Lung

Other interstitial pneumonitis / fibrosis

Cryptogenic organizing pneumonia

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

Minor changes: 26 October 2021

Copyright: 2002-2022, PathologyOutlines.com, Inc.

PubMed Search: Cryptogenic organizing pneumonia[title] lung pathology

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Table of Contents

Cite this page: Yoshikawa A, Bychkov A, Sathirareuangchai S. Cryptogenic organizing pneumonia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumorBOOP.html. Accessed January 19th, 2022.

Definition / general

Since 1901, organizing pneumonia (OP) has been described with the name bronchiolitis obliterans as an interstitial lung disease with granulation tissue plugs within alveolar ducts and small airways secondary to a variety of causes, including infection, fume exposure, drugs, collagen vascular disease, allergic reactions and obstruction (Chest 1983;83:161)
Davison et al. (1983) and Epler et al. (1985) reported a series of cases with organizing pneumonia and no evidence of infection or other etiological agents; after that, the term bronchiolitis obliterans organizing pneumonia (BOOP) was commonly used for a while (Q J Med 1983;52:382, N Engl J Med 1985;312:152)
In 2002, the American Thoracic Society / European Respiratory Society suggested the term cryptogenic organizing pneumonia to avoid confusion with airway disease, such as constrictive bronchiolitis obliterans and categorized cryptogenic organizing pneumonia into acute / subacute interstitial pneumonia (Am J Respir Crit Care Med 2002;165:277, Am J Respir Crit Care Med 2013;188:733)

Essential features

Organizing pneumonia is one of the most commonly seen lung lesions and is associated with a variety of diseases, such as infections and systemic diseases
Cryptogenic organizing pneumonia is a relatively rare disease but often needs to be considered, since its clinical and radiological manifestations are often varied and nonspecific
Histologically, both cryptogenic organizing pneumonia and secondary organizing pneumonia are characterized by polypoid fibroblastic aggregations, which plug alveolar sacs, ducts and bronchioles

Terminology

Organizing pneumonia (OP):
- Organizing pneumonia can be either a clinicopathological diagnosis (cryptogenic organizing pneumonia and secondary organizing pneumonia), histological pattern (organizing pneumonia pattern) or microscopic finding (e.g. Masson body)
Cryptogenic organizing pneumonia (COP):
- Idiopathic form of organizing pneumonia
- Also known as bronchiolitis obliterans, bronchiolitis obliterans organizing pneumonia (BOOP), idiopathic BOOP and cryptogenic organizing pneumonitis
Cicatricial organizing pneumonia (ciOP) (Histopathology 2021 Jun 8 [Epub ahead of print]):
- Also known as collagenized organizing pneumonia, cicatricial variant of organizing pneumonia, fibrosing organizing pneumonia, scarred organizing pneumonia
- Chronic fibrotic changes of conventional organizing pneumonia with formation of dense collagen fibers within the alveolar space, with no architectural destruction

ICD coding

ICD-10: J84.116 - cryptogenic organizing pneumonia
ICD-11: CB03.2 - cryptogenic organizing pneumonitis

Epidemiology

Incidence of cryptogenic organizing pneumonia is 6 - 9 per 100,000 (Medicine (Baltimore) 1995;74:201)
No sex predominance
Median age at onset is 50 - 60 years old (N Engl J Med 1985;312:152, Chest 2011;139:893, Int J Tuberc Lung Dis 2007;11:689)
No association with smoking history
Most patients are previously healthy individuals and lack history of lung disease

Sites

Bilateral or unilateral lobes of the lung

Pathophysiology

Organizing pneumonia is a repair process (wound healing) of the lung in response to preceding alveolar injury (Thorax 2000;55:318, Eur Respir J 2006;28:422)
- Injury to capillary endothelial cells and alveolar epithelial cells results in the leakage of plasma protein, especially coagulation factors
- Intra-alveolar coagulation of proteins and coagulation factors generate fibrin clotting on alveolar surfaces
- Fibroblasts / myofibroblasts migrate into the damaged area, proliferate and generate loose fibrosis in the form of a small polyp
IL6, IL8 and TGFβ1 may play an important role in pathogenesis (Adv Exp Med Biol 2016;911:77)
Galectin 9 and regulatory T cells are increased in the lung with cryptogenic organizing pneumonia (Lung 2015;193:683)

