acceptable: Kappa coefficient of
agreement only 0.4
Nicholson et al, Thorax 2004
68. Kappa coefficients of agreement
between 10 pathologists (Nicholson 2004)
Diagnosis
Lobar
diagnosis
(n=98)
Final
diagnosis
(n=48)
UIP
0.40
0.49
NSIP
0.32
0.32
DIP
0.67
0.71
OP
0.59
0.67
EAA
0.39
0.35
Sarcoidosis
0.76
0.82
Overall
0.39
0.43
70. HRCT in the Idiopathic
Interstitial Pneumonias
71. • A radiologist‟s view of the spectrum
of IIPs
• HRCT sketches of the IIPs
• Issues:
– “Added value” signs on HRCT
– Observer variation
– Overlap lung disease
72. Idiopathic interstitial pneumonias
a perception / definition:
“A group of disorders with a shifting
histopathological classification,
unclear clinical significance, and
largely unmemorable imaging
features.”
E.G.Journeyman 2001
73. IIPs included in the current classification:
•
•
•
•
•
Usual interstitial pneumonia (UIP)
Non-specific interstitial pneumonia (NSIP)
Respiratory Bronchiolitis (RB-ILD)
Desquamative interstitial pneumonia (DIP)
Diffuse alveolar damage / Acute interstitial
pneumonia (AIP)
• Organizing pneumonia (OP)
• Lymphoid interstitial pneumonia (LIP)
International Consensus (ATS/ERS) Classification
of Idiopathic Interstitial Pneumonias 2002
78. UIP: HRCT appearances
• Subpleural basal honeycombing
– May be component of ground glass opacification
and fine reticular elements
– Volume loss and traction bronchiectasis
– Enlarged mediastinal lymph nodes
87. NSIP: initial reports of CT
spectrum of findings:
• Ground glass opacification with or
without areas of consolidation
• Linear opacities and reticular pattern,
but honeycombing limited or absent
• Lower zone predominance, may be
subpleural predilection
Park et al Radiology 1995;195:645
Hartman et al Radiology 2000;217:701
88.
89. NSIP
A fibrosing lung disease
in which ground glass is
predominant and
honeycombing is minimal
or absent, often with a
peripheral basal
distribution
90. Some history:
• 1989: No histological difference between CFA
and fibrosing alveolitis in systemic sclerosis1.
• 1994: Fibrosing alveolitis associated with
systemic sclerosis has a better prognosis than
lone CFA2.
• 1992/4: Kitaichi, Katzenstein describe NSIP
• 1997: Chan et al paper in Thorax
• 1998 – : Clinicians, radiologists recognize NSIP
and its prognostic implications
1
Harrison et al Respir Med 1989;83:403-14
2
Wells et al Am J Respir Crit Care Med 1994;149:1583
91. “systemic sclerosis type”
“lone CFA type”
Chan et al. Thorax 1997;52:265
n.b. Subsequent pathological studies have shown that NSIP is the
most prevalent pattern in systemic sclerosis associated pulmonary
fibrosis
103. UIP
– The most frequently encountered and lethal IIP
– Characteristic HRCT features in approximately 50%
– Biopsy unnecessary when HRCT and clinical
features typical
NSIP
– Better prognosis than UIP
– Commonest IIP in connective tissue disease
– HRCT pattern recognisable but not specific (may be
a front for UIP)
105. Interobserver variation between pathologists
in diffuse parenchymal lung
AG Nicholson, BJ Addis1, H Bharucha2, CA Clelland3, B Corrin, AR
Gibbs4, PS Hasleton5, K Kerr6, NB Ibrahim7, S Stewart8, W Wallace9,
and AU Wells10.
Departments of Histopathology, Royal Brompton Hospital, Southampton
General Hospital1, Royal Victoria Hospital, Belfast2, John Radcliffe
Infirmary3, Llandough Hospital 4, Wythenshawe Hospital 5, Aberdeen
Royal Hospitals6, Frenchay Hospital 7, Papworth Hospital 8, Edinburgh
Royal Hospital9, and Department of Medicine10, Royal Brompton
Hospital, UK.
