Applied Radiology

Dr. Gotway is an Assistant Professor of Radiology at the University of California, San Francisco and Chief of Thoracic Imaging at San Francisco General Hospital, San Francisco, CA.

Interstitial lung diseases (ILDs) are a heterogeneous group of conditions that involve the lung parenchyma. These entities are characteristically diffuse and infiltrative in nature, involving the peribronchovascular interstitium of the lung, although alveolar involvement may occur as well. ILDs are not malignant or infectious in etiology, although they may cause significant morbidity and mortality. The precise causes of most ILDs are unknown. They are grouped together because they share similar clinical, radiographic, physiologic, and/or pathologic manifestations. ¹ Various approaches have been used to classify this heterogeneous group of disorders, and none are very satisfying.

In the following classification scheme, certain disorders are grouped together because of a common pathologic finding or a shared radiographic abnormality. Because numerous ILDs exist, it is inevitable that no classification scheme will satisfactorily categorize them with complete accuracy. For purposes of organization, in broad terms, they may be grouped as follows:

1) interstitial pneumonias (IPs):

a) usual interstitial pneumonia,

b) non-specific interstitial pneumonitis,

c) acute interstitial pneumonia,

d) alveolar macrophage pneumonia (formerly called desquamative IP), and

e) bronchiolitis obliterans organizing pneumonia;

2) diffuse infiltrative disease characterized by granulomas:

a) sarcoidosis

b) hypersensitivity pneumonitis;

3) lymphocytic interstitial pneumonia (LIP);

4) pneumoconioses;

5) ILD characterized by cysts (Langerhans' cell histiocytosis, lymphangiomyomatosis);

6) disorders characterized by interlobular septal thickening:

a) pulmonary lymphangitic carcinomatosis,

b) pulmonary edema, and

c) pulmonary alveolar proteinosis;

7) eosinophilic syndromes;

8) pulmonary hemorrhage syndromes;

9) vasculitis.

The diagnosis of these entities rests on integration of clinical, physiologic, and radiologic information. Frequently, a tissue diagnosis is required for definitive diagnosis. For some of the conditions, flexible fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy may suffice, but surgical lung biopsy is often required. A complete description of the above classification scheme of diffuse lung disease is beyond the scope of this article. We will instead focus on the IPs and several other diffuse lung diseases that may have characteristic high resolution computed tomography (HRCT) appearances: hypersensitivity pneumonitis, Langerhans cell histiocytosis, and lymphangiomyomatosis. Several authoritative texts and excellent review articles are available for a more complete discussion the imaging of diffuse lung diseases. ^1-5

Interstitial pneumonias

Liebow ⁶ initially classified IPs into 5 types based on their histologic appearance:

1) usual interstitial pneumonia (UIP);

2) desquamative interstitial pneumonia (DIP);

3) giant cell interstitial pneumonia (GIP);

4) lymphocytic interstitial pneumonia (LIP); and

5) bronchiolitis obliterans interstitial pneumonia (BIP).

These entities do not represent diseases per se; rather, they represent fundamental responses of the lungs to injury or a pathologic condition. Each of the IPs may be seen in association with several different diseases; conversely, several IPs may be seen in the same patient.

Recently, IPs have been reclassified. ^7-10 The current pathologic classification of the IPs includes:

1) UIP;

2) nonspecific interstitial pneumonitis (NSIP);

3) acute interstitial pneumonia (AIP);

4) alveolar macrophage pneumonia (AMP, which was previously known as DIP); and

5) bronchiolitis obliterans organizing pneumonia (BOOP).

LIP is no longer believed to represent an interstitial pneumonia. It is now thought to be a potentially malignant lymphoproliferative pulmonary disorder. GIP is now believed to be a hard metal pneumoconiosis, and is no longer considered among the IPs. The above classification scheme is commonly employed in the radiographic (chest radiograph, HRCT) approach to patients with IPs.

