High-resolution CT of diffuse interstitial lung disease: key findings in ...

Eur. Radiol. �2001) 11: 373±392 

Ó Springer-Verlag 2001 

Cornelia Schaefer-Prokop 

Mathias Prokop 

Dominik Fleischmann 

Christian Herold 

Received: 29 May 2000 

Accepted: 1 August 2000 

C.Schaefer-Prokop �) )´ 

M. Prokop ´ D. Fleischmann ´ C.Herold 

Department of Radiology, 

General Hospital, 

Währinger Gürtel 18±20, 

1090 Vienna, Austria 

mathias.prokop@univie.ac.at 

Introduction 

CHEST 

There are more than 100 entities of diffuse infiltrative 

lung disease, although most reported series are made up 

of relatively few conditions, and in clinical practice ten 

diseases account for approximately 90 % of cases [1, 2]. 

High-resolution computed tomography �HRCT) is now 

a mature technique with a generally accepted role in the 

diagnostic work-up of patients with known or suspected 

diffuse infiltrative lung disease [3, 4]. High-resolution 

CT is the radiological imaging technique currently 

available that most closely reflects changes in lung 

structure [3]. It has clearly been shown to be superior to 

chest radiography and standard thick section CT for 

detecting and clarifying the pattern and extent of parenchymal 

lung disease. However, as recently pointed 

out by D. Hansell, it still provides a macroscopic �not 

microscopic) view of pathology, the single morphological 

feature is non-specific, and conclusions about the 

etiology of lung findings are often based on indirect 

signs [4]. Thus, using that technique one has to be aware 

of its potential as well as its limitations. Although it 

High-resolution CT of diffuse 

interstitial lung disease: 

key findings in common disorders 

Abstract High-resolution CT 

�HRCT) is the radiological imaging 

technique that most closely reflects 

changes in lung structure. It represents 

the radiological method of 

choice for the diagnostic work-up of 

patients with known or suspected 

diffuse interstitial lung disease. A 

single HRCT finding is frequently 

nonspecific, but the combination of 

the various HRCT findings together 

with their anatomic distribution can 

suggest the most probable diagnosis. 

The purpose of this article is to 

summarize the classic HRCT fea- 

tures of the most common diffuse 

interstitial lung diseases. Lists of 

differential diagnoses and distinguishing 

key features are provided 

to improve diagnostic confidence. 

The presence of classic HRCT features 

often obviates the need for biopsy. 

In patients with atypical findings, 

HRCT can be used to determine 

the most appropriate biopsy 

site. 

Key words Diffuse interstitial lung 

disease ´ HRCT ´ Key features ´ 

Diagnostic accuracy 

represents the cornerstone within the diagnostic workup 

of diffuse lung disease presently, meaningful interpretation 

of HRCT requires consideration of clinical 

and laboratory findings. 

As with plain chest radiography, optimal technique 

and knowledgeable pattern recognition of diseases are 

the prerequisites to use the potential of the modality to 

its full advantage. 

For optimal assessment of infiltrative lung disease 

HRCT scans at 1-cm intervals in the supine position or 

at 2-cm intervals in both supine and prone positions are 

recommended. Techniques involving less scans and 

larger interscan gaps are certainly susceptible to the fact 

that subtle focal abnormalities may be missed [3]. The 

potential of multi-slice CT in this respect has to be 

evaluated in the future. 

Several recent publications have strengthened the 

fact that a systematic approach to the HRCT pattern is 

of great importance and allows for a mean diagnostic 

accuracy ranging between 57 and 95% depending on 

the study group and the disease entity. Even when taking 

into account that these results are based on more or

374 

a 

Fig.1a, b Typical and atypical appearance of lymphangitic carcinomatosis. 

a Characteristic presentation of lymphangitic carcinomatosis 

in a 45-year-old male with known pancreatic cancer. Highresolution 

CT scan shows a nodular thickening of interlobular 

septa as well as thickening of the broncho-vascular bundles. Note 

the additional nodules in the lung parenchyma, representing lung 

metastases. b Atypical presentation of lymphangitic carcinomatosis 

in a 42-year-old female patient with a history of gastric cancer. 

In contrast to a, the interlobular septal thickening is smooth without 

apparent nodularity. Areas of patchy ground-glass densities 

probably represent volume averaging of thickened septa 

less selected groups of diseases, and mostly radiologists 

with longstanding experience served as observers, the 

key point of these studies appears to be the demonstration 

of the potential of the technique if optimally applied. 

Thus, these results may also serve as motivation 

to radiologists to achieve the necessary knowledge of 

HRCT patterns. Collections of appropriate learning 

files in combination with a list of learning objectives and 

suited explanations that can be distributed using electronic 

devices �e. g., the EURORAD project by the 

European Association of Radiologists) may be an appropriate 

teaching tool allowing for a widely spread yet 

individual option for everybody to increase or update 

his or her knowledge. 

The purpose of this review is to summarize the very 

classic HRCT features of the most common diffuse interstitial 

lung diseases which may allow for making a 

diagnosis. Lists of differential diagnoses and distinguishing 

key features may be of help in strengthening 

diagnostic confidence. Atypical disease appearances 

and overlapping morphological features, however, limit 

the value of HRCT in determining the disease entity. In 

those cases HRCT is the ideal tool for choosing the 

next appropriate diagnostic procedure �e. g., transbronchial 

vs percutaneous vs open lung biopsy) and for 

guidance of the most appropriate biopsy site. 

b 

Key findings in the most common interstitial disorders 

Pulmonary lymphangitic carcinomatosis 

Pulmonary lymphangitic carcinomatosis �PLC) refers to 

tumor growth in the lymphatic system of the lungs. It 

occurs most commonly in patients with carcinoma of the 

breast, lung, stomach, pancreas, cervix, prostate, thyroid, 

or in patients with metastases of an adenocarcinoma 

of unknown primary site. It usually results from 

metastatic spread to the lung with subsequent interstitial 

and lymphatic invasion, but can also occur because 

of direct lymphatic spread of tumor. 

Pathologically the thickening of the axial, peripheral, 

and septal interstitium may be due to tumor filling of 

pulmonary vessels and lymphatics, to direct tumor infiltration 

of the interstitium itself, to secondary distension 

of the vascular and lymphatic channels distally to tumor 

emboli or tumor obstruction, and finally to interstitial 

fibrosis after longstanding edema or tumor infiltration. 

Dependent on the dominant pathological factor the 

thickening of the septa is smooth, nodular, or beaded. 

Typical HRCT features of PLC are: 

1. Smooth or beaded thickening of the central peribronchovascular 

interstitium �Fig.1) 

2. Smooth, nodular, or beaded interlobular septal 

thickening producing a characteristic reticular pattern 

�Fig. 1) 

3. Thickening of the intralobular axial interstitium resulting 

in prominent vascular and bronchiolar structures 

�centrilobular core structures) 

4. A preservation of normal lung architecture at the 

lobular level despite the presence of reticulo-nodular 

and linear opacities 

Stein et al. [5] described reticular opacities in the peripheral 

subpleural region in all patients �so-called peripheral 

arcades) and thickened septa outlining distinct 

pulmonary lobules �polygonal arcades) in 50 % of the 

patients. Polygonal septal thickening in combination 

with prominent centrilobular core structures are one of 

the most distinct features of PLC. In only few patients 

the centrilobular interstitial thickening is the predominant 

finding [6]. 

In approximately 50 % of patients the abnormalities 

appear focal, unilateral, or asymmetric, rather than diffuse. 

Axial, peripheral subpleural, or central perihilar 

bronchovascular thickening may occur all together, or 

one of these features predominates or occurs alone. 

Associated findings are intrapulmonary nodules, hilar 

or mediastinal lymphadenopathy �38±54 %), or pleural 

effusion.

Differential diagnosis 

The differential diagnosis includes interstitial edema, 

sarcoidosis, pneumoconiosis, and pulmonary fibrosis. 

Diagnostic clues for differentiation between PLC and 

interstitial edema, which are both characterized by 

perihilar peribronchovascular and reticular septal 

thickening, are the following: 

1. In PLC the thickened interstitium is sharply marginated 

from the adjacent aerated lung, and there is no 

filling in of the alveoli, which remain well aerated. 

2. In PLC the pulmonary arterial branches adjacent to 

the bronchi also appear larger than normal, that way 

maintaining the size relationship of the thick-walled 

bronchi and adjacent vessel [7]. 

3. Interlobular thickening due to PLC is more non-uniform 

as compared with interstitial edema: different 

degrees of thickening may occur within one septum 

as well as alterations between smooth or beaded 

contours. 

4. Whereas interstitial edema is most frequently bilateral 

and symmetrical, PLC may occur in a focal and 

asymmetrical distribution. 

5. The interstitial edema is dependently distributed, 

and various degrees of alveolar opacification represent 

airspace edema. The left ventricle and atrium 

may be enlarged, and pleural effusions are frequently 

associated. 

6. Administration of diuretics results in a decrease of 

interstitial edema within hours. 