Thorax 2004;59:500
106. Kappa values
for histopathological diagnosis
[<0.4 = poor, 0.4-0.6 = satisfactory, 0.6-0.8 = good, >0.8 = excellent]
Overall kappa value = 0.38 for lobar diagnoses
DIAGNOSIS (n=133)
KAPPA COEFFICIENT FOR LOBAR Dx
UIP
0.42
NSIP
0.29
OP
0.57
Hypersensitivity pneumonitis
0.36
Sarcoidosis
0.76
Other diffuse lung diseases
0.41
107. “The only use of a diagnostic test
is to reduce uncertainty”
EJ Potchen 1998
108. Change in diagnostic
perception:
1st choice diagnosis changed in
51% of cases after HRCT
• Significant increase in diagnostic
confidence
• Overall kappa for 1st choice diagnosis
before HRCT 0.47 (moderate)
after
HRCT 0.72 (good)
Aziz et al Radiology 2006;238:725
109. Weighted kappa coefficients of individual disease
categories for the entire cohort before and after HRCT
Kw before HRCT
Kw after HRCT
Idiopathic pulmonary fibrosis
0.58
0.89
Non-specific interstitial pneumonitis
0.20
0.63
Sarcoidosis
0.68
0.88
Hypersensitivity pneumonitis
0.65
0.67
Cryptogenic organizing pneumonia
0.51
0.71
Smoking related-interstitial lung disease
0.30
0.46
Interstitial pneumonias secondary to
connective tissue disease
0.69
0.78
111. When HRCT shows several
patterns, it may be that:
– Single disease has more than one HRCT
pattern
OR
– More than one disease present
OR
– Two phases of one disease
118. So, AIP, OP and NSIP are very
different entities…
119. Strands of evidence suggesting overlap
between in situations in which AIP/NSIP/OP
occur:
• Dilated airways (irreversible) in gr. glass of ARDS
(Howling et al 1998)
• Original description of NSIP; some cases = ARDS
survivors (Katzenstein et al 1994)
• Variable behaviour of patients with polymyositis
associated lung disease (Tazelaar et al 1990)
• Accelerated phase of UIP/NSIP→AIP
(Colby 2000)
• HRCT descriptions of NSIP with consolidation
(OP) (Park et al 1998)
122. HRCT and the Idiopathic Interstitial Pneumonias
• Value
– Some IIPs have diagnostic HRCT appearances
– Alternative diagnoses + complications
– Increased understanding of evolution
• Limitations
– NSIP masquerading as UIP
– Clinical significance of limited disease
– Experience / observer variation issues
136. Langerhans Cell Histiozytosis
Key Features
Upper lobe predominance
Combination of cysts and noduli
Characteristic stages
Increased Lung volume
Sparing of costophrenic angle
S
M
O
K
I
N
G
141. LIP = Lymphocytic Interstitial
Pneumonia
Benign lymphoproliferative
disorder
Diffuse interstitial infiltration of
mononuclear cells
Not limited to the air ways as
in follicular Bronchiolitis
143. LIP = Lymphocytic Interstitial
Pneumonia
Rarely idiopathic
In association with:
Sjögren‟s syndrome
Immune deficiency syndromes, AIDS
Primary biliary cirrhosis
Multicentric Castlemean‟s disease
144. Sjoegren disease
Dry eye and dry mouth
Fibrosis, bronchitis and bronchiolitis
LIP
Up to 40 x increased risk for lymphoma (mediastinal
adenopathy) and
2 x times increased risk for neoplasma
Overlap
Sarcoid, DM/PM, MXCT
SLE, RA (pleural effusion)
149. Outline
Typical HRCT patterns of lung diseases
with cysts
Mosaic pattern and its differential
Emphysema
Atypical HRCT patterns
Quiz
150.
