Lung nontumor
Other interstitial pneumonitis / fibrosis
Lymphoid interstitial pneumonia (LIP)

Author: Akira Yoshikawa M.D.
Editor: Andrey Bychkov, M.D., Ph.D.

Revised: 24 May 2018, last major update May 2018

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

PubMed search: lymphoid interstitial pneumonia [title]

Cite this page: Yoshikawa, A. Lymphoid interstitial pneumonia (LIP). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lungnontumorLIP.html. Accessed June 25th, 2018.
Definition / general
Essential features
  • Rare type of interstitial lung disease due to different diseases including Sjögren syndrome, rheumatoid arthritis and human immunodeficiency virus (HIV) infection
  • On histology, diffuse infiltration of polyclonal lymphocytes with scant interstitial fibrosis is characteristic
Terminology
  • Also called lymphocytic interstitial pneumonia
ICD-10 coding
  • J84.2: lymphoid interstitial pneumonia
Epidemiology
  • Rare
  • Typical onset at ages 40 - 70 years old but can occur at any age (Chest 2002;122:2150)
  • More common in women
  • No association with smoking history
Sites
  • Bilateral lower lobes of the lung
Pathophysiology
  • Pathogenic mechanisms of LIP are still unclear
  • Has aspects of lymphoproliferative disease and lymphoid hyperplasia of polyclonal T or B cells (Chest 2002;122:2150)
  • Although it may transform to lymphoma, especially MALT, the risk is lower than initially reported (Eur Respir J 2006;28:364)
Etiology
  • Associated with several systemic diseases and conditions (Chest 2002;122:2150, Respirology 2016;21:600, Eur Respir J 2006;28:364)
    • Autoimmune (most common)
      • Sjögren syndrome (SjS); 25% of LIP cases have SjS and 1% of SjS cases present with LIP
      • Rheumatoid arthritis
      • Systemic lupus erythematosus
      • Polymyositis / dermatomyositis
      • Hashimoto disease
      • Hypothyroidism
      • Castleman disease
      • Myasthenia gravis
      • Autoimmune hemolytic anemia
      • Pernicious anemia
      • Primary biliary cirrhosis
    • Infection
      • Human immunodeficiency virus (HIV)
      • Epstein-Barr virus
      • Human T cell lymphotropic virus type 1
      • Legionella pneumonia
      • Mycoplasma
      • Chlamydia
      • Tuberculosis
    • Immunodeficiency
      • Acquired immunodeficiency syndrome (AIDS); especially in children
      • Monoclonal or polyclonal gammopathy
      • Common variable immunodeficiency
    • Idiopathic LIP accounts for 20% of cases (Eur Respir J 2006;28:364)
Clinical features
  • Very slowly progressive respiratory symptoms
    • Dyspnea on exertion
    • Dry cough
    • Systemic symptoms such as malaise, fever and weight loss
    • Duration of the symptoms prior to diagnosis can exceed a year
  • Bibasilar inspiratory crackles on chest auscultation
Diagnosis
  • Based on clinical, radiological and pathological findings (multidisciplinary diagnosis)
  • No firm diagnostic criteria currently exist
Laboratory
  • Dysproteinemia (hypergammaglobulinemia is more common than hypogammaglobulinemia) is often present
  • Restrictive pattern on pulmonary function tests
    • Reduced forced vital capacity (FVC)
    • Reduced diffusing capacity of the lung for carbon monoxide (DLCO)
Radiology description
  • Chest radiography
    • Bibasilar opacities with lower lobe predominance
  • High resolution computed tomography (Eur J Radiol 2015;84:542, Respirology 2016;21:600)
    • Ground glass opacity with / without consolidation with lower lobe predominance
    • Cyst formation and thickening of bronchovascular bundle and interlobular septa are often present
    • Cysts often remain even after resolution of symptoms
Radiology images

Images hosted on other servers:

