Classification of Idiopathic Interstitial Pneumonias
The idiopathic interstitial pneumonias represent the most common and important group of interstitial lung diseases. In 1969, Liebow proposed the pathologic classification for interstitial pneumonia listed in Table 1. ³ The term "idiopathic" became attached to this group of interstitial pneumonias in subsequent years as it was recognized that these entities occurred in the absence of any detectable cause. The concept of a group of idiopathic interstitial pneumonias appears to have developed in the late 1970s and early 1980s.

In subsequent years it was shown that many cases that had been classified as LIP actually represented lymphoproliferative disorders and most cases of GIP were hard metal (cobalt) pneumoconiosis. Therefore during the 1980s these entities ceased to become included among the group of idiopathic interstitial pneumonias.

Although diffuse alveolar damage (DAD) was not a specific category in Liebow's classification he thought that DAD played an important role in the pathogenesis of UIP and he actually included the term DAD as part of the terminology for the category of Bronchiolitis obliterans and DAD (BIP) (Table 1). ³

Over the next several decades after Liebow's proposal, several new types of idiopathic interstitial pneumonias were described including idiopathic bronchiolitis obliterans organizing pneumonia (BOOP), ⁴ acute interstitial pneumonia (AIP), ⁵ and non-specific interstitial pneumonia/fibrosis (NSIP). ⁶ Katzenstein has proposed several revisions of the classification of idiopathic diffuse lung disorders in 1990 and 1993, with the most recent proposal in 1997 (Table 1). ⁷ The American Thoracic Society and European Respiratory Society have sponsored a panel of pathologists, radiologists and pulmonologists who are making a multidisciplinary proposal based on an integrated approach (Table 2). ¹

Histologic Patterns Are Distinctive but Not Specific
The histologic patterns seen in UIP, DIP, AIP and cryptogenic organizing pneumonia (COP or idiopathic BOOP) are distinctive but unfortunately they are non-specific and can be seen in a variety of other conditions. For example, the UIP histologic pattern can be seen in collagen vascular diseases as well as in asbestosis. Therefore recognition of an UIP-like or OP-like histologic pattern on a lung biopsy raises a differential diagnosis that includes idiopathic UIP and COP, respectively, as well as several other conditions. The final diagnosis requires careful clinical, radiologic and pathologic correlation.

Problems in Clinical and Pathologic Terminology
One of the problems with the nomenclature in idiopathic diffuse lung disorders is the confusion between clinical and pathologic terms. Both Liebow and Katzenstein, as pathologists, made their classifications based primarily on a pathologic approach, although both emphasized the importance of clinicopathologic correlation.

Clinicians have developed their own terminology and clinical approach to classification of idiopathic diffuse lung disorders. ⁸ During the 1970s the concept of idiopathic pulmonary fibrosis (IPF) was proposed by pulmonary clinicians and today it continues to be a widely used diagnostic term. In the 1970s the major pathologic subsets recognized in lung biopsies from patients with IPF included UIP and DIP. One of the major tenets of the concept of IPF was the belief that DIP represented the cellular phase and UIP the fibrotic spectrum of a single disease. ⁸ This contrasted with the concept of Liebow who regarded UIP and DIP to be separate entities. ³

Another source of confusion in terminology of the idiopathic diffuse lung disorders is the various clinical terms that have been used. For example, the concept of IPF is primarily used in North America and Asia while in Great Britain the term cryptogenic fibrosing alveolitis (CFA) is more popular. A similar difference in terminology applies to idiopathic BOOP, a term used mostly in North America and Asia while in Great Britain the term cryptogenic organizing pneumonia (COP) is more popular. Other terms that have been used for IPF include Hamman-Rich syndrome, diffuse interstitial fibrosis, "honeycomb lung", Osler-Charcot disease, diffuse pulmonary alveolar fibrosis, and interstitial pneumonias.

Since the mid-1980s after recognition of entities such as COP/idiopathic BOOP, AIP and NSIP, there has been some narrowing in the radiographic and pathologic criteria required to establish a diagnosis of IPF. Bjoraker et al recently showed how patients with the clinical picture of IPF as defined between 1976 and 1985 had a heterogeneous spectrum of lung biopsy findings including COP/idiopathic BOOP, DIP, AIP and NSIP. ⁹ This study demonstrated that the 2.8-year median survival of patients with the UIP pattern of interstitial fibrosis was significantly worse than that for patients with the other chronic interstitial pneumonias. ⁹ This and other data has supported the separation of DIP from UIP as distinct entities. ¹⁰ HRCT studies correlated with the lung pathology have greatly helped in understanding the importance of separating these disorders. ¹¹ This has led to a more precise definition of IPF so that for a diagnosis of IPF we require a radiographic and histologic pattern of UIP.