Usual interstitial pneumonia

Histologic findings--UIP is the most common IP. ^1,2,10 In the United Kingdon, UIP is known as cryptogenic fibrosing alveolitis. Pathologically, at low power magnification, UIP is characterized by areas of normal lung alternating with regions of interstitial inflammation, fibrosis, and honeycombing. ^1,2,10 Findings are predominantly subpleural. At higher power, the interstitial inflammation is seen to consist of lymphocytic and plasma cell infiltration within alveolar septa. Proliferating fibroblasts (fibroblastic foci) and dense collagen deposition are seen, as is hyperplasia of type 2 pneumocytes. These changes represent a response of the lung to injury, and are not specific to UIP. The simultaneous presence of multifocal areas of active inflammation, fibroblastic proliferation, and fibrosis interspersed with normal lung parenchyma ("temporal variegation") is the histologic hallmark of UIP.

The above pathologic pattern of UIP refers to a histologic abnormality. The clinical syndrome that is most commonly associated with this histologic pattern is idiopathic pulmonary fibrosis (IPF). Other conditions in which a UIP-like histologic pattern may be encountered include connective tissue diseases (such as rheumatoid arthritis and scleroderma), pneumoconiosis (particularly asbestosis), radiation injury, chronic aspiration, end-stage hypersensitivity pneumonitis, and drug reactions (e.g., nitrofurantoin). Because there may be other characteristic histopathologic features present in these other syndromes, the term UIP is best reserved for cases in which UIP histology is present but not associated with another condition; i.e., for patients with IPF.

Idiopathic pulmonary fibrosis

Clinical features--Patients with idiopathic pulmonary fibrosis (IPF) are typically aged 50 to 70 years, and men are more commonly affected than women. ^1,2,10 Typical symptoms include dry cough and dyspnea on exertion. Physical exam may reveal "velcro-type" inspiratory crackles, and digital clubbing may be found in 25% to 50% of cases. Chest pain and hemoptysis are uncommon. Laboratory investigations are generally unrevealing. Pulmonary function tests (PFTs) commonly reveal a restrictive defect, with decreased total lung capacity, functional residual capacity, and residual volume. ^1,2,10 The diffusing capacity of carbon monoxide (DLCO) is commonly reduced as well. Overall survival is poor, with a 30% to 50% 5-year survival rate. Treatment is often ineffective (<10% of patients will respond), and generally relies on the use of corticosteroids and immunosuppressive/cytotoxic agents. Single lung transplantation may be considered in selected patients.

Radiographic findings­­Chest radiographs: Plain chest radiographs typically show decreased lung volumes and bilateral, basilar and subpleural predominant reticulation and honeycombing (figure 1). ^1,2,10,11 Serial radiographs are particularly helpful in revealing slowly diminishing lung volumes over time. ² A ground glass appearance is uncommonly encountered, but is also typically basilar in distribution. ¹⁰ Small nodules are uncommonly seen, and radiographs are normal in less than 10% to 15% of cases. ^2,12-14 The severity of findings on the plain chest radiograph correlates poorly with the clinical functional status. ¹⁰

HRCT: HRCT commonly reveals patchy, basilar and subpleural irregular linear opacities (intralobular, interstitial thickening), characteristically associated with traction bronchiectasis and honeycombing (figure 2). ^1-3,10,15 Ground glass opacity may be encountered, and presumably reflects alveolitis and may indicate treatable disease. ^16,17 However, ground glass opacity has been shown to correlate with alveolar septal granulation tissue and fibrosis histologically, raising the possibility that ground glass opacity may actually reflect early lung fibrosis, but not necessarily reversible disease. ^2,18 When ground glass opacity is seen among other findings of fibrosis (reticular opacities, traction bronchiectasis, and honeycombing), the ground glass opacity likely represents fibrosis below the limit of resolution of HRCT. Ground glass opacity should be interpreted as potentially treatable disease only when there are no associated HRCT findings of fibrosis. ³ Fibrosis initially appears as fine reticular opacities; these reticular opacities become coarser as the disease progresses. Discrete nodules are seen occasionally. Irregular interlobular septal thickening may be present as well. Mild mediastinal lymph node enlargement is common, but lymph node enlargement in >2 cm is rare. ^10,19-22

Several studies have shown that CT and HRCT are superior to plain chest radiographs for the assessment of patients with IPF. ^23-28 For example, honeycombing may be seen in up to 90% of CT studies as compared with 30% of cases on plain radiographs. HRCT findings have been shown to correlate with symptoms and pulmonary function abnormalities in patients with IPF. ^29,30

HRCT allows a distinction of active, potentially reversible alveolitis from irreversible fibrosis in the majority of patients with IPF, obviating the need for surgical biopsy in characteristic cases. ^{24,25 27,28,31} HRCT can be helpful in predicting potential response to treatment and long-term prognosis in patients with IPF. ^30,32 HRCT is also useful for directing the optimal site for lung biopsy in difficult cases. ³³ Generally, biopsy is directed away from regions of obvious honeycombing and toward regions of ground glass opacity.