Etiology

Organizing pneumonia can be a complication or lung manifestation of other diseases (Thorax 2000;55:318, Chest 2011;139:893, Int J Tuberc Lung Dis 2007;11:689, J Thorac Imaging 2006;21:22)
- Idiopathic: cryptogenic organizing pneumonia
- Infection: bacterium / fungus / virus / parasite, pneumonia, lung abscess, empyema
- Other interstitial lung disease: nonspecific interstitial pneumonia, hypersensitivity pneumonitis, eosinophilic pneumonia, diffuse alveolar damage
- Autoimmune disease: rheumatoid arthritis, Sjögren syndrome, polymyositis / dermatomyositis, Sweet disease, etc.
- Aspiration
- Drug reaction, fume and toxic exposure
- Radiation
- Inflammatory bowel disease: Crohn's disease, ulcerative colitis
- Neoplasm: primary or metastatic lung cancer, lymphoma / leukemia, myelodysplastic syndrome (MDS)
- Lung infarction
Secondary organizing pneumonia is much more common than cryptogenic organizing pneumonia; 6.5:1 (Ann Transl Med 2020;8:763)

Diagrams / tables

Images hosted on other servers:

Classification of interstitial lung diseases

Imaging patterns of cryptogenic organizing pneumonia

Clinical features

Mild and slowly progressive respiratory failure (Chest 2011;139:893, N Engl J Med 1985;312:152, Int J Tuberc Lung Dis 2007;11:689)
- Dry cough
- Dyspnea
- Malaise, fatigue and fever
- Duration of symptoms more than 3 months
Abnormal chest auscultation
- End inspiratory fine crackles in affected lobes
Restrictive pattern is often observed in pulmonary function tests; however, the abnormality is slight or within the normal range in 30% (Chest 2011;139:893, N Engl J Med 1985;312:152)
- Decreased forced vital capacity (FVC)
- Decreased diffusing capacity of the lung for carbon monoxide (DLCO)

Diagnosis

Based on clinical features, radiology and histopathology (Am J Respir Crit Care Med 2002;165:277):
- Clinical investigation for a possible cause of the disease is necessary
- Surgical lung biopsy or transbronchial lung biopsy is required to establish a firm diagnosis since the clinical and radiological findings are often not specific
- However, a biopsy may not be necessary if the clinical and radiological features are suggestive enough

Laboratory

Increased serum surfactant proteins A and D
Negative serum antibodies of connective tissue diseases and hypersensitivity pneumonitis
Reference: Respiration 2019;98:534

Radiology description

Simple chest radiography
- Bilateral or unilateral ground glass opacity and consolidation
High resolution computed tomography (Respirology 2016;21:810, Chest 2017;151:1356)
- Typical pattern
  - Patchy ground glass opacity and consolidation with / without air bronchogram
  - Often bilateral and asymmetrical
  - Often peripheral and migratory
  - Size varies from a few centimeters to a whole lobe
  - Typical organizing pneumonia sometimes looks similar to eosinophilic pneumonia, pulmonary lymphoma and lepidic adenocarcinoma
- Less common patterns
  - Focal organizing pneumonia: nodular or mass-like consolidation mimicking lung cancer (Int J Clin Exp Pathol 2015;8:511)
  - Infiltrative organizing pneumonia: diffuse infiltrative opacity
  - Reversed halo sign: central ground glass opacity surrounded by round consolidation
  - Crazy paving pattern: areas of ground glass opacities superimposed to focal thickening of pulmonary parenchyma
  - Progressive fibrosis pattern: subpleural basal reticulations and architectural distortion, mimicking nonspecific interstitial pneumonia and usual interstitial pneumonia
  - Perilobular pattern: curved or arcade-like bands of parenchymal consolidation with blurred borders and thickening of the interlobular septa, resembling a Roman arch
  - Linear and band-like opacities: thick radial bands of consolidation containing an air bronchogram or subpleural curvilinear bands, parallel to the pleura

Radiology images

Images hosted on other servers:

Typical organizing pneumonia

Chest radiograph

Focal organizing pneumonia

Infiltrative organizing pneumonia

Prognostic factors

Good prognosis but frequent relapse; 20 - 58% with both cryptogenic organizing pneumonia and secondary organizing pneumonia relapse (Chest 2011;139:893, N Engl J Med 1985;312:152, Int J Tuberc Lung Dis 2007;11:689)
- Relapse predictors (Respiration 2007;74:624, Tuberc Respir Dis (Seoul) 2015;78:190, Am J Respir Crit Care Med 2000;162:571, Chest 1998;114:1599):
  - Delay of corticosteroid administration
  - Shorter maintenance of corticosteroid dose
  - Hypoxemia: lower PaO₂, lower PaO₂/FiO₂ ratio
  - Lower serum total protein
  - Lower forced vital capacity (FVC)
  - Multifocal opacity on radiology
Rarely progresses to severe respiratory failure and death
Myelodysplastic syndrome (MDS) related organizing pneumonia may be associated with worse prognosis
Cicatricial form of cryptogenic organizing pneumonia is more progressive or persistent and resistant to treatment (Hum Pathol 2017;64:76)

Case reports

23 year old woman with organizing pneumonia following influenza B (BMC Infect Dis 2017;17:572)
43 year old woman with organizing pneumonia related to trastuzumab (Springerplus 2016;5:1964)
57 year old man with severe organizing pneumonia following COVID-19 (Thorax 2021;76:201)
64 year old woman with organizing pneumonia related to pembrolizumab (Drug Target Insights 2016;10:9)
66 year old man with cryptogenic organizing pneumonia and atypical imaging findings (Case Rep Pulmonol 2020;2020:2094625)
70 year old man with cryptogenic organizing pneumonia presenting with mass-like lesion (J Int Med Res 2020;48:300060520920068)
74 year old woman with rapidly progressive cryptogenic organizing pneumonia (Intern Med 2017;56:1185)

Treatment

Most with cryptogenic organizing pneumonia and secondary organizing pneumonia completely recover with oral corticosteroids (N Engl J Med 1985;312:152, Chest 2011;139:893)
Clarithromycin was recently suggested as an alternative regimen with fewer adverse events (PLoS One 2017;12:e0184739)

Gross description

Multiple patchy fibrotic lesions
Ill defined, soft to firm gray areas
Volume of the lung is usually normal
Other changes overlap with secondary organizing pneumonia

Gross images

Contributed by Yale Rosen, M.D.

Pale area of nodular consolidation

Mass-like lesions

Images hosted on other servers:

Cryptogenic organizing pneumonia

Microscopic (histologic) description

Organizing pneumonia (Semin Respir Crit Care Med 2012;33:462):
- Fibroblastic plugs in alveolar sacs and ducts (organizing pneumonia) and bronchiolar lumen (bronchiolitis obliterans)
- Formed by spindled fibroblasts in pale staining matrix of immature loose collagen with polypoid shape (Masson body) or serpiginous or elongated form
- Organizing pneumonia sometimes extends from one alveolus to the next through interalveolar fenestrae (butterfly pattern)
Mild to moderate cellular infiltrate in background (Eur Respir J 2006;28:422, Clin Med Insights Circ Respir Pulm Med 2016;9:123):
- Thickened alveolar septa with lymphocytes, plasma cells and histiocytes
- Alveolar architecture is usually preserved in cryptogenic organizing pneumonia
  - Because interstitial dense fibrosis, architectural destruction and honeycomb change are not components of cryptogenic organizing pneumonia, the organizing pneumonia lesion is likely to be secondary to other lung disease if these findings are mixed or overlap (J Clin Pathol 2009;62:387)
Airspace changes (Thorax 2000;55:318):
- Foamy macrophage accumulation in surrounding airspace may be present
- Occasional fibrin deposition
  - If prominent, the lesion is more likely to be infection, eosinophilic pneumonia (especially after corticosteroids), vasculitis (e.g. granulomatosis with polyangiitis) or acute fibrinous organizing pneumonia (AFOP)
Cicatricial form of cryptogenic organizing pneumonia (Hum Pathol 2017;64:76):
- Organizing granulation tissue is collagenized or hyalinized and harbors eosinophilic, lamellar and dense fibers
- Airspaces can be filled with collagenized organizing pneumonia but alveolar architecture is mostly preserved

