High-resolution CT of diffuse interstitial lung disease: key findings in ...
High-resolution CT of diffuse interstitial lung disease: key findings in ...
High-resolution CT of diffuse interstitial lung disease: key findings in ...
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Eur. Radiol. �2001) 11: 373±392<br />
Ó Spr<strong>in</strong>ger-Verlag 2001<br />
Cornelia Schaefer-Prokop<br />
Mathias Prokop<br />
Dom<strong>in</strong>ik Fleischmann<br />
Christian Herold<br />
Received: 29 May 2000<br />
Accepted: 1 August 2000<br />
C.Schaefer-Prokop �) )´<br />
M. Prokop ´ D. Fleischmann ´ C.Herold<br />
Department <strong>of</strong> Radiology,<br />
General Hospital,<br />
Währ<strong>in</strong>ger Gürtel 18±20,<br />
1090 Vienna, Austria<br />
mathias.prokop@univie.ac.at<br />
Introduction<br />
CHEST<br />
There are more than 100 entities <strong>of</strong> <strong>diffuse</strong> <strong>in</strong>filtrative<br />
<strong>lung</strong> <strong>disease</strong>, although most reported series are made up<br />
<strong>of</strong> relatively few conditions, and <strong>in</strong> cl<strong>in</strong>ical practice ten<br />
<strong>disease</strong>s account for approximately 90 % <strong>of</strong> cases [1, 2].<br />
<strong>High</strong>-<strong>resolution</strong> computed tomography �HR<strong>CT</strong>) is now<br />
a mature technique with a generally accepted role <strong>in</strong> the<br />
diagnostic work-up <strong>of</strong> patients with known or suspected<br />
<strong>diffuse</strong> <strong>in</strong>filtrative <strong>lung</strong> <strong>disease</strong> [3, 4]. <strong>High</strong>-<strong>resolution</strong><br />
<strong>CT</strong> is the radiological imag<strong>in</strong>g technique currently<br />
available that most closely reflects changes <strong>in</strong> <strong>lung</strong><br />
structure [3]. It has clearly been shown to be superior to<br />
chest radiography and standard thick section <strong>CT</strong> for<br />
detect<strong>in</strong>g and clarify<strong>in</strong>g the pattern and extent <strong>of</strong> parenchymal<br />
<strong>lung</strong> <strong>disease</strong>. However, as recently po<strong>in</strong>ted<br />
out by D. Hansell, it still provides a macroscopic �not<br />
microscopic) view <strong>of</strong> pathology, the s<strong>in</strong>gle morphological<br />
feature is non-specific, and conclusions about the<br />
etiology <strong>of</strong> <strong>lung</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> are <strong>of</strong>ten based on <strong>in</strong>direct<br />
signs [4]. Thus, us<strong>in</strong>g that technique one has to be aware<br />
<strong>of</strong> its potential as well as its limitations. Although it<br />
<strong>High</strong>-<strong>resolution</strong> <strong>CT</strong> <strong>of</strong> <strong>diffuse</strong><br />
<strong><strong>in</strong>terstitial</strong> <strong>lung</strong> <strong>disease</strong>:<br />
<strong>key</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>in</strong> common disorders<br />
Abstract <strong>High</strong>-<strong>resolution</strong> <strong>CT</strong><br />
�HR<strong>CT</strong>) is the radiological imag<strong>in</strong>g<br />
technique that most closely reflects<br />
changes <strong>in</strong> <strong>lung</strong> structure. It represents<br />
the radiological method <strong>of</strong><br />
choice for the diagnostic work-up <strong>of</strong><br />
patients with known or suspected<br />
<strong>diffuse</strong> <strong><strong>in</strong>terstitial</strong> <strong>lung</strong> <strong>disease</strong>. A<br />
s<strong>in</strong>gle HR<strong>CT</strong> f<strong>in</strong>d<strong>in</strong>g is frequently<br />
nonspecific, but the comb<strong>in</strong>ation <strong>of</strong><br />
the various HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> together<br />
with their anatomic distribution can<br />
suggest the most probable diagnosis.<br />
The purpose <strong>of</strong> this article is to<br />
summarize the classic HR<strong>CT</strong> fea-<br />
tures <strong>of</strong> the most common <strong>diffuse</strong><br />
<strong><strong>in</strong>terstitial</strong> <strong>lung</strong> <strong>disease</strong>s. Lists <strong>of</strong><br />
differential diagnoses and dist<strong>in</strong>guish<strong>in</strong>g<br />
<strong>key</strong> features are provided<br />
to improve diagnostic confidence.<br />
The presence <strong>of</strong> classic HR<strong>CT</strong> features<br />
<strong>of</strong>ten obviates the need for biopsy.<br />
In patients with atypical <strong>f<strong>in</strong>d<strong>in</strong>gs</strong>,<br />
HR<strong>CT</strong> can be used to determ<strong>in</strong>e<br />
the most appropriate biopsy<br />
site.<br />
Key words Diffuse <strong><strong>in</strong>terstitial</strong> <strong>lung</strong><br />
<strong>disease</strong> ´ HR<strong>CT</strong> ´ Key features ´<br />
Diagnostic accuracy<br />
represents the cornerstone with<strong>in</strong> the diagnostic workup<br />
<strong>of</strong> <strong>diffuse</strong> <strong>lung</strong> <strong>disease</strong> presently, mean<strong>in</strong>gful <strong>in</strong>terpretation<br />
<strong>of</strong> HR<strong>CT</strong> requires consideration <strong>of</strong> cl<strong>in</strong>ical<br />
and laboratory <strong>f<strong>in</strong>d<strong>in</strong>gs</strong>.<br />
As with pla<strong>in</strong> chest radiography, optimal technique<br />
and knowledgeable pattern recognition <strong>of</strong> <strong>disease</strong>s are<br />
the prerequisites to use the potential <strong>of</strong> the modality to<br />
its full advantage.<br />
For optimal assessment <strong>of</strong> <strong>in</strong>filtrative <strong>lung</strong> <strong>disease</strong><br />
HR<strong>CT</strong> scans at 1-cm <strong>in</strong>tervals <strong>in</strong> the sup<strong>in</strong>e position or<br />
at 2-cm <strong>in</strong>tervals <strong>in</strong> both sup<strong>in</strong>e and prone positions are<br />
recommended. Techniques <strong>in</strong>volv<strong>in</strong>g less scans and<br />
larger <strong>in</strong>terscan gaps are certa<strong>in</strong>ly susceptible to the fact<br />
that subtle focal abnormalities may be missed [3]. The<br />
potential <strong>of</strong> multi-slice <strong>CT</strong> <strong>in</strong> this respect has to be<br />
evaluated <strong>in</strong> the future.<br />
Several recent publications have strengthened the<br />
fact that a systematic approach to the HR<strong>CT</strong> pattern is<br />
<strong>of</strong> great importance and allows for a mean diagnostic<br />
accuracy rang<strong>in</strong>g between 57 and 95% depend<strong>in</strong>g on<br />
the study group and the <strong>disease</strong> entity. Even when tak<strong>in</strong>g<br />
<strong>in</strong>to account that these results are based on more or
374<br />
a<br />
Fig.1a, b Typical and atypical appearance <strong>of</strong> lymphangitic carc<strong>in</strong>omatosis.<br />
a Characteristic presentation <strong>of</strong> lymphangitic carc<strong>in</strong>omatosis<br />
<strong>in</strong> a 45-year-old male with known pancreatic cancer. <strong>High</strong><strong>resolution</strong><br />
<strong>CT</strong> scan shows a nodular thicken<strong>in</strong>g <strong>of</strong> <strong>in</strong>terlobular<br />
septa as well as thicken<strong>in</strong>g <strong>of</strong> the broncho-vascular bundles. Note<br />
the additional nodules <strong>in</strong> the <strong>lung</strong> parenchyma, represent<strong>in</strong>g <strong>lung</strong><br />
metastases. b Atypical presentation <strong>of</strong> lymphangitic carc<strong>in</strong>omatosis<br />
<strong>in</strong> a 42-year-old female patient with a history <strong>of</strong> gastric cancer.<br />
In contrast to a, the <strong>in</strong>terlobular septal thicken<strong>in</strong>g is smooth without<br />
apparent nodularity. Areas <strong>of</strong> patchy ground-glass densities<br />
probably represent volume averag<strong>in</strong>g <strong>of</strong> thickened septa<br />
less selected groups <strong>of</strong> <strong>disease</strong>s, and mostly radiologists<br />
with longstand<strong>in</strong>g experience served as observers, the<br />
<strong>key</strong> po<strong>in</strong>t <strong>of</strong> these studies appears to be the demonstration<br />
<strong>of</strong> the potential <strong>of</strong> the technique if optimally applied.<br />
Thus, these results may also serve as motivation<br />
to radiologists to achieve the necessary knowledge <strong>of</strong><br />
HR<strong>CT</strong> patterns. Collections <strong>of</strong> appropriate learn<strong>in</strong>g<br />
files <strong>in</strong> comb<strong>in</strong>ation with a list <strong>of</strong> learn<strong>in</strong>g objectives and<br />
suited explanations that can be distributed us<strong>in</strong>g electronic<br />
devices �e. g., the EURORAD project by the<br />
European Association <strong>of</strong> Radiologists) may be an appropriate<br />
teach<strong>in</strong>g tool allow<strong>in</strong>g for a widely spread yet<br />
<strong>in</strong>dividual option for everybody to <strong>in</strong>crease or update<br />
his or her knowledge.<br />
The purpose <strong>of</strong> this review is to summarize the very<br />
classic HR<strong>CT</strong> features <strong>of</strong> the most common <strong>diffuse</strong> <strong><strong>in</strong>terstitial</strong><br />
<strong>lung</strong> <strong>disease</strong>s which may allow for mak<strong>in</strong>g a<br />
diagnosis. Lists <strong>of</strong> differential diagnoses and dist<strong>in</strong>guish<strong>in</strong>g<br />
<strong>key</strong> features may be <strong>of</strong> help <strong>in</strong> strengthen<strong>in</strong>g<br />
diagnostic confidence. Atypical <strong>disease</strong> appearances<br />
and overlapp<strong>in</strong>g morphological features, however, limit<br />
the value <strong>of</strong> HR<strong>CT</strong> <strong>in</strong> determ<strong>in</strong><strong>in</strong>g the <strong>disease</strong> entity. In<br />
those cases HR<strong>CT</strong> is the ideal tool for choos<strong>in</strong>g the<br />
next appropriate diagnostic procedure �e. g., transbronchial<br />
vs percutaneous vs open <strong>lung</strong> biopsy) and for<br />
guidance <strong>of</strong> the most appropriate biopsy site.<br />
b<br />
Key <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>in</strong> the most common <strong><strong>in</strong>terstitial</strong> disorders<br />
Pulmonary lymphangitic carc<strong>in</strong>omatosis<br />
Pulmonary lymphangitic carc<strong>in</strong>omatosis �PLC) refers to<br />
tumor growth <strong>in</strong> the lymphatic system <strong>of</strong> the <strong>lung</strong>s. It<br />
occurs most commonly <strong>in</strong> patients with carc<strong>in</strong>oma <strong>of</strong> the<br />
breast, <strong>lung</strong>, stomach, pancreas, cervix, prostate, thyroid,<br />
or <strong>in</strong> patients with metastases <strong>of</strong> an adenocarc<strong>in</strong>oma<br />
<strong>of</strong> unknown primary site. It usually results from<br />
metastatic spread to the <strong>lung</strong> with subsequent <strong><strong>in</strong>terstitial</strong><br />
and lymphatic <strong>in</strong>vasion, but can also occur because<br />
<strong>of</strong> direct lymphatic spread <strong>of</strong> tumor.<br />
Pathologically the thicken<strong>in</strong>g <strong>of</strong> the axial, peripheral,<br />
and septal <strong>in</strong>terstitium may be due to tumor fill<strong>in</strong>g <strong>of</strong><br />
pulmonary vessels and lymphatics, to direct tumor <strong>in</strong>filtration<br />
<strong>of</strong> the <strong>in</strong>terstitium itself, to secondary distension<br />
<strong>of</strong> the vascular and lymphatic channels distally to tumor<br />
emboli or tumor obstruction, and f<strong>in</strong>ally to <strong><strong>in</strong>terstitial</strong><br />
fibrosis after longstand<strong>in</strong>g edema or tumor <strong>in</strong>filtration.<br />
Dependent on the dom<strong>in</strong>ant pathological factor the<br />
thicken<strong>in</strong>g <strong>of</strong> the septa is smooth, nodular, or beaded.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> PLC are:<br />
1. Smooth or beaded thicken<strong>in</strong>g <strong>of</strong> the central peribronchovascular<br />
<strong>in</strong>terstitium �Fig.1)<br />
2. Smooth, nodular, or beaded <strong>in</strong>terlobular septal<br />
thicken<strong>in</strong>g produc<strong>in</strong>g a characteristic reticular pattern<br />
�Fig. 1)<br />
3. Thicken<strong>in</strong>g <strong>of</strong> the <strong>in</strong>tralobular axial <strong>in</strong>terstitium result<strong>in</strong>g<br />
<strong>in</strong> prom<strong>in</strong>ent vascular and bronchiolar structures<br />
�centrilobular core structures)<br />
4. A preservation <strong>of</strong> normal <strong>lung</strong> architecture at the<br />
lobular level despite the presence <strong>of</strong> reticulo-nodular<br />
and l<strong>in</strong>ear opacities<br />
Ste<strong>in</strong> et al. [5] described reticular opacities <strong>in</strong> the peripheral<br />
subpleural region <strong>in</strong> all patients �so-called peripheral<br />
arcades) and thickened septa outl<strong>in</strong><strong>in</strong>g dist<strong>in</strong>ct<br />
pulmonary lobules �polygonal arcades) <strong>in</strong> 50 % <strong>of</strong> the<br />
patients. Polygonal septal thicken<strong>in</strong>g <strong>in</strong> comb<strong>in</strong>ation<br />
with prom<strong>in</strong>ent centrilobular core structures are one <strong>of</strong><br />
the most dist<strong>in</strong>ct features <strong>of</strong> PLC. In only few patients<br />
the centrilobular <strong><strong>in</strong>terstitial</strong> thicken<strong>in</strong>g is the predom<strong>in</strong>ant<br />
f<strong>in</strong>d<strong>in</strong>g [6].<br />
In approximately 50 % <strong>of</strong> patients the abnormalities<br />
appear focal, unilateral, or asymmetric, rather than <strong>diffuse</strong>.<br />
Axial, peripheral subpleural, or central perihilar<br />
bronchovascular thicken<strong>in</strong>g may occur all together, or<br />
one <strong>of</strong> these features predom<strong>in</strong>ates or occurs alone.<br />
Associated <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> are <strong>in</strong>trapulmonary nodules, hilar<br />
or mediast<strong>in</strong>al lymphadenopathy �38±54 %), or pleural<br />
effusion.