Nonspecific interstitial pneumonitis

NSIP refers to interstitial pneumonia that cannot be classified into the known patterns of UIP, AIP, DIP, or BOOP. Some have considered NSIP a wastebasket diagnosis. However, because these patients may have a better prognosis than patients with IPF and treatment strategies are different for NSIP than for causes of UIP, NSIP has been classified separately from other forms of interstitial pneumonia. ^34-37

Histologic features--Pathologically, NSIP is characterized by varying degrees of inflammation and fibrosis within the walls of alveoli. ^2,34 Although the process may be patchy (with areas of normal lung interspersed), the histologic abnormalities are temporally uniform, unlike the temporal variegation characteristic of UIP histology. ³⁴ NSIP histology has been further subdivided into types I, II, and III depending on the degree of associated fibrosis. Type I NSIP consists of interstitial inflammation without fibrosis, type II NSIP by interstitial inflammation with roughly equal amounts of fibrosis, and type III NSIP by interstitial collagen deposition with minimal interstitial inflammation. ^37,38

Like UIP, the histologic lesion of NSIP may be associated with certain clinical syndromes, such as connective tissue diseases, hypersensitivity pneumonitis, and organic dust or other exposures. ^2,34,36

Clinical findings--Clinically, the most common presenting complaint is dyspnea. A non-productive cough may occur. The mean duration of symptoms is usually shorter with NSIP (months) than IPF (years). ³⁴

Radiographic findings­­Chest radiographs: Radiographically, NSIP may be difficult to distinguish from causes of UIP. Reticular and patchy areas ground glass opacities with a basilar, subpleural predominance are commonly encountered (figure 3). ¹⁰ Findings may closely resemble cases of UIP. Air space consolidation may also be seen. Lung volumes may be maintained if the lesion of NSIP is not associated with fibrosis.

HRCT: HRCT scan findings include basilar, subpleural reticular opacities consistent with intralobular interstitial thickening. Ground glass opacity is commonly seen and suggests active, treatable alveolitis when seen in the absence of discrete honeycombing (figure 4). Bronchial dilation may be seen in areas of ground glass opacity; this finding generally correlates with greater amounts of fibrosis histologically (Type III NSIP). ^{2,10,36,38,39} Honeycombing is rarely encountered, and generally suggests the diagnosis of UIP-related diseases as opposed to NSIP. It has been shown that the ground glass opacity seen with NSIP may improve markedly with treatment (figure 5), unlike UIP-related illnesses. ³⁸ Although some investigators have shown that ground glass opacity may evolve into linear and reticular opacities with honeycombing on follow-up HRCT, it is unclear if untreated NSIP inexorably progresses to honeycomb lung. The extent of improvement of abnormalities on HRCT have been shown to correlate with functional improvement following treatment. ⁴⁰

Acute interstitial pneumonia

Histologic features--Acute interstitial pneumonia (AIP) was previously known as Hamman-Rich syndrome. ^41,42 Pathologically, AIP is characterized by diffuse alveolar damage with hyaline membrane formation and alveolar wall edema during the acute, exudative phase (up to day 6). Later, fibroblast proliferation supervenes in the subacute proliferative phase (day 4 to 10). ⁴² Vascular thrombosis may also occur. Finally, after day 8, the chronic, fibrotic phase characterized by traction bronchiectasis and fibrosis may occur. ⁴³

Clinical findings--AIP is characterized by the abrupt onset of respiratory failure requiring mechanical ventilation in a previously healthy individual. ^2,43 Antecedent histories variously include cough, fever, and shortness of breath. AIP may be thought of as ARDS without a known cause. ² The mortality is high (60% to 100%), and significant parenchymal opacities on chest radiography and CT may occur in survivors. ^2,44

Radiographic findings­­Chest radiographs: Findings on plain radiographs include bilateral, symmetric ground glass opacities and foci of air space consolidation (figure 5). In some patients, subpleural reticulation and honeycomb lung may occur. ^2,10,45

