I n t e g r a t i ve I m a g i n g • R ev i ew Ferguson and Berkowitz CT of Interstitial Pneumonia

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Integrative Imaging Review

CME SAM

Emma C. Ferguson1 Eugene A. Berkowitz 2 Ferguson EC, Berkowitz EA

Lung CT

Lung CT: Part 2, The Interstitial Pneumonias—Clinical, Histologic, and CT Manifestations OBJECTIVE. The interstitial pneumonias are a group of heterogeneous nonneoplastic lung diseases that may be idiopathic or associated with an underlying abnormality. Although they share some features in common, they also exhibit diverse pulmonary manifestations. Imaging plays an essential role in characterizing this group of disorders and can often suggest the diagnosis, though the final interpretation requires a coordinated effort involving the radiologist, pathologist, and clinician. The purpose of this article is to review the imaging features of the interstitial pneumonias according to their histologic patterns and to provide a brief overview of their clinical presentations. CONCLUSION. This article reviews the interstitial pneumonias according to their histologic subtypes, including both idiopathic and secondary forms. On completion, the reader should have an improved understanding of the classification of the interstitial pneumonias, associated causes, characteristic imaging features, histologic descriptions, clinical manifestations, and prognoses.

T

Keywords: classification of interstitial pneumonias, chest CT, idiopathic and secondary lung disease, interstitial lung disease, pulmonary histology DOI:10.2214/AJR.10.7309 Received November 1, 2010; accepted after revision November 15, 2011. 1 Department of Radiology, University of Texas Houston Medical School, 6431 Fannin St, MSB 2.130B, Houston, TX 77030. Address correspondence to E. C. Ferguson ([email protected]). 2 Department of Radiology, Division of Cardiothoracic Imaging, Emory University, Atlanta, GA.

CME/SAM This article is available for CME/SAM credit. WEB This is a Web exclusive article. AJR 2012; 199:W464–W476 0361–803X/12/1994–W464 © American Roentgen Ray Society

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he interstitial pneumonias are a heterogeneous group of nonneoplastic diffuse parenchymal lung diseases that result from damage to the lungs by varying combinations of inflammation and fibrosis [1–3]. The primary site of injury is the interstitium, which includes the space between the epithelial and endothelial membranes, though adjacent structures such as the airspaces, airways, and vessels are often affected [1, 2]. Interstitial pneumonias may be idiopathic or can be secondary to a variety of other causes, including collagen vascular diseases, pneumoconioses, infection, and smoking [1]. Accurate diagnosis of these disorders requires interaction among pathologists, radiologists, and pulmonologists. The American Thoracic Society and European Respiratory Society defined and established diagnostic criteria for the idiopathic interstitial pneumonias in 2002 according to clinical manifestations and histologic and radiologic features [1]. In this classification, the histologic pattern provided by the pathologist serves as the basis for the clinical-radiologic-pathologic diagnosis. The term “pattern” can be added to the histopathologic diagnosis to distinguish it from the clinical-radiologicpathologic diagnosis [1]. The final clinicopathologic diagnosis is given after reviewing

the clinical and radiologic features [1, 2, 4]. The American Thoracic Society and European Respiratory Society classification includes seven clinicopathologic entities, listed in order of decreasing frequency: idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia, acute interstitial pneumonia (AIP), respiratory bronchiolitis (RB)–associated interstitial lung disease (ILD), desquamative interstitial pneumonia (DIP), and lymphoid interstitial pneumonia (LIP) [1]. Although the interstitial pneumonias can occur as idiopathic entities, many of them instead develop in association with some other abnormality. Thus, this article reviews the interstitial pneumonias on the basis of their histologic subtypes, examining both idiopathic and secondary forms of disease (Table 1). As such, the interstitial pneumonias will be grouped according to their histologic patterns, including usual interstitial pneumonia (UIP), NSIP, organizing pneumonia, diffuse alveolar damage (DAD), RB, DIP, and LIP. RB and DIP will be further categorized as smoking-related ILDs (Tables 2 and 3). Usual Interstitial Pneumonia The UIP pattern is most frequently associated with IPF. IPF is a chronic fibrotic disease

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CT of Interstitial Pneumonia TABLE 1: Idiopathic and Secondary Forms of the Interstitial Pneumonias According to Histologic Pattern

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Histologic Pattern

Idiopathic Clinicopathologic Diagnosis

Secondary Causes of Disease

Usual interstitial pneumonia

Idiopathic pulmonary fibrosis

Asbestosis, collagen vascular disease, chronic hypersensitivity pneumonitis, drug toxicity, and sarcoidosis

Nonspecific interstitial pneumonia

Nonspecific interstitial pneumonia

Collagen vascular disease, hypersensitivity pneumonitis, drug toxicity, and infection

Organizing pneumonia

Cryptogenic organizing pneumonia

Collagen vascular disease, infection, drug toxicity, inhalational injury, and sarcoidosis

Diffuse alveolar damage

Acute interstitial pneumonia

Acute respiratory distress syndrome

Respiratory bronchiolitis

Respiratory bronchiolitis–associated interstitial lung disease

Smoking

Desquamative interstitial pneumonia

Desquamative interstitial pneumonia

Smoking, infection, dust, and drug toxicity

Lymphoid interstitial pneumonia

Lymphoid interstitial pneumonia

Autoimmune disorder, immunodeficiency

of unknown cause and is the most common of the idiopathic interstitial pneumonias, accounting for 50–60% of cases [5]. Although IPF accounts for most patients with UIP, the UIP pattern may also develop in association with drug and dust exposure, chronic hypersensitivity pneumonitis, collagen vascular diseases, and asbestos exposure [1, 5]. Therefore, underlying causes such as these must be excluded before classifying UIP as idiopathic and rendering a clinicopathologic diagnosis of IPF. Clinical Presentation Most patients with IPF are older than 50 years at the time of diagnosis. The onset of symptoms is usually gradual, with progressive shortness of breath, dry cough, and dyspnea being most common. It is slightly more common among men [1, 3–5]. It is more common among smokers; thus, cigarette smoking seems