It is important to keep this evolution in mind when reading the literature on pulmonary fibrosis since articles published on IPF in the 1970s and 1980s probably included some cases of idiopathic BOOP, AIP, and NSIP. As each new subgroup of pulmonary fibrosis has been recognized, the definition of IPF has become narrower and the group more homogeneous. In addition most studies of IPF have included patients with both DIP and UIP patterns of lung fibrosis ^8,12 This continues to occur since there has been no widely accepted consensus regarding the separation of DIP and UIP. With the recent trend to require a UIP pattern as the pathologic basis for the diagnosis of IPF it will be important to realize that much of the data reported from previous decades will be contaminated by some of these other entities. The differences in comparing current to previous data will depend on how many patients with other pathologic subsets were included in the prior study. ⁹ There is a need for a consensus agreement on terminology to avoid further confusion.

If one examines how the idiopathic diffuse lung disorders are diagnosed comparing the perspective of the pathologist with that of the clinician and then the final clinicopathologic diagnosis, it is apparent that there is some inconsistency in how the terms are used and interpreted. It is important to keep in mind that many pathologists are expected to sign out lung biopsies with minimal clinical history, especially with the current emphasis on rapid turnaround time. This makes it difficult for a pathologist to be part of the final clinicopathologic diagnosis. For example, the diagnosis of AIP requires considerable clinical information. Much of the evaluation to exclude specific causes of the DAD histologic pattern is likely to be completed after the lung biopsy has been signed out. In fact, the published studies on the subject of AIP have been based on a series of patients narrowed from a larger group of cases where some patients were excluded on the basis of information that was probably not available at the time the biopsy was diagnosed. ^5,13 Therefore the best diagnosis many pathologists may be able to make in cases of AIP is "DAD, etiology undetermined" with an added comment that the differential diagnosis may include AIP. It will be difficult to make the final diagnosis of AIP unless a detailed history is provided. Even after making a careful diagnosis of AIP, an underlying condition such as a collagen vascular disease may declare itself after the initial pulmonary presentation and the original diagnosis of AIP may need to be revised.

In contrast to DAD/ARDS/AIP where there is a different term for the clinical vs pathologic perspective, the pathologic terms for DIP and BOOP are similar to the clinical (DIP and idiopathic BOOP/COP) and clinicopathologic terms (DIP and idiopathic BOOP/COP), respectively (Table 3). The clinical and clinicopathologic terms for what pathologists call the UIP-pattern include IPF, UIP and CFA. A more difficult problem is presented by the concept of NSIP, which is more of a diagnosis of exclusion to be separated from the other recognized idiopathic interstitial pneumonias of UIP, DIP, idiopathic BOOP and AIP.

Unclassifiable Interstitial Pneumonia
There is a subset of patients with interstitial pneumonia that remain unclassifiable after extensive clinical, radiologic and/or pathological examination. For interstitial lung disease this problem often exists in cases where some critical piece of data is unavailable; examples include: there is inadequate clinical information or inadequate chest radiologic images; the lung biopsy may be inadequate or nondiagnostic due to small size (a bronchoscopic or needle biopsy), poor sampling or the specimen may only show a nondiagnostic pattern of endstage fibrosis with honeycombing.

TABLE 1: Historical Classification of Interstitial Pneumonia

Liebow 1969 3	Kitaichi 1990 14	Katzenstein, 7 1997 7
Usual Interstitial Pneumonia	Usual Interstitial Pneumonia	Usual Interstitial Pneumonia
Desquamative Interstitial Pneumonia	Desquamative Interstitial Pneumonia	Desquamative Interstitial Pneumonia/Respiratory Bronchiolitis Interstitial Lung Disease
Bronchiolitis Obliterans and Diffuse Alveolar Damage	Bronchiolitis Obliterans Organizing Pneumonia
	Diffuse Alveolar Damage	Acute Interstitial Pneumonia
		Non-specific Interstitial Pneumonia
Lymphocytic Interstitial Pneumonia‡	Lymphocytic Interstitial Pneumonia‡	‡
	Unclassifiable Interstitial Pneumonia††
Giant Cell Interstitial Pneumonia‡‡	‡‡	‡‡

‡ Most cases of lymphocytic interstitial pneumonia as described by Liebow turned out to represent lymphoproliferative disorders or they were associated with other disorders such as collagen vascular disorders or HIV infection. For this reason this category was dropped from the group of idiopathic disorders, but it is retained in the new proposal since a few idiopathic cases remain.

