Interpretation of lung biopsy results in interstitial lung disease

INTRODUCTION — The diffuse parenchymal lung diseases, often collectively referred to as the interstitial lung diseases (ILDs), are a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations (algorithm 1). When the results of clinical evaluation, laboratory testing, imaging studies including high-resolution computed tomography (HRCT), and pulmonary function testing do not allow the clinician to make a confident diagnosis of a given type or stage of ILD, lung biopsy with careful examination of lung tissue is often necessary (algorithm 2).

The clinicopathologic interpretation of lung biopsy results in adults with ILD will be reviewed here. The clinical evaluation, diagnostic testing, radiographic patterns, role of bronchoalveolar lavage, and role of lung biopsy in ILD are discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "High resolution computed tomography of the lungs" and "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Role of lung biopsy in the diagnosis of interstitial lung disease".)

MULTIDISCIPLINARY DISCUSSION — Most cases of ILD require careful clinical, radiologic, and pathological correlation, preferably in the setting of a multidisciplinary discussion, to arrive at the most accurate final diagnosis [1-6]. Histologic abnormalities alone are rarely specific in ILD. More often, the findings are "characteristic" or "consistent with" a specific diagnosis. "Nonspecific" reaction patterns are common to several diseases that cause inflammation and/or fibrosis in the lungs [7]. Small tissue samples and substantial inter-observer variability among pathologists further complicate interpretation [8-10].

With a multidisciplinary approach, surgical lung biopsy produces a definitive diagnosis in more than 90 percent of cases of ILD occurring in immunocompetent hosts [1,11,12]. The role for sequential transbronchial lung cryobiopsy remains ill-defined [13-16].

Data provided to the pathologist by the clinician at the time of biopsy should include:

●The age and sex of the patient

●Duration of respiratory illness

●Immunocompetence of the patient

●Smoking history

●History of exposures to occupational or environmental agents (eg, asbestos, beryllium, silica, birds, diisocyanates, humidifier)

●Evidence for or against underlying connective tissue disease

●Radiographic findings including character, distribution, and time course of abnormalities

●Suspected clinical diagnosis, which will often lead to a more targeted search by the pathologist

●Detailed history of drug use (prescribed or illicit)

Virtually all histopathologic patterns of lung injury have been described in association with one or more drugs, including usual interstitial pneumonia, nonspecific interstitial pneumonia, desquamative interstitial pneumonia, eosinophilic pneumonia, hypersensitivity pneumonia, organizing pneumonia, diffuse alveolar damage, alveolar hemorrhage, and rarely, non-necrotizing granulomatosis, pulmonary veno-occlusive disease, and alveolar proteinosis. Thus, drug-induced lung toxicity is in the differential diagnosis of all of the following histopathologic patterns.

INTERPRETATION OF HISTOPATHOLOGIC PATTERNS — Histopathologic patterns of diffuse parenchymal lung disease can be broadly divided into interstitial pneumonias, granulomatous lung diseases, and other disorders (algorithm 1). Histopathologic patterns may be seen in combination and the pathologist should ascertain the predominant pattern, but also describe all that are present [17].

Interstitial pneumonias — The interstitial pneumonias, a distinct subentity of interstitial lung disease (ILD), are classified according to seven histologic patterns: usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis (RB), organizing pneumonia (OP), lymphoid interstitial pneumonia (LIP), and diffuse alveolar damage (DAD) (algorithm 1) [18]. The histologic patterns that characterize the idiopathic interstitial pneumonias are also associated with other disease processes that need to be considered in the differential diagnosis. (See "Idiopathic interstitial pneumonias: Classification and pathology".)

