, NSIP and their differential diagnoses Belfast Pathology Belfast Tuesday 20 th June 2017 Professor Andrew G Nicholson, DM, FRCPath Usual Interstitial Pneumonia () 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 Histologic features of Key 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 MINOR HISTOPATHOLOGICAL FEATURES IN USUAL INTERSTITIAL PNEUMONIA Micro Honeycombing NORMAL Fibroblast focus Dense scar Dense scar THIS IS 1
21/07/2017 diagnostic here 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 Diagnosis Idiopathic Pulmonary Fibrosis Idiopathic Nonspecific Interstitial Pneumonia Eventual outcome for the lobule Respiratory Bronchiolitis Interstitial Lung Disease pleuroparenchymal fibroelastosis Rare Histologic Patterns Acute fibrinous & organizing pneumonia Desquamative Interstitial Pneumonia Bronchiolocentric Cryptogenic Organizing Pneumonia Lobule destroyed Rare IIP Idiopathic LIP Idiopathic patterns of IP Unclassifiable IIP Acute Interstitial Pneumonia CO-EXISTING PATTERNS IN IPs = IPF in most cases RB = Smoking-related IP DIP PLEUROPARENCHYMAL FIBROELASTOSIS AND NSIP DAD AE of IPF OP = COP or 2ary causes Reddy TL et al: ERJ 2012;40:377-385 LIP Histologic pattern of in non-ipf patients. Most are seen in the context of IPF but Chronic Hypersensitivity Pneumonitis (EAA) Collagen Vascular Disease (RA, PM, SS) Asbestosis Familial Idiopathic Pulmonary Fibrosis Drug Toxicity (Usually cytotoxic drugs) = 1ary very rare and chronic HP Pathologic patterns and survival in Chronic HP. Churg et al. AJSP 2009;33:1765 24 subacute (cellular, nonfibrotic) and 25 chronic (fibrotic) HP. 72% chronic HP = -like; three BIP/F; 16% F-NSIP Only 2 -like cases could not be morphologically distinguished from idiopathic. Survival for patients with no fibrosis = 22.4 years Fibrotic NSIP = 2.1 years; -like pattern = 2.8 years 2
Chronic HP versus /IPF. BUILD 1 drug trial Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease Lee HK et al. Chest 2005;127:2019-27 Patient subset Diagnosis of IPF/ by local pathologist All cases reviewed by the central pathology panel Cases confirmed as IPF/ by central pathology panel All Placebo Bosentan patients 99 50 49 86 45 41 64 36 28 10, NSIP - 6, and airway disease/op -2. In three patients, ILD preceded RA; 3 simultaneous diagnosis NSIP Male/female 8/2 0/6 Smoking Hx 8/2 0/6 Death 5/10 0/6 Pathologic patterns and survival in chronic HP. Churg et al. AJSP 2009;33:1765 25% of cases rejected as not by reference pathologists 50% F-NSIP 23% EAA (8% in total) Interstitial pneumonia in RA Tansey D et al. Histopathology 2004;44:585-596 Pulmonary fibrosis seen in about <5% of patients NSIP and follicular bronchiolitis are commonest histologic patterns, often superimposed in Brompton experience. Early studies suggest survival similar to idiopathic NSIP Pathology of asbestosis- An update of the diagnostic criteria: Report of the asbestosis committee of the college of american pathologists and pulmonary pathology society. Roggli VL et al. Arch Pathol Lab Med. 2010 Mar;134(3):462-80 Interstitial fibrosis and asbestos bodies (2 or more per 1cm 2 in a normal thickness section. 1. Interstitial fibrosis of asbestosis is accompanied by very little inflammation, which, although not marked, is better developed in idiopathic pulmonary fibrosis. 2. In keeping with the slow tempo of the disease, the fibroblastic foci that characterize idiopathic pulmonary fibrosis are infrequent in asbestosis. 3. Asbestosis is almost always accompanied by mild fibrosis of the visceral pleura, a feature that is rare in idiopathic pulmonary fibrosis. AND ASBESTOSIS Usual interstitial pneumonia in asbestosexposed cohorts - concurrent idiopathic pulmonary fibrosis or atypical asbestosis? Attanoos RL, Alchami FS, Pooley FD, Gibbs AR. Histopathology. 