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

2. COI disclosures
More qualified as a clinician than as a pathologist

3. 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

4. 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

5. 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

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

7. 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

8. 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

9. cHP

10. 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

11. 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

12. 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

13. 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

14. CTD-NSIP

15. 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

16. 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

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

18. 2- Are there differences (presentation and outcome) among NSIPs according to respective underlying conditions ?

23. Patient survival according to aetiological group
Nunes ERJ 2015

27. 3- Do NSIP pathologic subtypes give information about settings and prognosis?

29. 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)

32. 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%

33. 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

34. NSIP histological variants and survival

35. 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