Diagnostic clues for differentiation of PLC from sarcoid, 

pneumoconiosis, and pulmonary fibrosis, which all 

may show nodular or beaded peribronchovascular 

thickening, are: 

1. In sarcoidosis and pneumoconiosis the septal thickening 

is less extensive than in patients with PLC and 

reticular opacities are not the predominant feature. 

2. In all three, sarcoidosis, pneumoconiosis, and pulmonary 

fibrosis, cicatricial distortion of the lung architecture 

and secondary lobule anatomy is common, 

especially when septal thickening is present. In PLC, 

however, lung architecture remains normal and the 

lobules preserve their size and shape. 

Diagnostic role of HRCT 

Particularly in patients with focal PLC, HRCTwas found 

to be more sensitive than conventional radiography and 

thick-slice standard CT [5, 7]. In patients with known 

tumor, who have symptoms of dyspnea and HRCT findings 

consistent with PLC, HRCT is usually considered 

diagnostic and no lung biopsy is performed [3]; however, 

in patients without known neoplasm or with unknown 

location of the primary tumor, HRCT serves as guidance 

to select the most appropriate biopsy site. 

Sarcoidosis 

375 

Sarcoidosis is a systemic disorder of unknown origin. It 

is characterized by non-caseating epitheloid cell granulomas 

in multiple organs, but morbidity and mortality 

are closely related to pulmonary manifestation occurring 

in 90 % of patients. The sarcoid granulomas are 

distributed primarily along the lymphatics in the axial 

peribronchovascular interstitial space �both in the perihilar 

and centrilobular region) and, to a lesser extent, in 

the interlobular septa and subpleural interstitium. Thus, 

beaded thickening of the central perihilar interstitium is 

highly suggestive for sarcoidosis particularly in combination 

with mediastinal adenopathy or further evidence 

of perilymphatic intrapulmonary nodules [8]. The CT 

appearance of pulmonary sarcoidosis varies greatly and 

is known to masquerade many other diffuse infiltrative 

lung diseases. 

Typical HRCT features of sarcoidosis are: 

1. Smooth or nodular peribronchovascular interstitial 

thickening. 

2. Small, well-defined nodules in a characteristic ªperilymphatic 

distributionº in relation to the subpleural 

surface, adjacent to the major fissures, along thickened 

interlobular septa and adjacent to vessels in the 

lobular core �Fig.2a). As a result, pulmonary vessels 

may be irregularly enlarged. 

3. The nodules may be evenly distributed throughout 

both lungs with predominance of the upper and middle 

lung zones; however, in most cases they are clustered 

in the perihilar and peribronchovascular region 

with relative sparing of the lung periphery, or they 

may be grouped in small areas uni- or bilaterally 

�Fig. 2 b). 

4. Confluence of granulomas results in large, mostly illdefined 

opacities or consolidations. Nodular densities 

measuring between 1 and 4 cm in diameter were 

seen in 15±25% of patients �so-called nodular sarcoidosis) 

[9, 10, 11, 12]. 

5. Patchy areas of ground-glass opacities, which may be 

superimposed over interstitial nodules or signs of fibrosis 

[13]. They are rarely seen on the radiograph 

�0.6 %) [14] but are commonly present on HRCT 

�20±60 %) mostly in association with small nodules. 

Pathological studies have shown that they represent 

interstitial granulomatous inflammation and occasionally 

microscopic foci of parenchymal fibrosis 

�Fig. 2 c). 

6. Approximately 20% of patients develop a pulmonary 

fibrosis with septal thickening, traction bron-

376 

a b 

c d 

Fig.2 The many faces of sarcoidosis. a A 36-year-old patient with a 

dyspnea on exertion. High-resolution CT shows small, well-defined 

interstitial nodules distributed along the axial as well as peripheral 

interstitium. In addition, nodules are seen in a subpleural 

distribution and along the fissures. b A 25-year-old male patient 

with erythema nodosum. In these patients with proven sarcoidosis, 

most nodules cluster in small groups and merge to areas of consolidation. 

This pattern which may also cause alveolar densities on 

chest X-rays is termed ªalveolar sarcoidº and is most frequently 

seen in Afro-American females. c In this female patient with a long 

history of sarcoidosis, the predominant manifestation of disease is 

ground-glass density; however, ground glass such as in this case is 

not a reliable ideal indicator of treatable and potentially reversible 

disease, since bronchiectasis �traction bronchiectasis) �arrows) indicates 

to the presence of fibrosis. d Fibrosing sarcoidosis: a 42year-old 

patient with known sarcoidosis involving only the lung 

parenchyma. Note the conglomerate masses in the hilar region 

with a characteristic dorsal retraction of the hila. Linear and 

patchy perihilar densities represent the peribronchiolar/perivascular 

localization of disease. In addition, small peripheral interstitial 

nodules are present, especially also in a subpleural location 

chiectasis, and honeycombing �Fig. 2 d). Irreversible 

fibrosis is most common in stage 3 �diffuse pulmonary 

disease unassociated with lymph-node enlargement). 

Conglomerate masses mostly in a perihilar 

location represent areas of fibrosis which cause characteristic 

traction bronchiectasis. The posterior displacement 

of the upper lobe bronchi �and later also 

of the main bronchi) is considered to be an early sign 

of lung distortion in sarcoidosis indicating loss of 

volume in the posterior segments of the upper lobes 

[15]. 


Conditions that most closely mimic the HRCT appearance 

of sarcoidosis are PLC, silicosis, and coal worker's 

pneumoconiosis �CWP). All of these show small perilymphatic 

nodules; however, differences of the predominant 

distribution and the combination with signs of 

fibrosis represent the diagnostic key factors.

In sarcoidosis the nodules are predominantly located 

along the central bronchovascular bundle and in the 

subpleural area; in PLC nodules are mostly located 

septal and bronchovascular, and in silicosis and pneumoconiosis 

they are predominantly located centrilobular 

and subpleural. 

In silicosis and CWP, nodules are mostly evenly distributed 

throughout the whole lung, a finding which is 

much less typical for sarcoidosis. Differentiation of 

conglomerate masses of fibrosis in sarcoidosis from 

those in silicosis can be readily made by the presence of 

air bronchograms in the former [2, 5, 7]. 

Septal thickening in sarcoidosis is a much less dominant 

feature as compared with PLC, and if present, it is 

usually combined with findings of fibrosis and lung distortion 

precluding the diagnosis of PLC. There are, 

however, descriptions of cases in which the parenchymal 

involvement of sarcoidosis and PLC are similar and indistinguishable 

[10, 16]. 

As fibrosis develops over time, sarcoidosis and idiopathic 

pulmonary fibrosis �IPF) increasingly share numerous 

findings. Both show irregular or nodular septal 

thickening, irregular interfaces, and traction bronchiectasis. 

In sarcoidosis, honeycombing is a less frequent 

feature of irreversible fibrosis as compared with 

IPF; however, there appear to be two types of fibrotic 

progression in sarcoidosis. Whereas most patients develop 

fibrotic changes with loss of volume, fibrotic bands, 

and cysts predominantly in the perihilar region and the 

upper lobes, suggesting the diagnosis of sarcoidosis, 

there are descriptions of a few cases which developed a 

diffuse fibrosis with predominant basal and subpleural 

honeycombing very similar in appearance to UIP [17]. 


As shown by a multitude of studies, CT is superior to 

chest radiography for detection and observation of involvement 

of the pulmonary parenchyma. Computed 

tomography is also superior for confirmation of mediastinal 

or hilar lymph nodes which represent meaningful 

information for the diagnosis of sarcoidosis [3, 18]. Highresolution 

CT is the method of choice for showing early 

fibrosis; however, it is important to know that HRCT 

cannot be used to rule out parenchymal involvement. 

Several authors report that intrapulmonary granulomas 

could be histologically shown in patients with normal 

HRCT appearance of the lung parenchyma [10, 19, 20]. 

The diagnosis of sarcoidosis is confirmed by the histological 

identification of epitheloid cells in granulomas. 

In patients without known extrathoracic involvement, 

transbronchial biopsy is the diagnostic procedure of 

choice. It may be performed simultaneously with BAL. 

Intrapulmonary granulomas may be confirmed even 

when no pathological HRCT findings are present. On the 

other hand, if no granulomas are detected by transbronchial 

biopsy, the possibility of sarcoidosis cannot be excluded. 

The sensitivity of transbronchial biopsy is reported 

to be 80 % [21]. The second-line procedure would 

be a mediastinoscopy since most patients also have enlarged 

mediastinal lymph nodes. When CT does not 

show mediastinal lymphadenopathy, or mediastinoscopy 

is difficult, video-assisted thoracoscopic lung biopsy or 

open-lung biopsy are the remaining alternatives. 

A lot has been written about the meaning of groundglass 

opacities in patients with sarcoid. One study [20] 

indicated that areas of ground-glass opacities are associated 

with disease activity as assessed by 67 Ga scintigraphy. 

Correlation with pathological specimen, however, 

could prove that ground-glass opacities reflect the 

presence of confluence of extensive interstitial sarcoid 

granulomas rather than active alveolitis [10, 12, 13, 22]. 