‡‡ Virtually all cases with a giant cell interstitial pneumonia pattern have a hard metal pneumoconiosis

TABLE 2: Histologic and Clinical Classification of Idiopathic Interstitial Pneumonias††*

HISTOLOGIC PATTERNS	CLINICAL-RADIOLOGIC-PATHOLOGIC DIAGNOSES
Usual Interstitial Pneumonia	Idiopathic Pulmonary Fibrosis/ Cryptogenic Fibrosing Alveolitis
Nonspecific Interstitial Pneumonia	Nonspecific Interstitial Pneumonia (Provisional)‡
Organizing Pneumonia	Cryptogenic Organizing Pneumonia †
Diffuse Alveolar Damage	Acute Interstitial Pneumonia
Respiratory Bronchiolitis	Respiratory Bronchiolitis Interstitial Lung Disease
Desquamative Interstitial Pneumonia	Desquamative Interstitial Pneumonia
Lymphocytic Interstitial Pneumonia	Lymphocytic Interstitial Pneumonia

* Unclassifiable interstitial pneumonia = Some cases are unclassifiable for a variety of reasons (see text)

† COP is the preferred term, but it is synonymous with Idiopathic Bronchiolitis Obliterans Organizing Pneumonia

‡ This group represents a heterogeneous group with poorly characterized clinical and radiologic features that needs further study.

†† Modified From the ATS/ERS Classification of Idiopathic Interstitial Pneumonias ¹

Usual Interstitial Pneumonia
The term usual interstitial pneumonia (UIP) has been used in two major ways: as a pathologic pattern and as a clinicopathologic syndrome. As an idiopathic clinicopathologic syndrome UIP is synonymous with IPF. However the UIP histologic pattern (Table 1) occurs in a variety of clinical settings particularly in patients with collagen vascular diseases (Table 2). Confusion occurs when it is not clearly stated whether one using the term UIP to describe a clinicopathologic entity or a histologic pattern. Pathologists can work around this problem by using the term UIP-pattern when referring only to lung histology.

A variety of other terms have been used for the idiopathic form of UIP. The term Classical, "Usual" or Undifferentiated Interstitial Pneumonia (UIP) was proposed by Liebow in 1969. ³ Over the past few decades the term idiopathic pulmonary fibrosis (IPF) has been used by pulmonary clinicians for a spectrum of pathologic forms of interstitial fibrosis. In Europe the term cryptogenic fibrosing alveolitis (CFA) is more popular and if there is no underlying collagen vascular disease, the term lone CFA is used. For the purposes of this discussion the clinicopathologic term IPF will be restricted to cases in which the lung shows a UIP pattern histologically or by high resolution CT scan. ¹⁵

The frequency of IPF is difficult to be certain, however, it has been estimated that IPF has a frequency of 3-5 cases per 100,000 persons in the United States. ²

Clinical Features:
IPF begins insidiously, with the gradual onset of dyspnea on exertion and dry cough. Patients with IPF present between the ages of 40 and 70 years with insidious onset of dyspnea usually over a period of several years. ² Pulmonary function tests reveal a restrictive pattern with a decreased diffusing capacity (DL_CO) and abnormal gas exchange. The clinical course for IPF is variable but the mean survival is 4-6 years. ² Clubbing of the fingers is common especially late in the course of disease. IPF is usually not responsive to medical therapy. Steroids are usually given and sometimes cyclophosphamide or azathioprine are administered.

Most patients with IPF who die have a gradual deterioration of their pulmonary status. Some patients develop fatal complications relative to their immunosuppressive therapy such as opportunistic infections. However, some IPF patients develop an acute exacerbation of their underlying disease with a rapid downhill clinical course. While this complication is well recognized there are only a few reports describing the pathologic details. ²

Radiologic Features:
Chest radiographs in IPF typically show bilateral, symmetric irregular linear opacities causing a reticular pattern. ² Common additional findings include ground glass opacities, honeycombing, and decreased lung volumes. The abnormalities may be diffuse but in approximately 80% of cases involve mainly the lower lung zones. In 10 to 15 % of patients the chest radiograph is normal.

The high-resolution CT manifestations of IPF are characteristic and consist of irregular lines (reticular pattern) and honeycombing involving mainly the subpleural lung regions. ² Honeycombing is evident at presentation on HRCT in 80 to 90% of patients with IPF compared to 30% of cases on the radiograph. Early findings of fibrosis on HRCT consist of fine irregular lines within the secondary lobules (intralobular linear opacities), irregular thickening of the interlobular septa and irregular pleural, vascular and bronchial interfaces with the lung parenchyma. With progression of fibrosis the irregular lines become coarser and there is progressive distortion of the lung architecture, dilatation of bronchioles and bronchi (traction bronchiectasis) and progressive honeycombing. The pattern of abnormalities on HRCT closely reflects the macroscopic pathologic findings. HRCT may demonstrate characteristic findings of IPF in patients who had normal radiographs or nonspecific radiographic findings. ² In approximately 70% of patients, areas of ground-glass attenuation are seen on high-resolution CT; these have shown to correlate with the presence of active alveolitis.

