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Chest ultrasonography in health surveillance of asbestos related pleural disease
Lung Cancer 111 (2017) 139–142
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Chest ultrasonography in health surveillance of asbestos related pleural disease
MARK
⁎
Simone Scarlata , Panaiotis Finamore, Gilda Giannunzio, Simona Santangelo, Raffaele Antonelli Incalzi Chair of Geriatrics- Unit of Respiratory Pathophysiology, Campus Bio Medico University and Teaching Hospital, Rome − Italy
A R T I C L E I N F O
A B S T R A C T
Keywords: Chest ultrasonography Pleural disease Health surveillance Asbestos exposure
High resolution computed tomography, (HRCT), is currently considered the diagnostic gold standard to diagnose early stage malignant pleural mesothelioma and other non-malignant pleural conditions, but it is expensive and exposes the patient to radiation dose. In a screening and population medicine perspective, Thoracic Ultrasounds may become a valuable alternative because it can detect minimal changes in pleural surface, is widely available and safe. On these bases, we therefore validated thoracic US in subjects with history of exposure to asbestos, having HRCT as the reference standard. One hundred-fifty subjects were screened and 117 were recruited. Pleural abnormalities at US and/or HRCT were detected in 66 out of 117 subjects (prevalence = 57%), and their prevalence was unrelated to both mansion and smoking habit, while mean age and mean length of exposure were higher in those having pleural abnormalities (age = 47 ± 5 vs 44 ± 6 years, p < 0.05; years of exposure = 20 ± 7 vs 17 ± 5, p < 0.05). Thirteen out of 19 subjects with pleural abnormalities at HRCT were also identified by thoracic US, whereas 47 participants had lesions seen at US, but not at the HRCT scan. Positive and negative percent agreement were 66.6% and 51.8%, respectively; the McNemar’s test for equality showed a p-value < 0.001. In conclusion, chest US might complement HRCT in the health surveillance of asbestos exposed population to detect earlier lesions or to follow up US approachable lesions. Further research is needed to clarify whether this approach may enhance early recognition of pleural mesothelioma and ameliorate prognosis.
1. Introduction Malignant pleural mesothelioma and other non-malignant pleural conditions such as pleural thickening, rounded atelectasis and pleural plaques may develop 20–50 years after the first exposure to high concentrations of asbestos dusts and, less commonly, also after a shorter exposure [1]. Small irregular opacities in the lower lung and irregular pleural thickening at chest x-ray are the most common key to the diagnosis. High resolution computed tomography, (HRCT), is currently considered the diagnostic gold standard [2]. On the other hand, restrictive lung function impairment is related more to parenchymal than to pleural abnormalities and, therefore, cannot qualify as a proxy for early detection of pleural abnormalities [3–6]. Unfortunately, HRCT scan is expensive, exposes the patient to high radiation dose and might cause psychological distress [7]. Thoracic Ultrasounds (US) is a valuable alternative because it can detect minimal
changes in pleural surface, is widely available, and safe. However, its diagnostic accuracy vs early pleural changes is unclear. In a recent study, US yielded a 90,9% sensitivity and 85.7% specificity in diagnosing chest wall invasion in subjects with non small cell lung cancer versus a 61.5% and 84.6%, respectively, provided by CT scan [8]. Similarly, in 52 consecutive patients with suspected malignant pleural effusion, US had a sensitivity for the diagnosis of malignancy of 73%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 79% vs a contrast-enhanced HRCT and hystology based diagnosis [9]; in the same study, parietal pleural thickening was identified with a sensitivity of 42% (95% CI:26–61), specificity of 95% (95% CI: 74–99) positive and negative predictive value of 93% and 49%, respectively. Unfortunately, a standard US cannot explore the whole pleural surface. Indeed, it cannot image the mediastinal pleura, whereas the sternum, clavicles, scapulas and vertebras limit pleural visualization to about 70% of the total. Furthermore, US are thought to
⁎ Corresponding author at: Unit of Respiratory Pathophysiology and Thoracic Endoscopy, Campus Bio Medico University and Teaching Hospital Via Alvaro del Portillo 200–00128 Rome, Italy. E-mail addresses: [email protected] (S. Scarlata), p.fi[email protected] (P. Finamore), [email protected] (G. Giannunzio), [email protected] (S. Santangelo), [email protected] (R. Antonelli Incalzi).
http://dx.doi.org/10.1016/j.lungcan.2017.07.019 Received 12 April 2017; Received in revised form 2 July 2017; Accepted 16 July 2017 0169-5002/ © 2017 Elsevier B.V. All rights reserved.
