Pleural Plaques And The Risk Of Pleural Mesothelioma Review Of The Jnci Journal
Pleural Plaques and the Risk of Pleural Mesothelioma Review of the JNCI journal
| Title | Pleural Plaques and the Risk of Pleural Mesothelioma |
| Journal Name | Journal of the National Cancer Institute (JNCI) |
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| Volume, Issue & Page | Volume 105, Issue 4 & Pages 293–301 |
| Date of published | 19 February 2013 |
| Authors |  Jean-Claude Pairon, François Laurent, Mickaël Rinaldo, Bénédicte Clin, Pascal Andujar, Jacques Ameille, Patrick Brochard, Soizick Chammings, Gilbert Ferretti, Françoise Galateau-Sallé. Antoine Gislard, Marc Letourneux, Amandine Luc, Evelyne Schorlé, Christophe Paris |
Abstract
Background
The association between pleural plaques and pleural mesothelioma remains controversial. The present study was designed to examine the association between pleural plaques on computed tomography (CT) scan and the risk of pleural mesothelioma in a follow-up study of asbestos-exposed workers.
Methods
Retired or unemployed workers previously occupationally exposed to asbestos were invited to participate in a screening jadwal for asbestos-related diseases, including CT scan, organized between October 2003 and December 2005 in four regions in France. Randomized, independent, double reading of CT scans by a panel of seven chest radiologists focused on benign asbestos-related abnormalities. A 7-year follow-up study was conducted in the 5287 male subjects for whom chest CT scan was available. Annual determination of the number of subjects eligible for free medical care because of pleural mesothelioma was carried out. Diagnosis certification was obtained from the French mesothelioma panel of pathologists. Survival regression based on the Cox model was used to estimate the risk of pleural mesothelioma associated with pleural plaques, with age as the main time variable and time-varying exposure variables, namely duration of exposure, time since first exposure, and cumulative exposure index to asbestos. All statistical tests were two-sided.
Results
A total of 17 incident cases of pleural mesothelioma were diagnosed. A statistically significant association was observed between mesothelioma and pleural plaques (unadjusted hazard ratio (HR) = 8.9, 95% confidence interval [CI] = 3.0 to 26.5; adjusted HR = 6.8, 95% CI = 2.2 to 21.4 after adjustment for time since first exposure and cumulative exposure index to asbestos).
Conclusion
The presence of pleural plaques may be an independent risk factor for pleural mesothelioma.
Because asbestos has been widely used in Western countries, a substantial proportion of retired workers have been occupationally exposed to it. It has been estimated that approximately 20% to 25% of male retirees in France have been previously exposed to asbestos ( 1 ). Occupational asbestos exposure is known to be associated with several benign diseases of the pleura and lungs, including pleural plaques, pleurisy, fibrosis of the visceral pleura, rounded atelectasis, and asbestosis, as well as several malignancies—mainly lung cancer and mesothelioma ( 2–4 ). The epidemiology of asbestos-related diseases has been largely documented over recent decades ( 2 , 3 , 5 ). However, several issues concerning asbestos-related diseases remain controversial, as underlined in a recent consensus expert statement (eg, the level of asbestos exposure required to cause lung cancer, the existence of a link between the extent of asbestos exposure and the presence and extent of pleural abnormalities, and the indication for chest computed tomography [CT] scanning to screen populations at risk for asbestos-related diseases) (6). Pleural plaques are circumscribed areas of thickening of parietal or diaphragmatic pleura composed of avascular collagen connective tissue. They are the most common disease in asbestos-exposed subjects ( 4 ). An association between pleural plaques and pleural mesothelioma has been reported in several consensus statements ( 4 , 6 ). Subjects with pleural plaques have been reported to have increased risks of lung cancer and pleural mesothelioma compared with the general population ( 7–9 ). However, these associations were mainly established by a small number of studies based on chest x-ray, with a limited number of subjects. It has been demonstrated that chest x-ray has a fairly poor sensitivity and specificity for the detection of pleural plaques compared with CT scan. The use of chest x-ray is therefore associated with a high risk of misclassification of subjects according to the presence or absence of pleural plaques. Moreover, only a few studies have taken cumulative exposure to asbestos into account. In a study of former workers and residents of the Australian crocidolite mining and milling town of Wittenoom, Reid et al. reported an association between benign pleural disease and an excess of peritoneal mesothelioma, but not pleural mesothelioma, after adjustment for cumulative exposure to asbestos and time since first exposure ( 10 ). The potential link between the most common benign asbestos-related disease (ie, pleural plaques) and pleural mesothelioma, therefore, cannot be considered to be formally demonstrated ( 11 ). Because pleural plaques are very frequent in asbestos-exposed subjects, it is crucial to establish whether or not they confer an increased risk of pleural mesothelioma in comparison with individuals free of pleural plaques but with similar levels of asbestos exposure.
