Clin Chest Med 27 (2006) S1 S10

Pulmonary Pathology for the Clinician

Kevin O. Leslie, MD
Department of Laboratory Medicine and Pathology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA

The idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of diffuse parenchymal lung diseases characterized by lung parenchymal damage with varying patterns of inflammation and fibrosis [1]. Their causes are unknown by definition. The interstitium (the space between the epithelial and endothelial basement membranes) is the primary site of damage, but these disorders also frequently affect the airspaces, peripheral airways, vessels, and corresponding epithelial and endothelial surfaces. As a group, the IIPs can be distinguished from other diffuse parenchymal lung diseases (such as systemic collagen vascular diseases with pulmonary manifestations, asbestosis, hypersensitivity, and sarcoidosis) on the basis of medical history, physical examination, and radiologic and pathologic findings. The IIPs differ sufficiently from one another that they can be considered separate disease entities. Because prognosis and management differ according to the specific IIP, it is critical that patients who have these disorders are diagnosed correctly. The surgical lung biopsy is required for many of these conditions. Unfortunately the esoteric nature of medical lung pathology makes interpretation of these specimens an extreme challenge for the general diagnostic pathologist (analogous to medical renal biopsies). A simple pattern-based approach facilitates cooperative interaction between pathologist and pulmonologist and helps ensure the accurate interpretation of the lung

biopsy together with the appropriate clinical and radiologic setting.

Historical perspective on idiopathic interstitial pneumonia classification We knew little about diffuse parenchymal lung diseases before the advent of the surgical (wedge) biopsy technique. This procedure initially was performed through an open thoracotomy incision, but has been refined in the past 10 years with advances in the use of the thoracoscopic approach. By the 1960s the increasing availability of lung biopsy specimens made it possible to distinguish interstitial pneumonias on the basis of histopathologic criteria. In 1969 Liebow published a classification scheme for cases of diffuse interstitial pneumonias unrelated to infection or malignancy, and described them as idiopathic because of their unknown cause [2]. He divided these disorders into five categories based on specific histopathologic features: usual interstitial pneumonia (UIP), bronchiolitis obliterans with interstitial pneumonia (BIP), desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia (LIP), and giant cell interstitial pneumonia (GIP). A European classification scheme also was described at approximately the same time [3]. Liebow noted that UIP was the most common type of diffuse lung fibrosis in older individuals [2]. Usual interstitial pneumonia was distinctive in that fibrosis started at the periphery of lobules and tended to spare the centrilobular regions. Each lobule was affected to a different degree; some were replaced entirely by honeycomb fibrosis, whereas others showed

Dr. Leslie has no conflict of interest to declare. E-mail address: leslie.kevin@mayo.edu

0272-5231/06/$ see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.08.002

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less advanced fibrosis with crescent-shaped fibroblastic foci existing at the interface edge between fibrotic lung and adjacent normal alveolar tissue. The same disorder was described in the European classification, but it was referred to as cryptogenic fibrosing alveolitis. This term recognized its unknown etiology and reflected the view that UIP was caused by progressive active fibrosis with some inflammatory disease at the level of the alveolus. BIP was described as a disease characterized by mild chronic interstitial inflammation and variably prominent aggregates of immature fibroblasts occupying the alveolar spaces [2]. This disorder was termed cryptogenic organizing pneumonia (COP) in the European classification because it showed a histologic appearance consistent with organizing pneumonia as seen with streptococcal infection [3] and many other forms of lung injury, but in these cases the cause was not identifiable. The other three histopathologic patterns in the Liebow classification were based on cell types found in the alveolar spaces or wall [2]. DIP was characterized by the presence of pink cells in the alveolar spaces, which Liebow initially believed were epithelial cells; hence, he used the term desquamation. The cells later were found by electron microscopy to be macrophages containing a fine brown pigment [4,5] related to inhaled cigarette smoke. The presence of this pigment material helped solidify the hypothesis that DIP might be an interstitial lung disease related to smoking. LIP was characterized by prominent accrual of lymphoid cells in the alveolar walls, with general sparing of the alveolar spaces. Finally, GIP was seen as a diffuse disease characterized by accumulation of peculiar cannibalistic multinucleated giant cells in the peribronchiolar region associated with centrilobular fibrosis and mild inflammation. These three IIPs were not recognized in the European classification. The Liebow classification evolved over the next decade. GIP and LIP were attributed to specific causation; DIP and BIP were modified or renamed. GIP was attributed to cobalt pneumoconiosis related to cobalt inhalation occurring as a consequence of industrial use of tungsten carbide machine tool work [6], whereas many of the original cases of LIP were shown to be mucosa-associated lymphoid tissue (MALT) lymphoma, a low-grade form of non-Hodgkin lymphoma [7]. DIP now is included in the most recent classification as a smoking-related IIP, together with a newly described entity, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) [8]. Finally, in the 1980s, BIP was renamed idiopathic bronchiolitis obliterans organizing pneumonia (iBOOP) [9].