Lung Cancer 111 (2017) 139–142
S. Scarlata et al.
Fig. 1. Chest CT scan showing a pleural plaque (large arrow) and ultrasonographic picture of the same lesion (thin arrow).
behind the head causes intercostal spaces to be extended and facilitated access. The examiner was able to visualize the region behind the shoulder blade, if the patient put his/her hand on the contralateral shoulder. The transducer was moved along the intercostal space from dorsal to ventral in longitudinal and transversal positions. Turning the probe in different positions provides the examiner with a three-dimensional image. Every accessible segment of the pleural space was systematically evaluated [11]. The followings were considered pathologic US findings: diffuse pleural thickening, defined as a smooth, well demarcated and hypoechogenic pleural tissue that displaces the lung from chest wall, but does not infiltrates the chest wall; focal pleural thickening or pleural plaques defined as smooth, elliptical, hypoechoic pleural thickenings, sometimes with inner calcifications; pleural tumors defined as diffuse pleural thickening, nodular and/or irregular, eventually associated with calcifications, focal pleural masses and pleural effusion [13]. Chest US was performed within three weeks after HRCT scan. As recommended, thin-section CT acquisition in full inspiration with a volume CT dose index of around 3–7 mGy were obtained for scanning the thorax [14]. US and HRCT findings were compared with regard to location, size and width of the lesions (Fig. 1). Data are expressed as means ( ± standard deviation, SD) for continuous variables or as a percentage for categorical variables. Comparison between groups was made by non parametric Wilcoxon test for continuous variables and Chi-square for categorical ones (statistical software: R version 3.3.0, Wien −Austria). Inter measurement agreement between HRCT and Chest ultrasound pleural abnormalities size was evaluated by Cohen’s k determination. Agreement between tests was determined by overall, positive and negative agreement calculation and McNemar’s test.
be associated with variable inter-observer agreement making the reproducibility of the method object of debate [10]. However, US technique is amenable to standardization according to a consensus statement recently elaborated by a multidisciplinary panel of 28 experts from eight countries [11]. On the other hand, pleural abnormalities, regardless of their nature, usually involve the parietal pleura of the lateral thoracic wall between the 6th and 9th ribs, the posterolateral chest wall between the 7th and the 10th ribs and, more rarely, the dome of the diaphragm, the mediastinum and the fissures [12]. Thus, it is unclear whether US may qualify as an autonomous diagnostic technique or should only complement HRCT in the screening of asbestos associated pleural changes. In this proof of concept study, we aimed at validating thoracic US as a diagnostic tool in the management of pleural changes in subjects with a history of occupational exposure to asbestos and to compare its diagnostic accuracy with that of HRCT scan of the chest.
2. Materials and methods Subjects with documented (workplace description, cohort demographics, time period of exposure and follow up) occupational exposure to crysothile asbestos were referred to a tertiary care teaching hospital, the Campus Bio Medico University, in Rome-Italy, for screening and early recognition of asbestos related pleural diseases. The only inclusion criteria for screening were: prolonged and continuative (over 15 years) exposure to crysotile asbestos; ability to perform pulmonary function tests, CT scan and chest ultrasound within a 3 week long time-laps. Excluded were subjects refusing to sign in the informed consent form. Findings pertaining to the first 150, enrolled from January 2016 to February 2017, are the object of the present report. Local Ethical Committee approval was obtained (Prot. 56/16 ComEt CBM) and all patients signed an informed consent for this study. All participants were males serving in aircraft and automotive industry with documented long lasting exposure to crysothile asbestos fibers. Smoke history and other relevant environmental exposure were also collected. The conventional screening panel included HRCT, a complete spirometry and DlCO measurement. Chest USs were performed by a single operator blinded to both CT scan and spirometry reports. US assessment was performed using an Exagyne™ machine (Echo Control Medical-ECM, Angoulème − France) equipped with linear (7–13 mHz) and convex (2 5 mHz) probes. Chest wall was systematically explored with the dorsal and lateral images obtained with the patient sitting, whereas the supine position was used for visualizing the ventral side. Raising the arms and crossing them