Murdoch and Müller described that ground-glass, nodular 

and irregular linear opacities, and interlobular septal 

thickening represent potentially reversible disease, 

whereas cystic air spaces and architectural distortion are 

irreversible findings [23]. The extent of consolidations 

and nodular densities showed higher correlations with 

other indicators of disease activity �serum-angiotensin 

converting enzyme essay, Ga scanning, and bronchoalveolar 

lavage) than reticular opacities and ground-glass 

attenuation [24]. 

Whereas CT is the superior method for demonstration 

and follow-up of extent and distribution of disease, 

results are controversial as to whether HRCT is superior 

to radiography in providing information about the 

functional impairment [9, 15, 25, 26, 27]. Differences of 

results reported in the literature are most likely due to 

different selection of patient groups and data analysis. It 

appears that signs of fibrosis �such as lung distortion and 

reticular densities) correlate better with impairment of 

lung function �obstruction) than extent and distribution 

of nodules and consolidations [28]. 

Silicosis/coal worker's pneumoconiosis 

377 

Silicosis and coal worker's pneumoconiosis �CWP) are 

pathologically distinct entities with differing histology, 

resulting from the inhalation of different inorganic dusts 

�dust containing crystallized silicon dioxide and coal 

dust, respectively); however, the radiographic and 

HRCT appearance are similar and cannot be reliably 

distinguished. 

Typical HRCT features of silicosis and CWP are: 

1. Small, well-defined nodules of usually 2±5 mm in 

diameter �rarely larger) scattered throughout both 

lungs with a predominance for the upper lung zones, 

especially posteriorly �Fig. 3 a). They may be calcified 

and are typically uniformly distributed in cen-

378 

a b 

Fig.3 The HRCT features of silicosis. a Patient with limited exposure 

of dust-containing crystallized silicone dioxid demonstrates a 

few small nodules predominantly located in the subpleural �arrows) 

and peribronchiolar �arrowheads) location. Despite its subtlety, 

the disease has a distinct upper lobe predominance �lower 

lung scans not shown). b Patient with long-term exposure and 

progressive massive fibrosis and silicosis. The mass lesions in these 

patients with complicated silicosis develop in the midportion or 

periphery of upper long zones. These masses potentially undergo 

necrosis and may also develop areas of cavitation 

trilobular �peribronchiolar) and subpleural locations 

rather than clustered or localized along septa. 

Sometimes the centrilobular densities show tiny 

short branches instead of being round corresponding 

to irregular fibrosis around the respiratory bronchioles 

surrounded by a small zone of focal emphysema. 

2. As simple silicosis and CWP progress, the number of 

nodules increase and increasingly coalesce resulting 

in distortion of the adjacent lung structure. Coalescence 

of small nodules to larger nodules � > 1 cm) and 

eventually to large, irregularly defined conglomerate 

masses reflect the transition from simple to complicated 

silicosis/pneumoconiosis �Fig. 3 b). The masses 

tend to develop in the midportion or periphery of the 

upper lung zones and migrate toward the hila [3]. 

They may cavitate due to ischemic necrosis, although 

this seems to be more common with CWP. 

3. Accompanying paracicatricial emphysema which reflects 

the process of pulmonary massive fibrosis 

�PMF) 


The differential diagnosis of silicosis/CWP includes all 

diseases that may develop numerous small, well-defined 

nodular opacities such as sarcoidosis, pulmonary lym- 

phangitic carcinomatosis, histiocytosis X, but also infectious 

diseases such as miliary tuberculosis, fungus infection, 

and hematogenous metastases. 

Depending on the profusion of the nodules in a 

seemingly random distribution, it may be impossible to 

distinguish miliary tuberculosis �perivascular nodules) 

from silicosis �peribronchiolar nodules). Also the differentiation 

between sarcoidosis and silicosis can be 

difficult when the sarcoid nodules are numerous and do 

not show the typical perilymphatic distribution but a 

diffuse centrilobular location. The differentiation between 

silicosis and histiocytosis X is difficult if the latter 

is characterized solely by the presence of nodules, 

whereas cystic lesions are completely missing. 

Perihilar mass-like fibrosis or upper lobe consolidations 

in combination with parenchymal distortion may 

occur in both, silicosis/CWP and end-stage sarcoidosis. 

Both entities are characterized by an upper lobe predominance 

and by potential calcifications of the nodules. 

They may only be distinguishable by associated 

findings such as the distribution of nodules. 

Silicosis/CWP and PLC can usually be differentiated 

quite easily by the different distribution of nodules. In 

silicosis and CWP, the nodules appear bilaterally, symmetrical, 

and more uniformly distributed. Beaded septa 

or reticular densities are usually absent. 

An acute form of silicosis has been described in 

which a large dose of silica was inhaled stimulating an 

alveolar lipoproteinosis and subsequently extensive 

production of fibrous tissue. The radiographic image 

showed alveolar ground-glass opacifications instead of 

discrete silica nodules resembling the image of alveolar 

proteinosis [29]. 


High-resolution CT has been shown to be superior to 

both conventional CT and chest radiography especially 

for the detection of small nodules and early fibrotic 

changes and emphysema [30, 31, 32]. Computed tomography 

is well suited to monitor disease progression 

and to detect secondary related disease such as tuberculosis 

and lung cancer [30, 31, 32]. 

In most patients the characteristic distribution of 

nodular densities should suffice for diagnosis; however, 

as pointed out previously, HRCT features alone may be 

indistinguishable especially from other infiltrative lung 

diseases �sarcoidosis, histiocytosis) or from infectious 

diseases �tuberculosis, fungus). Additional clinical information 

is required but usually sufficient to preclude 

further invasive diagnosis. Functional impairment and 

prognosis are usually poorer for patients with silicosis 

than for CWP. The extent of emphysema correlates 

more closely with functional impairment than does the 

degree of nodular profusion [30, 33].

Lymphangiomyomatosis and tuberous sclerosis 

Lymphangiomyomatosis �LAM) and pulmonary involvement 

in tuberous sclerosis �in 1 %) are radiologically 

and pathologically identical. Both are rare diseases 

that are characterized by progressive proliferation of 

spindle cells, resembling immature smooth muscle cells 

along the bronchovascular bundles, lymphatics, and pulmonary 

veins. Proliferation of spindle cells along the 

bronchioles leads to air trapping and hyperinflation, the 

development of emphysema, and formation of thin-walled 

cysts. Ruptures of pulmonary venoles lead to episodes 

of hemoptysis and pulmonary hemorrhage, obstruction 

of pulmonary lymphatics by smooth muscles 

cause chylous pleural effusions. Lymphangiomyomatosis 

exclusively occurs in women of child-bearing age. 

Typical HRCT features of LAM are: 

1. Numerous thin-walled cysts, surrounded by mostly 

normal parenchyma �Fig.4). The cysts range from 

2 mm to 5 cm in diameter but can occasionally become 

even larger. Their size tends to increase with 

disease progression. The cysts are primarily round in 

shape, and only some of them are confluent. In most 

patients the intervening parenchyma is normal; however, 

there are also reports of cases which show patchy 

ground-glass opacities or increased interstitial 

markings in the pericystic lung parenchyma and occasionally 

even signs of lung distortion. 

2. The cysts are distributed diffusely throughout the 

lungs, no lung zone is spared, and upper and lower 

lobes are involved to a similar degree. 

3. The wall thickness of the cysts range from rarely 

perceptible to 4 mm in thickness. 

4. Very rarely, few nodules may be seen. 

5. Approximately 50% of patients have mediastinal or 

hilar adenopathy, and �chylous) pleural effusions 

may be present. Recurrent pneumothoraces may occur. 


The differential diagnosis of diffuse lung diseases with 

primarily cystic lesions include histiocytosis X, centrilobular 

emphysema, end-stage interstitial fibrosis, and 

lymphoid interstitial pneumonitis �LIP). 

Lymphangiomyomatosis can be reliably differentiated 

from histiocytosis by the diffuse lung involvement �in 

LAM the lung bases or costophrenic sulci are not 

spared), the infrequency of nodules, and the regular 

shape of the cysts. Additionally, LAM is not associated 

with smoking history, whereas more than 90% of patients 

with histiocytosis are smokers. 

Emphysematous cystic air spaces have no perceptible 

walls �Fig. 5). In LAM, vessels are typically seen at 

379 

Fig.4 Complete replacement of the lung parenchyma by numerous 

thin-wall cysts in a 26-year-old female with lymphangiomyomatosis. 

Note the vessels seen at the margins of the cysts 

Fig.5 A 42-year-old male smoker with centrilobular emphysema. 

High-resolution CT shows predominantly ill-defined areas of low 

attenuation located mainly in the medulla portion of the lung. In 

some instances centrilobular emphysema can also form cystic 

spaces with discrete walls. Note bronchial wall thickening representing 

chronic bronchitis 

the margins of the cysts rather than at the centers of air 

spaces as is characteristically seen with emphysema. 

Differential diagnosis, however, my be difficult especially 

in early stages of LAM, and in advanced stages of 

paraseptal emphysema. 