Current American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias The lack of an international standard for classifying the IIPs resulted in confusing diagnostic criteria and terminology. In 2002 the American Thoracic Society (ATS) and European Respiratory Society (ERS) published a consensus classification system that combines histologic patterns with clinical and radiologic findings [1]. The ATS/ERS classification identifies seven distinct clinicopathologic entities in order of relative frequency: idiopathic pulmonary fibrosis (IPF; characterized by UIP pathology), nonspecific interstitial pneumonia (NSIP), COP (characterized by organizing pneumonia pathology), acute interstitial pneumonia (AIP; characterized by diffuse alveolar damage pathology), RB-ILD and DIP, characterized by smokers-type macrophage accumulation in the alveolar spaces, and LIP (characterized by lymphoplasmacytic infiltration of alveolar walls) (Table 1) [1]. Although it carries the same name, the latter
Table 1 American Thoracic Society/European Respiratory Society classification of the idiopathic interstitial pneumonias (in order of relative frequency) Histologic pattern Usual interstitial pneumonia (UIP) Nonspecific interstitial pneumonia (NSIP) Organizing pneumonia pattern Diffuse alveolar damage (DAD) Respiratory bronchiolitis with localized DIP-reaction Desquamative interstitial pneumonia-like reaction (DIP) Lymphoid interstitial pneumonia pattern (LIP) Clinico-radiologicpathologic diagnosis Interstitial pulmonary fibrosis (IPF) Nonspecific interstitial pneumonia (provisional)a Cryptogenic organizing pneumonia (COP)b Acute interstitial pneumonia (AIP) Respiratory bronchiolitisassociated interstitial lung disease (RB-ILD) Desquamative interstitial pneumonia (DIP) Lymphoid interstitial disease (LIP)

a NSIP should be considered a provisional diagnosis until there is further clarity on the corresponding clinical condition. b COP is the preferred term; it is synonymous with idiopathic bronchiolitis obliterans organizing pneumonia (iBOOP). Modified from Travis WD, King Jr TE, Bateman ED, et al. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002;165:55; with permission.

pulmonary pathology for the clinician Table 2 Comparison of histologic features of idiopathic interstitial pneumonias Feature Temporal appearance Interstitial inflammation Interstitial fibrosis (collagen) Interstitial fibrosis (fibroblasts) Organizing pneumonia pattern Fibroblastic foci Honeycomb areas Intra-alveolar macrophages Hyaline membranes Granulomas UIP Variegated Scant Patchy No No Yes Yes Occasional, focal No No NSIP Uniform Prominent Variable, diffuse Occasional, diffuse Occasional, focal Occasional, focal Rare Occasional, patchy No No COP Uniform Scant No No Prominent No No No No No AIP Uniform Scant No Yes, diffuse Occasional, focal No No No Yes, focal No DIP Uniform Scant Variable, diffuse No No No No Yes, diffuse No No LIP Uniform Prominent Occasional No No No

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Sometimes Occasional, patchy No Poorly formed, focal

Modified from Leslie KO. Pathology of interstitial lung disease. Clin Chest Med 2004;25:659; with permission.