A large-scale pilot screening jadwal for asbestos-related diseases was initiated in four regions of France in 2001 after a national consensus conference on the clinical surveillance strategy for workers previously exposed to asbestos, which proposed periodic chest CT scans and pulmonary function tests for workers with moderate to high exposure to asbestos ( 12 ). This study was designed to examine the association between pleural plaques, detected on CT scan, and the risk of pleural mesothelioma in a 7-year follow-up study of formerly asbestos-exposed workers.
Methods
Study Population
The Asbestos Post Exposure Survey (APEXS) screening jadwal for asbestos-related diseases was organized at the request of the French Ministry of Labour and National Health Insurance between October 2003 and December 2005 in four regions of France: Aquitaine, Rhône-Alpes, Haute-Normandie, and Basse-Normandie. Retired or unemployed workers previously occupationally exposed to asbestos and covered by the General National Health Insurance fund (which covers more than 80% of the French population) were eligible for the screening program. They were invited to participate in the jadwal in various ways according to the region (letters targeting age groups below 65 or 67 years and previous type of job; trade union, radio, television, and newspaper advertisements). As previously described, volunteers who agreed to participate had a free medical check-up that included chest CT scan and pulmonary function tests ( 12–14 ). Only male subjects with an available copy of their CT scan sent to our team centers were included in this study. The study was approved by the hospital ethics committee. All participants received information about the study and gave their written informed consent.
Asbestos Exposure and Tobacco Consumption
As described elsewhere, all subjects completed a standardized questionnaire, which allowed industrial hygienists to evaluate asbestos exposure on the basis of the complete work history of each subject ( 13 ). For each job associated with asbestos exposure, the duration (number of years) and dates of exposure were determined. The following weighting factors were attributed for the intensity level of exposure: low (passive exposure): 0.01; low intermediate: 0.1; high intermediate: 1; high: 10. A cumulative exposure index (CEI) to asbestos was calculated for each subject over his working life as the sum of exposures calculated for each exposed job (duration × weighting factor). Because of the absence of atmospheric measurements and the lack of detailed information on the frequency of exposure to asbestos (percentage of the working time), the CEI was expressed in exposure units × years rather than in fibers/mL × years. The latency was defined as the time elapsed between the beginning of the first job considered to have exposure to asbestos and the date of CT scan.
The questionnaire also collected information on tobacco consumption. Subjects were classified into three categories: current smokers, ex-smokers (defined as those who had stopped smoking for at least 1 year), and never smokers.
CT Scanning
Subjects underwent CT scan according to a specific protocol. The modalities for performing CT scan were established by a group of chest radiologists designated by the Société Française de Radiologie (French Radiology Society), with technical modalities designed to detect all CT scan changes related to asbestos-induced pleural and parenchymal diseases with a limited radiation burden. Briefly, the main parameters were as follows: the entire chest was screened in the supine position using a spiral acquisition without injection of contrast media; a slice thickness of 1.5 to 5mm was used; a pitch of 1.5 to 2.0, 120kV, 60 to 150 mA maximum was used; parenchymal images were reconstructed with sharp filters and visualized with a window width approximately 1600 Hounsfield Units (HU) and a window level of −600 HU; and soft tissue images were reconstructed with smooth filters and visualized with window width approximately 400 HU and window level of 50 HU. A minimum of five, high-resolution, 1-mm thick CT sections performed in the prone position between the carina and the pleural recess were also acquired ( 14 ).
All available CT scans were submitted for randomized, independent, double reading (and triple reading in the case of disagreement) focused on benign asbestos-related abnormalities by a panel of seven chest radiologists trained in the interpretation of asbestos-related CT abnormalities. (Two members of the panel are study authors [F. Laurent and G. Ferretti]. The five others are Y. Badachi, C. Beigelman, A. Jankowski, V. Latrabe, and M. Montaudon.) These experts were blinded to the subject’s cumulative exposure to asbestos and to the results of the initial reading by the radiologists who performed the CT scans. A standardized form was used to register interstitial or pleural abnormalities according to the Fleichner Society glossary of terms ( 15 ). Pleural plaques were considered to be present in the case of circumscribed quadrangular pleural elevations, with sharp borders and tissue density, sometimes calcified, with usual topography for at least some of the images ( 16 ). Pleural plaque thickness was classified by taking into account the thickest plaque (four categories: <2mm, 2–<5mm, 5–<10mm, and 10 mm or more). The cutpoints were chosen and adapted from the International Labour Office classification of radiographs of pneumoconiosis ( 17 ). In this classification, width/thickness of pleural abnormalities is categorized as “a” (3–5mm), “b” (5–10mm) or “c” (>10mm).