Differential diagnosis<br />
The differential diagnosis <strong>in</strong>cludes <strong><strong>in</strong>terstitial</strong> edema,<br />
sarcoidosis, pneumoconiosis, and pulmonary fibrosis.<br />
Diagnostic clues for differentiation between PLC and<br />
<strong><strong>in</strong>terstitial</strong> edema, which are both characterized by<br />
perihilar peribronchovascular and reticular septal<br />
thicken<strong>in</strong>g, are the follow<strong>in</strong>g:<br />
1. In PLC the thickened <strong>in</strong>terstitium is sharply marg<strong>in</strong>ated<br />
from the adjacent aerated <strong>lung</strong>, and there is no<br />
fill<strong>in</strong>g <strong>in</strong> <strong>of</strong> the alveoli, which rema<strong>in</strong> well aerated.<br />
2. In PLC the pulmonary arterial branches adjacent to<br />
the bronchi also appear larger than normal, that way<br />
ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g the size relationship <strong>of</strong> the thick-walled<br />
bronchi and adjacent vessel [7].<br />
3. Interlobular thicken<strong>in</strong>g due to PLC is more non-uniform<br />
as compared with <strong><strong>in</strong>terstitial</strong> edema: different<br />
degrees <strong>of</strong> thicken<strong>in</strong>g may occur with<strong>in</strong> one septum<br />
as well as alterations between smooth or beaded<br />
contours.<br />
4. Whereas <strong><strong>in</strong>terstitial</strong> edema is most frequently bilateral<br />
and symmetrical, PLC may occur <strong>in</strong> a focal and<br />
asymmetrical distribution.<br />
5. The <strong><strong>in</strong>terstitial</strong> edema is dependently distributed,<br />
and various degrees <strong>of</strong> alveolar opacification represent<br />
airspace edema. The left ventricle and atrium<br />
may be enlarged, and pleural effusions are frequently<br />
associated.<br />
6. Adm<strong>in</strong>istration <strong>of</strong> diuretics results <strong>in</strong> a decrease <strong>of</strong><br />
<strong><strong>in</strong>terstitial</strong> edema with<strong>in</strong> hours.<br />
Diagnostic clues for differentiation <strong>of</strong> PLC from sarcoid,<br />
pneumoconiosis, and pulmonary fibrosis, which all<br />
may show nodular or beaded peribronchovascular<br />
thicken<strong>in</strong>g, are:<br />
1. In sarcoidosis and pneumoconiosis the septal thicken<strong>in</strong>g<br />
is less extensive than <strong>in</strong> patients with PLC and<br />
reticular opacities are not the predom<strong>in</strong>ant feature.<br />
2. In all three, sarcoidosis, pneumoconiosis, and pulmonary<br />
fibrosis, cicatricial distortion <strong>of</strong> the <strong>lung</strong> architecture<br />
and secondary lobule anatomy is common,<br />
especially when septal thicken<strong>in</strong>g is present. In PLC,<br />
however, <strong>lung</strong> architecture rema<strong>in</strong>s normal and the<br />
lobules preserve their size and shape.<br />
Diagnostic role <strong>of</strong> HR<strong>CT</strong><br />
Particularly <strong>in</strong> patients with focal PLC, HR<strong>CT</strong>was found<br />
to be more sensitive than conventional radiography and<br />
thick-slice standard <strong>CT</strong> [5, 7]. In patients with known<br />
tumor, who have symptoms <strong>of</strong> dyspnea and HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong><br />
consistent with PLC, HR<strong>CT</strong> is usually considered<br />
diagnostic and no <strong>lung</strong> biopsy is performed [3]; however,<br />
<strong>in</strong> patients without known neoplasm or with unknown<br />
location <strong>of</strong> the primary tumor, HR<strong>CT</strong> serves as guidance<br />
to select the most appropriate biopsy site.<br />
Sarcoidosis<br />
375<br />
Sarcoidosis is a systemic disorder <strong>of</strong> unknown orig<strong>in</strong>. It<br />
is characterized by non-caseat<strong>in</strong>g epitheloid cell granulomas<br />
<strong>in</strong> multiple organs, but morbidity and mortality<br />
are closely related to pulmonary manifestation occurr<strong>in</strong>g<br />
<strong>in</strong> 90 % <strong>of</strong> patients. The sarcoid granulomas are<br />
distributed primarily along the lymphatics <strong>in</strong> the axial<br />
peribronchovascular <strong><strong>in</strong>terstitial</strong> space �both <strong>in</strong> the perihilar<br />
and centrilobular region) and, to a lesser extent, <strong>in</strong><br />
the <strong>in</strong>terlobular septa and subpleural <strong>in</strong>terstitium. Thus,<br />
beaded thicken<strong>in</strong>g <strong>of</strong> the central perihilar <strong>in</strong>terstitium is<br />
highly suggestive for sarcoidosis particularly <strong>in</strong> comb<strong>in</strong>ation<br />
with mediast<strong>in</strong>al adenopathy or further evidence<br />
<strong>of</strong> perilymphatic <strong>in</strong>trapulmonary nodules [8]. The <strong>CT</strong><br />
appearance <strong>of</strong> pulmonary sarcoidosis varies greatly and<br />
is known to masquerade many other <strong>diffuse</strong> <strong>in</strong>filtrative<br />
<strong>lung</strong> <strong>disease</strong>s.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> sarcoidosis are:<br />
1. Smooth or nodular peribronchovascular <strong><strong>in</strong>terstitial</strong><br />
thicken<strong>in</strong>g.<br />
2. Small, well-def<strong>in</strong>ed nodules <strong>in</strong> a characteristic ªperilymphatic<br />
distributionº <strong>in</strong> relation to the subpleural<br />
surface, adjacent to the major fissures, along thickened<br />
<strong>in</strong>terlobular septa and adjacent to vessels <strong>in</strong> the<br />
lobular core �Fig.2a). As a result, pulmonary vessels<br />
may be irregularly enlarged.<br />
3. The nodules may be evenly distributed throughout<br />
both <strong>lung</strong>s with predom<strong>in</strong>ance <strong>of</strong> the upper and middle<br />
<strong>lung</strong> zones; however, <strong>in</strong> most cases they are clustered<br />
<strong>in</strong> the perihilar and peribronchovascular region<br />
with relative spar<strong>in</strong>g <strong>of</strong> the <strong>lung</strong> periphery, or they<br />
may be grouped <strong>in</strong> small areas uni- or bilaterally<br />
�Fig. 2 b).<br />
4. Confluence <strong>of</strong> granulomas results <strong>in</strong> large, mostly illdef<strong>in</strong>ed<br />
opacities or consolidations. Nodular densities<br />
measur<strong>in</strong>g between 1 and 4 cm <strong>in</strong> diameter were<br />
seen <strong>in</strong> 15±25% <strong>of</strong> patients �so-called nodular sarcoidosis)<br />
[9, 10, 11, 12].<br />
5. Patchy areas <strong>of</strong> ground-glass opacities, which may be<br />
superimposed over <strong><strong>in</strong>terstitial</strong> nodules or signs <strong>of</strong> fibrosis<br />
[13]. They are rarely seen on the radiograph<br />
�0.6 %) [14] but are commonly present on HR<strong>CT</strong><br />
�20±60 %) mostly <strong>in</strong> association with small nodules.<br />
Pathological studies have shown that they represent<br />
<strong><strong>in</strong>terstitial</strong> granulomatous <strong>in</strong>flammation and occasionally<br />
microscopic foci <strong>of</strong> parenchymal fibrosis<br />
�Fig. 2 c).<br />
6. Approximately 20% <strong>of</strong> patients develop a pulmonary<br />
fibrosis with septal thicken<strong>in</strong>g, traction bron-
376<br />
a b<br />
c d<br />
Fig.2 The many faces <strong>of</strong> sarcoidosis. a A 36-year-old patient with a<br />
dyspnea on exertion. <strong>High</strong>-<strong>resolution</strong> <strong>CT</strong> shows small, well-def<strong>in</strong>ed<br />
<strong><strong>in</strong>terstitial</strong> nodules distributed along the axial as well as peripheral<br />
<strong>in</strong>terstitium. In addition, nodules are seen <strong>in</strong> a subpleural<br />
distribution and along the fissures. b A 25-year-old male patient<br />
with erythema nodosum. In these patients with proven sarcoidosis,<br />
most nodules cluster <strong>in</strong> small groups and merge to areas <strong>of</strong> consolidation.<br />
This pattern which may also cause alveolar densities on<br />
chest X-rays is termed ªalveolar sarcoidº and is most frequently<br />
seen <strong>in</strong> Afro-American females. c In this female patient with a long<br />
history <strong>of</strong> sarcoidosis, the predom<strong>in</strong>ant manifestation <strong>of</strong> <strong>disease</strong> is<br />
ground-glass density; however, ground glass such as <strong>in</strong> this case is<br />
not a reliable ideal <strong>in</strong>dicator <strong>of</strong> treatable and potentially reversible<br />
<strong>disease</strong>, s<strong>in</strong>ce bronchiectasis �traction bronchiectasis) �arrows) <strong>in</strong>dicates<br />
to the presence <strong>of</strong> fibrosis. d Fibros<strong>in</strong>g sarcoidosis: a 42year-old<br />
patient with known sarcoidosis <strong>in</strong>volv<strong>in</strong>g only the <strong>lung</strong><br />
parenchyma. Note the conglomerate masses <strong>in</strong> the hilar region<br />
with a characteristic dorsal retraction <strong>of</strong> the hila. L<strong>in</strong>ear and<br />
patchy perihilar densities represent the peribronchiolar/perivascular<br />
localization <strong>of</strong> <strong>disease</strong>. In addition, small peripheral <strong><strong>in</strong>terstitial</strong><br />
nodules are present, especially also <strong>in</strong> a subpleural location<br />
chiectasis, and honeycomb<strong>in</strong>g �Fig. 2 d). Irreversible<br />
fibrosis is most common <strong>in</strong> stage 3 �<strong>diffuse</strong> pulmonary<br />
<strong>disease</strong> unassociated with lymph-node enlargement).<br />
Conglomerate masses mostly <strong>in</strong> a perihilar<br />
location represent areas <strong>of</strong> fibrosis which cause characteristic<br />
traction bronchiectasis. The posterior displacement<br />
<strong>of</strong> the upper lobe bronchi �and later also<br />
<strong>of</strong> the ma<strong>in</strong> bronchi) is considered to be an early sign<br />
<strong>of</strong> <strong>lung</strong> distortion <strong>in</strong> sarcoidosis <strong>in</strong>dicat<strong>in</strong>g loss <strong>of</strong><br />
volume <strong>in</strong> the posterior segments <strong>of</strong> the upper lobes<br />
[15].<br />
Differential diagnosis<br />
Conditions that most closely mimic the HR<strong>CT</strong> appearance<br />
<strong>of</strong> sarcoidosis are PLC, silicosis, and coal worker's<br />
pneumoconiosis �CWP). All <strong>of</strong> these show small perilymphatic<br />
nodules; however, differences <strong>of</strong> the predom<strong>in</strong>ant<br />
distribution and the comb<strong>in</strong>ation with signs <strong>of</strong><br />
fibrosis represent the diagnostic <strong>key</strong> factors.
In sarcoidosis the nodules are predom<strong>in</strong>antly located<br />
along the central bronchovascular bundle and <strong>in</strong> the<br />
subpleural area; <strong>in</strong> PLC nodules are mostly located<br />
septal and bronchovascular, and <strong>in</strong> silicosis and pneumoconiosis<br />
they are predom<strong>in</strong>antly located centrilobular<br />
and subpleural.<br />
In silicosis and CWP, nodules are mostly evenly distributed<br />
throughout the whole <strong>lung</strong>, a f<strong>in</strong>d<strong>in</strong>g which is<br />
much less typical for sarcoidosis. Differentiation <strong>of</strong><br />
conglomerate masses <strong>of</strong> fibrosis <strong>in</strong> sarcoidosis from<br />
those <strong>in</strong> silicosis can be readily made by the presence <strong>of</strong><br />
air bronchograms <strong>in</strong> the former [2, 5, 7].<br />
Septal thicken<strong>in</strong>g <strong>in</strong> sarcoidosis is a much less dom<strong>in</strong>ant<br />
feature as compared with PLC, and if present, it is<br />
usually comb<strong>in</strong>ed with <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>of</strong> fibrosis and <strong>lung</strong> distortion<br />
preclud<strong>in</strong>g the diagnosis <strong>of</strong> PLC. There are,<br />
however, descriptions <strong>of</strong> cases <strong>in</strong> which the parenchymal<br />
<strong>in</strong>volvement <strong>of</strong> sarcoidosis and PLC are similar and <strong>in</strong>dist<strong>in</strong>guishable<br />
[10, 16].<br />
As fibrosis develops over time, sarcoidosis and idiopathic<br />
pulmonary fibrosis �IPF) <strong>in</strong>creas<strong>in</strong>gly share numerous<br />
<strong>f<strong>in</strong>d<strong>in</strong>gs</strong>. Both show irregular or nodular septal<br />
thicken<strong>in</strong>g, irregular <strong>in</strong>terfaces, and traction bronchiectasis.<br />
In sarcoidosis, honeycomb<strong>in</strong>g is a less frequent<br />
feature <strong>of</strong> irreversible fibrosis as compared with<br />
IPF; however, there appear to be two types <strong>of</strong> fibrotic<br />
progression <strong>in</strong> sarcoidosis. Whereas most patients develop<br />
fibrotic changes with loss <strong>of</strong> volume, fibrotic bands,<br />
and cysts predom<strong>in</strong>antly <strong>in</strong> the perihilar region and the<br />
upper lobes, suggest<strong>in</strong>g the diagnosis <strong>of</strong> sarcoidosis,<br />
there are descriptions <strong>of</strong> a few cases which developed a<br />
<strong>diffuse</strong> fibrosis with predom<strong>in</strong>ant basal and subpleural<br />
honeycomb<strong>in</strong>g very similar <strong>in</strong> appearance to UIP [17].<br />
Diagnostic role <strong>of</strong> HR<strong>CT</strong><br />
As shown by a multitude <strong>of</strong> studies, <strong>CT</strong> is superior to<br />
chest radiography for detection and observation <strong>of</strong> <strong>in</strong>volvement<br />
<strong>of</strong> the pulmonary parenchyma. Computed<br />
tomography is also superior for confirmation <strong>of</strong> mediast<strong>in</strong>al<br />
or hilar lymph nodes which represent mean<strong>in</strong>gful<br />
<strong>in</strong>formation for the diagnosis <strong>of</strong> sarcoidosis [3, 18]. <strong>High</strong><strong>resolution</strong><br />
<strong>CT</strong> is the method <strong>of</strong> choice for show<strong>in</strong>g early<br />
fibrosis; however, it is important to know that HR<strong>CT</strong><br />
cannot be used to rule out parenchymal <strong>in</strong>volvement.<br />
Several authors report that <strong>in</strong>trapulmonary granulomas<br />
could be histologically shown <strong>in</strong> patients with normal<br />
HR<strong>CT</strong> appearance <strong>of</strong> the <strong>lung</strong> parenchyma [10, 19, 20].<br />
The diagnosis <strong>of</strong> sarcoidosis is confirmed by the histological<br />
identification <strong>of</strong> epitheloid cells <strong>in</strong> granulomas.<br />
In patients without known extrathoracic <strong>in</strong>volvement,<br />
transbronchial biopsy is the diagnostic procedure <strong>of</strong><br />
choice. It may be performed simultaneously with BAL.<br />
Intrapulmonary granulomas may be confirmed even<br />
when no pathological HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> are present. On the<br />
other hand, if no granulomas are detected by transbronchial<br />
biopsy, the possibility <strong>of</strong> sarcoidosis cannot be excluded.<br />
The sensitivity <strong>of</strong> transbronchial biopsy is reported<br />
to be 80 % [21]. The second-l<strong>in</strong>e procedure would<br />
be a mediast<strong>in</strong>oscopy s<strong>in</strong>ce most patients also have enlarged<br />
mediast<strong>in</strong>al lymph nodes. When <strong>CT</strong> does not<br />
show mediast<strong>in</strong>al lymphadenopathy, or mediast<strong>in</strong>oscopy<br />
is difficult, video-assisted thoracoscopic <strong>lung</strong> biopsy or<br />
open-<strong>lung</strong> biopsy are the rema<strong>in</strong><strong>in</strong>g alternatives.<br />
A lot has been written about the mean<strong>in</strong>g <strong>of</strong> groundglass<br />
