interstitial lung disease - path · interstitial lung disease professor andrew g nicholson, dm, ......

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Interstitial lung disease

Professor Andrew G Nicholson, DM, FRCPath

Consultant Histopathologist, Royal Brompton and Harefield NHS Foundation Trust, and Honorary Professor of Respiratory Pathology National Heart and Lung Division Imperial College, London, United

Kingdom

Belfast Pathology

Belfast

Tuesday 20th June 2017

An approach to the diagnosis of interstitial pneumonias

Interstitial pneumonias (1999)

Too much terminology – Not enough disease

• UIP - Usual interstitial pneumonia

• DIP - Desquamative interstitial pneumonia

• BIP - With bronchiolitis obliterans

• LIP - Lymphocytic interstitial pneumonia

• GIP - Giant cell interstitial pneumonia

• DAD - Diffuse alveolar damage• AIP - Acute interstitial

pneumonia• Granulomatous interstitial

pneumonia• Hypersensitivity pneumonia• Hamman-Rich Syndrome

• COP - Cryptogenic organisingpneumonia

• BOOP - Bronchiolitis obliteransorganising pneumonia

• CPI - Chronic pneumonitis of infancy

• CPI – Cellular pneumonitis of infancy

• NSIP - Non-specific interstitial pneumonia

• MIP - Mixed interstitial pneumonia

• IPF - IDIOPATHIC PULMONARY FIBROSIS

• CFA - CRYTPOGENIC FIBROSING ALVEOLITIS

• IIP - IDIOPATHIC INTERSITIAL PNEUMONIA

AJRCCM 165:227, 2002

2002 – AREAS OF UNCERTAINTY

Am J Resp Crit Care Med 165:277-304, 2002

2002 – AREAS OF UNCERTAINTY

Many of these areas of uncertainty outlined in 2002 have now been

addressed in the literature – so now they are no longer uncertain

However, new areas of uncertainty are being generated

At ten years, it was considered timely to review the 2002 consensus statement.....

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Revised ATS/ERS IIP Classification(to be viewed as a supplement to the 2002 document)

Am J Respir Crit Care Med 2013; 188: 733-748

Clinical Radiologic Pathologic DiagnosisIdiopathic Pulmonary Fibrosis

Idiopathic Nonspecific Interstitial Pneumonia

Respiratory BronchiolitisInterstitial Lung DiseaseDesquamative Interstitial

PneumoniaCryptogenic Organizing

PneumoniaAcute Interstitial Pneumonia

• Rare IIP• Idiopathic LIP• Idiopathic

pleuroparenchymal fibroelastosis

• Rare Histologic Patterns• Acute fibrinous &

organizing pneumonia• Bronchiolocentric

patterns of IP • Unclassifiable IIP

ATS/ERS consensus classification of idiopathic interstitial pneumonias


HISTOLOGIC PATTERN CLINICOPATHOLOGIC DIAGNOSIS

Usual interstitial pneumonia Idiopathic Pulmonary Fibrosis

Non-specific interstitial pneumonia Non-specific interstitial pneumonia*

Respiratory Bronchiolitis (RB) RB- associated ILD (RB-ILD)

Desquamative interstitial pneumonia Desquamative interstitial pneumonia

Diffuse alveolar damage Acute interstitial pneumonia

Organising pneumonia Cryptogenic organising pneumonia

Lymphoid interstitial pneumonia Lymphoid interstitial pneumonia





Non-specific interstitial pneumonia Non-specific interstitial pneumonia






Why so little change to the basic structure of the IIP classification?

DIAGNOSIS KAPPA (lobe) WEIGHTED KAPPA (lobe)

WEIGHTED KAPPA (f inal)

UIP 0.42 0.53 0.59

NSIP 0.29 0.35 0.40

OP 0.57 0.68 0.70

EAA 0.36 0.46 0.47

SARCOID 0.76 0.86 0.75

Nicholson AG et al Thorax, 2004: 59: 500-505.

3 - 2002 Classification is reproducible in clinical practice[<0.4 = poor, 0.4-0.6 = satisfactory, 0.6-0.8 = good, >0.8 = excellent]

2 - The 2002 IIP Classification was used in 75% (157/208) of all clinical publications on the topic of IIPs between 2004 through 2011.

1 - Global uptake in patient management – clinical, imaging and histopathology.

Idiopathic Interstitial Pneumonia: Do Community and Academic Physicians Agree on Diagnosis?Flaherty K et al. Am J Resp Crit Care Med, 2007;175:1054-60

Final agreement was better within academic centers (kappa 0.55-0.71) than within community centers (kappa 0.32-0.44).