3. Results One hundred-fifty subjects were consecutively screened. Among these, 117 were effectively recruited, having performed a HRCT in the past 3 weeks and lung function tests within the past 6 weeks. Mean age was 46.8 years ( ± 6.0) and the mean length of asbestos exposure was 20 years ( ± 7); eighty-three (71%) served as aircraft and automotive maintenance operator, 12 (10%) were pilots, 6 (5%) were on-board system operators, and 15 (13%) were in charge of other mansions. Of the 117 participants, 16 (14%) were current smokers, 40 (34%) were former smokers with a mean pack/year of 11.9 ( ± 9.2) and 15.4 ( ± 13.0), respectively. A normal spirometry was observed in 108 subjects (93%), a mild obstructive pattern in 4 (4%), a mild restriction in 3 (3%) and a mixed pattern spirometry in 1 (1%). 140
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HRCT resulted effectively undetectable by US (Table 1, lower panel) seems to be due to anatomical obstacles preventing US from visualizing selected areas of the pleural surface [16] and the mediastinal pleura. Given the relatively low concordance, US and HRCT might be used as complementary appliances, at least for baseline screening. However, a higher concordance might be expected in subjects with longer asbestos exposure and, possibly, larger pleural lesions. These data are in accordance with those provided by the only existing work, to our knowledge, comparing chest US vs CT diagnosis [9]. However, this study focuses mainly on the ability of chest US to discriminate between malignancy and benign pleural abnormalities within a cohort of people with pleural effusion and is therefore limited to symptomatic patients with multifactorial risk factors. We proved that chest ultrasounds can detect most, but not all pleural changes in subjects with occupational exposure. However, the lack of follow up findings prevents us from assessing the US diagnostic accuracy vs clinically relevant pleural changes in comparison with HRCT gold standard. Nevertheless, we can reasonably speculate that thoracic US is highly specific in detecting abnormalities located along the external thoracic cavity. Theoretically, chest US may not qualify as an alternative instrument to HRCT in baseline screening of high risk subjects, but it looks as a promising, safe and cheaper alternative to HRCT for the follow up of US detectable lesions. The ongoing follow up is expected to clarify this issue. The potential clinical implications of our study deserve to be discussed more in details. First, the proposed approach could allow limit the annual screening to pulmonary function tests and chest US only for most of the patients, whilst HRCT could be planned at every 3–5 years interval unless some change in the lesions is detected at the US annual check. Consequently, the costs and radiation exposure sparing for the patients and the National Health System might be relevant. The prognostic significance of early detection of smaller pleural abnormalities in people at risk for pleural mesothelioma is still far from being clarified. We are aware, in fact, that most of the observed changes will never turn into clinically relevant disease. Nonetheless, the detection of pleural plaques and related abnormalities has been associated with a significantly higher risk of death for lung cancer (HR 2.91, 95% CI = 1.49–5.70)[17] and pleural mesothelioma (HR 6.8, 95%CI = 2.2–21.4) [18]. Limitations of this study deserve consideration. First, as already
Pleural abnormalities at US and/or HRCT were detected in 66 out of 117 subjects (prevalence = 57%), and their prevalence was unrelated to both mansion and smoking habit, while mean age and mean length of exposure were higher in those having pleural abnormalities (age = 47 ± 5 vs 44 ± 6 years, p < 0.05; years of exposure = 20 ± 7 vs 17 ± 5, p < 0.05).Thirteen out of the19subjects with pleural abnormalities at HRCT were also identified by thoracic US, whereas 47 participants had lesions seen at US, but not at the HRCT scan (see Table 1, upper panel). Four out of the six lesions seen only at HRCT were virtually not reachable by chest US, being located in the retro-scapular, retro-sternal and paravertebral areas; the remaining two, located along the axillary space, were the oretically visible at US observation (Table 1, lower panel).Overall, positive percent agreement and negative percent agreement were 54%, 66.6% and 51.8%, respectively; the McNemar’s test for equality showed a p value < 0.001. The size of the lesions seen only at US was 4.2 ( ± 7.5) millimeters vs 6.8 ( ± 4.2) of those seen only at HRCT and 6.6 ( ± 7.4) of those detected by both methods (p = 0.541).The US/HRCT measurement agreement in term of lesion’s size among the 13 lesions detectable by both methods was robust for those lesions > 8 mm (Cohen’s k = 0.81) and substantial for those < 8 mm (Cohen’s k = 0.69). Further details on the location of the observed pleural abnormalities are shown in Table 1, lower panel. As expected, US detectable abnormalities were mostly located in the mid-basal, subscapular dorsal pleural surface and along the costophrenic recess. On the opposite, HRCT was superior in visualizing retrosternal, retroscapular and paravertebral abnormalities.
