Imaging - Chest Radiology

Imaging, 16 (2004), 5060 E 2004 The British Institute of Radiology DOI: 10.
1259/imaging/59250435
Emphysema and smoking-related lung diseases

N J SCREATON, MRCP, FRCR and T KOH, FRCR
Department of Radiology, Papworth Hospital, Papworth Everard, Cambridgeshire CB3 8RE, UK
Smoking is a major cause of morbidity and mortality accounting for one in every ve deaths in the UK [1]. It is associated with a wide range of pulmonary disorders, which can be broadly divided into chronic obstructive pulmonary disease (COPD), smoking-related interstitial lung disease and lung cancer. The clinical, pathological and radiological features relating to the individual nonneoplastic smoking-related lung diseases are discussed below as discrete entities. However, lung injury resulting from cigarettes smoke commonly results in a spectrum of pathological response where, for example, emphysema, respiratory bronchiolitis, and Langerhans cell histiocytosis (LCH) may co-exist.
Summary
N Pulmonary complications of smoking include lung

cancer, chronic obstructive pulmonary disease (COPD) and smoking-related interstitial lung disease.
N Injury related to cigarette smoking may result in a

spectrum of response in the lungs in which several disease entities co-exist.
N High resolution CT is the imaging modality of choice

in patients with suspected emphysema or smokingrelated interstitial lung disease.
Chronic obstructive pulmonary disease

COPD is a functional denition consisting of a chronic, slowly progressive airway obstructive disorder resulting from some combination of emphysema and irreversible reduction in the calibre of small airways [2]. Typical denitions exclude specic causes of obstruction including asthma, bronchiectasis and bronchiolitis or cystic lung disease. COPD is the fth most important cause of death in the USA [3] and the 12th most important contributor to disability adjusted life years in the world [4]. Although several factors have been implicated in its aetiology [5] cigarette smoking accounts for the majority of cases. There is however considerable variation in response to cigarette smoke between individuals exemplied by the fact that only 1020% of heavy smokers develop symptomatic COPD [6, 7]. Although in the clinical syndrome of COPD chronic bronchitis and emphysema commonly co-exist they are described separately below. that in persistent smokers ill-dened centrilobular groundglass nodules on the initial HRCT, morphological features suggestive of respiratory bronchiolitis, were replaced by emphysematous spaces on the follow-up study in 26% of cases [12].
Histopathology
Emphysema is characterized by enlargement of the airspaces consequent upon destruction of the alveolar walls. On the basis of the predominant distribution of destructive changes within the acinus emphysema can be subdivided into centriacinar, paraseptal and panlobular varieties. Centrilobular (centriacinar or proximal acinar) emphysema consists of destruction predominantly at the centre of the acinus (respiratory bronchiole and proximal alveolar ducts) while in paraseptal (or distal acinar) emphysema destruction is predominantly in the peripheral portion of the acinus. In panacinar emphysema destruction is diffuse. Centrilobular and paraseptal emphysema often co-exist. Centrilobular emphysema is the most common form of emphysema and is associated with greater functional impairment than paraseptal emphysema. Early changes consist of fenestration of the alveolar walls which coalesce to result in complete destruction of alveolar walls. As the disease progresses emphysematous spaces become apparent which may enlarge to occupy the entire lobule. Panlobular emphysema is seen most commonly in patients with alpha-1-antitrypsin deciency. The lobule is affected diffusely and there is typically a lower lobe predominance, often worse in the anterior lung regions. Paraseptal emphysema involves the periphery of the acinus and is usually focal. Coalescence of emphysematous spaces may result in large bullae. The functional effects of paraseptal emphysema are usually mild.
Imaging, Volume 16 (2004) Number 1
Emphysema
Emphysema is a pathological diagnosis, dened as abnormal permanent enlargement of the air spaces distal to the terminal bronchioles accompanied by alveolar wall destruction without brosis [8].
Aetiology
Emphysema results from an imbalance between proteolytic and antiproteolytic factors. The potential mechanisms at molecular and cellular level by which cigarette smoke may promote this imbalance are beyond the scope of this review. It is considered that respiratory bronchiolitis is a precursor to the development of centrilobular emphysema [911]. A recent longitudinal study using high resolution CT (HRCT) supports this hypothesis. RemyJardin et al reviewed serial HRCTs in smokers with a mean follow-up interval of 5.5 years. They demonstrated
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Radiological ndings Chest radiograph Mild emphysema may be radiographically silent while moderate or severe emphysema are usually associated with abnormalities on the chest radiograph. Radiographic features of emphysema are consist of hypertransradiancy, due to destruction of the lung tissue, changes in vascular pattern, bullae, and hyperination. Bullae may be identied by their thin walls or by their distortion of the adjacent pulmonary vasculature. However even large bullae may be missed [13]. Emphysema is frequently associated with secondary effects on the pulmonary vessels. These include attenuation of the peripheral vasculature, often with a patchy appearance, and a disorganized branching pattern often associated with areas of hypovascularity (Figure 1). Although alterations in the pulmonary vascular pattern have a high specicity for emphysema they are insensitive. Attenuation or rapid tapering or the peripheral pulmonary vessels is, for example, seen in only 40% of patients with severe emphysema and 15% of those with mild disease [14]. In patients who develop pulmonary hypertension the proximal pulmonary arteries become enlarged with the right pulmonary artery measuring in excess of 16 mm at the hilar point. Hyperination is a more reliable feature for the identication of emphysema but is not specic, being seen in other forms of obstructive lung disease. Radiographic features of hyperination include attening of the diaphragm, an increase in the retrosternal clear space and depression of the diaphragm resulting in increased lung height. Flattening of the diaphragm is the most reliable sign or hyperination [15, 16]. It is present when the highest point of the diaphragm is less than
1.5 cm above a line joining either the costophrenic and vertebrophrenic angles, on the posteroanterior (PA) chest radiograph, or the posterior costophrenic angle and the sternophrenic angle on the lateral chest radiograph (Figure 1). Flattening of the diaphragm on the PA chest radiograph is present in 76% and 94% of patients with moderate and severe emphysema, respectively [17]. It is not reliable in patients with mild emphysema, seen in only 24%, but is present in only 4% of patients without emphysema [17]. On the lateral chest radiograph the retrosternal air space, the space between sternum and ascending aorta, usually measures less than 2.5 cm. When it measures greater than 2.5 cm it is suggestive of hyperination [15, 16]. Depression of the diaphragm such that the dome of the right hemidiaphragm lies below the seventh anterior rib is also suggestive of hyperination [15, 16]. Inevitably a combination of radiographic features of emphysema is more accurate than individual features taken in isolation.
Figure 1. Posteroanterior chest radiograph on a 50-year-old

patient with alpha-1-antitrypsin deciency demonstrates hyperexpansion with disorganized and attenuated vascular markings in the mid and lower zones typical of panlobular emphysema.
Computed tomography CT enables accurate detection of emphysema, evaluation of its distribution and quantication of its extent. Not surprisingly, the accuracy of conventional CT in the assessment of emphysema is greater than the chest radiograph and HRCT is more accurate still [18, 19]. The morphological features of emphysema, role of CT in emphysema quantication, and relevance of emphysema distribution to treatment, particularly in the form of lung volume reduction surgery (LVRS) are described separately. Emphysema morphology: On CT emphysema is characterized by the presence of areas of low attenuation typically without denable walls [20]. Secondary features such as vascular distortion and attenuation may also be observed. On HRCT vessels may be identied within the emphysematous lesions. In centrilobular emphysema the low attenuation areas are often small (,1 cm), multiple, and are located centrally within the secondary pulmonary lobule. The centrilobular core structure (artery and bronchiole) may be identied within the emphysematous spaces (Figure 2). As emphysematous spaces increase in size they may extend to involve the entire secondary pulmonary lobule, and mimic panlobular emphysema. At this stage emphysematous spaces may have denable but thin walls probably representing interlobular septae. In contrast to centrilobular emphysema, which most commonly has an upper lobe predominance, panlobular emphysema predominates in the lower lobes. Diffuse destruction of the alveolar walls may be difcult to identify due to lack of focal abnormalities, particularly in mild disease [21]. CT features consist of diffusely reduced attenuation particularly in the lower lobes with attenuation of the vascular markings (Figure 3). Bullae may be seen in 40% of cases [22] and there may be associated bronchiectasis in approximately 40% of cases [22, 23]. It may be difcult to differentiate panlobular emphysema from obliterative bronchiolitis on the basis of HRCT particularly when bronchiectasis is present. Paraseptal emphysema is frequently seen in association with centrilobular emphysema but may be seen in isolation. Paraseptal emphysema is characterized by areas of low attenuation in the subpleural regions often with thin, barely perceptible, walls representing interlobular septae
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N J Screaton and T Koh
Figure 2. High resolution CT image at the level of the azygos vein in a patient with centrilobular emphysema. Numerous well dened low attenuation emphysematous lesions without perceptible walls are present, many with the central core structure evident.
(Figure 4). Both centrilobular and paraseptal emphysema may lead to the development of large bullae (Figure 5). Emphysema quantication: The severity of emphysema can be quantied using either a semi-quantitative visual grading system or using objective quantication based on CT attenuation. Both methods demonstrate excellent correlation with pathological assessment of emphysema severity [2428]. In a study of patients undergoing lobectomy for carcinoma Miller et al [18] showed better correlation between the pathological score of emphysema and visual grading of emphysema on HRCT (r50.85) than on 10 mm collimation CT (r50.81). Visual scoring of emphysema extent using CT, however, consistently underestimated the pathological extent of emphysema [18]. The extent of panlobular emphysema is also consistently underestimated both using conventional CT and HRCT [21]. Mild emphysema can be missed using visual assessment.
Figure 4. High resolution CT at the level of the aortic arch demonstrates a subpleural distribution of emphysematous spaces many with visible walls in a patient with paraseptal emphysema.
The use of minimum intensity projection reconstructions improves the visualization of subtle emphysema [29]. While visual grading systems are simple to apply objective quantication benets from reproducibility permitting reliable comparisons between centres. The most widely used objective technique is the density mask analysis which identies hyper-expanded voxels with an attenuation below a dened cut-off value (between 2900 HU and 2950 HU) [24, 28]. Muller et al demonstrated excellent correlation between pathological scores of emphysema on lobectomy specimens and CT assessment of emphysema extent using the density mask technique with an attenuation cut-off level of 910 HU (r50.89) [28] using 10 mm collimation. Density mask assessment of emphysema extent correlated better with pathological score than subjective assessments and unlike subjective
Figure 3. Alpha-1-antitrypsin related panlobular emphysema.

High resolution CT image through the lower zones demonstrates diffusely reduced density of the lung parenchyma and attenuated vascular markings.
Figure 5. High resolution CT image through the mid zones

show generalized centrilobular emphysema with large bilateral bullae.
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Figure 6. Objective assessment of emphysema extent. (a) Image of the right lung at the level of the hilum. The lung has been segmented from the adjacent chest wall and mediastinum. (b) Emphysematous pixels with an attenuation below 2950 HU have been highlighted white using density mask technique for objective assessment of emphysema extent.
evaluation there was no tendency to underestimate emphysema extent. Gevenois et al have shown that a density mask cut-off value of 950 HU provides optimum correlation with pathological score of emphysema extent on thin section (1 mm collimation) CT [24] (Figure 6). Recently sophisticated quantitative techniques have emerged to assess emphysema heterogeneity. These include texture-based analysis [30] and the use of attenuationbased fractal dimension [31, 32]. Objective assessment of emphysema extent is currently largely a research tool. It is being widely utilized in longitudinal studies of pharmacological interventions in emphysema as well as in the selection of patients for LVRS. Lung volume reduction surgery: A small proportion of patients with severe emphysema are suitable for surgical intervention. This may take the form of bullectomy, in patients with large bullae, lung transplantation or LVRS. In recent years LVRS has received considerable attention as a palliative procedure in patients with severe emphysema. The procedure consists of the excision of areas of destroyed poorly function lung tissue which, in selected patients, leads to improvement in chest wall and diaphragm mechanics and improved lung elastic recoil with resultant symptomatic and physiological benet. Radiological evaluation plays an essential role in pre-operative assessment of patients for LVRS. The National Emphysema Treatment Trial (NETT), which recruited 1218 patients in total, is largest and most inuential randomized controlled trial of LVRS to date [33]. The conclusions of the NETT have claried our understanding of both clinical and radiological features, which affect outcome following LVRS [33]. Patients with a homogeneous distribution of emphysema and a forced expiratory volume in 1 s (FEV1) of 20% of predicted or less were at high risk of death following LVRS (30 day mortality of 18%) [34]. Benet from LVRS was greatest in patients with low exercise capacity and in those with upper lobe predominant disease. An upper-lobe predominant distribution of emphysema is associated with signicant
improvement in lung function and exercise capacity following LVRS (Figure 7). Signicant changes were not observed in patients with non-upper lobe predominant disease. Pre-operative, post-rehabilitation, exercise tolerance also plays a pivotal role in patient selection. Patients with low exercise capacity following rehabilitation and an upper lobe predominant distribution of emphysema have a signicant survival advantage following surgery over those undergoing medical therapy (p50.005) [33]. Although in most groups quality of life was improved following LVRS this was not the case in non-upper lobe predominant high exercise capacity patients. Advances in technology are likely to lead to novel, minimally invasive, approaches to
Figure 7. Coronal CT reconstruction demonstrates hyperexpansion with severe emphysema in the upper zones and preservation of the lung parenchyma in the mid and lower zones. A distribution of emphysema which is suitable for lung volume reduction surgery (LVRS). 53
lung volume reduction. Already several studies have sought to reduce lung volume without resecting lung tissue [3537]. Some have proposed the used of a bronchoscopic approach. Ingenito et al induced regional lung collapse using bronchoscopic administration of antisurfactant followed by the administration of a biological glue to prevent reination [36]. Brenner et al used a silicone elastomer sleeve to compress lung tissue with resultant reduction in volume in a rabbit animal model of emphysema [35]. Others have demonstrated functional benets in humans with severe emphysema following bronchial occlusion by one-way valves placed bronchoscopically [38].
increased airway wall area was associated with worse airow obstruction. They showed that although objective measurement of both airway wall thickening and emphysema extent correlated with measurements of lung function the combination of airway and emphysema measurements improved the estimate of lung function [45]. As would be expected evidence of air trapping may be identied on expiratory images in patients with chronic bronchitis.
Smoking-related interstitial lung disease

Cigarette smoking is associated with a number of interstitial lung diseases. These include respiratory bronchiolitis (RB), respiratory bronchiolitis associated interstitial lung disease (RB-ILD), desquamative intersitial pneumonia (DIP), LCH and smoking-related interstitial brosis. Although these diseases may occur as discrete entities they frequently co-exist in the same histological specimen often with superadded emphysema. A recent study of 14 patients with biopsy proven pulmonary LCH demonstrated RB/DIP-like changes in all patients on histology and HRCT showed areas of ground-glass opacity consistent with RB/DIP in 3 (21%) [46]. The increasing recognition that LCH, RB-ILD and DIP form a spectrum of interstitial patterns in response to smokingrelated lung injury has lead to the proposal of the term smoking-related interstitial lung disease to cover DIP, RB-ILD, LCH and interstitial brosis [4749].
Chronic bronchitis
Chronic bronchitis is a clinical diagnosis characterized by mucus hypersecretion and chronic expectoration of mucus on most days during at least 3 consecutive months for not less than 2 consecutive years [39].
Histopathology
Chronic bronchitis is characterized histologically by hypertrophy of the bronchial mucus glands, mucosal hyperplasia and hypertrophy of the bronchial wall smooth muscle and chronic inammation. Small airway obstruction is also present.
Radiological Findings Chest radiograph Radiographic ndings in chronic bronchitis are nonspecic and may be normal in 2150% of patients [4042]. They consist of bronchial wall thickening and increased lung markings. Bronchial wall thickening may be identied on the chest radiograph as tram track opacities but the bronchi are most easily assessed when seen end on such as in the anterior segments of the upper lobes and apical segments of the lower lobes. Subjective assessment of bronchial wall thickening on the chest radiograph is however both insensitive (67%) and non-specic, being seen in 42% of normals [43]. Objective evaluation of bronchial wall thickness on the chest radiograph shows greater thickness in patients with chronic bronchitis than normals but there is considerable overlap between the two groups. Increased lung markings consisting of linear opacities with reduced conspicuity of the pulmonary vessels relating to peribronchial inammation is seen in 19% of patients with chronic bronchitis [40]. HRCT There is little literature on CT features in chronic bronchitis. Some studies have however assessed bronchial wall thickness in smokers. One study demonstrated bronchial wall thickening in a third or smokers but this was non-specic, being present in 18% of non-smokers [44]. The subgroup of patients with bronchial wall thickening had a higher prevalence of a chronic productive cough. Nakano et al objectively evaluated airway wall thickening in 114 smokers using CT. They demonstrated that
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Desquamative interstitial pneumonia and respiratory bronchiolitis-interstitial lung disease

Respiratory bronchiolitis due to cigarette smoking was rst described by Niewoehner et al [50] in an autopsy study of young cigarette smokers. Respiratory bronchiolitis is almost invariably present as an incidental nding in cigarette smokers and is usually asymptomatic. Myers et al [51] described a subset of patients with RB who had clinical symptoms with interstitial abnormalities and a restrictive pattern on pulmonary function tests. This subgroup is generally referred to as RB-ILD [52]. As with DIP, RB-ILD is classied as an idiopathic interstitial pneumonia [53]. Both conditions however share many similarities with respect to demographics, clinical, histological and radiological features and hence many believe that they represent a continuum of the same disease process [54, 55]. Some however still regard DIP and RB-ILD as distinct clinical entities.
RB-ILD
Aetiology
RB-ILD is seen almost exclusively in current and former smokers although similar histological features may be seen with exposure to other irritant fumes.
Imaging ndings Chest radiograph In the majority of cases of RB-ILD there is abnormality in the plain lm. Lung volume is usually preserved. Depending on the series studied parenchymal changes vary
from bilateral ne reticulonodular opacities with a basal predominance [52] to airway wall thickening and ground glass opacity [56].
HRCT ndings A recent study described the HRCT appearance in 21 patients with pathologically proven RB-ILD [56]. Poorly dened centrilobular nodules (23 mm) predominating in the upper lobes were seen in 71%, areas of ground glass opacity were present in 67% and patchy areas of reduced attenuation in keeping with air trapping were present in 38% of cases. Diffuse bronchial wall thickening involving both central and peripheral bronchi was present in 86% of cases in one study presumably due to chronic bronchitis. A background of centrilobular and paraseptal emphysema is frequently seen but this is rarely extensive [57]. Interlobular septal thickening in keeping with interstitial brosis may be seen but is rarely a prominent feature. In practice it may be difcult for the radiologist to differentiate asymptomatic respiratory bronchiolitis from symptomatic RB-ILD and DIP due to the considerable overlap in the HRCT features. RB and RB-ILD are characterized by centrilobular nodules and patchy ground glass opacity and DIP by more extensive ground glass opacity (Figure 8). In many respects the HRCT features of RB-ILD mimic those of subacute extrinsic allergic alveolitis. Both diseases are centred on the airways and are characterized by centrilobular nodular opacities and patchy air trapping. Although the nodules in RB-ILD are usually less profuse and more patchy than in extrinsic allergic alveolitis there is considerable overlap. Ancillary signs that may assist diagnosis include bronchial wall thickening and emphysema which are more common in RB-ILD. Knowledge of a smoking history is also important as it is invariably present in RB-ILD but smoking affords protection to extrinsic allergic alveolitis [56].
Desquamative intersitial pneumonia

DIP is classied as a form of idiopathic interstitial pneumonia. Although initially considered a cellular precursor of usual interstitial pneumonia (UIP) this is no longer considered the case [58]. As a pure entity DIP is rare but DIP-like changes are commonly seen in association with other smoking-related conditions such as LCH.
Figure 8. Respiratory bronchiolitis associated interstitial lung

disease (RB-ILD). A high resolution CT image at the level of the left main pulmonary artery shows subtle centrilobular ground glass nodules.
lower zone predominance are present in only a minority of cases (16%) (Figure 9a) [62].
Aetiology
In adults cigarette smoking is the most common cause of DIP accounting for 90% of cases [52] but DIP may be seen in association with Gauchers disease or in association with drugs [59] or dust inhalation [60].
Imaging ndings Chest radiograph In DIP the chest lm may be normal [61] but in the majority of cases (89% in one series [52]) is abnormal. Lung volumes are typically reduced unless there is associated emphysema. Like RB-ILD the most common ndings are bibasal reticular nodular opacities [47]. Ground glass opacity either with a diffuse or a mid and
HRCT ndings The main feature is the presence of ground glass opacity [54, 6264] which is bilateral and symmetrical (Figure 9b). Three quarters of cases have a basal predominance and in half of cases the distribution is predominantly peripheral [64]. Irregular linear opacities associated with architectural distortion and traction bronchiectasis indicating brosis may also be present but are usually not a prominent feature [64] these also have a basal predominance. Cystic spaces within areas of ground glass opacity, representing dilated alveolar ducts and bronchioles, occur in approximately half of patients with DIP [65, 66] and may be a precursor to centrilobular emphysema. Interestingly some of these cysts may regress on serial HRCTs [66]. The pathological features of DIP and RB-ILD are described in the article on the Idiopathic Interstitial Pneumonias in this issue.
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Figure 9. Desquamative interstitial pneumonia (DIP). (a) Chest radiograph shows reduced lung volumes and ne reticular opacities in the mid and upper zones. (b) High resolution CT at the level of the carina demonstrates patchy ground glass opacity bilaterally with ne reticulation and some traction bronchiectasis in the right upper lobe indicating interstitial brosis.
Langerhans cell histiocytosis

LCH is characterized by the proliferation of and inltration of CD 1 positive histiocytes (Langerhans cells). The term LCH encompasses the previously described clinical entities of eosinophilic granuloma, Letterer-Siwe and Hand-Schuller-Christian disease. The disease may be localized, involving either a single organ or system, or systemic, with involvement of multiple organs or systems. Pulmonary involvement by LCH occurs most frequently in localized disease.
communicate with dilated airways [67], are commonly seen in LCH. In end-stage disease predominantly cystic changes are present and coalescence of the cysts may lead to a honeycomb appearance. LCH, because of the association with smoking, often coexists with emphysema, which together with conuent scarring produces a hyperinated honeycomb appearance to the lungs. A DIP like reaction, with inltration of the airspaces by pigmented macrophages is also commonly seen in association with LCH.
Pathogenesis
There is a strong association between pulmonary LCH and cigarette smoking, over 90% of patients with LCH are smokers. LCH is also rarely seen in association with lymphoma and leukaemia.
Clinical features
The age of onset of pulmonary LCH varies widely occurring both in children and the elderly but presentation is typically in the third and fourth decade. A male predominance of 4:1 has been described but the increased prevalence of smoking in females has now lead to an equal sex distribution. Patients typically present with dyspnoea or pneumothorax. Associated systemic symptoms include fever and weight loss. Pulmonary function tests usually demonstrate a mixed obstructive and restrictive pattern with reduced gas transfer. A rare complication of pulmonary LCH is the development of severe pulmonary hypertension disproportionate to the extent of parenchymal destruction. This is probably related to the peribronchovascular distribution of nodules with consequent vascular obstruction [68, 69].
Histopathology
Langerhans cells are rarely identied in normal airway epithelium but alterations in the airway epithelium induced by cigarette smoke appear to attract Langerhans cells. Temporal heterogeneity is typically seen histologically with both active (nodular) lesions and inactive (brotic) lesions co-existing. Early in the disease there are interstitial inltrates which typically demonstrate a peribronchiolar distribution (around the terminal and respiratory bronchioles) consistent with the hypothesis that the disease is a reactive condition in response to cigarette smoke. The inltrate is composed of Langerhans cells, eosinophils, neutrophils, lymphocytes and broblasts. As the disease progresses the inltrates become nodular and broblastic proliferation develops in a centripetal manner resulting in stellate scars. Cystic spaces with brous walls, which have been shown to
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Imaging features Chest radiograph Although the plain chest lm may be normal in early disease it is usually abnormal with a reticular, nodular or cystic pattern predominantly involving the mid and upper zones (Figure 10a). Nodules are usually less than 2 mm in
Figure 10. Pulmonary Langerhans cell histiocytosis. (a) Chest radiograph shows bilateral nodular opacities sparing the lower zones.
HRCT images through (b) the upper, (c) the mid and (d) the lower zones demonstrate numerous irregular nodular opacities some demonstrating central cavitation and thin walled cysts. There is a clear mid and upper zone predominance.
diameter but range up to 1 cm. Cavitation is rarely identied. Lung volumes are usually either preserved or, in up to one third of cases, hyperexpanded [70]. Hyperexpansion and cystic changes become more apparent as the disease progresses. Less common manifestations of LCH include pneumothoraces, pleural effusions or hilar adenopathy [70]. Sequential radiographic changes vary but smoking cessation commonly leads to improvement or complete resolution of the nodular opacities [71, 72].
HRCT The classical appearance of pulmonary LCH is a combination of centrilobular nodules of varying sizes (up to 20 mm) some demonstrating central cavitation and cysts of varying sizes (usually less than 1 cm) and often of bizarre shape [73]. Cysts may be derived from cavitating nodules or in some cases represent distorted airways (Figure 10bd). The HRCT appearances reect
the temporal heterogeneity seen on histopathology with early, predominantly nodular lesions, co-existing with more advanced, predominantly cystic lesions. Serial HRCT studies also demonstrate the evolution of lesions in LCH with the development of cavitation within nodules and the subsequent development of cysts [73]. HRCT elegantly demonstrates predominant involvement of the mid and upper zones with sparing of the extreme apices and costophrenic recesses. The mid and upper zone predominant distribution of disease and the presence of nodules in the intervening lung differentiates LCH from the other cystic lung diseases (lymphangioleiomyomatosis, tuberose sclerosis and lymphocytic interstitial pneumonia). The end stage appearances, when nodules have been largely replaced by cystic spaces, can be indistinguishable from diffuse emphysema. A honeycomb pattern resembling UIP may also be seen in end-stage LCH but the preservation of lung volume and upper zone distribution
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of LCH contrasts with the reduced lung volume and lower zone predominance of UIP usually enable straightforward differentiation.
including COPD, smoking-related interstitial lung disease and lung cancer. Although each disease entity may exist as a pure entity they frequently co-exist in the same patient.
Treatment and natural history

The mainstay of treatment of LCH is smoking cessation [72]. Steroids and cytotoxic therapy have also been utilized but none have demonstrated a clear improvement in the course of disease. End stage disease may be treated by lung transplantation but recurrence in the transplanted lung can occur [72]. In most cases pulmonary LCH follows a relatively benign course with clinical and radiological stabilization in 50% and regression in 25% even without treatment [74]. However, relapse has been described in patients who have initially shown regression of radiographic abnormalities [74]. A minority of patients experience inexorable disease progression leading to respiratory failure requiring lung transplantation. Some patients develop pulmonary hypertension, which is disproportionate to the degree of parenchymal disease relating to microvascular obstruction [69].
References
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Diseases characterized by interstitial brosis

There is evidence from clinical and epidemiological studies that smoking may either promote or inhibit interstitial inammation and brosis in different diseases. In some diseases including extrinsic allergic alveolitis, sarcoidosis and radiation pneumonitis, smoking is associated with a reduced incidence of disease [75, 76]. However, the relationship between smoking and the development of interstitial brosis remains controversial. It has been widely debated for years and is currently receiving increasing interest [7780]. Attention has been focused both on UIP and non-specic interstitial pneumonia (NSIP). With regard to UIP a history of cigarette smoking is described in 4183% of patients with cryptogenic brosing alveolitis (CFA) or idiopathic pulmonary brosis (IPF) [47] and a history of smoking, either current or prior, is associated with increased risk of developing CFA [81]. However, survival in smokers with UIP appears better than in non-smokers [82]. Some of the studies suggesting a link between smoking and UIP, however, pre-date the introduction of NSIP into the new American Thoracic Society/European Respiratory Society (ATS/ERS) classication of the idiopathic interstitial pneumonias [53] and therefore some of the cases would undoubtedly have represented NSIP. Fibrotic NSIP is characterized by interstitial brosis, which is temporally uniform. Although most cases of NSIP are idiopathic it may be seen in association with connective tissue disease [83, 84] as well as in extrinsic allergic alveolitis or following acute lung injury. It has been suggested that some cases of NSIP may represent the consequence of previous DIP/RB-ILD, resolution of the alveolar macrophage inltrate leaving a residue of temporally uniform interstitial brosis [85].
Conclusion
Cigarette smoking is a major cause of mortality and morbidity. It is associated with a wide spectrum of disease
58