Aziz et al. Thorax 2004:59:506-11 HRCT diagnosis of DPLDs: IO variation - kappa of 0.48 over all DPLDs

















Non-specific interstitial pneumonia Non-specific interstitial pneumonia






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• 60, male• Two years of exertional dyspnoea • No obvious steroid effect • on disease course• Bilateral basal crackles, not clubbed • Life-long non-smoker• No CTD symptoms• No occupational exposures• BAL: normal differential• Restrictive PFT. FVC 61%, • DLco 57%

CASE 1CASE 1

CASE 1 CASE 1

CASE 1

Usual InterstitialPneumonia (UIP)

Histologic features of UIPKey Histologic Features

• Dense fibrosis causing remodeling of lung architecture with frequent “honeycomb” fibrosis

• Fibroblastic foci typically scattered at the edges of the dense scars• (TEMPORAL HETEROGENEITY)• Patchy lung involvement• Frequent subpleural, paraseptal and/or bronchovascular distribution

Pertinent Negative Findings• Lack of active lesions of other interstitial diseases (i.e. sarcoidosis or

Langerhans cell histiocytosis• Lack of marked interstitial chronic inflammation• Granulomas: inconspicuous or absent• Lack of substantial inorganic dust deposits, i.e., asbestos bodies (except for

carbon black pigment)• Lack of marked eosinophilia

UIP – Patchy involvement of the lung by fibrosis. Interveninglung is normal or nearly normal.

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MINOR HISTOPATHOLOGICAL FEATURES IN USUAL INTERSTITIAL PNEUMONIA

NORMAL

Dense scarDense scar

Micro Honeycombing

THIS IS UIP

Fibroblast focus

UIP diagnostic here

Lobule destroyed

Lobule destroyed

UIP pattern(all four criteria)

Probable UIP pattern Possible UIP pattern(all three criteria)

Not UIP pattern (Any of the six criteria)

• Evidence of marked fibrosis/ architectural distortion, +/-honeycombing in a predominantly subpleural/ paraseptal distribution

• Presence of patchy involvement of lung parenchyma by fibrosis

• Presence of fibroblast foci

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

• Evidence of marked fibrosis / architectural distortion, +/-honeycombing

• Absence of e ither patchy involvement orfibroblastic foci, but not both

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

• 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

• Hyaline membranes *

• O rganizing pneumonia *†

• Granulomas †• Marked

interstitial inflammatory cell infiltrate away from honeycombing

• Predominant airway centered changes

• O ther features suggestive of an alternate diagnosis

OR• Honeycomb

changes only**

ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management.

Raghu G et al. Am J Respir Crit Care Med 2011;183:788-824.

HRCT Pattern *

Surgical Lung Biopsy Pattern *

(when performed)

Diagnosis of IPF? †

UIP

UIP

YESProbable UIP

Possible UIP

Non-classifiable fibrosis **

Not UIP No

c/w UIP

UIPYES

Probable UIP

Possible UIPProbable ††Non-classifiable

fibrosis

Not UIP No

Inconsistent with UIP

UIP Possible ††

Probable UIP

NoPossible UIP

Non-classifiable fibrosis

Not UIP

Idiopathic Interstitial Pneumonia: Do Community and Academic Physicians Agree on Diagnosis?

Flaherty K et al. Am J Resp Crit Care Med, 2006

Final agreement was better within academic centers (kappa 0.55-0.71) than within community centers (kappa 0.32-0.44).

Fibroblastic foci in UIP….

• Extent Of Fibroblastic fociPredict Mortality In Idiopathic Pulmonary FibrosisT.E. King Jr., et al AJRCCM 2001:164;1025-1032.

• The frequency of fibroblastic foci in usual interstitial pneumonia and their relationship to disease progression. Nicholson AG et al. AJRCCM, 2002; 166: 173-177

• Relationship between histopathologic features and course of IPF/UIP. Titto L et al. Thorax 2006:61:1091-5

? Site of initial injury that triggers fibrosing process

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Aetiology and treatment of UIP/CFAThannickal VJ et al. Ann Rev Med 2004;53:395-417 andSelman M et al. Drugs 2004;64:405-422.

N-acetyl cysteine

Nintedanib

Pirfenidone

Steroids and cyclophosphamide

Spagnolo P et al. Cochrane DatabaseSyst Rev 2010 CD003134

Valeyre D et al. Am J Respir Crit Care Med 2010;181:A6026.

IPF response to therapy

Richeldi L,et al. N Engl J Med. 2014 May 29;370(22):2071-82

CASE 2Case presentation

§ 57 year old female never smoker.§ Increasing shortness of breath § History of “Farmer’s Lung” 20 years

previously treated with steroids.§ Arthritis for 10 years (Autoimmune

screen negative). § On Omeprazole and Fesoterodine.

Case presentation

CT showed patchy ground-glass opacifications in mid and upper zones.

Case presentation

§ BAL• Eosinophilia (17%) and mild neutrophilia

(6%). No lymphocytosis (8%). § Lung function tests:

• Moderate restrictive defect• Reduction in lung volumes and impairment

of gas transfer. • Resting hypoxaemia on blood gas testing. • These changes are in keeping with the

known interstitial lung disease.

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Case presentationCryobiopsyundertaken.

Case presentation

Case presentation Case 2

The features favour fibrotic non-specific interstitial pneumonia (NSIP), possibly secondary to

progression of organising pneumonia

MDT REVIEW: Most likely to be F-NSIP. No serological evidence of connective tissue disease but could be associated given 10 year history of arthritis. Possibility of a drug

reaction also considered.