Complete absence of fibrotic changes or of signs of 

distortion facilitate the differential from IPF; however, 

in accordance to reported pathological findings [34], interstitial 

changes may be present in LAM more frequent 

than previously reported [35]. Interstitial changes can 

be explained by additional factors such as intercurrent 

relapsing infections. 

Lymphocytic interstitial pneumonia �LIP, as seen in 

patients with HIV infection, Sjögren syndrome, or Cas-

380 

tleman's disease) shows also cystic air spaces, which 

have perceptible walls. The cysts, however, are less uniform 

in size and are reportedly in a predominant subpleural 

location. They may also be scattered throughout 

the whole lung but rarely represent the dominant feature. 

Other findings usually seen in LIP include ill-defined 

centrilobular nodules �3 and 30 mm with being 

mostly small) and diffuse ground-glass opacification of 

the lung parenchyma. They represent the key features 

for differential diagnosis [36, 37]: The virtual absence of 

centrilobular nodules in LAM allows for ready distinction. 


High-resolution CT is significantly superior to chest radiography 

and conventional CT in determining the extent 

and distribution of air cysts [38, 39, 40]. It should, 

however, be noted that normal CT findings do not rule 

out parenchymal disease in patients with LAM [40]. 

The CT appearance of LAM is diagnostic in the correct 

clinical context [39, 40, 41]. The presence of many 

thin-walled, round, or geographic cystic airspaces scattered 

throughout both lungs in a young woman is virtually 

pathognomonic. Definite diagnosis, however, would 

require open-lung biopsy. 

Computed tomography correlates better than radiography 

with clinical and functional impairment. The 

extent of cystic disease was found to correlate well with 

impairment of gas exchange [35, 39] and severity of airway 

obstruction [41]. 

Histiocytosis X 

Pulmonary histiocytosis X is also known as eosinophilic 

granuloma, Langerhans' cell histiocytosis, or Langerhans' 

cell granulomatosis of the lung. In its early stages 

it is characterized by a bronchiolocentric granulomatous 

reaction with proliferation and infiltration of the bronchiolar 

wall and the adjacent blood vessels by Langerhans' 

histiocytes and eosinophils. Bronchiolar obliteration 

causes progressive alveolar wall fibrosis and cyst 

formation, eventually resulting in increasing fibrosis and 

parenchymal distortion. The HRCT findings closely 

mirror this stepwise histological progression. 

The etiology of histiocytosis is unknown; however, 

there is a striking relationship to smoking � > 90 % of 

patients with histiocytosis are active smokers). 

Typical HRCT features of Langerhans' cell histiocytosis 

are: 

1. Cystic airspaces usually smaller than 10 mm in diameter 

with walls that range from barely perceptible to 

being several millimeters thick. The cysts may be 

round, or have bizarre shapes, they may coalesce and 

then become larger than 20 mm �Fig. 6a). 

2. Nodules in peribronchiolar centrilobular location. 

They are usually small � < 5 mm in diameter). Larger 

nodules � > 10 mm) also occur but are less common. 

Nodules can be few or numerous depending 

on disease activity. The nodules have irregular contours 

particularly when they are surrounded by cystic 

or reticular disease. They may be solid or show 

small lucent centers. These ªcavitationsº are 

thought to represent dilated bronchioles surrounded 

by granulomas and thickened interstitium. Development 

of cavitated nodules into cysts was observed 

�Fig. 6 b,c). 

3. Cysts as well as nodules show an upper lobe predominance 

�in 57%); the lung bases and the costophrenic 

sulci are relatively spared. 

4. There may be patchy or diffuse ground glass opacification. 

5. The lung volume is usually increased. 

6. With disease progression the presence of nodules 

decreases, whereas the whole lung parenchyma consists 

increasingly of thin-walled cysts up to the extent 

that intact lung parenchyma will be present only in 

the basal areas �vanishing lung disease) 

7. Most patients show no evidence of fibrosis or septal 

thickening. Only few show an irregular interface sign 

or a fine reticular network correlating with intralobular 

fibrosis. Ground glass may be seen occasionally, 

but it is never a prominent feature. 

Each feature, nodules and cysts, can occur solely; the 

majority of the patients, however, show both. Nodules 

are the earliest finding. As they resolve, the cysts increasingly 

form as a result of progressive paracicatricial 

emphysema. The patients are prone to pneumothorax, 

probably from cyst rupture. 


The differential diagnosis includes LAM, cystic bronchiectasis, 

IPF, and LIP. 

The cysts found in LAM may have an appearance 

similar to those of histiocytosis but are not associated 

with nodular changes or an upper lobe lung distribution. 

In addition, the cysts in histiocytosis are less uniform as 

in LAM [42]. 

The round-shaped cystic air spaces ± especially when 

close to a vessel ± may mimic the appearance of cystic 

bronchiectasis �signet-ring sign), close inspection of serial 

sections above and below help to readily differentiate 

tubular from spherical structures. 

As opposed to IPF, the cysts show no predominant 

subpleural distribution. The cysts in histiocytosis are 

usually discrete rather than clustered, and most impor-

a b 

c 

tantly the lung volumes are usually preserved or even 

increased, rather than decreased as frequently seen with 

IPF. 

Both, histiocytosis and LIP, are characterized by 

centrilobular nodules and cystic airspaces. Distinguishing 

features of histiocytosis from LIP include the absence 

of interlobular thickening and lymphadenopathy, 

both of which were found in 82 and 70%, respectively, 

in patients with LIP [37]. 


The combination of pulmonary nodules and cysts is virtually 

diagnostic for pulmonary histiocytosis X [43, 44, 

45]. Grenier and coauthors showed that a first-choice 

diagnosis of histiocytosis had a 60% likelihood of being 

correct when based on the chest radiograph but a 90% 

likelihood of correctness with HRCT [44]. 

Although the HRCT findings are suggestive of disease, 

there are no other specific laboratory tests to further 

underline the diagnosis. Langerhans' cells can be 

identified in specimens obtained by BAL; however, they 

can also be seen in cases of pulmonary fibrosis of other 

etiology. A definite diagnosis is only established after 

examination of lung tissue. Whereas transbronchial biopsy 

has a very low yield due to the focal nature of the 

disease, open or video-assisted thoracoscopic lung biopsy 

is recommended [46]. 

The extent of lung abnormality as determined by CT 

correlates well with the lung diffusion capacity. Serial 

HRCT scans could show that regression of the nodules 

leaves multiple thin-walled cysts because of check-valve 

obstruction by bronchiole-centered granulomas, and 

these small cysts could only be detected by HRCT and 

not by radiography [44]. 

Alveolar proteinosis 

Fig.6a±c The HRCT findings of histiocytosis 

X are different according to disease stage. 

a A 41-year-old patient with a long history of 

smoking: HRCT shows round or bizarreshaped 

cysts with a broad range of size. There 

are also a few cavitating nodules and some fibrotic 

strands in the intervening parenchyma. 

b High-resolution CT through the lower lobes 

in a 11-year-old patient with histiocytosis X. 

This typical disease presentation includes 

small, well-defined nodular structures with 

central cavitation. c High-resolution through 

the upper lobes demonstrates multiple small 

nodules as well as partially cavitating and 

small clustered cysts in a 37-year-old patient 

with a smoking history and shortness of breath 

381 

Alveolar proteinosis is a disease characterized by filling 

of the alveolar spaces with a PAS-positive proteinaceous 

material rich in lipid. It is caused by a dysfunction 

of pneumocytes that desquamate in the alveolar spaces 

secondary to a defect of lipid metabolism at the intracellular 

level. An abnormality in surfactant production, 

metabolism, or clearance has been also strongly implicated 

as well as an association with a variety of immunocompromised 

settings �in children lymphopenia, thymic 

aplasia, immunoglobulin deficiency, and in adults

382 

Fig.7 A 43-year-old patient with a clinical history of tachypnea 

and cyanosis: HRCT through the upper lungs demonstrates patchy 

areas of ground glass in a geographic distribution. Superimposed 

on the ground glass is a network of thickened intralobular septa. 

This pattern is called crazy paving and is typical, yet not characteristic, 

for alveolar proteinosis 

lymphoma and leukemia) and infectious diseases �e. g., 

cytomegalovirus, mycobacteria, pneumocystis, histoplasma, 

Candida species). 

Typical HRCT features of alveolar proteinosis are: 

1. The crazy paving appearance which consists of a 

network of smooth reticular pattern superimposed 

on an area of ground-glass opacification �Fig.7). 

2. Opacifications range from ground glass to consolidation. 

They may be patchy or geographic with sharp 

demarcation from the surrounding normal parenchyma. 

While some borders follow anatomical structures 

of lobar or lobular septa, others are independent 

of anatomical boundaries. Each frame of the 

network ranges from 2 to 7 mm 

3. The smooth septal thickening is usually seen only in 

areas with ground-glass opacification. It is believed 

to be due to thickening of the interlobular septa or, as 

recently described, to accumulation of material adjacent 

to the interlobular septa. 