opacities <strong>in</strong> patients with sarcoid. One study [20]<br />
<strong>in</strong>dicated that areas <strong>of</strong> ground-glass opacities are associated<br />
with <strong>disease</strong> activity as assessed by 67 Ga sc<strong>in</strong>tigraphy.<br />
Correlation with pathological specimen, however,<br />
could prove that ground-glass opacities reflect the<br />
presence <strong>of</strong> confluence <strong>of</strong> extensive <strong><strong>in</strong>terstitial</strong> sarcoid<br />
granulomas rather than active alveolitis [10, 12, 13, 22].<br />
Murdoch and Müller described that ground-glass, nodular<br />
and irregular l<strong>in</strong>ear opacities, and <strong>in</strong>terlobular septal<br />
thicken<strong>in</strong>g represent potentially reversible <strong>disease</strong>,<br />
whereas cystic air spaces and architectural distortion are<br />
irreversible <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> [23]. The extent <strong>of</strong> consolidations<br />
and nodular densities showed higher correlations with<br />
other <strong>in</strong>dicators <strong>of</strong> <strong>disease</strong> activity �serum-angiotens<strong>in</strong><br />
convert<strong>in</strong>g enzyme essay, Ga scann<strong>in</strong>g, and bronchoalveolar<br />
lavage) than reticular opacities and ground-glass<br />
attenuation [24].<br />
Whereas <strong>CT</strong> is the superior method for demonstration<br />
and follow-up <strong>of</strong> extent and distribution <strong>of</strong> <strong>disease</strong>,<br />
results are controversial as to whether HR<strong>CT</strong> is superior<br />
to radiography <strong>in</strong> provid<strong>in</strong>g <strong>in</strong>formation about the<br />
functional impairment [9, 15, 25, 26, 27]. Differences <strong>of</strong><br />
results reported <strong>in</strong> the literature are most likely due to<br />
different selection <strong>of</strong> patient groups and data analysis. It<br />
appears that signs <strong>of</strong> fibrosis �such as <strong>lung</strong> distortion and<br />
reticular densities) correlate better with impairment <strong>of</strong><br />
<strong>lung</strong> function �obstruction) than extent and distribution<br />
<strong>of</strong> nodules and consolidations [28].<br />
Silicosis/coal worker's pneumoconiosis<br />
377<br />
Silicosis and coal worker's pneumoconiosis �CWP) are<br />
pathologically dist<strong>in</strong>ct entities with differ<strong>in</strong>g histology,<br />
result<strong>in</strong>g from the <strong>in</strong>halation <strong>of</strong> different <strong>in</strong>organic dusts<br />
�dust conta<strong>in</strong><strong>in</strong>g crystallized silicon dioxide and coal<br />
dust, respectively); however, the radiographic and<br />
HR<strong>CT</strong> appearance are similar and cannot be reliably<br />
dist<strong>in</strong>guished.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> silicosis and CWP are:<br />
1. Small, well-def<strong>in</strong>ed nodules <strong>of</strong> usually 2±5 mm <strong>in</strong><br />
diameter �rarely larger) scattered throughout both<br />
<strong>lung</strong>s with a predom<strong>in</strong>ance for the upper <strong>lung</strong> zones,<br />
especially posteriorly �Fig. 3 a). They may be calcified<br />
and are typically uniformly distributed <strong>in</strong> cen-
378<br />
a b<br />
Fig.3 The HR<strong>CT</strong> features <strong>of</strong> silicosis. a Patient with limited exposure<br />
<strong>of</strong> dust-conta<strong>in</strong><strong>in</strong>g crystallized silicone dioxid demonstrates a<br />
few small nodules predom<strong>in</strong>antly located <strong>in</strong> the subpleural �arrows)<br />
and peribronchiolar �arrowheads) location. Despite its subtlety,<br />
the <strong>disease</strong> has a dist<strong>in</strong>ct upper lobe predom<strong>in</strong>ance �lower<br />
<strong>lung</strong> scans not shown). b Patient with long-term exposure and<br />
progressive massive fibrosis and silicosis. The mass lesions <strong>in</strong> these<br />
patients with complicated silicosis develop <strong>in</strong> the midportion or<br />
periphery <strong>of</strong> upper long zones. These masses potentially undergo<br />
necrosis and may also develop areas <strong>of</strong> cavitation<br />
trilobular �peribronchiolar) and subpleural locations<br />
rather than clustered or localized along septa.<br />
Sometimes the centrilobular densities show t<strong>in</strong>y<br />
short branches <strong>in</strong>stead <strong>of</strong> be<strong>in</strong>g round correspond<strong>in</strong>g<br />
to irregular fibrosis around the respiratory bronchioles<br />
surrounded by a small zone <strong>of</strong> focal emphysema.<br />
2. As simple silicosis and CWP progress, the number <strong>of</strong><br />
nodules <strong>in</strong>crease and <strong>in</strong>creas<strong>in</strong>gly coalesce result<strong>in</strong>g<br />
<strong>in</strong> distortion <strong>of</strong> the adjacent <strong>lung</strong> structure. Coalescence<br />
<strong>of</strong> small nodules to larger nodules � > 1 cm) and<br />
eventually to large, irregularly def<strong>in</strong>ed conglomerate<br />
masses reflect the transition from simple to complicated<br />
silicosis/pneumoconiosis �Fig. 3 b). The masses<br />
tend to develop <strong>in</strong> the midportion or periphery <strong>of</strong> the<br />
upper <strong>lung</strong> zones and migrate toward the hila [3].<br />
They may cavitate due to ischemic necrosis, although<br />
this seems to be more common with CWP.<br />
3. Accompany<strong>in</strong>g paracicatricial emphysema which reflects<br />
the process <strong>of</strong> pulmonary massive fibrosis<br />
�PMF)<br />
Differential diagnosis<br />
The differential diagnosis <strong>of</strong> silicosis/CWP <strong>in</strong>cludes all<br />
<strong>disease</strong>s that may develop numerous small, well-def<strong>in</strong>ed<br />
nodular opacities such as sarcoidosis, pulmonary lym-<br />
phangitic carc<strong>in</strong>omatosis, histiocytosis X, but also <strong>in</strong>fectious<br />
<strong>disease</strong>s such as miliary tuberculosis, fungus <strong>in</strong>fection,<br />
and hematogenous metastases.<br />
Depend<strong>in</strong>g on the pr<strong>of</strong>usion <strong>of</strong> the nodules <strong>in</strong> a<br />
seem<strong>in</strong>gly random distribution, it may be impossible to<br />
dist<strong>in</strong>guish miliary tuberculosis �perivascular nodules)<br />
from silicosis �peribronchiolar nodules). Also the differentiation<br />
between sarcoidosis and silicosis can be<br />
difficult when the sarcoid nodules are numerous and do<br />
not show the typical perilymphatic distribution but a<br />
<strong>diffuse</strong> centrilobular location. The differentiation between<br />
silicosis and histiocytosis X is difficult if the latter<br />
is characterized solely by the presence <strong>of</strong> nodules,<br />
whereas cystic lesions are completely miss<strong>in</strong>g.<br />
Perihilar mass-like fibrosis or upper lobe consolidations<br />
<strong>in</strong> comb<strong>in</strong>ation with parenchymal distortion may<br />
occur <strong>in</strong> both, silicosis/CWP and end-stage sarcoidosis.<br />
Both entities are characterized by an upper lobe predom<strong>in</strong>ance<br />
and by potential calcifications <strong>of</strong> the nodules.<br />
They may only be dist<strong>in</strong>guishable by associated<br />
<strong>f<strong>in</strong>d<strong>in</strong>gs</strong> such as the distribution <strong>of</strong> nodules.<br />
Silicosis/CWP and PLC can usually be differentiated<br />
quite easily by the different distribution <strong>of</strong> nodules. In<br />
silicosis and CWP, the nodules appear bilaterally, symmetrical,<br />
and more uniformly distributed. Beaded septa<br />
or reticular densities are usually absent.<br />
An acute form <strong>of</strong> silicosis has been described <strong>in</strong><br />
which a large dose <strong>of</strong> silica was <strong>in</strong>haled stimulat<strong>in</strong>g an<br />
alveolar lipoprote<strong>in</strong>osis and subsequently extensive<br />
production <strong>of</strong> fibrous tissue. The radiographic image<br />
showed alveolar ground-glass opacifications <strong>in</strong>stead <strong>of</strong><br />
discrete silica nodules resembl<strong>in</strong>g the image <strong>of</strong> alveolar<br />
prote<strong>in</strong>osis [29].<br />
Diagnostic role <strong>of</strong> HR<strong>CT</strong><br />
<strong>High</strong>-<strong>resolution</strong> <strong>CT</strong> has been shown to be superior to<br />
both conventional <strong>CT</strong> and chest radiography especially<br />
for the detection <strong>of</strong> small nodules and early fibrotic<br />
changes and emphysema [30, 31, 32]. Computed tomography<br />
is well suited to monitor <strong>disease</strong> progression<br />
and to detect secondary related <strong>disease</strong> such as tuberculosis<br />
and <strong>lung</strong> cancer [30, 31, 32].<br />
In most patients the characteristic distribution <strong>of</strong><br />
nodular densities should suffice for diagnosis; however,<br />
as po<strong>in</strong>ted out previously, HR<strong>CT</strong> features alone may be<br />
<strong>in</strong>dist<strong>in</strong>guishable especially from other <strong>in</strong>filtrative <strong>lung</strong><br />
<strong>disease</strong>s �sarcoidosis, histiocytosis) or from <strong>in</strong>fectious<br />
<strong>disease</strong>s �tuberculosis, fungus). Additional cl<strong>in</strong>ical <strong>in</strong>formation<br />
is required but usually sufficient to preclude<br />
further <strong>in</strong>vasive diagnosis. Functional impairment and<br />
prognosis are usually poorer for patients with silicosis<br />
than for CWP. The extent <strong>of</strong> emphysema correlates<br />
more closely with functional impairment than does the<br />
degree <strong>of</strong> nodular pr<strong>of</strong>usion [30, 33].
Lymphangiomyomatosis and tuberous sclerosis<br />
Lymphangiomyomatosis �LAM) and pulmonary <strong>in</strong>volvement<br />
<strong>in</strong> tuberous sclerosis �<strong>in</strong> 1 %) are radiologically<br />
and pathologically identical. Both are rare <strong>disease</strong>s<br />
that are characterized by progressive proliferation <strong>of</strong><br />
sp<strong>in</strong>dle cells, resembl<strong>in</strong>g immature smooth muscle cells<br />
along the bronchovascular bundles, lymphatics, and pulmonary<br />
ve<strong>in</strong>s. Proliferation <strong>of</strong> sp<strong>in</strong>dle cells along the<br />
bronchioles leads to air trapp<strong>in</strong>g and hyper<strong>in</strong>flation, the<br />
development <strong>of</strong> emphysema, and formation <strong>of</strong> th<strong>in</strong>-walled<br />
cysts. Ruptures <strong>of</strong> pulmonary venoles lead to episodes<br />
<strong>of</strong> hemoptysis and pulmonary hemorrhage, obstruction<br />
<strong>of</strong> pulmonary lymphatics by smooth muscles<br />
cause chylous pleural effusions. Lymphangiomyomatosis<br />
exclusively occurs <strong>in</strong> women <strong>of</strong> child-bear<strong>in</strong>g age.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> LAM are:<br />
1. Numerous th<strong>in</strong>-walled cysts, surrounded by mostly<br />
normal parenchyma �Fig.4). The cysts range from<br />
2 mm to 5 cm <strong>in</strong> diameter but can occasionally become<br />
even larger. Their size tends to <strong>in</strong>crease with<br />
<strong>disease</strong> progression. The cysts are primarily round <strong>in</strong><br />
shape, and only some <strong>of</strong> them are confluent. In most<br />
patients the <strong>in</strong>terven<strong>in</strong>g parenchyma is normal; however,<br />
there are also reports <strong>of</strong> cases which show patchy<br />
ground-glass opacities or <strong>in</strong>creased <strong><strong>in</strong>terstitial</strong><br />
mark<strong>in</strong>gs <strong>in</strong> the pericystic <strong>lung</strong> parenchyma and occasionally<br />
even signs <strong>of</strong> <strong>lung</strong> distortion.<br />
2. The cysts are distributed <strong>diffuse</strong>ly throughout the<br />
<strong>lung</strong>s, no <strong>lung</strong> zone is spared, and upper and lower<br />
lobes are <strong>in</strong>volved to a similar degree.<br />
3. The wall thickness <strong>of</strong> the cysts range from rarely<br />
perceptible to 4 mm <strong>in</strong> thickness.<br />
4. Very rarely, few nodules may be seen.<br />
5. Approximately 50% <strong>of</strong> patients have mediast<strong>in</strong>al or<br />
hilar adenopathy, and �chylous) pleural effusions<br />
may be present. Recurrent pneumothoraces may occur.<br />
Differential diagnosis<br />
The differential diagnosis <strong>of</strong> <strong>diffuse</strong> <strong>lung</strong> <strong>disease</strong>s with<br />
primarily cystic lesions <strong>in</strong>clude histiocytosis X, centrilobular<br />
emphysema, end-stage <strong><strong>in</strong>terstitial</strong> fibrosis, and<br />
lymphoid <strong><strong>in</strong>terstitial</strong> pneumonitis �LIP).<br />
Lymphangiomyomatosis can be reliably differentiated<br />
from histiocytosis by the <strong>diffuse</strong> <strong>lung</strong> <strong>in</strong>volvement �<strong>in</strong><br />
LAM the <strong>lung</strong> bases or costophrenic sulci are not<br />
spared), the <strong>in</strong>frequency <strong>of</strong> nodules, and the regular<br />
shape <strong>of</strong> the cysts. Additionally, LAM is not associated<br />
with smok<strong>in</strong>g history, whereas more than 90% <strong>of</strong> patients<br />
with histiocytosis are smokers.<br />
Emphysematous cystic air spaces have no perceptible<br />
walls �Fig. 5). In LAM, vessels are typically seen at<br />
379<br />
Fig.4 Complete replacement <strong>of</strong> the <strong>lung</strong> parenchyma by numerous<br />
th<strong>in</strong>-wall cysts <strong>in</strong> a 26-year-old female with lymphangiomyomatosis.<br />
Note the vessels seen at the marg<strong>in</strong>s <strong>of</strong> the cysts<br />
Fig.5 A 42-year-old male smoker with centrilobular emphysema.<br />
<strong>High</strong>-<strong>resolution</strong> <strong>CT</strong> shows predom<strong>in</strong>antly ill-def<strong>in</strong>ed areas <strong>of</strong> low<br />
attenuation located ma<strong>in</strong>ly <strong>in</strong> the medulla portion <strong>of</strong> the <strong>lung</strong>. In<br />
some <strong>in</strong>stances centrilobular emphysema can also form cystic<br />
spaces with discrete walls. Note bronchial wall thicken<strong>in</strong>g represent<strong>in</strong>g<br />
chronic bronchitis<br />
the marg<strong>in</strong>s <strong>of</strong> the cysts rather than at the centers <strong>of</strong> air<br />
spaces as is characteristically seen with emphysema.<br />
Differential diagnosis, however, my be difficult especially<br />
<strong>in</strong> early stages <strong>of</strong> LAM, and <strong>in</strong> advanced stages <strong>of</strong><br />
paraseptal emphysema.<br />
Complete absence <strong>of</strong> fibrotic changes or <strong>of</strong> signs <strong>of</strong><br />
distortion facilitate the differential from IPF; however,<br />
<strong>in</strong> accordance to reported pathological <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> [34], <strong><strong>in</strong>terstitial</strong><br />
changes may be present <strong>in</strong> LAM more frequent<br />
than previously reported [35]. Interstitial changes can<br />
be expla<strong>in</strong>ed by additional factors such as <strong>in</strong>tercurrent<br />
relaps<strong>in</strong>g <strong>in</strong>fections.<br />
Lymphocytic <strong><strong>in</strong>terstitial</strong> pneumonia �LIP, as seen <strong>in</strong><br />
patients with HIV <strong>in</strong>fection, Sjögren syndrome, or Cas-
380<br />
tleman's <strong>disease</strong>) shows also cystic air spaces, which<br />