F- NSIP - ? Idiopathic, ?? Secondary to CTD or drug reaction

Treated with immunosuppression and stable at 3 months

ATS/ERS subdivision of NSIPCellular Fibrotic

• ATS/ERS workshop – AJRCCM 2008;177:1338-47• Sixty-seven cases (out of 305)• Mean age was 52 years, 67% were women, 69% were never

smokers,• Dyspnea (96%) and cough (87%); 69%had restriction.• HRCT - lower lung predominant, reticular pattern (87%) with• traction bronchiectasis (82%) and volume loss (77%). • Five-year survival was 82.3%.

• Distinct clinical entity that occurs mostly in middle-aged women who are never-smokers. The prognosis of NSIP is very good.

CT-Path of NSIP

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OP and cellular NSIP

Consolidation etc.

NSIP versus DIPSmoking-related interstitial lung disease

Histopathology: F-NSIP

• MDT review: • HRCT favours chr HP• History of bird exposure

• Levels cut on block…

ØFINAL DIAGNOSIS:Ø CHR HP

ATS/ERS workshop – “relatively few at the centre of the circle”

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• SOME PATIENTS WITH IDIOPATHIC NSIP SUBSEQUENTLY DEVELOP COLLAGEN VASCULAR DISEASES

• Kono M et al. Nonspecific interstitial pneumonia preceding diagnosis of collagen vascular disease. RespirMed. 2016 Aug;117:40-7.

• 17% developed CVD during the follow-up period (5.5 ± 5.0 years);• (DM = 3, DM/Sjogren's syndrome = 2, RA = 1)

• SUBDIVISION OF PATIENTS WITH A BIOPSY SHOWING NSIP PROVIDES PROGNOSTIC INFORMATION

• Kambouchner M. Non-specific interstitial pneumonia subdivision into pathological subgroups is clinically relevant from a prognostic and causal perspective. Histopathology. 2014 Oct;65(4):549-60. Nunes H Nonspecific interstitial pneumonia: survival is influenced by the underlying cause. Eur Respir J. 2015;45:746-55.

• Survival was better for UCTD than for idiopathic NSIP. • cHP survival tended to be poorer than that of idiopathic NSIP (p=0.087) and was

an independent predictor of mortality

• INTERSTITIAL PNEUMONIA WITH AUTOIMMUNE FEATURES (IPAF) - ? A NEW ENTITY

• Fischer A et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features.-NSIP. Eur Respir J. 2015 Oct;46(4):976-87.

• …a morphologic domain consisting of specific chest imaging, histopathologic (NSIP/OP/LIP) or pulmonary physiologic features.

• A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD.

Update on NSIP…

• PROS OF CRYOBIOPSY

• Surgical lung biopsy has a higher diagnostic yield than tranbronchial biopsy - 0.81 (0.75 – 0.87) vs 34% (1,2) Similar complication rate (2).

• Cryobiopsy has lower complication rates and mortality rates compared to SLB (1).

• Bronchoscopic cryobiopsy has a meaningful impact on diagnostic confidence in MDTs for ILDs, and may prove useful in the diagnosis of IPF. (3)

• Coste efficiency – “The systematic use of cryobiopsysaved up to €59,846 (over 3 years)” (4): £210 per patient in the first year and £647 in subsequent years (5).

• CONS OF CRYOBIOPSY

• Surgical lung biopsy has a higher diagnostic yield than cryobiopsy (0.987 vs 0.81 (0.75 –0.87)) (1)

• In one series for cryobiopsy, severe bleeding was reported as 53% (6)

• Lack of studies showing direct comparison of the two techniques (7,8)

• Not available routinely

1. Rav aglia C et al. Saf ety and Diagnostic Y ield of Transbronchial Lung Cry obiopsy in Dif f use Parenchy mal Lung Diseases: A Comparativ e Study v ersus Video-Assisted Thoracoscopic Lung Biopsy and a Sy stematic Rev iew of the Literature. Respiration. 2016;91(3):215-27

2. Pajares V et al. Diagnostic y ield of transbronchial cry obiopsy in interstitial lung disease: a randomized trial. Respirology . 2014 Aug;19(6):900-63. Tomassetti S et al. Bronchoscopic Lung Cry obiopsy Increases Diagnostic Conf idence in the Multidisciplinary Diagnosis of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2015 193:745-524. Hernández-González F et al. Cry obiopsy in the diagnosis of dif f use interstitial lung disease: y ield and cost-ef f ectiveness analy sis. Arch Bronconeumol. 2015;51:261-75. Sharp C et al. Use of transbronchial cry obiopsy in the diagnosis of interstitial lung disease-a sy stematic rev iew and cost analy sis. QJM. 2016 [Epub ahead of print]6. Hagmey er L, et al.The role of transbronchial cry obiopsy and surgical lung biopsy in the diagnostic algorithm of interstitial lung disease. Clin Respir J. 20157. Johannson KA y et al. Diagnostic Y ield and Complications of Transbronchial Lung Cry obiopsy f or Interstitial Lung Disease: A Sy stematic Rev iew and Meta-analy sis. Ann Am Thorac Soc. 2016;188-18388. Raparia K et al. Transbronchial Lung Cry obiopsy f or Interstitial Lung Disease Diagnosis: A Perspectiv e From Members of the Pulmonary Pathology Society Arch Pathol Lab Med. 2016 Jul. [Epub ahead of

print]