Pathologic Features:
The pathologic criteria for the UIP pattern have been narrowed from Liebow's descriptions in the 1960s and 1970s, due recognition of additional patterns of pulmonary fibrosis including DAD, BOOP, and NSIP. The variegated nature and the frequent honeycombing emphasized by Liebow are central aspects of the current pathologic definition of the UIP pattern. ^3,16

Gross Features:
The pleural surface of the lungs has a cobble-stoned appearance due to the retraction of scars along the interlobular septa. The overall lung size tends to be small. The cut surface typically shows diffuse fibrosis of the lung parenchyma with lower lobe predominance and a distinctive distribution in the subpleural regions and along the interlobular septa. The fibrosis is patchy with areas of fibrotic lung adjacent to relatively normal lung. The fibrosis consists of firm, rubbery, white connective tissue frequently associated with honeycomb cystic changes. In cases where an accelerated phase of IPF/UIP has occurred, the active areas may show patchy organizing fibrosis with a variegated tan-yellow, appearance alternating with areas of relatively preserved lung.

Histologic Features:
The histologic hallmark of the UIP pattern is patchy interstitial fibrosis often in a subpleural and/or paraseptal distribution alternating with areas of normal lung, best appreciated at low power magnification (Table 1). ^7,17 The fibrosis is temporally heterogeneous with two major types: dense scarring and honeycombing as well as fibroblastic foci scattered at the edges of the dense scars. The dense fibrosis causes remodeling of the lung architecture resulting in collapse of alveolar walls and formation of cystic spaces or honeycombing. The dense fibrosis is rich in collagen that stains strongly with a trichrome stain. The fibroblastic foci consist of a loose type of fibrosis that contains myofibroblasts within a loose stroma that has few collagen fibers. Smooth muscle proliferation may be found in areas of dense fibrotic scarring. When severe the term muscular cirrhosis of the lung has been applied.

The fibrotically thickened alveolar septa tend to be lined by hyperplastic cuboidal epithelial cells or a bronchiolar type of epithelium. Sometimes the epithelial cells overlying the fibroblastic foci are very hyperplastic with abundant cytoplasm, large hyperchromatic nuclei and prominent nucleoli.

Interstitial inflammation is usually mild to moderate consisting mostly of lymphocytes and a few plasma cells. Scattered lymphoid aggregates may be seen. A few interstitial mast cells, eosinophils and neutrophils may be seen. Occasionally, moderate numbers of interstitial and/or alveolar eosinophils may be seen, but they are typically focal and fall short of eosinophilic pneumonia. Alveolar macrophages are often seen, particularly if the patient is a cigarette smoker.

There is a spectrum of severity of fibrosis that can be seen in the UIP pattern. When the fibrosis is very extensive and no normal lung was obtained in the lung biopsy sample, one may only be able to identify the pattern of endstage or honeycomb fibrosis. This may reflect a sampling problem if the surgeon took the biopsy from an area of very fibrotic lung. In order to make a pathologic diagnosis of a UIP pattern one must have areas of normal lung present in the biopsy specimen. This is important since a UIP pattern can be seen as the advanced phase of other interstitial disorders. Therefore areas of relatively normal lung must be examined to exclude the presence of active lesions of other interstitial lung diseases such as sarcoid or histiocytosis X.

Biopsies from patients with UIP may show areas of NSIP pattern. Flaherty, et al demonstrated, in patients with biopsies from multiple lobes that show UIP in at least one lobe, up to 25% of cases may show an NSIP pattern in a specimen from a second or third lobe. ¹⁸ These findings were extended recently by Katzenstein, et al who showed in explanted specimens from patients with UIP that an NSIP pattern could be seen in 80% of cases. ¹⁹

There are differing levels of certainty in interpreting lung biopsies for the diagnosis of UIP. The following approach can be useful:

1. Definite UIP
2. Probable UIP
3. Possible UIP
4. Definitely not UIP

This approach can also be applied to interpreting lung biopsies for other interstitial disorders such as NSIP.

Differential Diagnosis
The differential diagnosis for the UIP pattern includes histologic and etiologic considerations (Table 2). This requires a careful clinical as well as pathologic approach. Things in the clinical history that must be excluded include drug intake and occupational exposures to minerals such as beryllium, cobalt, asbestos, silicosis, and aluminum. In addition, clinical and serologic manifestations of collagen vascular diseases should be investigated. A smoking history is important since a cigarette smoking is associated with an increased risk for developing IPF/UIP.

The histologic pattern of the UIP pattern must be separated from the patterns of DIP, DAD, and BOOP since the clinical course and management is so different. When the classical histologic features of the UIP pattern are present it may not be difficult to separate it from these other entities. However, the differential diagnosis is often difficult and may require careful clinical and radiologic correlation. The separation of the UIP and DIP patterns is usually not difficult, but some UIP cases have prominent alveolar macrophages and some DIP cases may show some focal scarring or honeycomb changes.

