Objectives

1. List all idiopathic interstitial pneumonias.
2. Discuss both the historical and current pathologic classification.
3. Describe the microscopic features of the idiopathic interstitial pneumonias.
4. Describe the pathologic differential diagnoses of the idiopathic interstitial pneumonias.
5. Understand the clinical significance of these pathologic diagnoses.

Abbreviations

AIP = acute interstitial pneumonia; ATS/ERS = American Thoracic Society/European Respiratory Society; BOOP = bronchiolitis obliterans-organizing pneumonia; COP = cryptogenic organizing pneumonia; DAD = diffuse alveolar damage; DIP = desquamative interstitial pneumonia; GIP = giant cell interstitial pneumonia; HP = hypersensitivity pneumonia; LIP = lymphocytic interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; RB-ILD = respiratory bronchiolitis-interstitial lung disease; UIP = usual interstitial pneumonia

Introduction

Classification

The idiopathic interstitial pneumonias are a group of diffuse infiltrative pulmonary diseases with a similar clinical presentation, characterized by dyspnea, restrictive physiology, and bilateral interstitial infiltrates on chest radiography.¹ From a pathologic perspective, these diseases have characteristic patterns of tissue injury with chronic inflammation and varying amounts of fibrosis. By recognizing these patterns, a pathologist can classify each of these diseases and predict prognosis. However, the pathologist cannot predict etiology, since these pathologic patterns can be seen in multiple clinical settings.

The pathologic characteristics of these diseases were originally classified by Liebow and Carrington in 1969² but have undergone three important revisions over the past 35 years, by Katzenstein in 1997,³ Muller and Colby in 1997,⁴ and the latest revision is by the American Thoracic Society/European Respiratory Society (ATS/ERS) in 2003⁵ (Table 1). The latest classification system includes four of the original five entities, eliminating giant cell interstitial pneumonia (GIP), which is now considered a pneumoconiosis, and has added three more entities: respiratory bronchiolitis-interstitial lung disease (RB-ILD), nonspecific interstitial pneumonia (NSIP) (cellular and fibrosing types), and acute interstitial pneumonia (AIP) (Table 2). Overall, the current ATS/ERS classification is the result of refinements to the previous classifications based on large clinical studies with more clearly defined patient pools, due to the improved detection of disease by more sensitive imaging studies and more lung biopsies. This classification system emphasizes the importance of an interdisciplinary approach on the part of the clinicians and pathologists when diagnosing these diseases.

The Role of the Pathologist

The role of the pathologist in diagnosing these diseases is twofold. First, the histologic patterns of these diseases are distinctive, and the pathologist must learn to recognize and categorize the abnormality using the current ATS/ERS classification. This must be done in the context of the clinical and radiologic information available. In addition, although the pathologist cannot define specific etiologies, he can provide etiologic possibilities that can help to direct the subsequent clinical investigations.

Tissue Requirements

Pathologic diagnosis of the idiopathic interstitial pneumonias requires the evaluation of large areas of tissue, as obtained from either video-assisted thoracoscopic biopsies or open biopsies. The role of the transbronchial biopsies in the pathologic diagnosis of these diseases is limited to ruling out other causes of interstitial lung disease, such as infection or tumor.⁶

Unclassifiable Pathologic Findings

Even when ample tissue is available for histologic examination, there are subsets of patients whose pathologic characteristics are not classifiable into any of the seven specific entities. The ATS/ERS classification proposes that these patients be given the diagnosis of unclassifiable interstitial pneumonia and acknowledges that, at least in a subset of patients with interstitial pneumonia, it may be impossible to make a specific pathologic and clinical diagnosis.⁴

Usual Interstitial Pneumonia

Definition

Usual interstitial pneumonia (UIP) is a histologic pattern characterized by patchy, temporally heterogenous areas of chronic lymphocytic inflammation with organizing and collagenous-type fibrosis. The patients usually present with gradually increasing shortness of breath and a nonproductive cough and have had these symptoms for many months or even years. Imaging studies usually reveal bilateral, basilar disease with a reticular pattern. Clinically, this entity may be referred to by clinicians as idiopathic pulmonary fibrosis or chronic fibrosing alveolitis.