USAGE OF CRYOBIOPSIES

• Johannson KA yet al. Diagnostic Yield and Complications of Transbronchial Lung Cryobiopsy for Interstitial Lung Disease: A Systematic Review and Meta-analysis. Ann Am Thorac Soc. 2016 Jul. [Epub ahead of print]

• Raparia K et al. Transbronchial Lung Cryobiopsy for Interstitial Lung Disease Diagnosis: A Perspective From Members of the Pulmonary Pathology Society Arch Pathol Lab Med. 2016 Jul. [Epub ahead of print]

• The diagnostic accuracy of transbronchial lung cryobiopsycannot be determined given the absence of studies directly comparing cryobiopsydiagnoses to diagnoses derived from with surgical lung biopsies interpreted within multidisciplinary discussions.

• The histopathological and multidisciplinary discussion-based diagnostic yield of transbronchial cryobiopsyappear high, but with variable frequencies of complications dominated by pneumothorax and moderate to severe hemorrhage.

• Hagmeyer L et al. Validation of transbronchial cryobiopsy in interstitial lung disease - interim analysis of a prospective trial and critical review of the literature. Sarcoidosis Vasc Diffuse Lung Dis. 2016;33:2-9.

• In 75% of cases, SLBx deemed unnecessary after Cry-bx. • In 12/13 subjects, an SLB was performed confirming Cryo-TBB results in 92%.

Rate of NSIP in cryobiopsies….• BIOPSY TYPE CBC SLB• Hagmeyer et al 19%• Ravaglia et al 8% vs 15%• Tomassetti et al 7% vs 5%

Bronchoscopic cryobiopsy

RB DIP

Should we combine RB-ILD and DIP into SR-IP?

PATHOLOGY: Craig PJ et al. Histopathology 2004 45:275-82.

• Nearly all cases of RB were in smokers but only 60% of DIP were smokers (probably nearer 85%)

• DIP showed greater extents of eosinophils, follicular hyperplasia and fibrosis.

• No difference histologically between smokers and non-smokers with DIP.

• Some cases of DIP are truly idiopathic.

• Best kept as separatehistologic patterns

Should we use the term SR-IP?• More review articles than investigative papers…

• Kawabata Y et al.Histopathology 2008;53:707. Smoking related changes in lung resections

• Katzenstein et al Human Pathology 2010;41:316-25. Clinically occult fibrosis in smokers:

• Yousem et al. Mod Pathol 2006; 19:1474-9. Respiratory bronchiolitis-associated interstitial lung disease with fibrosis is a lesion distinct from fibrotic nonspecific interstitial pneumonia: a proposal

• Vassallo R al. Chest 2003;124:1199-205. The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis: high-resolution CT, histologic, and functional correlations .

• ATS/ERS SR-ILD workshop….

Appropriate clinical categorisation for cases with a histological patterns of RB or DIP in the correct clin-rad-path context

Histopathologists should describe patterns present

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ACUTE INTERSTITIAL PNEUMONIA

EXUDATIVE PHASE

DIFFUSE ALVEOLAR DAMAGE

ORGANISING PHASE

FIBROTIC PHASE

Acute exacerbation of UIP/IPFDefinition

“An acute, clinically-significant deterioration in lung function of unidentifiable cause in a patient with underlying IPF.”

CT-Path of OP

EVG

Noise analysis (2 observers per differential diagnosis)

UIP NS IP DIP RB DA D O P LIP FB E A A S A RC NonDx Norm Orphan E S L UnclUIP 29 1 3 7 1 4 3 14 1NSIP 5 1 4 2 1 2 6 8 4 12 5DIP 1 2 1RB 2DAD 4 1 2OP 1 1 1LIP 2 2FB 2 1 4 3E AA 3 1S ARC 1NonDx 2 1 2NormOrphan 4E SLUncl

UIP OP Progression to interstitial fibrosis

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UIP OP???

Needs HRCT/clin correlation and sometimes longitudinal behaviour

Presence of interstitial fibrosis is an adverse prognostic indicator

CASE 350 year old female with ? ILD

CASE 350 year old female with ? ILD













CASE 3

Pleuroparenchymalfibroelastosis (PPFE)

• Rare idiopathic interstitial pneumonias• Idiopathic lymphoid interstitial pneumonia• Idiopathic pleuroparenchymal fibroelastosis

• Unclassifiable IIP

• Rare Histologic Patterns• (data insufficient for recognition clinically as IIP)

• Acute fibrinous & organizing pneumonia• Bronchiolocentric patterns of IP

TABLE 1: 2013 Revised ATS/ERS IIP Classification

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Pleuroparenchymal FibroelastosisFrankel SK et al Chest 2004;126:2007-13 and Becker CD et al. Mod Pathol 2008;21;784-7

• Idiopathic setting • Seven patients in two series • Average age 51, six being female.

