Abstract
Interpretation of lung biopsy specimens is an integral part in the diagnosis of interstitial lung disease (ILD). The process of evaluating a surgical lung biopsy for disease involves answering several questions. Unlike much of surgical pathology of neoplastic lung disease, arriving at the correct diagnosis in nonneoplastic lung disease often requires correlation with clinical and radiologic findings. The topic of ILD or diffuse infiltrative lung disease covers several hundred entities. This chapter is meant to be a launching point in the clinician’s approach to the histologic evaluation of lung disease.
Keywords
Lung injury, Biopsy, Fibrosis, Interstitial lung disease, Pneumonia, Pulmonary hypertension
Key Points
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Knowledge of normal anatomy can aid in the diagnosis of pulmonary interstitial disease.
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Recognition of patterns of fibrosis is important in generating a differential diagnosis.
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Evaluation of all compartments of the lung is essential in establishing a correct pathologic diagnosis.
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Clinical and radiologic correlation can aid the pathologist and refine the diagnosis.
Interpretation of lung biopsy specimens is an integral part in the diagnosis of interstitial lung disease. The process of evaluating a surgical lung biopsy for disease involves answering several questions. Unlike much of surgical pathology of neoplastic lung disease, arriving at the correct diagnosis in nonneoplastic lung disease often requires correlation with clinical and radiologic findings. The topic of interstitial lung disease or diffuse infiltrative lung disease covers several hundred entities, and the pathology of interstitial lung disease has been the topic of several comprehensive textbooks. This chapter is not meant to be an encyclopedic overview of the topic but is rather meant to be a launching point in the clinician’s approach to the histologic evaluation of lung disease.
What Does Normal Look Like?
The first step in evaluating abnormal lung tissue is to understand the normal appearance of the lung. Just as the pulmonologist knows the difference between a healthy and sick patient, so the pathologist must know the difference between normal and diseased tissue when evaluating factors such as inflammation and fibrosis.
The lung can be divided into separate anatomic compartments of alveolar spaces, alveolar interstitium, large airways, small airways, pulmonary vessels, and pleura. When examining the lung, it is important to recognize the possibility of disease in any and all of these components. In addition, the alveolar parenchyma can be divided into various zones that can aid in generation of differential diagnoses. Several definitions are required here. A primary lobule is defined as that portion of the lung supplied by one respiratory bronchiole. A secondary lobule is defined as a region of lung, centered on a respiratory bronchiole, bound on its peripheral margins by fibrous interlobular septa, and extending distally to the pleural surface ( Fig. 12.1 ). This histologic construct is more easily recognized microscopically than the primary lobule; therefore, pathologists (and radiologists) often use the term lobule interchangeably with secondary lobule.
Much of the histologic assessment of the lung is performed by evaluation of the structures of the secondary lobule. The central portion of a secondary lobule contains the bronchovascular bundle, consisting of a small airway with associated pulmonary artery. The surrounding tissue consists of alveolar spaces and alveolar septa. The interlobular septa, at the periphery of the lobule, contain the pulmonary veins. The distal boundary of the lobule consists of the visceral pleura. The pulmonary lymphatics are present in the bronchovascular bundles, the interlobular septa, and the subpleural connective tissue. Using the structural unit of the lobule, several patterns of distribution can be described. A diffuse interstitial process involves the majority of the alveolar septa within the lobule. A bronchiolocentric process shows accentuation of the disease in the tissue surrounding the small airways. A peripheral lobular pattern shows accentuation of inflammation or fibrosis in the subpleural and paraseptal regions. A lymphatic pattern shows a distribution of disease involving the subpleural regions, the interlobular septa, and the bronchovascular bundles. Other patterns of disease include angiocentric and random distribution. Several of these distribution patterns can also describe consolidative processes in which there is alveolar filling.
Once one is familiar with normal tissue, there are a series of questions that can be asked to help define the disease process within the lung biopsy.
Is This Acute Lung Injury?
Two common patterns of acute lung injury include diffuse alveolar damage and organizing pneumonia. Because these diseases can mimic other chronic fibrosing diseases, the first question to ask when evaluating a biopsy is if this can all be an acute process.