4. Discussion This is the first report on the role of US in the screening of pleural abnormalities in a population with a 20 years long asbestos exposure. In this setting, US could detect two thirds of the lesions also seen at HRCT, but, importantly, caught 47 lesions unrevealed by CT scan. This finding suggests a potential of US at improving the detection of early asbestos related pleural abnormalities. Indeed, these abnormalities were under the 10 millimeters minimally measurable lesion thickness threshold on CT scan stipulated by RECIST for mesothelioma [15]. Thus, US might help to provide an earlier diagnosis of asbestos related or other pleural conditions. On the other hand, the fact that two thirds of the lesion seen at
Table 1 Location and distribution of the observed pleural abnormalities at Chest CT scan and Ultrasound. Pleural solid abnormality
HRCT scan
Chest ultrasonography
Absent
Present
51 47
6 13
Absent Present
Ultrasound pleural thickness; mean (SD) Pleural thickenings location Anterior axillary line; N (%) Mid-axillary line; N (%) Posterior axillary line; N (%) Basal posterior; N (%) Mid-clavicular line; N (%) Sub-scapular; N (%) Costophrenic recess; N (%) Retro-sternal area; N (%) Retro-Scapular area; N (%) Para-vertebral area; N (%) Mediastinal Pleura; N (%)
Evidence of pleural thickening at ultrasonography only (N = 47)
Evidence of pleural thickening at HRCT only (N = 6)
Evidence of pleural thickening at both ultrasonography and HRCT (N = 13)
4.2 (7.5)
6.8 (4.2)
6.6 (7.4)
1 (2) 2 (5) 1 (2) 24 (56) 3 (7) 11 (23) 5 (11) 0 0 0 0
1 (16.6) 1(16.6) 0 0 0 0 0 2 (33.3) 1 (16.6) 1 (16.6) 0
0 0 1 8 1 2 0 0 0 0 0
141
(0) (0) (8) (67) (8) (17) (0)
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discussed, the follow up pending, the biological and clinical meaning of US detectable pleural thickness remains unknown. Second, our data were collected by a single operator, and it is therefore not possible to verify whether inter-observer variability might have affected the reproducibility and generalizability of results. Finally, a definitive estimate of US diagnostic accuracy would require thoracoscopic assessment and/or biopsy of the pleural lesion rather than HRCT. In conclusion, chest US might complement HRCT in the heath surveillance in asbestos exposed populations either to detect earlier lesions or to follow up US approachable lesions. Research is needed to assess the biological and clinical meaning of US, but not HRCT visible pleural lesions as well as to optimize the integration of HRCT and US.
[6]
[7]
[8]
[9] [10]
Conflict of interest disclosure
[11]
None of the authors of the present manuscript have any potential or real conflict of interest to declare. Funding [12]
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
[13]
References
[14]
[1] G. Hillerdal, Pleural plaques and risk for bronchial carcinoma and mesothelioma. A prospectivestudy, Chest 105 (1994) 144–150. [2] T. Vierikko, R. Järvenpää, T. Autti, P. Oksa, M. Huuskonen, S. Kaleva, J. Laurikka, S. Kajander, K. Paakkola, S. Saarelainen, E.R. Salomaa, A. Tossavainen, P. Tukiainen, J. Uitti, T. Vehmas, Chest CT screening of asbestos-exposed workers: lung lesions and incidental findings, Eur. Respir. J. 29 (2007) 78–84. [3] P. Oksa, H. Suoranta, H. Koskinen, A. Zitting, H. Nordman, High-resolution computed tomography in the early detection of asbestosis, Int. Arch. Occup. Environ. Health 65 (1994) 299–304. [4] D.A. Schwartz, J.R. Galvin, S.J. Yagla, S.B. Speakman, J.A. Merchant, G.W. Hunninghake, Restrictive lung function and asbestos-induced pleural fibrosis. A quantitative approach, J. Clin. Invest. 91 (1993) 2685–2692. [5] D. Spyratos, D. Chloros, B. Haidich, L. Dagdilelis, S. Markou, L. Sichletidis, Chest
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imaging and lung function impairment after long-term occupational exposure to low concentrations of chrysotile, Arch. Environ. Occup. Health 67 (2012) 84–90. B. Clin, C. Paris, J. Ameille, P. Brochard, F. Conso, A. Gislard, F. Laurent, M. Letourneux, A. Luc, E. Schorle, J.C. Pairon, Do asbestos-related pleural plaques on HRCT scans cause restrictive impairment in the absence of pulmonary fibrosis, Thorax 66 (2011) 985–991. C. Paris, M. Maurel, A. Luc, A. Stoufflet, J.C. Pairon, M. Letourneux, CT scan screening is associated with increased distress among subjects of the APExS, BMC Public Health 10 (2010) 647. M. Tahiri, M. Khereba, V. Thiffault, P. Ferraro, A. Duranceau, J. Martin, M. Liberman, Preoperative assessment of chest wall invasion in non-small