• Is this a distinct disease?

• Is it intra-alveolar fibrosis secondary to “petrification” of a peripheral OP of subpleural collapse secondary to pleural fibrosis, or indeed pneumothorax?

• Should we view as an unusual longitudinal presentation of OP?

Clinical data of cases in Japanese literature

Year Reporter age sex Dominant Sx SOB cough

Duration Sx (yr)

Recurrent infection PM/PT

Smoking history

cur/ex/nev

Family history

Occu/Env Exposure Drug Hx

Clinical course

im/sta/prg

Survival died (yr)

1 1992 Amitani 26-81(48.3) 9/4unkno

wnunkno

wn unknown 3/13 7/13 unknown 4/13(2) unknown 0/13 0/0/134/13(0.5-

13, 7)

2 1999 Shiota 25-83(49.4) 5/2 0/7 3/7 1-6(4.5) 1/7 3/7 2/2/3 4/7(2) 1/7(woods) 0/7 0/1/63/7(1.2-5,

3)

3 1999Kobayashi 27 1/0 1/1 0/1 3 0/1 1/1 0/0/1 1/1(1) 0/1 0/1 0/1/0 0/1

4 1999 Jingu 39-43(41) 0/2 1/2 2/2 4 0/2 2/2 0/0/2 0/2 0/2 0/2 0/1/1 0/2

5 2000 Kobashi 85 0/1 1/1 1/1 5 0/1 1/1 0/0/1 0/1 0/1 0/1 0/0/1 1/1(6)

6 2000Sakamoto 74 1/0 1/1 0/1 0.8 0/1 0/1 0/1/0 0/1 0/1 0/1 unknown 0/1

7 2006 Nei 82 1/0 1/1 1/1 2 0/1 0/1 0/1/0 0/1 0/1 0/1 0/0/1 1/1(2)

8 2010 Morimoto 49 1/0 0/1 0/1 none 0/1 0/1 0/1/0 0/1 0/1 0/1 unknown 0/1

9 1999 Azoulay 23-29(26.7) 0/3 3/3 3/3 4(4) 0/3 3/3 0/0/3 3/3(1) 0/3 0/3 0/0/32/3(1-2,1.5)

10 2004 Frankel 32-65(49.8) 2/3 3/4 3/4 10(10) 2/5 0/5 0/1/4 2/5(1) 0/5 2/5(2:MMK) 0/0/2 2/5(5-5, 5)

11 2008 Becker 51-59(55) 0/2 2/2 0/2 none 0/2 1/2 0/2/0 0/2 1/2(asbest) 1/2(ML) 0/0/1 1/2

Total 22-83(48.9) 20/17 13/23 13/23 0.8-10(5.8) 6/37 18/37 2/8/24 14(7) 2/24 3/37 0/3/28 14/37

Pleuroparenchymal fibroelastosis

• Sufficient evidence for PPFE to be recognised as a distinct idiopathic clin-rad-path entity

• Wider spectrum of appearances than in published series• Distant parenchymal fibrosis

frequent

• Non-idiopathic cases as causes and associations emerge• Immune-mediated, infection

related

• Not as rare as initially thought (n=40 since 2012)






Acute fibrinous and organising pneumonia (AFOP)Beasley M et al. Arch Path Lab Med 2002 (AFIP) Acute fibrinous organising pneumonia

Critical review….

• KEY QUESTIONS• Is this a distinct disease?• Should we view as a more acute variant of COP?• Should we view as closer to diffuse alveolar

damage/acute lung injury?

• LITERATURE EVIDENCE• Sufficient for recognition as a histological pattern• Not sufficient for a clinical entity - more evidence

required.

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Airway-centered interstitial fibrosis: a distinct form of

aggressive diffuse lung disease Churg A et al. Am J Surg Pathol.

2004;28:62-8

IDIOPATHIC BRONCHIOLOCENTRIC INTERSTITIAL PNEUMONIA (BrIP)(Yousem and Dacic in Mod Pathol

2002; 15:1148-1153)

PERIBRONCHIOLAR METAPLASIA AND FIBROSIS

(Fukuoka et al. in AJSP 2005;29:948-954)

Bronchiolocentric interstitial pneumonias…

…adapted from Colby synopsis (USCAP 2008) and critical review

• Female predilection and most patients in their 50s and 60s• Mortality between series is variable (0% - 45%). No statistical

differences in follow-up between series

• LITERATURE EVIDENCE• Sufficient for recognition as a histological pattern• Not sufficient for a clinical entity - more evidence required.