Although the crazy paving appearance is highly suggestive 

for alveolar proteinosis with a 100 % prevalence of 

this pattern, it is not specific. A recent publication listed 

14 airspace and interstitial lung diseases that showed 

crazy paving with varying mostly much lower prevalence 

of crazy paving [47]. 

The main differential diagnosis include diffuse alveolar 

damage superimposed on UIP �prevalence of crazy 

paving in 67 %), acute interstitial pneumonia �31 %), 

and ARDS �21 %). 

Other diseases with lower prevalences of crazy paving 

were drug-induced pneumonitis �12 %), pneumonias 

�bacterial 6 %, tuberculosis 1 %, mycoplasma 6 %, 

Pneumoncystis carinii 7%), bronchiolitis obliterans 

with organizing pneumonia �BOOP; 8 %), chronic eosinophilic 

pneumonia �8 %), radiation pneumonitis �4 %), 

and cardiogenic pulmonary edema �14 %). 

The wide differential diagnosis is understandable 

considering that any kind of fluid or cellular filling of 

the air spaces and the interstitial spaces cause crazy 

paving. In alveolar proteinosis, the crazy paving appearance 

was found to be due to an accumulation of 

PAS ± positive material in the air spaces adjacent to the 

interlobular septa rather than due to thickening of the 

septi themselves [48]. Most disease entities with similar 

HRCT features can be distinguished from alveolar proteinosis 

by clinical symptoms and associated HRCT 

findings. 

It is noteworthy that superimposed infection, frequently 

by Nocardia asteroides, is a common complication 

of alveolar proteinosis, and CT is limited in differentiating 

airspace consolidation due to infection from 

underlying disease. 


Pulmonary proteinosis is very rare. In addition to the 

suggestive HRCT pattern, diagnosis is usually based on 

characteristic features of BAL fluid. Occasionally, 

transbronchial lung biopsy is needed [49]. 

Resolution of airspace consolidation can be monitored 

radiographically or by HRCT. The overall extent 

of disease and the degree of opacifications correlate 

well with the impairment of pulmonary function and 

severity of hypoxemia. 

Extrinsic allergic alveolitis �hypersensitivity 

pneumonitis) 

Extrinsic allergic alveolitis �EAA) or hypersensitivity 

pneumonitis is an allergic lung disease caused by inhalation 

of antigens contained in a variety of organic dusts. 

The radiographic and pathological abnormalities are 

similar independent of the causing antigen. Abnormalities 

can be classified into acute, subacute, and chronic 

stages. Mostly HRCT is performed in the subacute and 

chronic stages. Patients with chronic EAA mostly show 

a mixture of active disease and chronic fibrotic changes. 

Typical HRCT features of subacute EAA are: 

1. Diffuse bilateral patchy or diffuse ground-glass opacifications 

�in 50±70%).

a 

b 

Fig.8a, b Exogenic allergic alveolitis. a A 41-year-old patient with 

fatigue and weight loss. High-resolution CT shows discrete ill-defined 

centrolubular nodules �arrows), in a relatively uniform distribution. 

This pattern is characteristic of acute EAA. b A 56-yearold 

farmer with chronic exposure to hay: The CT appearance in 

this patient is different from that shown in a. The CT shows subpleural 

nodules, sharply demarcated geographic regions with air 

trapping and subpleural septal, and non-septal linear densities 

compatible with fibrosis 

2. Small ill-defined centrilobular noduli, 1±5 mm in diameter 

�in 40±70 %; Fig. 8 a). 

3. Opacifications with a predominance for the middle 

and lower lung zones. Both nodular and diffuse 

ground glass may be seen as isolated findings or in 

conjunction. 

4. Slightly prominent bronchial walls. 

Typical HRCT features of recurrent EAA episodes and 

chronic EAA are: 

1. Findings of fibrosis and parenchymal distortion �irregular 

reticular opacities, intralobular interstitial 

and interlobular septal thickening, visible intralobu- 

lar bronchioles, traction bronchiectasis, and honeycombing; 

Fig. 8 b) 

2. The distribution of the fibrosis may be variable, 

sometimes predominantly subpleural, in others 

patchy or peribronchovascular. Honeycombing is 

usually localized subpleural. 

3. Divergent findings are reported about the lobar predominance 

of chronic fibrotic changes. Whereas one 

study reported a lower lobe predominance in 31 % of 

the patients, others described a mid-zone predominance 

or even distribution for the majority of patients. 


In patients with bilateral nodular, patchy, or diffuse 

ground glass, the differential diagnosis includes desquamative 

interstitial pneumonia �DIP) and alveolar 

proteinosis. Desquamative interstitial pneumonia, however, 

is very rare and usually shows a subpleural predominance 

of the ground-glass opacification and is not 

associated with centrilobular nodules. Classic alveolar 

proteinosis shows a crazy paving appearance and is 

readily distinguished by bronchoalveolar lavage; the 

latter is also suited to rule out infectious diseases, such 

as cytomegalovirus or Pneumomocystis carinii, as etiologies 

for diffuse ground glass. The differential diagnosis 

between an alveolar sarcoidosis and subacute EAA requires 

transbronchial biopsy. 

Patients with chronic EAA and UIP may show identical 

HRCT findings, and differential diagnosis may be 

possible only by the clinical history and laboratory 

findings. Only a predominant location of fibrotic changes 

in the upper and/or middle lung zones allow for a 

distinction between these entities. 


383 

Multiple studies have demonstrated that HRCT is more 

sensitive than chest radiography and standard CT in the 

assessment of EAA; however, the sensitivity of HRCT is 

not 100 %: especially in the acute and subacute stage 

[50]. 

A careful clinical history, typical HRCT findings, and 

concordant serological findings confirm the diagnosis of 

EAA thus precluding the need for lung biopsy. In patients 

with discrepant or atypical HRCT findings diagnosis 

is based mostly on transbronchial biopsy and abnormal 

T-lymphocytes in the bronchoalveolar lavage. 

The diagnostic yield of transbronchial biopsy is not 

precisely determined for EAA.

384 

Idiopathic interstitial pneumonias 

The idiopathic interstitial pneumonias are a heterogeneous 

group of inflammatory and interstitial fibrosing 

lesions that manifest as infiltrative lung disease. On the 

basis of differences in histological appearance, they 

were classified by Liebow into five subtypes: UIP; DIP; 

LIP; GIP, and bronchiolitis with interstitial pneumonia 

[51]. The latter term has been replaced by BOOP. Both, 

LIP and GIP, were dropped since many of the former 

turned out to be lymphoproliferative disorders and 

many of the latter were found to be hard metal pneumoconioses. 

Two other forms were recognized including 

acute interstitial pneumonia �AIP) most closely corresponding 

to the entity described in 1944 by Hamman 

and Rich [52], and nonspecific interstitial pneumonia 

and fibrosis �NSIP or NIPF, also called non-classifiable 

interstitial pneumonia) [53]. 

The heterogeneity with respect to histology, CT appearance, 

and etiology characterizing the group of interstitial 

pneumonias almost inevitably lead to controversies 

and an irritating multiplicity of terms: Although 

the term idiopathic is justified in many patients 

with no identifiable disease etiology, some of these interstitial 

disorders are also found in settings with 

known etiology particularly collagen vascular disease. 

The classifications proposed by Liebow and Katzenstein 

[53] were based primarily on the pathology. The 

concept of IPF, however, is largely founded on a clinical 

approach. 

Usual interstitial pneumonia 

There has been some debate concerning the distinctiveness 

of usual interstitial pneumonia �UIP) and 

desquamative interstitial pneumonia �DIP) from each 

other. While the original classification by Liebow and 

Katzenstein [53] suggested that the different histological 

and radiographic features of the two abnormalities 

and the favorable response of DIP to corticosteroid 

therapy implies that they have different etiologies and 

pathogenesis, other investigators have documented 

considerable overlap and have suggested that the patterns 

of DIP and UIP represent the cellular and fibrotic 

spectrum of a single disease. This interpretation is supported 

by reports describing patients showing both patterns, 

DIP and UIP, in a single lung or by patients 

showing originally DIP and later UIP patterns in a follow-up 

biopsy specimen obtained at the same parenchymal 

site. This unifying concept is reflected by the 

single term of cryptogenic fibrosing alveolitis �CFA), 

widely used in Europe. Of all patients with interstitial 

pneumonitis of unknown etiology, approximately 5 % 

have the histologic pattern of DIP, and most of the remainder 

have UIP. The term idiopathic pulmonary fi- 

brosis, which is widely accepted in North America, is 

recommended to be used only for patients with the UIP 

pattern of pulmonary fibrosis. 

Typical HRCT features of UIP are: 

1. Fine or irregular intralobular linear opacities �reticular 

pattern) often associated with traction bronchiectasis 

and bronchiolectasis 

2. Irregular pleural, vascular, and bronchial interfaces 

3. Honeycombing consisting of thick-walled cystic air 

spaces �2±20 mm in diameter) in 90 % of patients and 

predominantly in the basal and subpleural areas. 

Honeycomb cysts usually enlarge slowly over time 

�Fig. 9 a,b). Ground-glass attenuation is common but 

usually less extensive than the reticular abnormality. 

