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The Proceedings of the American Thoracic Society 3:322-329 (2006)
© 2006 The American Thoracic Society

Histologic Spectrum of Idiopathic Interstitial Pneumonias

Daniel W. Visscher and Jeffrey L. Myers

Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota; and Division of Anatomic Pathology, University of Michigan, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Daniel W. Visscher, M.D., Division of Anatomic Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: visscher.daniel{at}mayo.edu

ABSTRACT

Histopathologic classification plays a key role in separating multiple forms of idiopathic interstitial pneumonia into clinically meaningful categories with important differences in natural history, prognosis, and treatment. Microscopic criteria in diagnosis of these entities include the pattern and microanatomic distribution of inflammation, fibroblast proliferation, collagen deposition, and architectural remodeling. Usual interstitial pneumonia (UIP) defines idiopathic pulmonary fibrosis and is the most common of the idiopathic interstitial pneumonias. UIP has distinctive morphologic features that allow precise diagnosis in classical cases. Other forms of idiopathic interstitial pneumonia include desquamative interstitial pneumonia, respiratory bronchiolitis–associated interstitial lung disease, acute interstitial pneumonia, and nonspecific interstitial pneumonia. These latter categories differ from UIP in that the histopathologic findings do not, by themselves, allow specific diagnosis in most cases and require careful correlation with clinical and radiologic findings.

Key Words: idiopathic interstitial pneumonias • idiopathic pulmonary fibrosis • nonspecific interstitial pneumonia • usual interstitial pneumonia

By definition, the idiopathic interstitial pneumonias are characterized by expansion of the interstitial compartment by inflammatory cells. Fibrosis, either in the form of abnormal collagen deposition or proliferation of fibroblasts capable of collagen synthesis, occurs in many cases. The pioneering classification of idiopathic interstitial pneumonias into clinically relevant groups by Averill Liebow remains largely intact, as summarized in Table 1 (1–3). An important principle developed by Liebow is that pathologic classifications were histologic patterns rather than free-standing diagnostic entities, and that each could occur in a variety of clinical contexts (1). For example, patients with usual interstitial pneumonia (UIP) may have idiopathic pulmonary fibrosis (IPF), lung involvement attributable to an underlying systemic connective tissue disease, or drug-induced pulmonary disease. Nevertheless, appropriate histologic classification significantly limits the differential diagnosis in terms of potential etiologies or associations and each has implications for treatment and prognosis. In the setting of a patient with unexplained (i.e., idiopathic) interstitial lung disease, these histologically defined patterns are indeed specific diseases.


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  		TABLE 1. CLASSIFICATION OF IDIOPATHIC INTERSTITIAL PNEUMONIAS

 
USUAL INTERSTITIAL PNEUMONIA/IDIOPATHIC PULMONARY FIBROSIS

UIP/IPF is the most common of the idiopathic interstitial pneumonias, accounting for more than 60% of cases (4). As mentioned previously, UIP occasionally occurs in patients with other underlying conditions or etiologies. In most patients, however, UIP and IPF are interchangeable terms.

Pathologic Features of UIP/IPF
The hallmark and chief diagnostic criterion is a heterogeneous, variegated appearance with alternating areas of normal lung, interstitial inflammation, fibrosis, and honeycomb change; this results in a distinctive "patchwork" appearance at low magnification (Figure 1) (2, 3, 5, 6). Although subpleural parenchyma is most severely affected, this distribution may be difficult to appreciate in surgical lung biopsies. In such cases, correlation with radiographic findings including characteristic anatomic distribution (e.g., lower lung zones) can be helpful in reaching a specific diagnosis.


Figure 1
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  		Figure 1. Low-magnification photomicrograph illustrating variegated, patchwork distribution of abnormalities in a classical example of usual interstitial pneumonia (UIP) (hematoxylin and eosin stain; original magnification, x20).

