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Interstitial lung diseases

UIP / IPF

Authors: Akira Yoshikawa, M.D., Andrey Bychkov, M.D., Ph.D.

Last author update: 1 June 2017

Last staff update: 26 October 2022 (update in progress)

Copyright: 2003-2023, PathologyOutlines.com, Inc.

PubMed Search: usual interstitial pneumonia OR idiopathic pulmonary fibrosis

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Table of Contents

Cite this page: Yoshikawa A. UIP / IPF. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumorUIP.html. Accessed February 3rd, 2023.

Definition / general

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic interstitial lung disease of unknown cause, associated with histologic and radiologic pattern of usual interstitial pneumonia (UIP)

Essential features

Chronic and progressive respiratory failure due to fibrosis in the lung
One of the most common and most lethal lung diseases
Characterized by bibasilar patchy fibrosis and honeycomb

Terminology

UIP is the name of morphological pattern in histology and radiology, and also seen in other etiologies such as connective tissue diseases and hypersensitivity pneumonia
IPF was previously called chronic interstitial pneumonitis or cryptogenic fibrosing alveolitis

ICD coding

J84.112

Epidemiology

The first or second most common (17% - 86%) interstitial lung disease (Clin Epidemiol 2013;5:483)
Rarely younger than 50 years old (these patients may have a genetic factor or underlying disease)
Male predominance
U.S. incidence 93.7 per 100,000, prevalence 494.5 per 100,000 in population ≥ 65 years (Lancet Respir Med 2014;2:566)
Lower incidence and prevalence in Asia (Am J Respir Crit Care Med 2014;190:773, Respirology 2008;13:926, Respir Med 2012;106:1566)
Currently increasing globally (Respirology 2016;21:427, Clin Epidemiol 2013;5:483)

Sites

Bottom of lower lobes of bilateral (or "bibasilar") lung

Pathophysiology / etiology

Damage of alveolar epithelium (or pneumocytes) is a key event
Aberrant Wnt / β-catenin signaling pathway may be related to abnormal remodeling
Increased TGF-β1 activity likely has role in abnormal fibrosis
Although the etiology is still unknown, studies report several potential risk factors:
- Genetic factors, including several mutations (Proc Am Thorac Soc 2011;8:158, Respirology 2016;21:712):
  - SFTPC (surfactant protein C)
  - SFTPA2 (surfactant protein A2)
  - TERT, encoding protein component of telomerase
  - TERC, encoding RNA component of telomerase
  - MUC5B (mucin 5B)
- Cigarette smoking (Eur Respir Rev 2015;24:428)
- Gastroesophageal reflux (Am J Med 2010;123:304)

Diagrams / tables

Images hosted on other servers:

Schema of UIP pattern

Clinical features

Manifestations of chronic respiratory syndrome:
- Chronic dyspnea
- Dry cough
- Fatigue
- Digital clubbing
Abnormal chest auscultation
- End inspiratory fine crackles in bibasilar lung
Restrictive pattern in pulmonary function tests:
- Decreased total lung capacity (TLC)
- Decreased forced vital capacity (FVC)
- Decreased diffusing capacity of the lung for carbon monoxide (DLCO)
- Reduced diffusing capacity is mainly due to ventilation-perfusion mismatch from ventilation of lung tissue with capillary destruction and perfusion of under ventilated alveoli; smaller component due to reduced diffusion across a fibrotic alveolar septa

Diagnosis

Diagnosis of UIP / IPF is often challenging and strict criteria are still being discussed
Based on clinical features (including laboratory tests), high resolution computed tomography (HRCT) and surgical lung biopsy (SLB)
- It is necessary to rule out other etiologies such as particle exposure, connective tissue diseases and hypersensitivity pneumonia
- Transbronchial lung biopsy is sometimes performed instead of SLB, however pathologic diagnosis becomes more difficult due to the size of sample
The guidelines suggest multidisciplinary decision by physicians, radiologists and pathologists, especially when there is a discrepancy in between (Am J Respir Crit Care Med 2011;183:788)
Current guidelines do not recommend lung biopsy for cases with typical UIP pattern on HRCT; nevertheless histopathology remains an important diagnostic modality (Eur J Radiol 2014;83:20, Am J Respir Crit Care Med 2004;170:904, Eur Respir J 2010;35:1322, Thorax 2003;58:143)