entity differs from the original description by Liebow and requires the rigorous exclusion of lymphoma by special techniques. Accordingly, only IPF/UIP and COP (initially termed BIP) remain intact from the original Liebow classification. The clinicopathologic diseases can be grouped according to their presentation as acute, subacute, or chronic. They range across a spectrum from the rapidly progressive AIP (likely analogous to the acute disorder first described by Hamman and Rich) to the chronic, smoldering IPF/UIP, which follows a progressive course over many years. The other entities follow a subacute course ranging from weeks to months, and although characterized by ground-glass infiltrates on radiographic evaluation, they typically require histologic evaluation for further differentiation. The clinical differentiation of IPF/UIP from NSIPthe two most common IIPsis most important because of differences in prognosis and management. The various clinicopathologic entities sometimes can be distinguished on the basis of their clinical or radiographic features, but their definitive diagnosis requires histologic evaluation of a surgical lung biopsy specimen (Table 2) [10].

because interstitial lung diseases often elaborate different architectural patterns (Fig. 1) [10]. Several helpful patterns may aid in the diagnosis of the IIPs and all other lung diseases. Pattern 1 is acute lung injury (Fig. 2). Diffuse alveolar damage (DAD) with hyaline membranes is the prototype of this pattern, which classically is found in patients who have adult respiratory distress syndrome. Other causes of DAD include bacterial, viral, or fungal infection, inhaled or ingested toxins, drugs, shock, trauma, radiation, and acute pancreatitis. When the etiology is undiscovered despite extensive efforts, this pattern is referred to as AIP. Pattern 2 is fibrosis (Fig. 3). This pattern is characterized by the accrual of collagen in the lung with permanent structural remodeling. The prototype for this pattern is IPF/UIP, and it is the diagnosis of greatest clinical concern in older adults because of its poor prognosis. Other diseases with fibrosis and honeycombing include collagen vascular disease, asbestosis and other pneumoconioses, sarcoidosis, pulmonary Langerhans cell histiocytosis, chronic granulomatous infections, and chronic drug reactions. Other IIPs also may present with variable degrees of fibrosis, including NSIP, DIP, and LIP. Pattern 3 is cellular interstitial infiltrates (Fig. 4). This pattern is characterized by the presence of lymphocytes, plasma cells, and

The six patterns of pulmonary pathology Initial examination of a surgical lung biopsy specimen under low-power magnification is useful (if not essential) for narrowing the differential diagnosis,

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macrophages in the alveolar walls. Hypersensitivity pneumonitis is the prototype for this pattern. Cellular infiltrates also are found in the cellular pattern of NSIP, collagen vascular diseases with pulmonary manifestations, certain toxic or hypersensitivity drug reactions (eg, methotrexate, amiodarone), LIP associated with HIV infection, lymphoproliferative diseases, and idiopathic LIP. Pattern 4 is airspace filling (Fig. 5). This pattern is characterized by the presence of cells or other material filling the alveolar spaces. Organizing pneumonia is the prototype. Important clues about diagnosis may be provided by the cells or material occupying the alveolar spaces. Neutrophils in the alveoli may be suggestive of infectious bronchopneumonias; foamy casts may be suggestive of Pneumocystis infection in immunocompromised individuals; proteinaceous material may be suggestive of pulmonary alveolar proteinosis; and light brown-pigmented macrophages may be suggestive of DIP. Pattern 5 is nodules (Fig. 6). This pattern is characterized by the presence of discrete nodules in the lung parenchyma. When this pattern is observed, the differential diagnosis should include nodular infections, aspiration pneumonia, neoplasms, sarcoidosis, silicosis, pulmonary Langerhans cell histiocytosis, and various bronchiolocentric diseases. Wegener granulomatosis is the prototype of a large nodular pattern, whereas various miliary infections cause a small nodular pattern. Pattern 6 is near-normal lung (Fig. 7). Abnormalities may be barely discernible on low magnification. This pattern often results from diseases affecting the airways and pulmonary vessels. Small airway disease is the prototype, in which pruning, dilation, and generalized scarring may be subtle at low magnification. The differential diagnosis for this pattern includes vascular and cystic diseases.

