—  SHORT COURSE #26  —

Lung Biopsy Interpretation

Case 6 - Bronchiolitis Obliterans Organizing Pneumonia (BOOP) (Cryptogenic Organizing Pneumonia)

Anna-Luise A. Katzenstein & Jeffrey L. Myers


Clinical History
This 67 year old South American physician presented with a 9 month history of episodic cough and malaise associated with shortness of breath. Chest x-ray showed nonspecific patchy bilateral air-space opacities. Pulmonary function studies showed moderate restriction (FVC 51% of the predicted value) with reduction in diffusing capacity (DLCO 48% of the predicted value) and desaturation at rest and during exercise (O2 saturation 79% at rest and 72% after exercise). He underwent thoracotomy and open lung biopsy.

Microscopic Description:


Case 6 - Figure 1 - Low magnification photomicrograph showing an area of intraluminal fibrosis ("organizing pneumonia").
Case 6 - Figure 2 - Higher magnification view showing the polypoid configuration of the intraluminal fibroblastic plugs characteristic of BOOP.
Case 6 - Figure 3 - Photomicrograph showing another area of organizing pneumonia, here associated with prominent foamy histiocytes in surrounding air spaces. Although not specific, the presence of foamy histiocytes is characteristic of BOOP and is sometimes a helpful clue to the diagnosis.

Your section from his thoracoscopic lung biopsy show a distinctive pattern of intraluminal fibrosis. The striking finding is the presence of polypoid plugs of immature appearing fibroblastic tissue within distal bronchioles, alveolar ducts, and peribronchiolar air spaces. There is associated nonspecific alveolar septal thickening largely limited to the areas of intraluminal fibrosis. Thickened alveolar septa contain a mild infiltrate of mononuclear inflammatory cells and demonstrate hyperplasia of alveolar lining cells.

Discussion:
Bronchiolitis obliterans organizing pneumonia (BOOP) was the term proposed in 1985 by Epler and colleagues for a distinctive clinicopathological syndrome that had been previously described under a variety of terms including cryptogenic organizing pneumonitis, bronchiolitis obliterans with classical interstitial pneumonia (BIP), and bronchiolitis obliterans and organizing pneumonia-like process. Since then yet additional synonyms have been proposed including idiopathic intraluminal organizing pneumonia and seasonal cryptogenic organising pneumonia. The previously referenced consensus statement sponsored by the American Thoracic Society (see Case 1 – UIP) suggests use of the term cryptogenic organizing pneumonia (COP). By whatever name, idiopathic BOOP is a specific clinicopathological syndrome that must be distinguished from UIP.

Idiopathic BOOP affects males and females equally and occurs most commonly in middle aged adults with a peak incidence in the sixth decade. Most patients present with cough and shortness of breath of several weeks duration which are frequently accompanied by fevers. The classical description has been expanded by recognition of seasonal variation in some patients (so-called "seasonal cryptogenic organising pneumonia"). A minor subset of patients has also been identified associated with a more fulminant course, although it may be extremely difficult to separate this syndrome from acute interstitial pneumonia. The most common radiographic finding is patchy bilateral air space opacities which may have a "ground glass" appearance. Patients in this group have an excellent prognosis and nearly all recover with corticosteroid therapy. Localized air space opacities resembling lung neoplasms also can occur, as seen in this patient. Less commonly patients present with bibasilar interstitial opacities that mimick those seen in idiopathic pulmonary fibrosis. This latter radiographic pattern may be more common in patients with associated collagen vascular diseases and tends to be associated with a poorer prognosis.

The main pathologic abnormality is the presence of intraluminal fibrosis within distal airways, alveolar ducts, and peribronchiolar alveolar spaces. The intraluminal fibrosis consists of polyploid plugs of immature fibroblastic tissue which resemble granulation tissue. The intraluminal plugs show a characteristic configuration at low magnification resulting from their distribution within distal airways. Larger terminal bronchioles and peribronchiolar alveolar spaces also show varying degrees of involvement. At higher magnification the fibrosis consists of concentrically arranged spindle cells associated with a pale staining basophilic matrix. Chronic inflammatory cells and capillaries can also be identified within the granulation tissue plugs. An acute and chronic bronchiolitis is usually present away from the areas of intraluminal fibrosis and consists of a peribronchiolar infiltrate of acute and chronc inflammatory cells associated with varying degrees of epithelial necrosis. An acute inflammatory exudate may also be present within bronchiolar lumens.

A number of secondary changes accompany the intraluminal fibrosis. Foamy alveolar macrophages are present within peribronchiolar alveolar spaces and reflect the presence of proximal airway obstruction (i.e. endogenous lipid pneumonia). Interstitial pneumonia is present in most cases and is characterized by an alveolar septal infiltrate of mononuclear inflammatory cells with varying degrees of septal thickening and epithelial hyperplasia. For the most part, however, the areas of interstitial pneumonia are limited to the areas of intraluminal fibrosis and are not present in unaffected pulmonary parenchyma.

Ultrastructurally BOOP resembles other forms of acute lung injury. The main abnormality is necrosis of bronchiolar, alveolar duct, and alveolar epithelium resulting in denudation of the underlying basal lamina. Fibroblasts and myofibroblasts migrate from the interstitial compartment into the airways and peribronchiolar alveolar spaces through the damaged basement membranes, thus forming intraluminal fibroblastic plugs. Proliferating bronchiolar cells and type 2 pneumocytes eventually incorporate the fibroblastic plugs back into the interstitial compartment where they are broken down by mechanisms that are not yet well defined.

It should be emphasized that organizing pneumonia is a relatively nonspecific reaction to lung injury that can occur as a secondary finding adjacent to other pathologic processes or as a component of other primary pulmonary disorders (see Table). This is particularly important to bear in mind when interpreting small biopsy specimens, such as transbronchial or even thoracoscopic biopsies. Cryptococcosis, Wegener's granulomatosis, and eosinophilic pneumonia are three important conditions that can be associated with broad areas of organizing pneumonia.

Table 1: Clinical Syndromes Associated with Organizing Pneumonia ("BOOP")

Collagen vascular diseases
rheumatoid arthritis
systemic lupus erythematosus
dermatomyositis
mixed connective tissue disease
Toxic injuries
inhalants (NO2 -- silo fillers disease)
systemic (drugs -- bleomycin, amiodarone)
radiation (external beam irradiation for breast carcinoma)
Chronic ("organizing") infection
bacteria (legionella, nocardia)
viruses (influenza, CMV)
mycoplasma
Pneumocystis carinii
Idiopathic (BOOP; cryptogenic organizing pneumonia)

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