Architectural distortion is present reflecting lung fibrosis 

with lobar volume loss. A patchy distribution 

is apparent in most cases with areas with reticular 

pattern intermingled with areas of normal lung parenchyma. 

The crescent predominantly subpleural 

distribution of the reticular pattern and the honeycombing 

is evident in 80±95% of patients and represents 

the most characteristic feature of IPF on 

HRCT. Lack of this feature should suggest an alternative 

diagnosis. 

The fibrosis is more severe in the lower lung zones in 

70%. In approximately 20% of patients all zones are 

affected evenly and in as many as 10% mainly the upper 

lung zones are involved. 

Mediastinal lymph-node enlargement is evident only 

on CT in 70±90% of patients �10±15 mm in the short 

axis diameter, mostly right paratracheal nodes) and less 

severe in patients under steroid therapy. 


The CT pattern of UIP due to IPF is commonly indistinguishable 

from that found in UIP due to asbestosis 

and to collagen vascular diseases such as rheumatoid 

arthritis, sclerodermia, or to certain drug reactions, although 

the rate of progression is slower in patients with 

collagen vascular disease. 

The presence of pleural plaques helps for differentiation 

between IPF and asbestosis. Patients with chronic 

hypersensitivity pneumonitis or with end-stage sarcoidosis 

may uncommonly develop a CT pattern identical 

to UIP. Hypersensitivity pneumonitis should be considered 

when poorly defined small nodules are present or if 

there is sparing of the lung bases. Sarcoidosis should be 

suspected if the majority of cystic spaces are larger than 

10 mm, if peribronchovascular �perilymphatic) nodules 

are seen or if more extensive mediastinal lymphadenopathy 

is present � > 15 mm in the short-axis diameter 

and affecting several lymph-node groups).


a b c 

d e 

Fig.9a±e Idiopathic interstitial pneumonias. a, b High-resolution 

CTscans in 2 patients with usual interstitial pneumonitis. Computed 

tomography scans demonstrate advanced disease with subpleural 

honeycombing, traction bronchiectasis, and irregular bronchoparenchymal 

interfaces. c A 32-year-old patient with a history of 

smoking, increasing symptoms of cough, and dyspnea: HRCTshows 

small centrilobular nodules and bronchial wall thickening suggesting 

the diagnosis of respiratory bronchiolitis with interstitial disease. 

d, e Two patients with NSIP suffering from collagen vascular 

diseases. In d subpleural ground-glass opacification and faint subpleural 

lines indicating initial fibrosis. In e there is more extensive 

ground-glass opacification superimposed by fine reticular densities, 

cystic airspaces, and traction bronchiectasis. Note the location of 

ground glass and reticular densities along a subpleural line in the 

dorsal lung area. Honeycombing is not a typical feature in NSIP 

Several studies suggest that, especially in advanced 

stages, the chest radiograph is sufficient for suggesting 

the diagnosis of IPF [54, 55, 56, 57], and diagnostic advantages 

of HRCT over chest radiography may not be as 

great as previous studies suggested [4]. 

However, CT is superior to chest radiography in discriminating 

accurately �95 vs 87%) and confidently �73 

385 

vs 30 %) IPF from other chronic interstitial diseases 

[16]. In a study group of 129 patients with idiopathic interstitial 

pneumonia, two observers correctly diagnosed 

UIP in 71%, DIP in 63 %, BOOP in 79 %, and AIP in 

65%. 

The pattern and extent of parenchymal abnormality 

and the degree of volume loss correlate with the severity 

of functional impairment, length of survival, and overall 

prognosis of patients with IPF. The significance of 

ground-glass opacification in patients with IPF has been 

the focus of considerable interest and controversy. 

Ground glass, if a predominant feature �in a minority of 

patients, ca. 10%), may be completely or partially reversible 

on corticosteroid therapy, whereas if part of a 

mixed pattern with reticular opacifications, it was found 

to precede and predict development of lung fibrosis [58, 

59, 60, 61]. Hartman and colleagues found that groundglass 

attenuation in patients with histologically proven 

DIP �and ground glass is a predominant feature in those 

patients) were likely to improve under corticosteroids, 

whereas patients with UIP and ground glass �and those 

patients usually show a mixed pattern) showed progress 

under steroids [62]. Other factors with prognostic value 

were the extent of fibrosis on the pretreatment CT and

386 

the extent and the distribution of ground-glass attenuation 

[62, 63, 64]. The progression of honeycombing was 

significantly faster in patients who had extensive areas 

of ground-glass attenuation in a diffuse rather than 

patchy distribution. 

Open-lung biopsy or thoracoscopic biopsy are the 

only procedures that yield sufficient tissue to confirm a 

diagnosis of IPF. Although transbronchial biopsy does 

not allow the distinction of IPF from many other conditions, 

it is a valuable procedure in excluding sarcoidosis 

or lymphangitic spread of tumor in selected cases. 

Whether confirmation of IPF is routinely required is 

controversial. Whereas 22 of 23 responders in an 

American survey routinely obtain tissue �although 

mostly transbronchial), by contrast, British pulmonary 

specialists are content to make the diagnosis of IPF on 

the basis of clinical and radiological features. There is 

no investigation available that specifically addresses 

that issue. It is common understanding that especially in 

patients with advanced disease, when clinical, laboratory, 

and radiological features suggest the diagnosis of 

IPF, biopsy is not indicated particularly when no treatment 

decision will depend on the findings of the biopsy. 

In patients with early disease, particularly those with 

few or no symptoms, but who demonstrate radiographic 

infiltrates, thoracoscopic lung biopsy is recommended. 

Desquamative interstitial pneumonia and respiratory 

bronchiolitis-associated interstitial disease 

Desquamative interstitial pneumonia �DIP) and respiratory 

bronchiolitis-associated interstitial disease �RB- 

ILD) have recently been grouped together as part of a 

single spectrum since they have clinical similarities and 

significant overlapping of histological and HRCT features 

[65, 66]. Both diseases are strongly associated with 

cigarette smoking, a fact that questions the idiopathic 

etiology of RB-ILD but underlines the concept that 

they represent different degrees of severity of small airway 

and parenchymal reaction to cigarette smoking. 

RB-ILD is thought to represent an exaggerated respiratory 

bronchiolitis response, resulting in clinical 

symptoms of cough and shortness of breath. Histologically 

macrophage accumulation is confined to the peribronchiolar 

interstitium and air spaces. Desquamative 

interstitial pneumonia is also characterized by the presence 

of intra-alveolar macrophages, but the abnormalities 

are less bronchiolocentric and more diffuse than 

those described in respiratory bronchiolitis. 

Typical HRCT features of DIP are: 

1. Bilateral areas of ground-glass attenuation in all patients 

�100 % prevalence) with predominance in the 

peripheral �60 %) and lower lung zones �100%). The 

upper lung zones are also affected in approximately 

80%. The distribution may be patchy in 25 % or 

evenly diffuse in 20%. 

2. Irregular linear opacities �reticular pattern) are seen 

in 50 % of patients again in a predominantly subpleural 

and basal location but much more limited in 

extent as compared with patients with UIP 

3. Only very mild honeycombing is seen in approximately 

30% of patients and is located almost exclusively 

in the lower lung zones. 

Typical HRCT features of RB-ILD are: 

1. Bilateral areas of ground-glass attenuation mostly in 

a patchy distribution. 

2. Small centrilobular nodules are seen in approximately 

40 % of patients �Fig.9c). 

3. Subtle findings of fibrosis �honeycombing, intralobular 

lines) were seen in the lower lung zones in 

approximately 25% of patients. 

3. An upper lobe centrilobular emphysema is frequently 

present. 

4. Bronchial wall thickening may be an associated 

finding �Fig. 9 c). 


Similar findings as seen in RB-ILD are also seen in 

asymptomatic smokers, but the findings in RB-ILD are 

usually more extensive. They are usually reversible 

when the patient stops smoking and is treated with corticosteroids. 

The differential diagnosis from RB-ILD and DIP includes 

hypersensitivity pneumonitis, sarcoidosis, NSIP, 

and infections such as Pneumocystis carinii pneumonia. 

Centrilobular nodules represent the key feature for differential 

diagnosis since they are very uncommon in 

DIP and hypersensitivity pneumonitis. 

Nonspecific interstitial pneumonia 

Nonspecific interstitial pneumonia �NSIP) resembles 

IPF but appears to be associated with a significantly 

different course and outcome. Whereas IPF is characterized 

by a recurrent and progressive process resulting 

in a mixture with simultaneous signs of active inflammation 

and long standing chronic fibrous changes, NSIP 

shows a different, temporally more uniform histological 

picture in the way that the parenchymal changes appear 

to have occurred over a single relatively narrow time 

span. Originally, NSIP was attributed to IPF �approximately 

5±15 % of patients with IPF turn out to have 

NSIP); however, clinical symptoms are less severe and 

disease progression is considerably slower in NSIP resulting 

in a markedly superior prognosis [65].