Usual interstitial pneumonia — The histopathologic pattern of UIP is characterized by established fibrosis (collagen deposition) and loss of alveolar architecture with a patchy subpleural and paraseptal distribution; honeycombing may or may not be present. Fibroblastic foci (also known as fibrotic foci) are localized clusters of fibroblasts and myofibroblasts that lie in continuity with the established fibrosis and are a characteristic histologic feature of UIP (picture 1). These abnormalities are typically associated with a mild chronic inflammatory cell infiltrate. In addition to the presence of fibroblastic foci, a chief diagnostic criterion is temporal heterogeneity, such that areas of normal lung, interstitial inflammation, fibrosis, and honeycomb change are interspersed. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia'.)

The histologic pattern of UIP is most commonly associated with the type of idiopathic interstitial pneumonia called idiopathic pulmonary fibrosis (IPF, previously described as cryptogenic fibrosing alveolitis) [19]. However, UIP is also seen in diseases other than IPF, such as hypersensitivity pneumonitis, rheumatoid arthritis, scleroderma, and asbestosis. In these instances, there are often features that make a definite diagnosis of the UIP pattern less likely, such as the absence of fibroblastic foci or the presence of isolated giant cells, ill-formed granuloma, lymphoid follicles, or asbestos bodies. The histopathology should always be correlated with clinical (eg, asbestos or organic dust exposure, Raynaud’s phenomenon, dry eyes/mouth, joint pain/stiffness, skin changes) and radiographic (eg, calcified pleural plaques) findings to ensure that the rare situation in which UIP is associated with a disease other than IPF is not missed [20]. Potential causes (or associations) of UIP are shown in the table (table 1).

Nonspecific interstitial pneumonia — The main histologic feature of NSIP is diffuse and homogeneous interstitial and chronic inflammation, characterized by varying degrees of mononuclear cell inflammation with or without fibrosis. Some cases have a primarily chronic inflammatory/cellular pattern ("cellular NSIP") (picture 2), but most cases have a fibrotic pattern ("fibrotic NSIP") (picture 3) [21]. (See "Treatment and prognosis of nonspecific interstitial pneumonia" and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Nonspecific interstitial pneumonia'.)

While NSIP may have significant fibrosis, the overall histopathologic pattern is usually diffuse and has a pathologically uniform age. Fibroblastic foci and honeycombing, if present, are rare. These features are essential in distinguishing NSIP from UIP. Nonetheless, fibrotic NSIP can be difficult to reliably distinguish from UIP and there is significant inter-observer variability even among expert histopathologists [8,10].

NSIP can be idiopathic or associated with a number of medical conditions, such as healing viral pneumonias, connective tissue disease, HIV infection, hypersensitivity pneumonitis, and drug-induced toxicity (table 2). A large number of drugs have been associated with the NSIP pattern (eg, nitrofurantoin, methotrexate, amiodarone, chlorambucil, carmustine), so a careful review of drug use is essential. (See "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia", section on 'Definition'.)

Desquamative interstitial pneumonia — DIP is characterized by diffuse filling of alveoli with macrophages that have glassy eosinophilic cytoplasm and fine granular brown pigmentation (smoker’s macrophages). Other features that may be seen are mild interstitial chronic inflammation, type 2 cell hyperplasia, lymphoid follicles, and mild eosinophilic infiltration. Fibrosis may be present, but is generally mild [22].

DIP was originally thought to be a precursor of UIP. However, it now seems more likely that these are separate disease entities. The major cause of DIP is exposure to cigarette smoke. Other potential causes (or associations) of DIP are listed in the table (table 3). (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Desquamative interstitial pneumonia'.)

Respiratory bronchiolitis — Respiratory bronchiolitis (RB) is characterized by a mononuclear inflammatory process involving the submucosa of the membranous and respiratory bronchioles; these changes may be associated with mild fibrosis that extends into the surrounding alveolar walls [23]. An accumulation of alveolar macrophages with fine, granular, tan or golden pigmentation (smoker’s macrophages) in the alveoli and small airways is typical [23-25]. The airway epithelium is abnormal, with goblet cell hyperplasia and metaplastic cuboidal epithelium, which often extends into the nearby alveolar septa and ducts [23]. (See "Respiratory bronchiolitis-associated interstitial lung disease" and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Respiratory bronchiolitis-associated ILD'.)