to be a risk factor for the development of IPF [4, 5]. The clinical course is one of gradual deterioration. Unlike other interstitial pneumonias, IPF does not respond to corticosteroid therapy and thus has a substantially poorer prognosis. The median length of survival from the time of diagnosis is 2.5–3.5 years [1, 3, 5]. The most common cause of death is respiratory failure and cor pulmonale due to extensive interstitial fibrosis [6]. In contrast, studies have shown that patients with secondary forms of UIP, such as those associated with collagen vascular diseases, tend to have a better prognosis than do patients with idiopathic UIP [7]. Histologic Findings UIP is characterized histologically by a heterogeneous combination of interstitial inflammation, fibroblastic foci, fibrosis, and honeycombing, with normal intervening regions of lung within the same biopsy specimen. This

temporal heterogeneity is characteristic of UIP, reflecting different stages of fibrosis, including old and active lesions [1, 3–5]. The peripheral and basal lung regions are the most severely affected. UIP is primarily a fibrotic process, though mild to moderate interstitial inflammation consisting of lymphocytes, plasma cells, histiocytes, and hyperplastic type 2 pneumocytes may also be present [1, 3]. Unlike other interstitial pneumonias, idiopathic UIP can often be diagnosed on the basis of typical high-resolution CT features. If the imaging findings correlate with the clinical findings, then surgical biopsy may not be needed. However, definitive histologic diagnosis of UIP requires a surgical lung biopsy, especially when the clinical or imaging features are atypical [1, 4, 6]. Biopsy samples should be obtained from more than one lobe of the lungs, particularly because several subtypes of interstitial pneumonias can coexist in

TABLE 2: Comparison of CT Findings in the Interstitial Pneumonias Histologic Pattern

CT Findings

Distribution on CT

Usual interstitial pneumonia

Honeycombing, traction bronchiectasis, reticular opacities, architectural distortion, and volume loss, with or without ground-glass opacities

Peripheral and lower lobe predilection

Nonspecific interstitial pneumonia

Ground-glass opacities, reticular opacities, and bronchiectasis, with or without honeycombing

Lower lobe predilection and symmetric, with or without subpleural sparing

Organizing pneumonia

Patchy consolidation or ground-glass opacities, nodules, air bronchograms, and bronchiectasis, with or without perilobular opacities

Peripheral or peribronchovascular with lower lobe predilection

Diffuse alveolar damage

Ground-glass opacities with or without consolidation in early phase; architectural distortion, traction bronchiectasis, and honeycombing in later phase

Lower lobe predilection or diffuse

Respiratory bronchiolitis

Centrilobular ground-glass nodules, patchy ground-glass opacities, and bronchial wall thickening

Diffuse

Desquamative interstitial pneumonia

Ground-glass opacities, with or without cysts

Peripheral and lower lobe predilection

Lymphoid interstitial pneumonia

Ground-glass opacities, centrilobular nodules, thickened bronchovascular bundles and interlobular septa, and perivascular cysts

Diffuse or lower lobe predilection

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Ferguson and Berkowitz TABLE 3: Salient CT Findings in the Interstitial Pneumonias

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Histologic Pattern

CT Finding

Usual interstitial pneumonia

Lower lobe honeycombing

Nonspecific interstitial pneumonia

Lower lobe ground-glass opacities

Organizing pneumonia

Peripheral or bronchovascular opacities

Diffuse alveolar damage

Lower lobe or diffuse ground-glass opacities

Respiratory bronchiolitis

Centrilobular ground-glass nodules

Desquamative interstitial pneumonia

Lower lobe ground-glass opacities

Lymphoid interstitial pneumonia

Perilymphatic ground-glass opacities or nodules

the same lung. If the biopsy specimen reveals the presence of a UIP pattern along with another coexisting interstitial pneumonia such as NSIP, then the default pathologic diagnosis is UIP because the prognosis more closely resembles that of UIP [1, 8, 9]. Imaging Findings The CT findings of UIP are heterogeneous, with regions of fibrotic lung alternating with regions of normal lung. Characteristic CT features of UIP include reticular opacities, honeycombing, and traction bronchiectasis with a basal and peripheral predilection associated with lower lobe volume loss (Figs. 1A and 1B). Given the association of smoking with idiopathic UIP, volume loss may be less than expected in these patients secondary to coexisting emphysema. Another common finding in UIP is architectural distortion resulting from lung fibrosis [1–5]. Honeycombing is a prominent feature identified in most patients with idiopathic UIP (Fig. 2). The honeycomb cysts range in size from 2 to 20 mm and usually enlarge slowly over time [3–5]. Consolidation and nodules are typically absent [10]. Ground-glass opacities are commonly visible on CT in patients with idiopathic UIP, but they are limited in extent and less extensive than the reticular pattern [1, 3, 4]. Ground-glass opacities are often located in areas of architectural distortion, reflecting microscopic fibrosis rather than inflammation (Fig. 3). Ground-glass attenuation may, at times, represent potentially reversible inflammation, but only when there are no superimposed findings of fibrosis [5, 10]. Other sources of ground-glass opacity in patients with idiopathic UIP include honeycomb cysts filled with secretions, airspace filling by macrophages, or complications such as infection or drug reaction [1, 5]. Other entities in which the UIP pattern may be identified include collagen vascular diseases, such as rheumatoid arthritis and

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scleroderma, chronic hypersensitivity pneumonitis, and asbestos exposure. The CT appearance of UIP in these patients is similar to that found in idiopathic UIP, though additional imaging findings or differences in distribution of disease may aid in their differentiation. For example, esophageal dilatation may be seen in scleroderma; pleural disease, parenchymal bands, and subpleural lines may occur with asbestos exposure, and air trapping with mosaic attenuation and ground-glass opacities may be identified in patients with chronic hypersensitivity pneumonitis, often in the mid to upper lungs. In addition, honeycombing may be slightly less prominent in patients with chronic hypersensitivity pneumonitis and asbestosis [11]. A complication that some patients with idiopathic UIP may experience is accelerated deterioration, or acute exacerbation, of their disease. This is characterized by acute worsening of dyspnea within 1 month, accompanied by new bilateral pulmonary opacities at imaging without an identifiable cause [5, 6]. The prevalence is reported to range from 9.6% of patients over 2 years to 57% of patients over 3 years. The mortality ranges from 53% to 78% [5]. High-resolution CT typically shows ground-glass opacities or consolidation, which may be diffuse, multifocal, or peripheral [12]. The most common histologic finding in these patients is DAD, less commonly organizing pneumonia, or extensive fibroblastic foci superimposed on findings of UIP [1, 5, 6, 12]. The presence of DAD carries a worse prognosis [6, 12]. Another complication that can develop in some patients with UIP is lung cancer. The incidence of lung cancer is about 10–15% and usually occurs in the lower lobes [4]. Mild mediastinal lymph node enlargement is common in patients with UIP, usually involving one or two nodal stations and measuring less than 15 mm in short-axis diameter [5, 13]. Mediastinal lymph nodes