pneumonitis. When fibrosis is found with pleuritis, it is suggestive of collagen vascular disease and is typically more uniform in distribution (NSIP-like) than that seen in UIP. Finally, when fibrosis is diffusely distributed, it suggests collagen vascular disease, drug toxicity, sarcoidosis (if found with granulomas), pulmonary Langerhans cell histiocytosis (if found with stellate scars), pneumoconiosis, or fibrosing NSIP. A more extensive discussion of the patternbased approach has been published recently [10].

Pattern 1: acute lung injury Diffuse alveolar damage (acute interstitial pneumonia) AIP is associated with a histologic pattern of DAD (Fig. 8) [1,11]. The histopathologic features are distributed diffusely and usually have a uniform temporal appearance. Hyaline membranes are a hallmark and are helpful for distinguishing DAD from other acute histopathologic patterns. Edema and interstitial acute inflammation also are seen early on. As the disease progresses and enters the organizing phase (approximately 5 10 days after injury), however, hyaline membranes may no longer be conspicuous. At this stage, alveolar septal thickening with loose organizing fibrosis, reactive type II pneumocyte hyperplasia, and patchy or diffuse airspace organization all can be found to varying degrees. Smaller pulmonary arterioles commonly contain fibrin thrombi, likely a result of local acute injury factors.

Pattern 2: fibrosis Usual interstitial pneumonia (idiopathic pulmonary fibrosis) IPF is associated with a histological pattern of UIP (Fig. 9) [1,12]. The key features include dense peripherally accentuated fibrosis, architectural destruction with honeycombing, scattered fibroblastic foci at the interface between older fibrosis and adjacent normal lung, and peculiar smooth muscle hyperplasia within peripheral lobular fibrosis. These abnormalities are typically worse in the lower lobes. Over time the fibrosis extends inward from the peripheral aspects of the lobule toward the center until the alveolar walls are destroyed and replaced by dense fibrosis. Interstitial inflammation is usually mild or moderate, consisting of a patchy alveolar septal infiltrate of lymphocytes, plasma cells, and

Primary pattern, additional features, and combinations of patterns After the dominant pattern is determined, further microscopic evaluation helps to narrow the diagnostic possibilities (see Fig. 1) [10]. For example, when fibrosis (pattern 2) is variable, ranging from normal lung to honeycombing, it suggests IPF/UIP, asbestosis, rheumatoid arthritis, or chronic hypersensitivity

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Low magnification visualization of surgical lung biopsy slides

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Pattern 1 Acute lung injury

Pattern 2 Fibrosis

Pattern 3 Cellular interstitial infiltrates

With lymphocytes and plasma cells Cellular NSIP CVD HSP Drug toxicity Infection Lymphoma

Pattern 4 Airspace filling

Pattern 5 Nodules

Pattern 6 Near-normal lung

With hyaline membrances Infection CVD Drug toxicity Idiopathic (AIP)

With variable fibrosis (normal to HC) UIP/IPF Asbestosis RA Chronic HSP

With macrophages Smoking-related Local fibrosis

With lymphoid Follicuar bronchiolitis Wegeners Lymphoma

With SAD Constrictive bronchiolitis

With neutrophils Infection DPH With OP Infection Drug toxicity CVD With eosinophilc material Infection CVD Drug toxicity DPH CHF PAP With hemorrhage CVD DPH

With eosinophils AEP Drug toxicity DAD (smoker)

With HC only Late UIP if diffuse Many causes if focal With diffuse fibrosis CVD Drug toxicity Sarcoidosis (w/granuloma) PLCH (with stellate scars) Fibrosing NSIP With pleuritis CVD

With neutrophils Infection CVD Hemorrhage With granulomas Infection HSP Sarcoidosis Berylliosis Aspiration With focal OP Infection CVD With pleuritis CVD