 
Fibrosis predominates over inflammation in UIP. "Fibroblast foci" represent microscopic zones of acute lung injury set against a backdrop of chronic scarring, thus contributing to the variegated appearance or temporal heterogeneity of UIP (Figure 2). They are randomly distributed within areas of interstitial collagen deposition and consist of fibroblasts and myofibroblasts arranged in a linear fashion within a pale-staining matrix. The overlying epithelium is composed of hyperplastic pneumocytes or nonciliated bronchiolar cells. Fibroblast foci are not specific for UIP, but they are invariably present and therefore represent an important diagnostic criterion.


Figure 2
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  		Figure 2. High-magnification photomicrograph illustrating fibroblast focus (arrows) in a patient with UIP. The fibroblast focus comprises a localized area in which spindle cells are distributed in a somewhat linear fashion within pale-staining interstitial matrix associated with overlying hyperplastic pneumocytes (hematoxylin and eosin stain; original magnification, x200).

 
Honeycomb change is another important diagnostic feature, defined as cystically dilated bronchioles (containing mucus and leukocytes) lined by columnar respiratory epithelium in scarred, fibrotic lung tissue (Figure 3). Fibrotic scars (dense eosinophilic collagen without associated honeycomb change) are another form of obliterative architectural distortion characteristic of UIP. Smooth muscle hyperplasia, of striking degree in some cases, is commonly seen in both fibrotic scars and honeycomb change.


Figure 3
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  		Figure 3. Low-magnification photomicrograph showing honeycomb change in UIP. Cystically dilated airways corresponding to distended bronchioles are present with scarred, fibrotic lung. The cystic spaces are lined by columnar respiratory epithelium and contain mucus and inflammatory cells (hematoxylin and eosin stain; original magnification, x40).

 
Interstitial inflammation is inconspicuous in UIP, consisting of patchy alveolar septal infiltrates of mononuclear cells. Peribronchiolar lymphoid aggregates occur in some patients but are rarely a dominant feature. Other airway-centered changes can also occur including secondary ("traction") bronchiectasis and peribronchiolar fibrosis with associated epithelial hyperplasia, a phenomenon that has been dubbed "peribronchiolar metaplasia." Air spaces often contain clusters of lightly pigmented ("smokers'") histiocytes resulting in foci that superficially resemble "desquamative interstitial pneumonia (DIP)-like" foci (5). DIP-like changes serve only as markers of cigarette smoking rather than as evidence of a meaningful link between UIP and DIP. Another sometimes confusing finding is the presence of areas resembling eosinophilic pneumonia. Against a backdrop of otherwise typical UIP, "eosinophilic pneumonia-like" changes have no etiologic or clinical significance (7).

Patients who are biopsied during a period of "accelerated IPF" typically show a combination of UIP with superimposed diffuse alveolar damage (DAD) or organizing pneumonia (8). Studies suggest that this may be a common terminal event in UIP (9). Alveolar septa in these patients are expanded by more extensive fibroblast proliferation than that seen in conventional fibroblast foci. Other features of acute lung injury in these cases include marked hyperplasia of type 2 pneumocytes and hyaline membrane remnants. In some patients the superimposed pattern of acute lung injury more closely resembles organizing pneumonia and is characterized by intralumenal plugs or polyps of fibroblastic tissue.

Semiquantitative scoring systems have correlated various histologic features with physiologic and radiologic measures of disease severity, but these have limited value in evaluating individual patients (10–12). Patients with more extensive fibroblast foci have experienced shorter mean survivals in some but not all studies (13–15). Patients biopsied during an accelerated phase of illness may account, at least in part, for the link between extent of fibroblast proliferation and shortened survival observed by some authors.

Pathogenesis
The presence of multiple associations (including cigarette smoking, gastroesophageal reflux disease, occupational exposures, and hepatitis C infection) suggests that no single etiologic agent serves as a common inciting event in UIP. Patients are thus thought to share common, but as yet undefined, regulatory defects in wound healing/reparative pathways (16).