Katzenstein and Fiorelli [53] divided NSIP into three 

histological subgroups: primarily inflammation �I); both 

inflammation and fibrosis �II); and predominantly fibrosis 

�III), explaining the variability of HRCT morphological 

findings. The heterogeneity of CT features 

and their prevalence in the literature may also be due to 

different study populations or inconsistent interpretations 

of the histological findings in various institutions. 

Follow-up examinations of patients with NSIP show a 

good prognosis. 

Typical HRCT features of NSIP are: 

1. Patchy areas of ground-glass opacification with intervening 

areas of unaffected lung in approximately 

80 % of patients. They involve mainly the middle and 

lower lung zones with a predominance for the subpleural 

areas �Fig. 9 d,e). They are the sole abnormality 

in one-third of cases. 

2. A reticular pattern superimposed on the areas of 

ground glass in approximately 50 %. 

3. Consolidations are seen in 27 %. They are generally 

bilateral, symmetrical, and subpleural, and they were 

the sole abnormality in 4 % of patients. 

4. Honeycombing is seen strikingly rarely �4 %) or may 

be totally absent. Architectural distortion, traction 

bronchiectasis, and thickening of the bronchovascular 

bundle may be seen in group-III disease and reflect 

irreversible fibrosis. 


The differential diagnosis of NSIP depends on the CT 

pattern which it exhibits. The distinctive variety of disease 

patterns that have to be encountered, such as UIP, 

hypersensitivity pneumonitis, or BOOP, mirror the inconsistent 

CT pattern of NSIP. In a recent publication 

NSIP was the type of interstitial pneumonia with by far 

the lowest yield of diagnostic accuracy based on the assessment 

of HRCT by two independent observers [67]. 

Nonspecific interstitial pneumonia and fibrosis was 

confused most often with DIP and less frequently with 

UIP or BOOP. 

It is known that in patients with UIP areas of groundglass 

opacification progressively change into areas with 

irregular linear opacities and honeycombing. Serial 

HRCT findings in 13 patients with biopsy-proven NSIP, 

however, found that areas of ground-glass opacification 

significantly decreased over time corresponding to increasing 

pulmonary function tests. Even in the 3 patients 

with group-III disease, in which bronchial dilatation 

and linear densities were associated with ground 

glass, it did not progress to honeycombing. The authors 

assume that one underlying factor may be the better 

response to corticosteroid therapy, the other may be the 

relative absence of ongoing fibrosis in NSIP [68]. 

Acute interstitial pneumonia 

Acute interstitial pneumonia �AIP) is a fulminant condition 

of unknown cause that occurs in previously 

healthy persons and produces histologic findings of organizing 

diffuse alveolar damage �DAD). The clinical 

evolution and the pathological appearance can be divided 

into three interrelated and overlapping stages: in 

an early predominantly exudative �first to seventh day; 

proteinaceous exudates in air spaces with hyaline membrane 

formation, mild inflammation and interstitial 

edema); in the subacute fibro-proliferative phase 

�fourth to tenth day); and in the chronic fibrotic phase. 

Presumably the latter form led to the classification of 

the disease as interstitial fibrosis by Hamman and Rich 

[52], described as acute interstitial pneumonia �AIP) in 

subsequent classifications. The radiological, clinical, 

and also histological features of AIP are similar to 

ARDS �suggesting the term idiopathic ARDS). The 

prognosis is very poor with reported mortality rates of 

60±100 % within months. 

Typical HRCT features of AIP are: 

1. Extensive bilateral ground-glass attenuation in diffuse 

or patchy distribution with focal areas of spared 

almost normal lung parenchyma resulting in a geographic 

pattern. The extent of ground-glass attenuation 

correlates with disease duration. 

2. Consolidations are also seen but less frequently as 

ground-glass attenuations. 

3. As seen in patients with ARDS, there is an anteroposterior 

gradient of the ground-glass opacifications 

or consolidations with increasing attenuation in the 

depending parts. 

4. Ground glass is seen in all phases of AIP and its 

meaning depends on the stage: areas of increased attenuation 

without traction bronchiectasis are associated 

with the exudative or early proliferative phase 

of AIP �reflecting the presence of alveolar edema 

and hyaline membranes), whereas areas of opacity 

with traction bronchiectasis are associated with the 

chronic fibrotic phase �reflecting alveolar septal fibrosis) 

[69]. The combination of ground-glass attenuation, 

air space consolidation, traction bronchiectasis, 

and architectural distortion is seen in the majority 

of patients with AIP [70]. 

5. Smooth interlobular septal thickening, honeycombing, 

and pleural effusions occur occasionally but to a 

lower extent as seen in UIP. Honeycombing is not 

seen during the first week after onset of symptoms. 


387 

The differential diagnosis of AIP depends on the stage 

and includes hydrostatic edema, hemorrhage, alveolar

388 

a b c 

Fig.10a±c Bronchiolitis obliterans with organizing pneumonia can 

present with very different CT morphological appearances. a ACT 

scan in a 26-year-old patient after bone marrow transplantation 

and now presenting with dyspnea on exertion and cough. The most 

common appearance presents with patchy non-segmental consolidation 

in a subpleural distribution. Note the patent bronchi within 

the consolidation. b A 52-year-old patient with biopsy-proven 

BOOP. In this patient the consolidation shows a medullar distribution 

and spares the peripheral lung regions. This presentation of 

BOOP may mimic a pneumonia or edema. c Nodular BOOP may 

mimic malignant disorders: HRCT scan demonstrates nodular 

consolidation and ground-glass densities with irregular margins 

and discrete air bronchograms 

proteinosis, bronchoalveolar carcinoma, DIP, and diffuse 

infectious infiltrations. 

Patients with an accelerated form of IPF also showed 

multifocal areas of peripheral airspace consolidations 

�mimicking BOOP, DIP, or eosinophilic pneumonia). 

Follow-up CTs showed cystic lesions and traction bronchiectasis 

within the consolidations allowing for a distinction 

from BOOP �shows no honeycomb cysts). 

Whereas accelerated forms of IPF involve mainly the 

lung periphery, AIP involves both, the peripheral and 

central part [71]. Both, UIP and AIP, are distinct histologically: 

AIP is characterized by numerous fibroblasts 

but relatively little collagen deposition, whereas UIP 

shows only relatively few fibroblasts but extensive collagen 

deposition. The honeycomb cysts in AIP are lined 

within the alveolar epithelium, whereas in UIP they are 

lined in the bronchiolar epithelium. 

Bronchiolitis obliterans with organizing pneumonia 

Bronchiolitis obliterans organizing pneumonia �BOOP; 

also named cryptogenic organizing pneumonia = COP 

when without evident cause) is histologically characterized 

by �a) granulation tissue polyps within the lumina 

of bronchioles and alveolar ducts, and �b) patchy areas 

of cellular infiltrates �mainly mononuclear cells and 

macrophages) in the surrounding air spaces. Most cases 

are idiopathic, but a BOOP-like reaction may be seen in 

a variety of clinical situations �postinfectious, drug reaction, 

collagen vascular diseases, Wegener's granulomatosis, 

and after toxic inhalation). 

In a recent international consensus of a multidisciplinary 

American and European panel of clinicians, 

pathologists, and radiologists to standardize classification 

of idiopathic interstitial pneumonias, the idiopathic 

BOOP was included in the group of idiopathic interstitial 

pneumonias [72]. The decision had been debated. 

Arguments against inclusion were that the lesion 

is caused by airspace organization and is not primarily 

interstitial in a histological sense. Additionally, the 

morphological character of BOOP and UIP are usually 

distinctly different. The presence of consolidations and 

the absence of reticular opacities �as a dominant finding) 

in BOOP normally allow for distinction from UIP. 

Arguments in favor of including BOOP into the group 

of interstitial pneumonias were that there is a clinical, 

radiological, and pathological overlap of UIP and 

BOOP in certain cases, and the fact that idiopathic 

BOOP as an independent entity with a nonspecific pathology 

but a variety of etiologies causes widespread 

confusion. 

It has to be noted that Bronchiolitis obliterans has 

very distinct clinical, pathological, and radiological 

features, and should be clearly distinguished from 

BOOP. 

Typical HRCT features of BOOP are: 

1. Most commonly patchy �non-segmental) airspace 

consolidations in a subpleural �cortical) or central 

peribronchiolar distribution in more than 50 % of the 

patients. The patchy consolidations may be migratory, 

and they may show pleural tags or spiculae �in 

approximately 30±40 %; Fig. 10 a, b).

2. Whereas consolidations may be the only finding in 

approximately 50 % of the patients, ground-glass 

opacifications are mostly part of a mixed pattern. 

The size of the individual opacities ranges from 3 cm 

to nearly complete lobar consolidations. The margins 

of the consolidations are indistinct and may contain 

air bronchograms. 

3. Bronchial wall thickening and dilatation are seen in 

most patients and are usually restricted to areas of 

consolidation or ground-glass opacifications. It is not 

yet clarified how well these bronchial abnormalities 

are reversible. 