23. King MA, et al. Alpha 1-antitrypsin deciency: evaluation of bronchiectasis with CT. Radiology 1996;199:13741. 24. Gevenois PA, et al. Comparison of computed density and macroscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med 1995;152:6537. 25. Gevenois PA, et al. Pulmonary emphysema: quantitative CT during expiration. Radiology 1996;199:8259. 26. Kuwano K, et al. The diagnosis of mild emphysema: correlation of computed tomography and pathology scores. Am Rev Respir Dis 1990;141:16978. 27. Miller RR, et al. Limitations of computed tomography in the assessment of emphysema. Am Rev Respir Dis 1989;139:9803. 28. Muller NL, et al. Density mask: an objective method to quantitate emphysema using computed tomography. Chest 1988;94:7827. 29. Remy-Jardin M, et al. Sliding thin slab, minimum intensity projection technique in the diagnosis of emphysema: histopathologic-CT correlation. Radiology 1996;200:66571. 30. Uppaluri R, et al. Quantication of pulmonary emphysema from lung computed tomography images. Am J Respir Crit Care Med 1997;156:24854. 31. Nagao M, et al. Quantitative analysis of pulmonary emphysema: three-dimensional fractal analysis of singlephoton emission computed tomography images obtained with a carbon particle radioaerosol. AJR Am J Roentgenol 1998;171:165763. 32. Mishima M, et al. Complexity of terminal airspace geometry assessed by lung computed tomography in normal subjects and patients with chronic obstructive pulmonary disease. Proc Natl Acad Sci USA 1999;96:882934. 33. Fishman A, et al. A randomized trial comparing lungvolume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348:205973. 34. National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 2001;345:107583. 35. Brenner M, et al. 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Smoking-related interstitial lung diseases: a concise review. Eur Respir J 2001;17:12232. 48. Nagai S, et al. Smoking-related interstitial lung diseases. Curr Opin Pulm Med 2000;6:4159. 49. Aubry MC, Wright JL, Myers JL. The pathology of smokingrelated lung diseases. Clin Chest Med 2000;21:1135, vii. 50. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 1974;291:7558. 51. Myers JL, et al. Respiratory bronchiolitis causing interstitial lung disease. A clinicopathologic study of six cases. Am Rev Respir Dis 1987;135:8804. 52. Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 1989;64:137380. 53. ATS/ERS International Multidisciplinary Consensus Classication of Idiopathic Interstitial Pneumonias: General Principles and Guidelines. American Thoracic Society, Toronto, May 2000. 54. Heyneman LE, et al. Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process? AJR Am J Roentgenol 1999;173:161722. 55. Colby TV. Bronchiolitis. Pathologic considerations. Am J Clin Pathol 1998;109:1019. 56. Park JS, et al. Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic correlation. J Comput Assist Tomogr 2002;26:1320. 57. Desai SR, Ryan SM, Colby TV. Smoking-related interstitial lung diseases: histopathological and imaging perspectives. Clin Radiol 2003;58:25968. 58. Carrington CB, et al. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978;298:8019. 59. Hamadeh MA, Atkinson J, Smith LJ. Sulfasalazine-induced pulmonary disease. Chest 1992;101:10337. 60. Amir G, Ron N. Pulmonary pathology in Gauchers disease. Hum Pathol 1999;30:66670. 61. Gaensler EA, Goff AM, Prowse CM. Desquamative interstitial pneumonia. N Engl J Med 1966;274:11328. 62. Feigin DS, Friedman PJ. Chest radiography in DIP: a review of 37 patients. AJR Am J Roentgenol 1980;134:919. 63. Vedal S, et al. Desquamative interstitial pneumonia: computed tomographic ndings before and after treatment with corticosteroids. Chest 1988;93:2157. 64. Hartman TE, et al. Desquamative interstitial pneumonia: thin-section CT ndings in 22 patients. Radiology 1993; 187:78790. 65. Hartman TE, et al. Disease progression in usual interstitial pneumonia compared with desquamative interstitial pneumonia. Assessment with serial CT [see comments]. Chest 1996;110:37882. 66. Akira M, et al. Serial computed tomographic evaluation in desquamative interstitial pneumonia. Thorax 1997;52:3337. 67. Kambouchner M, et al. Three-dimensional characterization of pathologic lesions in pulmonary langerhans cell histiocytosis. Am J Respir Crit Care Med 2002;166:148390. 68. Travis WD, et al. Pulmonary Langerhans cell granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases. Am J Surg Pathol 1993;17:97186. 69. Fartoukh M, et al. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med 2000;161: 21623.
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70. Lacronique J, et al. Chest radiological features of pulmonary histiocytosis X: a report based on 50 adult cases. Thorax 1982;37:1049. 71. Von Essen S, et al. Complete resolution of roentgenographic changes in a patient with pulmonary histiocytosis X. Chest 1990;98:7657. 72. Mogulkoc N, et al. Pulmonary Langerhans cell histiocytosis: radiologic resolution following smoking cessation. Chest 1999;115:14525. 73. Brauner MW, et al. Pulmonary Langerhans cell histiocytosis: evolution of lesions on CT scans [see comments]. Radiology 1997;204:497502. 74. Tazi A, et al. Relapsing nodular lesions in the course of adult pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med 1998;157:200710. 75. Douglas JG, et al. Sarcoidosis: a disorder commoner in nonsmokers? Thorax 1986;41:78791. 76. Johansson S, et al. Effects of ongoing smoking on the development of radiation-induced pneumonitis in breast cancer and oesophagus cancer patients. Radiother Oncol 1998;49:417. 77. Weiss W. Cigarette smoking and diffuse pulmonary brosis. Am Rev Respir Dis 1969;99:6772. 78. Auerbach O, et al. Smoking habits and age in relation to pulmonary changes. rupture of alveolar septums, brosis and thickening of walls of small arteries and arterioles. N Engl J Med 1963;268:104554. 79. Cardoso WV, et al. Collagen and elastin in human pulmonary emphysema. Am Rev Respir Dis 1993;147:97581. 80. Lang MR, et al. Collagen content of alveolar wall tissue in emphysematous and non-emphysematous lungs. Thorax 1994;49:31926. 81. Baumgartner KB, et al. Cigarette smoking: a risk factor for idiopathic pulmonary brosis. Am J Respir Crit Care Med 1997;155:2428. 82. King TE Jr, et al. Predicting survival in idiopathic pulmonary brosis: scoring system and survival model. Am J Respir Crit Care Med 2001;164:117181. 83. Douglas WW, et al. Polymyositis-dermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med 2001;164:11825. 84. Katzenstein AL, Fiorelli RF. Nonspecic interstitial pneumonia/brosis. Histologic features and clinical signicance. Am J Surg Pathol 1994;18:13647. 85. Hansell D, Nicholson A. Smoking-related diffuse parenchymal lung disease: HRCT-pathological correlation. Sem Resp Crit Care Med 2003;24:37791.
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Imaging, 16 (2004), 2236 E 2004 The British Institute of Radiology DOI: 10.1259/imaging/49441582
Evaluation of the solitary pulmonary nodule: clinical management, role of CT and nuclear medicine
1 2
1
D R BALDWIN, MD, FRCP, 2J D BIRCHALL, FRCR, 3R H GANATRA, MRCP, FRCR and K S POINTON, MRCP, FRCR
Respiratory Medicine Unit, David Evans Centre and 2Department of Radiology, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB 3Medical Physics Department, Queens Medical Centre, University Hospital NHS Trust, Nottingham NG7 2UH, UK
Clinical management of the solitary pulmonary nodule

Clinical discussions about the best management of patients with solitary pulmonary nodules (SPNs) generate a surprising level of disagreement between clinicians. This is partly due to individual convictions based on little published evidence, but also to the confusing array of imaging options along with many other inuences (Figure 1). The new diagnostic investigations constantly raise the possibility of a change to policy. This article will review the published evidence for management strategies, explore the reasons why approaches vary signicantly and describe an algorithm for management of SPN.
Summary
N Solitary pulmonary nodule (SPN) is a common

clinical problem, and the clinical history is vital in assessing the pre-test probability of malignancy.
N Previous relevant imaging should be accessed. for be to a dened N CT scanningthat an SPN shouldstudies are protocol, so any follow-up
comparable. depreotide N Positron emission tomograpy andcharacterization, scanning both offer non-invasive which, with improved image registration, could be of use even in nodules than 10 mm in diameter.
Denition
In the clinical setting, management of the SPN is often confounded by application of guidelines to nodules or masses outside the accepted denition. It is therefore important to state at the outset the denition that this article relates to: An approximately round lesion that is less than 3 cm in diameter and that is completely surrounded by lung tissue. SPNs have been dened in the literature as rounded lesions surrounded by apparently normal lung parenchyma which do not cause symptoms [17]. In some publications the lack of symptoms is not thought to be appropriate as it is quite often difcult to be sure that certain symptoms (e.g. cough) are related or unrelated. In the majority of publications SPNs are dened as those 3 cm or less in
diameter on initial chest radiograph but some include those up to 4 cm. The arbitrary size cut-off is made for practical purposes and in reality the management of a nodule up to 4 cm diameter will be very similar to one of 3 cm nodule. Publications relevant to the management of SPN consist of a majority of review articles, often with very similar conclusions, which base their recommendations on other evidence. The latter may be categorised into descriptions of various techniques to predict or conrm malignancy, tests of management strategies using Bayes Theorem and decision analysis techniques designed to test the effect of additional information on outcome [8].
Figure 1. Factors inuencing the approach to the solitary pulmonary nodules. Local policy, inuenced by local resources may be a strong determinant of the management strategy. 22 Imaging, Volume 16 (2004) Number 1
Evaluation of solitary pulmonary nodule
Measuring the probability of malignancy

Although opinions differ about the most appropriate management of the SPN (varying from immediate resection of all nodules to establishment of a histological diagnosis in all prior to consideration of resection) most clinicians would agree that the essential rst step in management is to attempt to predict the probability of malignancy. This then guides both patient and clinician in deciding on appropriateness for resection or radical treatment. There are a number of known predictors of malignancy of which the most important (statistically) are age, smoking history, size of lesion and documentation of enlargement [16]. However, these factors are only pointers to malignancy and if taken as absolutes may lead to mistakes: a follow-up study of lesions that had not enlarged on chest radiograph over a 2 year period showed that 9 of 26 nodules were malignant, representing a predictive value of only 65% for a benign lesion [8]. The improved resolution of other imaging techniques will improve the accuracy of this predictor of malignancy but there is still need for careful follow-up even where the probability of malignancy is low. Whatever parameters are used, this initial assessment of likelihood of malignancy establishes a pre-test probability and this then constitutes the rst management decision immediate therapy (often resection), further investigations (to modify the pre-test probability) or observation.
Investigations
Commonly employed investigations for SPN include contrast enhanced CT, FDG-PET, ne needle biopsy (FNB) and bronchoscopy. There are a plethora of publications on CT, FDG-PET and lung biopsy that report on sensitivity and specicity [911]. From the clinical perspective there are some important principles: rst, the sensitivity and specicity of the tests vary considerably (even in research trials) so it is important to have a local estimate to guide institutions in deciding on best policy. Second, tests tend to be complimentary, and this can inuence their utility (and sensitivity and specicity) considerably. Third, any one sequence of tests cannot be recommended because of variation in resources and variations in accuracy. There are some general points about individual tests that merit discussion: CT is important to conrm that an SPN is indeed solitary and can suggest a change to the probability of malignancy by the appearance of the SPN. Measuring contrast enhancement can increase the predictive value of CT [12]. However, there are some practical problems with the performance of scans, including the accurate measurement of enhancement, especially for small lesions. FDG-PET helps to predict malignancy but more conditions producing a false positive scan are being recognised. PET may be particularly useful because of its ability to detect occult metastases in up to 14% of patients otherwise suitable for surgery [13]. There is merit in observing lesions that are 1 cm or more in diameter and negative on PET as they have a very low probability of malignancy [14]. FNB is a more invasive procedure that may harm the patient, so the risks, benets and alternatives should be carefully explained. The utility of the test is subject to the skill of the radiologist and the histopathologist. Correct interpretation of the result is also very important. The preferred method for diagnosis of SPN is cutting FNB [15]. The latter provides better histological samples but it is not clear that this equates to improved diagnostic yield. Elements in the biopsy material indicating a benign lesion are different from elements from normal lung that merely indicate a miss. The latter provides no extra information and implies the need for a repeat biopsy or different approach. Bronchoscopy is used where CT has demonstrated an airbronchus sign, but has a low overall diagnostic rate. Small (11.5 cm) nodules may be very difcult to sample. Ultra-thin bronchoscopy is not in general use for diagnosis of SPN, but may be useful as it has a low morbidity. Other imaging modalities may also be useful e.g. 99Tcm depreotide, employing a somatostatin analogue. Lastly, some clinicians advocate the more general use of thoracoscopic wedge resection, as both a diagnostic and therapeutic approach in those patients who are both t and have lesions readily amenable for the procedure [16]. The morbidity from thoracoscopic wedge resection is low, so it is argued that this is an acceptable approach even in low or intermediate probability lesions.
Missed cures versus unnecessary surgery

One of the most important questions when deciding on the merit of conservative or aggressive management approaches is which approach provides the best outcome for the patient? The role of the clinical team in the broad sense is to manage the cancers quickly, identify lesions that are denitely benign, and treat the infections. The worst scenarios are to delay curative treatment in a patient with a localized primary, a missed cure and to leave a patient with debilitating post-thoracotomy pain from unnecessary surgery. A conservative approach to the management of SPN carries with it the risk of missing a potential cure but this risk can be minimized by careful follow up when a watch policy is adopted [7, 8]. Aggressive management of SPN carries with it the risk of unnecessary procedures (resection of benign lesions) with attendant mortality and morbidity but is often considered to be the safest approach, provided the patient is t. An important paradox is that younger more t patients, in whom the risk of malignancy is less, are at less risk of being harmed by surgical treatment. The reduced operative risks may make surgeons more willing to operate and hence the risk of unnecessary surgery is increased in a group where, the probability of malignancy is low. Patient views will also be of crucial importance here, but they must be given accurate information in order to make a correctly informed decision. This is a further argument for the investigative approach. It is with these considerations in mind that consensus documents recommend that a low or intermediate pre-test probability of malignancy should invoke strategies that aim to obtain a histological diagnosis prior to surgery [7].
Tests of management strategies

The ultimate proof of a management strategy is that it has a favourable effect on outcome. This, in effect, takes into account all of the factors involved in clinical
23
D R Baldwin J D Birchall, R H Ganatra and K S Pointon
management, rather than just measuring the strengths and weakness of one particular test. Publications have addressed this in two ways: i) stratication of SPN by probability of malignancy and then applying different management strategies to obtain a predicted best outcome; and ii) by measuring, in populations with a known outcome, the effect of additional information. The former studies were published in the mid 1980s and used Bayesian statistics to measure the probability of malignancy based on likelihood ratios. These are calculated by measuring the probability of nding a given feature in a population of malignant SPN and dividing by the probability of nding the same feature in a population of benign SPN (Figure 2). The ratio may then be used to predict the likelihood of malignancy. These criteria have been applied to produce formulae which may be used to predict the probability of malignancy [7, 8]. Although these formulae include an adjustment for the prevalence of malignancy in the population, the individual likelihood ratios are based on populations that differ signicantly from UK populations and therefore there may be some inaccuracy when these formulae are applied to different populations. For this reason (and a certain scepticism for the Bayesian approach) these formulae are not often applied in the UK. After calculation of probability of malignancy using the Bayesian approach, Cummings et al looked at the effect of different management strategies on mortality, assuming dened values for factors inuencing mortality such as missed cure and operative mortality. By using this approach, they showed that the choice of management strategy was a close call, with immediate resection producing a small but signicant survival advantage where probability of malignancy was high whilst a more cautious approach provided a survival advantage for low probability lesions. Table 1 shows the effect on calculated life expectancy of different management strategies.
An alternative approach has been to derive multivariate models to predict malignancy by retrospectively studying a population of nodules with known outcome. Table 2 allows a quick reference to probabilities derived in this way. It should be remembered that this table is based on data from a US population. Tests of management strategies based on calculated factors have a mainly theoretical basis and for this reason may not convince clinicians. Other studies have looked at the effect of addition of information on the chance of making a successful management decision in a population of patients where the outcome of the patients is known. One such study looked at a population of 104 solitary pulmonary nodules managed at a tertiary centre where there was a policy to investigate all nodules with a CT thorax and FNB. The methodology was to present clinical data and chest radiograph report to six respiratory physicians (independently) and to ask them to estimate the probability of the lesions being malignant and to specify their management [17]. They were not allowed to request further investigations, but had to say whether they would recommend surgery, palliative treatment or observation of a presumed benign lesion. The same cases were presented to them (after an interval) twice more, rst with the addition of a CT report and second with both the CT and FNB report. The addition of CT and particularly the FNB had the effect of improving the number of successful management decisions, and this was mainly due to the avoidance of surgery for benign lesions. The strategy of employing CT and needle biopsy, whilst reducing morbidity, did not increase the chance of missing a cure and was found to be cost effective using UK Health Related Group costs. Table 3 shows the effect of additional information on the numbers of unsuccessful management decisions. If FNB was restricted to the SPN of low and intermediate probability of malignancy then the strategy was even more cost effective [17]. This study also demonstrated that
Figure 2. Likelihood ratios (LRs). Table 1. Average calculated life expectancies based on management strategies [7, 8]
Patient characteristics Estimated probability of malignancy (Pca) Strategy Biopsy 6.3 38.27a 18.55 5.79 7.90 Biopsy/ observation 7.28 38.24 18.82 6.33 7.99 Observation/ surgery 7.33 38.12 18.79 6.34 7.83 Immediate surgery 7.34a 38.04 18.76 6.39a 7.73
64-year-old smoker, 11K pack/day smoker, 2.5 cm nodule 35-year-old non-smoker 1.0 cm nodule 50-year-old, 1 pack/day smoker, 2.0 cm nodule 75-year-old, 1K pack-day smoker, 2.0 cm noduleb 75-year-old non-smoker, 2.0 cm nodule
a b
0.83 0.01 0.34 0.80 0.23
The longest life expectancy among the 4 strategies for this case. This case assumes higher risks of surgery and biopsy.
24
Evaluation of solitary pulmonary nodule Table 2. Multivariate approach to calculation of probability of malignancya
Probability of malignancy p 35 years Cigarettes 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1
a
55 years 20 mm 0.05 0.11 0.13 0.25 0.17 0.31 0.37 0.56 0.11 0.21 0.25 0.43 0.31 0.50 0.57 0.74 30 mm 0.16 0.30 0.36 0.55 0.43 0.62 0.68 0.82 0.30 0.49 0.55 0.73 0.62 0.78 0.82 0.91 10 mm 0.03 0.07 0.09 0.17 0.11 0.22 0.26 0.44 0.07 0.14 0.17 0.31 0.22 0.38 0.44 0.64 20 mm 0.11 0.21 0.25 0.43 0.31 0.50 0.56 0.74 0.21 0.37 0.43 0.62 0.50 0.69 0.74 0.86 30 mm 0.30 0.48 0.55 0.73 0.62 0.78 0.82 0.91 0.48 0.67 0.73 0.85 0.78 0.89 0.91 0.96
75 years 10 mm 0.07 0.14 0.17 0.31 0.22 0.38 0.44 0.63 0.14 0.26 0.31 0.50 0.38 0.57 0.63 0.79 20 mm 0.21 0.36 0.42 0.62 0.50 0.69 0.74 0.86 0.37 0.56 0.62 0.78 0.69 0.83 0.86 0.93 30 mm 0.48 0.67 0.73 0.85 0.78 0.89 0.91 0.96 0.67 0.82 0.85 0.93 0.89 0.95 0.96 0.98
Other cancer 0 0 0 0 1 1 1 1 0 0 0 0 1 1 1 1
Spiculation 0 0 1 1 0 0 1 1 0 0 1 1 0 0 1 1
Upper lobe 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 1
10 mm 0.02 0.03 0.04 0.09 0.06 0.11 0.14 0.27 0.03 0.07 0.09 0.17 0.11 0.22 0.27 0.44
For categorical predictors (cigarettes, other cancer, spiculation, and upper lobe), 0 indicates absent; 1, present. For p-values, 35, 55, and 75 refer to age of patient; 10, 20, and 30, size of solitary pulmonary nodule.
Table 3. The effect on chance of making unsuccessful management decisions of additional information provide by CT and ne
needle biopsy Strategy Unsuccessful surgery 32 28.5 28.5 30.5 28 Surgery for benign lesions 18.5* 13* 5* 5 7 Missed cure 5 3.5 2.5 1.5 3.5 Median cost per surgical cure () 22458 20431 19582 19258 18982
CXR alone all cases Addition of CT Addition of FNA Addition of FNA if lesion not high probability on CXR Addition of FNA if lesion not high probability on CT *p,0.01, Freidmans Test. CXR, chest radiograph; FNA, ne needle aspiration.
clinicians were more likely to make a correct management decision if a consensus was taken. This is encouraging for cancer multidisciplinary teams.
A suggested approach
At each point in the management pathway consideration should be given to patients preferences after informed discussion appropriate to the patients needs. This assumes good communication skills, a sound knowledge of the evidence to support suggested management options and the time to have a meaningful discussion. The following steps indicate where there are options and at these points it is especially important to engage the patient. (1) History. All patients with SPN should have a full clinical history and examination. This should include smoking history, exposure to carcinogens and past medical history. (2) Baseline investigations. A recent chest X-ray should be available and any previous chest radiology should be examined. A full blood count, clotting study and renal, liver and bone proles should be available. (3) Further investigations. Unless previous radiographs indicate otherwise, all patients should have a CT scan
of the thorax with contrast enhancement performed. If CT scanning suggests additional lesions or nodal involvement, then the lesion is not an SPN and the patient should be managed accordingly. Measurement of degree of enhancement may be used to assist estimation of probability of malignancy. (4) Where available, all patients should have PET scan prior to surgery, since this detects distant metastases in around 8% of lesions. (5) Based on the estimate of the probability of malignancy, the potential risk to the patient from surgery (including the tness of the patient) and the patients wishes decide on one of three strategies:
N N N
Immediate resection Biopsy (followed by resection if malignant or observe if positive benign) Observe (with potential for biopsy or resection if lesion is displays malignant characteristics)
Biopsy may include thoracoscopic wedge resection, but this is probably part of the immediate resection option. Biopsy here refers to FNB. Table 4 gives the most important factors and may be preferred by some clinicians to the multivariate statistical approach given in Table 2 (although this method has been
25
D R Baldwin J D Birchall, R H Ganatra and K S Pointon Table 4. Rapid assessment of probability of malignancy
Variable Risk of cancer Low Diameter of nodule Age (year) Smoking Smoking cessation Nodule margin ,1.5 ,45 Never Quit 7 years Smooth Intermediate 1.5 to 2.2 45 to 60 Current 20 cpd Quit ,7 years Scalloped High .2.2 .60 Current .20 cpd Never quit Corona radiata or spiculated
shown to be equivalent to assessment by expert clinicians [18]). If not formally calculating the probability of malignancy, a quick assessment of the likelihood of malignancy can be made using Table 4 [14]. For high probability lesions immediate resection will result in a minimal number of unnecessary resections but even in that group there may be some merit in a cautious approach. In one study consensus estimates of malignancy of pulmonary nodules 3 cm or less in diameter on the basis of clinical and CT criteria, showed only 6 of 71 nodules were benign and not all of these were suitable for resection for other reasons [17]. However, the same study also showed that even in this group there was a small reduction in the number of operations for benign lesions. Also these SPN are mostly larger and therefore rather easier to sample. The views of the patient and the tness for surgery should be over-riding considerations. If the probability of malignancy is intermediate, the preferred option should again be determined by assessment of risk to patient of immediate surgery and patient preference but because of the increased risk of operating on a benign lesion, a patient who is at high risk from surgery should be advised that investigation of the nodule prior to resection is the preferred option. Low probability lesions are generally less than 1.5 cm in diameter unless there is a previous chest X-ray that shows no evidence of the lesion. There is little evidence for a correct approach to these lesions. An assessment should be made of three factors: surgical risk; ease of sampling of lesion; and patient preference. This will guide three strategies: immediate resection (after PET scan), FNB, or observation including further imaging. For practical purposes, if the lesion is less than 1 cm, FNB is not an option, so the lesion is either resected, according to operative risk (including ease of resection) or observed. The strategy for observation should probably be guided by protocols adopted by screening studies. PET has a limited role in lesions of ,1 cm diameter. If after follow-up the lesion has enlarged then FNB should be performed or immediate resection. A negative needle biopsy is here dened as a biopsy yielding lung tissue from abnormal lung that suggests a benign diagnosis. Biopsies that yield normal lung should be classied as having missed the lesion and those containing necrotic material are not useful diagnostically. Missed biopsies should be repeated, possibly with improved imaging. A benign diagnosis should be reviewed with the clinical scenario and depending on the safeness of the diagnosis a decision made whether to treat, observe, or repeat the biopsy. The patients view need to be sought at this stage, in case the option preferred by the patient is resection.
26
Algorithm for the management of solitary pulmonary nodules

Figure 3 shows an adapted algorithm that summarizes the suggested management strategy [14].
The role of CT in assessing the SPN

This section of the article aims to review the current knowledge and issues relating to CT scanning of SPNs. Technological improvements allow faster, more accurate and reproducible assessment of the lung nodule [19, 20]. The nodule margin, rate of enhancement and other intrinsic characteristics such as the presence of internal calcications, and fat density can be assessed [2123]. The approach to SPNs should be rened based on evidence that has emerged from the literature over the last few years. For instance, the identication that sub-solid nodules (nodules that contain mixed soft tissue and ground glass density) carry an increased risk of malignancy [24]. The interval between repeat scans is variable between centres. The international lung cancer screening studies are generating useful databases, and have evolved protocols governing interval scans dependant on nodule size [2527].
Identifying an SPN
An SPN may be identied by chest radiography, or as an incidental nding at CT performed for other reasons. CT is used to conrm a lesion is solitary, and to characterize it further in terms of non-enhanced and then enhanced CT features, and to document nodule size. With the widespread availability of CT, many more solitary nodules are identied, and conversely some lesions on plain lms thought to be solitary can readily be seen to be multiple. When multiple lung nodules are identied the likelihood of current infection or metastases is increased. Once an SPN has been identied, no investigation is more useful than a previous chest radiograph or CT scan, especially if from 2 or more years ago, and previous imaging should be reviewed as a nodule not mentioned on a report may have been overlooked.
Aetiology
The more common causes of benign and malignant SPNs, and CT features are summarized in Tables 57.
CT technique
Imaging parameters may vary depending on the indication for CT, and whether the SPN is an incidental
Figure 3. Algorithm for the management of solitary pulmonary nodules [16].
nding. If the scan is performed to characterize an SPN a specic high-resolution protocol should be used. A collimation of 0.61.25 mm, pitch 1.21.5, rotation time 0.50.8 s, and exposure parameters between 80120 mAs and 100140 kV would be typical. Thin sections (1.25 mm or less) should be used, as wider 710 mm sections may fail to identify characteristic areas of calcication or fat. Images should be reviewed on a workstation with locally agreed window settings and
reconstruction algorithms. Lung cancer screening programmes are performed with low dose CT parameters, see below. The accuracy of assessing a nodule on the axial images is limited and where possible volume analysis software should be used [19, 31]. All subsequent examinations should follow the same protocol. A multislice CT dataset with contiguous reconstructions could contain 400 axial images for review. Review of each image is time consuming, and there is potential for
27
D R Baldwin J D Birchall, R H Ganatra and K S Pointon Table 5. Benign solitary pulmonary nodules
Healed granulomata secondary to tuberculosis or fungal infections Hamartoma Small regions of organizing pneumonia, inammatory pseudotumour or abscess Intrapulmonary lymph nodes May show characteristic laminate calcication [2022] Cause of 10% of resected SPNs in some series. May have characteristic fat density within nodule [20, 22]. May show resolution by time of interval scan More often located below the level of the carina, and close to pleural surfaces. On thin-section CT, they are well circumscribed, homogeneous, round or ovoid, and smaller than 12 mm in maximal diameter [28] Generally multifocal, and associated with mediastinal lymphadenopathy but occasionally in the differential Generally multifocal Generally multifocal Generally multifocal
Sarcoid nodule Pneumoconiosis Amyloid Wegeners Granulomatosis SPN, solitary pulmonary nodule.
Table 6. Malignant causes

Primary bronchogenic tumour Metastasis Adenocarcinoma, epidermoid, large-cell anaplastic, neuroendocrine or, small cell If T1 N0 M0 at diagnosis, the 5 year survival is between 67% and 83% Recorded as cause of 1030% nodules. The histology of the initial primary is important sarcomas, renal and GI cancers are much more likely to have metastasis in an SPN (60%) than breast or prostate (20%) [29] Peripheral bronchial carcinoids appear as well-dened, round or oval SPNs and may be slightly lobulated at CT. Calcication is common and is easily visualized at CT. Prognosis of bronchial carcinoid is dependant on histology: typical bronchial carcinoids better prognosis than atypical [30]
Carcinoid
SPN, solitary pulmonary nodule; GI, gastrointestinal.
the radiologist to overlook small nodules. Lung nodules may have similar density, and shape to blood vessels in cross-section. Computer-aided diagnosis is being developed to identify and ag nodules to the radiologist, and is most useful in the identication of the smallest nodules [32].
Accuracy of nodule measurement, and growth rate

