Lung nontumor
Other interstitial pneumonitis/fibrosis
UIP / IPF
Topic Completed: 1 June 2017
Minor changes: 4 July 2020
Revised: 30 January 2019, last major update January 2017
Copyright: (c) 2003-2018, PathologyOutlines.com, Inc.
PubMed Search: usual interstitial pneumonia OR idiopathic pulmonary fibrosis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology / etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Electron microscopy description | Videos | Differential diagnosis | Additional referencesCite this page: Yoshikawa A. UIP / IPF. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumorUIP.html. Accessed August 6th, 2020.
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)
- Genetic factors, including several mutations (Proc Am Thorac Soc 2011;8:158, Respirology 2016;21:712):
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
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)
Clinical images
Images hosted on other servers:
UIP pattern
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:
End stage IPF
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
- 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
- Either:
- 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
- Definite UIP pattern
- 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.
Images hosted on PathOut server:
Contributed by Akira Yoshikawa:
Case 1:
Case 2:
Case 3:
Contributed by Dr. Yale Rosen:
Images hosted on other servers:
Contributed by Akira Yoshikawa:
Case 1:
Low power magnification
Peripheral dense fibrosis adjacent to normal parenchyma
Honeycomb
PAP-like change within honeycomb
Fibroblastic focus
Respiratory bronchiolitis macrophage
Case 2:
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
von Gieson staining
Case 3:
Low power magnification
Perilobular involvement
Honeycomb
Peribronchiolar metaplasia
Squamous metaplasia
Bone metaplasia
Contributed by Dr. Yale Rosen:
Dense fibrosis and architectural destruction
Dense fibrosis and honeycomb
Honeycomb
Fibroblastic foci
Images hosted on other servers:
Schema of UIP pattern
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