Most agree that epithelial injury and activation in fibroblast foci are crucial early events that trigger a cascade of changes leading ultimately to reorganization of pulmonary tissue compartments (16–19). Sites of "acute" injury are characterized by denudation and collapse of damaged epithelial basement membranes, with migration of fibroblasts/myofibroblasts into air spaces, and extracellular matrix accumulation (16, 17, 20–22). Similar morphologic changes characterize DAD and bronchiolitis obliterans organizing pneumonia (BOOP), suggesting that differences may lie in regulation of the inflammatory process.

Cellular products elaborated by surviving and regenerating respiratory epithelium facilitate abnormal persistence of extracellular matrix, thereby impeding wound healing. These include tissue factor and plasminogen activator inhibitors, which abnormally sustain local antifibrinolytic activity. Fibrogenic cytokines and growth factors, including platelet-derived growth factor, transforming growth factor-ß1, tumor necrosis factor-{alpha}, and interleukin-18 and its receptor are important in recruitment and phenotypic modulation of fibroblasts and myofibroblasts (23–28).

Myofibroblasts amplify alveolar damage by inducing apoptosis in hyperplastic pneumocytes, impairing reepithelialization, and by failure to secrete antifibrotic cytokines such as hepatocyte growth factor. Basement membrane disruption is mediated through secretion of gelatinases by myofibroblasts. Extracellular matrix accumulation with angiogenesis and architectural remodeling results, at least in part, from an imbalance between collagenases and tissue inhibitors of metalloproteinases. Angiogenesis and vascular remodeling may in turn contribute to arteriovenous shunting (29, 30).

Despite the morphologic overlap, fibroblast foci of UIP differ functionally from intralumenal fibroblast proliferation (Masson bodies) in BOOP, including fibroblast/myofibroblast phenotype, rates of fibroblast/myofibroblast apoptosis, modulation of extracellular matrix deposition, extent of neovascularization, character and extent of reepithelialization, and ß-catenin expression. Differences between alveolar and bronchiolar epithelium in cell cycle regulation and activation of the Wnt/ß-catenin pathway may also contribute to architectural remodeling and honeycomb change in UIP.

Differential Diagnosis
Three major problems confront pathologists in reaching a diagnosis of UIP: the first is sampling, in which pathologic findings are indeterminate. The second is the presence of fibrotic changes resembling UIP in other conditions. Third, UIP cases may sometimes have microscopic findings (e.g., DIP-like areas) that resemble other conditions (5). Each of these problems underscores the need for clinical and radiographic correlation (31).

Chronic hypersensitivity pneumonia with fibrosis can mimic UIP but it is generally more cellular, usually with a granulomatous character, and predominantly bronchiolocentric in distribution. Granulomatous inflammation can be subtle, consisting of isolated multinucleated giant cells or ill-defined clusters of epithelioid histiocytes. Honeycomb change can occur in hypersensitivity pneumonia but typically is not associated with the same degree of peripheral subpleural fibrosis.

Cases of "burned out" Langerhans cell histiocytosis (LCH), in which fibrotic nodules predominate, may resemble UIP. The key features are the stellate configuration and bronchiolocentric distribution of the nodules in LCH coupled with often striking paracicatricial airspace enlargement ("scar emphysema"). Fibroblast foci are also rare in LCH. High-resolution computed tomography scans can be extremely useful in separating LCH from UIP in diagnostically challenging cases.

Organizing pneumonia is a nonspecific pattern of lung injury that often occurs in combination with various unrelated pathologic processes, including UIP. Idiopathic organizing pneumonia (i.e., BOOP, cryptogenic organizing pneumonia) is a specific syndrome in which patchy intralumenal fibrosis occurs as a primary pathologic process. The absence of interstitial pneumonia or fibrosis away from zones of intralumenal fibrosis is an important feature in separating BOOP from UIP (32).