cell lung cancer using surgeon-performed ultrasound, Ann. Thorac Surg. 98 (2014) 984–989. N.R. Qureshi, N.M. Rahman, F.V. Gleeson, Thoracic ultrasound in the diagnosis of malignant pleural effusion, Thorax 64 (2009) 139–143. G.A. Cibinel, G. Casoli, F. Elia, M. Padoan, E. Pivetta, E. Lupia, A. Goffi, Diagnostic accuracy and reproducibility of pleural and lung ultrasound in discriminating cardiogenic causes of acute dyspnea in the emergency department, Intern. Emerg. Med. 7 (2012) 65–70. G. Volpicelli, M. Elbarbary, M. Blaivas, D.A. Lichtenstein, G. Mathis, A.W. Kirkpatrick, L. Melniker, L. Gargani, V.E. Noble, G. Via, A. Dean, J.W. Tsung, G. Soldati, R. Copetti, B. Bouhemad, A. Reissig, E. Agricola, J.J. Rouby, C. Arbelot, A. Liteplo, A. Sargsyan, F. Silva, R. Hoppmann, R. Breitkreutz, A. Seibel, L. Neri, E. Storti, T. Petrovic, International liaison committee on lung ultrasound (ILC-LUS) for international consensus conference on lung ultrasound (ICC-LUS). international evidence-based recommendations for point-of-care lung ultrasound, Intensive Care Med. 38 (2012) 577–591. K.M. Alfudhili, D.A. Lynch, F. Laurent, G.R. Ferretti, V. Dunet, C. Beigelman-Aubry, Focal pleural thickening mimicking pleural plaques on chest computed tomography: tips and tricks, Br. J. Radiol. 89 (1057) (2016) 20150792. J. Ayres, F. Gleeson, Imaging of the pleura, Semin. Respir. Crit. Care Med. 31 (2010) 674–688. A.A. Bankier, D. Tack, Dose reduction strategies for thoracic multidetector computed tomography: background, current issues, and recommendations, J. Thoracic Imaging 25 (2010) 278–288. S.G. Armato 3rd, A.K. Nowak, R.J. Francis, M. Kocherginsky, M.J. Byrne, Observer variability in mesothelioma tumor thickness measurements: defining minimally measurable lesions, J. Thorac Oncol. 9 (2014) 1187–1194. F.J. Herth, H.D. Becker, Transthoracic ultrasound, Respiration 70 (2003) 87–94. J.C. Pairon, P. Andujar, M. Rinaldo, J. Ameille, P. Brochard, S. Chamming's, B. Clin, G. Ferretti, A. Gislard, F. Laurent, A. Luc, P. Wild, C. Paris, Asbestos exposure, pleural plaques, and the risk of death from lung cancer, Am. J. Respir Crit. Care Med. 190 (2014) 1413–1420. J.C. Pairon, F. Laurent, M. Rinaldo, B. Clin, P. Andujar, J. Ameille, P. Brochard, S. Chammings, G. Ferretti, F. Galateau-Sallé, A. Gislard, M. Letourneux, A. Luc, E. Schorlé, C. Paris, Pleural plaques and the risk of pleural mesothelioma, J. Natl. Cancer Inst. 105 (2013) 293–301.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Chest ultrasonography in health surveillance of asbestos related pleural disease
MARK
⁎
Simone Scarlata , Panaiotis Finamore, Gilda Giannunzio, Simona Santangelo, Raffaele Antonelli Incalzi Chair of Geriatrics- Unit of Respiratory Pathophysiology, Campus Bio Medico University and Teaching Hospital, Rome − Italy
A R T I C L E I N F O
A B S T R A C T
Keywords: Chest ultrasonography Pleural disease Health surveillance Asbestos exposure
High resolution computed tomography, (HRCT), is currently considered the diagnostic gold standard to diagnose early stage malignant pleural mesothelioma and other non-malignant pleural conditions, but it is expensive and exposes the patient to radiation dose. In a screening and population medicine perspective, Thoracic Ultrasounds may become a valuable alternative because it can detect minimal changes in pleural surface, is widely available and safe. On these bases, we therefore validated thoracic US in subjects with history of exposure to asbestos, having HRCT as the reference standard. One hundred-fifty subjects were screened and 117 were recruited. Pleural abnormalities at US and/or HRCT were detected in 66 out of 117 subjects (prevalence = 57%), and their prevalence was unrelated to both mansion and smoking habit, while mean age and mean length of exposure were higher in those having pleural abnormalities (age = 47 ± 5 vs 44 ± 6 years, p < 0.05; years of exposure = 20 ± 7 vs 17 ± 5, p < 0.05). Thirteen out of 19 subjects with pleural abnormalities at HRCT were also identified by thoracic US, whereas 47 participants had lesions seen at US, but not at the HRCT scan. Positive and negative percent agreement were 66.6% and 51.8%, respectively; the McNemar’s test for equality showed a p-value < 0.001. In conclusion, chest US might complement HRCT in the health surveillance of asbestos exposed population to detect earlier lesions or to follow up US approachable lesions. Further research is needed to clarify whether this approach may enhance early recognition of pleural mesothelioma and ameliorate prognosis.