With necrosis Infection Tumor Wegeners With atypical cells Infection Lymphoma Sarcoma With stellate scars PLCH With OP Infection CVD Drug toxicity Wegeners Infarct

With vascular pathology PHT VOD

With cysts PLCH LAM

With necrosis Infection (viral, bacterial, fungal)

With siderophages DPH CVD

Fig. 1. Pattern-based approach to distinguishing IIPs from other interstitial lung diseases. AEP, acute eosinophilic pneumonia; CHF, congestive heart failure; CVD, collagen vascular disease; DPH, diffuse pulmonary hemorrhage; HC, honeycomb; HSP, hypersensitivity pneumonitis; LAM, lymphangiomleiomyomatosis; OP, organizing pneumonia; PAP, pulmonary alveolar proteinosis; PHT, pulmonary hypertension; PLCH, pulmonary Langerhans cell histiocytosis; RA, rheumatoid arthritis; SAD, small airways disease; VOD, veno-occlusive disease. (Adapted from Leslie KO. Pathology of interstitial lung disease. Clin Chest Med 2004;25:661; with permission.)

histiocytes associated with hyperplasia of type II pneumocytes. Smooth muscle hyperplasia often is found in areas of fibrosis and honeycomb change. At low magnification, the UIP pattern has a heterogeneous appearance with alternating areas of normal parenchyma, fibrosis, and honeycomb cysts. A diagnosis of UIP requires areas of normal lung tissue. Usual interstitial pneumonia is the default histologic diagnosis. This pattern is the most predictive of outcome, even if specimens obtained from a second or third lobe/site suggest another histologic pattern.

Pattern 3: cellular infiltrates Nonspecific interstitial pneumonia

Fig. 2. Pattern 1, acute lung injury. Diffuse alveolar damage is the prototype, illustrated here with easily visible pink hyaline membranes lining alveolar spaces.

The histologic NSIP pattern consists of a spectrum of features with varying amounts of interstitial in-

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Fig. 3. Pattern 2, fibrosis. Dense fibrosis with architectural remodeling is the common feature of pattern 2. The distribution of fibrosis and the presence or absence of other qualitative features help separate different etiologies for fibrosis. This illustration highlights the wide areas of fibrosis that are typical of this pattern, but based on this image alone, this could be one of many causes of lung fibrosis, especially given the presence of chronic inflammation throughout the fibrosis here.

Fig. 5. Pattern 4, alveolar filling. The alveoli are filled with cells or other material. A case of alveolar [lipo]proteinosis is illustrated here with typical granular pink exudate filling alveolar spaces.

flammation and fibrosis [13]. At one end of the spectrum, the cellular pattern of NSIP consists of mild to moderate interstitial chronic inflammation (Fig. 10). The distribution of disease may be patchy, but the lung biopsy typically is uniformly involved and interstitial fibrosis is typically absent. Although intra-alveolar organizing fibrosis may be seen, it is considerably less diffuse than that seen in the organizing pneumonia pattern associated with COP.

At the other end of the spectrum, the fibrotic pattern of NSIP consists of varying degrees of dense or loose fibrosis (Fig. 11); however, unlike UIP, fibrosing NSIP lacks temporal heterogeneity and honeycomb remodeling. The fibroblastic foci seen in UIP are inconspicuous or absent in NSIP [1]. The lack of these features is important for distinguishing fibrosing NSIP from UIP in cases that may show more patchy involvement or areas of more subpleural or paraseptal distribution. In some cases of NSIP, a combination of cellular and fibrotic forms may be identified (Fig. 12).

Fig. 4. Pattern 3, cellular infiltrates. Increased cells are present in the alveolar walls, typically chronic inflammatory cells, as illustrated here in a case of hypersensitivity pneumonitis.

Fig. 6. Pattern 5, nodules. Large or small nodules in the biopsy (or on CT scan, if the entire biopsy is involved by one nodule) characterize pattern 5. Nodules invoke a differential to include infection, sarcoidosis (illustrated here), neoplasm, Langerhans cell histiocytosis, and Wegener granulomatosis.