HRCT: The findings of AIP on HRCT have been described ^2,10,45,46 and correlated with the pathologic stage of disease. ⁴² Predictably, bilateral, roughly symmetric areas of ground glass opacity and air space consolidation are encountered, often associated with interlobular septal thickening (figure 6). Traction bronchiectasis and architectural distortion may be seen, particularly in the proliferative subacute and chronic fibrotic phase. AIP is characterized by its rapid time course. ⁴⁶

Alveolar macrophage pneumonia (AMP), previously known as desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-interstitial lung disease (RB-ILD)

Histologic features--Desquamative interstitial pneumonia has recently been renamed alveolar macrophage pneumonia. ⁴⁷ AMP (DIP) is now considered to be primarily a smoking-related illness. ^1,10,48,49 AMP (DIP) may represent the most severe manifestation of smoking-related changes of the small airways and lung parenchyma. At the mild end of the spectrum of airway-related changes secondary to cigarette smoke is respiratory bronchiolitis; respiratory bronchiolitis-associated interstitial lung disease represents more severe airway inflammation due to cigarette smoke, ^10,49-52 with limited amounts of peribronchiolar inflammation accompanying alveolar macrophage accumulation. The characteristic histologic finding of AMP (DIP) is alveolar accumulation of macrophages. ^2,53 Minimal inflammatory cell infiltration and fibrosis may also be present. AMP (DIP) is distinguished from UIP by the fact that the former is a temporally uniform process that is not accompanied by fibroblastic foci, unlike UIP. Also, macrophage accumulation in AMP (DIP) is diffuse, whereas in UIP, it is focal. AMP (DIP) used to be thought of as early stage UIP, but the two are now considered to be separate entities.

Clinical findings--AMP (DIP) is essentially a rare disease of smokers. The peak incidence occurs in patients 30 to 50 years of age. Most patients present with dyspnea. In general, symptoms are more acute with DIP than with UIP. Pulmonary function testing may reveal a restrictive pattern with decreased diffusing capacity. ² Hypoxemia may be present. PFT abnormalities tend to be less severe than patients with UIP. The prognosis for patients with AMP (DIP) is quite favorable. The 10-year survival is about 70%.

RB-ILD is also a disease of heavy smokers. These patients typically have shortness of breath and cough. The prognosis of RB-ILD is excellent. Progression to end-stage lung fibrosis does not occur.

Radiographic findings­­Chest radiographs: The chest radiograph in cases of AMP (DIP) may reveal ground glass opacity or air space consolidation, particularly in a basilar and subpleural distribution (figure 7). ¹⁰ Patients with AMP (DIP) are more likely to demonstrate ground glass opacity than patients with UIP. Irregular linear opacities, often lower lung predominant, may also be seen. Nodules, adenopathy, and effusion are all uncommon. A normal chest radiograph has been reported in 3% to 22% cases. ^10,54,55

The chest radiograph in RB-ILD typically demonstrates bilateral, mid and lower lung predominant linear and reticular opacities, frequently associated with bronchial wall thickening. Honeycombing is not present (figure 8).

HRCT: HRCT findings of AMP (DIP) include basilar, subpleural, lower lobe predominant ground glass opacity and irregular reticular opacities (figure 9). ^10,56 Although the spectrum of findings of AMP (DIP) and UIP overlap, ground glass opacity is more commonly seen with AMP (DIP) than UIP. ⁵⁷ Up to half of patients with AMP (DIP) may show reticulation, ⁴⁹ and honeycombing may be seen in 30%. Compared to UIP, findings that suggest fibrosis are relatively mild. ^3,57 The HRCT findings of AMP (DIP) may improve with treatment. ^58,59

HRCT findings of RB-ILD typically include patchy areas of ground glass opacity, perhaps accompanied by airway thickening (figure 10). Nodules, interlobular septal thickening, effusions, and adenopathy are uncommon.