In the appropriate clinical setting (ie, clinical evidence of interstitial lung disease), the histologic pattern of RB indicates respiratory bronchiolitis-associated interstitial lung disease (RB-ILD). Other conditions that are associated with inflammation in the respiratory bronchioles are listed in the table (table 4). Like DIP, exposure to cigarette smoke is the most common association.

Organizing pneumonia — OP is the histologic pattern associated with cryptogenic organizing pneumonia (COP, previously called bronchiolitis obliterans organizing pneumonia or BOOP). (See "Cryptogenic organizing pneumonia".)

The distribution of OP is often patchy and peribronchiolar, reflecting the patchy pattern seen on high-resolution computed tomography (HRCT). However, the histopathologic appearance is relatively uniform within involved areas (picture 4). Numerous buds of granulation tissue (loose accumulations of collagen-embedding fibroblasts and myofibroblasts) are present within alveoli, often involving alveolar ducts and small airways. When the granulation tissue is primarily within the airways, this type of inflammation is sometimes called proliferative bronchiolitis. Foamy macrophages are commonly seen in the alveoli, presumably secondary to bronchiolar occlusion. Mild chronic inflammation (lymphocytes and plasma cells) may be present; eosinophils and neutrophils are usually few in number, and severe fibrotic changes are unusual. (See "Overview of bronchiolar disorders in adults", section on 'Proliferative bronchiolitis'.)

OP occurs more often as a nonspecific reaction to lung injury or to another disease process than as the idiopathic process, COP. Common associations with OP are listed in the table (table 5). In addition, OP can be seen in combination with the cellular interstitial changes of NSIP in cases of drug-toxicity (eg, methotrexate) and connective tissue disease (eg, rheumatoid arthritis) and as a minor feature in UIP. (See 'Nonspecific interstitial pneumonia' above and 'Usual interstitial pneumonia' above.)

Lymphoid interstitial pneumonia — In LIP, there is a dense diffuse interstitial infiltrate of lymphocytes, plasma cells, and histiocytes; germinal centers and multinucleated giant cells may be present (table 6). The lymphocytes are a polyclonal mixture of T and B cells. (See "Lymphoid interstitial pneumonia", section on 'Pathologic findings'.)

LIP was previously considered to be pre-neoplastic; however, it is now believed to be a reactive pulmonary lymphoid hyperplasia, similar to that seen in collagen vascular diseases or immunosuppression [26,27]. Potential causes (or associations) of LIP are listed in the table (table 7). The appearance of hypersensitivity pneumonitis is similar, but hypersensitivity pneumonitis (HP) is more patchy and is associated with exposure to characteristic agents. (See "Lymphoid interstitial pneumonia" and 'Granulomatous lung diseases' below.)

Diffuse alveolar damage — DAD is a nonspecific reaction to lung injury. The characteristic histopathologic features of DAD depend on when in the course of lung injury the biopsy is taken. During the exudative (acute) phase, there is interstitial edema, acute and chronic inflammation, type II cell hyperplasia, and hyaline membrane formation. Thrombi within small arteries are also common. During the organizing (healing) phase, the features are more similar to those of OP (picture 5 and picture 6 and picture 7 and picture 8) [28-30]. (See 'Organizing pneumonia' above.)

The histopathologic pattern of DAD is most common in patients with acute respiratory distress syndrome (ARDS), but is also seen in the other types of lung injury listed in the table (table 8). When DAD is idiopathic, it is called acute interstitial pneumonia (AIP), which can occur on its own or in combination with other forms of interstitial pneumonia, such as idiopathic pulmonary fibrosis. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Acute interstitial pneumonia' and "Acute interstitial pneumonia (Hamman-Rich syndrome)" and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Histopathology'.)