tend to increase in size with advancing disease, presumably because of reactive hyperplasia due to chronic inflammation [13]. This is considered to be part of the UIP process and occurs in the absence of superimposed infection or malignancy [14]. Nonspecific Interstitial Pneumonia In contrast to UIP, NSIP occurs more commonly in association with other conditions such as connective tissue diseases (especially scleroderma and polymyositis or dermatomyositis), hypersensitivity pneumonitis, drug toxicity, infection, and immunodeficiency, including HIV infection [1, 5]. NSIP may be the sole manifestation of hypersensitivity pneumonitis or may precede the diagnosis of collagen vascular disease by months or years [1]. Therefore, an underlying cause must be sought before making a diagnosis of idiopathic NSIP. When idiopathic, NSIP represents the second most common idiopathic interstitial pneumonia, accounting for 14–36% of cases [15]. NSIP is a chronic ILD characterized by homogeneous alveolar wall thickening caused by inflammation or fibrosis [2, 3, 5]. Lung biopsy findings in patients with NSIP are incompatible with other types of interstitial pneumonias but distinct enough to be categorized separately [16]. Clinical Presentation NSIP has a substantially better prognosis than UIP [1–5]. The symptoms of NSIP are also milder, including gradual worsening cough and dyspnea over several months, weight loss, and fatigue. Most patients are typically 40–50 years old at the time of diagnosis. There is no sex predilection. Cigarette smoking may be a risk factor for its development. Histologic Findings The histologic subtypes of NSIP are on a continuum, ranging from cellular to mixed cellular and fibrotic, depending on the amount of alveolar wall inflammation and fibrosis present at lung biopsy [3, 4, 16, 17]. A mixed cellular and fibrotic pattern is frequently encountered. Cellular NSIP consists primarily of chronic interstitial inflammation, usually with lymphocytes and a few plasma cells. Fibrotic NSIP results from interstitial thickening due to collagen accumulation. The histologic hallmark of NSIP is its temporal homogeneity, in which the lung lesions are all of approximately the same age and in the same stage at biopsy [3–5]. It is also spatially homogeneous. This contrasts with UIP,

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CT of Interstitial Pneumonia

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in which the biopsy sample reveals heterogeneous findings of dense collagen and fibroblastic foci representing old and active sites of disease, respectively. Fibroblastic foci are absent or inconspicuous in NSIP [1]. Imaging Findings The dominant CT finding in NSIP is ground-glass opacity, which is usually bilateral and symmetric with lower lobe predominance (Fig. 4). Pathologically, this groundglass attenuation corresponds to homogeneous interstitial inflammation, which is a key feature in distinguishing NSIP from UIP [1, 4]. Other common CT findings include fine reticulation, traction bronchiectasis, and lower lobe volume loss, which indicate the presence of interstitial fibrosis and microscopic honeycombing at histologic analysis [1–3, 5]. Honeycombing is not a predominant feature of NSIP and tends to be mild when present, occurring in 5–30% of patients [5] and almost exclusively in those with fibrotic NSIP [4, 17]. Severe fibrotic changes and honeycombing are typically absent in cellular NSIP [17] (Fig. 5). A unique imaging feature of NSIP that helps to bolster its diagnosis is relative subpleural sparing of the dorsal regions of the lower lobes, seen in about 20–65% of patients [5] (Fig. 6). Consolidation is not a common finding in NSIP [3, 5]. When chronic scattered consolidation is detected, it is usually due to superimposed organizing pneumonia [5]. Acute exacerbations are less common in NSIP than in UIP, occurring in 4.2% of patients with NSIP and manifesting as rapidly developing airspace consolidation or ground-glass attenuation in an acutely ill patient. Diffuse alveolar damage is often found at biopsy in these patients [6, 17]. About 80% of patients have mediastinal lymph node enlargement, which increases with greater extent of disease. Mediastinal adenopathy is usually mild, measuring 10–15 mm in short axis and involving one or two nodal stations, usually the right lower paratracheal or subcarinal regions [5]. CT characteristics of NSIP often change over time. Most parenchymal abnormalities, including ground-glass opacities, reticulation, and bronchial dilatation, improve with treatment. In general, patients with predominant ground-glass abnormality improve or resolve with treatment and do not progress to honeycombing [2–4]. In contrast, some patients with fibrotic NSIP have severe disease that may closely resemble UIP [18]. The prognosis of NSIP depends on the degree of fibrosis [2, 3]. Cellular NSIP has an

excellent prognosis, with a survival rate of nearly 100% [16, 17]. Fibrotic NSIP has a far worse prognosis, with 5-year survival rates ranging from 45% to 90% and 10-year survival rates of only 35% [17]. However, the survival rate for fibrotic NSIP remains better than that of UIP [17]. Most patients with NSIP, particularly cellular NSIP, improve or stabilize with corticosteroid therapy and cytotoxic drugs. Organizing Pneumonia Organizing pneumonia was previously referred to as “bronchiolitis obliterans organizing pneumonia,” though this latter term has since been abandoned to avoid confusion with airway diseases such as bronchiolitis obliterans [1, 4, 19, 20]. Organizing pneumonia is a nonspecific inflammatory response by the lung to various forms of injury. The organizing pneumonia pattern may occur in association with a wide variety of entities, including collagen vascular diseases, infections, inflammatory bowel disease, inhalational injury, drug toxicity, radiation therapy, and organ transplantation [4, 5, 19]. When no underlying cause is identified, the term “cryptogenic organizing pneumonia” may be used to refer to the associated idiopathic clinical syndrome [3]. Clinical Presentation Organizing pneumonia affects both men and women equally, with a mean age of onset of 55 years. Symptoms include cough and dyspnea that develop over a few weeks and are often preceded by an unconfirmed lower respiratory tract infection treated with antibiotics [1, 2, 4]. Additional symptoms may develop and persist, such as weight loss, chills, fever, and myalgias. Most patients are nonsmokers [2, 5] and most respond to corticosteroids and have a good prognosis [5]. However, relapses occur frequently within 1–3 months when corticosteroids are stopped or reduced. Therefore, prolonged treatment of 6 months or more is advised to avoid relapse [1, 2, 4]. In spite of therapy, about 15% of patients may have progressive disease leading to marked impairment of lung function, chronic severe fibrosis, and even death [21]. Histologic Findings The organizing pneumonia pattern is characterized histologically by the presence of intraluminal plugs of granulation tissue within the alveolar ducts and alveoli associated with variable amounts of interstitial and alveolar infiltrates of mononuclear cells and

