Lung - nontumor
Other interstitial pneumonitis / fibrosis
Nonspecific interstitial pneumonia

Author: Akira Yoshikawa, M.D. (see Authors page)
Edited by: Junya Fukuoka, M.D., Ph.D.

Revised: 29 August 2018, last major update March 2017

Copyright: (c) 2003-2018, PathologyOutlines.com, Inc.

PubMed search: nonspecific interstitial pneumonia / fibrosis

Cite this page: Yoshikawa, A. Nonspecific interstitial pneumonia. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lungnontumornonspecificintpneumo.html. Accessed November 17th, 2018.
Definition / general
Essential features
  • An interstitial lung disease with a histologic NSIP pattern, due to a variety of etiologies
  • The NSIP pattern is the second most common pattern, and always part of the differential diagnosis of the usual interstitial pneumonia (UIP) pattern, but NSIP has a better prognosis than UIP
  • Multidisciplinary discussion is necessary to make the diagnosis and decide treatment direction
Terminology
  • NSIP is the name of the morphologic (histologic) pattern
  • When no specific cause is identified, the clinical, radiological and pathological diagnosis of "idiopathic NSIP" is rendered
ICD-10 coding
  • Idiopathic nonspecific interstitial pneumonia: J84.113
Epidemiology
  • Idiopathic NSIP is the second most common idiopathic interstitial pneumonia, following idiopathic pulmonary fibrosis
  • The mean onset is 50 - 60 years old
  • Female predominant
  • No clear association with tobacco use
Sites
  • Bottom of lower lobes of bilateral (or "bibasilar") lung
Pathophysiology / etiology
Diagrams / tables

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Schema of NSIP pattern

Clinical features
  • Chronic and slowly progressive respiratory failure
    • Shortness of breath
    • Dyspnea on exertion
    • Cough
    • Fatigue
    • Weight loss
  • Abnormal chest auscultation
    • End inspiratory fine crackles in bibasilar lung
  • Restrictive pattern in pulmonary function tests:
    • Decreased forced vital capacity (FVC)
    • Decreased diffusing capacity of the lung for carbon monoxide (DLCO)
Diagnosis
  • It is often challenging to make the diagnosis for cases with an NSIP pattern, since it includes a variety of diseases
  • Therefore, two levels of diagnosis are recommended: histological diagnosis of NSIP pattern and multidisciplinary (clinical-radiological-pathological) diagnosis for its etiology (i.e. idiopathic, connective tissue, etc.), based on:
    • Clinical features, including laboratory tests
    • High resolution computed tomography (HRCT)
    • Surgical lung biopsy
  • The guidelines suggest multidisciplinary discussion by experienced physicians, radiologists and pathologists, especially when they disagree (Am J Respir Crit Care Med 2011;183:788, Am J Respir Crit Care Med 2004;170:904, Thorax 2003;58:143)
  • Some NSIP cases with inconclusive autoimmune features may fit the criteria for idiopathic NSIP under current guidelines, or be classified as interstitial pneumonia with autoimmune features (IPAF) (Eur Respir J 2015;46:976)
  • Some cases with NSIP pattern may be included in the newly described category of "Unclassifiable interstitial pneumonia (UCIP)" (Respirology 2016;21:51)
Laboratory
  • Serological autoantibody tests: can be positive but not conclusive for connective tissue disease
    • Antinuclear antibody
    • Rheumatoid factor
    • Anti-CCP antibody
    • Anti-SS-A, B antibody
    • Anti-Sm antibody
    • Anti-Scl-70 antibody
    • Anti-ARS antibody
  • Antibodies tests of hypersensitivity pneumonitis: pertinent negative for idiopathic NSIP (Am J Respir Crit Care Med 2012;186:314)
    • Avian antigens: pigeon, parakeet, budgerigar, chicken
    • Fungus: trichosporon, aspergillus
    • Bacteria: actinomycete
    • Mycobacteria: Mycobacterium avium-intracellulare
    • Chemicals
  • Increased serum KL-6 (normal limit is < 500 IU)
Radiology description
  • Chest xray and HRCT can detect lesions: however, it is usually not sensitive enough to render the diagnosis (PLoS One 2016;11:e0166168, Thorax 2003;58:143)
  • HRCT findings suggestive for NSIP pattern:
    • Diffuse ground glass opacity
    • Reticular opacity
    • Traction bronchiectasis
  • Not suggestive findings:
    • Irregular linear opacity
    • Honeycombing
    • Nodular opacity
Prognostic factors
  • Better prognosis than UIP / IPF, with a 5 year survival of ~ 70% for all NSIP (Am J Respir Crit Care Med 1998;157:199)
  • Survival rate depends on the background etiology (Eur Respir J 2015;45:746)
    • 5 year survival of 61% for idiopathic NSIP
    • 5 year survival of 42% for NSIP with chronic hypersensitivity pneumonitis
    • 5 year survival of 77% for autoimmune NSIP
Case reports
Treatment
  • There is no standard treatment for idiopathic NSIP, although 80% of cases could be improved or stabilized by glucocorticoids with / without other immunosuppressive drugs such as azathioprine and cyclophosphamide (Am J Respir Crit Care Med 1998;158:1286, Respir Med 1999;93:113)
  • Treat background diseases, including autoimmune diseases
  • Remove suspicious drugs; reduce inhalation exposure to possible disease promoters
Clinical images

