First published online October 16, 2007
British Journal of Radiology (2007) 80, 1015-1023
© 2007 British Institute of Radiology
doi: 10.1259/bjr/52225107
Pictorial review of the many faces of bronchioloalveolar cell carcinoma
D Patsios, BA, BM, BCh, MRCP, FRCR
H C Roberts, FRCPC, MD
N S Paul, MD, FRCPC
T Chung, FRCPC, MD
S J Herman, MD, FRCPC
A Pereira, MD
and
G Weisbrod, FRCPC
Department of Medical Imaging, University Health Network and Mt Sinai Hospitals, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
Correspondence: Dr Demetris Patsios, Medical Imaging, UHN and Mount Sinai Hospitals, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. E-mail: dapatsios{at}hotmail.com
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Abstract
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Bronchioloalveolar cell carcinoma (BAC) has a varied appearance on CT that often leads to an incorrect or delayed diagnosis. The purpose of this pictorial review is to define common CT characteristics that are specific to BAC. A retrospective review was undertaken of 20 CT scans of pathologically proven cases of BAC; tumours were categorized as focal or diffuse, single or multiple, and infiltrative or well defined. Additional radiological features noted include the density (solid, part solid, non-solid), the presence of unaffected vessels within the tumour(s), and the presence of internal air bronchograms. We illustrate cases of localized and diffuse BAC presenting as (i) solitary or multiple pulmonary nodules, with and without air bronchograms, (ii) bubble-like lucencies of pseudocavitation associated with nodules of varying density, (iii) unifocal or multifocal ground-glass opacities, (iv) crazy paving, (v) nodules and airspace opacities with unaffected vessels coursing through them and (vi) lobar or multilobar consolidation and cavitating nodules. In conclusion, BAC may present with a variety of CT appearances. However, there are typical features such as the CT-angiogram sign or air-brochochograms in solitary nodules and in the periphery of larger consolidations, persisting pure ground-glass opacities, unresolving consolidation and the combination of diffuse nodules and consolidation. These features should alert the radiologist to the diagnosis of BAC.
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Introduction
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The incidence of bronchioloalveolar cell carcinoma (BAC) has increased significantly from <5% to 24% of total lung cancers [1]. According to the revised World Health Organization lung tumour classification, BAC is defined as a subtype of adenocarcinoma with intraalveolar spread and lepidic growth along an intact interstitial framework, but with no evidence of stromal, vascular or pleural invasion [2]. Currently, BAC is classified into three subtypes: mucinous, non-mucinous and mixed adenocarcinoma with prominent BAC pattern. Many of the clinical and radiological features of BAC are distinct from other types of adenocarcinoma: BAC more commonly demonstrates aerogenous rather than lymphatic spread, and radiological diversity from focal to diffuse disease. Mucinous BAC is more likely to appear as multifocal and diffuse disease [3].
Several distinguishing pathological and epidemiological features of BAC are: a peripheral location, association with desmoplastic reaction, mucin production, a high frequency (30%) among non-smokers [4], a higher incidence in women, and a tendency to be multifocal in up to 25% of cases (compared with 5% for other non-small-cell lung cancers) [1].
The purpose of this review is to define common characteristics in the radiological manifestation of BAC that are specific to BAC. There are three different radiological patterns: (i) a solitary nodule or mass of varying density; (ii) focal consolidation; and (iii) multifocal or diffuse disease [5]. We illustrate these radiological patterns using selected pathologically proven cases of localized and diffuse BAC in patients who presented either as asymptomatic in the work-up of incidental pulmonary nodules or opacities on chest radiography (and through our participation in a lung cancer screening study) or following symptoms of cough, bronchorrhoea and progressive breathlessness.