Nodule size is important, as this is a strong predictor of malignancy. Up to 80% of SPNs with a diameter of over 2 cm may be malignant [33, 34]. Initial measurements need to be accurate in order to assess growth over a relatively short interval. The most signicant property of a malignant lung nodule is growth, but some benign lung nodules may also grow. Papers dating back to 1956 [35] have described nodule growth on serial chest radiographs, and rst introduced the concept of volume doubling time. Reported lung cancer doubling times range between 30 days and 490 days. There is marked overlap between this range and that reported for benign nodules (35 days to several years) [3335]. Very rapid doubling times however, of less than 7 days would indicate infection. Assuming an SPN is a perfect sphere, the equation for volume calculation is proportional to the cube of diameter. If lesion growth is followed, the accuracy of the measurements must be optimized, as a 10% increase in diameter equates to a 33% increase in volume. Such a change in volume over 3 months would suggest malignancy. The reliability of observer measurements of nodule size on CT, using electronic callipers has been reported [36].
28
Three readers made 3 serial measurements from 54 SPNs identied on standard dose multislice CT. The mean nodule size was 8.5 mm, with a standard deviation of 3.6 mm. The largest transverse diameter was measured on workstations from high-spatial resolution reconstructions, and identical window settings. The readers showed errors in repeated measurements. At the intraobserver level, an apparent change in size of a nodule of 1.32 mm had only a 5% chance of representing an actual change in nodule size. At interobserver level, a change in size of 1.73 mm had only a 5% chance of corresponding to a real change. This indicates that interval scanning to assess for growth may give misleading results when the assessment for size is so inaccurate, malignant growth may be missed, or unnecessary invasive investigations precipitated. Follow up CT studies for comparative measurements of cross-sectional diameters, in the x and y planes have inherent inaccuracies, as the third dimension (z-axis) of growth is not assessed and growth can be highly asymmetric. Automated volume analysis software available with the new generation multislice scanners is theoretically able to provide reproducible measurements with a volume error of less than 3%. A study by Revel et al demonstrated that when threedimensional volumetric analysis was performed the software could accurately assess 96% of nodules [19]. The maximum error calculated was 6.4% of the previous volume measurement, which corresponds to an error of 0.1 mm in the measurement of a 5 mm nodule. There are patient factors that will reduce the accuracy of automated measurements such as respiratory or cardiac movement. Some of these inaccuracies may be difcult to identify, but should be borne in mind, and results interpreted accordingly.
Evaluation of solitary pulmonary nodule Table 7. Nodule morphology

Feature Outline characteristics on CT [20, 21] Smooth Polygonal Lobulated Irregular and spiculated Pleural tag Position [20] Lobar location Peripheral, subpleural (,2 cm pleural surface) Intrinsic properties [20, 21] Cavitation Presence of air bronchogram Calcications Likelihood of malignancy Lower-even growth, more likely to be seen with a benign lesion Lower-angular margins suggest collapse/scarring Moderate-uneven growth, so more suggestive of neoplasia than a round lesion High-appearance also seen with tuberculosis, and nodular brosis Moderate-inammatory/desmoplastic response Lower lobe SPNs slightly more likely to be benign. Tuberculous scarring also more common in the upper lobes Moderate. Intrapulmonary lymph nodes seen subpleurally
Indeterminate. Seen in malignancy or infection. Thin, smooth walls are more likely a benign cause but in the context of an SPN, scale may be too small to assess Indeterminate. Seen with infection or malignancy especially bronchioloalveolar cell carcinoma, and occasionally lymphoma Between 38% and 63% of benign nodules are calcied. Areas of HU (Hounseld Unit) density greater than 200 are calcied. A tumour can engulf calcied nodules. Recognised patterns include: Laminated Benign. Seen with granulomas or hamartomas Popcorn Benign. Typical calcication for a hamartoma, which is also expected to contain areas of fat Diffuse punctate Indeterminate, seen in bronchogenic primary as well as granulomas, hamartomas, amyloid, carcinoid and some metastases Most common nodule. Most cancers are found in solid nodules, but a lower proportion of solid nodules are malignant compared with those that are part-solid Contains a solid component that does obliterate the lung parenchyma, and also a non-solid component. Of lung nodules less than 15 mm in diameter, this is the most likely to contain malignancy (4050%), and the risk rises as the nodule size increases Previously termed ground glass opacity. Aerated lung parenchyma remains visible through the nodule. Risk of malignancy relatively low 15%, but rises once the diameter exceeds 15 mm. May represent adenocarcinoma with bronchioloalveolar features, pre-malignant atypical adenomatous hyperplasia, or bronchioloalveolar hyperplasia. (This appearance also seen with acute infection, haemorrhage or oedema.)
Nodule density [23, 24] Solid Part-solid
Non-solid
SPN, solitary pulmonary nodule.
An additional challenge is the accurate volume measurement of subsolid nodules (see Table 2), as nodule margins are not as clearly dened [24]. The International Early Lung Cancer Action Project (I-ELCAP) is a multicentre, multinational project, screening asymptomatic smokers, using low dose CT parameters (120 kVp, 4080 mA, slice thickness 1.25 mm or less) without intravenous contrast. Following a negative study, a repeat screening examination is performed at 12 months. Nodules detected are measured:
Table 8. Current I-ELCAP nodule protocol (July 2004) [25]
Nodule size Negative nding No nodule seen Semi-positive nding Solid nodule,5 mm Non-solid nodule ,7 mm A positive nding in the study Solid or part-solid nodule 5 mm, or 8 mm non-solid nodule or an Endobronchial 5 mm nodule 15 mm nodule
nodule diameter is the average of the maximum length of the nodule, and the maximum diameter found perpendicular to that length [2527]. Subsequent management decisions are related to nodule size, see Table 8.
Contrast enhancement
A study published in 1996 [6] looked at whether lung nodule enhancement measured at CT was proportional to
Initial management protocol Routine follow up CT at 12 months Follow up CT at 12 months
Intermediate probability for malignancy. Either repeat CT or PET scan, which if positive should be followed by lung biopsy. An increasing solid component in a part-solid or non-solid nodule is suspicious for malignancy Immediate biopsy, or antibiotics and repeat CT at 1 month. If no resolution should have lung biopsy, or if partial resolution a repeat CT at 3 months
29
Figure 4. This 23 mm nodule has lobulation and spiculation,

suspicious for malignancy.
Figure 6. This low-density nodule has no solid component so

would be classied as non-solid, with a relatively low risk for malignancy.
the likelihood of malignancy and to nodule vascularity. 107 patients with indeterminate 730 mm pulmonary nodules were studied, prior to and following intravenous contrast medium Figures 46. Malignant neoplasms enhanced signicantly more than granulomas and benign neoplasms (p,0.001). The study demonstrated that by using an increase of 20 HU as the threshold for increased
likelihood of malignancy, a sensitivity of 98%, specicity of 73%, and accuracy of 85% could be achieved. A follow-up multicentre study published in 2000 analysed data from 356 nodules [12]. All patients were examined by CT with 3 mm-collimation, before and after intravenous injection of contrast material. Scans were obtained at 1 min, 2 min, 3 min, and 4 min following
(a)
(b)
Figure 5. Spiculate peripheral opacity. When viewed on bone windows has extensive central calcication indicating a benign nodule. 30 Imaging, Volume 16 (2004) Number 1
injection. Peak net nodule enhancement and timeattenuation curves were analysed. Malignant neoplasms enhanced (median 38.1 HU; range 14.0165.3 HU) signicantly more than granulomas and benign neoplasms (median 10.0 HU; range 220.096.0 HU; p,0.001). With a lowered threshold of 15 HU, the sensitivity was 98% (167 of 171 malignant nodules) the specicity was 58% (107 of 185 benign nodules) and the accuracy was 77% (274 of 356 nodules). From the initial full cohort of patients, over a quarter were excluded because either the surveillance was less than 2 years or the diagnosis could not be veried after death. 19 other patients studied were excluded because of inadequate compliance with breathing instructions. Absence of signicant lung nodule enhancement (15 HU) at CT was strongly predictive of benignity, but over 40% of benign nodules would still remain in the cohort suspicious for malignancy. Setting lower thresholds for density change following contrast will minimize the risk of missing a cancer, but does so at the expense of increasing numbers of benign nodules in the suspicious population. To be able to achieve the degree of nodule discrimination achieved in these studies there are technical factors to be considered: the timing of the contrast injection is critical, and partial voluming effects would decrease the reliability in smaller nodules, patients are required to breath-hold for each scan at a similar phase of the respiratory cycle, to enable accurate analysis of enhancement rates. A further reported feature of enhancement is the enhancing rim sign, to identify nodules which are benign granulomas [37]. The study suggests that a rim of enhancement is seen around a low-density (,15 HU) homogeneous centre in granulomatous disease. Preliminary results are promising, but patient numbers are limited to date.
Small (,1 cm) SPN

Despite improvements of CT and PET technology there is still difculty characterizing the smallest lung nodules as accurately as those larger than 10 mm. Supporting evidence for different investigation strategies for these smaller nodules is being validated through lung cancer screening programmes. The likelihood of identifying a malignant SPN needs to be balanced against the risk to the patient from the cumulative radiation dose from screening [38], and from the morbidity of unnecessary investigation of benign disease. Recent screening work involving the investigation of non-calcied nodules less than 5 mm, followed 205 such patients, with repeat CT scanning at between 4 months and 8 months and then 12 months. 18 patients refused follow-up [25], but otherwise no nodule demonstrated any evidence of growth. As a result, the advice for the frequency of interval scanning in the screening programme for such small nodules has changed (Table 8). Of note, within the same screening programme, when a patient had a non-calcied nodule 59 mm in diameter, the frequency of malignancy was 13 of 238.
decisions for some cases will require diagnostic histology, either by biopsy or surgical excision [39]. The most common modality used to biopsy an SPN is CT, bronchoscopic and video-assisted thoracoscopic biopsy will not be considered here. There is a morbidity (predominantly pneumothorax, which may require a chest drain, or haemoptysis), and a low mortality rate associated with the procedure [15]. Size has a signicant impact on diagnostic accuracy, with smaller nodules having reduced accuracy. Results reported range from an accuracy of 5270% for nodules under 10 mm, to 1115 mm, and 1620 mm nodule biopsy having an accuracy of 74% and 91%, respectively [40, 41]. A specic cell type can be characterized in 60% to 99% of malignant lesions and in 44% to 91% of benign lesions when evaluated histologically. A specic benign diagnosis is achieved in a greater proportion of cases with use of a core biopsy (1820 gauge cutting needle), rather than a ne needle aspiration for cytology alone, as it enables examination of cellular architecture as well as cytology [4248]. The rate of biopsy related complications using either a ne needle for cytology or a cutting needle for histology is similar [15]. A co-axial biopsy technique may be used to reduce the number of pleural punctures, and to enable more than one sample to be obtained without further discomfort to the patient. The presence of a cytopathologist is helpful if ne needle aspiration is being performed, to conrm that an adequate sample has been obtained. A denitive result from a biopsy would produce histology with a specic benign or malignant diagnosis. Some samples will consist of necrotic material, and so be categorised as non-diagnostic, others may contain inammation or cellular atypia, both of which can be found surrounding malignancy or infection and this is known as a non-specic benign report. A study looking at these categories of report has shown that 29% of non-diagnostic specimens and 13% of benign non-specic specimens were malignant at excision biopsy or radiological follow-up. This signicant level of malignancy in non-specic samples therefore warrants either repeat biopsy, or surgical excision. The clinicians and patient will need to discuss the next appropriate management decision [44].
Role of nuclear medicine in the SPN

Nuclear medicine techniques have the unique advantage of adding functionality to anatomical imaging making it possible to characterize a SPN as benign or malignant [49, 50]. The two main nuclear medicine methods currently available for SPN characterization are PET and somatostatin receptor imaging (SSR). However, both remain under utilized in the evaluation of SPNs, due mainly to availability and cost restraints [50, 51]. Other radiopharmaceuticals such as thallium-201, 99Tcm sestamibi and 99 Tcm tetrofosomin, which have traditionally been used for myocardial perfusion imaging, offer the potential of characterizing SPNs and mediastinal lymph nodes but these need further validation studies [5257]. This section will briey outline the use of PET and SSR imaging in the assessment of SPNs and highlight their main advantages and limitations.
31
CT guided biopsy
Once the risk for malignancy within a nodule has been stratied, by CT and perhaps PET imaging, management
Positron emission tomography

PET is a technology that uses short lived radionuclides attached to ligands to assess metabolic processes. The four most commonly used positron emitting radionuclides are uorine-18 (F-18), nitrogen-13 (N-13), carbon-11 (C-11) and oxygen 15 (O-15). F-18 has the advantage of having the longest half-life (110 min), making it the most readily available. It is easily attached to deoxyglucose to produce FDG, a molecule which can be used to assess glucose metabolism at a cellular level. A unique characteristic of tumour cells is that they show higher than normal levels of glucose metabolism. It is the neoplastic generation of tumour cells which causes the loss of efcient ATP production by the Krebs cycle which leads to an increased glucose demand by tumour cells [58]. This increase in glycolytic demand is achieved by several mechanisms. First, there is an increase in the glucose transport proteins in tumour cell membranes. Second, the cellular expression of hexokinase, which phosphorylates glucose, is increased. Third, once the glucose (or its analogue) is internalized, it is trapped within the cell because tumour cells do not contain sufcient glucose-6phosphase to cause dephosphorylation [59]. F-18 uorodeoxyglucose (FDG) is a positron emitting glucose analogue which can be used to monitor cellular glucose metabolism. F-18 is produced in a cyclotron from the bombardment of a H2O-18 target by neutrons and protons. The F-18 isotope decays by emitting a positron (a positive electron) which undergoes annihilations with a nearby electron, producing two opposed 511 KeV gamma rays [60]. The amount of FDG trapped within tumour cells can therefore be identied by imaging the F-18 decay using a PET capable camera. Dedicated PET camera systems use a full ring of thousands of bismuth germinate (BGO) or lutetium oxysilicate (LSO) crystals that give a system spatial resolution of 46 mm [61]. The image is corrected for depth attenuation to give a more representative account of relative activity from deeper tissue [62]. Like many other nuclear medicine techniques, PET scanning allows whole body imaging. This enables not only the characterization of an apparent SPN but also enables nodal and distant staging. The mean sensitivity and specicity of dedicated FDG PET in characterizing a pulmonary nodule is 93.9% and 85.8%, respectively [49]. This is better than the accuracy of CT (sensitivity 90% and specicity 6385%) for characterizing SPNs [61, 62]. The low specicity of PET is attributable to the increased FDG avidity of benign conditions such as granulomatous processes and other inammatory conditions. Certain malignant SPNs such as bronchoalveolar carcinoma and carcinoid tumours do not show high FDG avidity resulting in a small false negative rate (Table 9). Because the sensitivity of PET is not 100%, a negative PET study must be followed by re-evaluation with CT within 3 months to detect changes in size and morphology [62]. The characterization of an SPN on a PET scan into benign or malignant can be done visually or semiquantitatively. In experienced hands, visual assessment is adequate. The most commonly used semiquantitative method is the standardized uptake value (SUV). This is a ratio of tracer uptake to administered dose corrected for body weight and serum glucose. Any lesion with an SUV
32
Table 9. Causes of false positive and false negative results in the characterization of solitary pulmonary nodules using F-18 FDG
False positive Active granulamatous disease: Tuberculous Sarcoidosis Histocystosis X Inammatory anthrosilicosis Active fungal disease Asperigillosis Histoplasmosis Nocardiosis Other inammatory nodules Inammatory haematoma Lung abscess False negative, i.e. low grade malignant disease Bronchial carcinoid
Bronchoalveolar cell carcinoma
Well differentiated adenocarcinoma
greater than 2.5 is generally regarded as malignant. SUVs can also be used to determine prognosis. Generally the higher the SUV value the worse the prognosis [63]. Although PET is able to detect lesions as small as 4.0 5.0 mm, it is generally accepted that the accuracy of PET declines with reduction in lesion size. However, a recent retrospective study by a Netherlands group looking only at subcentimetre SPNs has shown sensitivity and specicity of PET of 93% and 77%, respectively, in this group [64]. Although, this is comparable with gures quoted for the characterization of larger lesions, further corroborative work is required.
Gamma camera PET

PET can be performed using a modied gamma camera with a thick sodium iodine crystal and coincidence timing windows. This system only detects 10% of the photons of a dedicated PET camera and therefore lesions less than 1.5 cm in diameter cannot be assessed accurately [64]. An example of a gamma camera FDG PET/CT study is given in Figure 7. Although gamma camera PET is potentially cheaper than a dedicated system, its inferior spatial resolution and smaller eld of view is likely to limit its clinical utility [61, 65].
Recent developments PET CT The recent introduction of PET/CT technology means that both a PET and a CT scan can be acquired simultaneously, allowing accurate co-registration of the two modalities [65]. A large proportion of the PET systems sold currently are dedicated PET/CT scanners. Their main limitation is the additional cost of the combined system. Although they are likely to be superior to PET only systems, further validation studies are required of this new technology, particularly in the evaluation of SPNs. An example of a dedicated PET/CT scan performed for lung cancer staging is given in Figure 8. New radiotracers New PET radiotracers are being developed not only to assess glucose metabolism more accurately, but also to assess other biological processes such as protein synthesis.
Figure 7. A 55-year-old women with a 2.8 cm solitary pulmonary nodule (SPN) in the apical segment of the left lower lobe. A
gamma camera coincidence PET/CT study was performed 1 h following the administration of 375 MBqs of F18-FDG. This demonstrated avid increased uptake within the SPN consistent with a malignant lesion. Histology from bronchoscopic washings proved this to represent an adenocarcinoma.
The proliferation marker 3-deoxy-3-[F-18]-uorothymidine (FLT), a thymidine analogue has shown promise in the assessment of non-small cell lung cancer [66]. In addition, the development of F-18 somatostatin receptor analogues such as F-18 octreotide have shown a potential role in the characterization of pulmonary nodules and masses [67].
99
Tcm depreotide imaging

99
Tcm depreotide is a somatostatin receptor analogue with a high afnity for receptor types 2, 3 and 5 [55]. These receptors, in particular type 2, are expressed by cells of small cell lung cancer in vitro and have been demonstrated by octreoscan (an Indium 111-octreotide analogue) to be expressed in non-small cell tumours in vivo
[6871]. 99Tcm depreotide is manufactured within the nuclear medicine unit by the addition of pertechnetate to a vial containing the depreotide ligand. 99Tcm emits a single photon of 140 KeV at the site of uptake and has a half-life of 6 h. Imaging of SPNs using 99Tcm depreotide has several major advantages over PET. It is not cyclotron produced and can be readily imaged on currently available single and dual headed gamma cameras using general purpose or low energy high-resolution collimators [55]. Depreotide comes in a kit preparation to which 600 MBq of pertechnetate is added. The cost of a cold depreotide vial however is about 450 which is more expensive than a single patient dose of FDG. Imaging is performed from 1530 min post-injection with acquisition of planar images and SPECT images of the chest and upper abdomen. A
33
(a)
(b)
Figure 8. PET/CT of a 58-year-old man with a spiculated 1.8 cm solitary pulmonary nodule (SPN) in left upper lobe, which was
indeterminate on needle biopsy. The PET/CT conrmed localized disease to the left upper lobe with no nodal disease, chest wall involvement or distant metastases. Chest wall involvement would have been difcult to exclude on the basis of PET scan alone. (Images courtesy of Drs S Barrington and M J ODoherty, The Clinical PET centre, Guys and St Thomas Hospital, London).
single bed position SPECT acquisition for a depreotide study covers the chest and upper abdomen whereas multiple bed positions are required on a PET scan to cover the same range. However, whole body imaging is not performed for a depreotide study because the product is not approved for nodal or distant staging. Unlike PET, 99Tcm depreotide has not yet been fully validated in the assessment of mediastinal disease [72]. The spatial resolution of SPECT is between 7 mm and 10 mm, hence subcentimetre lesions are difcult to characterize [55, 73]. An example of 99Tcm depreotide study in the assessment of an SPN is given in Figure 9. Low-grade depreotide uptake occurs in normal bone marrow which may obscure bone metastases [55, 72, 73]. Depreotide has recently been shown to classify patients with lung cancer masses into surgical or non-surgical
groups with a similar accuracy to dedicated PET. However, the same studies have shown PET/CT to be superior to both depreotide or PET alone [66, 73]. 99 Tcm depreotide has a similar sensitivity (96.1%) and specicity (73%) to PET performed on a dedicated camera in the characterization of the SPN. The overall accuracy is 91% in the published series [55, 73]. However, most studies using depreotide have only evaluated the larger SPNs so their value in characterizing subcentimetre lesions remains uncertain.
Conclusion
Both F-18 FDG and 99Tcm depreotide offer the potential of characterizing the SPN without using invasive techniques. Identifying the right management pathway for
(a)
99
(b)
Tcm depreotide revealed avid increased uptake within the nodule consistent with a broncho-
Figure 9. A 57-year-old man was found to have a 1 cm spiculated nodule in the apex of the right lung on CT (a). Axial SPECT
images following the administration of genic carcinoma (b).
34
each patient with an SPN is an immense challenge. The most recent advances in CT and PET technology need to be made use of in this group. Fastidious attention to detail is needed within CT, and cohesive working patterns between the physicians, surgeons and radiologists. The potential for non-invasive characterization offered by nuclear studies is expanding, especially in the challenging area of the subcentimetre nodule. With further developments in PET technology and the optimization of PET/CT scanners the accurate characterization of subcentimetre lesions is becoming a real possibility.
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36
Imaging in lung cancer

L N GOMERSALL, MBChB, FRCR and S OLSON, MBChB, FRCR
Department of Clinical Radiology, Aberdeen Royal Inrmary Trust, Foresterhill, Aberdeen AB25 2ZN, UK
The aim of this article is to provide an overview of the role of imaging in lung cancer its detection and staging together with relevant clinical background information. Lung cancer is a condition which almost all radiologists consider daily: we report chest radiographs performed for a variety of indications and we constantly weigh up the hila, double check our review areas, analyse areas of opacication, and recommend follow-up lms to ensure we do not miss a mass lesion. Yet it is known that at least 19% of lung cancers were missed on previous lms [1].
Summary
N Lung cancer is a common cancer with poor overall survival. N The staging of non-small cell lung cancer and small
cell lung cancer differ and a tissue diagnosis should be obtained where feasible.
N The minority of patients who are operable are

Epidemiology
Lung cancer is the second most common cancer in the UK: 14% of the total cancer incidence, in 1999. A male predominance is present with 7:4, male:female ratio. The incidence in men has been steadily decreasing, reecting smoking rates. Similarly, mirroring rates of cigarette consumption among women, female lung cancer rates increased through the 1970s and 1980s until the early 1990s, since when they have essentially reached a plateau. Breast cancer has a higher incidence, but there are more deaths from lung cancer [2]. Survival rates for lung cancer are very poor, with a median survival of 4 months from diagnosis. Mortality has changed little over the past decades, 5 year survival rates in men have dropped from 6% in the early 1970s to 5% amongst those diagnosed between 1991 and 1993 [2]. Lung cancer is unique amongst the big cancers to have a denite specic aetiological agent. Although much is yet to be learnt about an individuals susceptibility to the disease, 85% of pulmonary carcinoma is due to smoking [3] (Figure 1). Other risk factors include occupational exposures such as asbestos, pulmonary brosis and radiotherapy.
important to identify in the staging process to optimize their curative treatment. of available N A multitude CTtests are no longer for staging but reliance on alone is appropriate. emission tomography N Mediastinoscopy or positron is recommended. imaging of the mediastinum N The discussion for each individual patient within a multidisciplinary team optimizes the individuals care.
percentage of lung cancers, but has a distinctive pattern of growth with tumour cells growing on the alveolar surface with little invasion of the interstitium and preservation of the lung parenchyma to a greater extent than other tumour types. This may result in a vague area of consolidation rather than a mass lesion.
Pathology
Lung cancer refers to neoplasms that arise from the epithelium of the airways and alveoli. There are four main histological types.
Adenocarcinoma
Approximately 50% of adenocarcinomas present as a nodule or mass in the periphery of the lung, 15% as a hilar mass, and 35% as a combination of mass and hilar/ mediastinal lymphadenopathy [4]. Adenocarcinoma has overtaken squamous cell carcinoma as the most common histology. There are several subtypes of this tumour, but from a radiological perspective the most relevant distinction is the bronchoalveolar cell carcinoma. This accounts for only a small
Figure 1. Cause and effect: the cigarettes in the pocket point

to the diagnosis of lung cancer in the left lower lobe, with a bony metastasis to a right side rib.
L N Gomersall and S Olson
Squamous cell carcinoma

Squamous cell carcinoma most commonly arises in a lobar or segmental bronchus, occluding the lumen and causing distal collapse or consolidation. When it arises peripherally it may grow large before presentation.
are said to occur in up to 10% of patients, and in a few patients will be the presenting feature [6]. These include hypertrophic osteoarthropathy, cerebellar degeneration, inappropriate section of antidiuretic hormone, ectopic adrenocorticotrophic hormone production and Lambert Eaton syndrome. Making the diagnosis of lung cancer involves two processes. The rst is the initial identication of a suspicious lesion on imaging, usually the chest radiograph. Sometimes the initial pickup is on CT, performed for other reasons, or following a normal chest radiograph with high clinical suspicion of lung cancer. The second part of the process is to positively identify that this is a malignant lesion; cytology or histology is required in the vast majority of cases.
Large cell carcinoma

Histologically, the cells in large cell carcinoma neoplasms show no differentiation into glandular or squamous cells. Most typically they are large peripheral masses.
Small-cell carcinoma
Small-cell carcinomas most commonly arise from the main airways, but rapidly invade the submucosal tissues, with early vascular and lymphatic spread, resulting in high rates of metastatic lymph node involvement. Small-cell carcinoma is believed to have a neuroendocrine origin. Other rare subtypes and tumours with mixed histology exist. However, because of the different therapeutic approaches, the main distinction which is required of the pathologist is into small-cell (SCLC) or non-small cell lung cancer (NSCLC).
The chest radiograph

The complex process that is interpretation of the chest radiograph is beyond the scope of this article, sufce to say that a minority of lung cancers rst present as an obvious spiculated, irregular solitary lung mass and the following are some potential pitfalls to recognise: 85% of missed lung cancers are peripheral nodules less than 2 cm, often low contrast lesions, in areas (particularly the upper zones) where there is overlap with anatomical structures such as ribs and clavicle [7]. It is unusual for a lung cancer of less than 1 cm diameter to be detected. In an early lung cancer screening study, of high risk patients, with expert chest radiograph interpretation, double read, results showed that 90% of peripheral lung cancers and 75% of hilar cancers were visible in retrospect [8]. Thus despite best efforts, there is no certain way of diagnosing small lung cancers on chest radiography. Optimal viewing conditions and systematic review of the lm with particular attention to traditional review areas (apices, retrocardiac and hilar areas) are essential (Figure 3). Many radiologists strive to keep their false positive rate for reporting chest radiographs to an absolute minimum, and may subconsciously under-report abnormalities. We should be aware of this and consider obtaining alternative views or repeat radiographs to clarify. The presence of calcication is not always reassuring. Calcication within an opacity, particulary if larger than 3 cm, does not indicate that this is denitely benign, as eccentric calcication can occur due to a pre-existing calcied granuloma being engulfed by tumour [9]. Similarly occasional lung cancers show thin walled cavitation with cystic change, or an air crescent sign, and a high index of suspicion should be maintained, with a careful search of focal wall thickening and subsequently for growth of the lesion. Adenocarcinoma, particulary the bronchioloalveolar form may present as one or more areas of pulmonary consolidation, and should be considered when any such opacity is chronic, and not apparently infective in origin.
Diagnosis
Presenting clinical features
Approximately 10% of patients are asymptomatic at initial presentation [5], the diagnosis being suspected from an abnormal chest radiograph. The remaining patients present in three broad symptom groups:
N N N
Symptoms resulting from local chest disease: cough, haemoptysis, chest wall or mediastinal invasion (e.g. chest wall pain, superior vena cava (SVC) obstruction). Symptoms related to the presence of distant metastases (Figure 2). Non-specic constitutional symptoms such as malaise, weight loss and weakness. Paraneoplastic syndromes
Computed tomography
Having identied a solitary pulmonary nodule, the decision as to likelihood of malignancy is often aided by CT features. Size is an important criterion: a solitary solid abnormality of more than 3 cm is usually malignant.
Figure 2. Sites of distant metastases. 2
(a)
(b)
(c)
(d)
Figure 3. Careful inspection of the review areas is necessary to avoid misses: (a) behind the heart; (b) left hilum; (c) right lung apex;
(d) left lung apex (pancoast tumour with 1st rib destruction).
Other features such as the presence of lobulation, spiculation and pleural retraction suggest malignancy. When a decision has been taken to follow a lesion up, accurate measurement to assess growth is essential. Doubling times refer to volume not diameter, for example a nodule which has only increased in diameter from 1 cm to 1.26 cm has doubled in volume. Generally accepted doubling times in lung cancer are between 30 days and 490 days, but absolute reliance on this is not advised as dramatic changes in size of a tumour can occur due to surrounding haemorrhage, and cancers can remain static for a considerable time, then rapidly grow and disseminate. Follow-up for a minimum of 2 years is required [10].
Ideally CT scanning should occur early in the investigative process, as imaging can predict the likelihood of obtaining a positive tissue diagnosis at breoptic bronchoscopy: lesions with ill-dened margins, ,4 cm from the origin of the nearest lobar bronchus, with an endobronchial component, or a segmental or larger airway leading directly to the mass (lead bronchus sign), and particulary with more than one of these features, are more likely to yield positive diagnostic tissue at bronchoscopy [11]. Accurate CT reporting can guide the bronchoscopist to abnormal areas increasing diagnostic yield. It can also suggest alternative sites from which to obtain tissue, for example liver biopsy.
3
Tissue diagnosis
In the majority of cases, when feasible, a tissue diagnosis is required to guide further treatment. Locally, histology/ cytology is obtained on 70% of patients [12]. This should be obtained by the simplest and safest means possible. Sputum cytology is often performed, but has a low sensitivity only 1.9% of patients had their diagnosis made with sputum cytology in our region [12]. Patients with pleural effusions should have thoracentesis at an early stage. Patients with a solitary extrathoracic site, suspicious of metastasis should have needle aspiration or biopsy of this lesion, if accessible, in order to both make the diagnosis of lung cancer and stage disease. Where there are multiple metastases, tissue should be obtained from wherever is safest and easiest. In patients with suspected operable lung cancer including possible mediastinal nodes, these nodes should be examined by whatever means is used locally, e.g. mediastinoscopy. Denitive diagnosis of a solitary pulmonary nodule, including the role of image guided biopsy is dealt with in another article in this issue.
(Table 1). From the extent of disease in the T, N and M areas, patients are then further classied into pathological stages, and these stages are directly reected in survival gures (Table 2). Stages I to IIIA are generally considered operable.
The primary tumour