A marked interstitial inflammatory infiltrate or the presence of granulomatous inflammation should raise the consideration of hypersensitivity pneumonitis, pneumoconiosis, drug-induced pneumonitis, infection, or collagen vascular disease. The pathologist can help in identifying dust deposits such as asbestos bodies or infectious agents. The latter may require special stains for organisms, particularly Pneumocystis carinii. If there is a suspicion for asbestos exposure, iron stains should be performed unless asbestos bodies are seen on H&E stained sections. Polarization microscopy may also help to identify birefringent particles that could suggest significant dust deposits.

TABLE 1: Usual Interstitial Pneumonia Pattern: Histologic Features ²⁰

Major Features Patchy lung involvement Frequent subpleural, paraseptal and/or peribronchiolar distribution Dense fibrosis causing remodeling of lung architecture with frequent "honeycomb" fibrosis Fibroblast foci scattered at the edges of the dense scars Interstitial inflammation, mild to moderate Pertinent Negative Findings Lack of active lesions of other interstitial diseases (i.e. sarcoidosis or Langerhans histiocytosis) Lack of marked interstitial chronic inflammation Granulomas: inconspicuous or absent Lack of substantial inorganic dust deposits, i.e., asbestos bodies (except for carbon black pigment)

TABLE 2 : Histologic and Etiologic Differential Diagnosis for Usual Interstitial Pneumonia Pattern ²⁰

Histologic Patterns Nonspecific interstitial pneumonia, fibrosing pattern Desquamative interstitial pneumonia pattern Fibrotic phases of other interstitial disorders Langerhans cell histiocytosis Hypersensitivity pneumonitis pattern Diffuse alveolar damage Etiologic Possibilities Collagen vascular disease Drug-induced pneumonitis Radiation pneumonitis Familial idiopathic pulmonary fibrosis Hermansky Pudlak syndrome Pneumoconiosis, (i.e. asbestosis) Idiopathic UIP (Clinicopathologic term: Idiopathic pulmonary fibrosis)

Cryptogenic Organizing Pneumonia
Cryptogenic organizing pneumonitis (COP) is a clinicopathologic entity described by Davison, et al. in 1983. ²¹ In 1985, Epler and colleagues described the same entity under the term bronchiolitis obliterans organizing pneumonia (BOOP), and that latter term came into common usage (sometimes referred to as idiopathic BOOP). ⁴ The term cryptogenic organizing pneumonia (COP) is preferred because it conveys the essential features of the syndrome described below and avoids confusion with airway diseases such as constrictive bronchiolitis obliterans that can be problematic with the term BOOP. ¹ There are many causes of the organizing pneumonia pattern. Some of the more common ones are summarized in Table 1.

Clinical Features
Patients usually present at an age of 55 years and there is no sex predeliction. ² Presentation often follows 4-6 week history of a flu-like illnes. The most common symptoms are cough and dyspnea typically of short duration (less than 3 months). Pulmonary function tests usually show a mild to moderate restrictive ventilatory defect. ²

Clinical Course
The majority of patients recover completely on oral corticosteroids, but a significant number relapse within 1 to 3 months when the corticosteroids are reduced (usually below 15 mg/day) or stopped. ² Prolonged treatment for 6 months or longer is advised. A small proportion of patients recovers spontaneously.

In the appropriate clinical setting and with characteristic chest imaging studies, the diagnosis may be established by obtaining a transbronchial lung biopsy that shows consistent histopathologic features. However, if the follow-up and response to therapy are not appropriate, alternative diagnoses should be considered.

Radiologic Features
The characteristic CT finding in COP is patchy areas of air-space consolidation that are often subpleural or peribronchial and show air bronchograms. ²² Approximately half of patients may show small nodules situated along bronchovascular bundles or ground glass attenuation. Multiple large nodules may be seen in 15% of patients. ²³

TABLE 1: Clinical Settings Associated with Organizing Pneumonia Pattern †

As an idiopathic process that may be a localized nodule or infiltrative lung disease (COP) Organizing diffuse alveolar damage Organizing infections Organization distal to obstruction Organizing aspiration pneumonia Organizing drug reactions, fume, and toxic exposures Collagen vascular disease Extrinsic allergic alveolitis/hypersensitivity pneumonitis Eosinophilic lung disease Inflammatory bowel disease As a secondary reaction in chronic bronchiolitis As a reparative reaction around other processes (including abscesses, Wegener's granulomatosis, neoplasms, and others)

†From reference ¹

Histologic Features
The organizing pneumonia pattern is patchy and consists of polypoid plugs of loose organizing connective tissue involving alveolar ducts and alveoli with or without bronchiolar intraluminal polyps (Table2). ^4,24,25 The connective tissue is all the same age and the lung architecture is preserved. The majority of changes center on small airways. Interstitial inflammation is chronic and mild. Type II cell hyperplasia may be mild or moderate. Alveolar macrophages may be increased and have foamy cytoplasm. A small amount of airspace fibrin may be focally present. ^4,24,25