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Solitary nodules or masses
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The most common finding is a solitary peripheral, lobulated or ill-marginated pulmonary nodule or mass of solid consistency (
Figures 1–3). Common CT features include pseudocavitation (Figures 4–8), heterogeneous attenuation (Figures 8–11), irregular margins forming a star pattern (Figures 3, 5 and 6), and pleural tags (Figures 1, 2 and 4) [6]. Pleural tags are thought to be caused by a desmoplastic reaction in the peripheral septa of the lung. The nodular form may present with air bronchograms on CT (Figure 3) more commonly than other cell types [7]. The presence of intratumoral radiolucencies is an important feature of bronchioloalveolar carcinoma (Figures 4–8), and can be secondary to patent intratumoral bronchioles (air bronchiologram), pseudocavitations, true cavitation, serpentine radiolucencies, internal alveolograms and multiple cystic lesions [8]. True cavitation is unusual, but appearances resembling cavitation (pseudocavitation) may be produced by non-involved lobules [9], paracicatricial emphysema, and fibrosis with honeycombing and localized bronchiectasis [10].
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Figure 1. Asymptomatic solitary peripheral pulmonary nodule in the left lower lobe with a pleural tag shown on a chest radiograph.
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Figure 3. Patent intratumoral airways"air bronchograms" in a peripheral right-lower lobe ill-marginated nodule, which showed a slow growth pattern over 18 months.
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Figure 4. Pseudocavity(white arrow) and a pleural tag (black arrow) in a slow-growing (over 1 year) left-lower lobe nodule.
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Figure 5. Ill-marginated "star shaped" mass with a central pseudocavity and a peripheral air bronchogram in the right-upper lobe.
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Figure 6. (a, b) A central left-upper lobe cavitating mass on chest radiography demonstrates irregular margins and central air lucencies on CT, where no frank cavitation was demonstrated following surgical excision, thus attributing the radiological appearances to pseudocavity formation.
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Figure 7. Large pseudocavity within a BAC and no demonstration of a frank cavity on histology following right-lower lobectomy.
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Figure 8. A BAC that demonstrates mixed density, with a partly solid centre, bubble lucencies and a ground-glass peripheral halo.
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Figure 11. The presence of multifocal nodules is a feature of BAC that distinguishes it from other lung cancer cell types.(a) Right-upper lobe and left-upper lobe ground-glass nodules. (b) Solid nodules in the right-middle lobe and the left lung.
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BAC can also present as a solid or partly solid nodule, with associated areas of ground-glass opacification but without obscuration of the underlying lung parenchyma (Figure 8
). This appearance is attributed to the lepidic growth pattern of the malignant cells or mucin production. A focal isolated ground-glass opacity (GGO) has been described as an early finding of BAC, especially if associated with pseudocavities and air bronchograms (Figure 10b). A pure GGO has the highest predictive value for BAC (Figure 9), whereas a radiologically solid nodule with a ground-glass halo is most likely to represent a mixed adenocarcinoma with a bronchioloalveolar cell pattern (Figure 10c) [11].
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Figure 10. Lung cancer screening detected in asymptomatic smokers using low-dose CT and diagnosed following CT-guided fine needle aspiration biopsies prior to excision. (a) Pure ground-glass nodule in the right-lower lobe with no lung parenchymal distortion. (b) BAC presenting as a ground-glass peripheral nodule with intratumoral "bubble lucencies". (c) Partly solid peripheral nodule in an asymptomatic screening patient with the histological diagnosis of mixed adenocarcinoma with a BAC pattern of growth and no evidence of pleural invasion. (d) Part solidly, more central nodule.
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Figure 9. (a) Pure ground-glass peripheral right-upper lobe nodule without distortion of the underlying lung architecture, and (b) demonstration of unaffected vessels coursing through it.
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The CT patterns seen in BAC reflect the histological progression described by Noguchi et al [12] in their review of 236 small adenocarcinomas. In this review, 14 tumours were classified as Type A "BAC in situ" — defined as a solitary nodule with increased cellularity and cell atypia without fibrosis. The corresponding histology revealed preservation of the alveolar architecture but replacement of the cells lining the alveoli by tumour, causing mild thickening of the alveolar septa. Macroscopically, the boundary of the tumour was indistinct. Such a histological appearance would explain the "pure GGO" pattern and the "hazy" margin of the tumour on CT (Figures 9 and 10a). Type B "BAC in situ" was defined as having the same replacement pattern as Type A, but with more cellularity (Figure 10d), leading to alveolar collapse and fibrotic foci, often causing a pleural indentation. The alveolar collapse and fibrosis could explain the CT appearance of a "GGO mixed with consolidation" or even of a more solid opacity with a "GGO halo" [12].