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Fig. 7. Pattern 6, near normal lung. This pattern is characterized by a relative absence of findings at scanning magnification. A case of constrictive bronchiolitis is illustrated here. Note the absence of visible bronchioles in the low magnification view.

Fig. 9. Usual interstitial pneumonia (UIP). The case illustrated is UIP in the context of clinical idiopathic pulmonary fibrosis. Note the peripheral distribution of fibrosis and sparing of centrilobular regions.

Lymphoid interstitial pneumonia LIP is characterized by the presence of a dense interstitial inflammatory infiltrate containing lymphocytes, plasma cells, and histiocytes associated with type II cell hyperplasia (Fig. 13) [1]. The infiltrate shows a predominantly alveolar septal distribution. Lymphoid follicles, including those containing germinal centers, usually are distributed along the bronchioles and interlobular septa, generally following the pulmonary lymphatic system. Architectural derangement is often present and includes cysts and focal

honeycomb remodeling. Occasional non-necrotizing granulomas may be found and variable accumulation of macrophages also may be seen.

Pattern 4: alveolar filling Organizing pneumonia (cryptogenic organizing pneumonia) Cryptogenic organizing pneumonia is associated with a histologic pattern of organizing pneumonia

Fig. 8. Acute interstitial pneumonia (AIP). The pathology of AIP is diffuse alveolar damage. Pathologists cannot distinguish the DAD of AIP from the myriad of other causes of this pattern unless obvious infection is present.

Fig. 10. Nonspecific interstitial pneumonia (NSIP), cellular. The initial description of NSIP included three morphologic types: a cellular form, a fibrotic form, and a mixed form of cellular and fibrotic type. Here is an example of the pure cellular form of NSIP with lymphocytes and plasma cells in the alveolar walls.

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Fig. 11. Nonspecific interstitial pneumonia (NSIP), fibrotic. Here is an example of the fibrotic form of NSIP with diffuse alveolar septal fibrosis and pleuritis in this case.

(Fig. 14) [1]. Key features include alveolar spaces variably filled by organizing fibrosis that also may involve bronchioles and alveolar ducts. A patchy distribution and uniform temporal appearance (lesions all seem to be at the same stage of evolution) are expected [9,14]. The background lung architecture is preserved, and mild interstitial chronic inflammation is present. The idiopathic form of the organizing pneumonia pattern typically lacks evidence of interstitial fibrosis (except for incidental scars or apical fibrosis), granulomas, neutrophils, abscesses, necrosis, or vasculitis. Airspace fibrin and eosinophils may be present focally but are not prominent. Hyaline membranes are typically absent.

Fig. 13. Lymphoid interstitial pneumonia (LIP). The initial description of LIP included many examples of low-grade lymphoma in the lung. Current definition of LIP requires rigorous exclusion of lymphoma before this diagnosis is rendered. Here is an example of LIP occurring in a patient who has Sjogren syndrome. Note the intense lymphoid infiltrate and distortion of the background lung.

Respiratory bronchiolitis-associated interstitial lung disease Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) is defined by a histologic pattern of respiratory bronchiolitis and smokers macrophage accumulation in peribronchiolar alveoli [1] at

Fig. 12. Nonspecific interstitial pneumonia, mixed cellular and fibrotic. Here is an example of the mixed cellular and fibrotic form of NSIP with fibrosis and scant lymphocytes and plasma cells in the alveolar walls.

Fig. 14. Cryptogenic organizing pneumonia (COP, also known previously as idiopathic BOOP). When organizing pneumonia is identified in the lung biopsy and no etiology is identified clinically or by laboratory studies, the process is considered idiopathic or cryptogenic. The HRCT scan can be helpful, as is a typical clinical presentation.

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and fibrotic changes are temporally uniform without advanced fibrosis, fibroblastic foci, or microscopic honeycomb change.