Histological Differential Diagnosis
The following histologic features mitigate against a diagnosis of COP: airspace neutrophils, acute bronchiolitis, granulomas, necrosis, hyaline membranes, and prominent infiltration of eosinophils. The major histologic differential diagnostic considerations for the organizing pneumonia pattern include the DAD, NSIP, DIP, and UIP patterns. DAD is characterized by more uniform and diffuse lung injury with marked edematous thickening and organization in alveolar walls and, often, hyaline membranes. ^4,24,25

TABLE 2: Histologic Features of Organizing Pneumonia Pattern¹

Key Histologic Features Organizing pneumonia: intraluminal organizing fibrosis in distal airspaces (bronchioles, alveolar ducts and alveoli) Patchy distribution Preservation of lung architecture Uniform temporal appearance Mild interstitial chronic inflammation Pertinent negatives Lack of interstitial fibrosis (except for incidental scars or apical fibrosis) Absence of granulomas Lack neutrophils or abscesses Absence of necrosis Lack of hyaline membranes or prominent airspace fibrin Lack of prominent infiltration of eosinophils Absence of vasculitis

Acute Interstitial Pneumonia
AIP is an interstitial pneumonia characterized by widespread acute lung injury and a rapidly progressive clinical course. ¹ Diffuse alveolar damage (DAD) is the histologic manifestation. DAD usually is associated with known causes such as infection, sepsis, collagen vascular disease, uremia, or drug toxicity. When the etiology is undetermined, AIP is the appropriate clinicopathologic term. ⁵

Clinical Features
The mean age of patients with AIP is approximately 50 years and there is no sex predilection. ^5,13,26,27 Patients often present with acute respiratory failure often following an illness usually less than 3 weeks in duration that resembles an upper respiratory tract infection. ⁵ Virtually all patients require mechanical ventilation. ¹³

The mortality rate is approximately 50% with most deaths occurring 1-2 months after presentation. ⁵ If the patient survives, they may develop recurrences and chronic interstitial lung disease. ^28,29

Radiologic Features
Chest radiographs show bilateral airspace opacification with air bronchograms. ³⁰ The distribution is often patchy, with sparing of the costophrenic angles. By CT AIP is characterized by ground glass attenuation, bronchial dilatation, architectural distortion and consolidation. ³¹ During the organizing phase of AIP distortion of bronchovascular bundles, traction bronchiectasis and ultimately cystic changes may be seen.

Pathologic Features
The lung pathology of AIP is identical to that of the acute and/or organizing phases of DAD (Table 1). ^5,13,32 There is typically diffuse histologic involvement of the lung, but the severity may vary in different areas. Edema, hyaline membranes and interstitial acute inflammation characterize the acute phase. Loose organizing fibrosis mostly within alveolar septa and type II pneumocyte hyperplasia characterize the organizing phase. ¹³ Small to medium-sized pulmonary arterioles commonly show organized thrombi. ^5,13 The lung may return to normal if the patient survives, but progression to endstage honeycomb fibrosis may also occur.

Histologic Differential Diagnosis :
The major histologic differential diagnostic considerations include other patterns of diffuse parenchymal lung disorders such as organizing pneumonia, eosinophilic pneumonia and UIP as well as potential etiologic considerations such as infection. When hyaline membranes are prominent, the DAD pattern is usually readily recognizable. However, since patients with AIP often undergo surgical lung biopsy during the organizing phase, hyaline membranes may be difficult to identify. ⁷ The finding of granulomas, viral inclusions, foci of necrosis or neutrophilic abscesses suggest infection. Special stains for microorganisms should routinely be performed to investigate infection. Clinical correlation is required to exclude may of the conditions that can be associated with the DAD pattern (Table 2).

TABLE 1: Histologic Features of Diffuse Alveolar Damage ¹

Key Histologic Features Diffuse distribution Uniform temporal appearance Alveolar septal thickening due to organizing fibrosis, usually diffuse Airspace organization (may be patchy or diffuse) Hyaline membranes (may be focal or diffuse) Pertinent Negatives Lack of granulomas, necrosis, or abscesses Lack of infectious agents (no viral inclusions and negative special stains for organisms) Lack of prominent eosinophils and neutrophils Negative cultures

TABLE 2: Clinical Conditions Associated With DAD Pattern ¹

Idiopathic (Acute interstitial pneumonia) Infection Collagen vascular disease Drug toxicity Toxic inhalation Uremia Sepsis Transfusion related acute lung injury Shock Trauma