1. Introduction Malignant pleural mesothelioma and other non-malignant pleural conditions such as pleural thickening, rounded atelectasis and pleural plaques may develop 20–50 years after the first exposure to high concentrations of asbestos dusts and, less commonly, also after a shorter exposure [1]. Small irregular opacities in the lower lung and irregular pleural thickening at chest x-ray are the most common key to the diagnosis. High resolution computed tomography, (HRCT), is currently considered the diagnostic gold standard [2]. On the other hand, restrictive lung function impairment is related more to parenchymal than to pleural abnormalities and, therefore, cannot qualify as a proxy for early detection of pleural abnormalities [3–6]. Unfortunately, HRCT scan is expensive, exposes the patient to high radiation dose and might cause psychological distress [7]. Thoracic Ultrasounds (US) is a valuable alternative because it can detect minimal
changes in pleural surface, is widely available, and safe. However, its diagnostic accuracy vs early pleural changes is unclear. In a recent study, US yielded a 90,9% sensitivity and 85.7% specificity in diagnosing chest wall invasion in subjects with non small cell lung cancer versus a 61.5% and 84.6%, respectively, provided by CT scan [8]. Similarly, in 52 consecutive patients with suspected malignant pleural effusion, US had a sensitivity for the diagnosis of malignancy of 73%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 79% vs a contrast-enhanced HRCT and hystology based diagnosis [9]; in the same study, parietal pleural thickening was identified with a sensitivity of 42% (95% CI:26–61), specificity of 95% (95% CI: 74–99) positive and negative predictive value of 93% and 49%, respectively. Unfortunately, a standard US cannot explore the whole pleural surface. Indeed, it cannot image the mediastinal pleura, whereas the sternum, clavicles, scapulas and vertebras limit pleural visualization to about 70% of the total. Furthermore, US are thought to
⁎ Corresponding author at: Unit of Respiratory Pathophysiology and Thoracic Endoscopy, Campus Bio Medico University and Teaching Hospital Via Alvaro del Portillo 200–00128 Rome, Italy. E-mail addresses: [email protected] (S. Scarlata), p.fi[email protected] (P. Finamore), [email protected] (G. Giannunzio), [email protected] (S. Santangelo), [email protected] (R. Antonelli Incalzi).
http://dx.doi.org/10.1016/j.lungcan.2017.07.019 Received 12 April 2017; Received in revised form 2 July 2017; Accepted 16 July 2017 0169-5002/ © 2017 Elsevier B.V. All rights reserved.
Lung Cancer 111 (2017) 139–142
S. Scarlata et al.
Fig. 1. Chest CT scan showing a pleural plaque (large arrow) and ultrasonographic picture of the same lesion (thin arrow).
behind the head causes intercostal spaces to be extended and facilitated access. The examiner was able to visualize the region behind the shoulder blade, if the patient put his/her hand on the contralateral shoulder. The transducer was moved along the intercostal space from dorsal to ventral in longitudinal and transversal positions. Turning the probe in different positions provides the examiner with a three-dimensional image. Every accessible segment of the pleural space was systematically evaluated [11]. The followings were considered pathologic US findings: diffuse pleural thickening, defined as a smooth, well demarcated and hypoechogenic pleural tissue that displaces the lung from chest wall, but does not infiltrates the chest wall; focal pleural thickening or pleural plaques defined as smooth, elliptical, hypoechoic pleural thickenings, sometimes with inner calcifications; pleural tumors defined as diffuse pleural thickening, nodular and/or irregular, eventually associated with calcifications, focal pleural masses and pleural effusion [13]. Chest US was performed within three weeks after HRCT scan. As recommended, thin-section CT acquisition in full inspiration with a volume CT dose index of around 3–7 mGy were obtained for scanning the thorax [14]. US and HRCT findings were compared with regard to location, size and width of the lesions (Fig. 1). Data are expressed as means ( ± standard deviation, SD) for continuous variables or as a percentage for categorical variables. Comparison between groups was made by non parametric Wilcoxon test for continuous variables and Chi-square for categorical ones (statistical software: R version 3.3.0, Wien −Austria). Inter measurement agreement between HRCT and Chest ultrasound pleural abnormalities size was evaluated by Cohen’s k determination. Agreement between tests was determined by overall, positive and negative agreement calculation and McNemar’s test.
be associated with variable inter-observer agreement making the reproducibility of the method object of debate [10]. However, US technique is amenable to standardization according to a consensus statement recently elaborated by a multidisciplinary panel of 28 experts from eight countries [11]. On the other hand, pleural abnormalities, regardless of their nature, usually involve the parietal pleura of the lateral thoracic wall between the 6th and 9th ribs, the posterolateral chest wall between the 7th and the 10th ribs and, more rarely, the dome of the diaphragm, the mediastinum and the fissures [12]. Thus, it is unclear whether US may qualify as an autonomous diagnostic technique or should only complement HRCT in the screening of asbestos associated pleural changes. In this proof of concept study, we aimed at validating thoracic US as a diagnostic tool in the management of pleural changes in subjects with a history of occupational exposure to asbestos and to compare its diagnostic accuracy with that of HRCT scan of the chest.