M F Age F/U DOD Stable Improved AWPD Died

Yousem et al. IBIP 2 8 47 9 3 2 1 3 3

Churg et al. ACIF 4 8 54 9 4 2 3 1 4

Fukuoka et al. PBM 2 13 57 11 0 6 5 0 0

Important differential diagnostic considerations

• Coexisting patterns

• Hypersensitivity pneumonitis• Collagen vascular disease-associated IPs• Familial interstitial pneumonias

Unclassifiable pneumonias

Molecular aspects of IIPs

Inter-relationship of histologic patterns

• OP → F-NSIP• DIP → F-NSIP• DAD → OP → F-NSIP

• RB →← DIP• C-NSIP →← LIP• But…

• DIP does not progress to UIP

12 years later

Roberta Miller’s dog Christie

Chronic HP versus UIP/IPF….

Patient subset All patients

Placebo Bosentan

Diagnosis of IPF/UIP by local pathologist

99 50 49

All cases reviewed by the central pathology panel

86 45 41

Cases confirmed as IPF/UIP by central pathology panel

64 36 28

25% of cases rejected as not UIP by reference pathologists

50% F-NSIP 23% EAA (8% in total)

BUILD 1 drug trial

Silva, C. I. S. et al. Am. J. Roentgenol. 2007;188:334-344

Pathologic patterns and survival in chronic HP.

Churg et al. AJSP 2009;33:1765

CASE 454 year old female. SLE. Bilateral cystic lung disease with

nodule in left lung

RIGHT LUNG

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CASE 454 year old female. SLE. Bilateral cystic lung disease with

nodule in left lung

RIGHT LUNG

CASE 4RIGHT LUNG

Congo red – positive with apple-green birefringence

CASE 4

RIGHT LUNG 2

CASE 4CASE 4RIGHT LUNG

Mainly CD20-positive B-cellsIHC – Light chain restrictionPCR - Clonal

LEFT LUNG

Mainly CD3-positive T-cellsIHC – Light chain restrictionPCR – Polyclonal

CD20 CD20

CASE 4

54 year old female. SLE. Bilateral cystic lung disease with nodule in left lung

DIFFUSE LYMPHOID HYPERPLASIA AND AMYLOIDOSIS WITH DEVELOPMENT OF

MALT LYMPHOMA IN LEFT LUNG






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NSIP-C LIP

Clinicopathological correlation - LIP pattern

• Exclude lymphoma (Light chain restriction/PCR).

• Exclude other diseases such as EAA.• Look for clinical association….

• Infection (especially Pneumoncystis carinii, Hepatitis B, Epstein-Barr virus

• Collagen vascular disease, especially Sjogren’s syndrome, rheumatoid arthritis or systemic lupus erthematous

• Immunodeficiency (HIV, SCID)• Other immunologic disorders -

autoimmune hemolytic anemia; myasthenia gravis, pernicious anemia, Hashimoto’s thyroiditis, chronic active hepatitis, primary biliary cirrhosis

• Drug induced/toxic exposure

Is LIP a vanishing disease?

…but cases still exist.

Idiopathic (very rare) 3 of 15 in one series(Cha SI et al. ERJ 2006;28:364-9)

RA SLE SSc PM/DM SjSAmyloid

B’litis

UIP ++? +/- + + +/-

NSIP ++? +? +++ ++ ++

LIP/FB ++ +/- - - ++

OP + +/- +/- ++ +/-

DAD + ++ +/- +/- -

DIP/RB +/-* - +* - -

The prevalence of interstitial pneumoniasin patients with connective tissue diseases

The same spectrum of patterns exists in CTDs as for idiopathic disease• However…• The prevalence differs overall (NSIP common)• The prevalence of IP patterns differs for each CTD• Treatment and prognoses differ from idiopathic disease


B’litis

UIP ++? +/- + + +/-

NSIP ++? +? +++ ++ ++

LIP/FB ++ +/- - - ++

OP + +/- +/- ++ +/-

DAD + ++ +/- +/- -

DIP/RB +/-* - +* - -




B’litis

UIP ++? +/- + + +/-

NSIP ++? +? +++ ++ ++

LIP/FB ++ +/- - - ++

OP + +/- +/- ++ +/-

DAD + ++ +/- +/- -

DIP/RB +/-* - +* - -



When to biopsy (will a biopsy add something..)

• “Unexpected” longitudinal behaviour• Multiple anatomic compartments• Risk of malignancy

• Drug reaction or CTD-related disease

• Prognostication

• Rare diseases

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B’litis

UIP ++? +/- + + +/-

NSIP ++? +? +++ ++ ++

LIP/FB ++ +/- - - ++

OP + +/- +/- ++ +/-

DAD + ++ +/- +/- -

DIP/RB +/-* - +* - -


++ = frequent, + = not infrequent, +/- = rare; ? = prevalence currently uncertain;

* = Probable incidental to pulmonary symptoms

SSc – NSIP (80%)

Polymyositis-dermatomyositis-associated interstitial lung disease.

Douglas WW et al. Am J Respir Crit Care Med 2001;164:1182-5

• 70 patients with ILD and either PM or DM.

• Jo-1 antibody present in 38%. • Synchronous associated

malignancy in 5.7%.• NSIP in 18 of 22 patients

(82%)• DAD in 9%, OP in 4.5%, UIP in

4.5%.