Bronchiolitis obliterans organizing pneumonia

Histologic features--Idiopathic bronchiolitis obliterans organizing pneumonia (BOOP), also known as cryptogenic organizing pneumonia (COP) in the United Kingdom, is a disease characterized by granulation tissue polyps within the lumina of bronchioles and alveolar ducts and patchy areas of organizing pneumonia. ^2,60,61 Fibrosis and inflammation are not conspicuous features of BOOP. BOOP may be idiopathic (cryptogenic organizing pneumonia), although a BOOP-like reaction may be seen with pulmonary infections, drug reactions, as a complication of organ transplantation, collagen vascular disease, Wegener's granulomatosis, and following toxic fume inhalations. ^1,61

Clinical findings--Patients with idiopathic BOOP typically present with a several month history of non-productive cough. ^1,2 Most patients report symptoms being present for <6 months. ⁶² Low grade fevers, malaise, and shortness of breath are also seen. ² The presentation has been characterized as "flu-like" in 40% of patients. PFTs typically reveal a restrictive defect. The prognosis of idiopathic BOOP is good; patients usually respond to corticosteroids. ²

Radiographic findings--Chest radiographs: The characteristic chest radiographic features of idiopathic BOOP include bilateral, patchy, nonsegmental areas of air space consolidation and/or ground glass opacities. ¹⁰ A peripheral distribution is characteristic, although not seen in the majority of patients (14%) (figure 11). ¹⁰ Recurrent/migratory opacities, often in the upper lobe, have been reported. Small nodules may be present, most commonly accompanying air space consolidation. Irregular linear opacities are less common and generally are not dominant features on the radiograph. Pleural effusions are also uncommon. Adenopathy and honeycomb cysts are considered rare. ^10,63

CT and HRCT: CT and HRCT scans in BOOP may demonstrate: ^3,63-66

1) patchy air space consolidation (80%) or ground glass opacity (60%), often with a subpleural (50% to 60%) and/or peribronchiolar distribution. No particular zonal predilection is present (figures 12 and 13);

2) small ill-defined nodules have been reported in 30% to 50% of cases, and may be peribronchiolar in distribution;

3) bronchial wall thickening and bronchial wall dilation have also been described; and

4) irregular, large nodules or masses. ⁶⁷

Irregular linear opacities, pleural effusions, and adenopathy may variously be seen, but are generally less common. HRCT provides useful information for guiding surgical biopsy. ^3,5,10 Most patients respond well to treatment (figure 13), although relapses do occur and a small minority of patients may even die due to respiratory failure.

Interstitial lung diseases characterized by granulomas: Hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis in the United Kingdom, is an allergic lung disease that results from the inhalation of antigens contained in a variety of organic dusts. Farmer's lung, the most well known HP syndrome, results from the inhalation of fungal organisms (thermophilic actinomycetes) that grow in moist hay. Many other HP syndromes also result from exposure to fungi, and they are usually named after the setting in which the exposure occurs or the organic substance involved.

Pathologic features--HP is characterized by interstitial alveolitis, cellular bronchiolitis, and noncaseating epitheloid granulomas. ^2,68,69 The diagnosis of HP is confirmed by the presence of all three of these findings, but all three are not invariably present. Thus, the diagnosis often rests on a combination of the proper clinical scenario, characteristic radiographic findings, and suggestive histopathologic findings. The radiographic and pathologic findings in the various etiologies of HP are similar, thus the disease may be classified into acute, subacute, and chronic stages regardless of the responsible antigen.

Clinical findings--An acute, heavy exposure to an offending antigen may produce fever, chills, dry cough, and dyspnea. Long-term exposure can produce shortness of breath with few or minimal systemic symptoms. Recurrent exposure may result in recurrent acute episodes, possibly superimposed on chronic changes. Chronic HP may present with progressive respiratory impairment. It is not uncommon that, despite extensive questioning, a history of an exposure to an offending antigen cannot be elicited. Thus, a tissue diagnosis is frequently required.

Radiographic findings­­Chest radiographs: In the acute stage, heavy exposure to an enticing antigen may result in ill-defined, bilateral air space disease. These findings reflect alveolar inflammation due to neutrophils, eosinophils, lymphocytes, and large mononuclear cells and/or obstructive pneumonitis. Patients are rarely seen at this stage.

The acute phase may resolve in several days. Then, in the subacute phase, a fine nodular pattern may develop on the chest radiograph (figure 14). The nodular pattern correlates with alveolitis; interstitial infiltration; small, poorly defined granulomas; and cellular bronchiolitis. These histologic findings are usually most apparent in a peribronchiolar distribution. The classic radiographic appearance of HP is recurrent, transient areas of consolidation superimposed on a fine, nodular pattern. In the majority of patients, however, the chest radiograph is normal. ⁷⁰ The subacute presentation may be seen following a heavy acute exposure or with repeated, low-level exposures.