Checks and balances: the importance of communication between members of the multidisciplinary team The diagnosis of IIP requires a multidisciplinary approach, comprising an integration of clinical, radiologic, and pathologic evaluation [1]. Close communication among members of the team is mandatory. A pulmonary pathologist with information about medical history, clinical presentation, radiographic findings, smoking status, and comorbid conditions is able to interpret more accurately a surgical lung biopsy, and thereby can offer added value to the diagnostic process. Once a histologic pattern is identified, the physician may need to re-evaluate the patient to determine if clinical or laboratory findings can account for a specific diagnosis. After other possible diagnoses have been reasonably excluded, the diagnosis of IIP may be considered. All physicians on the multidisciplinary team (pulmonologists, primary care physicians, radiologists, and pathologists) must share their expertise and knowledge to diagnose accurately these disorders, for once an accurate diagnosis is made, important prognostic information becomes available and patient management can be optimized.

Fig. 15. Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD). This smoking-related interstitial lung disease may coexist with pulmonary Langerhans cell histiocytosis, another smoking-related ILD. Whether RB-ILD and DIP exist along a continuum of severity is a matter of unproven speculation, especially because these two conditions typically have different HRCT appearance. The characteristic findings are prominent respiratory bronchiolitis and variable airway-centered alveolar macrophage reaction.

low magnification, producing a patchy and bronchiolocentric distribution (Fig. 15). The macrophages contain a fine golden brown pigment with interspersed punctate black dots. A patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes is typically present [8,15] and mild peribronchiolar fibrosis may lead to expansion of adjacent alveolar septa.

Desquamative interstitial pneumonia The DIP histologic pattern affects the lung in a uniform and diffuse manner, unlike the bronchiolocentric distribution found in RB-ILD [1,15]. DIP is characterized by the presence of macrophages filling the most distal airspaces (Fig. 16). These macrophages, like those in RB-ILD, frequently contain a brown pigment with black punctation. A sparse inflammatory infiltrate (plasma cella, lymphocytes, and rare eosinophils) and minimal interstitial fibrosis leads to alveolar septal thickening. The septa are lined by plump cuboidal pneumocytes. Lymphoid aggregates may be found. Because many patients who have other IIPs also have a smoking history, the DIP pattern frequently overlies other histologic patterns [1]. DIP differs from UIP in that the interstitial changes in DIP are distributed more diffusely

Fig. 16. Desquamative intersitial pneumonia (DIP). This smoking-related interstitial lung disease is characterized by diffuse alveolar filling with macrophages, typically of the smokers type. Slight interstitial fibrosis is common in DIP.

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leslie [8] Myers JL, Veal Jr CF, Shin MS, et al. Respiratory bronchiolitis causing interstitial lung disease. A clinicopathologic study of six cases. Am Rev Respir Dis 1987;135:880 4. [9] Epler GR, Colby TV, McLoud TC, et al. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312:152 8. [10] Leslie KO. Pathology of interstitial lung disease. Clin Chest Med 2004;25:657 703. [11] Katzenstein AL, Myers JL, Mazur MT. Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol 1986;10: 256 67. [12] King Jr TE, Costabel U, Cordieer J-F, et al. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 2000;161:646 64. [13] Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol 1994;18:136 47. [14] Colby TV. Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 1992;102(1 Suppl): S38 43. [15] Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 1989;64:1373 80.

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[1] Travis WD, King Jr TE, Bateman ED, et al. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002;165:277 304. [2] Liebow AA, Carrington CB. The interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, editors. Frontiers of pulmonary radiology. New York7 Grune & Stratton; 1969. p. 102 41. [3] Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: clinical features and their influence on survival. Thorax 1980;35:171 80. [4] Liebow AA, Steer A, Billingsley JG. Desquamative interstitial pneumonia. Am J Med 1965;39:369 404. [5] Tubbs RR, Benjamin SP, Reich NE, et al. Desquamative interstitial pneumonitis. Cellular phase of fibrosing alveolitis. Chest 1977;72:159 65. [6] Ohori NP, Sciurba FC, Owens GR, et al. Giant-cell interstitial pneumonia and hard-metal pneumoconiosis. A clinicopathologic study of four cases and review of the literature. Am J Surg Pathol 1989;13:581 7. [7] 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 5.