• Survival was significantly better than idiopathic UIP

• More consistent with survival in idiopathic NSIP.

Interstitial pneumonia in RA

• Pulmonary fibrosis seen in about <5% of patients

• NSIP and follicular bronchiolitis are commonest histologic patterns, often superimposed in Brompton experience.

• Tansey D et al. Histopathology 2004;44:585-596

• Early studies suggest survival similar to ‘idiopathic’ NSIP

RA – NSIP, fibrotic + FB Airway and pleura (no interstitial pneumonia)

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Other anatomic compartments…Patient with SLE

54 year old with rheumatoid arthritis and obstructive LFTs

FB

OB

Coexistent pathologies in same anatomic compartment…

Differential diagnoses in cystic lung disease….

• Clinical • Idiopathic, Autoimmune, Smoking related, Neoplastic, Familial, Age

• Imaging• Distribution ++++• Ancillary features +++• Shape of cysts ++• Wall characteristics (+)• Size of cysts +• Profusion of cysts +

• Pathological• Various• Neoplastic versus Non-neoplastic

• Lymphangioleiomyomatosis• Langerhans cell histiocytosis• Lymphoid interstitial pneumonia• Centrilobular emphysema• Pulmonary metastases • Subacute hypersensitivity pneumonitis• Barotrauma / ARDS• Desquamative interstitial pneumonia• Necrobiotic nodules (late stage)• Birt Hogg Dubé syndrome• Amyloidosis/Light chain disease• Tracheal papillomatosis• Neoplasms…• ETC

Obvious versus Impossible

Sjogren’s and lung cysts (1997 case)• 44 year old female• Symptoms of diffuse lung

disease• Possible collagen

vascular disease – not fitting specific disease pattern.

• Working diagnosis of LAM but slightly atypical HRCT scan

Amyloidosis and lymphoid hyperplasia

In 2016 - Lymphocytosis on BAL andappropriate clinical/HRCT enough for confident diagnosis…

, Sjogren’s

…unless unexpected behaviour

Clinicopathologic approach to pulmonary amyloidosis

• Ensure the amyloid subtype (AL)

• COMPLETE SCREENING• SAP scan• CT• Echocardiography• Bone marrow investigation• Serum and urine studies• Immunohistochemical analysis of biopsy

samples

• More accurate prognostic data

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Amyloidosis OR Light chain deposition disease (LCDD)MZ-NHL OR LIP (+ Sjogren’s syndrome)

Solid AND/OR cystic, localised OR multifocal

CASE 5 17 male, chronic autoimmune osteomyelitis, working as a tree surgeon

CASE 5 17 year old tree surgeon with pulmonary nodules and consolidation, ? ILD

CASE 5

FUNGAL INFECTION (ADIASPIROMYCOSIS)

InfectionsTYPES OF INFECTION• Viral infections• Acute bacterial infections• Chronic bacterial infections • Fungal infections• Parasitic infections

• What can the clinician do to aid the histopathologist?

• What can the Histopathologistdo to aid the clinician?

Histopathology is a useful adjunct to microbiology in identifying certain organisms.Histologic diagnosis is not always specific!

Communicate clinical suspicions (history of travel, contacts, immunosuppression) prior to sending specimen.

Discuss with pathologist/microbiologist to ensure correct specimens for investigation are undertaken.

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Fungal infections - Identification• Identification of fungi in tissue may be first point of

recognition of diagnosis (patterns of fungal disease may mimic other entities, e.g. tumours).

• Most are opportunistic. Only a few are directly pathogenic to humans (eg C. Immitis). Consider immune compromise, especially in children.

• Varying patterns of disease (eg Aspergillus)• Consider in differential of granulomatous inflammation• History of travel to endemic areas.• Combination of microbiology and histology to obtain

diagnosis (eg Mucormycosis).

CASE 5

FUNGAL INFECTION (ADIASPIROMYCOSIS) DUE

TO CHRONIC GRANULOMATOUS

DISEASE OF CHILDHOOD

Interstitial lung disease in children

• Same definitions for histologic patterns can be applied to biopsies but…..

• Frequency of patterns differs from adults, especially for interstitial pneumonias• UIP is very rare• Commonest patterns are LIP and NSIP• Some additional patterns are unique to children

• Clinical correlates and prognoses differ from adults• Different differential diagnoses to consider -

mimics of ILD• Consider congenital disorders

•

Chronic pneumonitis of infancyKatzenstein A-LA et al. AJSP 1997;19:439-447.

• Uniform marked alveolar septal wall thickening by plump spindle cells

• No significant collagen deposition and minimal interstitial inflammation

• Florid type 2 cell hyperplasia

Infants and very young children

Possibly reflecting resolving/recurrent pneumonia, possibly lung immaturity

? Surf B abnormality.

Desquamative interstitial pneumonia in children.

Desquamative interstitial pneumonia in children.

Stillwell PC et al. Chest 1980;77:165-171.