have perceptible walls. The cysts, however, are less uniform<br />
<strong>in</strong> size and are reportedly <strong>in</strong> a predom<strong>in</strong>ant subpleural<br />
location. They may also be scattered throughout<br />
the whole <strong>lung</strong> but rarely represent the dom<strong>in</strong>ant feature.<br />
Other <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> usually seen <strong>in</strong> LIP <strong>in</strong>clude ill-def<strong>in</strong>ed<br />
centrilobular nodules �3 and 30 mm with be<strong>in</strong>g<br />
mostly small) and <strong>diffuse</strong> ground-glass opacification <strong>of</strong><br />
the <strong>lung</strong> parenchyma. They represent the <strong>key</strong> features<br />
for differential diagnosis [36, 37]: The virtual absence <strong>of</strong><br />
centrilobular nodules <strong>in</strong> LAM allows for ready dist<strong>in</strong>ction.<br />
Diagnostic role <strong>of</strong> HR<strong>CT</strong><br />
<strong>High</strong>-<strong>resolution</strong> <strong>CT</strong> is significantly superior to chest radiography<br />
and conventional <strong>CT</strong> <strong>in</strong> determ<strong>in</strong><strong>in</strong>g the extent<br />
and distribution <strong>of</strong> air cysts [38, 39, 40]. It should,<br />
however, be noted that normal <strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> do not rule<br />
out parenchymal <strong>disease</strong> <strong>in</strong> patients with LAM [40].<br />
The <strong>CT</strong> appearance <strong>of</strong> LAM is diagnostic <strong>in</strong> the correct<br />
cl<strong>in</strong>ical context [39, 40, 41]. The presence <strong>of</strong> many<br />
th<strong>in</strong>-walled, round, or geographic cystic airspaces scattered<br />
throughout both <strong>lung</strong>s <strong>in</strong> a young woman is virtually<br />
pathognomonic. Def<strong>in</strong>ite diagnosis, however, would<br />
require open-<strong>lung</strong> biopsy.<br />
Computed tomography correlates better than radiography<br />
with cl<strong>in</strong>ical and functional impairment. The<br />
extent <strong>of</strong> cystic <strong>disease</strong> was found to correlate well with<br />
impairment <strong>of</strong> gas exchange [35, 39] and severity <strong>of</strong> airway<br />
obstruction [41].<br />
Histiocytosis X<br />
Pulmonary histiocytosis X is also known as eos<strong>in</strong>ophilic<br />
granuloma, Langerhans' cell histiocytosis, or Langerhans'<br />
cell granulomatosis <strong>of</strong> the <strong>lung</strong>. In its early stages<br />
it is characterized by a bronchiolocentric granulomatous<br />
reaction with proliferation and <strong>in</strong>filtration <strong>of</strong> the bronchiolar<br />
wall and the adjacent blood vessels by Langerhans'<br />
histiocytes and eos<strong>in</strong>ophils. Bronchiolar obliteration<br />
causes progressive alveolar wall fibrosis and cyst<br />
formation, eventually result<strong>in</strong>g <strong>in</strong> <strong>in</strong>creas<strong>in</strong>g fibrosis and<br />
parenchymal distortion. The HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> closely<br />
mirror this stepwise histological progression.<br />
The etiology <strong>of</strong> histiocytosis is unknown; however,<br />
there is a strik<strong>in</strong>g relationship to smok<strong>in</strong>g � > 90 % <strong>of</strong><br />
patients with histiocytosis are active smokers).<br />
Typical HR<strong>CT</strong> features <strong>of</strong> Langerhans' cell histiocytosis<br />
are:<br />
1. Cystic airspaces usually smaller than 10 mm <strong>in</strong> diameter<br />
with walls that range from barely perceptible to<br />
be<strong>in</strong>g several millimeters thick. The cysts may be<br />
round, or have bizarre shapes, they may coalesce and<br />
then become larger than 20 mm �Fig. 6a).<br />
2. Nodules <strong>in</strong> peribronchiolar centrilobular location.<br />
They are usually small � < 5 mm <strong>in</strong> diameter). Larger<br />
nodules � > 10 mm) also occur but are less common.<br />
Nodules can be few or numerous depend<strong>in</strong>g<br />
on <strong>disease</strong> activity. The nodules have irregular contours<br />
particularly when they are surrounded by cystic<br />
or reticular <strong>disease</strong>. They may be solid or show<br />
small lucent centers. These ªcavitationsº are<br />
thought to represent dilated bronchioles surrounded<br />
by granulomas and thickened <strong>in</strong>terstitium. Development<br />
<strong>of</strong> cavitated nodules <strong>in</strong>to cysts was observed<br />
�Fig. 6 b,c).<br />
3. Cysts as well as nodules show an upper lobe predom<strong>in</strong>ance<br />
�<strong>in</strong> 57%); the <strong>lung</strong> bases and the costophrenic<br />
sulci are relatively spared.<br />
4. There may be patchy or <strong>diffuse</strong> ground glass opacification.<br />
5. The <strong>lung</strong> volume is usually <strong>in</strong>creased.<br />
6. With <strong>disease</strong> progression the presence <strong>of</strong> nodules<br />
decreases, whereas the whole <strong>lung</strong> parenchyma consists<br />
<strong>in</strong>creas<strong>in</strong>gly <strong>of</strong> th<strong>in</strong>-walled cysts up to the extent<br />
that <strong>in</strong>tact <strong>lung</strong> parenchyma will be present only <strong>in</strong><br />
the basal areas �vanish<strong>in</strong>g <strong>lung</strong> <strong>disease</strong>)<br />
7. Most patients show no evidence <strong>of</strong> fibrosis or septal<br />
thicken<strong>in</strong>g. Only few show an irregular <strong>in</strong>terface sign<br />
or a f<strong>in</strong>e reticular network correlat<strong>in</strong>g with <strong>in</strong>tralobular<br />
fibrosis. Ground glass may be seen occasionally,<br />
but it is never a prom<strong>in</strong>ent feature.<br />
Each feature, nodules and cysts, can occur solely; the<br />
majority <strong>of</strong> the patients, however, show both. Nodules<br />
are the earliest f<strong>in</strong>d<strong>in</strong>g. As they resolve, the cysts <strong>in</strong>creas<strong>in</strong>gly<br />
form as a result <strong>of</strong> progressive paracicatricial<br />
emphysema. The patients are prone to pneumothorax,<br />
probably from cyst rupture.<br />
Differential diagnosis<br />
The differential diagnosis <strong>in</strong>cludes LAM, cystic bronchiectasis,<br />
IPF, and LIP.<br />
The cysts found <strong>in</strong> LAM may have an appearance<br />
similar to those <strong>of</strong> histiocytosis but are not associated<br />
with nodular changes or an upper lobe <strong>lung</strong> distribution.<br />
In addition, the cysts <strong>in</strong> histiocytosis are less uniform as<br />
<strong>in</strong> LAM [42].<br />
The round-shaped cystic air spaces ± especially when<br />
close to a vessel ± may mimic the appearance <strong>of</strong> cystic<br />
bronchiectasis �signet-r<strong>in</strong>g sign), close <strong>in</strong>spection <strong>of</strong> serial<br />
sections above and below help to readily differentiate<br />
tubular from spherical structures.<br />
As opposed to IPF, the cysts show no predom<strong>in</strong>ant<br />
subpleural distribution. The cysts <strong>in</strong> histiocytosis are<br />
usually discrete rather than clustered, and most impor-
a b<br />
c<br />
tantly the <strong>lung</strong> volumes are usually preserved or even<br />
<strong>in</strong>creased, rather than decreased as frequently seen with<br />
IPF.<br />
Both, histiocytosis and LIP, are characterized by<br />
centrilobular nodules and cystic airspaces. Dist<strong>in</strong>guish<strong>in</strong>g<br />
features <strong>of</strong> histiocytosis from LIP <strong>in</strong>clude the absence<br />
<strong>of</strong> <strong>in</strong>terlobular thicken<strong>in</strong>g and lymphadenopathy,<br />
both <strong>of</strong> which were found <strong>in</strong> 82 and 70%, respectively,<br />
<strong>in</strong> patients with LIP [37].<br />
Diagnostic role <strong>of</strong> HR<strong>CT</strong><br />
The comb<strong>in</strong>ation <strong>of</strong> pulmonary nodules and cysts is virtually<br />
diagnostic for pulmonary histiocytosis X [43, 44,<br />
45]. Grenier and coauthors showed that a first-choice<br />
diagnosis <strong>of</strong> histiocytosis had a 60% likelihood <strong>of</strong> be<strong>in</strong>g<br />
correct when based on the chest radiograph but a 90%<br />
likelihood <strong>of</strong> correctness with HR<strong>CT</strong> [44].<br />
Although the HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> are suggestive <strong>of</strong> <strong>disease</strong>,<br />
there are no other specific laboratory tests to further<br />
underl<strong>in</strong>e the diagnosis. Langerhans' cells can be<br />
identified <strong>in</strong> specimens obta<strong>in</strong>ed by BAL; however, they<br />
can also be seen <strong>in</strong> cases <strong>of</strong> pulmonary fibrosis <strong>of</strong> other<br />
etiology. A def<strong>in</strong>ite diagnosis is only established after<br />
exam<strong>in</strong>ation <strong>of</strong> <strong>lung</strong> tissue. Whereas transbronchial biopsy<br />
has a very low yield due to the focal nature <strong>of</strong> the<br />
<strong>disease</strong>, open or video-assisted thoracoscopic <strong>lung</strong> biopsy<br />
is recommended [46].<br />
The extent <strong>of</strong> <strong>lung</strong> abnormality as determ<strong>in</strong>ed by <strong>CT</strong><br />
correlates well with the <strong>lung</strong> diffusion capacity. Serial<br />
HR<strong>CT</strong> scans could show that regression <strong>of</strong> the nodules<br />
leaves multiple th<strong>in</strong>-walled cysts because <strong>of</strong> check-valve<br />
obstruction by bronchiole-centered granulomas, and<br />
these small cysts could only be detected by HR<strong>CT</strong> and<br />
not by radiography [44].<br />
Alveolar prote<strong>in</strong>osis<br />
Fig.6a±c The HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>of</strong> histiocytosis<br />
X are different accord<strong>in</strong>g to <strong>disease</strong> stage.<br />
a A 41-year-old patient with a long history <strong>of</strong><br />
smok<strong>in</strong>g: HR<strong>CT</strong> shows round or bizarreshaped<br />
cysts with a broad range <strong>of</strong> size. There<br />
are also a few cavitat<strong>in</strong>g nodules and some fibrotic<br />
strands <strong>in</strong> the <strong>in</strong>terven<strong>in</strong>g parenchyma.<br />
b <strong>High</strong>-<strong>resolution</strong> <strong>CT</strong> through the lower lobes<br />
<strong>in</strong> a 11-year-old patient with histiocytosis X.<br />
This typical <strong>disease</strong> presentation <strong>in</strong>cludes<br />
small, well-def<strong>in</strong>ed nodular structures with<br />
central cavitation. c <strong>High</strong>-<strong>resolution</strong> through<br />
the upper lobes demonstrates multiple small<br />
nodules as well as partially cavitat<strong>in</strong>g and<br />
small clustered cysts <strong>in</strong> a 37-year-old patient<br />
with a smok<strong>in</strong>g history and shortness <strong>of</strong> breath<br />
381<br />
Alveolar prote<strong>in</strong>osis is a <strong>disease</strong> characterized by fill<strong>in</strong>g<br />
<strong>of</strong> the alveolar spaces with a PAS-positive prote<strong>in</strong>aceous<br />
material rich <strong>in</strong> lipid. It is caused by a dysfunction<br />
<strong>of</strong> pneumocytes that desquamate <strong>in</strong> the alveolar spaces<br />
secondary to a defect <strong>of</strong> lipid metabolism at the <strong>in</strong>tracellular<br />
level. An abnormality <strong>in</strong> surfactant production,<br />
metabolism, or clearance has been also strongly implicated<br />
as well as an association with a variety <strong>of</strong> immunocompromised<br />
sett<strong>in</strong>gs �<strong>in</strong> children lymphopenia, thymic<br />
aplasia, immunoglobul<strong>in</strong> deficiency, and <strong>in</strong> adults
382<br />
Fig.7 A 43-year-old patient with a cl<strong>in</strong>ical history <strong>of</strong> tachypnea<br />
and cyanosis: HR<strong>CT</strong> through the upper <strong>lung</strong>s demonstrates patchy<br />
areas <strong>of</strong> ground glass <strong>in</strong> a geographic distribution. Superimposed<br />
on the ground glass is a network <strong>of</strong> thickened <strong>in</strong>tralobular septa.<br />
This pattern is called crazy pav<strong>in</strong>g and is typical, yet not characteristic,<br />
for alveolar prote<strong>in</strong>osis<br />
lymphoma and leukemia) and <strong>in</strong>fectious <strong>disease</strong>s �e. g.,<br />
cytomegalovirus, mycobacteria, pneumocystis, histoplasma,<br />
Candida species).<br />
Typical HR<strong>CT</strong> features <strong>of</strong> alveolar prote<strong>in</strong>osis are:<br />
1. The crazy pav<strong>in</strong>g appearance which consists <strong>of</strong> a<br />
network <strong>of</strong> smooth reticular pattern superimposed<br />
on an area <strong>of</strong> ground-glass opacification �Fig.7).<br />
2. Opacifications range from ground glass to consolidation.<br />
They may be patchy or geographic with sharp<br />
demarcation from the surround<strong>in</strong>g normal parenchyma.<br />
While some borders follow anatomical structures<br />
<strong>of</strong> lobar or lobular septa, others are <strong>in</strong>dependent<br />
<strong>of</strong> anatomical boundaries. Each frame <strong>of</strong> the<br />
network ranges from 2 to 7 mm<br />
3. The smooth septal thicken<strong>in</strong>g is usually seen only <strong>in</strong><br />
areas with ground-glass opacification. It is believed<br />
to be due to thicken<strong>in</strong>g <strong>of</strong> the <strong>in</strong>terlobular septa or, as<br />
recently described, to accumulation <strong>of</strong> material adjacent<br />
to the <strong>in</strong>terlobular septa.<br />
Differential diagnosis<br />
Although the crazy pav<strong>in</strong>g appearance is highly suggestive<br />
for alveolar prote<strong>in</strong>osis with a 100 % prevalence <strong>of</strong><br />
this pattern, it is not specific. A recent publication listed<br />
14 airspace and <strong><strong>in</strong>terstitial</strong> <strong>lung</strong> <strong>disease</strong>s that showed<br />
crazy pav<strong>in</strong>g with vary<strong>in</strong>g mostly much lower prevalence<br />
<strong>of</strong> crazy pav<strong>in</strong>g [47].<br />
The ma<strong>in</strong> differential diagnosis <strong>in</strong>clude <strong>diffuse</strong> alveolar<br />
damage superimposed on UIP �prevalence <strong>of</strong> crazy<br />
pav<strong>in</strong>g <strong>in</strong> 67 %), acute <strong><strong>in</strong>terstitial</strong> pneumonia �31 %),<br />
and ARDS �21 %).<br />
Other <strong>disease</strong>s with lower prevalences <strong>of</strong> crazy pav<strong>in</strong>g<br />
were drug-<strong>in</strong>duced pneumonitis �12 %), pneumonias<br />
�bacterial 6 %, tuberculosis 1 %, mycoplasma 6 %,<br />
Pneumoncystis car<strong>in</strong>ii 7%), bronchiolitis obliterans<br />
with organiz<strong>in</strong>g pneumonia �BOOP; 8 %), chronic eos<strong>in</strong>ophilic<br />
pneumonia �8 %), radiation pneumonitis �4 %),<br />
and cardiogenic pulmonary edema �14 %).<br />
The wide differential diagnosis is understandable<br />
consider<strong>in</strong>g that any k<strong>in</strong>d <strong>of</strong> fluid or cellular fill<strong>in</strong>g <strong>of</strong><br />
the air spaces and the <strong><strong>in</strong>terstitial</strong> spaces cause crazy<br />
pav<strong>in</strong>g. In alveolar prote<strong>in</strong>osis, the crazy pav<strong>in</strong>g appearance<br />
was found to be due to an accumulation <strong>of</strong><br />
PAS ± positive material <strong>in</strong> the air spaces adjacent to the<br />
<strong>in</strong>terlobular septa rather than due to thicken<strong>in</strong>g <strong>of</strong> the<br />