foamy macrophages. Granulation tissue polyps may also be present within the respiratory bronchioles [1, 2, 5]. Imaging Findings Diverse imaging manifestations may be seen on chest CT in patients with organizing pneumonia. The most common finding is bilateral patchy opacities with a predominantly peripheral or peribronchovascular distribution, seen in up to 50% of cases [1, 3]. Most of these airspace opacities are consolidative, though ground-glass opacities are another frequent finding [3] (Fig. 7). The lower lungs are more often involved [1, 4]. Air bronchograms and mild bronchial dilatation are commonly evident in regions of consolidation [4, 5]. Occasionally, ground-glass opacities may be the predominant manifestation of organizing pneumonia, in which case they tend to be bilateral and random in distribution [5]. Organizing pneumonia may also mimic the appearance of pneumonia, producing airspace opacities that range from a few centimeters to an entire lobe [4]. Organizing pneumonia is also known to produce the crazy-paving pattern, which consists of ground-glass opacities with superimposed septal thickening [22] (Fig. 8). Pulmonary nodules may be seen in patients with organizing pneumonia. Small nodules (< 10 mm) are visible in about half of cases, usually located along the bronchovascular bundles [1]. Multiple large nodules (> 10 mm) are less common, occurring in about 15% of patients [1]. Pulmonary nodules may be well defined or spiculated with irregular margins simulating the appearance of carcinoma (Fig. 9). Air bronchograms, pleural tags, pleural thickening, and parenchymal bands may be seen in association with these nodules [1, 23]. Nodules may cavitate. Additional imaging findings may include other subpleural abnormalities, namely perilobular opacities and subpleural reticulation. Perilobular opacities are a unique finding identified in some patients. They appear as poorly defined, bowed, or polygonal opacities predominantly in the subpleural regions of the lungs involving the structures that border the secondary lobule, known as the perilobular region [21]. Perilobular opacities are thicker and more irregular than thickened interlobular septa. Subpleural reticulation is a less common finding in patients with organizing pneumonia that most commonly occurs in the lower lobes and signifies histologic evidence of fibrosis [3, 5, 23].

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Ferguson and Berkowitz Occasionally, crescentic or ring-shaped opacities surrounding regions of groundglass attenuation may be seen, referred to as the atoll sign and reversed halo sign (Fig. 10), respectively. Histopathologically, the crescentic or ring-shaped peripheries correspond to organizing pneumonia within the alveolar ducts, and the central ground-glass attenuation results from alveolar septal inflammation and cellular debris [23, 24]. Diffuse Alveolar Damage AIP is a rapidly progressive form of interstitial pneumonia that develops in an otherwise healthy person over a few days to weeks. It is characterized by the histologic finding of DAD [1, 2, 5]. It is indistinguishable both clinically and histologically from acute respiratory distress syndrome (ARDS), which is known to be associated with a variety of conditions, including sepsis, shock, uremia, trauma, pneumonia, and toxic inhalation [1, 3]. However, the term “acute interstitial pneumonia” is reserved for DAD of unknown cause. In most cases of AIP, the clinical criteria for ARDS are fulfilled [4]. Clinical Presentation AIP may affect a wide age range, though the mean age of involvement is 50 years. There is no sex predilection, nor is it associated with smoking. AIP is the only idiopathic interstitial pneumonia with an acute onset of symptoms. Patients often report a prodromal illness suggestive of a viral upper respiratory tract infection with symptoms such as fever, chills, myalgias, cough, and dyspnea followed by rapidly progressive severe exertional dyspnea that develops over a few days [1, 2]. Most patients present for medical attention within 3 weeks of the first symptom [4]. Hypoxemia and respiratory failure develop early, usually necessitating mechanical ventilation [3]. Otherwise, treatment is mostly supportive, consisting of oxygen supplementation and corticosteroid therapy, which may be effective in the early stage of disease. The prognosis for patients with AIP is poor. It carries a 50% or greater mortality rate [4], with most deaths occurring within 1–2 months from the time of presentation [2]. Those who survive may improve or develop progressive lung fibrosis [4]. Histologic Findings AIP and ARDS are characterized histologically by the presence of DAD, which may be categorized into three phases: the acute

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exudative phase, the subacute proliferative phase, and the chronic fibrotic phase [25]. The acute exudative phase results in edema, formation of hyaline membranes, and acute interstitial inflammation [1, 5]. This phase lasts for about the first 6 days [26]. The subacute proliferative phase is characterized by interstitial and airspace fibroblast proliferation and type 2 pneumocyte hyperplasia [5]. This phase lasts from about the fourth through tenth days [26]. The final phase is the chronic fibrotic phase in which collagen deposition and fibrosis ensue [5], seen after approximately the eighth day from the onset of disease [26]. Thrombi may form in smallto-medium pulmonary arterioles [1]. Imaging Findings The CT findings of AIP are similar to those of ARDS, though AIP more often produces symmetric and bilateral findings that are greater in the lower lobes but tend to spare the costophrenic recesses [1, 4]. The CT findings in patients with DAD vary depending on the phase of disease. In the early exudative phase, ground-glass opacities are the dominant CT finding and are usually bilateral and patchy, with areas of lobular sparing producing a geographic pattern [1, 3] (Figs. 11A and 11B). A crazy-paving pattern may be seen [5]. Ground-glass opacities reflect the presence of edema and hyaline membranes. Areas of consolidation are also usually present but are less extensive than the ground-glass opacities and are predominantly located in the dependent portions of the lung (Fig. 11C). In the early phase, this airspace consolidation may result from hemorrhage and edema or from dependent atelectasis produced by the weight of the more superior lung tissue [1, 4]. The distribution of disease is usually basilar but can occasionally be diffuse or, less commonly, upper lobe predominant. The later fibrotic phase of DAD is associated with architectural distortion, traction bronchiectasis, and honeycombing [2, 3, 5]. The CT features of fibrosis, such as a coarse reticular pattern and architectural distortion, may be more severe in the nondependent portions of the lungs [27]. This is because the dependent lungs are protected from the potentially damaging effects of mechanical ventilation during the acute phase by the presence of dependent consolidation and atelectasis [1, 4, 27]. During the fibrotic phase of DAD, most consolidation is replaced by ground-glass attenuation [1]. However, some consolidation may