Lymphocytic Interstitial Pneumonia
In 1969 Liebow and Carrington introduced the concept of lymphocytic interstitial pneumonia (LIP) as a form of interstitial pneumonia. ³ However, subsequently it was recognized that many of these cases represented lymphoproliferative disorders and so this entity was removed from the classification of idiopathic interstitial pneumonias. In the recent proposal by the ATS/ERS panel, LIP was returned to the group of idiopathic interstitial pneumonias, since it is recognized that not all cases of LIP are lymphoma and a few idiopathic cases remain after excluding known causes or associations. LIP a part of a family of benign lymphoid lesions of the lung which include intrapulmonary lymph nodes, follicular bronchitis/bronchiolitis, lymphocytic interstitial pneumonia, and nodular lymphoid hyperplasia. ^33,34 The terms lymphocytic interstitial pneumonia or diffuse lymphoid hyperplasia have sometimes been used for both lymphocytic interstitial pneumonia and follicular bronchiolitis. However, in this discussion lymphocytic interstitial pneumonia and follicular bronchiolitis are regarded separately.

Lymphocytic interstitial pneumonia is a form of interstitial pneumonia that is characterised by diffuse infiltration of the alveolar septa by a dense lymphocytic infiltrate. Several terms have been used for this lesion including lymphoid interstitial pneumonia, and plasma cell interstitial pneumonitis. In 1969 Liebow described lymphocytic interstitial pneumonia as a form of interstitial pneumonia to be separated from other interstitial pneumonias such as usual interstitial pneumonia and desquamative interstitial pneumonia. ³ However, a substantial percentage of the lesions that were classified by Liebow as lymphocytic interstitial pneumonia ³⁵ were subsequently recognized to be low grade B-cell lymphomas and today they would be classified as MALT lymphomas. ^36,37 As a result lymphocytic interstitial pneumonia was excluded from the classifications of idiopathic interstitial pneumonias for several decades. However, lymphocytic interstitial pneumonia exists as an inflammatory and non-neoplastic process and it may rarely be idiopathic. Therefore it has been included in an ATS/ERS international multidisciplinary consensus classification of idiopathic interstitial pneumonias. ¹

Clinical and Radiologic Features
Lymphocytic interstitial pneumonia is associated with a variety of conditions including dysproteinemia, autoimmune disorders, collagen vascular diseases, bone marrow transplantation, and the acquired immunodeficiency syndrome, but true idiopathic lymphocytic interstitial pneumonia is very rare (Table 1).

In patients with associated conditions the underlying disease (Table 1) usually dominates the clinical presentation of lymphocytic interstitial pneumonia. The presentation of idiopathic lymphocytic interstitial pneumonia is not well defined. ¹ Women are affected more than men and lymphocytic interstitial pneumonia presents most often in the fourth to sixth decade of life. ^35,38,39 Lymphocytic interstitial pneumonia is rare in HIV-infected adults, but in children under age 13 years it is one of the defining criteria for the acquired immunodeficiency syndrome (AIDS) proposed by the Center for Disease Control.

The most common symptoms are gradual onset of cough and dyspnea. Other possible manifestations include weight loss, fever, chest pain and arthralgias. Lymphadenopathy is found mostly in patients with Sjögren's syndrome. ³⁸ Pulmonary function often reveals a restrictive ventilatory defect with a low diffusing capacity. If laboratory analysis reveals a monoclonal gammopathy or hypogammaglobulinemia, the index of suspicion for a lymphoproliferative malignancy should be raised.

Little is known about the clinical behaviour of idiopathic lymphocytic interstitial pneumonia. If there is an underlying disease, this is what usually determines the clinical course. Optimal therapy is administration of corticosteroids, which usually results in improvement or resolution of symptoms. ^38,40

Several complications of lymphocytic interstitial pneumonia are reported in HIV infected patients with lymphocytic interstitial pneumonia. These include recurrent pneumococcal pneumonia, bronchiectasis, and lung cyst formation. ²

Chest radiographs may show basilar infiltrates with an alveolar component or diffuse infiltrates associated with honeycombing. ⁴¹ High resolution computerized tomography scans typically show ground glass opacities. Nodular lesions may be seen and rarely cysts occur in a peribronchovascular location.

Pathologic Features
Lymphocytic interstitial pneumonia is characterized by a marked lymphoid infiltrate that involves the alveolar septa extensively (Table 2). The lymphoid infiltrate consists mostly of lymphocytes with varying numbers of plasma cells. The process typically involves lung biopsy specimens diffusely. In some cases there may be sparing of some lung parenchyma if the lesions are somewhat nodular, however the involved areas show diffuse alveolar septal infiltration. Type II pneumocyte hyperplasia may be present. Lymphoid follicles, including follicles with germinal centers, are often present, usually in the distribution of pulmonary lymphatics or bronchioles (follicular bronchiolitis). The lymphoid cells consist of both B-cells and T-cells. The T-cells are seen mostly in the alveolar septal interstitium while the B-cells are mostly found in the lymphoid follicles. ⁴² Interstitial fibrosis and small foci of organizing pneumonia may be present. Non-necrotizing granulomas also may be seen. Epstein-barr virus has been identified in lung biopsies from both HIV-infected and non-HIV-infected patients with lymphocytic interstitial pneumonia. ²