septi themselves [48]. Most <strong>disease</strong> entities with similar<br />
HR<strong>CT</strong> features can be dist<strong>in</strong>guished from alveolar prote<strong>in</strong>osis<br />
by cl<strong>in</strong>ical symptoms and associated HR<strong>CT</strong><br />
<strong>f<strong>in</strong>d<strong>in</strong>gs</strong>.<br />
It is noteworthy that superimposed <strong>in</strong>fection, frequently<br />
by Nocardia asteroides, is a common complication<br />
<strong>of</strong> alveolar prote<strong>in</strong>osis, and <strong>CT</strong> is limited <strong>in</strong> differentiat<strong>in</strong>g<br />
airspace consolidation due to <strong>in</strong>fection from<br />
underly<strong>in</strong>g <strong>disease</strong>.<br />
Diagnostic role <strong>of</strong> HR<strong>CT</strong><br />
Pulmonary prote<strong>in</strong>osis is very rare. In addition to the<br />
suggestive HR<strong>CT</strong> pattern, diagnosis is usually based on<br />
characteristic features <strong>of</strong> BAL fluid. Occasionally,<br />
transbronchial <strong>lung</strong> biopsy is needed [49].<br />
Resolution <strong>of</strong> airspace consolidation can be monitored<br />
radiographically or by HR<strong>CT</strong>. The overall extent<br />
<strong>of</strong> <strong>disease</strong> and the degree <strong>of</strong> opacifications correlate<br />
well with the impairment <strong>of</strong> pulmonary function and<br />
severity <strong>of</strong> hypoxemia.<br />
Extr<strong>in</strong>sic allergic alveolitis �hypersensitivity<br />
pneumonitis)<br />
Extr<strong>in</strong>sic allergic alveolitis �EAA) or hypersensitivity<br />
pneumonitis is an allergic <strong>lung</strong> <strong>disease</strong> caused by <strong>in</strong>halation<br />
<strong>of</strong> antigens conta<strong>in</strong>ed <strong>in</strong> a variety <strong>of</strong> organic dusts.<br />
The radiographic and pathological abnormalities are<br />
similar <strong>in</strong>dependent <strong>of</strong> the caus<strong>in</strong>g antigen. Abnormalities<br />
can be classified <strong>in</strong>to acute, subacute, and chronic<br />
stages. Mostly HR<strong>CT</strong> is performed <strong>in</strong> the subacute and<br />
chronic stages. Patients with chronic EAA mostly show<br />
a mixture <strong>of</strong> active <strong>disease</strong> and chronic fibrotic changes.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> subacute EAA are:<br />
1. Diffuse bilateral patchy or <strong>diffuse</strong> ground-glass opacifications<br />
�<strong>in</strong> 50±70%).
a<br />
b<br />
Fig.8a, b Exogenic allergic alveolitis. a A 41-year-old patient with<br />
fatigue and weight loss. <strong>High</strong>-<strong>resolution</strong> <strong>CT</strong> shows discrete ill-def<strong>in</strong>ed<br />
centrolubular nodules �arrows), <strong>in</strong> a relatively uniform distribution.<br />
This pattern is characteristic <strong>of</strong> acute EAA. b A 56-yearold<br />
farmer with chronic exposure to hay: The <strong>CT</strong> appearance <strong>in</strong><br />
this patient is different from that shown <strong>in</strong> a. The <strong>CT</strong> shows subpleural<br />
nodules, sharply demarcated geographic regions with air<br />
trapp<strong>in</strong>g and subpleural septal, and non-septal l<strong>in</strong>ear densities<br />
compatible with fibrosis<br />
2. Small ill-def<strong>in</strong>ed centrilobular noduli, 1±5 mm <strong>in</strong> diameter<br />
�<strong>in</strong> 40±70 %; Fig. 8 a).<br />
3. Opacifications with a predom<strong>in</strong>ance for the middle<br />
and lower <strong>lung</strong> zones. Both nodular and <strong>diffuse</strong><br />
ground glass may be seen as isolated <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> or <strong>in</strong><br />
conjunction.<br />
4. Slightly prom<strong>in</strong>ent bronchial walls.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> recurrent EAA episodes and<br />
chronic EAA are:<br />
1. F<strong>in</strong>d<strong>in</strong>gs <strong>of</strong> fibrosis and parenchymal distortion �irregular<br />
reticular opacities, <strong>in</strong>tralobular <strong><strong>in</strong>terstitial</strong><br />
and <strong>in</strong>terlobular septal thicken<strong>in</strong>g, visible <strong>in</strong>tralobu-<br />
lar bronchioles, traction bronchiectasis, and honeycomb<strong>in</strong>g;<br />
Fig. 8 b)<br />
2. The distribution <strong>of</strong> the fibrosis may be variable,<br />
sometimes predom<strong>in</strong>antly subpleural, <strong>in</strong> others<br />
patchy or peribronchovascular. Honeycomb<strong>in</strong>g is<br />
usually localized subpleural.<br />
3. Divergent <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> are reported about the lobar predom<strong>in</strong>ance<br />
<strong>of</strong> chronic fibrotic changes. Whereas one<br />
study reported a lower lobe predom<strong>in</strong>ance <strong>in</strong> 31 % <strong>of</strong><br />
the patients, others described a mid-zone predom<strong>in</strong>ance<br />
or even distribution for the majority <strong>of</strong> patients.<br />
Differential diagnosis<br />
In patients with bilateral nodular, patchy, or <strong>diffuse</strong><br />
ground glass, the differential diagnosis <strong>in</strong>cludes desquamative<br />
<strong><strong>in</strong>terstitial</strong> pneumonia �DIP) and alveolar<br />
prote<strong>in</strong>osis. Desquamative <strong><strong>in</strong>terstitial</strong> pneumonia, however,<br />
is very rare and usually shows a subpleural predom<strong>in</strong>ance<br />
<strong>of</strong> the ground-glass opacification and is not<br />
associated with centrilobular nodules. Classic alveolar<br />
prote<strong>in</strong>osis shows a crazy pav<strong>in</strong>g appearance and is<br />
readily dist<strong>in</strong>guished by bronchoalveolar lavage; the<br />
latter is also suited to rule out <strong>in</strong>fectious <strong>disease</strong>s, such<br />
as cytomegalovirus or Pneumomocystis car<strong>in</strong>ii, as etiologies<br />
for <strong>diffuse</strong> ground glass. The differential diagnosis<br />
between an alveolar sarcoidosis and subacute EAA requires<br />
transbronchial biopsy.<br />
Patients with chronic EAA and UIP may show identical<br />
HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong>, and differential diagnosis may be<br />
possible only by the cl<strong>in</strong>ical history and laboratory<br />
<strong>f<strong>in</strong>d<strong>in</strong>gs</strong>. Only a predom<strong>in</strong>ant location <strong>of</strong> fibrotic changes<br />
<strong>in</strong> the upper and/or middle <strong>lung</strong> zones allow for a<br />
dist<strong>in</strong>ction between these entities.<br />
Diagnostic role <strong>of</strong> HR<strong>CT</strong><br />
383<br />
Multiple studies have demonstrated that HR<strong>CT</strong> is more<br />
sensitive than chest radiography and standard <strong>CT</strong> <strong>in</strong> the<br />
assessment <strong>of</strong> EAA; however, the sensitivity <strong>of</strong> HR<strong>CT</strong> is<br />
not 100 %: especially <strong>in</strong> the acute and subacute stage<br />
[50].<br />
A careful cl<strong>in</strong>ical history, typical HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong>, and<br />
concordant serological <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> confirm the diagnosis <strong>of</strong><br />
EAA thus preclud<strong>in</strong>g the need for <strong>lung</strong> biopsy. In patients<br />
with discrepant or atypical HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> diagnosis<br />
is based mostly on transbronchial biopsy and abnormal<br />
T-lymphocytes <strong>in</strong> the bronchoalveolar lavage.<br />
The diagnostic yield <strong>of</strong> transbronchial biopsy is not<br />
precisely determ<strong>in</strong>ed for EAA.
384<br />
Idiopathic <strong><strong>in</strong>terstitial</strong> pneumonias<br />
The idiopathic <strong><strong>in</strong>terstitial</strong> pneumonias are a heterogeneous<br />
group <strong>of</strong> <strong>in</strong>flammatory and <strong><strong>in</strong>terstitial</strong> fibros<strong>in</strong>g<br />
lesions that manifest as <strong>in</strong>filtrative <strong>lung</strong> <strong>disease</strong>. On the<br />
basis <strong>of</strong> differences <strong>in</strong> histological appearance, they<br />
were classified by Liebow <strong>in</strong>to five subtypes: UIP; DIP;<br />
LIP; GIP, and bronchiolitis with <strong><strong>in</strong>terstitial</strong> pneumonia<br />
[51]. The latter term has been replaced by BOOP. Both,<br />
LIP and GIP, were dropped s<strong>in</strong>ce many <strong>of</strong> the former<br />
turned out to be lymphoproliferative disorders and<br />
many <strong>of</strong> the latter were found to be hard metal pneumoconioses.<br />
Two other forms were recognized <strong>in</strong>clud<strong>in</strong>g<br />
acute <strong><strong>in</strong>terstitial</strong> pneumonia �AIP) most closely correspond<strong>in</strong>g<br />
to the entity described <strong>in</strong> 1944 by Hamman<br />
and Rich [52], and nonspecific <strong><strong>in</strong>terstitial</strong> pneumonia<br />
and fibrosis �NSIP or NIPF, also called non-classifiable<br />
<strong><strong>in</strong>terstitial</strong> pneumonia) [53].<br />
The heterogeneity with respect to histology, <strong>CT</strong> appearance,<br />
and etiology characteriz<strong>in</strong>g the group <strong>of</strong> <strong><strong>in</strong>terstitial</strong><br />
pneumonias almost <strong>in</strong>evitably lead to controversies<br />
and an irritat<strong>in</strong>g multiplicity <strong>of</strong> terms: Although<br />
the term idiopathic is justified <strong>in</strong> many patients<br />
with no identifiable <strong>disease</strong> etiology, some <strong>of</strong> these <strong><strong>in</strong>terstitial</strong><br />
disorders are also found <strong>in</strong> sett<strong>in</strong>gs with<br />
known etiology particularly collagen vascular <strong>disease</strong>.<br />
The classifications proposed by Liebow and Katzenste<strong>in</strong><br />
[53] were based primarily on the pathology. The<br />
concept <strong>of</strong> IPF, however, is largely founded on a cl<strong>in</strong>ical<br />
approach.<br />
Usual <strong><strong>in</strong>terstitial</strong> pneumonia<br />
There has been some debate concern<strong>in</strong>g the dist<strong>in</strong>ctiveness<br />
<strong>of</strong> usual <strong><strong>in</strong>terstitial</strong> pneumonia �UIP) and<br />
desquamative <strong><strong>in</strong>terstitial</strong> pneumonia �DIP) from each<br />
other. While the orig<strong>in</strong>al classification by Liebow and<br />
Katzenste<strong>in</strong> [53] suggested that the different histological<br />
and radiographic features <strong>of</strong> the two abnormalities<br />
and the favorable response <strong>of</strong> DIP to corticosteroid<br />
therapy implies that they have different etiologies and<br />
pathogenesis, other <strong>in</strong>vestigators have documented<br />
considerable overlap and have suggested that the patterns<br />
<strong>of</strong> DIP and UIP represent the cellular and fibrotic<br />
spectrum <strong>of</strong> a s<strong>in</strong>gle <strong>disease</strong>. This <strong>in</strong>terpretation is supported<br />
by reports describ<strong>in</strong>g patients show<strong>in</strong>g both patterns,<br />
DIP and UIP, <strong>in</strong> a s<strong>in</strong>gle <strong>lung</strong> or by patients<br />
show<strong>in</strong>g orig<strong>in</strong>ally DIP and later UIP patterns <strong>in</strong> a follow-up<br />
biopsy specimen obta<strong>in</strong>ed at the same parenchymal<br />
site. This unify<strong>in</strong>g concept is reflected by the<br />
s<strong>in</strong>gle term <strong>of</strong> cryptogenic fibros<strong>in</strong>g alveolitis �CFA),<br />
widely used <strong>in</strong> Europe. Of all patients with <strong><strong>in</strong>terstitial</strong><br />
pneumonitis <strong>of</strong> unknown etiology, approximately 5 %<br />
have the histologic pattern <strong>of</strong> DIP, and most <strong>of</strong> the rema<strong>in</strong>der<br />
have UIP. The term idiopathic pulmonary fi-<br />
brosis, which is widely accepted <strong>in</strong> North America, is<br />
recommended to be used only for patients with the UIP<br />
pattern <strong>of</strong> pulmonary fibrosis.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> UIP are:<br />
1. F<strong>in</strong>e or irregular <strong>in</strong>tralobular l<strong>in</strong>ear opacities �reticular<br />
pattern) <strong>of</strong>ten associated with traction bronchiectasis<br />
and bronchiolectasis<br />
2. Irregular pleural, vascular, and bronchial <strong>in</strong>terfaces<br />
3. Honeycomb<strong>in</strong>g consist<strong>in</strong>g <strong>of</strong> thick-walled cystic air<br />
spaces �2±20 mm <strong>in</strong> diameter) <strong>in</strong> 90 % <strong>of</strong> patients and<br />
predom<strong>in</strong>antly <strong>in</strong> the basal and subpleural areas.<br />
Honeycomb cysts usually enlarge slowly over time<br />
�Fig. 9 a,b). Ground-glass attenuation is common but<br />
usually less extensive than the reticular abnormality.<br />
Architectural distortion is present reflect<strong>in</strong>g <strong>lung</strong> fibrosis<br />
with lobar volume loss. A patchy distribution<br />
is apparent <strong>in</strong> most cases with areas with reticular<br />
pattern <strong>in</strong>term<strong>in</strong>gled with areas <strong>of</strong> normal <strong>lung</strong> parenchyma.<br />
The crescent predom<strong>in</strong>antly subpleural<br />
distribution <strong>of</strong> the reticular pattern and the honeycomb<strong>in</strong>g<br />
is evident <strong>in</strong> 80±95% <strong>of</strong> patients and represents<br />
the most characteristic feature <strong>of</strong> IPF on<br />
HR<strong>CT</strong>. Lack <strong>of</strong> this feature should suggest an alternative<br />
diagnosis.<br />
The fibrosis is more severe <strong>in</strong> the lower <strong>lung</strong> zones <strong>in</strong><br />
70%. In approximately 20% <strong>of</strong> patients all zones are<br />
affected evenly and <strong>in</strong> as many as 10% ma<strong>in</strong>ly the upper<br />
<strong>lung</strong> zones are <strong>in</strong>volved.<br />
Mediast<strong>in</strong>al lymph-node enlargement is evident only<br />
on <strong>CT</strong> <strong>in</strong> 70±90% <strong>of</strong> patients �10±15 mm <strong>in</strong> the short<br />
axis diameter, mostly right paratracheal nodes) and less<br />
severe <strong>in</strong> patients under steroid therapy.<br />
Differential diagnosis<br />
The <strong>CT</strong> pattern <strong>of</strong> UIP due to IPF is commonly <strong>in</strong>dist<strong>in</strong>guishable<br />
from that found <strong>in</strong> UIP due to asbestosis<br />
and to collagen vascular <strong>disease</strong>s such as rheumatoid<br />
arthritis, sclerodermia, or to certa<strong>in</strong> drug reactions, although<br />
the rate <strong>of</strong> progression is slower <strong>in</strong> patients with<br />
collagen vascular <strong>disease</strong>.<br />
The presence <strong>of</strong> pleural plaques helps for differentiation<br />
between IPF and asbestosis. Patients with chronic<br />
hypersensitivity pneumonitis or with end-stage sarcoidosis<br />
may uncommonly develop a <strong>CT</strong> pattern identical<br />
to UIP. Hypersensitivity pneumonitis should be considered<br />
when poorly def<strong>in</strong>ed small nodules are present or if<br />
there is spar<strong>in</strong>g <strong>of</strong> the <strong>lung</strong> bases. Sarcoidosis should be<br />
suspected if the majority <strong>of</strong> cystic spaces are larger than<br />
10 mm, if peribronchovascular �perilymphatic) nodules<br />
are seen or if more extensive mediast<strong>in</strong>al lymphadenopathy<br />
is present � > 15 mm <strong>in</strong> the short-axis diameter<br />
and affect<strong>in</strong>g several lymph-node groups).