The chest radiograph may have already established the site and size of the primary tumour, for peripheral lesions. However, in the absence of radiographic signs of advanced disease, for example denite rib destruction, or clinical signs such as palpable chest wall mass or laryngeal nerve palsy, the primary tumour requires further evaluation with CT. 94% of lung cancer patients in Grampian have CT [12]. In a central lesion, bronchoscopy will dene the proximal endobronchial extent of the tumour, combined with assessment on CT. Where a lesion is causing distal collapse and consolidation it can be surprisingly difcult to distinguish the tumour margins, leading to incorrect estimation of size. Generally distal collapsed lung enhances more than the central tumour, and with careful windowing, the tumour margins may be identied. The critical question that CT is required to address is the distinction between T3 and T4 tumours between thoracotomy and non-surgical treatment. Extensive mediastinal involvement, when the vessels or airways are surrounded by tissue is reliably identied on CT. Similarly there are well established features of resectability: less than
Table 2. Stage grouping and corresponding survival rates
Stage IA IB IIA IIB IIIA IIIB IV TNM T1 N0 M0 T2 N0 M0 T1 N1 M0 T2 N1 M0/T3 N0 M0 T3 N1 M0/T3 N2 M0 T4 N02 M0/T14 N3 M0 Any T Any N M1 % 5 year survival 67 57 55 39 23 5 1
Staging
Having established an imaging diagnosis of likely lung cancer, conrmed by a tissue diagnosis of NSCLC or SCLC, accurate staging is the next step. Staging provides useful prognostic information, and determines the optimum management, whether potentially curative or palliative. The most crucial issue is whether the patient is a candidate for surgical resection. As well as information from imaging, other factors impact on suitability for resection, including pulmonary function and performance status. NSCLC and SCLC are staged using different systems, and will be dealt with separately.
Staging of NSCLC
The most widely used staging scheme is the TNM International system, most recently revised in 1997 [13]
Table 1. TNM classication of lung cancer
Primary tumour TX Primary tumour cannot be assessed, e.g. positive sputum cytology, normal bronchoscopy and CT T0 No evidence of primary tumour Tis Carcinoma in situ T1 Tumour 3 cm, surrounded by lung or pleura and no more proximal than lobar bronchus T2 Tumour .3 cm, can involve main bronchus but still 2 cm from carina, can invade visceral pleura. Atelectasis/obstructive pneumonitis but not entire lung T3 Tumour can directly invade chest wall, diaphragm, pleura, parietal pericardium, or tumour within 2 cm of carina, or atelectasis/pneumonitis entire lung T4 Tumour invading mediastinum, heart, great vessels, trachea, oesophagus, vertebral body, carina. Malignant pleural or pericardial effusion. Satellite nodules within the same lobe as the primary tumour Regional lymph nodes N0 No regional lymph node metastasis N1 Metastasis to ipsilateral peribronchial or hilar lymph nodes and direct involvement of intrapulmonary nodes by primary tumour N2 Metastasis to ipsilateral mediastinal and/or subcarinal nodes N3 Metastasis to contralateral mediastinal, contralateral hilar nodes or scalene or supraclavicular nodes on either side Distant metastasis M0 No distant metastasis M1 Distant metastasis present
3 cm of contact with the mediastinum, less than 90 contact with the aorta, and an intact fat plane [14]. However in between these categories no hard and fast criteria have been identied to indicate irresectability (Figure 4). MRI may be helpful in a small number of patients in specic areas, such as around the aortopulmonary window and aortic arch, but in general is no more accurate. MRI is only proven to be superior in apical tumours, where coronal imaging and inherent contrast between tissue types shows involvement of vessels and nerves at the root of the neck [15] (Figure 5). Limited chest wall involvement is not a contraindication to surgery, but requires modied surgical technique, and preferably pre-operative planning. CT diagnosis of chest wall invasion is similarly fraught with difculties. Again resectability is reliably predicted with less than 3 cm contact and preservation of the extrapleural fat plane. Cortical bone destruction or tumour tissue seen to extend through the intercostal muscles or beyond the line of the ribs are denite signs of invasion. In between, there is again a grey area, with invasion being suggested, when there is an obtuse angle between tumour and chest wall, with obliteration of the fat plane, or soft tissue outwith the line of the pleura. Local chest wall pain remains more specic (94%) than any imaging test [16].
Figure 5. MRI is useful in superior sulcus tumours, in this

case showing that the tumour was not involving the brachial plexus.
Nodal stage Tumour usually spreads to ipsilateral hilar nodes, then into the ipsilateral mediastinum (which includes the subcarinal region), then into the contralateral side of the mediastinum and supraclavicular nodes, although skip metastases can occur. N3 disease is a contraindication to surgery, but radical radiotherapy may be possible. Management of patients with N2 disease is variable across
the UK, with minimal N2 disease usually being considered for surgery. Until recently the non-invasive assessment of nodal stage has been the domain of CT scanning. There are widely accepted criteria for identication and description of lymph nodes. Enlarged nodes are dened by short axis diameter of over 10 mm. They are classied according to internationally recognised lymph node groups [17]. Intravenous contrast is desirable, particularly for the
(a)
(b)
Figure 4. (a) Clear evidence of inoperability, due to encasement of mediastinal structures by tumour. (b) In more equivocal cases
such as this the patient must be given the benet of the doubt. This patient had a T3 tumour completely resected, but pericardial resection was required.
hilar regions, and in patients with little mediastinal fat, and has become standard practice in the UK. However, CT is not sensitive and specic enough for pre-operative nodal staging. It is sensitive and specic for lymphadenopathy, that is enlarged nodes, but their enlargement does not prove their involvement with tumour, so the whole process is fundamentally awed. Normal sized nodes may be involved with tumour, particularly in adenocarcinoma, in up to 25% [18]. Enlarged nodes, even in the 24 cm range proved to be benign in 37% of cases in one series, particularly where post obstructive pneumonitis or atelectasis is present [19]. For staging the mediastinum with CT, sensitivity is between 57% and 64% and specicity between 62% and 82% [19, 20]. As a rule a patient with an otherwise operable tumour and lymphadenopathy should proceed to lymph node sampling by mediastinoscopy or needle aspiration. A patient with no lymph node enlargement on CT scan will often proceed to surgery without any conrmation, but the evidence also supports routine pre-operative mediastinoscopy. Positron emission tomography (PET) with 18Fuorodeoxyglucose (referred to in this article simply as PET) has been added to the armamentarium for the non invasive staging of lung cancer in recent years. It has been in clinical use for lung cancer for a decade, and is widely used in the USA. It currently remains limited to a few centres in the UK, but is becoming more widespread. PET provides no additional information for staging the primary tumour, but it does add signicantly to the information available regarding the mediastinum. In a recent meta-analysis the median sensitivity and specicity of PET for nodal disease were 85% and 90%, mirroring previous ndings that PET is more accurate at staging the mediastinum than CT [21]. An interesting nding was that PET is more accurate in the population that were node negative on CT than node positive, reecting some of the causes for false positive PET scans (Table 3). The implication of the specicity of 90% is that in the node positive patient, as with CT, this still needs to be histologically conrmed, so as to not deny any patient potentially curative surgery. Its high negative predictive value (92%, see Table 4) implies that if the study is negative the patient can safely proceed to surgery. There has only been one randomized controlled trial comparing conventional workup with conventional workup and PET in 188 patients. Primary outcome measure was the number of futile thoracotomies, dened as benign
Table 3. Nodal staging with positron emission tomography; causes of false positive and negatives
False positive Hyperplastic lymph nodes Tuberculosis Bronchiectasis Abscess Rheumatoid disease Wegeners Sarcoid Pneumoconiosis False negative Low metabolic activity (including well-dened adeno or bronchoalveolar cell carcinoma) Microscopic nodal metastases Nodes adjacent to primary tumour Nodes adjacent to each other Misclassication of nodal stations
Table 4. Comparison of modalities in mediastinal staging

CT [22] Sensitivity Specicity PPV NPV 65 79 58 81 PET [22] 83 92 77 92 TBNA [23] .53 99 99 80 Mediastinoscopy [24] 89 100 100 96
PET, positron emission tomography; TBNA, transbronchial needle aspiration; PPV, positive predictive value; NPV, negative predictive value.
disease, stage IIIA-N2 disease (unless minimal), stage IIIB disease or recurrent disease or death within 1 year. More patients in the conventional workup group underwent thoracotomy, 42% of which were futile, compared with 21% in the PET group: a relative reduction of 51%. Most of the avoided thoracotomies in the upstaged PET group were related to N2/N3 disease [25]. The poor anatomical localization of stand alone PET is largely addressed with combined PET-CT [26]. The cost effectiveness of PET is still a subject of debate, and this is a particularly difcult area because previous studies have been heterogeneous in the selection of patients undergoing PET, and at what point in the investigative algorithm. Nevertheless the authors have found PET useful on a problem solving basis (Figure 6) and it is likely to become a routine part of workup in potential surgical candidates.
Invasive staging of nodal disease Methods for obtaining cytological or histological conrmation of involvement of a suspicious node are as follows:
N N
Transbronchial needle aspiration (TBNA) this is limited to a few regional nodal stations and is hampered by being a blind technique. Transthoracic needle aspiration (TTNA) percutaneous guidance of a ne needle or core biopsy needle, by radiological methods, usually CT. Like TBNA this can be complicated by bleeding, and also by pneumothorax, and is limited in which areas can be safely reached. Endoscopic ultrasound needle aspiration (EUS-NA) is performed at oesophagoscopy or bronchoscopy. The assessment of nodes by ultrasound is useful in guiding which particular node to needle, by looking for positive features of involvement and avoiding features such as necrosis. It too is only able to sample certain groups. Mediastinoscopy this is performed surgically under general anaesthetic, through a small incision above the suprasternal notch, followed by dissection of the tissue planes and sampling under direct vision via the mediastinoscope. Standard cervical mediastinoscopy can sample the right and left paratracheal groups and the subcarinal nodes. Extended cervical mediastinoscopy requires passage of the scope between brachiocephalic and left common carotid artery to reach the aortopulmonary window. Anterior mediastonotomy is performed through a separate parasternal incision, and allows assessment of aortopulmonary window and pre-aortic nodes. All have a risk of bleeding, with
(a)
(b)
(c)
(d)
Figure 6. (a) 70-year-old smoker with left lower lobe mass.

(b) At CT a small nodule was seen in the right lower lobe, as well as an apparently operable tumour in the left lower lobe. No mediastinal lymphadenopathy. (c) Sagittal positron emission tomography (PET) showed high activity in mediastinal nodes. (d) Coronal PET showed high activity in the primary tumour and the right lower lobe nodule. (e) Chest radiograph performed 3 months later, showing growth in the contralateral nodule.
(e)
the extended procedure having an additional risk of embolic stroke from the great vessels, and an anterior approach risks pneumothorax and internal mammary artery damage, and hence these extended techniques are now rarely performed. Video-assisted thoracoscopic surgery (VATS) involves general anaesthesia and single lung ventilation. Ipsilateral mediastinal nodes can be sampled, and indeed the entire hemithorax and lung surface can be examined and pulmonary and pleural lesions can also be biopsied, all through a small incision, with minimal pain and morbidity.
resected without a pre-operative tissue diagnosis should be referred for adjuvant chemotherapy and radiotherapy. SCLC is usually regarded as a systemic disease, but despite this, the extent to which asymptomatic metastases are sought varies between centres, with routine cranial CT and bone scan in some, but no investigation unless suggestive symptoms in others. Use of PET in SCLC is less well investigated. A small series of use of PET in patients with apparent limited disease upstaged 7 out of 24 patients to extensive disease [29].
Accuracy values for some of these invasive techniques are shown in Table 4, alongside those for PET and CT. Having established the requirement for lymph node biopsy which procedure is carried out will be chosen by the location of suspicious nodes and local availability.
Management of lung cancer

Assessment and management of lung cancer involves a number of disciplines, and multidisciplinary team working is now regarded as a key standard of cancer care. The radiologist is an important player, particularly at rst diagnosis and treatment planning, but also with advice on follow-up and sometimes palliation. As indicated above, surgical removal of NSCLC offers the best possibility of cure, and each patient should be considered for this option. The UK lags behind the rest of Europe in thoracotomy rates, even allowing for epidemiological factors. If stage or co-morbid disease precludes surgery alternative treatments are considered. Radical radiotherapy, i.e. with curative intent, is indicated in patients with stage I and II disease, who are unt for surgery, or who have good performance status and stage III disease, which can be encompassed within a radical volume. Palliative radiotherapy for advanced disease is effective for symptoms including haemoptysis, chest pain, dyspnoea and cough. Cisplatin based chemotherapy regimens have been shown to improve survival and also control symptoms in advanced disease, compared with best supportive care. Use of chemotherapy in adjuvant and neoadjuvant settings is evolving. Small-cell cancer is treated with primary chemotherapy because of its chemoresponsiveness and frequent occult metastases at the time of diagnosis. It is also the most radiosensitive lung cancer and in limited disease consolidative thoracic radiotherapy and prophylactic cranial irradiation prolong survival compared with chemotherapy alone. Optimal timing is not established.
Metastatic disease It is routine practice to continue the contrast enhanced thoracic CT down to cover the liver and adrenals. Unfortunately in doing so, a number of indeterminate lesions, mainly small benign liver lesions or adrenal adenomas, will be identied. Asymptomatic adrenal metastases are relatively common in lung cancer, and would preclude curative thoracotomy or radiotherapy, but non-functioning adenomas occur in around 3% of the normal population [27]. Inevitably these adrenal or liver lesions require further investigation, with unenhanced CT, MRI or dedicated ultrasound examination, and in some cases the exact nature of the radiological abnormality will be impossible to establish non-invasively and percutaneous needle biopsy will be required. Bone scintigraphy and cranial CT are used where symptoms are suggestive of involvement of these organs, but investigation for asymptomatic metastases is not indicated. The additional benet of PET, is identication of unsuspected distant metastases in approximately 9% more patients than conventional modalities, with 10% also being correctly shown to have no distant metastases, where conventional imaging was suspicious. However, the false positive rate is again unacceptably high, around 10%, and a positive scan should be followed by biopsy before the patient is deemed inoperable [28]. Overall, studies have reported a change in management as a result of the PET scan of between 24% and 40% [22]. Staging of SCLC
This is a simpler process with two groups, as dened below:
Screening for lung cancer

The failure of primary prevention programmes and disappointing lack of improvement in treatments for lung cancer has led to widespread interest in screening for lung cancer. Chest radiograph screening is not sufciently sensitive, but low dose CT scanning has been evaluated in pilot trials with promising results. 1000 high risk patients (smokers, aged .60 years) in the New York trial had CT, of whom 233 had non-calcied nodules requiring further evaluation. Nodules over 10 mm were biopsied, while smaller nodules were followed up to detect growth, which was then regarded as suspicious. 28 patients were recommended biopsy, 27 of these were malignant: thus only 1 patient had a biopsy for benign disease, and no thoracotomies were carried out for benign disease [30]. Results of the rst annual screen are also available, and
Limited disease tumour conned to one hemithorax, including ipsilateral or contralateral mediastinal and supraclavicular nodes. The main issue is that disease may be encompassed within tolerable radiotherapy elds. Extensive disease disease beyond these bounds.
These stages have direct inuence on patient management, with thoracic and prophylactic cranial irradiation, combined with chemotherapy for limited disease, and systemic chemotherapy at the outset for extensive disease. Very few patients are suitable for surgical treatment, and patients
8
positive ndings are much less frequent than in the baseline screen, and can be managed according to their protocol, in most cases without resort to biopsy [31]. A valid screening programme, above all, must do more good than harm. There remains concern on many issues. One is the idea of overdiagnosis, that is the identication of cancer that in fact is not going to shorten the patients life. This is especially important as thoracotomy has signicant morbidity and mortality. It will be some time before it will be possible to ascertain the effect of screening on mortality, and early survival is a poor surrogate marker for mortality, but particularly in the USA, screening programmes are likely to become widespread before the evidence base is adequately established. Other questions have yet to be answered, including exact denitions of risk groups, the safest algorithm for workup of positive screens and interval for follow-up of people with negative scans. On the clinical side optimum management of small peripheral cancers, which outwith screening programmes are in the signicant minority, will also require renement. The immense cost of running such a screening programme will obviously have huge resource implications.
Conclusion
The early diagnosis and non-invasive staging of lung cancer remains an immense challenge for radiology. PET or combined PET-CT is likely to become more widely available in the UK, and establishing its exact role in the investigative algorithm is an important future development. Other potential roles for PET are in follow-up of lung cancer and assessment of treatment response. The radiologist will continue to play a key role in the multidisciplinary management of lung cancer patients.
References
1. Quekel LG, Kessels AG, Goel R, van Engelshoven JM. Miss rate of lung cancer on the chest radiograph in clinical practice. Chest 1999;115:7204. 2. Lung cancer fact sheet, January 2003. Cancer Research UK. 3. Bartecchi CE, MacKenzie TD, Schrier RW. The human costs of tobacco use. New Engl J Med 1994;330:90712. 4. Quinn D, Gianlupi A, Broste S. The changing radiographic presentation of bronchogenic carcinoma with reference to cell types. Chest 1996;110:14749. 5. Pulmonary neoplasms. In: Muller NL, Fraser RS, Colman NC, Pare PD. Radiologic diagnosis of diseases of the chest. Philadelphia, PA: WB Saunders, 2001:213. 6. Patel AM, Davila DG, Peters SG. Paraneoplastic syndromes associated with lung cancer. Mayo Clin Proc 1993;68:27887. 7. Woodring JH. Pitfalls in the radiologic diagnosis of lung cancer. AJR Am J Roentgenol 1990;154:116575. 8. Muhm JR, Miller WE, Fontana RS, Sanderson DR, Uhlenhopp MA. Lung cancer detected during a screening program using four-month chest radiographs. Radiology 1983;148:60915. 9. Pulmonary neoplasms. In: Muller NL, Fraser RS, Colman NC, Pare PD. Radiologic diagnosis of diseases of the chest. Philadelphia, PA: WB Saunders, 2001:217. 10. Nathan MH, Collins VP, Adams RA. Differentiation of benign and malignant pulmonary nodules by growth rate. Radiology 1962;79:22132.
11. Bungay HK, Pal CR, Davies CWH, Davies RJO, Gleeson FV. An evaluation of computed tomography as an aid to diagnosis in patients undergoing bronchoscopy for suspected bronchial carcinoma. Clin Radiol 2000;55:55460. 12. Audit of Lung Cancer Patients 2002. Grampian University Hospitals Trust, Clinical Effectiveness Department. February 2004. 13. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:17107. 14. Glazer HS, Kaiser LR, Anderson DJ, Molina PL, Emami B, Roper CL, et al. Indeterminate mediastinal invasion in bronchogenic carcinoma: CT evaluation. Radiology 1989;173:3742. 15. Heelan RT, Demas BE, Caravelli JF, Martini N, Bains MS, McCormack, PM, et al. Superior sulcus tumours: CT and MR imaging. Radiology 1989;170:63741. 16. Glazer HS, Duncan-Meyer J, Aronberg DJ, Moran JF, Levitt RG, Sagel SS. Pleural and chest wall invasion in bronchogenic carcinoma: CT evaluation. Radiology 1985;157:1914. 17. Mountain CF, Dresler CM. Regional lymph node classication for lung cancer staging. Chest 1997;111:171823. 18. Kerr KM, Lamb D, Wathen CG, Walker WS, Douglas NJ. Pathological assessment of mediastinal lymph nodes in lung cancer: implications for non-invasive mediastinal staging. Thorax 1992;47:33741. 19. McLoud TC, Bourgouin PM, Greenberg RW, Kosiuk JP, Templeton PA, Shepard JA, et al. Bronchogenic carcinoma: analysis of staging in the mediastinum with CT by correlative lymph node mapping and sampling. Radiology 1992;182:31923. 20. Toloza EM, Harpole L, McCrory DC. Non-invasive staging of non-small cell lung cancer. Chest 2003;123:137S146S. 21. Gould MK, Kuschner WG, Rydzak CE, Maclean CC, Demas AN, Shigemitsu H, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer. Ann Intern Med 2003;139:87992. 22. Ho Shon I, ODoherty MJ, Maisey MN. Positron emission tomography in lung cancer. Semin Nucl Med 2002;32:24071. 23. Harrow EM, Abi-Saleh W, Blum J, Harkin T, Gasparini S, Addriozzo-Harris DJ, et al. The utility of transbronchial needle aspiration in the staging of bronchogenic carcinoma. Am J Respir Crit Care Med 2000;161:6017. 24. Gdeedo A, Van Schil P, Corthouts B, Van Mieghem F, van Meerbeeck J, Van Marck E. Prospective evaluation of computed tomography and mediastinoscopy in mediastinal lymph node staging. Eur Respir J 1997;10:154751. 25. Van Tinteren H, Hoekstra OS, Smit EF, Van den Bergh JHAM, Schreurs AJM, Stallaert RALM, et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 2002;359:138892. 26. Lardinois D, Weder W, Hany TF, Kamel EM, Korom S, Seifert B, et al. Staging of non-small cell lung cancer with integrated PET and CT. N Engl J Med 2003;348:25007. 27. Peppercorn D, Reznek R. Adrenal glands. In: Husband JES, Reznek RH, editors. Imaging in oncology. London: Isis Medical Media Ltd, 1998:834. 28. Marom EM, McAdams HP, Erasmus JJ, Goodman PC, Culhane DK, Coleman RE, et al. Staging non-small cell lung cancer with whole-body PET. Radiology 1999;212:8039. 29. Schumacher T, Brink I, Mix M, Reinhardt M, Herget G, Digel W, et al. FDG-PET imaging for the staging and followup of small cell lung cancer. Eur J Nucl Med 2001;28:4838. 30. Henschke CI, McCauley DI, Yankelevitz DF, Naidich, DP, McGuinness G, Miettinen OS, et al. Early Lung Cancer Action Project: overall design and ndings from baseline screening. Lancet 1999;354:99105. 31. Henschke CI, Naidich DP, Yankelevitz DF, McGuinness G, McCauley DI, Smith JP, et al. Early Lung Cancer Action Group: initial ndings on repeat screening. Cancer 2001; 92:1539.
Imaging of pleural disease

D R WARAKAULLE, MRCP, FRCR and Z C TRAILL, MRCP, FRCR
Department of Radiology, The Churchill Hospital, Oxford OX3 7LJ, UK
Introduction
The plain radiograph remains the imaging modality of choice for the initial investigation of pleural disease. However, ultrasound (US), CT and MRI may also be useful. Image guided biopsy and other interventional procedures (primarily the placement of intercostal drainage catheters) may be required for the management of pleural disease. The aims of this review are to present the imaging appearances of the most important pleural diseases and to discuss the role of image guided intervention in their management.
Summary
N Chest radiography is the imaging modality of choice in the initial investigation of pleural disease. N Ultrasound is useful in the detection of pleural uid
and in guiding interventional procedures such as thoracentesis, needle biopsy and placement of drainage catheters. It may have a role in the rapid detection of pneumothorax in the acute setting.
N CT is used for further characterization of pleural

abnormalities seen on ultrasound and chest radiography and may also be used to guide interventional procedures.
Normal anatomy
Chest radiography
Posteroanterior (PA) and lateral chest radiographs (CXRs) are both of value in assessing the pleura. It is common practice to initially perform a standard PA CXR and to obtain a lateral lm to further assess abnormalities seen on the frontal lm. On a standard CXR, the normal pleura is seen where the visceral pleura invaginates the lung to form the ssures and where the two lungs contact to form junctional lines. The horizontal and oblique ssures are double layers of infolded visceral pleura, and are only seen when they are tangential to the X-ray beam. They are often incomplete [1].
N MRI and nuclear medicine have a limited role at present.

be administered for soft tissue enhancement if an effusion is present, or if malignant pleural thickening is suspected. CT can be used to determine whether probable pleural thickening or plaques seen on CXR are genuine [5]. On conventional CT, the ssures are seen as avascular band-like areas. However, high resolution CT (HRCT) demonstrates the ssures as sharply dened opacities, normally less than 1 mm thick. The extrapleural fat separates the pleura from the endothoracic fascia. These structures, together with the innermost intercostal muscle,
Ultrasound
The intercostal space is used as a sonographic window for US examination of the pleura. A 3.55.0 MHz sector transducer with a small footprint provides good images of the pleura in most patients, and can also be used to guide interventional procedures [2, 3]. Higher frequency transducers, while providing superior spatial resolution, may be limited by insufcient penetration. The pleural surface forms a reective band, which is readily differentiated from the relatively hypoechoic tissues of the chest wall. The reective band results mainly from high amplitude echoes at the interface of pleura and aerated lung, but also consists of endothoracic fascia, parietal and visceral pleura [4]. There is a predominantly homogeneous zone of reverberation echoes distally (Figure 1).
Computed tomography
CT is used to characterize further pleural abnormalities seen on CXR or US. Intravenous contrast medium should
Address correspondence to Dr Zoe Traill, Department of Radiology, The Churchill Hospital, Oxford OX3 7LJ, UK
Figure 1. Ultrasound image of the normal pleura shows the echogenic pleuropulmonary interface with distal reverberation artefact. Imaging, Volume 16 (2004) Number 1
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form the intercostal stripe on HRCT [6]. The visceral and parietal pleura and endothoracic fascia are not normally visualized passing internal to the ribs on HRCT unless pathologically thickened (Figure 2).
Magnetic resonance imaging