Pathologic Findings

The abnormality is characterized by a leading edge of chronic inflammation with fibroblastic foci that begin in different areas of the lung at different times and produce a variegated pattern of fibrosis (Fig 1). The progression from inflammation to fibrosis includes interstitial widening, epithelial injury and sloughing, fibroblastic infiltration, and the organizing fibrosis. These fibroblastic foci are characteristic of this abnormality and represent the new fibrosis. Deposition of collagen by these fibroblasts occurs in the latter stages of repair, and, therefore, the histopathologic picture of UIP is a continuum of inflammation at the peripheral edge of ongoing injury to irreversible, dense collagen within the older, inactive areas of the lesion. The presence of the abundant collagen produces stiff lungs that are unable to clear the airway secretions, leading to recurrent inflammation of the bronchiolar epithelium with eventual fibrosis and breakdown of the airway structure. This remodeling produces mucous-filled ectatic spaces, giving rise to the honeycomb spaces of the advanced abnormality.⁷ Because it occurs predominantly in the periphery of the lung, involving the subpleura and interlobular septae, the gross picture is one of more advanced peripheral disease.

Differential Diagnosis

The pathologic differential diagnosis for UIP is fibrosing NSIP or desquamative interstitial pneumonia (DIP). The distinction from fibrosing NSIP can be difficult if the UIP is in an early stage. UIP, unlike fibrosing NSIP, has a variegated, temporally heterogenous, low-power view and, as it advances, forms honeycomb spaces not seen in the latter. Distinguishing UIP from DIP is easier because of the lack of significant macrophage infiltration in UIP and the presence of fibrosis and honeycombing in DIP.

Nonspecific Interstitial Pneumonia

Definition

NSIP is an interstitial pneumonia with a distinct pathologic pattern that is characterized by a temporally uniform pattern of inflammation and/or fibrosis. NSIP was originally defined as "unclassifiable interstitial pneumonia,"⁴ because it could not be put into any of the other six categories of UIPs. Subsequently, Katzenstein and Fiorelli⁸ introduced the term "nonspecific" to differentiate it from UIP. Though this term remains problematic as it can be used in a more generic sense when the pathologic features may, indeed, be nondiagnostic, it remains in the ATS/ERS classification.

Pathologic Findings

NSIP is distinguished from UIP by its uniform and diffuse appearance with chronic inflammation dispersed throughout the biopsy specimen (Fig 2). In recent years, it has been subdivided into two major subtypes: cellular NSIP and fibrosing NSIP.⁹ In cellular NSIP, the chronic inflammation contains both lymphocytes and some plasma cells and widens the alveolar interstitium. Lymphocyte aggregates may be present. Foci of organizing fibrosis, as is seen predominantly in cryptogenic organizing pneumonia (COP), can be present but are not common. In fibrosing NSIP, collagen deposition occurs within the inflamed interstitium and diffusely involves the lung. However, unlike UIP, no significant architectural remodeling occurs.

Differential Diagnosis

The major pathologic differential diagnosis with fibrosing NSIP is UIP. This may be difficult to distinguish, especially in early UIP, however, neither fibroblastic foci nor honeycombing is seen in fibrosing NSIP. Cellular NSIP should be distinguished from hypersensitivity pneumonia (HP) and lymphocytic interstitial pneumonia (LIP). HP has either giant cells or loosely-formed granulomas, features not seen in NSIP. Also, intra-alveolar organizing fibrosis is more common in HP. Although the distinction of cellular NSIP from LIP can be quite difficult, the lymphocytic infiltrate of LIP is much more prominent and contains many more lymphoid aggregates and reactive germinal centers than is seen in cellular NSIP.

