NSIP subtypes Dominique Valeyre Paris 13 University COMUE Sorbonne Paris Cité Assistance publique hôpitaux de Paris Trieste 04/12/2016

COI disclosures More qualified as a clinician than as a pathologist

Outline Introduction: history, definition and settings, epidemiology of respective settings with NSIP 1- What is the impact of evidencing a NSIP pattern in respective settings (NSIP in clinical settings being considered as NSIP subtypes)? 2- Are there differences (presentation and outcome) among NSIPs according to respective underlying conditions ? 3- Do NSIP pathologic subtypes give information about settings and prognosis? Conclusion * Due to time limitations, no development on CT or BAL findings

NSIP history and underlying conditions 1994: Katzenstein & Fiorelli: NSIP defined as a (wastebasket) histopathologic presentation which does not fit Liebow’s classification of IIP 2002: ATS/ERS international consensus panel Accepted as a provisional entity 2008: ATS project report: idiopathic NSIP is a distinct clinical entity with a better survival than IPF 2013: ATS/ERS: update of the multidisciplinary classification of IIP Idiopathic NSIP confirmed as a distinct clinical entity NSIP occurs as: Idiopathic (one of the two fibrosing IIP with IPF) Diverse settings: CVD; HP; drug toxicity; familial pulmonary fibrosis Usefulness of MDD Travis AJRCCM 2008; Poletti & Chilosi SRCCM 2012; Travis AJRCCM 2013

NSIP: pathological definition The NSIP histological pattern includes Variable degrees of inflammation and fibrosis Homogeneity of lesions (spatial and temporal) Preservation of the lung architecture Courtesy M Kambouchner Kambouchner Histopathology 2014

Epidemiology of NSIPs among ILD Overall prevalence 76.04/105 Overall Incidence 15.08/105/yr

1- What is the impact of evidencing a NSIP pattern in respective settings (NSIP in clinical settings being considered as NSIP subtypes)? - IIP - cHP - CTD - Familial PF

Interstitial lung diseases ILD with a known cause: drugs, exposures, CTD… Idiopathic Interstitial Pneumonias Granulomatoses: sarcoidosis Particular ILD: LCH, LAM, ALP, CEP… IPF / UIP others Les pneumopathies interstitielles diffuses se divisent en 4 catégories : les PID de cause connue, les granulomatoses pulmonaires dont l’archétype est la sarcoïdose, les PID particulières dont par exemple l’hystiocytose X ou la lymphangiomyomatose et les pneumopathies interstitielles idiopathiques. Dans la classification 2002, les pneumopathies interstitielles idiopathiques regroupent 7 entités auxquelles correspondent un pattern histologique, le substratum de la fibrose pulmonaire idiopathique étant la pneumopathie interstitielle commune ou usual interstitial pneumonia ou UIP. Nicholson et al. Am J Respir Crit Care Med 2000 Travis et al. Am J Surg Pathol 2000

cHP

Morphologic diversity of chronic pigeon breeder ’s disease: clinical features and survival 110 biopsies: typical HP (n=58); NSIP-pattern (n=22, =20%) UIP-pattern (n=10) Mixed (9); OP (3); ACIF (3); non-classified (5) Presentation No difference for age (~45); gender; symptoms % BAL Ly 52% (between HP 65% and UIP-pattern 36%) « inflammatory » pattern at CT between HP and UIP-pattern Survival rate NSIP-pattern: better survival than typical HP; UIP-pattern: worse survival than typical HP Gaxiola Respiratory Medicine 2010

Pathologic patterns and survival in cHP Chronic (fibrotic) HP (n=25) and subacute (nonfibrotic) HP (n=24) Exposure histories: Mold/humidifier (15); miscellaneous (14); farmer (8); bird (8); hot tub (4) NSIP Subacute HP → 21% NSIP (cellular) Chronic HP → 16% (n=4) NSIP (fibrotic) Survival As low for fibrotic-NSIP-cHP (median=2.4 yrs) as for UIP-cHP Churg Am J Surg Pathol 2009

NSIP as the sole histologic expression of HP In 6 cases out of 84 From cellular to fibrotic NSIP Confirmation of Katzenstein’s observation Vourlekis Am J Med 2002

Significance of NSIP in cHP Is NSIP-cHP less severe than, or as severe as UIP-cHP? Hypotheses to explain differences: Cellular- versus fibrotic-NSIP Causes: birds versus molds/humidifiers Age: patients older in Churg’s series than Gaxiola’s

CTD-NSIP

CTD/ILD specificities CTD-ILDs in general are reputed to be associated to a more favourable prognosis than IIP of equivalent severity Earlier detection? Less progressive? Benefit from antiinflammatory drugs? Specific impact of NSIP in CTD Good prognosis and no difference in survival in NSIP and UIP pattern In a miscellaneous series of CTD (37 SSC; 28 RA; 11 SjS; 8 PM/DM; 9 others) In SSc respective 5 yrs survival 91% and 82% for respectively NSIP and UIP patterns Probably no impact of NSIP pattern in SSC but in other conditions? Need for further studies dedicated to NSIP in RA, DM/PM/ASS, mixed CVD etc…respectively Bouros AJRCCM 2002; Park AJRCCM 2007; Kim ERJ 2010; Fischer Lancet 2012

NSIP in familial PF NSIP pattern in ~10% vs UIP (85%) Sometimes, different IIP patterns in a same family (UIP; unclassifiable; NSIP etc…) Is there any link between histopathology and genetic background? In Surfactant protein mutations; the pattern is often unclassifiiable, sometimes NSIP and very rarely UIP In TERT/TERC/RTLE1 mutations: UIP is seen in 49% and NSIP is seen in 7% of cases Is NSIP-PF associated to a more favourable survival? Steele AJRCCM 2005; Borie COPM 2012

Pulmonary diagnosis in the French cohort of TERT/TERC mutated patients Courtesy Raphaël Borie and Bruno Crestani Secondary ILD 13%

2- Are there differences (presentation and outcome) among NSIPs according to respective underlying conditions ?

Patient survival according to aetiological group Nunes ERJ 2015

3- Do NSIP pathologic subtypes give information about settings and prognosis?

Adapted from Travis Initial NSIP diagnosis (MK); confirmed (AN) Double-blind analysis (MK and JFB) Good interobserver concordance (κ=0.87) Most cases were classifiable (only 3.7% unclassified)

Results (1) N= 136 cases studied Respective frequency Essential NSIP → 36% NSIP/UIP → 26% NSIP/cHP → 10% NSIP/OP → 6% NSIP/organizing DAD → 10% NSIP/DIP → 7% NSIP/LIP → 2%

Results : correlation with clinical settings NSIP/cHP ↔ clinical cHP (p=0.02) NSIP/OP ↔ CTD (p=0.038) NSIP/organizing DAD: more rapid course No ≠ for age, gender, smoking habits

NSIP histological variants and survival

Conclusion A NSIP histopathology is shared by different clinical settings and may have a different prognosis signification according to causes Altogether, NSIP is a relevant entity for clinicians that is enriched when they take into account: The underlying setting The histopathological NSIP subtype Studies are needed to better explore the clinical signification of a NSIP histopathology in some CTD, cHP and familial PF