Granulomatous lung diseases — Granulomas are discrete aggregates of epithelioid histiocytes and T lymphocytes, with varying numbers of multinucleated Langhans-type giant cells (contain multiple nuclei arranged peripherally in a horseshoe pattern) (picture 9).

The noninfectious interstitial lung diseases associated with granuloma formation typically cause nonnecrotizing granulomas, rather than the necrotizing granulomas seen with infections. Regardless of whether necrosis is present, the first step in the evaluation is to exclude infection (eg, fungal, mycobacterial). Then, attention is turned to the noninfectious causes of granulomatous lung disease, which are listed in the table (table 9).

Features of the more common granulomatous lung diseases are described in the following sections.

Sarcoidosis — Sarcoidosis usually has a lymphangitic distribution with granulomas and comparatively little lymphocytic inflammation most commonly found in the alveolar septa and bronchial and pulmonary arterial walls. The granulomas are generally non-necrotizing, but focal central necrosis is occasionally present. Additional features that are sometimes seen include asteroid bodies, Schaumann bodies, and birefringent crystalline particles (calcium oxalate and other calcium salts) (picture 10 and picture 11 and picture 12). Bronchoalveolar lavage (BAL) shows an increase in the proportion of lymphocytes and elevation in the CD4/CD8 ratio >1. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Lymphocytic BAL'.)

A sarcoid-like disorder with granulomatous infiltration of the lungs and other organs may occur in patients with common variable immunodeficiency [31,32]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

Chronic beryllium disease — The histopathology of chronic beryllium disease looks virtually identical to sarcoidosis with nonnecrotizing granulomas and/or mononuclear cell infiltrates in the bronchial walls or lung interstitium. Chronic beryllium disease is characterized by a history of beryllium exposure, a positive blood or BAL beryllium lymphocyte proliferation test, and noncaseating granulomas on lung or bronchial biopsy. (See "Chronic beryllium disease (berylliosis)", section on 'Diagnosis'.)

Hypersensitivity pneumonitis — In HP (also called extrinsic allergic alveolitis), the granulomas are generally bronchocentric [33]. Compared with sarcoid granulomas, HP granulomas are smaller, less discrete, and associated with greater interstitial chronic inflammation (picture 13 and picture 14). Other key features in differentiating HP and sarcoidosis are the history of exposure to an agent known to cause HP, serologic evidence of exposure, and a CD4/CD8 ratio in the BAL <1. Fibrotic HP can be difficult to distinguish from other fibrosing interstitial pneumonias in biopsy specimens [34,35]. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Surgical lung biopsy' and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Lymphocytic BAL'.)

Langerhans cell granulomatosis — The histopathology of pulmonary Langerhans cell histiocytosis (Histiocytosis X, eosinophilic granuloma) is characterized by cysts and variably dense aggregates of Langerhans cells (mononuclear dendritic cells, S-100 and CD1a positive), lymphocytes, plasma cells, and a few eosinophils. On electron microscopy, Langerhans cells have classic pentalaminar cytoplasmic inclusions or Birbeck granules. The disease is dynamic; thus, sometimes only stellate fibrous scars remain as the disease progresses. (See "Pulmonary Langerhans cell histiocytosis", section on 'Lung biopsy' and "Pulmonary Langerhans cell histiocytosis", section on 'Background'.)

Most cases of pulmonary Langerhans cell histiocytosis are diagnosed by HRCT showing mid to upper lung zone cysts and nodules in combination with the clinical history (eg, age 20 to 40 years, cigarette smoking). (See "Pulmonary Langerhans cell histiocytosis", section on 'Evaluation' and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Pathologic features'.)

Erdheim-Chester disease — Another histiocytic proliferation that rarely affects the lungs is Erdheim-Chester disease (ECD). It has a more lymphangitic distribution, often with marked visceral pleural thickening. The hallmark of ECD is a dense infiltration of tissues by foamy or lipid-laden histiocytes, due to the accumulation of lipids within their cytoplasm. (See "Erdheim-Chester disease", section on 'Other organs' and "Erdheim-Chester disease", section on 'Pathology'.)