2. Materials and methods Subjects with documented (workplace description, cohort demographics, time period of exposure and follow up) occupational exposure to crysothile asbestos were referred to a tertiary care teaching hospital, the Campus Bio Medico University, in Rome-Italy, for screening and early recognition of asbestos related pleural diseases. The only inclusion criteria for screening were: prolonged and continuative (over 15 years) exposure to crysotile asbestos; ability to perform pulmonary function tests, CT scan and chest ultrasound within a 3 week long time-laps. Excluded were subjects refusing to sign in the informed consent form. Findings pertaining to the first 150, enrolled from January 2016 to February 2017, are the object of the present report. Local Ethical Committee approval was obtained (Prot. 56/16 ComEt CBM) and all patients signed an informed consent for this study. All participants were males serving in aircraft and automotive industry with documented long lasting exposure to crysothile asbestos fibers. Smoke history and other relevant environmental exposure were also collected. The conventional screening panel included HRCT, a complete spirometry and DlCO measurement. Chest USs were performed by a single operator blinded to both CT scan and spirometry reports. US assessment was performed using an Exagyne™ machine (Echo Control Medical-ECM, Angoulème − France) equipped with linear (7–13 mHz) and convex (2 5 mHz) probes. Chest wall was systematically explored with the dorsal and lateral images obtained with the patient sitting, whereas the supine position was used for visualizing the ventral side. Raising the arms and crossing them
3. Results One hundred-fifty subjects were consecutively screened. Among these, 117 were effectively recruited, having performed a HRCT in the past 3 weeks and lung function tests within the past 6 weeks. Mean age was 46.8 years ( ± 6.0) and the mean length of asbestos exposure was 20 years ( ± 7); eighty-three (71%) served as aircraft and automotive maintenance operator, 12 (10%) were pilots, 6 (5%) were on-board system operators, and 15 (13%) were in charge of other mansions. Of the 117 participants, 16 (14%) were current smokers, 40 (34%) were former smokers with a mean pack/year of 11.9 ( ± 9.2) and 15.4 ( ± 13.0), respectively. A normal spirometry was observed in 108 subjects (93%), a mild obstructive pattern in 4 (4%), a mild restriction in 3 (3%) and a mixed pattern spirometry in 1 (1%). 140
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HRCT resulted effectively undetectable by US (Table 1, lower panel) seems to be due to anatomical obstacles preventing US from visualizing selected areas of the pleural surface [16] and the mediastinal pleura. Given the relatively low concordance, US and HRCT might be used as complementary appliances, at least for baseline screening. However, a higher concordance might be expected in subjects with longer asbestos exposure and, possibly, larger pleural lesions. These data are in accordance with those provided by the only existing work, to our knowledge, comparing chest US vs CT diagnosis [9]. However, this study focuses mainly on the ability of chest US to discriminate between malignancy and benign pleural abnormalities within a cohort of people with pleural effusion and is therefore limited to symptomatic patients with multifactorial risk factors. We proved that chest ultrasounds can detect most, but not all pleural changes in subjects with occupational exposure. However, the lack of follow up findings prevents us from assessing the US diagnostic accuracy vs clinically relevant pleural changes in comparison with HRCT gold standard. Nevertheless, we can reasonably speculate that thoracic US is highly specific in detecting abnormalities located along the external thoracic cavity. Theoretically, chest US may not qualify as an alternative instrument to HRCT in baseline screening of high risk subjects, but it looks as a promising, safe and cheaper alternative to HRCT for the follow up of US detectable lesions. The ongoing follow up is expected to clarify this issue. The potential clinical implications of our study deserve to be discussed more in details. First, the proposed approach could allow limit the annual screening to pulmonary function tests and chest US only for most of the patients, whilst HRCT could be planned at every 3–5 years interval unless some change in the lesions is detected at the US annual check. Consequently, the costs and radiation exposure sparing for the patients and the National Health System might be relevant. The prognostic significance of early detection of smaller pleural abnormalities in people at risk for pleural mesothelioma is still far from being clarified. We are aware, in fact, that most of the observed changes will never turn into clinically relevant disease. Nonetheless, the detection of pleural plaques and related abnormalities has been associated with a significantly higher risk of death for lung cancer (HR 2.91, 95% CI = 1.49–5.70)[17] and pleural mesothelioma (HR 6.8, 95%CI = 2.2–21.4) [18]. Limitations of this study deserve consideration. First, as already