Diagnostic role <strong>of</strong> HR<strong>CT</strong><br />
a b c<br />
d e<br />
Fig.9a±e Idiopathic <strong><strong>in</strong>terstitial</strong> pneumonias. a, b <strong>High</strong>-<strong>resolution</strong><br />
<strong>CT</strong>scans <strong>in</strong> 2 patients with usual <strong><strong>in</strong>terstitial</strong> pneumonitis. Computed<br />
tomography scans demonstrate advanced <strong>disease</strong> with subpleural<br />
honeycomb<strong>in</strong>g, traction bronchiectasis, and irregular bronchoparenchymal<br />
<strong>in</strong>terfaces. c A 32-year-old patient with a history <strong>of</strong><br />
smok<strong>in</strong>g, <strong>in</strong>creas<strong>in</strong>g symptoms <strong>of</strong> cough, and dyspnea: HR<strong>CT</strong>shows<br />
small centrilobular nodules and bronchial wall thicken<strong>in</strong>g suggest<strong>in</strong>g<br />
the diagnosis <strong>of</strong> respiratory bronchiolitis with <strong><strong>in</strong>terstitial</strong> <strong>disease</strong>.<br />
d, e Two patients with NSIP suffer<strong>in</strong>g from collagen vascular<br />
<strong>disease</strong>s. In d subpleural ground-glass opacification and fa<strong>in</strong>t subpleural<br />
l<strong>in</strong>es <strong>in</strong>dicat<strong>in</strong>g <strong>in</strong>itial fibrosis. In e there is more extensive<br />
ground-glass opacification superimposed by f<strong>in</strong>e reticular densities,<br />
cystic airspaces, and traction bronchiectasis. Note the location <strong>of</strong><br />
ground glass and reticular densities along a subpleural l<strong>in</strong>e <strong>in</strong> the<br />
dorsal <strong>lung</strong> area. Honeycomb<strong>in</strong>g is not a typical feature <strong>in</strong> NSIP<br />
Several studies suggest that, especially <strong>in</strong> advanced<br />
stages, the chest radiograph is sufficient for suggest<strong>in</strong>g<br />
the diagnosis <strong>of</strong> IPF [54, 55, 56, 57], and diagnostic advantages<br />
<strong>of</strong> HR<strong>CT</strong> over chest radiography may not be as<br />
great as previous studies suggested [4].<br />
However, <strong>CT</strong> is superior to chest radiography <strong>in</strong> discrim<strong>in</strong>at<strong>in</strong>g<br />
accurately �95 vs 87%) and confidently �73<br />
385<br />
vs 30 %) IPF from other chronic <strong><strong>in</strong>terstitial</strong> <strong>disease</strong>s<br />
[16]. In a study group <strong>of</strong> 129 patients with idiopathic <strong><strong>in</strong>terstitial</strong><br />
pneumonia, two observers correctly diagnosed<br />
UIP <strong>in</strong> 71%, DIP <strong>in</strong> 63 %, BOOP <strong>in</strong> 79 %, and AIP <strong>in</strong><br />
65%.<br />
The pattern and extent <strong>of</strong> parenchymal abnormality<br />
and the degree <strong>of</strong> volume loss correlate with the severity<br />
<strong>of</strong> functional impairment, length <strong>of</strong> survival, and overall<br />
prognosis <strong>of</strong> patients with IPF. The significance <strong>of</strong><br />
ground-glass opacification <strong>in</strong> patients with IPF has been<br />
the focus <strong>of</strong> considerable <strong>in</strong>terest and controversy.<br />
Ground glass, if a predom<strong>in</strong>ant feature �<strong>in</strong> a m<strong>in</strong>ority <strong>of</strong><br />
patients, ca. 10%), may be completely or partially reversible<br />
on corticosteroid therapy, whereas if part <strong>of</strong> a<br />
mixed pattern with reticular opacifications, it was found<br />
to precede and predict development <strong>of</strong> <strong>lung</strong> fibrosis [58,<br />
59, 60, 61]. Hartman and colleagues found that groundglass<br />
attenuation <strong>in</strong> patients with histologically proven<br />
DIP �and ground glass is a predom<strong>in</strong>ant feature <strong>in</strong> those<br />
patients) were likely to improve under corticosteroids,<br />
whereas patients with UIP and ground glass �and those<br />
patients usually show a mixed pattern) showed progress<br />
under steroids [62]. Other factors with prognostic value<br />
were the extent <strong>of</strong> fibrosis on the pretreatment <strong>CT</strong> and
386<br />
the extent and the distribution <strong>of</strong> ground-glass attenuation<br />
[62, 63, 64]. The progression <strong>of</strong> honeycomb<strong>in</strong>g was<br />
significantly faster <strong>in</strong> patients who had extensive areas<br />
<strong>of</strong> ground-glass attenuation <strong>in</strong> a <strong>diffuse</strong> rather than<br />
patchy distribution.<br />
Open-<strong>lung</strong> biopsy or thoracoscopic biopsy are the<br />
only procedures that yield sufficient tissue to confirm a<br />
diagnosis <strong>of</strong> IPF. Although transbronchial biopsy does<br />
not allow the dist<strong>in</strong>ction <strong>of</strong> IPF from many other conditions,<br />
it is a valuable procedure <strong>in</strong> exclud<strong>in</strong>g sarcoidosis<br />
or lymphangitic spread <strong>of</strong> tumor <strong>in</strong> selected cases.<br />
Whether confirmation <strong>of</strong> IPF is rout<strong>in</strong>ely required is<br />
controversial. Whereas 22 <strong>of</strong> 23 responders <strong>in</strong> an<br />
American survey rout<strong>in</strong>ely obta<strong>in</strong> tissue �although<br />
mostly transbronchial), by contrast, British pulmonary<br />
specialists are content to make the diagnosis <strong>of</strong> IPF on<br />
the basis <strong>of</strong> cl<strong>in</strong>ical and radiological features. There is<br />
no <strong>in</strong>vestigation available that specifically addresses<br />
that issue. It is common understand<strong>in</strong>g that especially <strong>in</strong><br />
patients with advanced <strong>disease</strong>, when cl<strong>in</strong>ical, laboratory,<br />
and radiological features suggest the diagnosis <strong>of</strong><br />
IPF, biopsy is not <strong>in</strong>dicated particularly when no treatment<br />
decision will depend on the <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>of</strong> the biopsy.<br />
In patients with early <strong>disease</strong>, particularly those with<br />
few or no symptoms, but who demonstrate radiographic<br />
<strong>in</strong>filtrates, thoracoscopic <strong>lung</strong> biopsy is recommended.<br />
Desquamative <strong><strong>in</strong>terstitial</strong> pneumonia and respiratory<br />
bronchiolitis-associated <strong><strong>in</strong>terstitial</strong> <strong>disease</strong><br />
Desquamative <strong><strong>in</strong>terstitial</strong> pneumonia �DIP) and respiratory<br />
bronchiolitis-associated <strong><strong>in</strong>terstitial</strong> <strong>disease</strong> �RB-<br />
ILD) have recently been grouped together as part <strong>of</strong> a<br />
s<strong>in</strong>gle spectrum s<strong>in</strong>ce they have cl<strong>in</strong>ical similarities and<br />
significant overlapp<strong>in</strong>g <strong>of</strong> histological and HR<strong>CT</strong> features<br />
[65, 66]. Both <strong>disease</strong>s are strongly associated with<br />
cigarette smok<strong>in</strong>g, a fact that questions the idiopathic<br />
etiology <strong>of</strong> RB-ILD but underl<strong>in</strong>es the concept that<br />
they represent different degrees <strong>of</strong> severity <strong>of</strong> small airway<br />
and parenchymal reaction to cigarette smok<strong>in</strong>g.<br />
RB-ILD is thought to represent an exaggerated respiratory<br />
bronchiolitis response, result<strong>in</strong>g <strong>in</strong> cl<strong>in</strong>ical<br />
symptoms <strong>of</strong> cough and shortness <strong>of</strong> breath. Histologically<br />
macrophage accumulation is conf<strong>in</strong>ed to the peribronchiolar<br />
<strong>in</strong>terstitium and air spaces. Desquamative<br />
<strong><strong>in</strong>terstitial</strong> pneumonia is also characterized by the presence<br />
<strong>of</strong> <strong>in</strong>tra-alveolar macrophages, but the abnormalities<br />
are less bronchiolocentric and more <strong>diffuse</strong> than<br />
those described <strong>in</strong> respiratory bronchiolitis.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> DIP are:<br />
1. Bilateral areas <strong>of</strong> ground-glass attenuation <strong>in</strong> all patients<br />
�100 % prevalence) with predom<strong>in</strong>ance <strong>in</strong> the<br />
peripheral �60 %) and lower <strong>lung</strong> zones �100%). The<br />
upper <strong>lung</strong> zones are also affected <strong>in</strong> approximately<br />
80%. The distribution may be patchy <strong>in</strong> 25 % or<br />
evenly <strong>diffuse</strong> <strong>in</strong> 20%.<br />
2. Irregular l<strong>in</strong>ear opacities �reticular pattern) are seen<br />
<strong>in</strong> 50 % <strong>of</strong> patients aga<strong>in</strong> <strong>in</strong> a predom<strong>in</strong>antly subpleural<br />
and basal location but much more limited <strong>in</strong><br />
extent as compared with patients with UIP<br />
3. Only very mild honeycomb<strong>in</strong>g is seen <strong>in</strong> approximately<br />
30% <strong>of</strong> patients and is located almost exclusively<br />
<strong>in</strong> the lower <strong>lung</strong> zones.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> RB-ILD are:<br />
1. Bilateral areas <strong>of</strong> ground-glass attenuation mostly <strong>in</strong><br />
a patchy distribution.<br />
2. Small centrilobular nodules are seen <strong>in</strong> approximately<br />
40 % <strong>of</strong> patients �Fig.9c).<br />
3. Subtle <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>of</strong> fibrosis �honeycomb<strong>in</strong>g, <strong>in</strong>tralobular<br />
l<strong>in</strong>es) were seen <strong>in</strong> the lower <strong>lung</strong> zones <strong>in</strong><br />
approximately 25% <strong>of</strong> patients.<br />
3. An upper lobe centrilobular emphysema is frequently<br />
present.<br />
4. Bronchial wall thicken<strong>in</strong>g may be an associated<br />
f<strong>in</strong>d<strong>in</strong>g �Fig. 9 c).<br />
Differential diagnosis<br />
Similar <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> as seen <strong>in</strong> RB-ILD are also seen <strong>in</strong><br />
asymptomatic smokers, but the <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>in</strong> RB-ILD are<br />
usually more extensive. They are usually reversible<br />
when the patient stops smok<strong>in</strong>g and is treated with corticosteroids.<br />
The differential diagnosis from RB-ILD and DIP <strong>in</strong>cludes<br />
hypersensitivity pneumonitis, sarcoidosis, NSIP,<br />
and <strong>in</strong>fections such as Pneumocystis car<strong>in</strong>ii pneumonia.<br />
Centrilobular nodules represent the <strong>key</strong> feature for differential<br />
diagnosis s<strong>in</strong>ce they are very uncommon <strong>in</strong><br />
DIP and hypersensitivity pneumonitis.<br />
Nonspecific <strong><strong>in</strong>terstitial</strong> pneumonia<br />
Nonspecific <strong><strong>in</strong>terstitial</strong> pneumonia �NSIP) resembles<br />
IPF but appears to be associated with a significantly<br />
different course and outcome. Whereas IPF is characterized<br />
by a recurrent and progressive process result<strong>in</strong>g<br />
<strong>in</strong> a mixture with simultaneous signs <strong>of</strong> active <strong>in</strong>flammation<br />
and long stand<strong>in</strong>g chronic fibrous changes, NSIP<br />
shows a different, temporally more uniform histological<br />
picture <strong>in</strong> the way that the parenchymal changes appear<br />
to have occurred over a s<strong>in</strong>gle relatively narrow time<br />
span. Orig<strong>in</strong>ally, NSIP was attributed to IPF �approximately<br />
5±15 % <strong>of</strong> patients with IPF turn out to have<br />
NSIP); however, cl<strong>in</strong>ical symptoms are less severe and<br />
<strong>disease</strong> progression is considerably slower <strong>in</strong> NSIP result<strong>in</strong>g<br />
<strong>in</strong> a markedly superior prognosis [65].