In the chronic phase, fibrosis develops months or years following the initial exposure. The fibrosis can be patchy in distribution, often with a mid-lung predominance. ⁷⁰

HRCT: HRCT findings in the acute phase of HP include bilateral air space consolidation and small, (1 to 3 mm diameter) ill-defined nodules. ⁶⁸ Patients are uncommonly imaged in this phase.

HRCT findings of HP in the subacute phase include ground glass opacities with poorly defined centrilobular nodules. ^71-74 Occasionally, the poorly defined centrilobular nodules may be the predominant finding (figure 15). HP centrilobular nodules are commonly mid- and lower-lung predominant, although a diffuse distribution may occur. Acute and subacute HP may be very difficult to distinguish from DIP. Centrilobular nodules favor diagnosis of the latter. Areas of decreased lung attenuation on inspiratory HRCT images (mosaic perfusion) may be seen in subacute HP, and air trapping may be demonstrated on postexpiratory scans. ^75-77 In a few cases, air trapping on postexpiratory scans may be the only finding of HP (figure 16). ⁷⁵ Occasionally the finding of ground glass opacity, normal lung, and mosaic perfusion on the same inspiratory scan image (the "headcheese" sign) may reflect the combination of alveolitis and air flow obstruction that characterize this disease (figure 17). ⁷⁸

Chronic HP is characterized by fibrosis on HRCT (figures 18 and 19), although the findings of active disease may be superimposed. Fibrosis in HP often shows a mid-lung predominance, although the findings may be distributed evenly throughout the upper, mid, and lower lungs. ^79,80 Relative sparing of the lung bases, seen in a majority of cases of chronic HP, may allow chronic HP and UIP to be distinguished (figure 18). ³¹ The headcheese sign (figure 19) may be seen in chronic HP also. HRCT is more sensitive than chest radiographs in the assessment of patients with HP, ^70,71,80 although the sensitivity of HRCT is not 100%. ³¹

Sarcoidosis may also be considered as an interstitial lung disease characterized by granulomas. The clinical and radiographic features of sarcoidosis have been described extensively elsewhere ^1-3 and will not be considered further here.

Although early in its course, granulomas may be seen histologically, the radiographic presentation (in particular the HRCT manifestations) of Langerhans cell histiocytosis are dominated by pulmonary cysts. Thus, this disorder will be considered under ILDs characterized by cyst formation.

Interstitial lung diseases characterized by cyst formation: Langerhans' cell histiocytosis

Histologic features--Langerhans' cell histiocytosis, also known as histiocytosis X or eosinophilic granuloma of the lung (EG), is an idiopathic disease of the lung characterized in its early stages by granulomatous nodules containing Langerhans' histiocytes and eosinophils, which are primarily peribronchial in distribution. In its later stages, the cellular granulomas are replaced by fibrosis and the formation of cysts. ^2,81,82

Clinical findings--EG is an uncommon condition. The majority of patients with EG are young or middle-aged adults (average age of presentation is 32 years). Affected patients present with nonspecific symptoms such as cough, dyspnea, chest pain, weight loss, and fever. ⁸² The physical examination is usually normal, and routine laboratory measurements are usually not helpful. ² Up to 20% of patients present with pneumothorax. There is a slight male predominance, and more than 90% of patients are smokers. ⁸³ A causal relationship with smoking is likely. ⁸¹ A diminished DLCO is common, ² with varying degrees of restriction and airflow obstruction also possible.

Radiographic findings­­Chest radiographs: The radiographic findings consist of reticular, nodular, reticulonodular, and cystic disease, often in combination. Abnormalities are usually bilateral, involving predominately the middle and upper lung zones with relative sparing of the costophrenic angles (figure 20). Lung volumes are characteristically normal or increased.