Foreign body granulomatosis — The histopathology of foreign body granulomatosis (FBG) typically consists of perivascular fibrosis and aggregates of multinucleated giant cells and granulomas. Polarizable material may be seen within the granulomas and giant cells, or extracellularly in the vessel wall. FBG is caused by intravenous injection, or less commonly inhalation, of pulverized tablets. The talc or other foreign material from the tablets migrates through the pulmonary arterial wall to the surrounding perivascular and pulmonary interstitial tissue where it incites the granulomatous response.

The radiographic and pathologic changes of FBG occur predominately in a perihilar and upper lobe distribution. The clinical presentation, evaluation and management of foreign body granulomatosis is discussed separately. (See "Foreign body granulomatosis".)

Diseases with associated vascular inflammation — Granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss), necrotizing sarcoid granulomatosis, and pulmonary lymphomatoid granulomatosis are differentiated from sarcoidosis by their angiocentric pattern of inflammation and associated evidence of vasculitis. Well-formed granulomas without necrosis are uncommon [3]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement" and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Pulmonary lymphomatoid granulomatosis" and "Bronchocentric granulomatosis".)

Bronchocentric granulomatosis — In bronchocentric granulomatosis, granulomatous inflammation is centered on the bronchi and is typically associated with mucoid impaction of the bronchus. Frequently, bronchocentric granulomatosis is seen in the context of allergic bronchopulmonary aspergillosis (ABPA). In ABPA, septated fungal hyphae with acute dichotomous branching may be seen in the mucus-filled bronchial lumen, but the fungi do not invade the mucosa. (See "Bronchocentric granulomatosis" and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)

Other diffuse parenchymal lung diseases — There are numerous additional causes of diffuse parenchymal lung disease that are not classified as interstitial pneumonias, but are considered in the differential diagnosis. These include eosinophilic pneumonia, pulmonary hemorrhage syndromes, alveolar proteinosis, amyloid deposition, smooth muscle proliferation, honeycomb lung, and unclassifiable interstitial pneumonia.

Eosinophilic pneumonia — The histologic features of eosinophilic pneumonia are similar to those of OP described above, except there is significant eosinophilic infiltration. The eosinophilic infiltration is often accompanied by foci of necrosis and proteinaceous debris, termed eosinophilic microabscesses (picture 15 and picture 16 and picture 17). Acute and organizing DAD may also be present, particularly in acute eosinophilic pneumonia.

In addition to the idiopathic acute and chronic eosinophilic pneumonias, potential causes (or associations) of eosinophilic pneumonia are listed in the table and include parasitic infections, drugs, EGPA, allergic bronchopulmonary aspergillosis, neoplasms, and the hypereosinophilic syndromes (table 10). (See "Overview of pulmonary eosinophilia", section on 'Idiopathic acute eosinophilic pneumonia' and "Overview of pulmonary eosinophilia", section on 'Chronic eosinophilic pneumonia'.)

Pulmonary hemorrhage syndromes — The important histopathologic finding in the pulmonary hemorrhage syndromes is the filling of alveoli with red blood cells and macrophages containing darkly pigmented clumps of hemosiderin (hemosiderin-laden macrophages). When greater than 20 percent of 200 macrophages stain positive for hemosiderin, a diagnosis of diffuse alveolar hemorrhage is usually made. The presence of hemosiderin-laden macrophages helps exclude surgical bleeding as the cause of alveolar red blood cells. Causes of the diffuse alveolar hemorrhage syndromes are listed in the table (table 11). (See "The diffuse alveolar hemorrhage syndromes".)