still be observed during the fibrotic phase because of intraalveolar fibrosis [4]. In general, when ground-glass attenuation or consolidation is accompanied by traction bronchiectasis, then the proliferative and fibrotic phases of DAD are implicated, whereas groundglass opacities or consolidation occurring in the absence of traction bronchiectasis corresponds to the acute exudative phase [1, 28]. Follow-up imaging of patients who survive DAD shows progressive clearing of the ground-glass attenuation and consolidation. The lungs may return to normal [1]. However, common residual high-resolution CT findings include reticulation, architectural distortion, and honeycombing [3]. Honeycombing is seen more frequently in AIP than in ARDS and tends to be more symmetric in distribution [3, 25]. Smoking-Related Interstitial Lung Disease (Respiratory Bronchiolitis and Desquamative Interstitial Pneumonia) RB, RB-associated ILD, and DIP represent a continuum of smoking-related lung injury because of significant overlap in their clinical, imaging, and histologic findings [4]. RB is asymptomatic and is an incidental finding in smokers [29]. Some patients who are heavy smokers may develop ILD, resulting in significant pulmonary symptoms and imaging abnormalities, in which case it is referred to as RB-associated ILD [1, 3, 30]. Despite the clear association with smoking, RB-associated ILD has been classified as an idiopathic interstitial pneumonia. DIP represents the end spectrum of RB-associated ILD, which is usually but not always associated with smoking [1, 3, 29]. The incidence of smoking is lower in patients with DIP (60–90%) than in patients with RB and RB-associated ILD [31]. Thus, pure DIP is usually smoking related, whereas the DIP pattern has also been reported in nonsmokers in a variety of conditions, including lung infections, exposure to organic dusts, drug reactions, and even passive exposure to cigarette smoking found in second-hand smokers [1, 4, 29, 31, 32]. Clinical Presentation Most patients with RB-associated ILD and smoking-related DIP are in their fourth and fifth decades of life. The average cigarette smoking history in patients with RBassociated ILD is 30 pack-years, whereas the average history in pure DIP is lower at 18 pack-years [4]. Men are affected about

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CT of Interstitial Pneumonia twice as often as women. Symptoms include gradual onset of dyspnea and dry cough and, sometimes, hypoxemia. Patients with RB-associated ILD and pure DIP generally have a good prognosis and improve after cessation of smoking, which is the most important therapy [1–4]. No deaths have been reported in RB-associated ILD, and progressive pulmonary fibrosis is not a feature of this disease. However, DIP can progress to respiratory failure with restrictive pulmonary fibrosis and eventual death, especially in patients with persistent cigarette smoking. The overall long-term survival rate in DIP is about 70% after 10 years [2]. Histologic Findings Both RB and RB-associated ILD show the same histopathologic lesion of respiratory bronchiolitis at biopsy, characterized by the intraluminal accumulation of pigmented macrophages centered on the respiratory bronchioles [29, 31]. DIP is considered to be a more extensive and severe form of RB-associated ILD in which the pigmented macrophages diffusely fill the alveolar spaces throughout greater areas of the lung. Although the interstitium becomes thickened by mild fibrosis and inflammatory infiltrates, the alveolar wall architecture remains preserved. Honeycombing is minimal or absent [23, 24]. Of note, the term “desquamative interstitial pneumonia” is considered a misnomer because it was previously thought to be due to desquamation of epithelial cells, which has since been disproven. In view of this fact, changing the name to “alveolar macrophage pneumonia” has been contemplated; however, given its rarity, the term “desquamative interstitial pneumonia” has been retained [1, 2]. Imaging Findings The most common CT findings in patients with RB-associated ILD are small centrilobular ground-glass nodules, patchy groundglass opacities, and bronchial wall thickening [1, 4, 31] (Fig. 12). The centrilobular nodules correspond to macrophage accumulation within the respiratory bronchioles and surrounding airspaces [29, 30]. The distribution is mostly diffuse [4]. Patchy regions of lobular hypoattenuation may be seen, reflecting small airways disease and air trapping [31]. Coexisting centrilobular emphysema is common, given that most patients have an extensive cigarette smoking history. The CT findings of RB-associated ILD may be reversible in patients who stop smoking [3].

Ground-glass opacities are a characteristic finding of DIP, visible on CT in all cases [1–4]. The mid and lower lungs are predominantly involved with a peripheral predilection [1–3, 29, 31] (Figs. 13A–13C). The groundglass opacities may be patchy or homogeneous. Diffuse and uniform involvement is seen in a minority of patients. Ground-glass opacities correlate histologically with the intraalveolar accumulation of macrophages and thickened alveolar septa [1, 3, 4]. The presence of reticulation signifies fibrosis, usually limited to the lung bases [3, 4]. Honeycombing occurs in less than one third of cases [2]. Well-defined cysts may occur in regions of ground-glass attenuation and are usually thin walled, round, and smaller than 2 cm in diameter [3, 29]. Emphysema may also be visualized in patients with smoking-related DIP. The main difference between RB-associated ILD and DIP is the distribution of disease, which is centrilobular in RB-associated ILD and diffuse in DIP. Centrilobular nodules are uncommon in DIP. Groundglass opacities are usually patchier, less well defined, and less extensive in RB-associated ILD [3]. Despite the imaging differences that may exist between RB-associated ILD and DIP, they can at times be indistinguishable from one another. Because RB-associated ILD and DIP are considered to represent a spectrum of macrophage-related disorders stemming from cigarette smoking, it is not unusual for features of both entities to be present on a single lung biopsy specimen. Lymphoid Interstitial Pneumonia LIP is regarded as a variant of diffuse pulmonary lymphoid hyperplasia primarily affecting the interstitium. It was previously considered a pulmonary lymphoproliferative disorder that progressed to malignant lymphoma in up to 30% of cases [33]. However, many patients who were previously diagnosed with LIP in whom malignancy subsequently developed were reclassified as having lymphoma from the outset [4, 34]. The actual risk of malignant transformation in patients with definite LIP is quite low, estimated to be about 5% [33]. LIP must be distinguished from lowgrade malignant lymphoproliferative diseases with immunohistochemical analysis [33]. Progression to lymphoma is quite uncommon when the LIP is due to a polyclonal lymphocyte proliferation. Idiopathic LIP is rare. LIP is much more frequently associated with systemic disorders such as Sjögren syndrome, AIDS, autoimmune thy-