DESQUAMATIVE INTERSTITIAL PNEUMONIA/RESPIRATORY BRONCHIOLITIS INTERSTITIAL LUNG DISEASE

DIP and respiratory bronchiolitis interstitial lung disease (RBILD) are related, and in some cases inseparable conditions accounting for 15–20% of biopsied patients with idiopathic interstitial pneumonias (4, 33–35). Despite historical suggestions that DIP was an early form of UIP, current authorities agree that they are unrelated. Liebow and coworkers noted a patchy and distinctly bronchiolocentric distribution of histologic abnormalities in patients with mild or early DIP (36). Niewoehner and colleagues, in a study of smokers with small airway disease, subsequently coined the term respiratory bronchiolitis for this lesions (37). Since then respiratory bronchiolitis and "DIP-like" changes have been recognized as markers of cigarette smoking that frequently occur as incidental findings in lung biopsies (38). As originally noted by Liebow, however, a subset of patients with respiratory bronchiolitis have a syndrome of diffuse interstitial lung disease (i.e., RBILD) with many of the clinical and histologic attributes of DIP (39–42).

Pathologic Features
The most striking feature of DIP is uniform filling of distal airspaces by numerous pigmented alveolar macrophages, including occasional multinucleated cells, eosinophils, and lymphocytes. (Figure 4) (2, 3, 36, 39, 42). These clusters are unusually cohesive, prompting Liebow's original speculation that they might be desquamated pneumocytes. The macrophages are distinctive in that they have abundant cytoplasm, usually containing finely granular dusty brown pigment (Figure 5).


Figure 4
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  		Figure 4. Low-magnification photomicrograph showing classical desquamative interstitial pneumonia (DIP). Alveolar septa are uniformly thickened by a combination of inflammation and mild fibrosis while air spaces contain clusters of histiocytes resulting in a nearly solid appearance (hematoxylin and eosin stain; original magnification, x40).

 

Figure 5
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  		Figure 5. High-magnification photomicrograph illustrating the pigmented alveolar histiocytes typical of both DIP and respiratory bronchiolitis (hematoxylin and eosin stain; original magnification, x400).

 
Recognition of DIP as a specific diagnosis also requires a concomitant interstitial pneumonia. Alveolar septa are thickened by a sparse inflammatory infiltrate and lined by uniform, plump cuboidal pneumocytes. Peribronchiolar lymphoid hyperplasia is seen in the majority of cases. Collagen deposition is mild, uniformly expanding alveolar septa and peribronchiolar interstitium without architectural distortion or honeycombing. On occasion, lesions resembling fibroblast foci can occur but they are not prominent. Absence of architectural distortion and temporal variegation are key features in separating DIP from UIP (5).

Pigmented macrophages are also a striking histologic feature of RBILD. The changes are patchy at low magnification, however, and have a distinctly bronchiolocentric distribution without the associated interstitial pneumonia necessary for a diagnosis of DIP (Figure 6). The pigmented macrophages also tend to lack the cohesive clustering typical of DIP. A mild infiltrate of lymphocytes and histiocytes (often with pigment) expands peribronchiolar interstitium in RBILD. Mild peribronchiolar fibrosis is present, sometimes expanding contiguous alveolar septa, which are lined by hyperplastic type 2 cells and bronchiolar-type epithelium. The combination of peribronchiolar interstitial thickening, epithelial hyperplasia, and pigmented intralumenal macrophages mimicks the appearance of DIP, and the distinction may be arbitrary in some cases (42).


Figure 6
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  		Figure 6. Low-magnification photomicrograph of surgical lung biopsy from patient with respiratory bronchiolitis interstitial lung disease (RBILD). Pigmented histiocytes are present within lumens of distal airways and immediately adjacent peribronchiolar spaces, resulting in a more patchy and bronchiolocentric distribution than in DIP (hematoxylin and eosin stain; original magnification, x40).

 
Pathogenesis of DIP
Although related to cigarette smoking and various occupational or drug exposures, little is known regarding the specific events leading to fibrosis in DIP. Lung histiocytes from smokers demonstrate increased numbers of cytoplasmic lysosomes and phagolysosomes, some containing platelike crystalline inclusions composed of various metals (e.g., kaolin) contained within cigarette smoke. Marked increases in cytoplasmic iron and iron-binding proteins are also characteristic of smokers' histiocytes. It is unknown how or whether these alterations spark inflammation and fibrosis. Comparisons with UIP have demonstrated differences in tenascin accumulation, cell cycle regulatory proteins, and Wnt/ß-catenin pathway activation.