Cardiac gating and respiratory compensation are routinely required for chest MRI. The normal pleural surfaces, ssures and junctional lines are usually not seen on MRI. However, it can be useful for the assessment of tumour extension through the pleura and for the detection of pleural malignancy [7].
Pneumothorax
While the majority of pneumothoraces are accurately demonstrated on CXR (Figure 3), subtle pneumothoraces, particularly in the supine patient, may not be readily visible. Free air within the pleural space is seen at the apices on erect radiographs. However, in the supine patient, the only sign of a pneumothorax may be an unusually sharp denition of the cardiophrenic contour and/or deepening of the cardiophrenic and costophrenic recesses. CT can be used to demonstrate pneumothoraces with greater sensitivity than CXR [8]. The CXR features of tension pneumothorax (a medical emergency) are contralateral mediastinal shift and attening of the ipsilateral hemidiaphragm.
Figure 3. Plain chest radiograph shows a large right pneumothorax. The underlying lung is abnormal, with extensive bullous change.
The lung sliding sign is the to-and-fro movement of the visceral and parietal pleural surfaces with normal respiration, seen on US as the echogenic interface between the chest wall soft tissues and aerated lung [9]. The loss of the lung sliding sign and the normal reverberation echoes distal to the reective band are the signs of a pneumothorax on US. It has been suggested that US may be sensitive and accurate in the detection of pneumothorax in the traumatic [10] and non-traumatic [11] setting.
Bronchopleural stula
Bronchopleural stulae are communications between the pleural cavity and the bronchial tree. Pulmonary infections (necrotizing pneumonia, septic infarcts and tuberculosis), iatrogenic causes (pneumonectomy, thoracentesis, positive pressure ventilation), chest trauma and malignancy (cavitating peripheral tumours or local recurrence postpneumonectomy) are the most common causes of bronchopleural stulae [1215]. On CXR, a bronchopleural stula appears as a pneumothorax or hydropneumothorax, and its presence should be inferred in the appropriate clinical context (prolonged chest tube air leak, recalcitrant pneumothorax or massive surgical emphysema). Post-pneumonectomy a bronchopleural stula should be suspected if there is less uid or more air in the operated hemithorax than would normally be expected at that stage or if the ratio of air to uid increases with time, along with an absence of the usual ipsilateral mediastinal shift. Several months postpneumonectomy, the development of a bronchopleural stula is suggested by the appearance of pleural air in a previously uid-lled hemithorax. CT is the imaging
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Figure 2. High resolution CT image of the normal pleura. The normal pleura and endothoracic fascia are not visible internal to the ribs. Imaging, Volume 16 (2004) Number 1
D R Warakaulle and Z C Traill
Pleural effusion
Approximately 10 ml of pleural uid is formed each day [18]. While some of this uid is drained by the visceral pleura, the majority drains via parietal pleural lymphatics. Approximately 15 ml of pleural uid is present in normal individuals [19]. 200 ml of pleural uid is sufcient to cause blunting of the costophrenic angle, usually the earliest sign of a pleural effusion on a frontal CXR, although 500 ml of uid may be present with no appreciable blunting [20]. With progressive accumulation of pleural uid, a meniscus sign is typically seen on the frontal CXR. Complete opacication of the hemithorax with contralateral mediastinal shift occurs with a massive effusion (Figure 4). A massive effusion with no mediastinal shift raises the possibility of associated pulmonary collapse or mediastinal xation [21]. Large effusions can invert the ipsilateral hemidiaphragm, particularly on the left, which can revert to a normal position following thoracentesis, causing an apparent radiographic failure of drainage [7]. Free uid within the ssures or loculated uid collections elsewhere in the pleural space can simulate a pulmonary or mediastinal mass [22] (Figure 5). Loculated effusions tend to have sharp medial margins, hazy lateral margins and form obtuse angles with the chest wall [1]. Socalled lamellar pleural effusions actually consist of uid in the connective tissues deep to the visceral pleura and may be seen in cardiac failure [7]. On a supine CXR, generalized hazy opacication of a hemithorax suggests the presence of pleural uid. Pooling at the dependent apices causes an apical cap on these studies [22] (Figure 6). Subpulmonary effusions are usually transudates, which can be unilateral (usually right sided) or bilateral. The hemidiaphragm usually appears elevated,
Figure 4. Plain chest radiograph shows a massive left pleural

effusion with contralateral mediastinal shift. A sclerotic lesion is seen in the left 7th rib, with lytic skeletal lesions elsewhere. These appearances were due to metastatic tumour.
modality of choice, and may allow direct visualization of the communication [16]. Ventilation scanning is a simple test for a bronchopleural stula [17], and can be used to detect air leak post-pneumonectomy if there is clinical or bronchoscopic doubt.
(a)
(b)
Figure 5. (a) Plain chest radiograph shows an oval right lower zone opacity. (b) The CT image shows the lesion to be a pleural
uid collection loculated within the right oblique ssure. A large hiatus hernia is also seen.
12
Figure 6. Supine chest radiograph shows generalized hazy

opacication of the right hemithorax with an apical pleural cap due to a pleural effusion. An intercostal drainage catheter is seen within the effusion.
Figure 7. Chest ultrasound in a patient with an empyema demonstrates a heavily septated effusion.
with lateral displacement of its peak [7]. Increased density of the hemidiaphragm, the absence of vessels passing below it [23] and an abnormal separation of the gastric air bubble from the apparent hemidiaphragm on the left may also be seen. US can be used to further evaluate pleural effusions seen on CXR. Transudates always appear anechoic on US, while exudates can be either anechoic or echogenic, and may also be septated. The detection of pleural nodules associated with an effusion is indicative of malignancy, while homogeneously echogenic effusions are most commonly due to a haemorrhagic effusion or an empyema [24]. The presence of septation can be useful for differentiating pleural uid from pleural thickening, as both can be anechoic or echogenic (Figure 7). Respiratory and cardiac motion induce movement in pleural uid, which can be detected with colour Doppler [25]. Pleural uid can occasionally be difcult to distinguish from ascites on CT. A sharp interface between the uid and the liver or spleen is seen in ascites, while interposition of the diaphragm causes a hazy interface between pleural uid and the abdominal viscera [26]. Pleural uid is seen peripheral to the hemidiaphragm on CT, while ascites is seen internally. Ascites cannot extend into the bare area posterior to the right lobe of the liver, where there is no peritoneal covering [27] (Figure 8). Contrast enhancement allows differentiation of pleural thickening from small effusions [27], and pleural enhancement indicates that an effusion is an exudate. A pleural exudate without pleural thickening or enhancement is usually due to malignancy or uncomplicated parapneumonic effusion [28]. CT is much less sensitive than US for the detection of septation within an effusion, although its presence may be inferred if gas, when present, collects in separate pockets [29] (Figure 9).
Figure 8. Axial CT image shows ascites forming a sharp interface with the liver. A pleural effusion would be peripheral to the right hemidiaphragm and extending posterior to the bare area of the liver.
Triple-echo pulse sequences with normalized MR intensities can be used to differentiate transudates, simple exudates and complex exudates, which return progressively higher signal on these sequences [30]. The presence of haemoglobin breakdown products [7] and chyle [2] may also be detectable on MRI. However, it has a fairly limited role at present in the evaluation of pleural effusions. US and occasionally CT guided diagnostic and therapeutic thoracentesis is frequently performed for pleural effusions. Diagnostic thoracentesis allows the differentiation of transudates from exudates by measuring parameters such as lactate dehydrogenase and protein concentration. Transudates and uncomplicated parapneumonic exudates rarely require therapeutic thoracentesis. The use of a brinolytic (urokinase) has been reported to
13
Figure 9. Axial CT image shows thickened enhancing pleura with pleural uid containing multiple separate gas locules in a heavily septated empyema.
enhance drainage of loculated malignant pleural effusions [31, 32]. However, this may partly be due to pleural weep caused by the brinolytic, rather than better drainage of the effusion due to the breakdown of loculations [33]. Our practice is to drain malignant pleural effusions under ultrasound guidance with 8 Fr non-locking pigtail catheters, without the routine use of brinolytics. Therapeutic thoracentesis for malignant pleural effusion occasionally results in a hydropneumothorax, which is most commonly asymptomatic. If there is underlying visceral pleural thickening or disease causing pulmonary collapse such as compression of a lobar airway, the lung may fail to re-expand following aspiration or chest tube drainage. However, these patients may still improve symptomatically following the initial thoracentesis, probably due to an increased ability of the intercostal muscles to stretch during respiration, thereby maintaining more normal neural afferent responses to the brain, with a resultant reduction in the subjective sensation of dyspnoea. Pneumothoraces in this group of patients should probably not be drained routinely, as they either resolve spontaneously or reaccumulate uid [34]. Talc pleurodesis is an established method of treating malignant pleural effusions, chylothorax and recurrent spontaneous pneumothoraces [35]. CT following the procedure frequently shows variable degrees of pleural thickening and nodularity, often with a residual loculated effusion. Focal areas of high attenuation, presumed to represent talc deposits, are also seen, predominantly in the posterior and caudal aspects of the pleural space [36].
side is usually larger [13]. The effusion may become loculated as it evolves. The majority of complicated parapneumonic effusions and empyemas are loculated on US. Frankly purulent effusions may be anechoic [37], or uniformly echogenic [24]. There is no correlation between the US appearance and the stage of evolution of the effusion or with the response to treatment [29]. Pleural enhancement is seen on contrast-enhanced CT, as with other exudative effusions [28]. Thickening of the parietal pleura and extrapleural subcostal tissues and increased attenuation of the extrapleural fat are also seen on CT in cases of empyema (Figure 9). However, these features may also be present, albeit less commonly, in exudative effusions due to other causes, particularly malignancy [38]. A pulmonary abscess abutting the pleural surface may be difcult to differentiate from an empyema. Pulmonary abscesses tend to appear rounder than empyemas on CXR and CT. They often form an acute angle with the chest wall, while empyemas usually form an obtuse angle. Abscesses tend to have thicker walls, and do not, unlike empyemas, cause passive atelectasis of the adjacent lung [7]. The split pleura sign referring to the separation of enhancing parietal and visceral pleura in empyema may also help in this differentiation (Figure 10). Tuberculous empyema has a signicantly different appearance to pyogenic pleural space infections. A large, loculated pleural effusion is typically seen, with pleural calcication, and often, enlargement of the overlying ribs [39]. Complications of tuberculous empyema include bronchopleural stula and empyema necessitans, which is seen as a thick-walled, encapsulated calcied mass on CT [40]. Pleural pH has been shown to be the most reliable measurement indicating the need for pleural drainage, while the measurement of glucose and lactate dehydrogenase did not improve diagnostic clarity. A pleural pH of less than 7.217.29 has been identied as the best indication for pleural drainage in patients with complicated parapneumonic effusions [41]. The placement of a chest tube under US or occasionally CT guidance in
Empyema
Empyema (pyothorax) is dened as pus within the pleural cavity. The diagnosis is made on the basis of grossly purulent pleural uid or Gram stain or culture of organisms [27]. On CXR, empyemas appear as pleural effusions, often with associated consolidation. The effusion is commonly unilateral, and if bilateral, the infected
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Figure 10. Axial CT image demonstrates the split pleura sign in a patient with an empyema. Imaging, Volume 16 (2004) Number 1
conjunction with appropriate antibiotic therapy is currently the rst-line management of these conditions. There is no evidence to suggest that large bore catheters are more effective than small bore (1214 Fr) catheters for the treatment of parapneumonic effusions, empyema, pneumothorax and malignant pleural effusions [42]. A literature review [43] found the success rate for radiologically guided small bore (814 Fr) catheters for the treatment of pleural space infections to be higher (81%, range 7292%) than for conventional chest tubes (47%, range 693%), probably due to optimal placement of the catheter within the collection with the former. Our practice is to drain empyemas with 1214 Fr non-locking pigtail drains placed under US guidance. There have been many reports on the use of intrapleural brinolytics to facilitate pleural drainage in empyema [44, 45]. However, as there has been no study to date which conrms a benet of clinical importance (i.e. patient mortality, surgery rate, residual lung function decit and the duration of hospital stay), this application of brinolytic therapy remains controversial, as even the increased drainage of pleural uid is at least partly attributable to pleural weep or increased uid production by the pleura in animal models [33].
Figure 11. Plain chest radiograph shows calcied pleural

plaques in the pleura underlying the chest wall and on the diaphragmatic surfaces.
Focal pleural disease

The most common focal pleural abnormalities are pleural plaques, localized pleural tumours and local extension of bronchogenic carcinomas [27].
Pleural plaques
Pleural plaques are circumscribed collections of dense collagenous connective tissue. They are the most common manifestation of asbestos exposure, occurring in 2060% of workers exposed to high concentrations [46, 47]. Pleural plaques mainly involve the posterior and lateral aspects of the pleura, following the contours of the posterolateral 7th to 10th ribs (Figure 11). They involve the anterior chest wall less commonly and spare the apices and costophrenic recesses. [27]. They nearly always involve the parietal pleura. However, they can occasionally arise from the visceral pleura in the interlobar ssures, where they can simulate pulmonary nodules [48]. On CXR, pleural plaques can be difcult to distinguish from the normal muscle and fat companion shadows of the chest wall, although extrapleural fat tends to have a bilateral, symmetrical distrbution [7]. Pleural plaques are unilateral on CXR in about 25% of cases, when they are more commonly seen on the left. When bilateral, they are usually asymmetrical [49]. Non-calcifed asbestos-related pleural plaques appear hypoechoic with an echogenic surface on US. They are usually well-dened, with smooth, even contours. Calcied plaques tend to have echogenic anterior margins with posterior acoustic shadowing and irregular borders, while calcied diaphragmatic plaques can have additional ring down or comet tail artefacts [50]. HRCT is superior to CXR in the detection of pleural plaques. The patient should be scanned in the prone position, as this allows evaluation of the lung parenchyma for possible co-existent asbestos-related disease [51]. Small
foci of calcication within pleural plaques are also detectable on HRCT [52]. However, a study of 72 retired workers with previous occupational asbestos exposure [53] showed no signicant difference between HRCT and low dose multislice spiral CT in the detection of asbestosrelated pleural and pulmonary parenchymal changes. Pleural plaques appear as well-circumscribed areas of pleural thickening separated from the underlying rib and extrapleural fat by a thin layer of fat [7] (Figure 12). Visceral pleural plaques may be associated with adjacent pulmonary parenchymal abnormalities (e.g. short interstitial lines radiating from the plaque so-called hairy plaques) [54]. MRI is less sensitive than CT in the detection of pleural plaques.
Figure 12. Axial CT image shows bilateral pleural plaques, with calcication in the larger right-sided lesion. 15
Localized pleural tumours Localized brous tumour of the pleura These are rare neoplasms, accounting for less than 5% of pleural tumours [55]. They appear as smooth, rounded or oval homogeneous masses on CXR, which usually form obtuse angles with the pleural surface. Pedunculated tumours may be mobile, changing in position with respiration and posture or on serial imaging [56]. They are homogeneous and well demarcated on unenhanced CT, and rarely calcify. There is usually a smooth tapering margin at the junction of the mass with the pleura [57]. There is variable enhancement with contrast: most commonly homogeneous, but heterogeneous in up to 40% of cases [58]. Central necrosis may be seen in tumours with malignant degeneration [59]. On MRI localized brous tumours return low signal on T1 and heterogeneous high signal on T2 weighted images. A peripheral low signal rim is sometimes seen on T1 weighted images. MR can be superior to CT or CXR in showing the pleural origin of the mass [7].
Pleural lipoma and liposarcoma There are no features to distinguish these tumours from other soft tissue masses or collections on CXR. On CT, they appear as well-dened masses with homogeneous fat density forming obtuse angles with the chest wall and displacing the adjacent lung parenchyma [27]. The presence of attenuation values greater than 250 Hounseld Units within the mass together with a heterogeneous appearance merits consideration of a liposarcoma [60]. These tumours return high signal on T1 and intermediate signal on T2 weighted MRI due to their fat content [7] (Figure 13).
Pleural extension of bronchogenic carcinoma A primary bronchogenic tumour invading visceral pleura is classied as a T2 lesion, while mediastinal or parietal pleural invasion is classied as T3. If a pleural effusion is present, then aspiration conrming malignancy precludes resection and changes the T stage to T4 [61].
(a)
(b)
(c)
(d)
Figure 13. (a) Plain chest radiograph, (b) axial CT, (c) axial T1 weighted and (d) coronal short tau inversion recovery (STIR) MRIs
show a left apical pleural lipoma. The lesion has similar attenuation to the subcutaneous fat on the CT image, and returns fat signal (high signal on T1, uniform signal suppression on STIR) on the MRIs.
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Diffuse pleural disease

Diffuse benign pleural thickening
Diffuse benign pleural thickening related to previous asbestos exposure causes a smooth, continuous pleural density extending over at least 25% of the chest wall, which often appears as a subtle increase in density, sometimes with associated blunting of the costophrenic angle [62]. It is much less common than pleural plaques, and involves the visceral pleura [46]. On CT, there is continuous pleural thickening more than 5 cm wide, more than 8 cm in craniocaudal extent and more than 3 mm thick. It commonly involves the posterior and posteromedial pleura over the lower lobes, often with associated rounded atelectasis [63]. The CXR appearance of rounded atelectasis is of a round peripheral mass, sometimes with associated parenchymal distortion (Figure 14). The CT features are of a round or oval mass abutting the pleura, adjacent pleural thickening and a comet tail of bronchovascular structures passing into the mass [54] (Figure 15). With non-asbestos related diffuse benign pleural thickening, radiological features differ depending on the underlying cause (previous trauma, thoracotomy, tuberculous and non-tuberculous empyema). The CXR abnormalities are usually unilateral, with smooth, often angular pleural thickening without the meniscus sign usually seen in pleural effusions [7]. Extensive pleural calcication and associated parenchymal abnormality favour tuberculosis and empyema (Figure 16). CT is useful to determine the exact extent of diffuse benign pleural thickening, as asbestos related pulmonary parenchymal changes can be difcult to differentiate from pleural abnormalities on CXR [64]. Low dose multislice CT has been shown to be as sensitive as HRCT for this purpose [53].
Figure 15. Rounded atelectasis. The axial CT image shows a peripheral mass, pleural thickening and bilateral pleural effusions in a patient with previous asbestos exposure. The characteristic comet-tail appearance of bronchi and blood vessels converging into the mass is less obvious in this example.
Several scoring systems have been developed for grading diffuse pleural thickening in an attempt to correlate the imaging appearances with the functional decit. Copley et al [65] found that a simple CT scoring system, which measured the mean thickness of the pleural disease, the percentage circumference of the pleural surfaces involved (excluding the mediastinal pleura) and the presence of rounded atelectasis at ve different levels within the
Figure 14. Rounded atelectasis. Lateral chest radiograph

shows a round mass associated with pleural thickening in the right lower lobe.
Figure 16. Extensive pleural calcication on a plain chest

radiograph in a patient with a previous tuberculous empyema.
17
hemithorax had good interobserver agreement and imagingfunctional correlation, and was easy to perform. This study also showed that pleural plaques had no signicant detrimental effect on lung function.
Diffuse malignant pleural thickening

Metastatic disease accounts for the vast majority of malignant pleural thickening. About 40% of pleural metastases arise from primary bronchogenic tumours, 20% from breast carcinomas, 10% from lymphoma and the remaining 30% from other primary sites [66]. Invasive thymoma is a tumour that uncommonly but characteristically extends into the pleura, where it can cause either widespread pleural thickening or discrete masses. It can be radiographically indistinguishable from mesothelioma [67]. CT allows assessment of the pleura, lungs and mediastinum in patients with diffuse pleural thickening. Spiral acquisitions should be performed with intravenous contrast. Studies investigating the role of CT in the differentiation of benign from malignant pleural thickening in the absence of pleural uid have found that the following features are highly specic for malignant pleural disease: circumferential thickening, pleural nodularity, parietal pleural thickening greater than 1 cm and mediastinal pleural involvement [68] (Figure 17). However, circumferential pleural thickening was less specic for malignancy in the presence of a pleural effusion [69]. MR signal intensity can be useful in differentiating benign from malignant pleural disease. In particular, signal hypointensity relative to the intercostal muscles on long TR (time to repetition) sequences has been shown to be a reliable predictor of benign disease [70]. MRI may also be superior to CT for evaluating mediastinal, chest wall and diaphragmatic involvement [71]. Malignant pleural mesothelioma is the most common primary pleural neoplasm, which typically affects people exposed to asbestos. Men are more frequently affected
(M:F 26:1), with a peak incidence in the 6th and 7th decades [72]. It is expected that the incidence will continue to rise until around 2020 [73]. Unilateral pleural effusion and pleural thickening are the most common CXR ndings in malignant mesothelioma (Figure 18). Less than 25% of patients have distinct pleural masses without an effusion [72]. Benign calcied or non-calcied plaques may also be present. Solid pleural lesions can be focal masses or diffuse thickening that encases the entire lung surface. Rib destruction occurs with advanced disease [67]. Tumour extension into the interlobar ssures is common (4086% of patients) [74] (Figure 19). The CT and MRI features of malignant mesothelioma are similar to those seen with other causes of malignant pleural thickening [7]. While volume loss is commonly seen with malignant mesothelioma, this is a non-specic nding, which can occur with other benign and malignant pleural processes [74, 75]. Image guided cutting needle pleural biopsy has been shown to have a higher diagnostic yield than unguided biopsies. Diagnostic rates of 70% have been achieved with US guided cutting needle biopsy [76] and a sensitivity of 83% and a specicity of 100% has been reported for CT guided cutting needle biopsy [77]. A recent randomized study comparing image guided pleural biopsy to unguided Abrams needle biopsy [78] conrmed the benet of targeted biopsies, showing a sensitivity of 87% and a specicity of 100% for CT guided biopsy compared with a sensitivity of 47% and a specicity of 100% for unguided biopsies in patients with negative aspiration cytology. These results were independent of the degree of pleural thickening. While thoracoscopic and open pleural biopsy have a high sensitivity and yield due to direct visualization of the pleural surface and the ability to sample multiple areas of both parietal and visceral pleura, in a large series of 620 patients, thoracoscopic biopsy was only able to obtain the diagnosis in half of the 8% of patients in whom the diagnosis remained unresolved following pleural uid cytology and percutaneous biopsy [79]. The complications
Figure 17. Axial CT image in a patient with metastatic carcinoma shows nodular pleural thickening and a pleural effusion.
Figure 18. Left-sided pleural effusion and marked nodular

pleural thickening in a patient with malignant mesothelioma.
18
(a)
(b)
Figure 19. (a) Plain chest radiograph and (b) axial CT scan in a patient with malignant mesothelioma show tumour extension along an azygos ssure.
of cutting needle biopsy of the pleura include pneumothorax, haemothorax and laceration of the diaphragm, lung, liver and spleen. Tumour seeding along the needle tract is relatively common in mesothelioma but rare in other pleural malignancies [80]. Early local radiotherapy has been shown to prevent malignant seeding [81].
Conclusion
Imaging has an important role in the diagnosis and management of pleural disease. CXR is the initial investigation of choice. US and CT are useful for further diagnostic evaluation and for guiding interventional procedures such as thoracentesis, placement of drainage catheters and needle biopsy. The use of MR and nuclear medicine studies in the evaluation of pleural disease is currently more limited.
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21
MRI of the chest: present and future

C HILL, FRCR and E J R VAN BEEK, FRCR
Unit of Academic Radiology, Royal Hallamshire Hospital, Shefeld S10 2JF, UK
MRI of the chest has been developed relatively recently compared with other body areas. Several technical challenges needed to be overcome, such as the lack of protons within the chest, motion of both heart and lungs, and susceptibility artefacts due to the interfaces between air and soft tissues producing eld inhomogeneities. Consequently, conventional proton MRI has provided limited anatomical information at the eld strengths used for routine clinical imaging. Combined with the fact that MRI is more time consuming and expensive than CT, its use in the clinical setting has been restricted to that of a problem-solving tool in the investigation of vascular, mediastinal and chest wall abnormalities. The development of contrast-enhanced MR angiography (MRA) enabled imaging of the large vessels. New sequences have since been developed to enable lung perfusion MR, perfusionventilation MR and direct thrombus imaging of the entire venous system. These techniques are currently being evaluated in the initial diagnosis and follow-up of patients with pulmonary embolism (PE). Potential gains include its non-invasive nature, safe contrast agents and perhaps most importantly, its lack of ionizing radiation. This latter point has been emphasised both in general use and in pregnant patients [1, 2]. After the introduction of hyperpolarized noble (i.e. chemically inert) gases, such as helium-3 (3-He) and xenon-129 (129-Xe), in the 1990s, the technology has expanded into clinical studies. The use of these gases has paved the way for pulmonary assessment using MRI. Although some attempts have been made to introduce dynamic CT imaging for ventilation assessment, both with the use of standard multidetector CT and with xenonenhanced electron beam CT, these techniques have not been introduced into clinical practice due to technical constraints and due to ionizing radiation issues [37]. An alternative technology, ventilation scintigraphy, lacks both spatial and temporal resolution and also requires ionizing radiation, albeit that doses are small [810]. Thus, it is apparent that the use of MRI for lung assessment has great potential. Again, the lack of ionizing radiation renders it an ideal technique for young patients as well as for those who require regular follow-up imaging. Another benet includes the potential of ultrafast sequences, allowing assessment of the lungs during the ventilatory cycle. Novel data on gas exchange and lung physiology can also be obtained due to certain physical
Address correspondence to Dr Edwin J R van Beek, Unit of Academic Radiology, Floor C, Royal Hallamshire Hospital, Glossop Road, Shefeld S10 2JF, UK. The authors wish to acknowledge support (either nancially or in kind) from the European Community Framework 5 programme (Polarized Helium Imaging of the Lung (www.phil.ens.fr), Amersham Health and Spectra Gases UK Ltd.
Summary
N MRI techniques have been developed for imaging of

pulmonary vascular disease and for perfusion and ventilation studies.
N Patients with chronic lung diseases, who require

repeated investigations, may be most likely to benet as these techniques are safe and do not carry ionizing radiation burden.
N MR angiography will become the preferred method of

imaging in patients with chronic pulmonary vascular diseases. Furthermore, this technique may replace CT in therapeutic trials for the assessment of thrombus resolution.
N Ventilation MRI, using hyperpolarized 3-He gas, has

the opportunity to non-invasively study pulmonary physiology and pathophysiology. The method has potential for the assessment of therapy effects in patients of all ages.
properties of hyperpolarized noble gases, allowing for measurements that were not feasible with any other technique. Lung imaging using MRI shows great promise, not only using perfusion and angiographic techniques [11], but also using hyperpolarized noble gases. This review will discuss some of the technical considerations and subsequently will focus on their potential clinical applications.
Technical considerations
Proton MR techniques Gadolinium-enhanced MR angiography After initial attempts to perform time-of-ight, nongadolinium (Gd) enhanced MRA, the introduction of more powerful MRI systems enabled the development of single breath-hold three-dimensional (3D) Gd-enhanced MRA as the standard for angiography in the body [1214]. The technique can offer a trade-off between high spatial resolution [1419] and high temporal resolution [20, 21], which can be tailored to the patients ability to hold his/ her breath. The use of shorter scan times allows the investigation even of severely breathless patients. Monophasic MRA protocols, which use a bolus injection of contrast and imaging during a single breath-hold, offer high spatial resolution for diagnostic accuracy for the detection of PE comparable with helical CT [19].
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C Hill and E J R van Beek
The method of time-resolved MRA protocols, which use repeated data sampling during contrast infusion, is undergoing assessment and its diagnostic accuracy in patients with PE remains unknown. Parallel MRI techniques will further improve the feasibility in patients, while retaining spatial resolution [2226]. Gadolinium, at a dose of 0.2 mmol kg21, should be injected using a power injector and a saline ush [21]. Gadolinium concentration in the vessels of interest should be optimal at the time of central k-space acquisition, as this will determine the vascular signal intensity [27]. Spherical and centricelliptic phase encoding ordering offer optimum contrast with conventional k-space sampling [28] whilst interleaved spiral [26] and radial acquisitions [29] inherently over sample central k-space and are thus less sensitive to bolus passage timing. Time resolved Gd enhanced 3D MRA methods [30] are the obvious extension whereby continuous 3D data sets are acquired thus capturing the arterial and venous phases and obviating the need for precise bolus synchronization. In sequences that require 2030 s breath-holds, a trial bolus may be useful to obtain the optimal injection-imaging delay time [19]. However, in ultrafast imaging sequences this is no longer required in the majority of patients and a routine delay time of 5 s following the initiation of contrast injection will result in excellent quality images in patients with suspected acute PE [31]. Images should be assessed on a workstation, with allows full use of multiplanar reformatting techniques and source image review.
[36]. The subtraction can be performed through a pixel-bypixel post-processing technique, which allows dynamic changes as well as steady-state assessment. Using the postprocessing, a correlation map of ventilation within the lung can be obtained [37].
Hyperpolarized noble gas ventilation MRI