The extent of pleural plaques was assessed using a semiquantitative method. The cumulative extent of pleural plaques detected on each section was calculated and expressed as the percentage of the lateral chest contour as measured on a single axial section at the level of the carina. This cumulative extent was graded according to four categories: less than 1cm, between 1cm and less than 25% of the chest contour, between 25% and less than 50% of the lateral chest contour, and 50% or more of the lateral chest contour. Because there is no available consensus for classification of the extent of pleural plaques on CT scan, the categories were adapted from the International Labour Office classification of radiographs of pneumoconiosis ( 17 ). A fourth category for plaques with a cumulative extent less than 1cm, very likely identified on CT scan only, was added to the three International Labour Office categories. The choice of adapting International Labour Office classification to CT scan has been previously used by Jarad et al. ( 18 ) in their anjuran for a scoring system. Parietal pleural plaques were defined in our study as “typical” when they were bilateral, thicker than 2mm, and with an extent greater than 1cm, regardless of whether they were calcified.
Mesothelioma Diagnosis
A follow-up study was organized in subjects who had participated in the APEXS jadwal using free cancer medical care data. In France, all cancers must be reported to the French National Health Insurance to provide full coverage of medical expenses, including treatment. Annual determination of all new subjects applying for free medical care for pleural mesothelioma was therefore carried out for the 7 years between January 1, 2004, and March 31, 2011, in subjects who had participated. Patients with mesothelioma were considered to be incident when there was no suspicion of mesothelioma on the baseline CT scan. The French mesothelioma panel of pathologists (MESOPATH) was asked to certify the diagnosis of mesothelioma in all mesothelioma patients of this study ( 19 ). Each mesothelioma patient submitted to MESOPATH underwent a standardized diagnostic confirmation procedure, including transmission to MESOPATH of histological slides or blocks. Morphological analysis on hematoxylin and eosin–stained slides and systematic immunohistochemical analysis including at least two positive and two negative markers were then performed to maximize the reliability of diagnosis. Slides were reviewed by at least three expert members of MESOPATH (and a consensus opinion with a quorum of 10 experts in the case of disagreement between the first three experts), blinded to evaluation of asbestos exposure. Final pathological certification was classified as certain mesothelioma, uncertain mesothelioma (not definitively certified and not definitively excluded), or unclassifiable tumor because of inadequate material. In some patients, mesothelioma could be ruled out in favor of another diagnosis. Complementary analysis on available histological material was performed by a single pathologist for determination of fibrohyaline pleural plaques associated with the tumor on histology slides. This pathologist evaluated the presence or absence of hyaline fibrous plaques composed of hyaline acellular collagen with basket weave reticulin.
Statistical Analysis
The variables used to characterize asbestos exposure were duration of exposure to asbestos, CEI, and time since first exposure (TSFE) to asbestos until CT scan. Statistical associations between pleural plaques and incidence of pleural mesothelioma were studied using survival regression analysis based on the Cox proportional hazards model (34 091 subject-years). Age was the main time variable, thus accounting for age in a nonprespecified way, whereas duration of exposure, CEI [expressed as Ln(CEI +1)], and TSFE to asbestos were independent variables. Only the latter (TSFE to asbestos) was a time-varying variable because the subjects were no longer exposed at the time of inclusion. For each subject, date of diagnosis of mesothelioma or date of last update—namely, March 31, 2011—was used. Proportionality assumption of Cox model was verified graphically. Unadjusted hazard ratios (HRs) and adjusted hazard ratios for these time-varying variables were calculated for the risk of pleural mesothelioma associated with typical pleural plaques and with other less typical pleural plaques, with subjects free of pleural plaques as reference subjects according to CT scan date. All mesothelioma cases were initially used in the analysis, and then only those definitely confirmed by MESOPATH. The Fisher–Freeman–Halton test was used to compare characteristics (age, smoking status, asbestos exposure parameters) of mesothelioma patients with those of nonmesothelioma subjects. Statistical analysis was carried out using SAS software version 9.2 (SAS Institute, Inc, Cary, NC) and STATA for survival analyses, release 11 (StataCorp, College Station, TX). All statistical tests were two-sided, and statistical significance was defined as P less than .05.
Results
Overall, 13 859 eligible subjects agreed to participate in the screening program, 7275 underwent CT scan, and 5825 of these CT scans were sent to our team centers. After exclusion of subjects with missing data for asbestos exposure parameters, subjects considered to be unexposed to asbestos by industrial hygienists, subjects with unreadable CT scan, and one subject considered to have a probable pleural tumor at the time of CT scan (effusion and irregular pleural nodular thickening, which was finally diagnosed as a prevalent mesothelioma), the study population consisted of 5287 male subjects ( Figure 1 ).
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