Differential Diagnosis of Chronic Diffuse Infiltrative Lung Disease on High-Resolution Computed Tomography By Nestor L. Miiller
LARGE NUMBER of chronic diseases may cause diffuse infiltration of the lung parenchyma. Although they are often referred to as chronic interstitial lung diseases, most involve both the interstitium and the airspaces and are therefore better classified as chronic infiltrative lung diseases.‘,’The radiological findings of most of these diseasesare nonspecific. In a review of the radiographs of 365 patients, McLoud et al included the correct diagnosis in the first two radiological choices in only 50% of cases.’ The chest radiograph may also be normal even when there is severe disease clinically and pathologically. Of 458 patients with biopsyproven chronic infiltrative lung disease described by Epler et al, 9.6% had normal chest radiographs.3 First introduced in 1985,4several studies have since shown that high-resolution computed tomography (HRCT) can play a major role in the assessment of patients with chronic infiltrative lung disease. HRCT may demonstrate clinically suspected abnormalities undetected on the radiograph, may have characteristic features in patients with nonspecific changes on the radiographs, and may be useful in determining the type of biopsy and the optimal site for lung biopsy.5,6 The signs that indicate the presence of chronic infiltrative lung disease on HRCT include the
presence of thickened interlobular septa, irregular linear opacities, cystic airspaces, small nodules, ground-glass pattern, and airspace consolidation. The aim of this review is to present a simplified diagnostic approach to chronic diffuse infiltrative lung diseases on HRCT based on the type and distribution of the abnormalities as summarized in Table 1. THICKENED INTERLOBULAR SEPTA
On HRCT in normal individuals, a few interlobular septa can be identified as smooth lines 11 mm thick outlining the secondary pulmonary lobule. These lines are normally seen only in areas where the interlobular septa are most developed, ie, in the anterior and lateral aspects of the lower lobes. Thickening of the septa may occur due to edema, tumor, or fibrosis.7-1’The thickened septa are usually most evident in the lung periphery where they are seen as lines running perpendicular to the pleura. More Table 1. Computed Tomography Patterns Infiltrative Lung Disease
Thickened interlobular septa Lymphatic spread of tumor Pulmonary edema Irregular linear opacities IPF Asbestosis Sarcoidosis Cystic airspaces Lymphangioleiomyomatosis Pulmonary histiocytosis X IPF Nodular opacities Silicosis Coal-worker’s pneumoconiosis Sarcoidosis Extrinsic allergic alveolitis Pulmonary histiocytosis X Ground-glass opacities Extrinsic allergic alveolitis IPF Desquamative interstitial pneumonia Alveolar proteinosis Airspace consolidation Chronic eosinophilic pneumonia BOOP Bronchioloalveolar carcinoma Lymphoma
ABBREVIATIONS BOOP, bronchiolitis obliterans organizing pneumonia; CT, computed tomography; HRCT, highresolution computed tomography; IPF, idiopathic pulmonary fibrosis; UIP, usual interstitial pneumonia
From the Department of Radiology, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada. Address reprint requests to Nestor L. Miiller, MD, PhD, Department of Radiology, University of British Columbia and Vancouver General Hospital, 855 W 12th Ave, Vancouver, British Columbia, Canada V5Z IM9. Copyright 8 1991 by W B. Saunders Company 0037-198X/91/2602-0007$5.00/0 132
Vol XXVI, No 2 (April), 1991: pp 132-142
centrally in the lung, thickening of interlobular septa of several adjacent secondary pulmonary lobules is seen on HRCT as a pattern of multiple polygonal arcades (Fig 1). In pulmonary edema and in lymphatic spread of tumor, the septa have smooth margins whereas in fibrosis, the margins are irregular and the architecture of the secondary lobule is distorted (Fig 2). Irregular thickening of the interlobular septa due to fibrosis is frequently seen in idiopathic pulmonary fibrosis and in asbestosis. A feature helpful in distinguishing lymphatic spread of tumor from edema or fibrosis is nodular or beaded thickening of the interlobular septa and bronchovascular bundles.7-9This beaded thicken-
Fig 1. HRCT findings of lymphatic epmad of tumor. (A) A 55-veer-old women with lymphangftk cercinometoeb due to metaatatb cereinoma of the stomach.tfRcroftherightupperbbe&owssmodb(etmlght awows) and nodubr (wwed arrows) thbkenlng of the [email protected]
@tpfeurd effwion Is also prawt. (B) A 5%yeer-old men with lymphangltb riarchomatwis. HRCT through long apbee shows bifetera1 polygonal arcades.