Pleural abnormalities at US and/or HRCT were detected in 66 out of 117 subjects (prevalence = 57%), and their prevalence was unrelated to both mansion and smoking habit, while mean age and mean length of exposure were higher in those having pleural abnormalities (age = 47 ± 5 vs 44 ± 6 years, p < 0.05; years of exposure = 20 ± 7 vs 17 ± 5, p < 0.05).Thirteen out of the19subjects with pleural abnormalities at HRCT were also identified by thoracic US, whereas 47 participants had lesions seen at US, but not at the HRCT scan (see Table 1, upper panel). Four out of the six lesions seen only at HRCT were virtually not reachable by chest US, being located in the retro-scapular, retro-sternal and paravertebral areas; the remaining two, located along the axillary space, were the oretically visible at US observation (Table 1, lower panel).Overall, positive percent agreement and negative percent agreement were 54%, 66.6% and 51.8%, respectively; the McNemar’s test for equality showed a p value < 0.001. The size of the lesions seen only at US was 4.2 ( ± 7.5) millimeters vs 6.8 ( ± 4.2) of those seen only at HRCT and 6.6 ( ± 7.4) of those detected by both methods (p = 0.541).The US/HRCT measurement agreement in term of lesion’s size among the 13 lesions detectable by both methods was robust for those lesions > 8 mm (Cohen’s k = 0.81) and substantial for those < 8 mm (Cohen’s k = 0.69). Further details on the location of the observed pleural abnormalities are shown in Table 1, lower panel. As expected, US detectable abnormalities were mostly located in the mid-basal, subscapular dorsal pleural surface and along the costophrenic recess. On the opposite, HRCT was superior in visualizing retrosternal, retroscapular and paravertebral abnormalities.
4. Discussion This is the first report on the role of US in the screening of pleural abnormalities in a population with a 20 years long asbestos exposure. In this setting, US could detect two thirds of the lesions also seen at HRCT, but, importantly, caught 47 lesions unrevealed by CT scan. This finding suggests a potential of US at improving the detection of early asbestos related pleural abnormalities. Indeed, these abnormalities were under the 10 millimeters minimally measurable lesion thickness threshold on CT scan stipulated by RECIST for mesothelioma [15]. Thus, US might help to provide an earlier diagnosis of asbestos related or other pleural conditions. On the other hand, the fact that two thirds of the lesion seen at
Table 1 Location and distribution of the observed pleural abnormalities at Chest CT scan and Ultrasound. Pleural solid abnormality
HRCT scan
Chest ultrasonography
Absent
Present
51 47
6 13
Absent Present
Ultrasound pleural thickness; mean (SD) Pleural thickenings location Anterior axillary line; N (%) Mid-axillary line; N (%) Posterior axillary line; N (%) Basal posterior; N (%) Mid-clavicular line; N (%) Sub-scapular; N (%) Costophrenic recess; N (%) Retro-sternal area; N (%) Retro-Scapular area; N (%) Para-vertebral area; N (%) Mediastinal Pleura; N (%)
Evidence of pleural thickening at ultrasonography only (N = 47)
Evidence of pleural thickening at HRCT only (N = 6)
Evidence of pleural thickening at both ultrasonography and HRCT (N = 13)
4.2 (7.5)
6.8 (4.2)
6.6 (7.4)
1 (2) 2 (5) 1 (2) 24 (56) 3 (7) 11 (23) 5 (11) 0 0 0 0
1 (16.6) 1(16.6) 0 0 0 0 0 2 (33.3) 1 (16.6) 1 (16.6) 0
0 0 1 8 1 2 0 0 0 0 0
141
(0) (0) (8) (67) (8) (17) (0)
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discussed, the follow up pending, the biological and clinical meaning of US detectable pleural thickness remains unknown. Second, our data were collected by a single operator, and it is therefore not possible to verify whether inter-observer variability might have affected the reproducibility and generalizability of results. Finally, a definitive estimate of US diagnostic accuracy would require thoracoscopic assessment and/or biopsy of the pleural lesion rather than HRCT. In conclusion, chest US might complement HRCT in the heath surveillance in asbestos exposed populations either to detect earlier lesions or to follow up US approachable lesions. Research is needed to assess the biological and clinical meaning of US, but not HRCT visible pleural lesions as well as to optimize the integration of HRCT and US.
[6]
[7]
[8]
[9] [10]
Conflict of interest disclosure
[11]
None of the authors of the present manuscript have any potential or real conflict of interest to declare. Funding [12]
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
[13]
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