Diffuse alveolar damage is a histologic pattern of lung injury that results from damage to the endothelial and epithelial component of the alveolus: the alveolar capillary and type 1 pneumocyte. Histologically, the appearance of diffuse alveolar damage varies based on the time from the initial injury. In the first hours after injury, the leaky alveolar vascular-epithelial barrier results in an accumulation of proteinaceous fluid within the alveolar spaces. Over the course of 12–24 h, the alveolar septa become thickened by edema and minimal acute and chronic inflammation. As the injury progresses, the alveolar walls have the appearance of granulation tissue–like fibrosis with proliferating fibroblasts within a myxoid matrix. The alveolar spaces show additional filling by hyaline membranes ( Fig. 12.2 ). These hyaline membranes appear homogenously eosinophilic with a slight waxy appearance (the term is based on hyalos , Greek for glass). They are present in close apposition to the alveolar surface. Although appearing quite uniform on light microscopy, when viewed ultrastructurally, these hyaline membranes appear to be composed of a porridge of nucleoplasm, cytoplasm, fibrin, and other proteins secondary to the cell death that resulted from the acute injury. Often small vessels (usually pulmonary arteries ≤2 mm) show small luminal fibrin thrombi. This is thought to be secondary to activation of the coagulation cascade due to tissue damage.
Over the course of days to weeks, the lung begins the process of attempted healing. This is termed organization and is characterized histologically by thickened alveolar septa, often with a sparse chronic inflammatory infiltrate, with a loose granulation tissuelike fibrosis. The alveolar walls are lined by type 2 pneumocytes, and there may be an increase in alveolar macrophages ( Fig. 12.3 ). Often squamous metaplastic changes are observed in the distal bronchioles. The histologic changes of acute lung injury are summarized in Box 12.1 .
Uniform alveolar septal thickening (may occasionally spare adjacent lobules)
Alveolar septal edema
Granulation tissue–like fibrosis
Hyaline membranes (pathognomonic of diffuse alveolar damage)
Fibrin and edema in airspaces
Type 2 pneumocyte hyperplasia
Small vessel thrombi
Squamous metaplasia of distal airways and alveolar ducts
Clinical picture of acute respiratory compromise
The differential diagnosis in cases of acute lung injury includes infection, drug reaction, connective tissue disease, and fume inhalation injury. Many cases are idiopathic. Despite the prominence of neutrophils in alveolar lavage in patients with diffuse alveolar damage, most cases lack marked histologic neutrophilia. In patients with increased neutrophil levels, the differential diagnosis includes pulmonary infection, sepsis, trauma, and transfusion-related acute lung injury.
Organizing pneumonia is characterized histologically by alveolar filling with polypoid plugs of granulation tissue ( Fig. 12.4A ). These plugs are rounded, are often branching, and have a myxoid edematous quality. One can usually identify a separation from the alveolar septa at the periphery of these regions of airspace organization, a feature that differentiates them from interstitial fibroplasia. The term bronchiolitis “obliterans organizing pneumonia” has been used synonymously with organizing pneumonia, but this has been discouraged because of its confusion with bronchiolitis obliterans (also known as constrictive bronchiolitis or cicatricial bronchiolitis), a disease characterized by circumferential scarring of small airways and physiologic obstruction. In organizing pneumonia, the airspace polyps are often present within the bronchiolar lumens, mimicking bronchiolar obliteration. Often the central portion of the polypoid plug contains the organized contents of the alveolar space. These may be chronic inflammatory cells, macrophages, or aspirated foreign material. Although etiologic clues may sometimes be found within these cores ( Fig. 12.4B ), most often the polyps have only the appearance of bland granulation tissue. In these cases, histologic separation of cryptogenic organizing from an organizing infectious pneumonia or some other secondary organizing pneumonia (e.g., from connective tissue disease) can be a futile task.
A third pattern of acute lung injury is acute fibrinous organizing pneumonia. This pattern has a hybrid appearance between diffuse alveolar damage and organizing pneumonia and is characterized histologically by polypoid plugs of fibrin within airspaces ( Fig. 12.5 ).
Is There Fibrosis?
Lung fibrosis can be simply defined as excess collagen deposition in the lung. This can be in the form of loose edematous granulation tissue–like fibrosis, as in organizing diffuse alveolar damage or organizing pneumonia, or dense collagenous fibrosis, as in fibrosing interstitial pneumonias.
Fibrotic lung disease can be evaluated using a pattern-based system categorized by the distribution within the secondary lobule. Certain diseases tend to follow a characteristic pattern of fibrosis. Whether the disease shows a peripheral lobular pattern, a diffuse pattern, a bronchiolocentric pattern, or a combination of these patterns can help establish a diagnosis or differential diagnosis ( Fig. 12.6 ).
Is This Usual Interstitial Pneumonia?