4. In 15±50 % patients of the various study populations 

multiple peribronchiolar �centrilobular) nodules 

were seen mostly measuring between 1 and 10 mm 

�Fig. 10c). These have mostly irregular margins 

�88 %) and may also show air bronchograms �45 %). 

Nodules are the only finding in approximately onethird 

of the patients who show nodules. 

5. Occasionally, bilateral areas of ground-glass opacities 

are seen with overlying thickened intralobular 

septal lines. Nodules and ground-glass attenuation 

are seen more frequently in the immunocompromised 

than in the immunocompetent patient. 

6. Additional findings are pleural thickening �33 %), 

small pleural effusions �30 %), and parenchymal 

bands �25 %). 


Dependent on the range of distinctive patterns, the differential 

diagnosis for BOOP is extensive. Clinical history 

may be helpful for differential diagnosis: BOOP 

usually appears as a subacute illness with duration of 

symptoms before diagnosis for approximately 

2±6 months. In many patients the clinical and radiographic 

signs of disease remit completely after systemic 

corticosteroid therapy. Only a subset of patients show a 

rapid progression and have a worse prognosis. In these 

patients, BOOP is frequently associated with connective 

tissue disease or drug therapy. Whereas infectious 

diseases may be excluded on the basis of clinical symptoms, 

lung biopsy is usually performed because of suspicion 

of a carcinoma. 

In cases with solitary mass-like focal consolidations 

that have morphological criteria for malignancy, such as 

spiculae, pleural tagging, or regional pleural thickening, 

a bronchial carcinoma cannot be differentiated from 

BOOP [73, 74]. 

Multiple patchy airspace opacities may also be associated 

with alveolar cell carcinoma, lymphoma, vasculitis, 

or pulmonary hemorrhage. 

Numerous bilateral small nodules in BOOP have to 

be differentiated from sarcoidosis or acute infectious 

bronchiolitis �atypical and typical mycobacteria). 

Chronic eosinophilic pneumonia has to be considered 

for differential diagnosis if the pattern is dominantly 

peripheral. 


Computed tomography provides a superior assessment 

of disease pattern and distribution as compared with 

chest radiography. Depending on the CT pattern as well 

as clinical and laboratory findings, it may be possible to 

exclude infectious disease and eosinophilic pneumonia. 

For differentiation from a carcinoma, CT is recommended 

as a guide to determine the optimal site for 

transbronchial or open-lung biopsy. The radiological 

pattern is also related to prognosis: Bilateral airspace 

consolidations demonstrate a better therapy response 

and prognosis than localized mass-like lesions or widespread 

reticulonodular disease. 

When to be sure of the diagnosis in HRCT: 

practical conclusions 

389 

High-resolution CT is known to greatly assist in the 

recognition and diagnosis of numerous diffuse lung diseases. 

Yet, whether HRCT findings can provide adequate 

diagnostic information to establish the final diagnosis 

and to substitute or decrease the need for lung biopsy 

varies for the different entities and is highly dependent, 

not only on the classic appearance of the disease 

but also on the skills of the radiologist. 

Many studies have been published in recent years 

which examined the diagnostic accuracy of HRCT 

based on pattern analysis [54, 55, 56, 67, 75, 76, 77, 78]. 

Reviewing these studies, readers should closely evaluate 

the following aspects since they largely influence the 

results and determine how well the results are transferable 

into the daily clinical routine. These aspects include 

the availability of clinical information, the study population 

and disease prevalence, the impact of misdiagnosis 

on patient treatment, and the reader's experience. 

Most reports agree that clinical information is very 

important and may even provide the diagnostic key for 

differential diagnosis. A detailed history is the first step 

in assessing the plausibility of an interstitial lung disease 

and narrowing the diagnostic possibilities. Firstly, it is 

useful to identify any risk factors for any type of immunodeficiency 

or immunosuppression, because diagnostic 

work-up should focus primarily on opportunistic infections 

in these patients and interstitial disease of unknown 

etiology is less likely. Secondly, the history 

should concentrate on clinical features that are indicative 

of specific diseases such as hypersensitivity pneumonitis, 

occupational disease, systemic diseases, and 

familial forms of IPF and sarcoid. A temporary associa-

390 

tion between exposure to a known fibrogenic factor and 

the onset of symptoms is highly suggestive and may be 

confirmed by the fact that pulmonary manifestations 

resolve after avoidance of further exposure to the antigen. 

In chronic hypersensitivity pneumonitis, however, 

establishing a temporal relationship between causing 

agent and pulmonary disease may be difficult and surgical 

biopsy cannot be avoided. A history of aspiration, 

recurrent sinusitis, arthritis, dermatological abnormalities, 

and hemoptysis raise the suspicion for collagen 

vascular diseases and pulmonary hemorrhage syndromes, 

respectively. Subsequent directed laboratory 

tests may provide sufficient information for making the 

diagnosis without biopsy in the appropriate clinical setting. 

One important feature of studies evaluating the diagnostic 

accuracy of HRCT is the selection of the study 

group that inevitably introduces a bias based on the fact 

that some diseases can be clearly more easily differentiated 

than others. The study population does not necessarily 

reflect the case mix encountered in daily routine 

work, in which the proportion of patients with cardiogenic 

interstitial markings, smoking-related disease, infectious 

diseases, or normal HRCT patterns is much 

higher. Primack and colleagues assessed the diagnostic 

accuracy of high resolution CT in 87 patients with endstage 

lung disease [79]. Whereas the overall accuracy 

was only 87 %, it was 100 % correct in silicosis and 

Langerhans' cell granulomatosis and 90 % correct in 

asbestosis. Other studies showed that certain HRCT 

features, such as cystic changes, have a narrow differential 

limited to LAM, tuberous sclerosis, or Langerhans' 

cell granulomatosis [77]. Tung and colleagues [56] 

showed that HRCT accurately distinguished IPF from 

other interstitial diseases in 88% of cases; however, the 

study did not appear to sufficiently address the wide 

range of interstitial lung disease: 41 of the 86 patients 

�48 %) included in the study had cryptogenic fibrosing 

alveolitis. Sarcoidosis, histiocytosis, EAA, and BOOP 

were included at least five times each, whereas eight 

other diseases were represented only once. In most 

studies well-experienced experts serve as readers to assess 

diagnostic accuracy, and their performance may not 

always be comparable to that of general radiologists; 

thus, reported diagnostic accuracies that exceed 90% 

may not encourage the reader to be unrealistically optimistic 

in the diagnostic capabilities of HRCT. Whereas 

in one patient the HRCT pattern in combination with 

clinical history allows for making a diagnosis with sufficient 

confidence, in other patients HRCT may allow 

only for narrowing the differential diagnosis and exclusion 

of certain conditions, or may be even completely 

non-specific. Eventually, clinicians must decide what the 

acceptable rate of misdiagnosis is in order to avoid biopsy. 

This may be different in various clinical situations 

and depends on therapeutic and prognostic conse- 

quences. In a study that evaluated the use of HRCT to 

distinguish IPF from chronic hypersensitivity pneumonitis, 

diagnosis could be made with confidence in 

only 62% of cases due to the fact that both entities may 

have identical HRCT features. Treatment, however, 

would be different given the fact that the chronic hypersensitivity 

pneumonitis has a better prognosis under 

treatment with corticosteroids and absence of the allergen 

[80]. Sometimes additional thoracic findings �e. g., 

mediastinal adenopathy in patients with sarcoid), extrathoracic 

findings �e. g., skin involvement in patients 

with collagen vascular diseases), or knowledge of patient 

history �e. g., allergic alveolitis) provide sufficient 

evidence to determine the etiology, and diagnosis is 

made without the need for lung biopsy. 

There is no doubt that HRCT is by far superior for 

detection of interstitial disease in comparison with chest 

radiography or conventional thick-section CT, and this 

is true for all disease entities [16, 54, 55, 67, 75, 76]. 

However, in this context it should not be forgotten that 

its diagnostic sensitivity to assess parenchymal involvement 

may not be 100 %. There are reports of mainly 

selected cases that describe normal HRCT findings in 

patients with histologically proven pulmonary fibrosis 

[81], sarcoidosis [10, 19, 20], and acute or subacute hypersensitivity 

pneumonitis [82]. 

Thus, in addition to the detection of lung disease and 

the characterization of parenchymal disorders, one of 

the most important contributions of HRCT to the diagnostic 

work-up of diffuse infiltrative lung disease is to 

assist the determination of the biopsy site. High-resolution 

CT is the tool of choice in identifying relatively unaffected, 

actively inflamed, and fibrotic areas. If extensive 

fibrotic changes and honeycombing are seen on 

HRCT, the disease is likely to be end-stage and not 

particularly amenable to treatment, regardless of the 

specific etiology. These findings may give clinicians 

pause in pursuing an invasive diagnostic work-up, particularly 

in elderly patients with comorbidity. Other 

conditions, such as patchy ground-glass opacities or 

ground glass with linear opacifications, need to be biopsied, 

because HRCT findings are non-specific and 

agreeable with various diseases having different prognoses 

and requiring different therapeutic approaches 

�e. g., alveolar sarcoid, DIP, UIP, NSIP, or chronic 

EAA).

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