Analysis of 222 nodules detected in a 3 year lung cancer screening programme in Nagano, Japan, suggested that tumour margins and size were not useful parameters for differentiating benign from malignant GGO lesions, and that benign lesions with GGO were more difficult to distinguish from malignant pure ground-glass nodules [13]. However, certain features, such as a round shape or a combination of peripheral GGO with a high-attenuation centre, were observed more frequently in malignant GGO nodules. The most useful discriminator of malignancy is short-term follow-up imaging, as all of the benign pure GGO lesions in this series, and the majority of benign mixed GGO lesions, partially or completely resolved within 3 months [13].
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Multifocal disease and consolidation
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The radiological feature that distinguishes BAC from other cell types is the demonstration of multifocal and lobar pneumonic opacities. The consolidative form of BAC accounts for approximately 30% of all BAC tumours and corresponds to a mucinous histological subtype. Lobar consolidation on plain radiography is often difficult to differentiate from pneumonia; therefore, the diagnosis is often delayed (Figures 12 and 13). Consolidation may be focal, ill-defined, ground-glass, lobar or multifocal (Figures 12–18). Evaluation with CT provides additional information regarding the neoplastic potential of the opacities.
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Figure 12. The combination of air-filled bronchi within an area of persistent unresolving consolidation in the right-upper and the left-upper lobes, multiple ill-defined nodules and areas of ground-glass opacity are characteristic features of diffuse BAC, as demonstrated in this case.
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Figure 13. Increasing consolidation following multiple courses of antibiotics over 3 months between studies (a) and (b) in a young female non-smoker with bronchorrhoea alerted the radiologist to the diagnosis of diffuse consolidative lobar BAC.
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Figure 14. "Crazy paving" pattern of airspace opacity in mucinous BAC shown as extensive ground-glass airspace opacities and septal thickening.
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Figure 15. The non-specific CT angiogram sign in diffuse consolidative BAC, where unaffected pulmonary vessels course through lobar consolidation.
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Figure 16. (a) Diffuse ground-glass opacification of the right-lower lobe associated with centrilobular nodules in the right-middle lobe and the lingula. (b) In the basal segments, there is a mixture of ground-glass, consolidation and a pseudocavity.
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Figure 17. Multilobar consolidation involving the right-lower and right-middle lobes. Some of the centrilobular nodules demonstrated in the lingula are thought to be acinar opacities secondary to the aerogenous spread of the tumour cells in alveolar spaces.
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Figure 18. Multifocal and lobar air space involvement as a mixture of consolidation with air bronchograms, ground-glass opacities, crazy paving and nodules.
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Non-resolving central or peripheral consolidation, especially with associated nodules, raises the possibility of BAC (Figure 13) [14]. The stretching, attenuation, sweeping and widening of branching air-filled bronchi within an area of consolidation on CT favour the diagnosis of BAC (Figure 12). This appearance reflects the pattern of growth, as the tumour seldom obliterates the original architecture of the lung [15]. As tumour fills the alveolar spaces and infiltrates the alveolar septa and bronchial walls, the bronchus becomes narrowed, stretched and rigid. Bulging of the interlobar fissure is a characteristic finding in consolidative BAC, and is probably caused by mucin production in the tumour resulting in swelling of the lobe (Figure 16b) [15].