Hyperpolarized noble gases, such as 3-He and 129-Xe, have a nuclear spin of K, which renders them sensitive to nuclear magnetic resonance techniques. Using laser optical pumping techniques, these atoms can be brought into a higher energy state [3840]. This results in a net spin alignment along an external magnetic eld, resulting in a 100 000 fold increase in polarization, so called hyperpolarization. This situation compensates for the low overall spin density introduced into the lungs, resulting in adequate signal for MRI. Although initial work took place using hyperpolarized 129-Xe [4144], it was the introduction of hyperpolarized 3-He imaging that seems to have made the most impact [4549]. The main reason for this development is the relative safety of helium, whereas xenon has anaesthetic properties. Furthermore, higher polarization levels can be achieved using 3-He, which improve signal to noise ratio. Finally, helium is not transported across membranes, which means that all signal is directly proportional to the ventilated air spaces. Hyperpolarization can be achieved through two different methods: spin-exchange optical pumping [50] and metastability exchange [39]. The interested reader is referred to an excellent review on this topic [51]. This has led to both local instruments and central production facilities to be developed. In Europe, one project specically aimed to demonstrate the use of a productiondistribution network [52]. Prior to any imaging, the MR system requires tuning to the Larmor frequency of helium, which is 48 MHz at 1.5 T. Dedicated RF coils need to be installed. Most imaging has, thus far, taken place at 1.5 T machines, although the technique is very suitable for application at low eld strengths due to the high signal that is introduced. Hyperpolarized 3-He MRI is limited due to the non-renewable nature of the gas (contrary to standard proton MRI), which means that low ip angle pulse sequences or radial and spiral sequences had to be developed to make optimal use of the 3-He spin [53]. Two further problems that had to be circumvented are the destruction of polarization by paramagnetic effects of oxygen and the high diffusivity of the 3-He gas. Figure 1 demonstrates a healthy volunteer study using proton MRI and hyperpolarized 3-He MRI. Overall, sequence development has resulted in interesting and novel ways to ascertain aspects of lung function and morphology, which will be discussed below. An important issue is the safety of 3-He delivery in human subjects with lung diseases. Some of the pioneers in this work, at the University of Virginia, recently presented data of a period of 3 years involving 343 subjects, ranging from normal volunteers to patients with severe lung disease who inhaled more than 1000 doses of the gas [54]. Only mild adverse events in less than 10% of the subjects were recorded. At the sites of the European Community framework 5 the collaborators in Mainz,
MR perfusion imaging Both non-contrast and contrast-enhanced techniques have been developed and tried, as described in a recent overview [11]. At present, Gd-enhanced perfusion images seem to have the best combination of temporal and spatial resolution. Quantication of perfusion is feasible using this method [32]. Nevertheless, the technique is still experimental and not in routine clinical use. Direct thrombus imaging Direct thrombus imaging is based on the predictable signal changes of blood as it transforms into a thrombus [33]. The technique applies a heavily T1 weighted magnetization prepared 3D gradient echo sequence with a wateronly excitation radiofrequency (RF) pulse with effective inversion time to nullify the blood signal [34]. It has the advantage that thrombus is depicted without the need for intravenous contrast, and that the entire venous system can be imaged in one setting. Furthermore, as it is aimed at (sub) acute thrombosis, it may be able to differentiate acute from chronic thrombosis. Oxygen-enhanced ventilation MRI Oxygen-enhanced ventilation MRI utilizes the paramagnetic properties of oxygen [35]. It has advantages over hyperpolarized gases (see below), as oxygen is readily available and simple proton technology can be employed. Oxygen-enhanced ventilation MRI is a subtraction technique, which uses a mask while the patient breathes room air and subsequently the patient breathes high ow (15 l min21) 100% oxygen over a period of several minutes
62
MRI of the chest
(a)
(b)
Figure 1. (a) Coronal image of the chest in a normal volunteer using standard proton MRI sequence. (b) Coronal image of the
chest in a normal volunteer using hyperpolarized 3-He MRI sequence.
Copenhagen and Shefeld, have obtained similar safety data [55].
Clinical applications
Pulmonary embolism
PE is a common clinical condition. Although acute PE can be diagnosed using MRA, direct clot imaging or a combination of perfusion and ventilation MRI, it is unlikely that this approach will nd routine implementation due to the technical requirements and the fact that MRI may be less readily available compared with multidetector CT [11]. However, MR techniques may have a role to play in the assessment of therapy response (Figure 2) and probably more signicantly, in the assessment of pulmonary hypertension (Figures 3 and 4). Not only pulmonary vascular assessment is feasible using MRA, but the application of oxygen-enhanced ventilation
MRI or hyperpolarized 3-He MRI may become relevant, as these techniques appear to be capable of providing information about the ventilation perfusion mismatch and oxygen uptake of the lung [5658]. Knowledge of these basic pulmonary function parameters could prove helpful in planning therapy, both from a medical and surgical point of view. Furthermore, the information provided by these techniques may allow a more comprehensive noninvasive diagnostic work-up of these patients than is currently possible. Several studies have been performed to assess the value of MRA in the diagnosis of PE [11], demonstrating good sensitivity and specicity with comparable gures to helical CT. Furthermore, direct thrombus imaging seems to be as effective as more comprehensive and complicated diagnostic strategies in the setting of acute PE [59]. Similarly, MRA has been used in the work-up of patients with pulmonary hypertension. However, no studies in humans to assess the value of ventilation MRI techniques have
Figure 2. Comparison of digital subtraction angiography (left frame) with 3D Gdenhanced MR angiography (centre frame) in a patient with acute pulmonary embolism. The MR angiogram was repeated following anticoagulant therapy (right frame), demonstrating thrombus resolution.
63
(a)
(b)
Figure 3. Patient with pulmonary hypertension, axial images using breath-hold single shot fast spin echo sequence. There is right
atrial dilatation and right ventricular hypertrophy (a). Furthermore, there is ow abnormality and thrombus in the main pulmonary arteries (b).
(a)
(b)
Figure 4. Patient with chronic thromboembolic pulmonary hypertension, 3D Gd-enhanced MR angiography. The pulmonary artery
is dilated and the lobar vessels to right upper and lower lobes demonstrate tortuous appearances (a). Different projection demonstrates ow void with evidence of arterial stenosis due to web formation (b).
been performed, other than those performed to validate the technique of 3-He based oxygen tension imaging as discussed above [57, 58].
Chronic obstructive pulmonary diseases

Chronic obstructive pulmonary diseases (COPD) are characterized by obstruction of airow and air trapping. COPD affects around 1 million people in the UK, with emphysema being the major subgroup [60]. Emphysema leads to progressive destruction of the airway wall, resulting in permanent enlargement of the airspaces distal to the terminal bronchioles [61]. The main factors associated with emphysema are smoking, ageing, inherited
64
alpha-1-antitrypsin deciency (Figure 5) and toxic gases in industrial settings. Several studies demonstrated excellent correlation of spirometry with the number and size of ventilation defects as demonstrated by 3-He MRI [48, 49, 6264]. In addition to ventilation distribution, apparent diffusion coefcient (ADC) measurements have demonstrated the ability to distinguish normal lung tissue from tissue with increased air spaces, such as emphysema [65, 66]. ADC maps can give an overview of diseased lung tissue on a slice-by-slice basis. A drawback of ADC maps is that the data for calculating these maps can only be derived in ventilated lung areas. Thus, ADC maps will have to be interpreted in conjunction with ventilation distribution images. Furthermore, posture and gravity effects will inuence
MRI of the chest
Figure 5. Hyperpolarized 3-He MRI of patient with proven

alpha-1-antitrypsin deciency. There are ventilation defects, which particularly involve the lower lobes.
ADC values, which is relevant as most studies are performed with the patient supine [67]. Dynamic ventilation techniques are capable of demonstrating airow abnormalities (Figure 6) [6870]. One recent study was able to demonstrate delayed outow of 3-He gas in subjects with COPD, thought to reect the presence of air trapping within the lung [67]. The future role of hyperpolarized 3-He MRI in the context of COPD is still under discussion, and the outcome of the PHIL project (Polarised Helium Imaging of the Lung, www.phil.ens.fr EC Framework 5) is eagerly awaited in this respect. Anticipated applications include the pre- and post-operative assessment of patients who undergo lung volume reduction surgery, the early diagnosis of COPD and use in therapy trials to assess effectiveness of new medications.
Figure 6. Dynamic hyperpolarized 3-He MRI series, demonstrating progression of gas bolus into the lungs (limited number of images shown from a series at 5 ms intervals). Courtesy of Dr J Wild, University of Shefeld.
Asthma
Asthma is a chronic disease that affects large numbers of predominantly young people [60]. It fundamentally differs from COPD in that airway obstruction is reversible by controlling the inammation and hyper-responsiveness of the small airways [71]. Although spirometry is the mainstay of management, this is insensitive for early detection of airway inammation and does not give regional information. The role of imaging has been limited, and chest radiographs tend to be normal in uncomplicated cases [72]. During acute asthma episodes, hyperination and thickened bronchi are present in up to 40% of patients [73]. High resolution CT (HRCT) is more sensitive in depicting airtrapping and bronchial wall thickening, but the correlation with disease severity is questionable and therefore HRCT is not routinely used in mild or moderate cases [74, 75]. Hyperpolarized 3-He studies have demonstrated that
varying degrees of ventilation defects are detectable in asthma and that small ventilation defects also vary in location over time. In a study that compared 10 healthy volunteers with 10 asthmatics, 7 of the asthmatics had generally small ventilation defects distributed throughout the lungs, while no defects were present in the normal controls. Two symptomatic patients had larger and a greater number of ventilation defects. One subject who was studied after 3 weeks demonstrated resolution of the defects, while another subject showed resolution of defects following bronchodilator therapy [76]. It was, however, not possible to conclusively dene the severity of asthma, as reported by patients, based on the ndings of hyperpolarized 3-He MRI [77]. Nevertheless, good correlation was demonstrated between MRI and spirometry, which possibly demonstrates that objective ndings are not necessarily linked to subjective well-being. In another study in six subjects with exercise-induced asthma, four subjects with ventilation defects and normal spirometry at baseline demonstrated ventilation defects that changed in size and location following metacholine challenge [78]. Overall, the number and size of defects increased in parallel to a decrease in lung function. More recently, a study in nine asthmatics and two healthy
65
volunteers demonstrated that both exercise and metacholine challenge induced, on the average, a three-fold increase in the percentage of non-ventilated lung [79]. Furthermore, a study in one subject demonstrated that it is feasible to detect airway calibre changes following metacholine challenge [80]. In addition to static (and rapid) ventilation distribution images, which have higher spatial resolution than traditional scintigraphic methods, hyperpolarized 3-He MRI also offers the potential to evaluate the dynamics of airow. This temporal resolution cannot be achieved by scintigraphic methods, which take many minutes to acquire. Hyperpolarized 3-He MRI appears to have the potential to increase our knowledge on the mechanism of asthma and its treatment by offering regional visualization of ventilation changes in the lung. It is particularly sensitive in detecting small airway changes and is fast enough to be able to give insight into the airways response to bronchoconstrictive challenge as well as therapy.
Cystic brosis and bronchiectasis

Cystic brosis (CF) is an inherited disorder leading to increased viscosity of mucus. Several attempts have been made to improve the prognosis of patients, such as screening programs and supportive therapies including antibiotic prophylaxis, mucolytics, physiotherapy and enzyme substitution. Image scoring systems have been used clinically and as objective measurement tools for assessment of therapeutic effects in research trials for CF [81, 82]. Both HRCT [81, 82] and nuclear medicine techniques [83] have been shown to give useful information, but for fear of cumulative radiation doses they are not uniformly used, and evaluation of lung function in patients with CF is largely limited to chest radiography and lung function tests. CF causes non-uniform changes in the lungs, and information on the site(s) of disease could have an effect on treatment. For instance, postural changes during
physiotherapy could be aimed at draining those lung segments that demonstrate ventilation defects. Earlier intervention and identication of patients has resulted in more subtle changes early in life, which makes assessment of therapeutic effects more difcult as the standard techniques used are relatively insensitive. Thus, it seems of utmost importance to develop novel techniques, which have no ionizing radiation burden, and which can provide regional lung function data. An initial study in four adult subjects with CF demonstrated good acceptance of the 3-He MRI technique [84]. Widespread ventilation defects were observed in all subjects, predominantly situated in the upper lung zones (Figure 7). There was good correlation between the extent of ventilation defects and pulmonary function tests. A second study in three subjects with CF comparing 3-He MRI with spirometry before and after mucus clearance therapy [85] showed good correlation between 3-He MRI ndings and spirometry before therapy. In two of the three subjects who underwent a second MR examination immediately following therapy for mucus clearance, spirometry only improved slightly in one, whereas a signicant decrease in ventilation defects was demonstrated in both. This nding would suggest greater sensitivity of 3-He MRI than spirometry in this setting. More recent experience in eight children with CF (age range 715 years) also demonstrated good acceptance of the technique (unpublished data). Ventilation defects correlated well with spirometry ndings and in two children with antibiotic-resistant pseudomonas aeruginosa infection the defects were more extensive in the upper lobes compared with the subjects without resistant infection.
Smokers lungs
Increased mucus production and enzymatic changes are amongst the diverse effects of smoking on the lungs. Small airways are initially involved, however chronic changes also involve the major airways. Chronic obstruction of the small airways leads to bronchiolitis, with emphysema developing secondary to the destruction of alveolar walls by enzymatic and toxic changes. Most studies in emphysema using hyperpolarized 3-He MRI were performed in patients with smoking related lung diseases (as described above). One study compared the number and size of ventilation defects in seven smokers and ve non-smokers with normal mean forced expiratory volume in 1 s (FEV1) [86]. This demonstrated more numerous and more extensive defects in the smoking group. Another study also showed a correlation between the extent of 3-He ventilation defects, smoking history and extent of emphysema [62]. A study comparing quantitative 3-He and proton lung volumes in 7 smokers and 6 non-smokers demonstrated a reduction in ventilated lung volume of 37% in the smokers and 12% in the non-smokers [87]. In summary, 3-He MRI may not only be able to detect early lung damage due to smoking, the extent of disease (and possible progression or treatment effects) may also become quantiable [88, 89].
Figure 7. Hyperpolarized 3-He MRI of adult patient with

cystic brosis. There are ventilation defects, which particularly affect the upper lobes.
66
MRI of the chest
Lung transplant (bronchiolitis obliterans)

Lung transplantation frequently fails due to chronic host versus graft reaction, manifesting as bronchiolitis obliterans [90]. Increased immunosuppressive therapy is required and early diagnosis is vital. However, early diagnosis can be difcult due to the inhomogeneous distribution of disease within the lungs. If a relatively normal section of the lung is biopsied bronchoscopically, the extent of disease may be underestimated. As hyperpolarized 3-He MRI appears to be sensitive in detecting areas of abnormal ventilation in the transplanted lung, the technique may assist with management by guiding the biopsy. An initial study in six lung transplant patients compared the ndings of 3-He MRI with a clinical grading system for bronchiolitis obliterans [91]. The 3-He MR detected focal ventilation defects in all six patients, with more extensive defects seen than those on corresponding 133-Xe scintigraphy (two patients) and HRCT (three patients). There was good correlation between the 3-He MRI ndings and the clinical grading system. In another study, the hyperpolarized 3-He MR ndings were compared with HRCT in 14 lung transplant patients [92]. A total of 59 ventilation defects were demonstrated, and only 63% of these correlated with focal CT ndings. This study suggests that 3-He MRI may allow earlier detection of bronchiolitis obliterans due to its increased sensitivity in detecting ventilation abnormalities over HRCT. A more recent study compared hyperpolarized 3-He MRI with spirometry (FEV1) in 9 patients following single or double lung transplant for either emphysema or idiopathic pulmonary brosis [93]. There was good correlation between the decrease in ventilated volume of the lung graft as shown by hyperpolarized 3-He MRI and the degree of bronchiolitis obliterans. In addition, 3-He MRI demonstrated changes prior to apparent changes in the spirometry. Furthermore, one study used dynamic imaging to detect airow changes as a possible early marker of lung rejection in lung transplant patients [94]. These studies suggest that hyperpolarized 3-He MRI could have a role in the management of patients following lung transplantation.
References
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Conclusion
MRI of the chest is a rapidly evolving eld. Pulmonary vascular assessment, especially in chronic thromboembolic disease, will increasingly be taking place using MRI methods. The use of hyperpolarized 3-He gas in MRI is offering the potential for pulmonary ventilatory functional assessment, capable of providing regional information on both lung morphology and function. This technology has also resulted in novel physiological measurements not feasible with any other technique. With its advantages of noninvasiveness and lack of ionizing radiation, it is expected to be of use in a variety of clinical settings. It not only has the ability to provide further insight into conditions currently difcult to assess by other diagnostic means, but also could potentially be used to assess the action and effectiveness of therapeutic interventions of the lung.
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The idiopathic interstitial pneumonias: a beginners guide

1
T FISCHER, FRCR, 1J H REYNOLDS, FRCR and 2S E TROTTER, FRCPath
Departments of 1Radiology and 2Cellular Pathology, Birmingham Heartlands and Solihull NHS Trust, Bordesley Green East, Birmingham B9 5ST, UK
The idiopathic interstitial pneumonias are a group of diffuse parenchymal lung diseases of unknown aetiology, which primarily involve the lung interstitium, but which may also involve airspaces, peripheral airways and vessels. The subject is inherently complex and often off-putting to the newcomer. The situation has not been helped by the fact that the interstitial pneumonias are referred to by a seemingly bewildering array of acronyms. There has been disagreement amongst experts on the inter-relationships between the idiopathic interstitial pneumonias and there have been several classications. The confusion has lead to the subject being referred to as an alphabet soup [1, 2]. In this article, the idiopathic interstitial pneumonias as currently recognised will be considered. Prior to describing these, the relevant high resolution computed tomography (HRCT) terminology for describing lung abnormalities will be reviewed along with a brief review of relevant anatomy. At the conclusion of the article the diagnostic process relating to the interstitial pneumonias will be discussed with particular reference to the role of imaging.
Summary
N The latest classication of the idiopathic interstitial

pneumonias recognises seven such entities, the most common being idiopathic pulmonary brosis (or cryptogenic brosing alveolitis).
N High resolution CT has a pivotal role in the diagnostic pathway. N Knowledge of the anatomy of the pulmonary lobule is essential in interpreting high resolution CT of the lung. N A reliable diagnosis is most likely to occur when
there is a consensus view taking into account radiological, pathological and clinical opinion.
Anatomy
The interstitial tissues of the lung, put simply, are the support or scaffolding that holds the structure together. Weibel and Crystal [3] dened the interstitium as the portion of lung between the bronchial epithelium, the vascular endothelium and the pleura. The interstitium includes collagen bres (for tensile strength) elastic bres, a variety of cell types, mainly related to host defence and immunity, broblasts, and also pulmonary veins and lymphatic vessels which can be found in the so-called interlobular septa. A secondary pulmonary lobule (or lobule the terms are synonymous as the term primary lobule is no longer in use) has been dened as a unit of lung surrounded by a connective tissue septum [4]. Pulmonary lobules are roughly polyhedral in shape and vary in size from around 1.0 cm to 2.5 cm in diameter. Between the septum of one lobule and the next is a potential space, the interlobular septum and it is within this space that pulmonary veins and lymphatic vessels can be found. A pulmonary artery branch and bronchiole supply each pulmonary lobule and travel towards its centre before branching (Figure 1). Interstitial tissues can be found in a number of wellrecognised locations within the lung [5]. Surrounding the pulmonary arteries and bronchi as they travel out into the lung is the peribronchovascular interstitium. As the pulmonary artery and bronchiole enter the pulmonary lobule they are supported by the centrilobular interstitium. At the lung periphery, between the septum of the pulmonary lobule and the visceral pleura is the subpleural
interstitium. This envelopes the whole lung and extends inwards at intervals within the interlobular septa. Within the pulmonary lobule, the acini and alveoli are supported by the intralobular interstitium. In the normal lung, many of these structures are not delineated on HRCT. Interlobular septa are only very occasionally seen in the normal individual but become apparent in the presence of a pathological process (e.g. brosis or lymphangitis carcinomatosa), which thickens the septa and when this occurs, the pulmonary lobules are outlined. In normal lung the location of pulmonary lobules can be deduced from the position of the pulmonary vein tributaries, which meet at right angles, in contrast to the pulmonary arteries which branch forming acute angles (Figure 2). The structures of the intralobular interstitium are too ne to be resolved by HRCT, but these tissues lead to an overall increase in lung parenchymal density causing it to have a faintly grey appearance on standard lung
Figure 1. Diagram of a pulmonary lobule with the centrilobular artery and bronchiole situated centrally and veins and lymphatic vessels located within the interlobular septa. 37
T Fischer, J H Reynolds and S E Trotter
cystic lesions or with air trapping associated with bronchiolar pathology.
Clinical presentation
The clinical presentation of patients with one of the idiopathic interstitial pneumonias is usually non-specic. Typical features include a gradual onset of dyspnoea, a non-productive paroxysmal cough and crackles are typically heard on lung auscultation [9]. Lung function tests reveal a restrictive defect with decreased vital capacity, reduced carbon monoxide diffusing capacity and a widened alveolar arterial oxygen tension. In general, most of the interstitial pneumonias have an insidious or subacute onset though acute interstitial pneumonia develops very rapidly over the course of a few days.
Figure 2. Normal high resolution CT examination of the lung. Pulmonary veins can be identied as they meet at right angles as they marginate the pulmonary lobules (arrowed).
window settings and giving lung tissue an average CT density of around 2850 Hounseld units [6].
The American Thoracic Society/European Respiratory Society Classication

The idiopathic interstitial pneumonias were rst studied in detail in the 1960s. Liebow and Carrington [10] rst classied these disorders but their classication has undergone subsequent modication [11, 12]. The latest classication was developed by the working groups of the American Thoracic Society (ATS) and European Respiratory Society (ERS) and was ratied by both organizations in June 2001 [13]. The following clinicopathological entities are recognised under the ATS/ERS classication and these will be considered more fully in the subsequent sections:
Basic signs in pulmonary HRCT

Over recent years there has been increasing conformity in the descriptive terms used to convey pathological appearances of the lung on HRCT. Four key patterns of abnormality have now been adopted by most authoritative texts [7] and can be summarized as follows: 1. 2. 3. 4. reticular or linear pattern nodular pattern areas of increased lung density areas of decreased lung density/cystic lesions
N N N N N N N
A reticular pattern may be seen in a variety of ways including thickening of the interlobular septa or thickening of the peribronchovascular or intralobular interstitium. The interface sign describes the appearance of an irregular boundary between lung and a vessel, bronchus or pleural surface this is usually due to thickening of the subpleural interstitium. The formation of honeycomb cysts can be seen at the end-stage of a variety of lung diseases and is also regarded as a type of reticular pattern. Lung nodules are generally subdivided according to their distribution into perilymphatic, centrilobular or random in type. Perilymphatic nodules are classically seen in sarcoid; centrilobular nodules (located at the centre of the pulmonary lobule) usually imply bronchiolar disease; and random nodules imply blood borne pathology such as miliary tuberculosis or metastases. Increased lung density may be recognised as either ground glass opacity or consolidation. With ground glass opacity there is a hazy increase in lung parenchymal density through which pulmonary vessels are still visible. This implies partial displacement of air from lung parenchyma and may be seen with either partial lling of alveoli (with cells, protein, blood etc.) or with thickening of the interstitial tissues [8]. With consolidation vessels are obscured and air-bronchograms may be present. Reduced lung density may be seen with a variety of disease processes including emphysema, in the presence of
38
Idiopathic pulmonary brosis/cryptogenic brosing alveolitis (IPF/CFA) Non-specic interstitial pneumonia (NSIP) (provisional) Cryptogenic organizing pneumonia (COP) Acute interstitial pneumonia (AIP) Respiratory bronchiolitis interstitial lung disease (RB-ILD) Desquamative interstitial pneumonia (DIP) Lymphoid interstitial pneumonia (LIP)
Idiopathic pulmonary brosis/cryptogenic brosing alveolitis

The term idiopathic pulmonary brosis (IPF) is used in the USA whilst cryptogenic brosing alveolitis (CFA) has been the term used most frequently in the UK. The condition occurs typically in middle aged patients and is characterized by the insidious onset of dyspnoea and dry cough, associated systemic symptoms such as malaise, weight loss and nger clubbing and ne crackles are heard on chest auscultation. The term usual interstitial pneumonia (UIP) refers to the histopathological pattern found on a surgical biopsy in patients with IPF. According to the ATS/ERS criteria, for the diagnosis to be made in the presence of a surgical biopsy showing UIP, there must be no other known cause of lung brosis (such as a collagen vascular disease or environmental exposure), the characteristic radiological ndings must be present and lung function tests should indicate a restrictive defect [13]. If the diagnosis is to be made in the absence of a surgical biopsy (as happens much of the time in practice) then additional
Idiopathic interstitial pneumonias
criteria need to be satised including a bronchial lavage that does not suggest any alternative diagnosis. IPF is probably the most common of the idiopathic interstitial pneumonias accounting for 62% of cases in the series of Bjoraker et al [14]. Even this gure is likely to be an underestimate as this series related to surgical lung biopsies and most patients with classic features of IPF do not undergo a biopsy. The prognosis of patients with IPF is poor with the reported duration from diagnosis to death ranging from 2.8 years to 6 years [12].
considered to be immature organizing brosis, often referred to as the broblast focus (Figure 3a). A chronic inammatory cell inltrate composed of lymphocytes and plasma cells is often seen within the areas of scarring.
Imaging
The chest radiograph in patients with IPF typically shows a reticulonodular pattern with a mid to lower zone and a subpleural predominance. As the disease progresses honeycomb cysts may become apparent [15, 16]. Lung volumes decrease with disease progression unless there is concomitant emphysema. HRCT features that correspond with a clinical diagnosis of IPF (and a histopathological pattern on biopsy of UIP) include a reticular pattern of opacity with a subpleural and basal predominance, honeycombing with numerous small cyst like spaces, irregular pleural surfaces, traction bronchiectasis and bronchiolectasis, and irregular bronchial wall thickening (Figure 3b) [17, 18]. The reticular pattern may be seen in the form of intralobular interstitial thickening (creating a net-like linear pattern within pulmonary lobules) [18]. Interlobular septal thickening may be seen but due to the architectural distortion that occurs with UIP this is not normally a prominent feature.
Pathology of UIP
The histology of UIP is that of a patchy process typically described as showing temporal heterogeneity [12]. This implies, that under microscopic low-power, relatively normal lung is admixed with lung showing recently formed and organizing brosis, and in other areas, there is more established (older) brosis. Severe interstitial brosis results in honeycombing with loss of the normal alveolar architecture, which is replaced by airspaces of varying size. There is often subpleural accentuation of the brosis. A common nding, which some authors consider an essential feature [12], is the presence of loosely textured bromyxoid tissue within the interstitium, which is
Figure 3. (a) Histological appearance of usual interstitial

pneumonia. High power view showing the loosely textured bromyxoid tissue (or broblast focus) within the interstitium (arrowed). This is a useful diagnostic feature. (b) High resolution CT (HRCT) in usual interstitial pneumonia with subpleural reticular opacity, traction bronchiectasis and honeycombing. (c) HRCT in the same patient in an accelerated phase with extensive ground glass opacication superimposed on the reticular pattern.
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Peribronchovascular thickening and irregularity is common as are irregular pleural surfaces. The small cyst-like spaces correspond with remodelled air spaces lined by bronchiolar epithelium found at pathological examination [17]. These cyst-like spaces have been shown to enlarge on serial HRCT [19, 20]. Localized areas of ground glass opacity may be seen in UIP. These may represent either areas of (potentially reversible) inammation or may represent ne intralobular interstitial thickening with brosis, which is too ne to be resolved by the scanner. The presence of traction bronchiectasis or bronchiolectasis in association with the ground glass opacity increases the likelihood that the appearances are due to brosis [21, 22]. HRCT can give an indication of likely response to treatment. In one study involving 37 patients with UIP, improved survival was seen in patients whose scans showed less extensive brosis and honeycombing and patients with a greater extent of ground glass opacity were more likely to respond favourably to treatment [23]. The radiological differential diagnosis would include brosis secondary to collagen vascular disease, drugs and asbestosis [13]. Very rarely sarcoidosis [24] and chronic extrinsic allergic alveolitis [25] can mimic UIP on HRCT. Patients with IPF usually undergo a gradual deterioration in their symptoms and lung function testing. A minority of patients may present with a more dramatic deterioration, which has been termed an accelerated phase of idiopathic pulmonary brosis [26]. This phase is generally associated with extensive ground glass opacity on HRCT superimposed on the typical subpleural reticular pattern (Figure 3c). This ground glass opacity has been shown to correspond most frequently with diffuse alveolar damage, the same pathological process responsible for acute respiratory distress syndrome (ARDS) and AIP [26, 27]. There is an increased incidence of lung cancer in patients with IPF [28]. Whether this increase is related to the brosis or is due to the increased incidence of cigarette smoking in patients with IPF is a matter of conjecture [13]. In these patients the cancer is typically seen radiologically as either a mass or as a more ill-dened area of consolidation and a peripheral and lower zone distribution has been reported [28].
the biopsy shows NSIP, my work has just begun [33]. Possible causes or associations might be underlying collagen vascular disease, drug reactions or extrinsic allergic alveolitis [12]. If investigation reveals no known cause then the clinical entity may be regarded as idiopathic NSIP.
Pathology
Typically, NSIP does not have the well-dened criteria of other more distinct interstitial pneumonias. Histologically, the disease shows a patchy interstitial inammatory and brosing process [30]. In contrast to the situation with UIP, the pattern of involvement is temporally uniform (i.e. the brosis all appears to be of about the same age) and the brosis is often less severe. The inammatory inltrate consists of mature lymphocytes and plasma cells, which typically widen the interstitium, although the amount is often less than that seen in lymphoid interstitial pneumonia (LIP) (Figure 4a). There are no granulomas, but a peribronchial accentuation of the inammation is not uncommon. Honeycomb areas, although described, are infrequent. Fibroblast foci, a helpful diagnostic feature of UIP are seldom seen in NSIP. The degree of inammation and brosis vary; this has prompted some workers to subdivide NSIP into cellular and brotic variants [34]. Those cases, which show predominantly more brosis, have a worse prognosis than those that have predominantly a cellular inammatory inltrate [34].
Imaging
The chest radiograph is abnormal in the majority of cases typically showing patchy bilateral inltrates with a mid and lower zone predominance [35]. As may be expected with an entity that began life as a waste basket diagnosis for pathologists, a range of appearances have been reported on HRCT in patients with biopsy proven NSIP. The most common nding is of bilateral ground glass opacity which typically has a lower zone and subpleural predominance (Figure 4b). Kim et al studied 23 patients and found the most frequent abnormality to be ground glass opacity with or without associated consolidation [36]. Irregular linear opacities, peribronchovascular thickening and bronchial dilatation were also frequently seen. All parenchymal abnormalities had a subpleural distribution. In another study of 55 patients there was evidence of ground glass opacity and a degree of architectural distortion in all cases [37]. Intralobular interstitial reticular opacities and traction bronchiectasis were seen predominantly in patients whose biopsies showed the brotic variant of NSIP. Hartman et al emphasised the wide range of ndings and in their series 32% of patients had features more in keeping with UIP [38]. In general honeycombing is seen less frequently in NSIP than with UIP and when present usually indicates the brotic variant [37]. The subpleural predominance of abnormality seen in many patients with NSIP can give a similar radiological appearance to UIP. MacDonald et al compared the HRCT appearances of patients with UIP and NSIP and found that ground glass opacity was seen more frequently in NSIP and was either the predominant abnormality or was seen with an associated reticular
Non-specic interstitial pneumonia (NSIP)