Desquamative Interstitial Pneumonia

Definition

DIP is a pathologic entity that is characterized by a diffuse infiltration of the alveolar spaces by pigmented "smokers" macrophages, reactive epithelium, and a mild interstitial chronic inflammatory infiltrate within the alveolar interstitium.¹⁰ It is found overwhelmingly in current or former smokers, usually in the fourth or fifth decade of life and is relatively uncommon, found in less than 19% of biopsy results from those patients with suspected interstitial lung disease.¹¹ With a clinical picture very similar to UIP and once thought to be a precursor to UIP,¹³ DIP is now considered a distinct entity with a prognosis that is considerably better with a mortality of < 20%.¹⁰

Pathologic Findings

DIP has diffuse, temporally uniform, alveolar, interstitial inflammation and fibrosis and a characteristic feature of abundant pigmented macrophages filling the alveolar spaces (Fig 3). The accumulation of the macrophages begins around the respiratory bronchioles and gradually spreads peripherally to include the majority of the alveolar spaces present. Unlike UIP and NSIP, fibrosis is not a component of DIP, and no chronic architectural changes of the lung parenchyma occur. The macrophages comprising the alveolar infiltrate contain brown, anthracotic pigment, as is typical of those in the lungs of smokers. Due to the abundant number of these macrophages, scattered multinucleated giant cells can be seen; however, granulomas are not a part of the histologic picture.

Differential Diagnosis

DIP must be distinguished pathologically from those interstitial diseases that may contain a DIP-like pattern of injury. These include UIP, NSIP, chronic eosinophilic pneumonia, GIP, and RB-ILD. Unlike UIP, DIP contains no fibroblastic foci or honeycombing and has a uniform pattern.¹⁰ NSIP, both cellular and fibrosing types, should not contain a predominance of macrophages, as is seen in DIP. GIP does contain a significant macrophage infiltrate; however, this infiltrate contains many multinucleated giant cells with macrophages within their cytoplasm. RB-ILD, as discussed next, is very similar to DIP and many combine these two terms into a single entity, called "smokers interstitial lung disease." However, the ATS/ERS has separated these two entities, given the different clinical picture, imaging studies, and the less extensive pathologic findings in RB-ILD.⁵ The DIP-like reactions that can be seen in chronic eosinophilic pneumonia may be difficult to distinguish from true DIP, especially in patients receiving steroid treatment. Clinical correlation with peripheral eosinophilic counts and imaging studies may be most useful in eliminating this possibility.

Respiratory Bronchiolitis Interstitial Lung Disease

Definition

RB-ILD is a disease of smokers, characterized by a chronic bronchiolitis with pigmented macrophages involving the surrounding peribronchiolar space with some extension into the surrounding alveolar interstitium.¹¹ The clinical and radiologic features of RB-ILD are not well defined and, many times, nonspecific. Like DIP, the disease almost exclusively affects current or former smokers, usually 50 to 60 years of age, with pack-year histories of greater than 30-pack years.¹²

Pathologic Findings

The abnormality of RB-ILD is patchy, temporally uniform, and consists predominantly of a mononuclear infiltrate of the characteristic brown-pigmented macrophages of smokers' lungs (Fig 4). These cells infiltrate around the bronchiolar and peribronchiolar areas and cause mild interstitial widening and reactive epithelial changes. As the abnormalities progress, peribronchiolar fibrosis can be seen.

Differential Diagnosis

As previously discussed, the main differential diagnosis with RB-ILD is DIP. In addition to this, however, one should also consider pulmonary histiocytosis X, another lesion seen in smokers but with clusters of Langerhans cells strongly immunoreactive to CD1a. Upon progression, pulmonary histiocytosis X develops into stellate scars and, because of these characteristic lesions, the imaging studies are usually quite helpful in distinguishing this lesion from RB-ILD.

Cryptogenic Organizing Pneumonia

Definition

COP is a lesion characterized by fibroblastic proliferations within terminal and respiratory bronchioles and alveoli ducts and sacs. This entity has provided a significant amount of controversy since first described in 1985 by Epler and colleagues.¹⁴ The term initially used by Epler and colleagues, idiopathic bronchiolitis obliterans-organizing pneumonia (BOOP), caused confusion because clinicians understood it as a distinct clinical entity, yet pathologists used this term as a pattern of injury that could be the idiopathic form or could be secondary to many different causes. Because of this confusion, the ATS/ERS distinguished the idiopathic BOOP from the nonspecific BOOP-type pattern of injury by renaming it COP. Thus, the clinical setting in which this abnormality arises is important for both the pathologist and the clinician to consider.