151. Where is the pathology ???????
in the areas with increased density
meaning there is ground glass
in the areas with decreased density
meaning there is air trapping
152. Pathology in black areas
Airtrapping: Airway
Disease
Bronchiolitis obliterans (constrictive bronchiolitis)
idiopathic, connective tissue diseases, drug reaction,
after transplantation, after infection
Hypersensitivity pneumonitis
granulomatous inflammation of bronchiolar wall
Sarcoidosis
granulomatous inflammation of bronchiolar wall
Asthma / Bronchiectasis / Airway diseases
153. Airway Disease
what you see……
In inspiration
sharply demarcated areas of seemingly increased
density (normal) and decreased density
demarcation by interlobular septa
In expiration
„black‟ areas remain in volume and density
„white‟ areas decrease in volume and increase in
density
INCREASE IN CONTRAST
DIFFERENCES
AIRTRAPPING
160. Pathology in white Areas
Alveolitis / Pneumonitis
Ground glass
desquamative intertitial pneumoinia (DIP)
nonspecific interstitial pneumonia (NSIP)
organizing pneumonia
In expiration
both areas (white and black) decrease in
volume and increase in density
DECREASE IN CONTRAST
DIFFERENCES
166. Radiographic Patterns in ILD
Pleural Involvement
Lymphangitic Carcinomatosis
LAM
Drug Induced
Radiation Pneumonitis
Asbestosis
Effusion
Thickening
Plaques
Mesothelioma
Collagen vascular disease
Adenopathy
Sarcoidosis
Lymphoma
Lymphangitic CA
LIP
Amyloidosis
Berylliosis
Silicosis
Kerley B lines
Chronic LV failure
Lymphangitic CA
Lymphoma
LAM
Veno-occlusive disease
Acute Eosinophilic Pneumonia
167. Probability of Histologic Diagnosis of Diffuse Diseases
Transbronchial
Biopsy
Surgical
Biopsy
1. Granulomatous diseases
2. Malignant tumors/lymphangitic
3. DAD (any cause)
4. Certain infections
Often
5. Alveolar proteinosis
6. Eosinophilic pneumonia
7. Vasculitis
8. Amyloidosis
9. EG/HX/PLCH
Sometimes
10. LAM
11. RB/RBILD/DIP
12. UIP/NSIP/LIP COP
13. Small airways disease
14. PHT and PVOD
Courtesy of Kevin O. Leslie, MD.
Never
170. Linear Pattern
A linear pattern is seen when there is
thickening of the interlobular septa,
producing Kerley lines.
Kerley A lines
Kerley B lines
Kerley A lines
The interlobular septa contain
pulmonary veins and lymphatics.
The most common cause of interlobular
septal thickening, producing Kerley A
and B lines, is pulmonary edema, as a
result of pulmonary venous
hypertension and distension of the
lymphatics.
Kerley B lines
171. DD of Kerly Lines:
Pulmonary edema is the most common cause
Mitral stenosis
Lymphangitic carcinomatosis
Malignant lymphoma
Congenital lymphangiectasia
Idiopathic pulmonary fibrosis
Pneumoconiosis
Sarcoidosis
172.
173. b. Reticular Pattern
A reticular pattern results from the summation or
superimposition of irregular linear opacities.
The term reticular is defined as meshed, or in the
form of a network. Reticular opacities can be
described as fine, medium, or coarse, as the width of
the opacities increases.
A classic reticular pattern is seen with pulmonary fibrosis, in
which multiple curvilinear opacities form small cystic
spaces along the pleural margins and lung bases
(honeycomb lung)
174. This 50-year-old man presented with end-stage lung fibrosis
PA chest radiograph shows medium to coarse reticular
B: CT scan shows multiple small cysts (honeycombing) involving
predominantly the subpleural peripheral regions of lung. Traction
bronchiectasis, another sign of end-stage lung fibrosis.
175. c. Nodular pattern
A nodular pattern consists of multiple round opacities,
generally ranging in diameter from 1 mm to 1 cm
Nodular opacities may be described as miliary (1 to 2 mm,
the size of millet seeds), small, medium, or large, as the
diameter of the opacities increases
A nodular pattern, especially with predominant distribution,
suggests a specific differential diagnosis
177. Hematogenous metastases and nodular ILD. This 45-yearold woman presented with metastatic gastric carcinoma.
The PA chest radiograph shows a diffuse pattern of
nodules, 6 to 10 mm in diameter.
