Are pleural plaques an appropriate endpoint for risk analyses?

Figures & data

Figure 1. Best-fit equation relating the prevalence of pleural plaques, TSFE and mean exposure (f/ml) as determined by Paris et al. (2008).

Figure 2. Contour lines of the best fit model shown in Figure 1.

Table 1. Studies that have attempted to correct for confounders in assessing the relation between pleural plaques and malignant effects.

Sources	Findings/quotations
Harber et al. (1987)	These investigators reported findings of a case–control study of male lung-cancer patients and controls among 1500 asbestos workers receiving screening for asbestos-related diseases. Controls were matched on the basis of race, smoking status, hospital, duration of asbestos exposure and pack-years of smoking. No significant differences were found comparing workers with plaques compared to those without. However, The number of malignancies was small (16).
Weiss (1993)	This was largely a review article (see section below on review studies) but did combine results of several studies to determine the weighted ratio of observed to expected lung cancers for four studies as 1.01 [CI = 0.75–1.33]. Weiss concluded that the weight of evidence is against the hypothesis that persons with asbestos-related pleural plaques are at increased risk of lung cancer compared with unexposed persons.
Koskinen et al. (2002)	These investigators reported results of a study of 16 696 male construction workers. They computed both univariate and multivariate analyses of the relative risks of lung cancer and mesothelioma in this group. The RR in lung cancer for pleural plaques was 1.3 [CI = 1.0–1.7] for the univariate analysis, but 1.2 [CI = 0.9–1.6] for the multivariate model, which included age, smoking, PP and an asbestos exposure index. For mesothelioma, the RR for plaques was 0.7 [CI = 0.3–1.6] for the univariate analysis and 0.6 [CI = 0.3–1.4] for the multivariate analysis.
Cullen et al. (2005)	Among 2089 asbestos-exposed workers for which the presence or absence of pleural plaques was known and with no radiographic evidence of asbestosis, the RR for lung cancer was 1.91 [CI = 1.25–2.92] after adjustment for age, smoking history and asbestos exposure duration. However, the authors wrote: “We offer no specific hypothesis for this, other than the likelihood that persons with plaques had more exposure on average than those without them”.
Reid et al. (2005)	These investigators studied a cohort of former workers and residents of the crocidolite mining and milling town of Wittenoom, Australia. A key strength of this study was the accurate determination of asbestos exposure in this cohort. Pleural diseases were detected using CXR. The relative risks for either pleural or peritoneal mesothelioma for all benign pleural diseases and calcified plaques were smaller when adjusted for age, time since first exposure and cumulative exposure (f/ml-years). For either pleural or peritoneal mesotheliomas the confidence intervals on RR included unity based on all benign pleural diseases. The authors concluded: “These findings are consistent with the notion that the presence of pleural disease is dose related and are simply a surrogate for exposure in cohorts where exposure has not been measured”.
Barbot et al. (2012)	These investigators studied a cohort of 5825 unemployed or retired asbestos-exposed workers covered by French National Health Insurance. Pleural plaques were detected using CT. There were 73 cases of lung cancer in workers for which the presence or absence of pleural plaques were determined. They found there was no significant difference between the frequency of lung cancer in patients with and without pleural plaques when adjusted for age and cumulative exposure index.
Pairon et al. (2013a)	These investigators studied the relation between pleural plaques and mesothelioma among a cohort of retired or unemployed workers previously exposed to asbestos. Pleural plaques were diagnosed using CT. A total of 17 incident cases of pleural mesothelioma were found. The authors computed a hazard ratio (HR) for pleural plaques of 6.8 [CI = 2.2–21.4] in this group and concluded: “The presence of pleural plaques may be an independent risk factor for pleural mesothelioma”.
Pairon et al. (2014)	These investigators conducted a 6-year follow-up study of lung cancer in 5402 male subjects participating in an asbestos-related disease screening program. Pleural plaques were diagnosed using CT. A total of 36 deaths from lung cancer were recorded. The computed hazard ratio for pleural plaques was 2.41 [CI = 1.21–4.85] when adjusted for smoking and asbestos cumulative exposure index. The authors concluded: “Pleural plaques may be an independent risk factor for lung cancer death”.