Pathologic Findings

The abnormality consists of areas of organization, characterized by plugs of loose connective tissue within the alveolar ducts and sacs and that sometimes, but not always, extend into the small (terminal and respiratory) bronchioles (Fig 5). The abnormality is patchy, with normal lung adjacent to the areas of organization, and temporally homogeneous. In some cases, the surrounding interstitium may contain an infiltrate of lymphocytes or plasma cells, but the overall architecture of the lung is preserved with no fibrosis seen.

Differential Diagnosis

The pathologic differential diagnosis for COP includes the organizing pattern of diffuse alveolar damage (DAD), although imaging studies for the latter show more diffuse disease, and the clinical course is more acute. In addition, because of the scattered fibroblastic foci of UIP, this may be included in the pathologic differential diagnosis. However, the fibroblastic foci of UIP are invariably adjacent to dense, collagenous fibrosis that is not seen in COP, and imaging studies of UIP may highlight these underlying chronic architectural changes not seen in COP.

Acute Interstitial Pneumonia

Definition

AIP is the idiopathic variant of DAD, a tissue pattern of injury that occurs in many different clinical settings and results from epithelial and endothelial damage. The injury produces an early exudative phase, characterized by hyaline membrane formation, and progresses through a proliferative phase to an organizing phase that, in 50% of the cases, produces end-stage, honeycomb fibrotic changes in the affected lungs.¹⁵ Idiopathic AIP can be referred to clinically as Hamman-Rich syndrome or acute respiratory distress syndrome.

Pathologic Findings

The abnormal features reflect the pathogenetic mechanisms involved in diffuse injury to the alveolar wall. The early, exudative stage results from breakdown of the epithelial and endothelial barriers; this results in exudation of plasma proteins into the alveolar space (Fig 6). The alveolar fibrin is then formed into hyaline membranes as a result of the positive air pressures within the alveoli. As a result of this alveolar wall injury, the type I pneumocytes undergo extensive necrosis and slough off. In the subsequent proliferative phase of the disease, the type II pneumocytes proliferate in an attempt to re-epithelialize the alveolar surface and produce the proliferative abnormality seen. Finally, as the injury begins to resolve, the hyaline membranes and extensive cellular debris are organized into the alveolar walls and alveolar space, producing the organizing fibrotic plugs characteristic of this phase of the disease. This organization marks the steroid-responsive phase of the disease, and, also, the remodeling phase of the disease when honeycombing changes may occur.¹⁶

Differential Diagnosis

The differential diagnosis of AIP is usually not extensive given the characteristic acute clinical features and diffuse imaging patterns. Pathologically, COP may be confused with the organizing phase of AIP; however, hyaline membranes are not seen in COP and, when present in early organizing AIP, they may be helpful in making this distinction. In addition, the organizing fibroblastic foci of COP are restricted to the alveolar space, unlike those of AIP that are both within the alveolar space and within the interstitium. Finally, the organizing and fibrotic phases of AIP may be confused with UIP. However, unlike UIP, AIP has a temporally uniform pattern.

Lymphocytic Interstitial Pneumonia

Definition

LIP is a term that applies to a number of different disorders that are associated with either a monoclonal or polyclonal gammopathy and can be seen in the setting of Sjögren's syndrome, AIDS, or viral infections. It is rare to be a primary disorder, but when seen in this context, it is referred to as idiopathic LIP.