Chest radiograph

Ground glass opacity with cyst formation and nodules

Cyst formation

Prognostic factors
  • Prognosis varies from resolution without treatment to progression to end stage (Respirology 2016;21:600)
  • Median survival was 11.5 years in a case series (Eur Respir J 2006;28:364)
  • No characteristic prognostic factor has been found so far
Case reports
Treatment
  • No treatment data from a controlled study is available so far (Respirology 2016;21:600)
    • Corticosteroid therapy is commonly used as a first line treatment and improves the symptoms in most cases
    • Immunosuppression (eg, cyclophosphamide, azathioprine, cyclosporine A) may be used as a second line
  • Treatment for underlying disease is also essential for secondary LIP
Gross description
  • Ill defined lesion
  • Mild increase in lung weight
Microscopic (histologic) description
  • Diffuse interstitial infiltration of polymorphous lymphocytes and plasma cells
    • Lymphoid follicles with germinal centers, histiocytes and macrophages are often present
    • Bronchovascular bundles and interlobular septa are usually involved
    • Alveolar structure is often inflated and disrupted
    • Typically CD8+ or CD4+ T cells or B cells predominate, with an admixture of other lymphocytes
    • Immunohistochemistry or molecular testing are necessary to confirm polyclonality
  • Additional findings
    • Loose ill defined epithelioid granulomas
    • Interstitial or intra-alveolar giant cells
    • Intra-alveolar macrophages
    • Type II pneumocyte hyperplasia
    • Cyst formation without marked fibrosis
  • Pertinent negative findings
    • Loose and dense fibrosis (more common in fibrotic / cellular nonspecific interstitial pneumonia (NSIP))
    • Fibroblastic focus (more common in usual interstitial pneumonia or fibrotic NSIP)
    • Honeycomb change (more common in usual interstitial pneumonia or fibrotic NSIP)
    • Organizing pneumonia (more common in hypersensitivity pneumonitis)
  • See: Respirology 2016;21:600, Chest 2002;122:2150, Am J Respir Crit Care Med 2002;165:277
Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Akira Yoshikawa M.D.

69 year old woman with a 1 year history of mouth dryness presented with mild dyspnea, dry cough and abnormal chest Xray. ANA and anti-ssDNA antibody were elevated. Two open lung biopsies of S9 were performed:

Biopsy 1

Low power

Bronchovascular bundle

Granuloma and lymphocytes


Septal thickening

Giant cells and lymphocytes

Massive lymphocytic infiltration



Biopsy 2

Low power

Lymphocytic infiltration


Architectural destruction

Giant cells and lymphocytes



Contributed by Dr. Yale Rosen

Diffuse cellular pattern


Lymphoplasmacytic infiltration



Images hosted on other servers:

LIP

Numerous lymphoid follicles

EBV related LIP

Cytology description
  • Increase in the number of lymphocytes (especially CD8 positive) of bronchoalveolar lavage, without clonality (Eur Respir J 2006;28:364)
Positive staining - disease
Molecular / cytogenetics description
  • EBNA ISH and EBER ISH are helpful to detect EBV infection
Differential diagnosis
  • Follicular bronchitis / bronchiolitis
    • Lymphocytic infiltration into bronchial / bronchiolar walls with multiple lymphoid follicles
    • No or slight lymphocytic aggregation in intralobular septa
  • Hypersensitivity pneumonitis (HP)
    • History of an antigen exposure such as animals, birds and chemicals
    • Less diffuse but bronchocentric distribution
    • Loose ill defined granuloma and giant cells can be seen in both LIP and HP
  • Lymphoma, especially mucosa (bronchus) associated lymphoid tissue lymphoma
    • Monomorphous infiltration of lymphocytes, distortion of alveolar architecture, Dutcher bodies, pleural infiltration are more common in lymphoma
    • Immunohistochemistry is often helpful
  • Nonspecific interstitial pneumonia
    • Lymphoplasmacytic infiltration is also seen in NSIP but less severe
    • Alveolar structure is usually preserved compared with LIP
Board review question #1
Which of following is not usually seen in this entity?

  1. Cyst formation
  2. Giant cells
  3. Honeycomb change
  4. Lymphocytic interstitial infiltration
  5. Nonnecrotizing granuloma
Board review answer #1
C. Honeycomb change. Lymphoid interstitial pneumonia is predominantly a cellular interstitial pneumonia. Fibrotic processes such as dense fibrosis or honeycomb change usually exclude a diagnosis of LIP.