Pathologists have recognised for some time that many lung biopsy specimens demonstrate features of inammation or brosis which do not show features characteristic of any particular interstitial pneumonia. In 1990 Kitachi proposed the term unclassied interstitial pneumonia to describe such biopsy ndings [29]. In 1994 Katzenstein and Fiorelli suggested the term non-specic interstitial pneumonia [30]. Although intended as a term to describe pathological ndings, it became apparent in subsequent years that patients whose biopsy was classied as NSIP faired better than patients whose biopsy showed characteristic features of UIP [31]. Although there has been a tendency to start regarding NSIP as a clinical diagnosis in its own right [32], the ATS/ERS document suggests that NSIP should be regarded as a provisional clinical diagnosis whilst a search for underlying causes is carried out. The American respiratory physician, Talmadge King, has been quoted as saying when my pathologist tells me
40
Figure 4. (a) Medium power view of the histopathological appearance of non-specic interstitial pneumonia (NSIP) showing a
temporally uniform chronic pneumonitis with widening of the interstitium. In this case, brosis is minimal. (b) High resolution CT in from a patient with NSIP found on surgical lung biopsy. There is evidence of ground glass opacity along with a reticular pattern in keeping with a mixture of brotic and cellular components.
pattern [39]. Reticular opacities, when present were ner with NSIP than UIP although the authors concluded that there was a signicant overlap in appearances in the HRCT studies of patients with NSIP and UIP. The radiological differential diagnosis will depend to an extent on the proportions of ground glass and reticular opacities but may include UIP, extrinsic allergic alveolitis, drug induced lung disease, collagen vascular disease and possibly infection [12, 13].
published by Eplar et al in 1985 [42]. Eplar and colleagues termed the condition bronchiolitis obliterans with organizing pneumonia or BOOP and this term has since been widely used in the medical literature. However, the term cryptogenic organizing pneumonia is now preferred as it more accurately reects the disease process and avoids confusion with constrictive obliterative bronchiolitis [13].
Pathology
COP is essentially an airway disease the disease involves bronchioles as well as alveolar spaces. The histological hallmark of the disease is loosely textured plugs of bromyxoid tissue, which occlude, either totally or partially, the bronchioles, alveolar ducts and adjacent alveolar space [43]. The disease is invariably patchy with involved areas sharply demarcated from uninvolved lung (Figure 5a). It is common to identify secondary changes as a result of the airway occlusion. These include accumulation
Cryptogenic organizing pneumonia (COP)

Patients with COP are typically 4060 years of age and present with a persistent non-productive cough, dyspnoea, crackles on auscultation and bilateral inltrates on the chest radiograph [40]. Non-specic systemic symptoms such as malaise or low grade fever may be present. This clinical entity was rst described by Davison et al in 1983 [41] and the same condition was described in a series
Figure 5. (a) Low power view of organizing pneumonia showing plugs of loose granulation tissue lling alveoli (arrowed). (b) High
resolution CT in a patient with cryptogenic organizing pneumonia with extensive ground glass opacity and consolidation with a peripheral predominance.
41
of foamy macrophages, and there may also be interstitial changes, including widening of alveolar septae and an accompanying non-specic chronic inammatory cell inltrate. COP is distinct from obliterative bronchiolitis [44]. The latter entity is also a disease of bronchioles and the typical nding in this entity is that of total or partial occlusion of an airway by dense brous tissue. Obliterative bronchiolitis is a recognised complication of graft versus host disease as well as a variety of connective tissue disorders.
Acute interstitial pneumonia (AIP)

AIP differs from the other idiopathic interstitial pneumonias in its rapidity of onset and rapid progression. It typically affects previously healthy individuals (though some patients report a preceding viral-like illness) and patients can progress from being well to having respiratory failure requiring ventilation within a matter of days. There is a high mortality of the order of 60% though patients who survive the initial illness have a reasonable long term prognosis [12].
Pathology Imaging
On plain radiographs there is generally multifocal (often bilateral) peripheral consolidation. In the series of Eplar et al, diffuse patchy ground glass opacity was seen in 69% of patients chest radiographs and smaller numbers of patients demonstrated irregular linear opacities and nodular opacities [42]. On HRCT Lee et al found consolidation to be the most frequent nding in their series of 43 cases [45]. The consolidation had a subpleural and/or peribronchovascular distribution in 63% of cases. Ground glass attenuation and nodules were seen in 60% and 30% of patients, respectively. They concluded that in immunocompetent patients the most common nding consisted of bilateral areas of consolidation involving mainly the subpleural or peribronchovascular regions though in immunocompromised patients the ndings were more variable. Muller et al reviewed the CT ndings in 14 patients and found that all had areas of consolidation, small nodules or both [40]. 10 of the 14 patients had patchy unilateral or bilateral consolidation, seven had small nodules and two had irregular lines of increased attenuation. A predominantly subpleural distribution of the consolidation was seen in approximately half of patients. In one series of 129 patients with inltrative lung disease, 24 had COP and the CT ndings consisted of ground glass opacity, air-space consolidation, intralobular reticular opacities and nodules [18]. A peripheral predominance was seen in the majority (Figure 5b). The majority of patients (around 85%) with COP show a rapid response to steroid therapy but there is a minority of 10% to 15% in whom the disease remains progressive [46]. Patients with this poorer outcome tend to have reticulonodular shadowing on chest radiography [47]. It may be that some of these cases represent UIP with organizing pneumonia occurring as a secondary reaction, but the precise relationship between UIP and COP has not been fully elucidated [46]. The aetiology in most cases of COP is unknown but the pathological process in the lungs may be seen in association with infection, drugs and collagen vascular disease [48]. Organizing pneumonia may also occur at the margins of focal lung pathology such as Wegeners granulomatosis, abscesses or tumours so a biopsy result of organizing pneumonia should always be related to the clinical and imaging ndings [49]. Radiologically the differential diagnosis might include chronic eosinophilic pneumonia, alveolar cell carcinoma, lymphoma, sarcoid or infection [13].
42
The pathological process is essentially the same as that seen in ARDS and many authorities regard AIP as an idiopathic form of ARDS [12]. This disease, histologically, is that of diffuse alveolar damage and represents acute lung injury with damage to type I pnemeuocytes and/or endothelial cells with erosion of the alveolar/capillary interface and outpouring of oedema uid into the interstitium and air spaces [50]. This phase is referred to as the early or exudative phase and histologically, there is interstitial widening, broblast proliferation, a conspicuous chronic inammatory inltrate and loss of the lining alveolar epithelium. Tatty eosinophilic brin-rich strips, representing proteinaceous and type I pneumocyte debris line the perimeter of the alveolar spaces to form hyaline membranes (Figure 6a). Despite a typical history of a preceding viral-like illness, viral inclusions are not seen. With disease progression, the proliferative phase is seen, which is characterized by type II pneumocyte hyperplasia which occurs as a repair process, and this is often particularly exuberant. If the patient survives, healing by extensive scarring often supervenes, leading to permanent brosis.
Imaging
On the chest radiograph the appearance is of bilateral ground glass opacity with consolidation. There is usually no overall zonal predominance and there is usually preservation of the costophrenic angles, cardiac silhouette and hila. Primack et al reviewed the CT ndings in nine patients with AIP [51]. Bilateral symmetrical areas of ground glass opacity were seen in all cases (Figure 6b). No overall zonal predominance was seen in most patients and in some patients the ground glass opacity had a patchy distribution with areas of sparing seen. Areas of air-space consolidation were seen in six of nine patients, usually with a basal predominance. Ichikado and colleagues studied 14 patients who had undergone CT and lung biopsy [52]. They found that the exudative phase was characterized by ground glass opacity with areas of sparing within and areas of air space consolidation without traction bronchiectasis. The proliferative phase was characterized by ground glass opacity with or without traction bronchiectasis. Traction bronchiectasis with ground glass opacity and consolidation characterized the brotic phase and one patient demonstrated honeycombing. In the study of 36 patients by Johkoh et al, CT ndings included extensive ground glass opacity, areas of consolidation, traction bronchiectasis and architectural distortion [53]. Less common ndings
Figure 6. (a) High power view of acute interstitial pneumonia (AIP) showing scattered cellular debris in alveoli which are partly
lined by hyaline membranes (arrowed) a characteristic feature of the disease. (b) High resolution CT in AIP with bilateral patchy ground glass opacity and consolidation.
included bronchovascular and interlobular septal thickening, effusions and lymphadenopathy. CT ndings in long-term survivors include a coarse reticular pattern with distortion of the lung parenchyma. This pattern has a striking anterior distribution [54]. The radiological differential diagnosis would include ARDS from other causes, fulminant infection and possibly acute eosinophilic lung inltration [12, 55].
Pathology
In smokers it is not uncommon histologically to see aggregates of pigmented macrophages, predominantly around bronchioles. This is referred to as respiratory bronchiolitis or smokers bronchiolitis (Figure 7a). In some patients the pathological changes are more extensive and this may be associated with symptoms such as chronic cough or dyspnoea and the condition is then termed respiratory bronchiolitis-interstitial lung disease (RB-ILD). The clinical features are important in establishing the diagnosis [56]. The pigment within the macrophages is golden brown and is nely dispersed. Studies have indicated that pigment is related to particulate matter, especially silicates, within tobacco smoke. Fibrosis is minimal and the disease has an excellent prognosis, once smoking is curtailed. Furthermore,
Respiratory bronchiolitis-interstitial lung disease (RB-ILD)

As a clinical diagnosis RB-ILD is very rare and is associated with cigarette smoking. The onset of symptoms is insidious though there is normally a good response to smoking-cessation and steroid therapy [12].
Figure 7. (a) Low power view of respiratory bronchiolitis showing aggregates of pigmented macrophages (arrowed) surrounding a
small bronchiole (B). (b) High resolution CT in a case of respiratory bronchiolitis-interstitial lung disease (RB-ILD) with ground glass opacity and interlobular septal thickening (Courtesy of Dr A Anbarasu, Coventry, UK).
43
as described below, DIP also reects an accumulation of macrophages, and it seems likely that these diseases represent part of the same disease spectrum based on their presentation, an inevitable association with smoking and their clinical similarities [57, 58].
Imaging
The chest radiograph appearances are non-specic and consist of bilateral lower zone reticular shadowing [57]. Reported ndings on HRCT in RB-ILD include ground glass opacity, bronchial wall thickening, and centrilobular nodules. There may be very mild brosis with interlobular septal thickening (Figure 7b). Upper zone centrilobular emphysema and areas of reduced lung density due to air trapping are common [5861].
RB-ILD, they show similar pigment inclusions within the cytoplasm. Accompanying these changes, there is often a mild interstitial pneumonitis. Fibroblast foci are not normally present. It should be remembered that accumulation of alveolar macrophages might be present as a non-specic nding in a number of the interstitial pneumonias as well as from inhalation of diverse agents including asbestos, talc and silica.
Imaging
Chest radiographs are normal in up to a fth of patients. In others there may be ground glass opacication, predominantly in the lower zones and peripherally [62]. On HRCT, ground glass opacity is seen in the majority of patients (Figure 8b). All 23 patients with DIP in one series demonstrated this nding [18]. The ground glass opacity is usually patchy in distribution with a lower zone predominance. Reticular opacities may occasionally be seen but these are likely to be limited in extent. Small subpleural cyst-like opacities have also been described [63]. The radiological differential diagnosis would include subacute extrinsic allergic alveolitis, sarcoidosis, and infection if the patient is immunocompromised [12, 13].
Desquamative interstitial pneumonia

As has been mentioned, there are similarities between DIP and RB-ILD and many authorities now regard these two conditions as part of a spectrum of smoking-related interstitial lung disease. As with RB-ILD the onset of dyspnoea is insidious and there is normally a good response to steroids and smoking cessation.
Pathology
Histologically, the disease is typied by diffuse pulmonary involvement of mononuclear cells, which ll alveolar lumens (Figure 8a). The term desquamative is now considered a misnomer, as studies have shown that the collections of these cells seen within alveolar spaces are in fact macrophages rather than desquamated pneumocytes [12]. As a result, the lung is frequently consolidated and occasionally brotic foci may be evident, although this is mild in the early course of the disease, Later, more severe scarring including honeycombing may be present. The macrophages within the alveolar spaces not infrequently coalesce to form giant cells and typically, as with
Lymphoid interstitial pneumonia (LIP)

The inclusion of LIP in the classication of idiopathic interstitial pneumonias is contentious as this condition seldom occurs as an isolated disease but is usually seen in association with other diseases such as collagen vascular disease, particularly Sjogrens syndrome; lymphoma, particularly low grade non-Hodgkins B-cell lymphoma; and in children with human immunodeciency virus infection. The prognosis is likely to depend on the underlying disorder [64].
Figure 8. (a) Medium power view of desquamative interstitial pneumonia (DIP) showing alveoli lled by macrophages some have fused to form giant cells (arrowed). (b) High resolution CT in a case of DIP with subtle ground glass opacication along with subpleural cyst formation seen anteriorly in the right upper lobe. 44 Imaging, Volume 16 (2004) Number 1
Pathology
The histological features of LIP are a predominantly interstitial inltrate composed of mature lymphocytes and plasma cells and histiocytes [65]. The inltrate is often intense and diffuse involvement of the lung is characteristically seen. In places, the lymphoid inltrate often condenses to form hyperplastic lymphoid follicles with germinal centres. The interstitium is often widened as a result of this process. Occasionally sarcoid-like granulomas may be encountered and a variable amount of brosis may be present. It is not uncommon that the intensity of the cellular inltrate compresses the alveolar spaces and occasionally some of the lymphoid cells may spill over into airspaces. Importantly, necrosis is not a feature of this condition, but lymphoma is an important differential diagnosis. The use of special stains, particularly immunocytochemistry, maybe helpful in distinguishing between benign and malignant processes.
treatment regimen. AIP stands out as having the most rapid onset and the highest early mortality.
Making a diagnosis
The ATS/ERS document on the idiopathic interstitial pneumonias emphasises two points in relation to establishing a diagnosis in patients with a suspected idiopathic interstitial pneumonia [12]. These are: 1. The diagnostic process should be dynamic, with those involved willing to reconsider their diagnoses as new information comes to light. 2. The process should be multidisciplinary with the gold standard being represented by a consensus opinion between physician, radiologist and pathologist. HRCT and a lung biopsy should be regarded as being complementary with the HRCT limited by resolution and the biopsy by sampling. HRCT, which looks at the whole of both lungs can help put the pathology report into context. Both the HRCT and biopsy need to be considered in relation to the clinical setting. The initial step will involve a patient with suspected diffuse lung disease being assessed with clinical history, examination, chest radiograph and lung function tests. If these support the possibility of an idiopathic interstitial pneumonia then the next investigation should be a HRCT of the lungs. This may show features in keeping with UIP and if the clinical picture is in keeping with IPF (with all the caveats mentioned in the UIP section above taken into account), then the patient can be treated as such without the need for a surgical lung biopsy. Hunninghake et al studied 91 patients with suspected diffuse lung disease and found that when an experienced radiologist made a condent diagnosis of UIP on the HRCT they were almost always correct, with the positive predictive value being 96% [68]. No patient whose biopsy showed UIP had a normal HRCT. The HRCT may show appearances suggestive of an interstitial pneumonia other than UIP or appearances may be equivocal between UIP and another interstitial pneumonia such as NSIP. In this case the patient will require further assessment, usually initially with transbronchial biopsy and bronchial lavage. If these should prove inconclusive then a surgical lung biopsy may be required. Some patients may proceed directly from HRCT to a surgical biopsy, particularly if the radiological abnormality has a subpleural predominance. The HRCT may show features of other types of diffuse lung disease such as granulomatous disorders, Langerhans cell histiocytosis etc. and these can then be assessed further as appropriate. A simple algorithm illustrating the diagnostic pathway is shown in Figure 10. Interpreting surgical biopsy results is not always straightforward for the pathologist. Occasions can occur when a sample from one lobe may show UIP histologically whilst that from another lobe may show an NSIP pattern [69]. In such cases, patients normally progress in line with UIP and this should be regarded as the pathological diagnosis in this case. It should always be kept in mind that a number of the processes described in this article can occur as secondary phenomena adjacent to or on a background of another process. Organizing pneumonia for
45
Imaging
The radiographic appearance is classically described as that of a bilateral lower zone abnormality with reticular or reticulonodular shadowing [66, 67]. On HRCT features include ground glass opacity and ne nodules with a centrilobular distribution (Figure 9). Other ndings include interlobular septal thickening, thickening of the peribronchovascular interstitium. Cystic air spaces in the lung parenchyma occur rarely and mediastinal lymphadenopathy may be seen [67].
Overview
Table 1 summarizes the key clinical, pathological features of the idiopathic interstitial pneumonias. Note that UIP alone is regarded as being a condition from which a complete recovery cannot be made. The pathological process centred on the broblast focus appears to progress relentlessly and be impervious to any current
Figure 9. High resolution CT in lymphoid interstitial pneumonia with ground glass opacity, septal thickening and numerous parenchymal nodules (Courtesy of Dr S Worthy, Newcastle, UK). Imaging, Volume 16 (2004) Number 1
46 Table 1. An overview of the idiopathic interstitial pneumonias. (Information taken from data in references [12] and [13])
Clinical diagnosis IPF/CFA Pathological pattern UIP Radiographic features Typical HRCT ndings Mean age of onset 57 years Mortality (and mean survival) 68% (56 years) Response to steroids Poor Complete recovery possible No Radiological differential diagnosis Asbestosis, collagen vascular disease, extrinsic allergic alveolitis, sarcoidosis, Extrinsic allergic alveolitis, UIP, DIP, COP Basal reticular shadowing with volume loss Ground glass and reticular opacity NSIP provisional NSIP COP AIP OP DAD Patchy bilateral consolidation Progressive diffuse ground glass opacity and consolidation Ground glass opacity DIP DIP RB-ILD RB Ground glass opacity, bronchial wall thickening Reticular opacities, nodules LIP LIP Subpleural reticular pattern, traction bronchiectasis, architectural distortion Ground glass opacity and reticular opacity, often lower zone and subpleural predominance Patchy consolidation and/or nodules Ground glass opacity and consolidation. Traction bronchiectasis later Ground glass opacity, peripheral and lower zone predominant Patchy ground glass opacity, centrilobular nodules, bronchial wall thickening Ground glass opacity, centrilobular nodules, septal and bronchovascular thickening, thin walled cysts 49 years 11% (17 months) Good Yes 49 years 62% (1 to 2 months) 27% (12 years) Poor Yes 42 years Good Yes Eosinophilic pneumonia, vasculitis, NSIP, infection ARDS, hydrostatic oedema, acute eosinophilic lung disease, infection RB-ILD, extrinsic allergic alveolitis, sarcoidosis, PCP DIP, NSIP, extrinsic allergic alveolitis Sarcoidosis, lymphangitis carcinomatosa, Langerhans cell histiocytosis 36 years 0% Good Yes
HRCT, high resolution CT; IPF/CFA, idiopathic pulmonary brosis/cryptogenic brosing alveolitis; UIP, usual interstitial pneumonia; NSIP, non-specic interstitial pneumonia; COP, cryptogenic organizing pneumonia; OP, organizing pneumonia; AIP, acute interstitial pneumonia; DAD, diffuse alveolar damage; DIP, desquamative interstitial pneumonia; RB-ILD, respiratory bronchiolitis-interstitial lung disease; LIP, lymphoid interstitial pneumonia, ARDS, acute respiratory distress syndrome, PCP, pneumocystis carinii pneumonia.
Figure 10. Diagnostic algorithm for patients

with a suspected interstitial pneumonia (based on algorithms provided in [13]).
example can occur around a lung tumour or in lungs with diffuse changes of UIP. Focal areas of DIP may be seen on a background of UIP [12]. Correlation of pathology, clinical and radiological ndings can help ensure that the appropriate diagnosis is applied to the patient. Distinguishing between UIP and NSIP can be particularly difcult. Flaherty et al found that many patients in whom the HRCT was indeterminate or suggestive of NSIP had UIP on surgical lung biopsy [70]. This study also found that HRCT provided prognostic information. Patients whose biopsy showed UIP had a poorer prognosis when the HRCT also showed a UIP pattern, rather than a pattern suggestive of NSIP.
that is most likely to accurately reect the patients underlying disease process.
References
1. McAdams HP, Rosado-de-Christainson ML, Wehunt WD, Fishback NF. The alphabet soup revisited: the chronic interstitial pneumonias in the 1990s. Radiographics 1996;16: 100933. 2. Nicholson AG. Classication of the idiopathic interstitial pneumonias: making sense of the alphabet soup. Histopathology 2002;41:38191. 3. Weibel ER, Crystal RG. Structural organization of the pulmonary interstitium. In: Crystal RG, West JB, et al, editors. The Lung: Scientic Foundations. Philadelphia: Lippincott-Raven Publishers, 1977. 4. Miller WS. The lung. Springeld, IL: Charles C. Thomas, 1947:3942. 5. Weibel ER. Looking into the lung: What can it tell us. AJR Am J Roentgenol 1979;133:102131. 6. Webb WR, Muller NL, Naidich DP. Normal lung anatomy. In: Webb WR, Muller NL, Naidich DP. High-resolution CT of the lung, (3rd edn). Philadelphia: Lippincott Williams and Wilkins, 2001:4970. 7. Webb WR, Muller NL, Naidich DP. High-resolution computed tomography ndings of lung disease. In: Webb WR, Muller NL, Naidich DP. High-resolution CT of the lung, (3rd edn). Philadelphia: Lippincott Williams and Wilkins, 2001:71192.
Conclusion
Imaging plays an important role in patients with a suspected idiopathic interstitial pneumonia. The chest radiograph may provide the rst indication of such a disease being present. HRCT has a pivotal role in helping distinguish patients with UIP from those with other interstitial pneumonias. For patients who go on to have a bronchoscopic or surgical biopsy the HRCT can guide the optimum type and location of the biopsy. In certain situations HRCT can also give an indication of likely response to therapy and prognosis. In patients who undergo a biopsy, the radiological ndings are an important piece of the jigsaw of the consensus opinion
47

8. Engeler CE, Tashjian JH, Trenkner SW, Walsh JW. Ground glass opacity of the lung parenchyma: a guide to analysis with high-resolution CT. AJR Am J Roentgenol 1993;160:24951. 9. Green FHY. Overview of pulmonary brosis. Chest 2002; 122:334S339S. 10. Liebow AA, Carrington CB. The interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, editors. Frontiers of pulmonary radiology. New York, NY: Grune & Stratton, 1969;10241. 11. Muller NL, Colby TV. Idiopathic interstitial pneumonias: high-resolution CT and histologic ndings. Radiographics 1997;17:101622. 12. Katzenstein A-LA, Myers JL. Idiopathic pulmonary brosis: clinical relevance of the pathologic classication. Am J Respir Crit Care Med 1998;157:130115. 13. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classication of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002;165:277304. 14. Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, Schroeder DR, et al. Prognostic signicance of histopathological subsets in idiopathic pulmonary brosis. Am J Respir Crit Care Med 1998;157:199203. 15. Muller NL, Guerry-Force ML, Staples CA, Wright JL, Wiggs B, Coppin C, et al. Differential diagnosis of bronchiolitis obliterans organising pneumonia and usual interstitial pneumonitis: clinical, functional and radiologic ndings. Radiology 1987;162:1516. 16. Primack SL, Hartman TE, Hansell DM, Muller NL. Endstage lung disease: CT ndings in 61 patients. Radiology 1993;189:6816. 17. Nashimura K, Kitaichi M, Izumi T, Nagai S, Kanaoka M, Itoh H. Usual interstitial pneumonia: histologic correlation with high-resolution CT. Radiology 1992;182:33742. 18. Johkoh T, Muller NL, Cartier T, Kavanagh PV, Hartman TE, Akira M, et al. Idiopathic interstitial pneumonias; diagnostic accuracy of thin section CT in 129 patients. Radiology 1999;211:55560. 19. Akira M, Sakatani M, Ueda E. Idiopathic pulmonary brosis: progression of honeycombing at thin-section CT. Radiology 1993;189:68791. 20. Mino M, Noma S, Kobashi Y, Iwata T. Serial changes of cystic air spaces in brosing alveolitis: a CT-pathologic study. Clin Radiol 1995;50:35763. 21. Leung AN, Miller RR, Muller NL. Parenchymal opacica tion in chronic inltrative lung disease: CT-pathologic correlation. Radiology 1993;188:20914. 22. Remy-Jardin M, Giraud F, Remy J, Copin MC, Gosselin B, Duhamel A. Importance of ground-glass attenuation in chronic diffuse inltrative lung disease: pathologic-CT correlation. Radiology 1993;189:6938. 23. Gay SE, Kazerooni EA, Toews GB, Lynch JP, Gross BH, Cascade PN, et al. Idiopathic pulmonary brosis: predicting response to therapy and survival. Am J Respir Crit Care Med 1998;157:106372. 24. Padley SP, Padhani AR, Nicholson A, Hansell DM. Pulmonary sarcoidosis mimicking cryptogenic brosing alveolitis. Clin Radiol 1996;51:80710. 25. Lynch DA, Newell JD, Logan PM, King TE Jr, Muller NL. Can CT distinguish idiopathic pulmonary brosis from hypersensitivity pneumonitis? AJR Am J Roentgenol 1995;165:80711. 26. Akira M, Hamada H, Sakatani M, Kobayashi C, Nishioka M, Yamamoto S. CT ndings during phase of accelerated deterioration in patients with idiopathic pulmonary brosis. AJR Am J Roentgenol 1997;168:7983. 27. Kondoh Y, Taniguchi H, Kawabata Y, et al. Acute exacerbation in idiopathic pulmonary brosis: analysis of clinical and pathological ndings in three cases. Chest 1993;103:180812. 28. Lee JH, Im JG, Ahn JM, Yeon KM. Lung cancer in patients with idiopathic pulmonary brosis: CT ndings. J Comput Assist Tomog 1996;20:97982. 29. Kitachi M. Pathologic features and the classication of interstitial pneumonia of unknown etiology. Bulletin of the Chest Disease Research Institute, Kyoto University 1990; 23:118. 30. Katzenstein A-LA, Fiorelli RF. Nonspecic interstitial pneumonia/brosis: histologic features and clinical signicance. Am J Surg Pathol 1994;18:13647. 31. Cottin V, Donsbeck AV, Revel D, Loire R, Cordier JF. Nonspecic interstitial pneumonia: individualization of a clinicopathologic entity in a series of 12 patients. Am J Respir Crit Care Med 1998;158:128693. 32. Daniil ZD, Gilchrist FC, Nicholson AG, Hansell DM, Harris J, Colby TV, et al. A histologic pattern of nonspecic interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic brosing alveolitis. Am J Respir Crit Care Med 1999;160: 899905. 33. Nicholson AG, Wells AU. Non-specic interstitial pneumonia: nobody said its perfect. Am J Respir Crit Care Med 2001;164:15534. 34. Travis WD, Matsui K, Moss J, Ferrans VJ. Idiopathic nonspecic interstitial pneumonia: prognostic signicance of cellular and brosing patterns: survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia. Am J Surg Pathol 2000;24:1933. 35. Park JS, Lee KS, Kim JS, Park CS, Suh YL, Choi DL, et al. Nonspecic interstitial pneumonia with brosis: radiographic and CT ndings in seven patients. Radiology 1995;195:6458. 36. Kim TS, Lee KS, Chung MP, Han J, Park JS, Hwang JH, et al. Nonspecic interstitial pneumonia with brosis: high resolution CT and pathologic ndings. AJR Am J Roentgenol 1998;171:164550. 37. Johkoh T, Muller NL, Colby TV, Ichikado K, Taniguchi H, Yasuhiro Kondoh Y, et al. Nonspecic interstitial pneumonia: correlation between thin-section CT ndings and pathologic subgroups in 55 patients. Radiology 2002;225: 199204. 38. Hartman TE, Swenson SJ, Hansell DM, Colby TV, Myers JL, Tazelaar HD, et al. Nonspecic interstitial pneumonia: variable appearance at high-resolution chest CT. Radiology 2000;217:7015. 39. MacDonald SLS, Rubens MB, Hansell DM, Copley SJ, Desai SR, du Bois RM, et al. Nonspecic interstitial pneumonia and usual interstitial pneumonia: comparative appearances and diagnostic accuracy of thin-section CT. Radiology 2001;221:6005. 40. Muller NL, Guerry-Force ML, Staples CA, et al. Differential diagnosis of bronchiolitis obliterans with organizing pneumonia and usual interstitial pneumonia: clinical, functional, and radiologic ndings. Radiology 1987;162:1516. 41. Davison A, Heard B, McAllister WAC, Turner-Warwick MEH. Cryptogenic organizing pneumonitis. QJM 1983;52: 382. 42. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985;312:1528. 43. Colby TV. Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 1992;102(1 Suppl):38S43S. 44. Muller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic ndings. Radiology 1995;196:312. 45. Lee KS, Kullnig P, Hartman TE, Muller NL. Cryptogenic organizing pneumonia: CT ndings in 43 patients. AJR Am J Roentgenol 1994;162:5436. 46. Yousem SA, Lohr RH, Colby TV. Idiopathic bronchiolitis obliterans organizing pneumonia/cryptogenic organizing pneumonia with unfavourable outcome: pathologic predictors. Mod Pathol 1997;10:86471.
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47. Cordier J-F, Loire R, Brune J. Idiopathic bronchiolitis obliterans organizing pneumonia. Denitions of clinical proles in a series of 16 patients. Chest 1989;96:9991004. 48. Muller NL, Fraser RS, Lee KS, Johkoh T. Interstitial pneumonia. In: Muller NL, Fraser RS, Lee KS, Johkoh T. Diseases of the lung: radiologic and pathologic considerations. Philadelphia, PA: Lippincott Williams and Wilkins, 2003:16382. 49. Colby TV, Carrington CB. Interstitial lung disease. In: Thurlbeck WM, Churg AM, editors. Pathology of the lung, (2nd edn). New York: Thieme Medical Publishers Inc., 1995:589738. 50. Katzenstein AL, Myers JL, Mazur MT. Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol 1986;10:25667. 51. Primack SL, Hartman TE, Ikezoe J, Akira M, Sakatani M, Muller NL. Acute interstitial pneumonia: radiographic and CT ndings in nine patients. Radiology 1993;88:81720. 52. Ichikado K, Suga M, Muller NL, Taniguchi H, Kondoh Y, Akira M, et al. Acute interstitial pneumonia: high resolution CT ndings correlated with pathology. AJR Am J Roentgenol 1997;168:3338. 53. Johkoh T, Muller NL, Taniguchi H, Kondoh Y, Akira M, Ichikado K, et al. Acute interstitial pneumonia: thin-section CT ndings in 36 patients. Radiology 1999;211:85963. 54. Desai SR, Wells AU, Rubens MB, Evans TW, Hansell DM. Acute respiratory distress syndrome: CT abnormalities at long term follow up. Radiology 1999;210:2935. 55. Philit F, Etienne-Mastroianni B, Parrot A, Guerin C, Robert D, Cordier JF. Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med 2002;166:11578. 56. Myers JL, Veal CF Jr, Shin MS, Katzenstein AL. Respiratory bronchiolitis causing interstitial lung disease. A clinicopathologic study of six cases. Am Rev Respir Dis 1987;135:8804. 57. Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitisassociated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 1989; 64:137380. 58. Heyneman LE, Ward S, Lynch DA, Remy-Jardin M, Johkoh T, Muller NL. Respiratory bronchiolitis, respiratory bronchiolitis associated interstitial lung disease and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process. AJR Am J Roentgenol 1999;173:161722. 59. Gruden JF, Webb WR. CT ndings in a proved case of respiratory bronchiolitis. AJR Am J Roentgenol 1993;161: 446. 60. Holt RM, Schmidt RA, Godwin D, Raghu G. High resolution CT in respiratory bronchiolitis - associated interstitial lung disease. J Comput Assist Tomogr 1993;17:4650. 61. Moon J, du Bois RM, Colby TV, Hansell DM, Nicholson AG. Clinical signicance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease. Thorax 1999;54:100914. 62. Feigin DS, Friedman PJ. Chest radiography in desquamative interstitial pneumonitis: a review of 37 patients. AJR Am J Roentgenol 1980;134:919. 63. Hartman TE, Primack SL, Swensen SJ, et al. Desquamative interstitial pneumonia: thin-section CT ndings in 22 patients. Radiology 1993;187:78790. 64. Koss MN. Pulmonary lymphoid disorders. Semin Diagn Pathol 1995;12:15871. 65. Nicholson AG, Wotherspoon AC, Diss TC, Hansell DM, du Bois R, Sheppard MN, et al. Reactive pulmonary lymphoid disorders. Histopathology 1995;26:40512. 66. Julsrud PR, Brown LR, Li CY, Rosenow EC, Crowe JK. Pulmonary processes of mature-appearing lymphocytes: pseudolymphoma, well differentiated lymphocytic lymphoma and lymphocytic interstitial pneumonitis. Radiology 1978; 127:28996. 67. Johkoh T, Muller NL, Pickford HA, Hartman TE, Ichikado K, Akira M, et al. Lymphocytic interstitial pneumonia: thin-section CT ndings in 22 patients. Radiology 1999;212: 56772. 68. Hunninghake GW, Zimmerman MB, Schwartz DA, King TE Jr, Lynch J, Hegele R, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary brosis. Am J Respir Crit Care Med 2001;164:1936. 69. Flaherty KR, Travis WD, Colby TV, Toews GB, Kazerooni EA, Gross BH, et al. Histopathological variability in UIP and NSIP. Am J Respir Crit Care Med 2001;164:17227. 70. Flaherty KR, Thwaite EL, Kazerooni EA, Gross BH, Colby TV, Travis WD, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003;58:1438.
49
RCR accredited
Multiple-choice questionnaire: Chest radiology

