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: 22 March 2017, last major update March 2017

Copyright: (c) 2003-2017, PathologyOutlines.com, Inc.

PubMed search: nonspecific interstitial pneumonia / fibrosis

Cite this page: Nonspecific interstitial pneumonia. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lungnontumornonspecificintpneumo.html. Accessed June 27th, 2017.
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

Cellular and fibrotic NSIP


Comparison of cellular and 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