Laboratory

Increased serum KL-6
Increased serum surfactant proteins A and D (Chest 2009;135:1557, Sarcoidosis Vasc Diffuse Lung Dis 2009;26:155)
Negative serum antibodies of connective tissue diseases
Negative serum antibodies of hypersensitive pneumonia

Radiology description

Chest Xray can detect lesions: however, it is usually not sensitive enough to render the diagnosis
UIP pattern on HRCT:
- Subpleural bibasilar reticular opacity
- Honeycomb change; clustered cystic airspaces, 3 - 10 mm in diameter (Eur J Radiol 2014;83:27)
- Traction bronchiectasis is often seen

Radiology images

Images hosted on other servers:

UIP pattern

Prognostic factors

5 year survival rate is 20% - 30% (Am J Respir Crit Care Med 2011;183:431)
Median survival is 2 - 3 years
Acute exacerbation (Am J Respir Crit Care Med 2016;194:265)
- Incidence of 4.1 per 100 patient years
- Precedes up to 46% of the deaths
- Median survival of patients with IPF who experience an acute exacerbation is 3 - 4 months
- Low FVC is the most consistent risk factor
Severity of elastofibrosis on histology (Respir Med 2013;107:1608)
Comorbidity:
- Pulmonary hypertension (Chest 2006;129:746)
- Lung cancer (Chest 2015;147:157)
- Emphysema - in this case, patient may be diagnosed as combined pulmonary fibrosis and emphysema (Chest 2012;141:222, Eur Respir J 2005;26:586)

Case reports

45 year old man with IPF and adenocarcinoma (Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2011;155:403)
58 year old woman with acute exacerbation of IPF associated with interferon-α therapy for hepatitis C (Springerplus 2013;2:101)
58 year old man with IPF and polyarteritis nodosa (Fukushima J Med Sci 2003;49:141)
73 and 83 year old men with IPF probably due to exposure of wood dust (Med Pr 2015;66:739)
79 year old male man died of tracheobronchomegaly (Mounier-Kuhn syndrome) caused by IPF (Eur J Intern Med 2017;S0953-6205:30031)

Treatment

No treatment has been found to substantially improve its prognosis
Recommended by the guidelines (Am J Respir Crit Care Med 2015;192:e3)
- Pirfenidone, an antifibrotic drug reducing TGF-β-induced myofibroblast differentiation (N Engl J Med 2014;370:2083)
- Nintedanib, an inhibitor targeting multiple tyrosine kinases (N Engl J Med 2014;370:2071)
- Lung transplantation
Experimental treatments
- Intratracheal transplantation of type II pneumocytes (Chest 2016;150:533)
- Gastroesophageal reflux medications (Am J Respir Crit Care Med 2011;184:1390, Chest 2006;129:794)

Gross description

Fibrotic changes in lower lobes
- Shrunken lung with "hobnailed" pleura due to scarring
- Elastic hard consistency
- Diffuse (relatively subpleural dominant) destruction of lung mesenchyme
- Multiple air cysts due to honeycomb change
- Traction bronchiectasis can be seen

Gross images

Images hosted on other servers:

Honeycomb lung

Microscopic (histologic) description

Major findings consistent with UIP pattern
- Dense fibrosis
  - The lesion representing UIP pattern is mainly composed of hyalinized collagen
  - Often destructs alveolar architecture
  - Smooth muscle and elastofibrosis are often present
  - Mild to moderate infiltration by inflammatory cells can be seen
- Patchy and peripheral / perilobular involvement
  - Temporal heterogeneity of the lesions evident on low power
  - Fibrosis tends to be remarkable in perilobular or subpleural area
  - Normal lung parenchyma can remain in the center of the lobule
- Honeycomb
  - Cystic spaces lined by bronchiolar epithelium and fibrotic wall
  - The lung in the end stage fibrosis is called "honeycomb lung"
- Fibroblastic foci
  - Active fibrotic lesions composed of myofibroblasts
  - Aggregation of spindle cells with gray to pale purple matrix adjacent to dense fibrosis
Clinical guidelines suggest 4 levels of certainty for pathologic diagnosis (Am J Respir Crit Care Med 2011;183:788)
- Definite UIP pattern
  - Marked fibrosis / architectural distortion
  - Patchy involvement
  - Fibroblast foci
- Probable UIP pattern
  - Either:
    - A: marked fibrosis / architectural distortion AND [patchy involvement OR fibroblastic foci]
    - Or B: honeycomb change only
- Possible UIP pattern
  - Patchy or diffuse involvement of fibrosis
- Not UIP pattern (whenever any of findings below is present)
  - Hyaline membranes
  - Organizing pneumonia
  - Granulomas
  - Marked interstitial inflammatory cell infiltrate away from honeycombing
  - Predominant airway centered changes
  - Other features suggestive of an alternate diagnosis
- Some criteria of these findings (e.g., how many granulomas to be considered significant) are still not clear
Additional findings
- Squamous metaplasia: squamoid epithelium without cilia, predictor of acute exacerbation (USCAP 2016)
- Interstitial emphysema: a cystic space without epithelial lining, predictor of pneumothorax (Am J Surg Pathol 2014;38:339)
- Respiratory bronchiolitis macrophage: accumulation of macrophages in air spaces, especially in smokers; marked lesion is called desquamative interstitial pneumonia-like reaction
- Pulmonary alveolar proteinosis-like change: eosinophilic and fine granular proteinaceous material in airspace (Respir Investig 2016;54:272)
- Centriacinar emphysema, especially in smokers
- Peribronchiolar metaplasia, replacement of bronchiolar epithelium in alveolar walls and terminal bronchioles (Am J Surg Pathol 2005;29:948)
- Fat metaplasia
- Bone metaplasia
- Kuhn's hyaline (Mallory's hyaline): dense, waxy, eosinophilic clumps within cytoplasm of reactive type 2 pneumocytes (Hum Pathol 1980;11:59)
- Fibrin deposition

Microscopic (histologic) images

Scroll to see all images.

Contributed by Akira Yoshikawa, M.D. and Yale Rosen, M.D.

Low power magnification

Peripheral dense fibrosis adjacent to normal parenchyma

Honeycomb

PAP-like change within honeycomb

Fibroblastic focus

Respiratory bronchiolitis macrophage

Low power magnification

Dense fibrosis with smooth muscle hyperplasia

Fat metaplasia

Fibroblastic focus

Peribronchiolar metaplasia

Peripheral / perilobular involvement of dense fibrosis

Peripheral / perilobular elastosis on elastic van Gieson staining

Low power magnification

Perilobular involvement

Honeycomb

Peribronchiolar metaplasia

Squamous metaplasia

Bone metaplasia

Fibroblastic foci

Images hosted on other servers:

Findings in UIP pattern

Dense fibrosis and honeycomb

Fibroblastic foci

Honeycomb

Patchy and peripheral involvement

Peripheral / perilobular involvement

Case with UIP

Positive stains

Elastica van Gieson staining to highlight fibrosis

Electron microscopy description

Fibrosis due to migration of activated mesenchymal cells through defects in epithelial lining and its basement membrane from interstitial to intraluminal compartment
Replacement of alveolar type I cells by hyperplastic alveolar type II cells

Videos

Pathogenesis of IPF

Differential diagnosis

Nonspecific interstitial pneumonia: diffuse involvement, loose fibrosis
Connective tissue diseases: lymphoid aggregates with germinal centers, lymphoplasmacytic infiltration, pleuritis (Eur Respir J 2015;46:976)
Hypersensitivity pneumonitis: airway centered changes, granulomas, giant cells, peribronchiolar metaplasia (Am J Respir Crit Care Med 2012;186:314, Histopathology 2012;61:1026)
Diffuse alveolar damage: hyaline membranes, hemorrhage
Cryptogenic organizing pneumonia: organizing pneumonia
Pleuroparenchymal fibroelastosis (PPFE): diffuse elastofibrosis in upper lung
Pneumoconiosis: foreign particles such as carbon, silica and asbestos
Sarcoidosis: well formed granulomas of epithelioid histiocytes and multinucleated giant cells
Combined pulmonary fibrosis and emphysema (CPFE): centriacinar emphysema in upper lobes, UIP pattern in lower lobes

Additional references

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