Katzenste<strong>in</strong> and Fiorelli [53] divided NSIP <strong>in</strong>to three<br />
histological subgroups: primarily <strong>in</strong>flammation �I); both<br />
<strong>in</strong>flammation and fibrosis �II); and predom<strong>in</strong>antly fibrosis<br />
�III), expla<strong>in</strong><strong>in</strong>g the variability <strong>of</strong> HR<strong>CT</strong> morphological<br />
<strong>f<strong>in</strong>d<strong>in</strong>gs</strong>. The heterogeneity <strong>of</strong> <strong>CT</strong> features<br />
and their prevalence <strong>in</strong> the literature may also be due to<br />
different study populations or <strong>in</strong>consistent <strong>in</strong>terpretations<br />
<strong>of</strong> the histological <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>in</strong> various <strong>in</strong>stitutions.<br />
Follow-up exam<strong>in</strong>ations <strong>of</strong> patients with NSIP show a<br />
good prognosis.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> NSIP are:<br />
1. Patchy areas <strong>of</strong> ground-glass opacification with <strong>in</strong>terven<strong>in</strong>g<br />
areas <strong>of</strong> unaffected <strong>lung</strong> <strong>in</strong> approximately<br />
80 % <strong>of</strong> patients. They <strong>in</strong>volve ma<strong>in</strong>ly the middle and<br />
lower <strong>lung</strong> zones with a predom<strong>in</strong>ance for the subpleural<br />
areas �Fig. 9 d,e). They are the sole abnormality<br />
<strong>in</strong> one-third <strong>of</strong> cases.<br />
2. A reticular pattern superimposed on the areas <strong>of</strong><br />
ground glass <strong>in</strong> approximately 50 %.<br />
3. Consolidations are seen <strong>in</strong> 27 %. They are generally<br />
bilateral, symmetrical, and subpleural, and they were<br />
the sole abnormality <strong>in</strong> 4 % <strong>of</strong> patients.<br />
4. Honeycomb<strong>in</strong>g is seen strik<strong>in</strong>gly rarely �4 %) or may<br />
be totally absent. Architectural distortion, traction<br />
bronchiectasis, and thicken<strong>in</strong>g <strong>of</strong> the bronchovascular<br />
bundle may be seen <strong>in</strong> group-III <strong>disease</strong> and reflect<br />
irreversible fibrosis.<br />
Differential diagnosis<br />
The differential diagnosis <strong>of</strong> NSIP depends on the <strong>CT</strong><br />
pattern which it exhibits. The dist<strong>in</strong>ctive variety <strong>of</strong> <strong>disease</strong><br />
patterns that have to be encountered, such as UIP,<br />
hypersensitivity pneumonitis, or BOOP, mirror the <strong>in</strong>consistent<br />
<strong>CT</strong> pattern <strong>of</strong> NSIP. In a recent publication<br />
NSIP was the type <strong>of</strong> <strong><strong>in</strong>terstitial</strong> pneumonia with by far<br />
the lowest yield <strong>of</strong> diagnostic accuracy based on the assessment<br />
<strong>of</strong> HR<strong>CT</strong> by two <strong>in</strong>dependent observers [67].<br />
Nonspecific <strong><strong>in</strong>terstitial</strong> pneumonia and fibrosis was<br />
confused most <strong>of</strong>ten with DIP and less frequently with<br />
UIP or BOOP.<br />
It is known that <strong>in</strong> patients with UIP areas <strong>of</strong> groundglass<br />
opacification progressively change <strong>in</strong>to areas with<br />
irregular l<strong>in</strong>ear opacities and honeycomb<strong>in</strong>g. Serial<br />
HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>in</strong> 13 patients with biopsy-proven NSIP,<br />
however, found that areas <strong>of</strong> ground-glass opacification<br />
significantly decreased over time correspond<strong>in</strong>g to <strong>in</strong>creas<strong>in</strong>g<br />
pulmonary function tests. Even <strong>in</strong> the 3 patients<br />
with group-III <strong>disease</strong>, <strong>in</strong> which bronchial dilatation<br />
and l<strong>in</strong>ear densities were associated with ground<br />
glass, it did not progress to honeycomb<strong>in</strong>g. The authors<br />
assume that one underly<strong>in</strong>g factor may be the better<br />
response to corticosteroid therapy, the other may be the<br />
relative absence <strong>of</strong> ongo<strong>in</strong>g fibrosis <strong>in</strong> NSIP [68].<br />
Acute <strong><strong>in</strong>terstitial</strong> pneumonia<br />
Acute <strong><strong>in</strong>terstitial</strong> pneumonia �AIP) is a fulm<strong>in</strong>ant condition<br />
<strong>of</strong> unknown cause that occurs <strong>in</strong> previously<br />
healthy persons and produces histologic <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>of</strong> organiz<strong>in</strong>g<br />
<strong>diffuse</strong> alveolar damage �DAD). The cl<strong>in</strong>ical<br />
evolution and the pathological appearance can be divided<br />
<strong>in</strong>to three <strong>in</strong>terrelated and overlapp<strong>in</strong>g stages: <strong>in</strong><br />
an early predom<strong>in</strong>antly exudative �first to seventh day;<br />
prote<strong>in</strong>aceous exudates <strong>in</strong> air spaces with hyal<strong>in</strong>e membrane<br />
formation, mild <strong>in</strong>flammation and <strong><strong>in</strong>terstitial</strong><br />
edema); <strong>in</strong> the subacute fibro-proliferative phase<br />
�fourth to tenth day); and <strong>in</strong> the chronic fibrotic phase.<br />
Presumably the latter form led to the classification <strong>of</strong><br />
the <strong>disease</strong> as <strong><strong>in</strong>terstitial</strong> fibrosis by Hamman and Rich<br />
[52], described as acute <strong><strong>in</strong>terstitial</strong> pneumonia �AIP) <strong>in</strong><br />
subsequent classifications. The radiological, cl<strong>in</strong>ical,<br />
and also histological features <strong>of</strong> AIP are similar to<br />
ARDS �suggest<strong>in</strong>g the term idiopathic ARDS). The<br />
prognosis is very poor with reported mortality rates <strong>of</strong><br />
60±100 % with<strong>in</strong> months.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> AIP are:<br />
1. Extensive bilateral ground-glass attenuation <strong>in</strong> <strong>diffuse</strong><br />
or patchy distribution with focal areas <strong>of</strong> spared<br />
almost normal <strong>lung</strong> parenchyma result<strong>in</strong>g <strong>in</strong> a geographic<br />
pattern. The extent <strong>of</strong> ground-glass attenuation<br />
correlates with <strong>disease</strong> duration.<br />
2. Consolidations are also seen but less frequently as<br />
ground-glass attenuations.<br />
3. As seen <strong>in</strong> patients with ARDS, there is an anteroposterior<br />
gradient <strong>of</strong> the ground-glass opacifications<br />
or consolidations with <strong>in</strong>creas<strong>in</strong>g attenuation <strong>in</strong> the<br />
depend<strong>in</strong>g parts.<br />
4. Ground glass is seen <strong>in</strong> all phases <strong>of</strong> AIP and its<br />
mean<strong>in</strong>g depends on the stage: areas <strong>of</strong> <strong>in</strong>creased attenuation<br />
without traction bronchiectasis are associated<br />
with the exudative or early proliferative phase<br />
<strong>of</strong> AIP �reflect<strong>in</strong>g the presence <strong>of</strong> alveolar edema<br />
and hyal<strong>in</strong>e membranes), whereas areas <strong>of</strong> opacity<br />
with traction bronchiectasis are associated with the<br />
chronic fibrotic phase �reflect<strong>in</strong>g alveolar septal fibrosis)<br />
[69]. The comb<strong>in</strong>ation <strong>of</strong> ground-glass attenuation,<br />
air space consolidation, traction bronchiectasis,<br />
and architectural distortion is seen <strong>in</strong> the majority<br />
<strong>of</strong> patients with AIP [70].<br />
5. Smooth <strong>in</strong>terlobular septal thicken<strong>in</strong>g, honeycomb<strong>in</strong>g,<br />
and pleural effusions occur occasionally but to a<br />
lower extent as seen <strong>in</strong> UIP. Honeycomb<strong>in</strong>g is not<br />
seen dur<strong>in</strong>g the first week after onset <strong>of</strong> symptoms.<br />
Differential diagnosis<br />
387<br />
The differential diagnosis <strong>of</strong> AIP depends on the stage<br />
and <strong>in</strong>cludes hydrostatic edema, hemorrhage, alveolar
388<br />
a b c<br />
Fig.10a±c Bronchiolitis obliterans with organiz<strong>in</strong>g pneumonia can<br />
present with very different <strong>CT</strong> morphological appearances. a A<strong>CT</strong><br />
scan <strong>in</strong> a 26-year-old patient after bone marrow transplantation<br />
and now present<strong>in</strong>g with dyspnea on exertion and cough. The most<br />
common appearance presents with patchy non-segmental consolidation<br />
<strong>in</strong> a subpleural distribution. Note the patent bronchi with<strong>in</strong><br />
the consolidation. b A 52-year-old patient with biopsy-proven<br />
BOOP. In this patient the consolidation shows a medullar distribution<br />
and spares the peripheral <strong>lung</strong> regions. This presentation <strong>of</strong><br />
BOOP may mimic a pneumonia or edema. c Nodular BOOP may<br />
mimic malignant disorders: HR<strong>CT</strong> scan demonstrates nodular<br />
consolidation and ground-glass densities with irregular marg<strong>in</strong>s<br />
and discrete air bronchograms<br />
prote<strong>in</strong>osis, bronchoalveolar carc<strong>in</strong>oma, DIP, and <strong>diffuse</strong><br />
<strong>in</strong>fectious <strong>in</strong>filtrations.<br />
Patients with an accelerated form <strong>of</strong> IPF also showed<br />
multifocal areas <strong>of</strong> peripheral airspace consolidations<br />
�mimick<strong>in</strong>g BOOP, DIP, or eos<strong>in</strong>ophilic pneumonia).<br />
Follow-up <strong>CT</strong>s showed cystic lesions and traction bronchiectasis<br />
with<strong>in</strong> the consolidations allow<strong>in</strong>g for a dist<strong>in</strong>ction<br />
from BOOP �shows no honeycomb cysts).<br />
Whereas accelerated forms <strong>of</strong> IPF <strong>in</strong>volve ma<strong>in</strong>ly the<br />
<strong>lung</strong> periphery, AIP <strong>in</strong>volves both, the peripheral and<br />
central part [71]. Both, UIP and AIP, are dist<strong>in</strong>ct histologically:<br />
AIP is characterized by numerous fibroblasts<br />
but relatively little collagen deposition, whereas UIP<br />
shows only relatively few fibroblasts but extensive collagen<br />
deposition. The honeycomb cysts <strong>in</strong> AIP are l<strong>in</strong>ed<br />
with<strong>in</strong> the alveolar epithelium, whereas <strong>in</strong> UIP they are<br />
l<strong>in</strong>ed <strong>in</strong> the bronchiolar epithelium.<br />
Bronchiolitis obliterans with organiz<strong>in</strong>g pneumonia<br />
Bronchiolitis obliterans organiz<strong>in</strong>g pneumonia �BOOP;<br />
also named cryptogenic organiz<strong>in</strong>g pneumonia = COP<br />
when without evident cause) is histologically characterized<br />
by �a) granulation tissue polyps with<strong>in</strong> the lum<strong>in</strong>a<br />
<strong>of</strong> bronchioles and alveolar ducts, and �b) patchy areas<br />
<strong>of</strong> cellular <strong>in</strong>filtrates �ma<strong>in</strong>ly mononuclear cells and<br />
macrophages) <strong>in</strong> the surround<strong>in</strong>g air spaces. Most cases<br />
are idiopathic, but a BOOP-like reaction may be seen <strong>in</strong><br />
a variety <strong>of</strong> cl<strong>in</strong>ical situations �post<strong>in</strong>fectious, drug reaction,<br />
collagen vascular <strong>disease</strong>s, Wegener's granulomatosis,<br />
and after toxic <strong>in</strong>halation).<br />
In a recent <strong>in</strong>ternational consensus <strong>of</strong> a multidiscipl<strong>in</strong>ary<br />
American and European panel <strong>of</strong> cl<strong>in</strong>icians,<br />
pathologists, and radiologists to standardize classification<br />
<strong>of</strong> idiopathic <strong><strong>in</strong>terstitial</strong> pneumonias, the idiopathic<br />
BOOP was <strong>in</strong>cluded <strong>in</strong> the group <strong>of</strong> idiopathic <strong><strong>in</strong>terstitial</strong><br />
pneumonias [72]. The decision had been debated.<br />
Arguments aga<strong>in</strong>st <strong>in</strong>clusion were that the lesion<br />
is caused by airspace organization and is not primarily<br />
<strong><strong>in</strong>terstitial</strong> <strong>in</strong> a histological sense. Additionally, the<br />
morphological character <strong>of</strong> BOOP and UIP are usually<br />
dist<strong>in</strong>ctly different. The presence <strong>of</strong> consolidations and<br />
the absence <strong>of</strong> reticular opacities �as a dom<strong>in</strong>ant f<strong>in</strong>d<strong>in</strong>g)<br />
<strong>in</strong> BOOP normally allow for dist<strong>in</strong>ction from UIP.<br />
Arguments <strong>in</strong> favor <strong>of</strong> <strong>in</strong>clud<strong>in</strong>g BOOP <strong>in</strong>to the group<br />
<strong>of</strong> <strong><strong>in</strong>terstitial</strong> pneumonias were that there is a cl<strong>in</strong>ical,<br />
radiological, and pathological overlap <strong>of</strong> UIP and<br />
BOOP <strong>in</strong> certa<strong>in</strong> cases, and the fact that idiopathic<br />
BOOP as an <strong>in</strong>dependent entity with a nonspecific pathology<br />
but a variety <strong>of</strong> etiologies causes widespread<br />
confusion.<br />
It has to be noted that Bronchiolitis obliterans has<br />
very dist<strong>in</strong>ct cl<strong>in</strong>ical, pathological, and radiological<br />
features, and should be clearly dist<strong>in</strong>guished from<br />
BOOP.<br />
Typical HR<strong>CT</strong> features <strong>of</strong> BOOP are:<br />
1. Most commonly patchy �non-segmental) airspace<br />
consolidations <strong>in</strong> a subpleural �cortical) or central<br />
peribronchiolar distribution <strong>in</strong> more than 50 % <strong>of</strong> the<br />
patients. The patchy consolidations may be migratory,<br />
and they may show pleural tags or spiculae �<strong>in</strong><br />
approximately 30±40 %; Fig. 10 a, b).