• Report of 28 cases. • 61% survival - higher incidence

of death than adults.

Familial desquamative interstitial pneumonitis occurring in infants. Buchino JJ

et al. Am J Med Genet Suppl 1987;3:285-91

• 4 infants: 2 sibs in each of 2 separate families. All 4 infants died despite intensive care and immunosuppressive therapy.

• ? familial cases carries a worse prognosis than that reported in sporadic cases.

• ? Inborn errors of metabolism

2016 - Some are related to surfactant protein disorders- Other inborn errors of metabolism

2 year old female

Increasing shortness of breath, ?ILD

c.218T>C in the SFTPC gene

Fibrotic NSIP

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Diffuse lung disease in infancy and childhood: expanding the chILDclassification (0-2 years/2-18 years/mimics of ILD).

Rice A et al. Histopathology. 2013;63:743-55.Deutsch G et al. AJRCCM 2007:176:1120-8

Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILDClassification Scheme.

Fan LL et al. Ann Am ThoracSoc. 2015;12:1498-505

Histologic patterns specific to children

Pulmonary Interstitial Glycogenosis (PIG)CanakisAM et al ARJCCM 2002:165:1557-65

Neuroendocrine cell Hyperplasia of infancy (NEHI)

Deterding RR et al Pediatr Pulmonol. 2005:40:157-65

Deutsch G et al. AJRCCM 2007:176:1120-8

Persistent Tachypnea of Infancy. Usual and Aberrant. Rauch D et al. AJRCCM 2016:193:438-47

Includes both PIG and NEHIUsual – does not usually require biopsy as typical clinical and CT presentationAberrant – additional localized CT findings

GROUP A: HISTOLOGICAL PATTERNS MORE PREVALENT IN CHILDREN <2 YEARS

• Diffuse developmental and growth disorders • Alveolar capillary dysplasia• Congenital alveolar dysplasia • Alveolar hypoplasia/simplification• Other

• Specific conditions of undefined aetiology• Neuroendocrine cell hyperplasia of infancy• Pulmonary interstitial glycogenosis

• Surfactant protein disorder-associated histological patterns• Chronic pneumonitis of infancy • Pulmonary alveolar proteinosis• Desquamative interstitial pneumonia• Non-specific interstitial pneumonia (cellular and fibrotic)

*more than one pattern of disease may be present, especially in group A

GROUP B: HISTOLOGICAL PATTERNS MORE PREVALENT IN CHILDREN OF 2-18 YEARS

• Interstitial pneumonias (idiopathic, or with known cause/association other than SPD)• Organising pneumonia• Acute fibrinous organising pneumonia• Diffuse alveolar damage • Usual interstitial pneumonia• Desquamative interstitial pneumonia• Non-specific interstitial pneumonia (cellular and fibrotic)• Other

• Other patterns of diffuse lung disease• Haemosiderosis• Alveolar microlithiasis• Sarcoidosis• Langerhans cell histiocytosis (localised and systemic)• Other

• Lymphoproliferative disease• Lymphoid interstitial pneumonia• Diffuse lymphoid hyperplasia• Lymphomatoid granulomatosis• Follicular bronchiolitis• Other


GROUP C: DISORDERS MIMICKING DIFFUSE LUNG DISEASE

• Small airways disease• Acute, acute and chronic, chronic bronchiolitis• Obliterative bronchiolitis• Follicular bronchiolitis• Eosinophilic bronchiolitis/asthma• Other

• Vascular disorders (primary and secondary pulmonary involvement)• Primary pulmonary arterial hypertension• Pulmonary veno-occlusive disease• Pulmonary capillary haemangiomatosis• Thromboembolic disease• Lymphangiomatosis• Lymphangectasia (primary and secondary)• Secondary vasculopathies (e.g. due to cardiac disease)• Primary and secondary pulmonary vasculitis• Other

• Infections (Viral, Bacterial, Fungal, Parasitic)• Neoplasms(Any)


Diffuse lung disease in infancy and childhood: expanding the chILD classification. Rice et al. Histopathology, 2013

4 year old post adenovirus infection

10 year old, ?ILD and effusions

17 male, chronic autoimmune osteomyelitis, working as a tree surgeon

Chronic granulomatous disease of childhood

Granulomatous-lymphocytic interstitial lung disease (GL-ILD)as a presentation of CVID

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12 month old femaleBorn three weeks prematurely (birth weight 3.5kg) with

severe hyaline membrane disease that required ventilation for 10 days.

Has since had recurrent respiratory tract infections 2003 2013

Non-specific interstitial pneumonia in children

Surfactant protein dIisorders

• Pre-operative targeting• Size: <2.0 cm – suboptimal/inadequate

>3.0 cm (and deep) – optimal• Number: 2 or more sites recommended

SLBx:Discuss with surgeon pre-operatively

By following this protocol, no cases were considered“Inadequate” or “End-stage” whilst this was 11% in those

not following protocol

Gentle inflation fixation with a small bore needle

interstitial lung disease - path · interstitial lung disease professor andrew g nicholson, dm, ......

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