Differential Diagnosis
DIP-like changes commonly occur in cigarette smokers with other lung diseases, including UIP (see above) (5). However, most patients with these changes (i.e., discovered incidentally in lung biopsies) lack the characteristic syndrome of DIP/RBILD (38). There are no histologic features that reliably separate incidental respiratory bronchiolitis and DIP-like reactions from patients with the clinical syndromes of RBILD or DIP, respectively. Neither RBILD nor DIP can be diagnosed on small biopsy specimens and, given the dangers of sampling bias, they should be diagnosed only when other forms of interstitial lung disease have been vigorously excluded, a process that requires correlation with clinical and radiologic findings.

Langerhans cell histiocytosis, a lesion seen almost exclusively in cigarette smokers, is often associated with respiratory bronchiolitis and "DIP-like" changes (43). Recognition of stellate bronchiolocentric nodules containing distinctive Langerhans cells is a key to the differential diagnosis. Eosinophilic pneumonia may be characterized by variable numbers of intraalveolar macrophages and hence may resemble DIP. However, it is often accompanied by a fibrinous exudate and eosinophilic abscesses. Absence of respiratory bronchiolitis away from areas of air space consolidation is also helpful in separating eosinophilic pneumonia from DIP.

The presence of iron-containing cytoplasmic pigment in DIP may cause confusion with alveolar hemorrhage syndromes. The pigment in DIP and RBILD tends to be more finely granular without the coarse refractile hemosiderin particles resulting from hemorrhage. Iron stains also tend to be more faintly positive in the cytoplasmic granules attributable to cigarette smoking. Extracellular hemosiderin is common in hemosiderosis and does not occur in either DIP or RBILD.

ACUTE INTERSTITIAL PNEUMONIA

Although most idiopathic interstitial pneumonias are chronic processes, a subset of patients present with acute onset of respiratory symptoms followed by rapid progression to respiratory failure. Most patients in this category have so-called acute interstitial pneumonia (AIP), also referred to as Hamman-Rich disease (2, 44, 45). AIP is analogous to acute respiratory distress syndrome, differing only in that it is not preceded by an identifiable catastrophic event.

Pathologic Features
Biopsies from patients with AIP demonstrate DAD, usually in the late or organizing stage. There are no histologic features that reliably distinguish DAD in the setting of AIP from DAD of other known causes. For that reason a biopsy diagnosis of DAD should prompt a search for histologic clues to potential (especially infectious) etiologies. Extensive fibroblast proliferation is the dominant finding (Figure 7). Alveolar septa are uniformly thickened and distorted by proliferating fibroblasts and myofibroblasts within a myxoid basophilic matrix. The uniformity of the findings contrasts sharply with the patchwork distribution of highly variegated abnormalities in UIP. Focally the fibroblast proliferation may include intralumenal, polypoid structures indistinguishable from those seen in BOOP (45).


Figure 7
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  		Figure 7. Low-magnification photomicrograph illustrating the organizing phase of diffuse alveolar damage (DAD) in a patient with acute interstitial pneumonia (AIP). Alveolar septa are collapsed on one another and expanded by proliferating fibroblasts and myofibroblasts, resulting in a uniform appearance that is distinctly different from the variegated pattern typical of UIP (compare with Figure 1) (hematoxylin and eosin stain; original magnification, x40).

 
Other manifestations of acute lung injury include marked hyperplasia of alveolar lining cells, often with nuclear enlargement and prominent nucleoli. Remnants of hyaline membranes are sometimes present but are rarely prominent (Figure 8). Fibrin thrombi are often present and together with squamous metaplasia of bronchiolar epithelium are additional clues to the diagnosis. Extensive architectural remodeling may develop in as little as 3 to 4 wk, resulting in honeycomb change with concomitant collapse and fibrosis of distal lung parenchyma. Honeycomb change complicating DAD is diffusely and uniformly distributed without the peripheral, subpleural, and bibasilar localization seen in UIP.