2. Whereas consolidations may be the only f<strong>in</strong>d<strong>in</strong>g <strong>in</strong><br />
approximately 50 % <strong>of</strong> the patients, ground-glass<br />
opacifications are mostly part <strong>of</strong> a mixed pattern.<br />
The size <strong>of</strong> the <strong>in</strong>dividual opacities ranges from 3 cm<br />
to nearly complete lobar consolidations. The marg<strong>in</strong>s<br />
<strong>of</strong> the consolidations are <strong>in</strong>dist<strong>in</strong>ct and may conta<strong>in</strong><br />
air bronchograms.<br />
3. Bronchial wall thicken<strong>in</strong>g and dilatation are seen <strong>in</strong><br />
most patients and are usually restricted to areas <strong>of</strong><br />
consolidation or ground-glass opacifications. It is not<br />
yet clarified how well these bronchial abnormalities<br />
are reversible.<br />
4. In 15±50 % patients <strong>of</strong> the various study populations<br />
multiple peribronchiolar �centrilobular) nodules<br />
were seen mostly measur<strong>in</strong>g between 1 and 10 mm<br />
�Fig. 10c). These have mostly irregular marg<strong>in</strong>s<br />
�88 %) and may also show air bronchograms �45 %).<br />
Nodules are the only f<strong>in</strong>d<strong>in</strong>g <strong>in</strong> approximately onethird<br />
<strong>of</strong> the patients who show nodules.<br />
5. Occasionally, bilateral areas <strong>of</strong> ground-glass opacities<br />
are seen with overly<strong>in</strong>g thickened <strong>in</strong>tralobular<br />
septal l<strong>in</strong>es. Nodules and ground-glass attenuation<br />
are seen more frequently <strong>in</strong> the immunocompromised<br />
than <strong>in</strong> the immunocompetent patient.<br />
6. Additional <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> are pleural thicken<strong>in</strong>g �33 %),<br />
small pleural effusions �30 %), and parenchymal<br />
bands �25 %).<br />
Differential diagnosis<br />
Dependent on the range <strong>of</strong> dist<strong>in</strong>ctive patterns, the differential<br />
diagnosis for BOOP is extensive. Cl<strong>in</strong>ical history<br />
may be helpful for differential diagnosis: BOOP<br />
usually appears as a subacute illness with duration <strong>of</strong><br />
symptoms before diagnosis for approximately<br />
2±6 months. In many patients the cl<strong>in</strong>ical and radiographic<br />
signs <strong>of</strong> <strong>disease</strong> remit completely after systemic<br />
corticosteroid therapy. Only a subset <strong>of</strong> patients show a<br />
rapid progression and have a worse prognosis. In these<br />
patients, BOOP is frequently associated with connective<br />
tissue <strong>disease</strong> or drug therapy. Whereas <strong>in</strong>fectious<br />
<strong>disease</strong>s may be excluded on the basis <strong>of</strong> cl<strong>in</strong>ical symptoms,<br />
<strong>lung</strong> biopsy is usually performed because <strong>of</strong> suspicion<br />
<strong>of</strong> a carc<strong>in</strong>oma.<br />
In cases with solitary mass-like focal consolidations<br />
that have morphological criteria for malignancy, such as<br />
spiculae, pleural tagg<strong>in</strong>g, or regional pleural thicken<strong>in</strong>g,<br />
a bronchial carc<strong>in</strong>oma cannot be differentiated from<br />
BOOP [73, 74].<br />
Multiple patchy airspace opacities may also be associated<br />
with alveolar cell carc<strong>in</strong>oma, lymphoma, vasculitis,<br />
or pulmonary hemorrhage.<br />
Numerous bilateral small nodules <strong>in</strong> BOOP have to<br />
be differentiated from sarcoidosis or acute <strong>in</strong>fectious<br />
bronchiolitis �atypical and typical mycobacteria).<br />
Chronic eos<strong>in</strong>ophilic pneumonia has to be considered<br />
for differential diagnosis if the pattern is dom<strong>in</strong>antly<br />
peripheral.<br />
Diagnostic role <strong>of</strong> HR<strong>CT</strong><br />
Computed tomography provides a superior assessment<br />
<strong>of</strong> <strong>disease</strong> pattern and distribution as compared with<br />
chest radiography. Depend<strong>in</strong>g on the <strong>CT</strong> pattern as well<br />
as cl<strong>in</strong>ical and laboratory <strong>f<strong>in</strong>d<strong>in</strong>gs</strong>, it may be possible to<br />
exclude <strong>in</strong>fectious <strong>disease</strong> and eos<strong>in</strong>ophilic pneumonia.<br />
For differentiation from a carc<strong>in</strong>oma, <strong>CT</strong> is recommended<br />
as a guide to determ<strong>in</strong>e the optimal site for<br />
transbronchial or open-<strong>lung</strong> biopsy. The radiological<br />
pattern is also related to prognosis: Bilateral airspace<br />
consolidations demonstrate a better therapy response<br />
and prognosis than localized mass-like lesions or widespread<br />
reticulonodular <strong>disease</strong>.<br />
When to be sure <strong>of</strong> the diagnosis <strong>in</strong> HR<strong>CT</strong>:<br />
practical conclusions<br />
389<br />
<strong>High</strong>-<strong>resolution</strong> <strong>CT</strong> is known to greatly assist <strong>in</strong> the<br />
recognition and diagnosis <strong>of</strong> numerous <strong>diffuse</strong> <strong>lung</strong> <strong>disease</strong>s.<br />
Yet, whether HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> can provide adequate<br />
diagnostic <strong>in</strong>formation to establish the f<strong>in</strong>al diagnosis<br />
and to substitute or decrease the need for <strong>lung</strong> biopsy<br />
varies for the different entities and is highly dependent,<br />
not only on the classic appearance <strong>of</strong> the <strong>disease</strong><br />
but also on the skills <strong>of</strong> the radiologist.<br />
Many studies have been published <strong>in</strong> recent years<br />
which exam<strong>in</strong>ed the diagnostic accuracy <strong>of</strong> HR<strong>CT</strong><br />
based on pattern analysis [54, 55, 56, 67, 75, 76, 77, 78].<br />
Review<strong>in</strong>g these studies, readers should closely evaluate<br />
the follow<strong>in</strong>g aspects s<strong>in</strong>ce they largely <strong>in</strong>fluence the<br />
results and determ<strong>in</strong>e how well the results are transferable<br />
<strong>in</strong>to the daily cl<strong>in</strong>ical rout<strong>in</strong>e. These aspects <strong>in</strong>clude<br />
the availability <strong>of</strong> cl<strong>in</strong>ical <strong>in</strong>formation, the study population<br />
and <strong>disease</strong> prevalence, the impact <strong>of</strong> misdiagnosis<br />
on patient treatment, and the reader's experience.<br />
Most reports agree that cl<strong>in</strong>ical <strong>in</strong>formation is very<br />
important and may even provide the diagnostic <strong>key</strong> for<br />
differential diagnosis. A detailed history is the first step<br />
<strong>in</strong> assess<strong>in</strong>g the plausibility <strong>of</strong> an <strong><strong>in</strong>terstitial</strong> <strong>lung</strong> <strong>disease</strong><br />
and narrow<strong>in</strong>g the diagnostic possibilities. Firstly, it is<br />
useful to identify any risk factors for any type <strong>of</strong> immunodeficiency<br />
or immunosuppression, because diagnostic<br />
work-up should focus primarily on opportunistic <strong>in</strong>fections<br />
<strong>in</strong> these patients and <strong><strong>in</strong>terstitial</strong> <strong>disease</strong> <strong>of</strong> unknown<br />
etiology is less likely. Secondly, the history<br />
should concentrate on cl<strong>in</strong>ical features that are <strong>in</strong>dicative<br />
<strong>of</strong> specific <strong>disease</strong>s such as hypersensitivity pneumonitis,<br />
occupational <strong>disease</strong>, systemic <strong>disease</strong>s, and<br />
familial forms <strong>of</strong> IPF and sarcoid. A temporary associa-
390<br />
tion between exposure to a known fibrogenic factor and<br />
the onset <strong>of</strong> symptoms is highly suggestive and may be<br />
confirmed by the fact that pulmonary manifestations<br />
resolve after avoidance <strong>of</strong> further exposure to the antigen.<br />
In chronic hypersensitivity pneumonitis, however,<br />
establish<strong>in</strong>g a temporal relationship between caus<strong>in</strong>g<br />
agent and pulmonary <strong>disease</strong> may be difficult and surgical<br />
biopsy cannot be avoided. A history <strong>of</strong> aspiration,<br />
recurrent s<strong>in</strong>usitis, arthritis, dermatological abnormalities,<br />
and hemoptysis raise the suspicion for collagen<br />
vascular <strong>disease</strong>s and pulmonary hemorrhage syndromes,<br />
respectively. Subsequent directed laboratory<br />
tests may provide sufficient <strong>in</strong>formation for mak<strong>in</strong>g the<br />
diagnosis without biopsy <strong>in</strong> the appropriate cl<strong>in</strong>ical sett<strong>in</strong>g.<br />
One important feature <strong>of</strong> studies evaluat<strong>in</strong>g the diagnostic<br />
accuracy <strong>of</strong> HR<strong>CT</strong> is the selection <strong>of</strong> the study<br />
group that <strong>in</strong>evitably <strong>in</strong>troduces a bias based on the fact<br />
that some <strong>disease</strong>s can be clearly more easily differentiated<br />
than others. The study population does not necessarily<br />
reflect the case mix encountered <strong>in</strong> daily rout<strong>in</strong>e<br />
work, <strong>in</strong> which the proportion <strong>of</strong> patients with cardiogenic<br />
<strong><strong>in</strong>terstitial</strong> mark<strong>in</strong>gs, smok<strong>in</strong>g-related <strong>disease</strong>, <strong>in</strong>fectious<br />
<strong>disease</strong>s, or normal HR<strong>CT</strong> patterns is much<br />
higher. Primack and colleagues assessed the diagnostic<br />
accuracy <strong>of</strong> high <strong>resolution</strong> <strong>CT</strong> <strong>in</strong> 87 patients with endstage<br />
<strong>lung</strong> <strong>disease</strong> [79]. Whereas the overall accuracy<br />
was only 87 %, it was 100 % correct <strong>in</strong> silicosis and<br />
Langerhans' cell granulomatosis and 90 % correct <strong>in</strong><br />
asbestosis. Other studies showed that certa<strong>in</strong> HR<strong>CT</strong><br />
features, such as cystic changes, have a narrow differential<br />
limited to LAM, tuberous sclerosis, or Langerhans'<br />
cell granulomatosis [77]. Tung and colleagues [56]<br />
showed that HR<strong>CT</strong> accurately dist<strong>in</strong>guished IPF from<br />
other <strong><strong>in</strong>terstitial</strong> <strong>disease</strong>s <strong>in</strong> 88% <strong>of</strong> cases; however, the<br />
study did not appear to sufficiently address the wide<br />
range <strong>of</strong> <strong><strong>in</strong>terstitial</strong> <strong>lung</strong> <strong>disease</strong>: 41 <strong>of</strong> the 86 patients<br />
�48 %) <strong>in</strong>cluded <strong>in</strong> the study had cryptogenic fibros<strong>in</strong>g<br />
alveolitis. Sarcoidosis, histiocytosis, EAA, and BOOP<br />
were <strong>in</strong>cluded at least five times each, whereas eight<br />
other <strong>disease</strong>s were represented only once. In most<br />
studies well-experienced experts serve as readers to assess<br />
diagnostic accuracy, and their performance may not<br />
always be comparable to that <strong>of</strong> general radiologists;<br />
thus, reported diagnostic accuracies that exceed 90%<br />
may not encourage the reader to be unrealistically optimistic<br />
<strong>in</strong> the diagnostic capabilities <strong>of</strong> HR<strong>CT</strong>. Whereas<br />
<strong>in</strong> one patient the HR<strong>CT</strong> pattern <strong>in</strong> comb<strong>in</strong>ation with<br />
cl<strong>in</strong>ical history allows for mak<strong>in</strong>g a diagnosis with sufficient<br />
confidence, <strong>in</strong> other patients HR<strong>CT</strong> may allow<br />
only for narrow<strong>in</strong>g the differential diagnosis and exclusion<br />
<strong>of</strong> certa<strong>in</strong> conditions, or may be even completely<br />
non-specific. Eventually, cl<strong>in</strong>icians must decide what the<br />
acceptable rate <strong>of</strong> misdiagnosis is <strong>in</strong> order to avoid biopsy.<br />
This may be different <strong>in</strong> various cl<strong>in</strong>ical situations<br />
and depends on therapeutic and prognostic conse-<br />
quences. In a study that evaluated the use <strong>of</strong> HR<strong>CT</strong> to<br />
dist<strong>in</strong>guish IPF from chronic hypersensitivity pneumonitis,<br />
diagnosis could be made with confidence <strong>in</strong><br />
only 62% <strong>of</strong> cases due to the fact that both entities may<br />
have identical HR<strong>CT</strong> features. Treatment, however,<br />
would be different given the fact that the chronic hypersensitivity<br />
pneumonitis has a better prognosis under<br />
treatment with corticosteroids and absence <strong>of</strong> the allergen<br />
[80]. Sometimes additional thoracic <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> �e. g.,<br />
mediast<strong>in</strong>al adenopathy <strong>in</strong> patients with sarcoid), extrathoracic<br />
<strong>f<strong>in</strong>d<strong>in</strong>gs</strong> �e. g., sk<strong>in</strong> <strong>in</strong>volvement <strong>in</strong> patients<br />
with collagen vascular <strong>disease</strong>s), or knowledge <strong>of</strong> patient<br />
history �e. g., allergic alveolitis) provide sufficient<br />
evidence to determ<strong>in</strong>e the etiology, and diagnosis is<br />
made without the need for <strong>lung</strong> biopsy.<br />
There is no doubt that HR<strong>CT</strong> is by far superior for<br />
detection <strong>of</strong> <strong><strong>in</strong>terstitial</strong> <strong>disease</strong> <strong>in</strong> comparison with chest<br />
radiography or conventional thick-section <strong>CT</strong>, and this<br />
is true for all <strong>disease</strong> entities [16, 54, 55, 67, 75, 76].<br />
However, <strong>in</strong> this context it should not be forgotten that<br />
its diagnostic sensitivity to assess parenchymal <strong>in</strong>volvement<br />
may not be 100 %. There are reports <strong>of</strong> ma<strong>in</strong>ly<br />
selected cases that describe normal HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> <strong>in</strong><br />
patients with histologically proven pulmonary fibrosis<br />
[81], sarcoidosis [10, 19, 20], and acute or subacute hypersensitivity<br />
pneumonitis [82].<br />
Thus, <strong>in</strong> addition to the detection <strong>of</strong> <strong>lung</strong> <strong>disease</strong> and<br />
the characterization <strong>of</strong> parenchymal disorders, one <strong>of</strong><br />
the most important contributions <strong>of</strong> HR<strong>CT</strong> to the diagnostic<br />
work-up <strong>of</strong> <strong>diffuse</strong> <strong>in</strong>filtrative <strong>lung</strong> <strong>disease</strong> is to<br />
assist the determ<strong>in</strong>ation <strong>of</strong> the biopsy site. <strong>High</strong>-<strong>resolution</strong><br />
<strong>CT</strong> is the tool <strong>of</strong> choice <strong>in</strong> identify<strong>in</strong>g relatively unaffected,<br />
actively <strong>in</strong>flamed, and fibrotic areas. If extensive<br />
fibrotic changes and honeycomb<strong>in</strong>g are seen on<br />
HR<strong>CT</strong>, the <strong>disease</strong> is likely to be end-stage and not<br />
particularly amenable to treatment, regardless <strong>of</strong> the<br />
specific etiology. These <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> may give cl<strong>in</strong>icians<br />
pause <strong>in</strong> pursu<strong>in</strong>g an <strong>in</strong>vasive diagnostic work-up, particularly<br />
<strong>in</strong> elderly patients with comorbidity. Other<br />
conditions, such as patchy ground-glass opacities or<br />
ground glass with l<strong>in</strong>ear opacifications, need to be biopsied,<br />
because HR<strong>CT</strong> <strong>f<strong>in</strong>d<strong>in</strong>gs</strong> are non-specific and<br />
agreeable with various <strong>disease</strong>s hav<strong>in</strong>g different prognoses<br />
and requir<strong>in</strong>g different therapeutic approaches<br />
�e. g., alveolar sarcoid, DIP, UIP, NSIP, or chronic<br />
EAA).
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