Usual interstitial pneumonia (UIP) is characterized by peripheral lobular fibrosis such that the fibrosis is accentuated subpleurally and along interlobular septa. The histologic diagnosis is more accurately made when evidence of chronic active disease is seen; the chronicity is represented by fibrosis and microscopic honeycombing and the activity is represented by fibroblast foci. Microscopic honeycombing really does not look much like honeycomb. Honeycomb, the wax structure made by bees, consists of a series of uniform hexagonal cells with thin partitions. Microscopic honeycombing of the sort observed in UIP is rarely uniform appearing and is characterized by irregular enlarged airspaces, lined by bronchiolar or cuboidal epithelium, frequently filled with mucin-containing occasional macrophages and neutrophils, surrounded by dense collagenous fibrosis often with interspersed smooth muscle. Fibroblast foci are usually present at the interface between the dense peripheral fibrosis and the central less involved lung tissue. These foci are composed of fibroblasts within an edematous myxoid matrix. The fibroblasts are often arranged with their spindled nuclei parallel to the alveolar surface. An overlying layer of plump reactive epithelial cells is frequently present at the alveolar border. Fibroblast foci can occasionally be difficult to separate from organizing pneumonia but can be recognized by histologic clues and a clinical history of chronicity ( Table 12.1 ). This variation in the stage of fibrosis from chronic to active within the same biopsy specimen has been termed temporal heterogeneity. This term has to be used with caution, however, for not everything that shows temporal heterogeneity is UIP (e.g., a patient with fibrosis from smoking who has an acute pneumonia shows temporal heterogeneity). The temporal heterogeneity of UIP is often stereotypical with the worst fibrosis in subpleural regions, normal lung adjacent to bronchovascular bundles, and fibroblast foci at the interface between the two ( Fig. 12.7 ). When one sees this classic temporal heterogeneity, the diagnosis is UIP and often correlates with the clinical entity idiopathic pulmonary fibrosis (IPF).
| Organizing Pneumonia | Fibroblast Foci |
|---|---|
| Rounded or polypoid appearance | Bulgelike or crescentic |
| Airspace visible on most surfaces | Dense collagen present along half of surface |
| Located within airway or airspace | Located within interstitium |
| Branching common | Branching rare |
| Thin or absent surface epithelial layer | Reactive surface epithelial layer |
| Haphazardly arranged fibroblasts | Fibroblasts often parallel to alveolar surface |
There are other diseases that may show similar histology, and it is important to look for clues that might separate them from IPF ( Box 12.2 ). Chronic hypersensitivity pneumonia may show peripheral fibrosis but is often also associated with bronchiolocentric fibrosis and poorly formed granulomas. Connective tissue disease may show a partial UIP pattern, but often the more central tissue is not normal and will have a uniform alveolar septal thickening (combining this UIP pattern with a nonspecific interstitial pneumonia [NSIP] pattern). Connective tissue disease may also show pleural inflammation or prominent parenchymal lymphoid aggregates. Other diseases may show similar peripheral lobular fibrosis, but the distribution within the lung may be wrong. Examples of this include apical fibrous cap, subpleural fibrosis in a patient with prior spontaneous pneumothorax, or idiopathic pleuroparenchymal fibroelastosis (PPFE). Similar to UIP, PPFE can show extensive subpleural fibrosis; however, both the distribution and the character of the fibrosis differ from UIP . In PPFE, the fibrosis appears slightly paler on H&E stain, and an elastic tissue stain reveals that the tissue does not show marked alveolar septal destruction but rather appears slightly collapsed and filled with fibrous tissue (atelectatic fibroelastosis) ( Fig. 12.8 ). This last point emphasizes why it is important to correlate all histologic findings with the imaging data.
Pathologic findings
Basilar and peripheral fibrosis grossly/radiographically
Subpleural and paraseptal fibrosis microscopically
Microscopic honeycombing subpleurally
Fibroblast foci at interface between fibrotic and less involved lung
Normal appearance of the lung in centrilobular regions
Clues for alternative diagnoses
Bronchiolocentric fibrosis: chronic HP, CTD, smoking-related lung disease
Granulomas: chronic HP
Centrilobular lung shows diffuse NSIP-like thickening: CTD
Pleural inflammation/fibrosis: CTD
Apical distribution: apical fibrous cap, prior pneumothorax, pneumoconiosis
Alveolar macrophage accumulation: smoking-related lung disease, drug reaction
Age <50 years: CTD, familial interstitial fibrosis (surfactant C mutations, telomerase mutations)
CTD , connective tissue disease; HP , hypersensitivity pneumonia; NSIP , nonspecific interstitial pneumonia.
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