2016 ;69:492-8 >25 000 persons to the UK Pneumoconiosis Unit, Cardiff. Over the 17-year period, 233 subjects were identified; 210 had f-nsip and subpleural accentuation, and three showed. All three of these cases showed grade 4 fibrosis (honeycombing) with no asbestos fibre dose-response correlation. A Poisson distribution of probability analysis indicated that the observed cases of in this workforce could be wholly accounted for by the prevalence of idiopathic pulmonary fibrosis (IPF) in the population. CONCLUSIONS: pattern fibrosis is rarely observed in asbestos-exposed subjects, and shows no dose-response correlation with asbestos fibres on mineral analysis; this points to an alternative disease, such as IPF Asbestosis: demonstration of distinctive interstitial fibroelastosis: a pilot studynn Wick MR et al Diagn Pathol. 2009;13:297-302. AND ASBESTOSIS Asbestosis vs other forms of interstitial lung disease. Asbestosis - Variable, with the pattern being peribronchialand perivascular in 100%. Non-asbestosis - 71% showed interstitial fibrosis with a variable (usually modest) amount of admixed elastic tissue IPF also showed fibroelastosis, but confined to regions of overt "honeycomb" change. Asbestos exposure increases the incidence of histologically confirmed usual interstitial pneumonia. Kawabata Y et al. Histopathology. 2016;68:339-46. 1718 cases (1202 males; mean age 66.7 years) who underwent lobectomy for resection of pleuropulmonary tumours. 183 with asbestos exposure, and 239 with histological. The 183 cases with asbestos exposure had higher rates of positive occupational history and histological (31%) than the remaining 1535. Among the asbestos-exposed group, small numbers of asbestos bodies were found in histological specimens of 21 cases of histological. PPs and asbestos bodies were more frequent in the 239 patients with histological than in the remaining 1479 -negative patients. CONCLUSION: Asbestos exposure causes asbestosis and increases the incidence of histological Familial idiopathic interstitial pneumonia: histopathology and survival in 30 patients. Leslie KO et al. Arch Pathol Lab Med. 2012;136:1366-76. F-IIP: unexplained occurrence of diffuse parenchymal lung disease in related individuals, said to be indistinguishable from /IPF. 30 patients - consensus diagnosis was unclassifiable parenchymal fibrosis (60%), with a high incidence of histopathologic honeycombing, fibroblast foci, and smooth muscle in fibrosis., strictly defined, was identified in less than half of the F-IIP cases (range, 23%-50%). Interobserver agreement was fair (κ = 0.37). Subjects with had a shorter survival and younger age at death. Drug reactions May not be the systemic disease but its treatment that causes pulmonary pathology Very rarely is a histologic pattern specific for a drug reaction (eg amiodarone) May however be pointers 1. Eosinophilia 2. Cytologic atypia within epithelial cells 3. pattern is rare www.pneumotox.com 3
21/07/2017 ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidencebased Guidelines for Diagnosis and Management. Conclusion: Histologic pattern of in non-ipf patients. Raghu G et al. Am J Respir Crit Care Med 2011;183:788-824. patte rn (all four criteria) Most are seen in the context of IPF but Chronic Hypersensitivity Pneumonia (HP) Collagen Vascular Disease (RA, PM, SS) Drug Toxicity (Usually cytotoxic drugs) Asbestosis Familial Idiopathic Pulmonary Fibrosis If a pattern of is made on histology, look for features that argue against a diagnosis of IPF and comment, if present Evide nce of marked fibrosis/ architectural distortion, +/honeycombing in a pre dominantly subpleural/ paraseptal distribution Pre sence of patchy involvement of lung pare nchyma by fibrosis Pre sence of fibroblast foci Abse nce of fe atures against a diagnosis of suggesting an alternate diagnosis(see fourth column) Probable pattern OR Evide nce of marked fibrosis / architectural distortion, +/honeycombing Abse nce of e ither patchy involvement or fibroblastic foci, but not both Abse nce of fe atures against a diagnosis of suggesting an alternate diagnosis(see fourth column) Possible pattern (all three criteria) Patchy or diffuse involvement of lung pare nchyma by