Often the underlying lesion in pulmonary hemorrhage is a capillaritis with neutrophilic infiltration of the alveolar septa. This leads to necrosis of these structures, loss of capillary structural integrity, and extravasation of erythrocytes into the alveolar space. Many of the tissue neutrophils are fragmented and eventually become pyknotic; the fragmented neutrophils and nuclear dust fibrin may also enter the alveoli with the red blood cells. True fibrinoid necrosis of the interstitium is sometimes seen, and erythrocytes may also be observed within the interstitial space.

Pulmonary hemorrhage can also occur in the setting of diffuse alveolar damage when the severity of the lung injury leads to marked capillary fragility and leakiness. Diffuse alveolar damage is discussed separately. (See 'Diffuse alveolar damage' above and "The diffuse alveolar hemorrhage syndromes", section on 'Diffuse alveolar damage'.)

Pulmonary hemorrhage without inflammation of the alveolar structures may be seen in coagulation disorders and in idiopathic pulmonary hemosiderosis. (See "Idiopathic pulmonary hemosiderosis", section on 'Histopathology'.)

Pulmonary alveolar proteinosis — In pulmonary alveolar proteinosis (PAS), the alveoli are filled with acellular pink and finely granular lipoproteinaceous material that stains positively with a PAS stain for glycogen. Scattered clefts of cholesterol crystals may be seen within the alveolar exudate [36]. The alveolar septa may be slightly thickened, but the normal alveolar architecture tends to be preserved. Typically, there is little or no inflammatory cell infiltration.

Potential causes (or associations) of alveolar proteinosis are listed in the table (table 12). (See "Pulmonary alveolar proteinosis in children", section on 'Diagnosis' and "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults" and "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults", section on 'Diagnostic evaluation'.)

Pulmonary amyloidosis — Deposition of amyloid in the lung can cause diffuse alveolar septal thickening, single or multiple pulmonary nodules, or diffuse tracheobronchial lesions. The amyloid deposits appear as amorphous hyaline material on light microscopy. The amyloid fibrils bind Congo red (leading to green birefringence under polarized light) and thioflavine T (producing an intense yellow-green fluorescence). (See "Overview of amyloidosis", section on 'Selection of biopsy site'.)

Amyloid deposition can be localized to the lung or be systemic, with the latter having a worse prognosis. It may be seen in association with multiple myeloma, LIP, or primary pulmonary marginal zone lymphomas of mucosa associated lymphoid tissue (MALT) origin. AL-type of amyloid is typical in symptomatic patients. (See "Overview of amyloidosis", section on 'Pulmonary disease' and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Smooth muscle proliferation — Metaplastic smooth muscle proliferation within the lung interstitium can been seen in several conditions, including lymphangioleiomyomatosis (LAM), benign metastasizing leiomyoma, and diffuse primary or metastatic spindle cell malignancy. Most cases of LAM are diagnosed without lung biopsy due to the diagnostic accuracy of HRCT. The evaluation and diagnosis of LAM are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis".)

Honeycomb lung — Honeycomb lung is indicative of end-stage pulmonary fibrosis. Many disorders (eg, IPF, sarcoidosis, hypersensitivity pneumonia, eosinophilic granuloma) can progress to end-stage fibrosis, but cannot be distinguished reliably by pathologists at this stage of the disease processes. Thus, biopsy of extensive honeycomb lung is not helpful and should be avoided.

Rare histopathologic interstitial pneumonia patterns — Rare histologic interstitial pneumonia patterns have been described: idiopathic pleuroparenchymal fibroelastosis, acute fibrinous and organizing pneumonia, and bronchiolocentric fibroinflammation. It is not clear that these are separate entities or are variants of existing idiopathic interstitial pneumonias, connective tissue diseases, or drug reactions.

●Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare process that consists of upper lobe pleural and subpleural lung parenchymal fibrosis [37]. Special stains are required to reveal the an abnormal accumulation of elastin in the lung tissue. The histologic presentation may include other patterns, such as UIP or NSIP in other parts of the lung [38-40].