roid disease, and Castleman disease [1, 4, 35]. Therefore, the identification of this pattern should prompt a search for a potential underlying cause. Clinical Presentation The majority of patients with LIP are women, typically during the fifth decade of life. The onset of symptoms is slow with gradually increasing dyspnea and cough. Occasionally, systemic symptoms such as fever, night sweats, chest pain, weight loss, and arthralgias may be found [1]. Approximately 80% of patients with LIP have serum dysproteinemias [33], in the form of a polyclonal increase in gammaglobulin or a monoclonal increase in IgG or IgM. The risk of a lymphoproliferative malignancy is increased in patients with a monoclonal gammopathy or hypogammaglobulinemia [1]. The treatment of LIP is corticosteroid therapy, which arrests or improves symptoms in many patients, though response to therapy is unpredictable [1, 4]. More than one third of patients have progressive disease despite treatment, resulting in end-stage interstitial fibrosis and honeycombing [1, 34, 36]. Deaths in patients with LIP may result from infections associated with immunosuppression, progressive pulmonary fibrosis, or transformation to malignant lymphoma [33]. Histologic Findings Histologically, LIP is characterized by extensive lymphoid infiltration of the interstitium with lymphocytes, plasma cells, and histiocytes that result in widening of the alveolar septa [1, 33, 34, 36]. Reactive lymphoid follicles are often identified along the highly inflamed peribronchiolar regions [4, 33, 36]. Nonnecrotizing granulomas may be seen [36]. Advanced cases may reveal interstitial fibrosis and honeycombing [1]. Although the primary site of involvement is the interstitium, the airspaces may secondarily become filled with interstitial infiltrates, proteinaceous fluid, or macrophages [4, 33]. Imaging Findings Abnormalities on CT in patients with LIP are usually bilateral and may be diffuse or have lower lung predominance [4]. LIP tends to be most severe in the inflamed perilymphatic interstitium, including the peribronchovascular bundles, pleural surfaces, and interlobular septa [34]. Thus, thickening of the bronchovascular bundles and interlobular septa is a frequent finding. Ground-glass opacities are

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Ferguson and Berkowitz a typical feature of this disease, reflecting the histologic finding of diffuse interstitial inflammation [33, 34, 36]. Centrilobular nodules are also common, owing to the inflammatory infiltration of the peribronchiolar interstitium [34] (Fig. 14). Perivascular cysts are identified in up to 80% of cases [36] (Fig. 15). These cysts are thin walled, typically few in number, measure less than 3 cm, and are seen in close association with adjacent blood vessels [4, 33–36]. The combination of perivascular cysts and ground-glass opacities is highly suggestive of LIP [4] (Fig. 16). Perivascular honeycombing is less common, usually developing in areas of previous airspace abnormality [34]. Conclusion The interstitial pneumonias are a heterogeneous group of diffuse parenchymal lung diseases with diverse imaging manifestations, clinical features, and outcomes. They may be idiopathic or secondary to some other cause. Imaging plays a vital role in helping to differentiate and classify this group of diseases. Some of the interstitial pneumonias may have CT features that are diagnostic, though many of them share common imaging characteristics with significant overlap. Thus, evaluation of all the combined clinical, radiologic, and pathologic data are needed before rendering a final diagnosis. References 1. American Thoracic Society and European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165:277–304 2. Pandit-Bhalla M, Diethelm L, Ovella T, Sloop GD, Valentine VG. Idiopathic interstitial pneumonias: an update. J Thorac Imaging 2003; 18:1–13 3. Lynch DA, Travis WD, Müller NL, et al. Idiopathic interstitial pneumonias: CT features. Radiology 2005; 236:10–21 4. Mueller-Mang C, Grosse C, Schmid K, Stiebellehner L, Bankier AA. What every radiologist should know about idiopathic interstitial pneumonias. RadioGraphics 2007; 27:595–615 5. Silva CI, Müller NL. Idiopathic interstitial pneumonias. J Thorac Imaging 2009; 24:260–273 6. Silva CI, Müller NL, Fujimoto K, et al. Acute exacerbation of chronic interstitial pneumonia: highresolution computed tomography and pathologic findings. J Thorac Imaging 2007; 22:221–229 7. Song JW, Do KH, Kim MY, et al. Pathologic and

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radiologic differences between idiopathic and collagen vascular disease-related usual interstitial pneumonia. Chest 2009; 136:23–30 8. Monaghan H, Wells AU, Colby TV, du Bois RM, Hansell DM, Nicholson AG. Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias. Chest 2004; 125:522–526 9. Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001; 164:1722–1727 10. Souza CA, Müller NL, Flint J, Wright JL, Churg A. Idiopathic pulmonary fibrosis: spectrum of highresolution CT findings. AJR 2005; 185:1531–1539 11. Misumi S, Lynch DA. Idiopathic pulmonary fibrosis/usual interstitial pneumonia: imaging diagnosis, spectrum of abnormalities, and temporal progression. Proc Am Thorac Soc 2006; 3:307–314 12. Akira M, Kozuka T, Yamamoto S, Sakatani M. Computed tomography findings in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 178:372–378 13. Souza CA, Müller NL, Lee KS, Johkoh T, Mitsuhiro H, Chong S. Idiopathic interstitial pneumonias: prevalence of mediastinal lymph node enlargement in 206 patients. AJR 2006; 186:995–999 14. Bergin C, Castellino RA. Mediastinal lymph node enlargement on CT scans in patients with usual interstitial pneumonitis. AJR 1990; 154:251–254 15. Collard HR, King TE. Demystifying idiopathic interstitial pneumonia. Arch Intern Med 2003; 163:17–29 16. Travis WD, Matsui K, Moss J, Ferrans VJ. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns. Am J Surg Pathol 2000; 24:19–33 17. Kligerman SJ, Groshong S, Brown KK, Lynch DA. Nonspecific interstitial pneumonia: radiologic, clinical, and pathologic considerations. RadioGraphics 2009; 29:73–87 18. Silva CI, Müller NL, Hansell DM, Lee KS, Nicholson AG, Wells AU. Nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis: changes in pattern and distribution of disease over time. Radiology 2008; 247:251–259 19. Lee JS, Lynch DA, Sharma S, Brown KK, Müller NL. Organizing pneumonia: prognostic implication of high-resolution computed tomography features. J Comput Assist Tomogr 2003; 27:260–265 20. Müller NL, Staples CA, Miller RR. Bronchiolitis obliterans organizing pneumonia: CT features in 14 patients. AJR 1990; 154:983–987 21. Ujita M, Renzoni EA, Veeraraghavan S, Wells AU, Hansell DM. Organizing pneumonia: perilobular pattern at thin-section CT. Radiology 2004;