Lymphocytic interstitial pneumonia must be differentiated histologically from malignant lymphoma, follicular bronchiolitis , nodular lymphoid hyperplasia, and infection. It also must be distinguished from other interstitial lung disorders such as nonspecific interstitial pneumonia, organizing pneumonia, and usual interstitial pneumonia. The term lymphocytic interstitial pneumonia has been used previously for cases of follicular bronchiolitis with extensive lung involvement even in the absence of infiltration of the alveolar septae, but this does not fit our current definition. There is a continuum of lymphoid infiltration between follicular bronchiolitis and lymphocytic interstitial pneumonia, but in most cases the patterns can be distinguished ⁴² and the term lymphocytic interstitial pneumonia is limited to those cases with extensive alveolar septal infiltration. ¹

The major differential diagnosis from a clinical standpoint is the separation of lymphocytic interstitial pneumonia from low-grade lymphoma. This distinction can be difficult on Hematoxylin and Eosin-stained sections and may require immunohistochemistry and molecular gene rearrangement studies such as polymerase chain reaction testing for clonal rearrangement of the immunoglobulin heavy chain gene . The malignant lymphomas that are likely to be confused with lymphocytic interstitial pneumonia are extranodal marginal zone B-cell lymphoma of MALT and small lymphocytic lymphoma. In contrast to lymphocytic interstitial pneumonia, in malignant lymphoma the lymphoid infiltrate is more dense and monomorphous and it may show destruction of lung architecture. Other features that favor lymphoma include the presence of tracking along lymphoid routes, infiltration of the parietal pleura and lymph nodes. The presence of Dutcher bodies (intranuclear inclusions in B-lymphocytes) also favors lymphoma. A complicating feature of low-grade lymphomas is that there are frequently reactive lymphoid follicles and lymphoid infiltrates at the periphery that may give a misleading impression of a reactive process. Rarely does lymphocytic interstitial pneumonia progress to malignant lymphoma. In most cases where this has been reported to occur the lesion may have actually represented malignant lymphoma from the outset.

Certain infections can cause a lymphocytic interstitial pneumonia histologic pattern, especially Pneumocystis carinii pneumonia. ⁴³ For this reason, special stains should be performed on cases with marked lymphoid infiltrates to exclude the presence of micro-organisms.

The lymphocytic interstitial pneumonia pattern also must be separated from the patterns of hypersensitivity pneumonitis, cellular NSIP, and organizing pneumonia. In the hypersensitivity pattern differs from lymphocytic interstitial pneumonia in that the lymphoid infiltrates are less prominent, there is a peribronchiolar distribution, and poorly formed granulomas and organizing intraluminal fibrosis are often present. ³⁶ . The cellular pattern of nonspecific interstitial pneumonia consists of a mild to moderate interstitial lymphocytic and/or plasma cell infiltrate, ²⁰ but it falls short of the extensive alveolar septal infiltration seen in lymphocytic interstitial pneumonia. Prior to the description of the cellular pattern of nonspecific interstitial pneumonia, ^6,20 some of these cases were probably included in reports of lymphocytic interstitial pneumonia. Based on the more narrow definition of lymphocytic interstitial pneumonia the existing literature on this subject may need to be reassessed.

TABLE 1: Clinical Conditions Associated with the Lymphocytic Interstitial Pneumonia Pattern

Collagen vascular disease, Sjögren's syndrome Systemic lupus erythematosus Other immunologic disorders Autoimmune hemolytic anemia, Pernicious anaemia, Myasthenia gravis, Hashimoto's thyroiditis, Primary biliary cirrhosis, Celiac sprue Dysproteinemia Immunodeficiency Acquired immunodeficiency syndrome particularly in children Common variable immunodeficiency Infections Pneumocystis carinii Legionella pneumonia Chronic active hepatitis, Drug induced/toxic exposure Dilantin (phenytoin) Allogeneic bone marrow transplantation Familial Idiopathic

TABLE 2: Histologic Features of Lymphocytic Interstitial Pneumonia †

Major Features Diffuse interstitial infiltration of involved areas Predominantly alveolar septal distribution Infiltrates comprise mostly T-lymphocytes, plasma cells and macrophages Lymphoid hyperplasia (BALT hyperplasia) - frequent Pertinent Negatives Lack of tracking along lymphatic routes (bronchovascular bundles, pleura and interlobular septae), characteristic of lymphomas Organizing pneumonia, inconspicuous or absent Lack of Dutcher bodies Lack of monoclonal light chain staining pattern of plasma cells (polyclonal pattern present) Lack of extensive pleural involvement or lymph node involvement Lack of necrotizing granulomas

†From reference ¹

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