●Acute fibrinous and organizing pneumonia (AFOP) is a histologic pattern characterized by intraalveolar fibrin deposition and associated OP, but without the hyaline membranes found in DAD [41-44]. The distribution of AFOP is patchy, typically involving the alveoli and terminal bronchioles, whereas DAD is diffuse and affects all aspects of the lung parenchyma. It is unclear whether AFOP is a distinct entity or a part of the spectrum of DAD and OP. It is associated with a clinical picture of acute lung injury and can be idiopathic or associated with other processes such as hypersensitivity pneumonitis, infection, drug toxicity, eosinophilic pneumonia, and rheumatic disease [41,42,45-47].

●Bronchiolocentric fibroinflammatory changes consisting of peribronchiolar metaplasia are a common focal finding in a variety of idiopathic interstitial pneumonias. Rarely, however, peribronchiolar metaplasia is the only major histologic finding in surgical lung biopsies from patients with interstitial lung disease [48,49]. The term, airway-centered interstitial fibrosis, has been applied to this presentation in some cases. Affected patients are commonly women in middle to older age. (See "Overview of bronchiolar disorders in adults", section on 'Airway-centered interstitial fibrosis'.)

Unclassifiable interstitial pneumonia — Unclassifiable interstitial pneumonia exists when histologic features do not allow classification into one of the above categories (table 13) [17,21,50,51]. Some of these cases result from sampling error or inadequate specimens. This finding on a transbronchial lung biopsy should prompt a surgical lung biopsy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

SUMMARY AND RECOMMENDATIONS

●Use of histopathology in the diagnosis of ILD – Collaboration between the clinician, radiologist, and pathologist is needed to identify the most accurate diagnosis when analyzing lung biopsy findings in diffuse parenchymal lung disease. Histopathologic patterns are often "consistent with" a specific diagnosis rather than being diagnostic, so information regarding age, sex, drug use, smoking, occupational and environmental exposures, co-morbid disease, and radiographic findings contributes to the diagnostic process. (See 'Multidisciplinary discussion' above.)

●Histopathologic patterns – Histopathologic patterns of diffuse parenchymal lung disease can be broadly divided into interstitial pneumonias, granulomatous lung diseases, and other disorders (algorithm 1). (See 'Interpretation of histopathologic patterns' above.)

●Idiopathic interstitial pneumonias – The idiopathic interstitial pneumonias are classified according to seven histologic patterns: usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis (RB), organizing pneumonia (OP), lymphoid interstitial pneumonia (LIP), and diffuse alveolar damage (DAD). (See 'Interstitial pneumonias' above.)

The histologic patterns that typify the idiopathic interstitial pneumonias can also be seen in other disease processes that need to be considered in the differential. Disease processes associated with the histopathologic patterns of UIP (table 1), NSIP (table 2), DIP (table 3), RB-ILD (table 4), OP (table 5), LIP (table 7), and DAD (table 8) are listed in the tables. (See 'Interstitial pneumonias' above.)

●Granulomatous lung diseases – When evaluating granulomatous lung disease, the first step is to exclude infection (eg, mycobacteria, fungi). The common noninfectious granulomatous lung diseases include sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans cell histiocytosis, and chronic beryllium disease. Other granulomatous lung diseases are listed in the table (table 9). (See 'Granulomatous lung diseases' above.)

The granulomas seen in granulomatosis with polyangiitis are typically angiocentric and associated with evidence of vascular inflammation. (See 'Granulomatous lung diseases' above and "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement", section on 'Histopathology'.)

●Other diffuse parenchymal lung diseases – Causes of diffuse parenchymal lung disease that are not classified as interstitial pneumonias, but are considered in the differential diagnosis, include eosinophilic pneumonia, the pulmonary hemorrhage syndromes, alveolar proteinosis, amyloid deposition, smooth muscle proliferation, and honeycomb lung. (See 'Other diffuse parenchymal lung diseases' above.)