Figure 8
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  		Figure 8. Higher magnification photomicrograph of the same case illustrated in Figure 7, showing collapsed alveolar septa associated with hyaline membrane remnants (arrows) (hematoxylin and eosin stain; original magnification, x100).

 
Pathogenesis
Combined endothelial and epithelial injury in AIP leads to basement membrane denudation, resulting in collapse of alveolar septa (20, 21). Wrinkled and invaginated segments of denuded basal lamina become permanently apposed when the lumenal surfaces are reepithelialized by proliferating type 2 pneumocytes. In a process analogous to UIP, fibroblasts and myofibroblasts migrate through gaps in damaged basement membranes into air spaces. Proliferation of reparative pneumocytes and bronchiolar epithelium results in "mural incorporation" of intraalveolar exudates between type II cells and denuded alveolar septal basement membranes. Both alveolar collapse and mural incorporation of intraalveolar exudates contribute to the alveolar septal thickening seen by light microscopy.

Differential Diagnosis
In nonimmunocompromised patients who lack a history of antecedent catastrophic injury the main etiologic considerations are unidentified causes for DAD (e.g., influenza) and accelerated IPF. The changes in AIP are much more uniform than in IPF; this may be appreciated well at low magnification. Also, the fibrosis in AIP consists of extensive fibroblast and myofibroblast proliferation rather than the dense collagen deposition of UIP. Peripheral subpleural honeycomb change set against a backdrop of eosinophilic scarring does not occur in DAD and can be a helpful clue in separating the two. Distinguishing AIP from "accelerated IPF" depends not only on recognizing underlying UIP but also on correlation with the clinical and radiologic findings.

NONSPECIFIC INTERSTITIAL PNEUMONIA

Katzenstein and Fiorelli applied the term nonspecific interstitial pneumonia/fibrosis (NSIP) to a set of interstitial pneumonias that undoubtedly were included in prior studies of IPF as "early" or "cellular" UIP (46). NSIP may be idiopathic or may occur as a manifestation of systemic connective tissue diseases, hypersensitivity pneumonia, drug-induced lung disease, and chronic interstitial lung disease complicating DAD. Findings indistinguishable from NSIP can occur focally in other conditions, most importantly UIP (5, 47). Carefully defined, however, NSIP is a distinctive form of diffuse interstitial lung disease that should be separated from other idiopathic interstitial pneumonias because of substantial differences in treatment and natural history. NSIP accounts for 14 to 35% biopsies performed for interstitial pneumonia.

As implied above, NSIP is largely defined on the basis of exclusionary criteria (i.e., lung biopsies that fail to show features diagnostic of another form of diffuse interstitial lung disease). However, Katzenstein and Fiorelli also emphasized a fundamentally important criterion for inclusion in this category: "All cases were characterized by an interstitial inflammatory or fibrosing process or both . . . [that] appeared temporally uniform within each case" (46). In other words, NSIP is a form of chronic interstitial pneumonia in which there is relatively uniform expansion of alveolar septa by inflammation and/or fibrosis without the degree of heterogeneity that defines UIP.

Pathologic Features
NSIP spans a morphologic spectrum ranging from a predominantly cellular process (i.e., cellular NSIP) to paucicellular lung fibrosis (i.e., fibrotic NSIP). Cellular forms exhibit uniform alveolar septal infiltrates of lymphocytes and plasma cells (Figure 9). Neutrophils, eosinophils, and histiocytes are inconspicuous. Granulomas are rare in NSIP and, if present, should raise other considerations. Most important is that the character of the inflammatory process in NSIP is the same throughout the affected areas, without the temporal heterogeneity inherent in UIP.


Figure 9
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  		Figure 9. Low-magnification photomicrograph showing "cellular" nonspecific interstitial pneumonia (NSIP) characterized by diffuse uniform expansion of alveolar septa by a cellular infiltrate of lymphocytes (hematoxylin and eosin stain; original magnification, x40).