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NSIP pattern on HRCT

Gross description
  • Diffuse involvement with mild to moderate increase in lung weight
  • Fibrotic changes in lower lobes
    • Homogeneous and diffuse compared to UIP
    • Shrunken lung
    • Traction bronchiectasis can be seen
    • Honeycomb change can be seen but limited
Microscopic (histologic) description
  • Since there are few specific findings for NSIP pattern, it is essential to exclude other lung diseases on histology (Am J Respir Crit Care Med 2008;177:1338)
  • Characteristic findings of NSIP pattern
    • Diffuse and uniform inflammation ("temporal homogeneity") on low power of alveolar wall, bronchovascular bundles and pleura
      • There are usually no normal alveolar walls in the affected lobules
    • Cellular or fibrotic change
      • Lymphocytic or plasmacytic infiltration
      • Loose fibrosis
      • Lung architecture is frequently preserved
      • "Cellular NSIP" or "fibrotic NSIP" can be stated specifically in pathologist report
  • Features of interstitial pneumonia with autoimmune features (IPAF) (Chest 2010;138:251):
    • Lymphoid aggregates with germinal center
    • Extensive pleuritis
    • Prominent plasmacytic infiltration
    • Dense perivascular collagen
  • It is quite rare to see pure NSIP on histology - typically there are focal findings of other interstitial lung disease (Histopathology 2014;65:549)
  • Pertinent negative findings (Am J Respir Crit Care Med 2008;177:1338)
    • UIP-like change
      • Marked architectural distortion
      • Dense fibrosis with smooth muscle hyperplasia or elastosis
      • Fibroblastic foci
      • Honeycomb change
    • Hypersensitivity pneumonitis-like change
      • Airway centered change
      • Peribronchiolar metaplasia
      • Granulomas or interstitial giant cells with cholesterol cleft
    • Extensive organizing pneumonia (areas more than 20% of disease)
    • Desquamative interstitial pneumonia-like change
      • Aggregation of respiratory bronchiolitis macrophages in alveolar sacs and respiratory bronchioles
    • Diffuse alveolar damage-like change
      • Hyaline membrane
      • Alveolar hemorrhage
    • Lymphoid interstitial pneumonia-like change
      • Marked and extensive infiltration of lymphocytes in alveolar wall
      • Light chain restriction
    • Smoking related interstitial fibrosis (J Clin Pathol 2013;66:882)
      • Alveolar hyalinized septal thickening with little cellular infiltration
      • Centriacinar emphysema
Microscopic (histologic) images
Scroll to see all images.

Images hosted on PathOut server:

Contributed by Akira Yoshikawa, M.D. from the Department of Pathology, Nagasaki University Hospital
Case 1: cellular and fibrotic NSIP:


Low power

Uniform involvement

Less inflamed

Lymphocytic infiltration and fibrosis

Lymphoid follicles with germinal center

Lympho-plasmacytic infiltration



Case 2: fibrotic NSIP:

Low power

Uniform involvement

Sparse architectural distortion

Peribronchiolar metaplasia

A few honeycomb changes

Dense fibrosis



Case 3: cellular and fibrotic NSIP:

Low power

Uniform involvement

Lymphocytic infiltration and fibrosis


Pleuritis

Organizing pneumonia

Lymphocytic aggregation

Airway centered change



Case 4: cellular NSIP:

Low power; note diffuse lymphoid follicles

Uniform involvement with lymphoid follicles

Lymphoid follicles with germinal center

Pleuritis with lymphoid follicles

Dense fibrosis are sparsely seen



Images hosted on other servers:

Diffuse and uniform inflammation

Cellular NSIP


Fibrotic NSIP

Pleuritis

Organizing pneumonia in NSIP

Series of slides of fibrotic NSIP

Positive stains
Differential diagnosis
  • Desquamative interstitial pneumonia: smoking history, aggregates of alveolar macrophages
  • Diffuse alveolar damage: hyaline membrane, alveolar hemorrhage
  • Hypersensitivity pneumonitis: exposure to antigens, airway centered change
  • Infectious disease (TB, fungal)
  • Interstitial pneumonia with autoimmune features (IPAF): lymphoid aggregates with germinal center, extensive pleuritis, prominent plasmacytic infiltration, dense perivascular collagen
  • Lymphoid interstitial pneumonia: viral infection such as HIV, CMV and HTLV1
  • Organizing pneumonia: marked organizing pneumonia on histology
  • Smoking related interstitial fibrosis: smoking history, acellular fibrosis
  • UIP / IPF: patchy and peripheral involvement, fibroblastic focus, honeycomb change