ing is due to tumor growth and is not seen with edema or fibrosis.‘-” Thickening of the interlobular septa may also be seen in sarcoidosis. However, in sarcoidosis the septal thickening is rarely a major feature. When present, it is often associated with distortion of the architecture of the secondary pulmonary lobules due to fibrosis (Fig 2).12-14 Nodules are almost always present in sarcoidosis and they tend to have irregular margins (Fig 3). Nodules are uncommon in lymphangitic carcinomatosis, but when present they are smooth. Sarcoidosis usually predominantly involves the perihilar regions and central portions of the mid and upper lung zones. Lymphangitic carcinoma-
NESTOR L. MiiLLER
tosis may be seen in all lung zones but it is usually more diffuse or mainly involves the lower lung zones. IRREGULAR LINEAR OPACITIES
Fig 2. A 53.year-old woman with pulmonary Rbrosir related to aarcoidosis. HBCT through the right lung at the level of the tracheal carina shows thickened interlobular repta farrows). The margins of the thickened septa are irregular and the architecture of the secondary pulmonary lobufes is distorted, indicating tha present e of fibroafa. Small nodular densities, presumably representing gramdomes, are present poatariorly.
Irregular linear opacities (= reticular pattern) and abnormal interfaces between vessels, bronchi, and visceral pleura with the surrounding parenchyma indicate the presence of pulmonary fibrosis. Characteristic patterns of fibrosis have been described in idiopathic pulmonary fibrosis (IPF), sarcoidosis, and asbestosis. In IPF (= fibrosing alveolitis, usual interstitial pneumonia [UIP]), the reticular opacities are characteristically most evident in the subpleural lung regions and in the lower lung zones (Fig Early in the course of the disease there 9 15,16 may be marked aIveolitis and mild fibrosis, the main finding being hazy airspace opacification (Fig 5). As the disease progresses, irregular opacities become the main feature, and in the end stage there is extensive honeycombing (Fig 6). Pathologically and on CT, the process is most severe in the lung periphery whether the disease is mild or severe, early in the course, or end stage. The pattern and distribution of interstitial fibrosis associated with collagen vascular disease are indistinguishable from IPF.6S’7 On the other hand, the fibrosis in patients with sarcoidosis is usually more severe centrally along the bronchovascular bundles.‘218This leads to a
Fig 3. A 30.year-old man with rarcoidosk Beaded thkkanhrg of the interlobular septa is seen in both lower lobes and in the tingula (straight arrows). Features characteristic of sarcoidosis include marked nodularity along bronchovascular bundles (curved arrows) and the irregular margins of the nodules.
Fig 4. A Wyear-old man with IPF. HRCT shows characteristic distribution of small irregular linear opacities in the subpleural lung regions (arrows).
characteristic central clustering of bronchi and vessels (Fig 7). HRCT findings characteristic of asbestosis include: (1) subpleural lines, defined as linear densities less than 2 cm long, radiating to the pleura; (2) parenchymal bands, defined as linear densities 2 to 5 cm in length running through the lung, usually extending to a pleural surface; (3) thickened interlobular septal lines and intralobular core structures; and (4) honeycombing, seen as cystlike spaces less than 1 cm in diameter and with discrete thin walls (Fig
8).19-”The diagnosis can be confidently made on HRCT when these findings are present in a patient with a history of asbestos exposure. Although pleural and parenchymal abnormalities may occur independently of one another, Aberle et al demonstrated a strong correlation between the severity of pleural disease and the presence and severity of asbestosis. CYSTIC AIRSPACES
Cystic airspaces are most commonly seen in lymphangioleiomyomatosis, pulmonary histiocy-
Fig 5. A 63.year&l woman w&h WF. MtCT shows hazy alrmatnly in the space subpleural lung regloss. Mild flbrosls Is p?eunt as shown by bilateral subpbral retkhr densitll end lmgular tblekening of the interlobular septa (arrows).
Fig 6. HRCT at level of tracheal carina in a 66-year-old man with IPF. Cystic spaces representing end-stagefibrosisand honey combing are present bilaterally, mainly in the subpleural lung regions.
tosis X, and IPF. Lymphangioleiomyomatosis is characterized on HRCT by the presence of numerous thin-walled cystic airspaces of various sizessurrounded by relatively normal lung parenchyma.22-25 The cysts range from 2 mm to 5 cm in diameter and the wall of the cysts ranges from barely perceptible to 2 mm in thickness (Fig 9). The presence of walls differentiates cystic airspaces from emphysema (Fig 10). Computed tomography (CT) may show cysts in patients with apparently normal pulmonary parenchyma on chest radiographs.