 
The extent of interstitial fibrosis is highly variable and takes the form of uniform collagen accumulation resulting in expansion of alveolar septa, peribronchiolar interstitium, interlobular septa, or visceral pleura (Figure 10). Purely fibrotic forms are characterized by dense collagen deposition with only minimal inflammation (Figure 11). Smooth muscle hyperplasia tends to be less extensive than in UIP. Patchy organizing pneumonia is common but should be a focal and relatively inconspicuous finding that is overshadowed by the interstitial changes. As in any form of interstitial pneumonia, NSIP may be accompanied by hyperplasia of alveolar and bronchiolar cells.


Figure 10
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  		Figure 10. Low-magnification photomicrograph showing NSIP in which a combination of inflammation and fibrosis expands alveolar septa in a uniform fashion without associated architectural distortion (hematoxylin and eosin stain; original magnification, x40).

 

Figure 11
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  		Figure 11. Low-magnification photomicrograph showing "fibrotic" NSIP in a surgical lung biopsy from a patient with rheumatoid arthritis. Although the lesion is fibrotic, it lacks the patchwork distribution and associated architectural distortion in the form of honeycomb change typical of UIP (hematoxylin and eosin stain; original magnification, x40).

 
The presence of fibrosis has been associated with a more aggressive course (33–35, 46, 48). For this reason the international consensus classification of idiopathic interstitial pneumonias divides NSIP into cellular and fibrotic patterns (3). Disease-specific mortality rates for patients with fibrosis vary widely, ranging from 11 to 68% in various studies, partly reflecting the difficulty in consistently separating patients with fibrotic NSIP from those with UIP (33–35, 48). Nonetheless, pathology reports should comment on the presence and extent of fibrosis in individual cases of NSIP.

Differential Diagnosis
The pathologic differential diagnosis for "cellular" NSIP with minimal associated fibrosis includes hypersensitivity pneumonia, lymphoid interstitial pneumonia (LIP), and BOOP. In contrast to NSIP, the interstitial pneumonia in hypersensitivity pneumonia is centered on small bronchioles and accompanied by a chronic bronchiolitis and poorly formed granulomas, seen in 70–80% of biopsies. Even in the absence of granulomatous inflammation, however, any cellular interstitial pneumonia that has a bronchiolocentric distribution should prompt a vigorous investigation of the patient's environment for potential antigenic exposures. LIP is similar to NSIP but includes not only a cellular interstitial infiltrate but also lymphoid hyperplasia in the form of peribronchiolar lymphoid aggregates. Granulomatous inflammation accompanies lymphoid hyperplasia in LIP in nearly half of cases. Foci of organizing pneumonia are common in NSIP, but comprise only a minor component of the process that is overshadowed by the interstitial changes. BOOP, in contrast, is characterized by patchy zones of intralumenal fibrosis separated by areas of normal lung. Alveolar septa in areas of intralumenal fibrosis are frequently expanded by a mild inflammatory infiltrate, but interstitial pneumonia is absent in areas of unaffected lung. Nonetheless the distinction is somewhat arbitrary and there are undoubtedly cases diagnosed as NSIP that represent poorly sampled cases of BOOP.

Distinguishing fibrotic NSIP from UIP is complicated because areas indistinguishable from NSIP commonly occur in what are otherwise typical cases of UIP (5). In patients with either UIP or NSIP from whom more than one site is biopsied, about one in four will show "discordant" results, meaning that one piece of tissue is diagnostic of UIP whereas another shows NSIP (47, 49). The presence of UIP in any piece of tissue is the single most important predictor of outcome in this circumstance, attesting to the specificity of UIP as a clinicopathologic entity. Histopathologic features that are most helpful in distinguishing UIP include (1) a patchwork pattern of lung involvement characterized by abrupt transitions from one area of abnormality to the next, (2) architectural distortion in the form of honeycomb change and/or interstitial scarring, and (3) fibroblast foci (5). None of these features taken on its own is diagnostic, but if taken together and correlated with findings in high-resolution computed tomography scans, a specific diagnosis is possible in most cases.

FOOTNOTES

Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form February 14, 2006; accepted in final form March 6, 2006)

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