The following multiple-choice questions are based entirely on the contents of this issue of Imaging, and are accredited by the Royal College of Radiologists for continuing medical education. Photocopy and complete the reader response form on pages 7576answers must be received by the BIR no later than 10 November 2004. If you achieve a score of 75% or above you will be awarded 1 Category One CPD Credit. Up to 6 Credits per year may be obtained through journal CME. Answers will be printed in Imaging 16(3), and will also be available on the BIRs website www.bir.org.uk following the above submission deadline. (c) The predominant HRCT appearance will depend on the relative extents of the brosis and inammation present in any one case. (d) Ground glass opacity, if present, typically has a subpleural distribution. (e) On HRCT it can be easily distinguished from usual interstitial pneumonia in the vast majority of cases.
Question 4
Cryptogenic organizing pneumonia: (a) Typically results in multifocal consolidation or ground glass opacity. (b) Responds well to steroids in most cases. (c) When suggested by radiological and pathological ndings should lead to a search for an underlying cause. (d) May have a predominantly peribronchovascular distribution of consolidation in some patients. (e) When suggested on the pathology report of a needle biopsy of a mass lesion excludes the possibility of a carcinoma.
Question 1
In making a diagnosis of an idiopathic interstitial pneumonia: (a) The pathologists report from a surgical lung biopsy is the gold standard. (b) A transbronchial biopsy is the best approach if the high resolution CT (HRCT) shows subtle, indeterminate changes of usual interstitial pneumonia. (c) If the HRCT shows a typical appearance of usual interstitial pneumonia a surgical lung biopsy is advisable for conrmation. (d) The HRCT may provide prognostic information in some situations. (e) The patients social and occupational history are usually irrelevant when considering the possibility of an interstitial pneumonia.
Question 5
In acute interstitial pneumonia (AIP): (a) The pathological process is essentially the same as that seen in acute respiratory distress syndrome (ARDS). (b) Onset of symptoms is insidious, usually over a period of several weeks. (c) There is a good response to steroids in the majority of patients. (d) Widespread ground glass opacity or consolidation are typical ndings in the early stages. (e) Long-term survivors may have mild brosis evident on HRCT in the anterior portions of the lungs.
Question 2
Cryptogenic brosing alveolitis (idiopathic pulmonary brosis): (a) Typically presents in early adulthood. (b) Responds well to steroids in most cases. (c) Ground glass opacity is usually the predominant HRCT nding. (d) Honeycomb cysts may be seen on HRCT and these may enlarge with the passage of time. (e) Has an appearance on HRCT, which in occasional patients may be mimicked by chronic extrinsic allergic alveolitis.
Question 6
Regarding the pathology in lung cancer: (a) Adenocarcinoma most often presents as a hilar mass. (b) Large cell carcinoma often metastasises early. (c) Mixed histology, i.e. adenosquamous carcinoma, can co-exist. (d) Small cell carcinoma is associated with endobronchial disease. (e) Bronchoalveolar cell carcinoma shows a distinctive pattern of growth on the alveolar surface.
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Question 3
Regarding non-specic interstitial pneumonia (NSIP): (a) It is primarily a clinical diagnosis. (b) An underlying cause is readily apparent in the majority of patients.
Question 7
The following features in a peripheral lung lesion would suggest malignancy: (a) Lobulation. (b) A 1 cm pulmonary mass with calcication. (c) A 4 cm pulmonary mass with calcication. (d) A pleural tag. (e) Well-dened margins.
(e) 3-He MRI can give both static and dynamic information of lung ventilation.
Question 12
3-He MRI may be useful for the following clinical applications: (a) Pulmonary brosis. (b) Emphysema. (c) Asthma. (d) Cystic brosis. (e) Pulmonary perfusion studies.
Question 8
When staging non-small cell lung cancer: (a) MRI is superior to CT for chest wall invasion. (b) MRI is superior to CT for pancoast tumours. (c) Local chest wall pain is more specic than CT to indicate chest well invasion. (d) CT is superior to 18 FDG PET for T staging. (e) PET with 18 FDG is superior to CT in the detection of brain metastases.
Question 13
Regarding chronic obstructive pulmonary disease (COPD): (a) Cigarette smoking is the most common cause. (b) Chronic bronchitis is a histological diagnosis. (c) The chest radiograph is abnormal in the majority of patients with chronic bronchitis. (d) Bronchial wall thickening is a sensitive marker of chronic bronchitis on the chest radiograph. (e) Bronchial wall thickening is rarely seen in non-smokers.
Question 9
Regarding TNM staging in lung cancer: (a) Pulmonary metastases within the same lobe are considered M1 disease. (b) Subcarinal lymph node involvement at mediastinoscopy is considered N3 disease. (c) A 2 cm tumour .2 cm from the carina is T1 disease. (d) Chest wall invasion equates to T3 disease. (e) Supraclavicular lymph node involvement on the ipsilateral side equates to N3 disease.
Question 14
Concerning smoking-related interstitial lung disease: (a) Pulmonary Langerhans cell histiocytosis occurs exclusively in cigarette smokers. (b) Desquamative interstitial pneumonia occurs exclusively in cigarette smokers. (c) Pulmonary Langerhans cell histiocytosis is characterized on HRCT by nodules and irregular cysts with a diffuse distribution. (d) Desquamative interstitial pneumonia is characterized on HRCT by ground glass opacity which has a basal predominance on around three quarters of cases. (e) Histological features of desquamative interstitial pneumonia are frequently seen in patients with pulmonary Langerhans cell histiocytosis.
Question 10
Regarding MR angiography of the pulmonary arteries: (a) The current standard is using time-of-ight sequences. (b) If gadolinium is used, a bolus injection of 0.4 mmol kg21 should be used. (c) Parallel (ultrafast) imaging techniques are less useful in breathless patients. (d) Test bolus injection of gadolinium is no longer required if parallel (ultrafast) imaging is used. (e) Images should be evaluated on a workstation, using post-processing techniques and core images.
Question 15
Concerning emphysema: (a) Panlobular emphysema usually predominates in the upper lobes. (b) Centrilobular emphysema is associated with greater functional impairment than paraseptal emphysema. (c) Flattening of the diaphragm is the most reliable sign of hyperination on the posteroanterior chest radiograph. (d) Subjective assessment of emphysema extent on HRCT consistently overestimates the pathological extent of disease.
Question 11
Regarding hyperpolarized 3-helium MR imaging: (a) 3-He at 1.5 T has a Larmor frequency of 48 MHz. (b) 3-He MRI is best performed using 90 ip angles. (c) 3-He gas has high diffusivity in air. (d) 3-He gas often shows severe adverse events, such as hypoxia.
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(e) Lung volume reduction surgery improves survival, and exercise tolerance, and forced expiratory volume in 1 s (FEV1) in patients with upper lobe predominant emphysema.
Question 20
Regarding malignant mesothelioma: (a) Early rib destruction is common. (b) The majority of patients have an associated pleural effusion. (c) Focal pleural masses are more common than diffuse irregular pleural thickening. (d) Tumour seeding along biopsy needle and drain tracts is a recognised complication. (e) The incidence is declining.
Question 16
Regarding smoking-related interstitial lung disease: (a) Interstitial brosis is absent in patients with emphysema. (b) Respiratory bronchiolitis may precede the development of centrilobular emphysema. (c) Desquamative interstitial pneumonia has a peribronchiolar distribution histologically. (d) In pulmonary Langerhans cell histiocytosis the chest radiography usually shows normal lung volumes. (e) Usual interstial pneumonia is more common in smokers than non-smokers.
Question 21
The following isotopes emit positrons (a positive electron): (a) Fluorine-18. (b) Fluorine-19. (c) Oxygen-15. (d) Carbon-11. (e) Carbon-13.
Question 17
Regarding localized brous tumour of the pleura: (a) These comprise approximately 50% of pleural tumours. (b) They are typically well-dened on CT. (c) Pedunculated tumours are usually benign. (d) Calcication is common. (e) They are related to previous asbestos exposure.
Question 22
Other potential radionuclide tracers for the imaging of the solitary pulmonary nodule: (a) Indium-111 octreotide. (b) 99Tcm tetrofosmin. (c) Iodine-123 mIBG. (d) Thallous-201 chloride. (e) 99Tcm MDP.
Question 23 Question 18
Regarding the staging of bronchogenic carcinoma: (a) Tumour invading the visceral pleural is classied as T3. (b) Involvement of the mediastinal pleural is classied as T4. (c) Parietal pleural invasion is classied as T3. (d) Tumour with an associated malignant pleural effusion is classied as T4. (e) T4 tumour is always stage IV. Which of the following statements are true? (a) F-18 FDG is proven to be effective in assessment of the solitary pulmonary nodule less than 1 cm in diameter. (b) 99Tcm depreotide is proven to be effective in assessment of the solitary pulmonary nodule less than 1 cm in diameter. (c) The 140 KeV photon emitted by 99Tcm depreotide require a gamma camera, which has coincidence timing for detection. (d) Gamma camera PET is as effective in the assessment of the 2 cm solitary pulmonary nodule alone. (e) Dynamic contrast enhanced CT has a similar sensitivity and specicity in the assessment of the solitary pulmonary nodule as F-18 FDG.
Question 19
Regarding rounded atelectasis: (a) A central location is characteristic. (b) There is evidence of volume loss in the adjacent lung. (c) Malignant transformation may occur. (d) Rounded atelectasis can be reliably differentiated from malignancy in equivocal cases using dynamic contrast-enhanced CT. (e) Previous haemothorax is a recognised association.
Question 24
Regarding F-18 FDG PET in the assessment of the solitary pulmonary nodule: (a) Squamous cell carcinoma of the lung is a frequent cause of a false negative study. (b) Sarcoidosis is a know cause for a false positive study.
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(c) Uptake by tumour reects the increase expression of glucose transport proteins by the tumour cells. (d) Imaging post administration of F-18 FDG is best performed within 30 min of injection due to short physical half-life of 110 min. (e) Insulin infusion will improve the visualization of a tumour compared with adjacent tissues.
Question 25
Regarding 99Tcm depreotide SPECT in the assessment of the solitary pulmonary nodule: (a) Is a radioligand specic for somatostatin receptor types 1, 4 and 5
(b) In the solitary pulmonary nodule greater than 1 cm as accurate as F-18 FDG in distinguishing benign from malignant disease. (c) Granulomatous diseases are cause for false positive results. (d) Is a radioactive labelled antibody specic for lung tumour cells. (e) Is currently more accessible than F-18 FDG for the provision of the functional assessment of the nature of the solitary nodule.
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Answers to multiple-choice questionnaire: Chest radiology [from Imaging 16(1)]

Answer 1
(a) False. The gold standard is a consensus opinion taking into account the radiological, pathological and clinical ndings. (b) False. With subtle subpleural changes suggestive of usual interstitial pneumonia (UIP), the patient should proceed to a surgical lung biopsy. (c) False. If the radiological ndings are typical of UIP and the clinical picture ts with crytogenic brosing alveolitis/idiopathic pulmonary brosis (CFA/IPF) and other causes such as collagen vascular disease have been excluded, the patient can be treated without the need for a surgical biopsy. (d) True. (e) False. The occupational and social history are of crucial importance as conditions such as extrinsic allergic alveolitis or asbestosis may be considered in the differential diagnosis.
Reference: Fischer T, Reynolds JH, Trotter SE. The idiopathic interstitial pneumonias: a beginners guide. Imaging 2004; 16:3749.
(e) False. There is signicant overlap in the appearances of UIP and non-specic interstitial pneumonia (NSIP), particularly if extensive brosis is present in the case of NSIP.
Answer 4
(a) True. (b) True. However, in around 1015% of patients the response is poor and these patients may go on to develop pulmonary brosis. (c) True. Such causes might include drug reactions, collagen vascular disease, noxious fume inhalation or inammatory bowel disease. (d) True. (e) False. Organizing pneumonia can often be found at the margins of tumours or lung abscesses. If the radiological appearances are suspicious of a tumour the biopsy should be repeated, either under imaging guidance or via a surgical approach.
Answer 2
(a) False. CFA/IPF typically presents in middle age. (b) False. Response to steroids is poor and the prognosis is poor. (c) False. A reticular pattern with a subpleural distribution with associated traction bronchiectasis and cysts formation typify the HRCT appearance of this condition. Ground glass opacity may be present but will not be the predominant abnormality. (d) True. (e) True.
Answer 5
(a) True. (b) False. Onset of symptoms is rapid the patient may require mechanical ventilation within a day or so of the onset of symptoms. (c) False. The response to steroids is poor the mortality rate is at least 60%. (d) True. (e) True. This may be due to the protective effect that consolidation in the dependent areas of lung has which reduced the severity of ventilator induced lung injury.
Answer 3
(a) False. It is, strictly speaking a pathological diagnosis the term was devised by pathologists to describe lung biopsy ndings. (b) False. Most patients will require detailed investigation and even then many cases will remain idiopathic. (c) True. (d) True.
Answer 6
(a) False. (b) False.
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Answers to multiple-choice questionnaire: Chest radiology
(c) True. (d) False. (e) True.

Reference: Gomersall LN, Olson S. Imaging in lung cancer. Imaging 2004;16:19.
(d) False. (e) True.

Reference: Hill C, van Beek EJR. MRI of the chest: present and future. Imaging 2004;16:6170.
Answer 7
(a) (b) (c) (d) (e) True. False. True. True. False.
Answer 12
(a) (b) (c) (d) (e) False. True. True. True. False.
Answer 8
(a) (b) (c) (d) (e) False. True. True. True. False.
Answer 13
(a) True. Although several factors have been implicated in its aetiology cigarette smoking accounts for the majority of cases. (b) False. Chronic bronchitis is a clinical diagnosis characterized by mucus hypersecretion and chronic expectoration of mucus on most days during at least 3 consecutive months for not less than 2 consecutive years. (c) False. Radiographic ndings in chronic bronchitis are non-specic and may be normal in 2150% of patients. (d) False. Bronchial wall thickening may be seen on HRCT in a third of smokers and up to 42% of normals on chest radiographs. (e) False. Bronchial wall thickening is seen in 18% of non-smokers and is commonly seen in asthma.
Reference: Screaton NJ, Koh T. Emphysema and smokingrelated lung diseases. Imaging 2004;16:5060.
Answer 9
(a) (b) (c) (d) (e) False. False. True. True. True.
Answer 10
(a) (b) (c) (d) (e) False. False. False. True. True.
Answer 14
(a) False. 90% of patients with pulmonary Langerhans cell histiocytosis (PLCH) are smokers but PLCH may also be seen in association with lymphoma or leukaemia. (b) False. 90% of cases of desquamative interstitial pneumonia (DIP) occur in smokers but it may be seen in association with metabolic disease, drugs and dust inhalaton. (c) False. Distribution is typically mid and upper zone predominant. (d) True. (e) True.
Reference: Screaton NJ, Koh T. Emphysema and smokingrelated lung diseases. Imaging 2004;16:5060. Imaging, Volume 16 (2004) Number 3
Answer 11
(a) True. (b) False. (c) True.
282
Answer 15
(a) False. Panlobular emphysema usually predominates in the lower lobes. (b) True. Centrilobular emphysema is the most common form of emphysema and is associated with greater functional impairment than paraseptal emphysema. (c) True. Flattening of the diaphragm is present when the highest point of the diaphragm is less than 1.5 cm above a line joining either the costophrenic and vertebrophrenic angles on the posteroanterior (PA) chest radiograph. On the PA chest radiograph it is present in 24%, 76%, and 94% of patients with mild, moderate, and severe emphysema, respectively. (d) False. Subjective assessment of emphysema extent on HRCT consistently underestimates the pathological extent of both centrilobular and panlobular emphysema. (e) False. An upper-lobe predominant distribution of emphysema is associated with signicant improvement in lung function and exercise capacity following lung volume reduction surgery (LVRS). Only patients with low pre-operative exercise capacity and upper lobe predominant emphysema have a signicant survival advantage following surgery compared with those undergoing medical therapy (p50.005).
Reference: Screaton NJ, Koh T. Emphysema and smokingrelated lung diseases. Imaging 2004;16:5060.
Answer 17
(a) False. These tumours account for less than 5% of all pleural tumours. (b) True. (c) True. (d) False. Calcication is present in less than 5% of cases. (e) False.
Reference: Warakaulle DR, Traill ZC. Imaging of pleural disease. Imaging 2004;16:1021.
Answer 18
(a) (b) (c) (d) (e) False. This is classied as T2. False. This is classied as T3. True. True. False. Stage IV comprises patients with distant metastatic disease (M1).
Answer 19
(a) (b) (c) (d) (e) False. These are peripheral lesions. True. False. False. True.
Answer 16
(a) False. Emphysema and interstitial brosis may be seen together since respiratory bronchiolitisinterstitial lung disease (RB-ILD), and DIP, NSIP and UIP are also associated with cigarette smoking. (b) True. A longitudinal HRCT study demonstrated progression to emphysematous spaces in 26% of smokers with centrilobular ground glass opacities, morphological features consistent with respiratory bronchiolitis. (c) False. DIP, RB-ILD and respiratory bronchiolitis are all characterized by inltration of pigmented macrophages. In DIP the distribution is diffuse while in RB-ILD and RB a peribronchiolar distribution is present. (d) True. Lung volumes are preserved in the majority of cases and increased in up to one third. (e) True. However the is sign is also seen in stable femoral components.
Reference: Screaton NJ, Koh T. Emphysema and smokingrelated lung diseases. Imaging 2004;16:5060. Imaging, Volume 16 (2004) Number 3
Answer 20
(a) False. Bone involvement usually occurs in advanced disease. (b) True. (c) False. (d) True. Local radiotherapy is recommended to prevent this complication. (e) False.
Answer 21
(a) True. Fluorine-18, oxygen-15 and carbon-11 are all positron emitting radionuclides. Fluorine-18 has the longest half-life (110 min) and is used within the tracer uorine-18-uorodeoxyglucose to assess cellular glucose metabolism.
283
(b) False. Fluorine-19 and carbon-13 both have a paramagnetic moment and have been used for the magnetic resonance spectroscopy assessment of metabolic pathways in animals. (c) True. (d) True. (e) False.
Reference: Baldwin DR, Birchall JD, Ganatra RH, Pointon KS. Evaluation of the solitary pulmonary nodule: clinical management, role of CT and nuclear medicine. Imaging 2004;16:2236.
although the specicity is less at 73% versus 86% for FDG PET.
Answer 24
(a) False. Bronchoalveolar cell carcinoma, bronchial carcinoid and well-differentiated bronchial adenocarcinoma can have low metabolic activity with F-18 FDG and hence be false negative for malignancy. (b) True. Granulamatous disease such as tuberculosis and sarcoidosis can be false positive for malignancy when active due to hypermetabolism for F-18 FDG. (c) True. Tumour cells due to their increased glycolytic metabolism up-regulate the expression of glucose transport proteins at the cell membrane. (d) False. Following administration of F-18 FDG prior to imaging conventionally the patient waits quietly for 60 min to allow uptake of FDG by the tumour cells and clearance from the adjacent tissues. (e) False. Insulin causes increased FDG uptake in muscle and liver cells and hence can hinder tumour detection.
Answer 22
(a) True. Type 2 somatostatin receptor imaging with indium-111 octreotide is an alternative method of somatostatin imaging to 99Tcm depreotide, which is effective in the assessment of the solitary pulmonary nodule. (b) True. The myocardial perfusion single photon emission agents 99Tcm tetrofosmin, 99Tcm sestamibi and thallous-201 chloride all have the potential to characterize solitary pulmonary nodules. (c) False. Iodine-123 mIBG is used in the assessment of neural crest tumours such as phaemochromocytoma in adults or neuroblastoma in children. (d) True. The myocardial perfusion single photon emission agents 99Tcm tetrofosmin, 99Tcm sestamibi and thallous-201 chloride all have the potential to characterize solitary pulmonary nodules. (e) True. Conventional bone scintigram agents such as 99Tcm MDP and HMDP have often been demonstrated to have uptake within primary lung tumours.
Answer 25
(a) (b) (c) (d) (e)
99
Answer 23
(a) True. F-18 FDG has been show to effectively discriminate the nature of solitary pulmonary nodules greater than 5 mm in size. (b) False. Intrinsic gamma camera resolution effectively limits the assessment of solitary pulmonary nodules with 99Tcm depreotide to those greater than 1 cm in diameter. (c) False. Do not use coincidence timing for conventional single photon emission tomography. (d) True. Gamma camera coincidence PET with F-18 FDG is readily capable of assessing the solitary pulmonary nodule greater 1.5 cm. (e) False. The sensitivity of dynamic enhanced CT is similar to that of F-18 FDG in the order of 95%
284
False. True. True. False. True.
Tcm depreotide is a radiolabelled peptide that is specic for somatostatin receptor types 2, 3 and 5. These somatostatin receptors are also expressed by other tumours, such as breast cancer and lymphoma. False positive results have been reported in granulomatous disease. Currently there is only very limited provision of PET cameras and cyclotrons within the UK and hence 99Tcm depreotide, which can be performed on SPECT capable gamma cameras, is more accessible.
Reference: Baldwin DR, Birchall JD, Ganatra RH, Pointon KS. Evaluation of the solitary pulmonary nodule: clinical management, role of CT and nuclear medicine. Imaging 2004;16:2236. Imaging, Volume 16 (2004) Number 3

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Imaging, 16 (2004), 5060 E 2004 The British Institute of Radiology DOI: 10.

Emphysema and smoking-related lung diseases

N Pulmonary complications of smoking include lung

N Injury related to cigarette smoking may result in a

N High resolution CT is the imaging modality of choice

Chronic obstructive pulmonary disease

Emphysema and smoking-related lung diseases

Figure 1. Posteroanterior chest radiograph on a 50-year-old

Imaging, Volume 16 (2004) Number 1

N J Screaton and T Koh

Figure 3. Alpha-1-antitrypsin related panlobular emphysema.

Figure 5. High resolution CT image through the mid zones

Imaging, Volume 16 (2004) Number 1

Emphysema and smoking-related lung diseases

N J Screaton and T Koh

Smoking-related interstitial lung disease

Desquamative interstitial pneumonia and respiratory bronchiolitis-interstitial lung disease

Emphysema and smoking-related lung diseases

Desquamative intersitial pneumonia

Figure 8. Respiratory bronchiolitis associated interstitial lung

N J Screaton and T Koh

Langerhans cell histiocytosis

Emphysema and smoking-related lung diseases

N J Screaton and T Koh

Treatment and natural history

Diseases characterized by interstitial brosis

Imaging, Volume 16 (2004) Number 1

Emphysema and smoking-related lung diseases

Imaging, Volume 16 (2004) Number 1

N J Screaton and T Koh

Imaging, Volume 16 (2004) Number 1

Clinical management of the solitary pulmonary nodule

N Solitary pulmonary nodule (SPN) is a common

Evaluation of solitary pulmonary nodule

Measuring the probability of malignancy

Missed cures versus unnecessary surgery

Tests of management strategies

D R Baldwin J D Birchall, R H Ganatra and K S Pointon

0.83 0.01 0.34 0.80 0.23

Imaging, Volume 16 (2004) Number 1

Algorithm for the management of solitary pulmonary nodules

The role of CT in assessing the SPN

Evaluation of solitary pulmonary nodule

Figure 3. Algorithm for the management of solitary pulmonary nodules [16].

Table 6. Malignant causes

SPN, solitary pulmonary nodule; GI, gastrointestinal.

Accuracy of nodule measurement, and growth rate

Evaluation of solitary pulmonary nodule Table 7. Nodule morphology

Nodule density [23, 24] Solid Part-solid

SPN, solitary pulmonary nodule.

Initial management protocol Routine follow up CT at 12 months Follow up CT at 12 months

Imaging, Volume 16 (2004) Number 1

D R Baldwin J D Birchall, R H Ganatra and K S Pointon

Figure 4. This 23 mm nodule has lobulation and spiculation,

Figure 6. This low-density nodule has no solid component so

Evaluation of solitary pulmonary nodule

Small (,1 cm) SPN

Role of nuclear medicine in the SPN

D R Baldwin J D Birchall, R H Ganatra and K S Pointon

Positron emission tomography

Bronchoalveolar cell carcinoma

Well differentiated adenocarcinoma

Gamma camera PET