fibrosis, with or without interstitial inflammation Abse nce of other criteria for (se e pattern column) Abse nce of fe atures against a diagnosis of Not pattern (Any of the six criteria) Hyaline me mbranes * O rganizing pne umonia * Granulomas Marke d interstitial inflammatory ce ll infiltrate away from honeycombing Pre dominant airway centered changes O ther features suggestive of an alternate diagnosis HRCT Pattern * Surgical Lung Biopsy Pattern * (when performed) Diagnosis of IPF? Probable YES Possible Non-classifiable fibrosis ** Not No YES Probable c/w Possible Non-classifiable fibrosis Honeycomb changes only** Probable Not No Possible Probable Inconsistent with Possible Non-classifiable fibrosis No Not Granulomas, bronchocentricity, areas of inflammation without fibrosis, areas of organising pneumonia, asbestosis bodies, pathology in other anatomic compartments (pleura, vasculature, airways), prominent eosinophils Non-specific Interstitial Pneumonia (NSIP) ATS/ERS consensus classification of idiopathic interstitial pneumonias Am J Respir Crit Care Med 2002; 165: 266-301 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 ATS/ERS subdivision of NSIP Cellular Fibrotic ATS/ERS consensus classification of idiopathic interstitial pneumonias Am J Respir Crit Care Med 2013; 188: 733-748 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 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. 4
OP and cellular NSIP Consolidation etc. NSIP versus DIP Smoking-related interstitial lung disease 58, male No obvious steroid effect on disease course Life-long non-smoker No CTD symptoms No occupational exposures BAL: normal differential Restrictive PFT. FVC 61%, DLco 57% Two years of exertional dyspnoea Bilateral basal crackles, not clubbed, consistent with IPF 5
Histopathology: F-NSIP MDT review: HRCT favours chr HP History of bird exposure Levels cut on block FINAL DIAGNOSIS: CHR HP Update on NSIP SOME PATIENTS WITH IDIOPATHIC NSIP SUBSEQUENTLY DEVELOP COLLAGEN VASCULAR DISEASES Kono M et al. Nonspecific interstitial pneumonia preceding diagnosis of collagen vascular disease. Respir Med. 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) ATS/ERS workshop relatively few at the centre of the circle 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. The prevalence of interstitial pneumonias in patients with connective tissue diseases RA SLE SSc PM/DM SjS Amyloid Blitis ++? +/- + + +/- NSIP ++? +? +++ ++ ++ LIP/FB ++ +/- - - ++ OP + +/- +/- ++ +/- DAD + ++ +/- +/- - DIP/RB +/-* - +* - - 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 The prevalence of interstitial pneumonias in patients with connective tissue diseases RA SLE SSc PM/DM SjS Amyloid Blitis ++? +/- + + +/- NSIP ++? +? +++ ++ ++ LIP/FB ++ +/- - - ++ OP + +/- +/- ++ +/- DAD + ++ +/- +/- - DIP/RB +/-* - +* - - 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 6
Disease overlap in Interstitial Lung Disease Disease overlap in Interstitial Lung Disease LIP AIP RB-ILD OP LIP AIP RB-ILD OP DIP sarcoid NSIP DIP sarcoid NSIP LAM HP Idiopathic pulmonary haemorrhage Langerhans cell histiocytosis LAM HP Idiopathic pulmonary haemorrhage Langerhans cell histiocytosis Sameness. Coexistence Transformation. Sameness. Coexistence, Transformation.. Other anatomic compartments Patient with SLE 2000 2003 2005 Diffuse lung disease in infancy and childhood: expanding the child classification (0-2 years/2-18 years/mimics of ILD). 2 year old female Increasing shortness of breath,?ild Deutsch G et al. AJRCCM 2007:176:1120-8 Rice A et al. Histopathology. 2013;63:743-55. Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the child Classification Scheme. Fibrotic NSIP Fan LL et al. Ann Am Thorac Soc. 2015;12:1498-505 c.218t>c in the SFTPC gene 7