Fig 7. HRCT at level of right upper lobe bronchus in a Bgyearold woman with sarcoidosis. The patient has severe fibrosis Ieading to central conglomeration and dilatation of bronchi. The perlhilar predominance of the fibrosis is particularly evident on the rfght side.
Cystic airspaces similar to those seen in lymphangioleiomyomatosis have been described in a small percentage of patients with pulmonary histiocytosis X.26*27 However, in most patients with histiocytosis X, a nodular component is also present. Furthermore, histiocytosis X characteristically involves the upper two thirds of the lungs and spares the costophrenic angles, whereas lymphangioleiomyomatosis involves the lungs diffusely.25,26The combination of thinwalled cysts and nodules of varying sizes suggests the diagnosis of histiocytosis X, but nei-
lesser extent, visceral pleura and interlobular septa. These are seen as nodules or as nodular thickening of bronchi, vessels, and interlobular septa (Fig 12).” The nodules are usually less than 5 mm in diameter. Their margins may be smooth but are more commonly irregular.‘z-‘4 In silicosis, the nodules are usually more numerous in the posterior aspect of the upper lung zones.28’29 They vary in size from 1 to 10 mm in diameter. In patients with mild silicosis, the nodules may be seen only in the upper lobes. More severe silicosis is characterized on CT by an increase in the number and size of nodules and confluence of nodules. Small nodules are also seen in coal-worker’s pneumoconiosis, graphite pneumoconiosis, and talcosis..” GROUND-GLASS
Bilateral patchy areas of hazy increased density or ground-glass opacities without obscura-
Fii 8. HRCT in patient with asbestosis shows thickened interlobular septal Bnes rating to the pleura (straight arrows) and subpkural reticular densities (curved arrows).
ther finding is specific. Nodules are the predominant feature early on. As the disease progresses, cystic airspaces predominate and in the end stage there is extensive honeycombing (Fig 11). Regardless of the stage, the lower lung zones are relatively spared.26p27 End-stage IPF is characterized by the presence of cystic airspaces (honeycombing), predominantly in the subpleural regions and in the lung bases,unlike the distribution of lymphangioleiomyomatosis, which is more diffuse. In IPF, the honeycomb cysts are surrounded by abnormal parenchyma (Fig 6), whereas in the majority of casesthe cysts in lymphangioleiomyomatosis are surrounded by normal lung.tl,Z NODULAR
Nodules 1 to 10 mm in diameter are seen most commonly in patients with sarcoidosis, silicosis, and coal-worker’s pneumoconiosis. Sarcoidosis is characterized pathologically by the presence of noncaseating granulomas along lymphatics in the bronchovascular bundles and, to a
arepresentmimk)rbrgh~.Mowever,~ekno evidence of Rbrosk between the cystk speaes. The pounce of walls distinguishes these cystic spaces from emphysema.
NESTOR L. MijLLER
interlobular septa is present within the areas of airspace opacification3223giving a “crazy paving” appearance?3The airspace opacification in most patients is sharply demarcated from surrounding normal parenchyma, without any apparent anatomic reason accounting for this sharp edge.32p33 This geographic and “crazy paving” pattern is characteristic for alveolar proteinosis (Fig 14).33 AIRSPACE
Fig 10. HRCT in a 63-year-old man with centriacinar emphysema. The emphysema is seen as localized areas of abnormally low attenuation. These do not have visible walls. When the entire secondary lobule is involved, the interlobular septa may become clearly visible.