179. d. Reticulonodular pattern
A reticulonodular pattern results from a
combination of reticular and nodular opacities.
This pattern is often difficult to distinguish from
a purely reticular or nodular pattern, and in
such a case a differential diagnosis should be
developed based on the predominant pattern.
If there is no predominant pattern, causes of both
nodular and reticular patterns should be
considered.
181. Rule no. 1
An acute appearance suggests pulmonary
edema, acute milliary TB, or acute interstitial
neumonia,acute esinophillic pneumonia
182. Disseminated histoplasmosis and reticulonodular ILD.
A: PA chest radiograph, close-up of right upper lung, shows reticulonodular
ILD.
B: CT scan shows multiple circumscribed round pulmonary nodules, 2 to 3
mm in diameter.
186. Systemic sclerosis.
A: PA chest radiograph shows a bibasilar and subpleural distribution of fine
reticular ILD. The presence of a dilated esophagus (arrows) provides a clue
to the correct diagnosis.
B: CT scan shows peripheral ILD and a dilated esophagus (arrow).
187. Rule no. 3
A middle or upper lung predominant distribution
suggests: (Mycobacterium Settle Superiorly in
Lung)
1. Mycobacterial or fungal disease
2. Silicosis
3. Sarcoidosis
4. Langerhans Cell Histiocytosis
188. Complicated silicosis. PA chest radiograph shows multiple
nodules involving the upper and middle lungs, with coalescence
of nodules in the left upper lobe resulting in early progressive
massive fibrosis
189. Sarcoidosis. CT scan shows nodular thickening of the bronchovascular
bundles (solid arrow) and subpleural nodules (dashed arrow), illustrating the
typical perilymphatic distribution of sarcoidosis.
190. Langerhan cell histiocytosis.
This 50-year-old man had a
30 pack-year history of
cigarette smoking.
A: PA chest radiograph
shows hyperinflation of the
lungs and fine bilateral
reticular ILD.
B: CT scan shows multiple
cysts (solid arrow) and
nodules (dashed arrow).
195. Cardiogenic pulmonary edema.
PA chest radiograph shows enlargement of the cardiac
silhouette, bilateral ILD, enlargement of the azygos vein
(solid arrow), and peribronchial cuffing (dashed arrow).
196. Lymphangitic carcinomatosis. This 53-year-old man
presented with chronic obstructive pulmonary disease and
large-cell bronchogenic carcinoma of the right lung.
CT scan shows unilateral nodular thickening (arrows) and a
malignant right pleural effusion.
198. Lymphangioleiomyomatosis
(LAM).
A: PA chest radiograph shows a
right basilar pneumothorax and
two right pleural drainage
catheters. The lung volumes are
increased, which is
characteristic of LAM, and there
is diffuse reticular ILD.
B: CT scan shows bilateral thinwalled cysts and a loculated
right pneumothorax (P).
199.
200. A p p ro a c h to th e IL D P a tie n t
P a tie n t w ith S u sp e c te d
IL D
H x, P E , C X R , P F T , L a b s
D x lik e ly b y
b ro n c h ?
Y es
Y es
Is b ro n ch
d ia g n o stic?
No
STO P
HRCT
H x and H R C T
co n siste n t
w ith IP F
H x and H R C T
D x o f o th e r
IL D
S u sp e cte d
o th e r IL D
STOP
D x lik e ly b y
b ro n c h ?
STOP
A typ ica l
clin ica l o r C T
fe a tu re s o f IP F
Y es
Is b ro n ch
d ia g n o stic?
No
No
Y es
STO P
VATS
U IP
N S IP
R B IL D
D IP
DAD
OP
L IP
N o n IIP
M a rtine z F , F la h erty K . A va ila ble a t: h ttp ://w w w .ch e stn e t.o rg /e d u ca tion /onlin e /p ccu /vol1 8 /lesso n s03 _ 04 /le sso n 03 .p hp .