Surfactant protein diisorders 12 month old female Born 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 Non-specific interstitial pneumonia in children USAGE OF CRYOBIOPSIES 2003 2013 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). CONS OF CRYOBIOPSY Surgical lung biopsy has a higher diagnostic yield than cryobiopsy (0.987 vs 0.81 (0.75 0.87)) (1) Cryobiopsy has lower complication rates and mortality rates compared to SLB (1). In one series for cryobiopsy, severe bleeding was reported as 53% (6) 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 cryobiopsy saved up to 59,846 (over 3 years) (4): 210 per patient in the first year and 647 in subsequent years (5). 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 Yield 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):900-6 3. 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 193:745-52 4. 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;51:261-7 5. 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. Hagmeyer L, et al.the role of transbronchial cry obiopsy and surgical lung biopsy in the diagnostic algorithm of interstitial lung disease. Clin Respir J. 2015 7. Johannson KA y et al. Diagnostic Yield 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;188-1838 8. 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] Bronchoscopic cryobiopsy in NSIP diagnosis 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 cryobiopsy cannot be determined given the absence of studies directly comparing cryobiopsy diagnoses to diagnoses derived from with surgical lung biopsies interpreted within multidisciplinary discussions. The histopathological and multidisciplinary discussion-based diagnostic yield of transbronchial cryobiopsy appear 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%. USAGE OF CRYOBIOPSIES IN THE DIAGNOSIS OF NSIP 57 year old female never smoker. History of Farmers Lung 20 years previously treated with steroids. Arthritis for 10 years (autoimmune screen negative). On Omeprazole and Fesoterodine. CT - Patchy ground-glass changes in mid and upper zones. BAL - Eosinophilia (17%) and mild neutrophilia (6%). No lymphocytosis (8%). Lung function tests: Moderate restrictive defect, in keeping with the known interstitial lung disease. Histopathology (cryobiopsy): The features favour fibrotic non-specific interstitial pneumonia (NSIP), possibly secondary to progression of organising pneumonia 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% MDT REVIEW: Probable 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 currently,? secondary to CTD or drug reaction Treated with immunosuppression and stable at 3 months 8
NSIP and overlapping histology on cryobiopsy L O W E R L O B E ON CRYOBIOPSY U P P E R L O B E, NSIP and their differential diagnoses SIZE AND NUMBER OF BIOPSY SITES AND NUMBER OF BIOPSIES Lower lobe: is the prognostic indicator Middle lobe: NSIP K. R. Flaherty et al Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 164 (9):1722-1727, 2001. Monaghan H et al. Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias. Chest. 2004 Feb;125(2):522-6. ATS/ERS Revised 2013 Classification Clin-Rad- Pathologic Diagnosis Idiopathic Pulmonary Fibrosis Idiopathic Nonspecific Interstitial Pneumonia Respiratory Bronchiolitis Interstitial Lung Disease Desquamative Interstitial Pneumonia Cryptogenic Organizing Pneumonia Acute Interstitial Pneumonia Rare IIPs Idiopathic Lymphoid interstitial pneumonia Idiopathic Pleuroparenchymal Fibrolastosis Rare histologic patterns Acute fibrinous and organising pneumonia Bronchiolocentric patterns of IP Unclassifiable IIP - most are seen in the context of IPF but Chronic Hypersensitivity Pneumonitis (EAA) Collagen Vascular Disease (RA, PM, SS) Asbestosis Familial Idiopathic Pulmonary Fibrosis Drug Toxicity (Usually cytotoxic drugs) ATS/ERS IIP Classification Revision: Updates existing entities NSIP accepted and defined NSIP subtypes - 1ary and 2ary have clinical and prognostic relevance. IPAF should be considered as another entity with an NSIP pattern NSIP in children should warrant investigation for Surfactant Protein Gene Mutations. NSIP and can be diagnosed on cryobiopsy but need identical MDT review as for SLBx, possibly even more important. Revisions of guidelines in 2018.. 9