Pathologic Findings

The abnormality consists of a temporarily homogenous infiltrate of lymphocytes and scattered plasma cells within the alveolar wall and interstitium. There can be variable numbers of germinal centers and scattered, multinucleated, giant cells, or ill-formed granulomas can also be seen. Though significant fibrosis is not part of this disease, in advanced LIP, interstitial fibrosis may be seen, as well as areas of organizing pneumonia.¹⁷

Differential Diagnosis

The pathologic differential diagnosis of LIP includes a collection of lymphocytic-rich disorders that involve the lung. In follicular bronchiolitis, the lymphocytes are predominantly surrounding airways with little or no extension into the interstitium. In nodular hyperplasia, the lymphocytic infiltrate is present as one or two localized lesions rather than a diffuse interstitial infiltrate. HP should be considered in the differential diagnosis; however, the bronchiolitis of HP is much more significant, and the infiltrate of LIP much denser. Finally, it is important to rule out low-grade lymphomas, such as low-grade marginal zone B cell lymphomas (MALTomas). These lymphomas show more aggressive biological activity, such as invasion into bronchial cartilage, vessels, and overlying pleura;¹⁸ and, in general, monoclonal populations can be detected by either immunohistochemistry or molecular studies.¹⁹

Conclusions

References

1. Chapman JT, Farver CF. Idiopathic interstitial lung disease: a review of recent classifications. Clin Pulm Med 2004; 11:1-8
2. Liebow AA, Carrington, CB. The interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, eds. Frontiers of pulmonary radiology. New York, NY: Grune & Stratton; 1969:102-141
3. Katzenstein AL. Katzenstein and Askin's surgical pathology of non-neoplastic lung disease . Philadelphia, PA: WB Saunders; 1997:48-80  
4. Muller NL, Colby TV. Idiopathic interstitial pneumonias: high-resolution CT and histologic findings. Radiographics 1997; 17:1016-1022  
5. Travis WD, King TE, Bateman ED, et al. International multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Joint statement adopted June 2001: American Thoracic Society and European Respiratory Society. Am J Respir Crit Care Med 2002; 165:277-304  
6. Dacic S, Yousem SA. Histologic classification of idiopathic chronic interstitial pneumonias. Am J Respir Cell Mol Biol 2003; 29:S5-S9  
7. Farver CF. Pathology of advanced interstitial diseases: pulmonary fibrosis, sarcoidosis, histiocytosis X, autoimmune pulmonary disease, lymphangioleiomyomatosis. In: Maurer, JR. ed. Non-neoplastic advanced lung disease. In: Lung biology in health and disease. New York, NY: Marcel Dekker Inc, 2003: 29-58  
8. Katzenstein AL, Fiorelli R. Nonspecific interstitial pneumonia/fibrosis: histologic features and clinical significance. Am J Surg Pathol 1994; 18:136-147  
9. Travis W, Matsui K, Moss J, et al. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns: survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia. Am J Surg Pathol 2000; 24:19-33  
10. Carrington CB, Gaensler EA, Coutu RE, et al. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1987; 298:801-809  
11. Myers JL, Veal CH, Jr., Shin MS, et al. Respiratory bronchiolitis causing interstitial lung disease: a clinicopathologic study of six cases. Am Rev Respir Dis 1985; 135:880-884  
12. Moon J, du Bois RM, Colby TV, et al. Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease. Thorax 1999; 54:1009-1014  
13. Crystal RG, Bitterman PB, Rennard SI, et al. Interstitial lung disease of unknown cause: disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med 1984; 310:154-166  
14. Epler GY, Colby TV, McLoud TC, et al. Bronchiolitis oblterans organizing pneumonia. N Engl J Med 1985; 312:152-158
15. Katzenstein AL, Myers JL, Mazur MT. Acute interstitial pneumonia: aclinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol 1986; 10:256-276  
16. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342:1339-1344  
17. Koss M, Hochholzer L, Langloss J, et al. Lymphoid interstitial pneumonia: clinicopathological and immunopathological findings in 18 cases. Pathology 1987; 19:178-185  
18. Colby TV, Yousem SA. Pulmonary lymphoid neoplasms. Semin Diagn Pathol 1985; 2:183-196
19. Elenitoba-Johnson K, Medeiros LJ, Khorsand J, et al. Lymphoma of the mucosa-associated lymphoid tissue of the lung: a multifocal case of common clonal origin. Am J Clin Pathol 1995; 103:341-345