232:757–761 22. Rossi SE, Erasmus JJ, Volpacchio M, Franquet T, Castiglioni T, McAdams HP. “Crazy-paving” pattern at thin-section CT of the lungs: radiologic-pathologic overview. RadioGraphics 2003; 23:1509–1519 23. Akira M, Yamamoto S, Sakatani M. Bronchiolitis obliterans organizing pneumonia manifesting as multiple large nodules or masses. AJR 1998; 170:291–295 24. Kim SJ, Lee KS, Ryu YH, et al. Reversed halo sign on high-resolution CT of cryptogenic organizing pneumonia: diagnostic implications. AJR 2003; 180:1251–1254 25. Tomiyama N, Müller NL, Johkoh T, et al. Acute respiratory distress syndrome and acute interstitial pneumonia: comparison of thin-section CT findings. J Comput Assist Tomogr 2001; 25:28–33 26. Johkoh T, Müller NL, Taniguchi H, et al. Acute interstitial pneumonia: thin-section CT findings in 36 patients. Radiology 1999; 211:859–863 27. Desai SR, Wells AU, Rubens MV, Evans TW, Hansell DM. Acute respiratory distress syndrome: CT abnormalities at long-term follow-up. Radiology 1999; 210:29–35 28. Ichikado K, Johkoh T, Ikezoe J, et al. Acute interstitial pneumonia: high-resolution CT findings correlated with pathology. AJR 1997; 168:333–338 29. Attili AK, Kazerooni EA, Gross BH, Flaherty KR, Myers JL, Martinez FJ. Smoking-related interstitial lung disease: radiologic-clinical-pathologic correlation. RadioGraphics 2008; 28:1383– 1396; discussion, 1396–1398 30. Kanne JP, Bilawich AM, Lee CH, Im JG, Müller NL. Smoking-related emphysema and interstitial lung diseases. J Thorac Imaging 2007; 22:286– 291 [Erratum in J Thorac Imaging 2008; 23:144] 31. Galvin JR, Franks TJ. Smoking-related lung disease. J Thorac Imaging 2009; 24:274–284 32. Woo OH, Yong HS, Oh YW, Lee SY, Kim HK, Kang EY. Respiratory bronchiolitis–associated interstitial lung disease in a nonsmoker: radiologic and pathologic findings. AJR 2007; 188:1263; [web]W412–W414 33. Swigris JJ, Berry GJ, Raffin TA, Kuschner WG. Lymphoid interstitial pneumonia: a narrative review. Chest 2002; 122:2150–2164 34. Johkoh T, Ichikado K, Akira M, et al. Lymphocytic interstitial pneumonia: follow-up CT findings in 14 patients. J Thorac Imaging 2000; 15:162–167 35. Lee KH, Lee JS, Lynch DA, Song KS, Lim TH. The radiologic differential diagnosis of diffuse lung diseases characterized by multiple cysts or cavities. J Comput Assist Tomogr 2002; 26:5–12 36. Silva CI, Flint JD, Levy RD, Müller NL. Diffuse lung cysts in lymphoid interstitial pneumonia: high-resolution CT and pathologic findings. J Thorac Imaging 2006; 21:241–244

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CT of Interstitial Pneumonia

A

B

Fig. 1—63-year-old man with idiopathic pulmonary fibrosis and progressive dyspnea. This diagnosis was based on typical high-resolution CT findings and on clinical evaluation, which did not reveal any underlying disorder, exposure, or other predisposing abnormality in this patient to account for this finding. A and B, Unenhanced axial high-resolution CT images obtained in prone position through left mid (A) and lower (B) lung show peripheral honeycombing, which is greatest in lower lobe, accompanied by traction bronchiectasis and scattered peripheral reticular opacities. Honeycombing is most prominent feature in this patient, typical for idiopathic pulmonary fibrosis.

A

B

Fig. 2—66-year-old man with idiopathic pulmonary fibrosis (IPF) and worsening shortness of breath and cough, without underlying clinical cause. This diagnosis was based on biopsy, given atypical distribution of disease. A and B, Contrast-enhanced axial high-resolution CT images obtained in prone position through mid (A) and upper (B) lungs show abundant honeycombing with upper lung predilection with scattered peripheral reticular opacities. Distribution is asymmetric, with regions of normal intervening lung. Some honeycomb cysts in upper lung measure at least 2 cm in size because of gradual enlargement over time. Honeycombing is main finding in this patient, though upper lung predominance is atypical for IPF.

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Ferguson and Berkowitz

Fig. 3—58-year-old man with idiopathic pulmonary fibrosis (IPF) and symptoms including shortness of breath and cough. Unenhanced axial high-resolution CT image obtained in prone position through left lower lobe shows peripheral honeycombing, reticular opacities, and bronchiectasis, with superimposed ground-glass opacities. Ground-glass opacities are often identified in patients with IPF, usually in regions of architectural distortion reflecting fibrotic changes, rather than inflammation. This diagnosis was ultimately proven by biopsy.