In a study of 38 patients with pathologically proven diffuse BAC, high-resolution CT findings included a combination of GGOs, consolidation, nodules, centrilobular nodules, peripheral distribution and air bronchograms [16]. These could be classified into three patterns: predominantly ground-glass (Figure 16a), consolidative (Figures 16b, 17 and 18) and multinodular (Figure 11). The combination of consolidation, nodules (with centrilobular nodules) and remote areas of ground-glass attenuation are characteristic of diffuse BAC (Figures 12, 16 and 17) [16]. Extensive ground-glass airspace opacification and septal thickening, similar to a "crazy paving" pattern, have also been described (Figure 14), in which the ground-glass attenuation reflects low-density intra-alveolar material (glycoprotein) and the superimposed reticular attenuation is caused by interstitial infiltration by inflammatory or tumour cells [17].
Air collections can be seen within areas of consolidation (Figure 16b), in nodules (Figures 4–6 and 8) and in masses (Figure 7) [8–10]. Frank cavitation is unusual. In one reported case, the wall of a pre-existing lung cavity was thickened, presumably by tumour growth around the wall of a bronchogenic cyst [18].
The CT-angiogram sign initially referred to clearly visible vessels coursing through the low-attenuation tumour on contrast-enhanced CT studies (Figure 15). When first described, this sign was felt to have a specificity of 92.3% for the diagnosis of BAC [19]. Since the original description, this sign has been described as a common finding in lobar consolidations, owing to several aetiologies, when evaluated by contrast-enhanced CT [20]. However, it is still considered a useful radiological sign, as it represents enhancement of unaffected pulmonary vessels coursing through low-attenuation consolidated lung parenchyma. This feature is seen in BAC, obstructive pneumonitis, pneumonia, pulmonary lymphoma and lipoid pneumonia [21].
It is important to be aware of the varied manifestations of BAC, as the prognosis varies with cell type. The 5-year survival for resected sub-centimetre pure ground-glass nodules, partly solid ground-glass nodules and solid nodules is 100%, 100% and 94%, respectively [22]. A similar 5-year disease-free survival rate of 100% for a BAC of diameter 3 cm or less has been reported in a retrospective Japanese study [23]. However, the 5-year survival rate for the multifocal and the consolidative radiological patterns is 40% and 0%, respectively [24].
Screening with low-dose CT improves the detection of lung cancer, especially of peripherally located adenocarcinomas, at an earlier and potentially more curable stage [25]. Isolated nodules can be surgically removed using minimally invasive techniques; however, multifocal disease remains problematic, as treatment options are limited. Lung transplantation for multifocal BAC is unlikely to be curative, even if incidentally discovered in the explanted lung (Figures 19 and 20). One multicentre review of lung transplantation for multifocal BAC reported a 5-year survival rate of 39% [26]. Although it is rarely curative, lung transplantation remains a valuable option for patients with impending respiratory failure secondary to advanced multifocal BAC [26].
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Figure 19. (a) Multifocal BAC treated with bilateral lung transplantation [27]. (b) Recurrence of multifocal BAC in the transplanted lung in the same radiographical and histological pattern, with slow progression.
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Figure 20. (a) Left-upper lobe peripheral consolidation (arrow) before lung transplantation in a patient with interstitial lung disease secondary to scleroderma showed slow growth and an adjacent large cavity; this was diagnosed as a BAC in the explanted lung. (b) After double lung transplantation, recurrence of multifocal BAC demonstrates small bilateral lung nodules with air lucencies within them.
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As demonstrated, BAC can present with a variety of CT appearances and variable prognosis depending on the presence of focal vs diffuse/multifocal disease. However, there are a few helpful features such as unaffected vessels through nodules (Figure 9), the CT-angiogram sign representing normal vessels within consolidation, and the presence of air bronchograms in solitary nodules and the periphery of larger consolidations. More specific radiological signs include non-resolving pure GGOs with or without bubble-like lucencies of pseudocavitation, unresolving consolidation, and the combination of diffuse nodules and consolidation, the presence of which should alert the radiologist to the diagnosis of BAC.
Received for publication September 10, 2005.
Revision received March 11, 2006.
Accepted for publication March 28, 2006.
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Abstract
Introduction