Microscopic (histologic) images

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

Patchy involvement

Fibroblast plug

Mononuclear cell infiltrate

Foamy macrophages

Cicatricial variant

Bronchiolitis obliterans

Virtual slides

Images hosted on other servers:

Cryptogenic organizing pneumonia

Cicatricial organizing pneumonia

Organizing pneumonia in transplant biopsy

Positive stains

Elastica van Gieson staining is helpful to evaluate if architecture of alveoli is preserved or not

Negative stains

Organizing polyps are negative for elastica van Gieson staining except in cicatricial variant

Electron microscopy description

Type I pneumocyte necrosis in the early phase (Thorax 2000;55:318)

Videos

Cryptogenic organizing pneumonia

Focal organizing pneumonia

Fibrosing organizing pneumonia

Sample pathology report

Lung, right middle lobe, transbronchial biopsy:
- Organizing pneumonia (see comment)
- Negative for granuloma, vasculitis and malignancy
- Comment: Based on the provided patient information, the diagnosis of cryptogenic organizing pneumonia is favored. However, secondary organizing pneumonia from various causes (infection, drug toxicity, autoimmune disease, malignancy, etc.) needs to be excluded clinically.

Differential diagnosis

Acute interstitial pneumonia (AIP) / acute respiratory distress syndrome (ARDS):
- Diffuse alveolar damage (DAD) of AIP or ARDS may have a prominent organizing pneumonia (organizing DAD) radiologic pattern
- If organizing pneumonia is so diffusely distributed that it almost completely occupies the surgical sample, organizing DAD should be favored
- Hyaline membranes, architectural destruction and myofibroblastic aggregation with less extracellular matrix are other clues of DAD pattern
Eosinophilic pneumonia:
- Pink macrophages (not foamy)
- More fibrin
- Frequent type II pneumocyte atypia
Granulomatosis with polyangiitis:
- Geographic necrosis, hemorrhage, capillaritis
- More eosinophils
- More fibrin deposition
Inflammatory myofibroblastic tumor:
- Nodule / mass of spindle cells
- More plasma cells
- ALK+, SMA+, desmin+
Inflammatory pseudotumor (IgG4 related / NOS):
- Nodule / mass of spindle cells
- SMA+, ALK+
Nonspecific interstitial pneumonia (NSIP):
- Organizing pneumonia is often seen in NSIP pattern but it does not exceed more than 20% of area
- Interstitial change (cellular or fibrotic) is more predominant
Spindle cell carcinoma (sarcomatoid carcinoma):
- Nodule / mass of atypical spindle cells
Usual interstitial pneumonia (UIP):
- Fibroblastic focus in UIP pattern is another type of myofibroblastic aggregation but usually adjacent to dense fibrotic lesion, unlike in organizing pneumonia
- Dense interstitial fibrosis, architectural destruction and honeycomb change are other clues of UIP

Additional references

Leslie: Practical Pulmonary Pathology - A Diagnostic Approach, 3nd Edition, 2017, Cagle: Lung and Pleural Pathology, 1st Edition, 2015

Board review style question #1

Which of the following findings is against the histologic diagnosis of organizing pneumonia?

Interstitial mononuclear infiltrate
Fibrin deposition
Fibroblastic focus
Foamy macrophage accumulation
Masson body

Board review style answer #1

C. Fibroblastic focus. This finding is rather suggestive for usual interstitial pneumonia (UIP) pattern.

Comment Here

Reference: Cryptogenic organizing pneumonia

Board review style question #2

A 70 year old woman presented with cough, chest tightness and dyspnea. She was a former smoker with 20 pack years. High resolution CT scan of the chest showed bilateral patchy ground glass opacities in the lungs. A transbronchial biopsy was performed. What is the pathologic diagnosis based on the image provided?

Bronchial asthma
Desquamative interstitial pneumonia
Diffuse alveolar damage
Organizing pneumonia
Respiratory bronchiolitis

Board review style answer #2

D. Organizing pneumonia. Fibroblast plug is the diagnostic feature for organizing pneumonia.

Comment Here

Reference: Cryptogenic organizing pneumonia