Fig. 4—48-year-old woman with scleroderma, cough, and dyspnea and biopsyproven nonspecific interstitial pneumonia. Unenhanced axial high-resolution CT image obtained in prone position through lower lungs shows scattered ground-glass opacities that are relatively symmetric in distribution, accompanied by bronchiectasis. Honeycombing is absent. Note dilated esophagus, finding associated with scleroderma.

Fig. 5—54-year-old woman with scleroderma, progressive cough, and dyspnea and biopsy-proven fibrotic nonspecific interstitial pneumonia. Unenhanced axial high-resolution CT image obtained in prone position through lower lobes reveals combination of ground-glass opacities, bronchiectasis, and peripheral honeycombing. Note patulous esophagus.

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Fig. 6—51-year-old woman with scleroderma, significant shortness of breath, and biopsyproven nonspecific interstitial pneumonia (NSIP). Unenhanced axial high-resolution CT image obtained in prone position through right mid to lower lung shows marked honeycombing with lower lobe predilection. Severe fibrotic changes are seen in minority of patients with NSIP. Note relative subpleural sparing of dorsal aspect of right lower lobe (arrow), finding that supports diagnosis of NSIP. Esophagus is dilated.

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CT of Interstitial Pneumonia

Fig. 7—58-year-old woman with biopsy-proven cryptogenic organizing pneumonia and history of dyspnea and fever. Contrast-enhanced axial CT image through mid to lower lungs shows classic distribution of peripheral airspace opacities in lungs bilaterally, consisting of combination of consolidative and ground-glass opacities. Note also perilobular opacities (arrows), which are curvilinear or bowed opacities in subpleural lungs involving perilobular region.

Fig. 8—51-year-old woman with history of rheumatoid arthritis, progressive shortness of breath, and biopsy-proven organizing pneumonia. Unenhanced axial CT image through mid to lower lungs illustrates diffuse ground-glass opacities with superimposed interlobular septal thickening, consistent with crazy-paving pattern. Air bronchograms are visible in left upper lobe and right lower lobe.

Fig. 9—44-year-old man with cough and recent abnormal chest radiograph that prompted further evaluation with chest CT, showing irregular mass. Appearance of this lesion prompted biopsy, which revealed organizing pneumonia. Contrastenhanced axial CT image through upper lungs shows irregular and spiculated mass surrounded by mild ground-glass attenuation in right upper lobe. Organizing pneumonia can, at times, simulate appearance of primary bronchogenic carcinoma.

Fig. 10—42-year-old woman with biopsy-proven cryptogenic organizing pneumonia and clinical symptoms including dyspnea and cough. Contrastenhanced axial CT image through right lower lobe illustrates reversed halo sign, produced by ring of consolidation encircling ground-glass attenuation.

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Ferguson and Berkowitz

A

B Fig. 11—47-year-old woman with rapid onset of cough, shortness of breath, and fatigue that evolved into respiratory failure over few days requiring intubation. Lung biopsy revealed diffuse alveolar damage (DAD), and patient was ultimately diagnosed with acute interstitial pneumonia. A–C, Unenhanced axial CT images through upper, mid, and lower lungs show mostly ground-glass opacities, which are patchy, bilateral, and asymmetric in distribution with some geographic regions of sparing. Consolidation is present in left lower lobe, located in dependent region, and not as extensive as groundglass opacities. This combination of findings favors early exudative phase of DAD. Architectural distortion, traction bronchiectasis, and honeycombing which may be seen in proliferative and fibrotic phases of DAD are absent.

C

Fig. 12—50-year-old man with long-standing history of heavy cigarette smoking, dyspnea, cough, and smoking-related interstitial lung disease, proven at biopsy. Unenhanced axial CT image through mid to lower lungs shows diffuse centrilobular ground-glass nodules bilaterally. These centrilobular nodules result from macrophage accumulation within and around respiratory bronchioles.

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CT of Interstitial Pneumonia

A

B Fig. 13—49-year-old woman with persistent and progressive cough, dyspnea, and hypoxemia, prompting biopsy of her lungs, which revealed chronic desquamative interstitial pneumonia (DIP) related to extensive cigarette smoking history. A–C, Unenhanced axial CT images through mid and lower lungs show patchy ground-glass opacities in all lobes of both lungs with peripheral predilection accompanied by lower lobe bronchial wall thickening. These ground-glass opacities are due to accumulation of macrophages within alveolar spaces. Note small cysts scattered mostly in right lung in regions of ground-glass attenuation, finding that can occur in DIP.

C

Fig. 14—58-year-old woman with Sjögren syndrome, persistent dyspnea, and biopsy-proven lymphoid interstitial pneumonia. Unenhanced axial CT image through mid lungs reveals centrilobular ground-glass nodules, finding that develops as consequence of peribronchiolar interstitial inflammation.

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Ferguson and Berkowitz

Fig. 15—73-year-old woman with Sjögren syndrome symptoms, including dyspnea and arthralgias, and biopsy-proven lymphoid interstitial pneumonia (LIP). Contrast-enhanced coronal reformatted image through lungs shows numerous thin-walled cysts mostly located adjacent to blood vessels. These perivascular cysts are identified in most patients with LIP.

Fig. 16—71-year-old woman with Sjögren syndrome, chest pain, cough, dyspnea, and biopsy-proven lymphoid interstitial pneumonia (LIP). Contrast-enhanced axial CT image shows both perivascular cysts and lower lobe ground-glass opacities, combination of findings that strongly supports diagnosis of LIP.

F O R YO U R I N F O R M AT I O N

This article is part of a self-assessment module (SAM). Please also refer to ”Lung CT: Part 1, Mimickers of Lung Cancer— Spectrum of CT Findings With Pathologic Correlation,“ which can be found on page W454. Each SAM is composed of two journal articles along with questions, solutions, and references, which can be found online. You can access the two articles at www.ajronline.org, and the questions and solutions that comprise the Self-Assessment Module by logging on to www.arrs.org, clicking on AJR (in the blue Publications box), clicking on the article name, and adding the article to the cart and proceeding through the checkout process. The American Roentgen Ray Society is pleased to present these SAMs as part of its commitment to lifelong learning for radiologists. Continuing medical education (CME) and SAM credits are available in each issue of the AJR and are free to ARRS members. Not a member? Call 1-866-940-2777 (from the U.S. or Canada) or 703-729-3353 to speak to an ARRS membership specialist and begin enjoying the benefits of ARRS membership today!

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