tion of the underlying vascular markings are a characteristic feature of the subacute stage of extrinsic allergic alveolitis being seen from 1 week to several months after exposure to the antigen (Fig 13).31The hazy areas of increased density presumably represent active alveolitis with filling of the airspaces by mononuclear cells. Approximately 50% of patients also have ill-defined small nodules. These presumably represent focal areas of cellular bronchiolitis. Hazy areas of increase in density have also been shown to correlate with filling of the airspaces with histiocytes and with alveolar septal inflammation, the hallmarks of disease activity in IPF (Fig 5)” Irregular opacities are usually also present. Airspace opacification may be the only finding in desquamative interstitial pneumonia. Another condition that usually presents with hazy areas of increased density on HRCT is pulmonary alveolar proteinosis. The HRCT features of the airspace disease in alveolar proteinosis have a variable appearance ranging from ill-defined nodular densities to large areas of confluent airspace consolidation.32 In most patients, the pulmonary vascular markings can be clearly seen on HRCI and thickening of the
Although the distinction between areas of hazy increased density and airspace consolidation is somewhat arbitrary, I consider the distinction useful in the differential diagnosis of chronic infiltrative lung disease on HRCT. In airspace consolidation, the vascular markings can no longer be identified and air bronchograms are often present. Chronic diseases associated with airspace consolidation include chronic eosinophilic pneumonia, bronchiolitis obliterans organizing pneumonia (BOOP), lymphoma, and bronchioloalveolar carcinoma. Mayo et a134reviewed the chest radiographs and CT scansin six patients with chronic eosinophilic pneumonia. All patients had patchy, bilateral airspace consolidation, and in five of six casesthe consolidation was most marked in the middle and upper lung zones. The classic pattern of airspace consolidation confined to the outer third of the lungs was readily apparent on the radiograph in only one patient. In three patients, the consolidation appeared to be diffuse, although a slight peripheral predominance was noted. In two patients, a peripheral predominance was difficult to appreciate even in retrospect. In all six cases,a characteristic peripheral airspace consolidation was clearly seen on CT (Fig 15). This study showed that CT may be helpful in the diagnosis of chronic eosinophilic pneumonia when the clinical findings are suggestive but the radiographic pattern is nonspecific. The CT features of BOOP consist of patchy unilateral or bilateral airspace consolidation and small nodular opacities.35A predominantly subpleural distribution of the airspace consolidation is apparent on CT in 50% of patients (Fig 16). This pattern can be identical to that of chronic eosinophilic pneumonia. Unilateral or bilateral airspace consolidation
w~plbn0Mw-x. (A)MRClatlewttdup)rrlebes shows-bibhalheaeyCOtlDbhgOh?dfbhO-~-
ties dua to fwweals. (B) WllcT tbfoughlowerlebeashowschetacteristic rparfng of the lung bases.
may also be a presenting feature of pulmonary lymphoma and bronchioloalveolar carcinoma. These conditions should be suspected if the consolidation progresses over several months or is associated with lung nodules. ACCURACY COMPUTED
OF THE HIGH-RESOLUTION TOMOGRAPHY DIAGNOSIS
Based on the pattern and distribution of abnormalities, Mathieson et al6 compared the accuracies of chest radiography and CT in the prediction of specific diagnoses in 118 consecutive patients with chronic diffuse infiltrative lung disease. The radiographs and CT scans
were independently assessedby three observers without knowledge of clinical or pathological data. The three observers made a confident diagnosis with 23% of radiographic and 49% of CT scan readings. This diagnosis was correct with 77% and 93% of those readings, respectively. The observers were most often correct in the CT diagnosis of IPF, lymphatic spread of tumor, sarcoidosis, and silicosis. Although these data show that CT is superior to the chest radiograph, they also indicate that the CT findings are not pathognomonic. The CT scans illustrated in this article, although representative and characteristic, do not reflect the range
NESTOR L. MiiLLER
Fig 12. A 50.year-old patient with sarcoidosis. HRCT shows nodular thickening of the bronchovascular bundles (straight arrows) and subpleural nodules (curved arrows).
Fig 13. A 50-year-old man wfth extrinsic allergic alveolitis. HRCT shows hazy areas of increased density invohdng most of the upper lobe at this level. The increesad density is subtle but can be identified when thasa areas ara compared with the normal parenchyma in the most anterior aspact of the upper lobe and the medial aspect of the superior segment of the right lower lobe.
Fig 14. A 44.year-old man with pulmonary alveolar osis. HRCT through left lower lobs shows extensive opacification without obscuration of the underlying markings. The thickened Interlobular septa within the hazy increased density give a characteristic “crazy appearance.
proteinairspace vascular areas of paving”
Fig 15. A 43.year-old woman with chroni c eosinophilic pneumonia. HRCT shows i subpleural airspace consolidation.
of abnormalities seen in the various chronic infiltrative lung diseases. Clearly there is some overlap of the HRCT findings of the various diseases. Therefore, the CT findings must be analyzed in the context of the clinical history, physical findings, pulmonary function tests, and laboratory data. In the appropriate clinical setting, characteristic HRCT findings may allow a confident diagnosis. This is particularly true in
asbestosis, silicosis, and IPF. In some patients, CT may suggest a previously unsuspected diagnosis. The combination of clinical history and laboratory tests may then be sufficient for an accurate diagnosis, precluding the need for lung biopsy. In my experience, this has been most common in extrinsic allergic alveolitis. In other patients, CT is used as a guide to the optimal biopsy site.
Fig 16. A 66.year-old woman with BOOP. HRCT shows airspace consolidation in the subpkurel lung regions of the lower lobes and around the bronchi (arrows).
NESTOR L. MiiLLER
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