HRCT: Cystic air spaces, which are usually <10 mm in diameter, are typically seen on HRCT. The lung cysts have walls up to several millimeters thick. The presence of distinct walls allows differentiation of these cysts from areas of emphysema, which can also be seen in some patients. Although many cysts appear round, they can also have bizarre shapes, appearing bilobed, clover-leaf shaped, or branching (figure 21). An upper-lobe predominance of cysts is common; the lung bases and the costophrenic sulci are relatively spared. In some patients, cysts are the only abnormality visible on HRCT, but in the majority of cases, small nodules (usually <5 mm in diameter) are also present (figure 21). The nodules are usually solid in appearance, but larger nodules (approximately 1 cm in diameter) sometimes show lucent centers, presumably corresponding to small 'cavities' (figure 21). ⁸⁴ These cavitating nodules may eventually evolve into cysts. ^49,85 In many patients with cysts or nodules, the intervening lung parenchyma appears normal on HRCT, without evidence of fibrosis or septal thickening. ^{3,50,82,84,86} Mediastinal adenopathy in EG has been reported. ⁸⁷ The findings of EG may stabilize or even regress with smoking cessation, ^85,88 although recrudescence has also been observed. ⁸⁹

Interstitial lung diseases characterized by cyst formation: Lymphangiomyomatosis

Histologic features--Lymphangiomyomatosis (LAM) is a rare disease characterized by progressive proliferation of spindle cells, resembling immature smooth muscle, in the lung parenchyma and along lymphatic vessels in the chest and abdomen. Proliferation of spindle cells along the bronchioles leads to air trapping and the development of emphysema and thin-walled lung cysts. Rupture of these cysts can result in pneumothorax. The spindle cell proliferation can also involve the hilar, mediastinal, and extrathoracic lymph nodes, sometimes resulting in dilation of intrapulmonary lymphatics and the thoracic duct. Involvement of the lymphatics can lead to chylous pleural effusion. Proliferation of cells in the walls of pulmonary veins may cause venous obstruction and lead to pulmonary hemorrhage. ^2,90,91

Clinical findings--The majority of patients present with dyspnea. Sixty percent develop chylous pleural effusions; 40% develop pneumothorax; ⁹² and 30% to 40% develop blood-streaked sputum or frank hemoptysis. Almost all patients die within 10 years of the onset of symptoms. Recently, improved prognosis has been reported following treatment with progesterone or oophorectomy. ^2,91

Lymphangiomyomatosis essentially occurs only in women of child-bearing age, usually between 17 and 50 years old. ⁹¹ Rarely, however, it may be seen in postmenopausal women; the oldest patient described was 69 years of age. Caucasians are more commonly affected than other racial groups. Identical clinical, radiologic, and pathologic pulmonary changes may be seen in about 1% of patients with tuberous sclerosis. ^2,90 Although tuberous sclerosis affects both sexes equally, the pulmonary changes have been described almost exclusively in women.

Radiographic findings--Chest radiographs: The plain radiologic manifestations of LAM include reticular, miliary, and honeycomb patterns (figure 22). Lung volumes can be increased in patients with this disease. The radiologic findings may precede, accompany, or postdate other manifestations of the disease such as pneumothorax and chylous pleural effusion. ⁹³ In patients treated for recurrent pneumothoraces, extensive parenchymal abnormalities not visible on radiographs have been demonstrated at surgery.

HRCT: On HRCT, patients with LAM characteristically show numerous thin-walled cysts, surrounded by relatively normal lung parenchyma (figure 23). These cysts usually range from 2 to 5 mm in diameter, but can be larger. Their size tends to increase with progression of the disease. Irregularly shaped lung cysts, as are seen in patients with EG, are uncommon. ^3,94

In the majority of patients, the cysts are distributed diffusely throughout the lungs and no lung is spared; diffuse lung involvement is seen even in patients with mild disease. In most patients, the lung parenchyma between cysts appears normal on HRCT. Small nodules are occasionally seen, but are not a prominent feature of this disease as they are with EG. ^2,3

Other features of LAM, which can be seen on HRCT, include hilar, mediastinal, and retrocrural adenopathy. ⁹⁰ Pleural effusion can also be seen, and is helpful in distinguishing LAM from EG. ³

Conclusion

Although no classification scheme is entirely satisfying, the interstitial lung diseases may be broadly grouped into categories based on common clinical, radiographic, or histologic findings. The radiographic findings are usually nonspecific, HRCT findings may narrow the differential diagnosis and occasionally allow a specific diagnosis to be made. Organization of these diseases into a structural framework facilitates understanding of their histologic and radiographic findings, and increases the likelihood that an accurate diagnosis will be made. AR