Table 2. Conclusions of various review articles regarding whether pleural plaques are an independent risk factor for either lung cancer or mesothelioma.

Sources	Findings/quotations
Sheers (1979)	“The risk of the later development of pulmonary fibrosis appears broadly similar in all varieties of pleural abnormality, and it can no longer be assumed that a pleural plaque related to work in a dockyard is a marker of exposure and nothing more”.
Rom & Lockey (1982)	“Current knowledge indicates that pleural plaques, per se, do not increase the risk for this tumor [mesothelioma] beyond that of the previous asbestos exposure alone”.
Epstein (1984)	“What is still required but as yet is unavailable is a study comparing the incidence of lung cancer and other types of respiratory tract malignancy in a group of patients with pleural plaques versus a control group without pleural plaques who are matched for asbestos exposure, age and smoking habits in the absence of pulmonary fibrosis”.
Edelman (1988)	“However, based on the present review, it seems unlikely that persons with pleural plaques, compared to those without pleural plaques, are at any increased risk of lung cancer”.
Weiss (1993)	“Thus, the weight of the evidence favors the conclusion that persons with asbestos-related pleural plaques do not have an increased risk of lung cancer in the absence of parenchymal asbestosis”.
Smith (1994)	Supports conclusions of Weiss (1993).
Rudd (1996)	“Pleural plaques are not themselves precursors of malignant change but, insofar as they reflect exposure to asbestos, they may be associated with an increased risk of asbestos related malignancy”.
Jones et al. (1996)	“Pleural plaques have not proved to be a reliable marker for increased risk of lung cancer”.
Jones (1997)	“Plaques develop after relatively low exposures and are thus not reliable indicators of elevated risk of asbestos-attributable lung fibrosis or lung cancer … In most settings, plaques indicate an elevated risk of mesothelioma, in comparison to the general population. In comparison to similarly exposed persons, plaques do not have any prognostic significance”.
Hillerdal (1997)	“Plaques are in themselves harmless. They may be regarded as an objective sign of previous asbestos inhalation, and it is this exposure that is of possible importance for future health”.
Hillerdal & Henderson (1997)	This article reviews several articles, but provides the following comment regarding plaques: “They are in themselves harmless and can be regarded as an objective sign of previous asbestos inhalation. If there is a linear dose-response relationship between lung cancer and asbestos, the logical consequences would be that persons with plaques should have an increased incidence of bronchial carcinoma. On the other hand, if the ‘asbestosis-cancer hypothesis’ is correct, there should be no increased risk unless the plaques are combined with asbestosis”.
Weiss (1999)	“Workers with pleural plaques but no asbestosis have no increase in lung cancer in well-designed studies”.
Letourneux (1999)	“Pleural plaques occur even when the level of asbestos exposure is low. They are not only dose-dependent but are also latency-related. They have no prognostic significance in asbestos-exposed workers, but are associated with an increased risk for the subsequent development of mesothelioma and bronchial carcinoma when compared to the risk of the general population”.
Cugell & Kamp (2004)	“At the present time, the preponderance of the evidence indicates that plaques do not increase the cancer risk, but this is far from a universal view”.
Crapo (2005)	“When compared to other individuals with similar asbestos exposure but no pleural manifestations, patients with pleural plaques have not been shown to be at increased risk of more serious asbestos-related diseases”.
Goldberg (2005)	Addressing the results of the Reid et al. (2005) study: “These results are in favor of the common cause without interaction hypothesis for pleural cancer, pleural abnormalities and asbestosis being proxies of asbestos exposure without bearing a specific contribution to the increase in the risk of mesothelioma”.
Gevenois & De Vuyst (2006)	“Nevertheless, it seems that there is no difference in the incidence of lung cancer between individuals with pleural plaques and controls matched for exposure but without pleural plaques … As a summary, the presence or absence of plaques does not appear to modify the risk for mesothelioma or lung cancer among individuals who have the same level and type of exposure”.
Kamp (2009)	“Importantly, no firm evidence suggests that pleural plaques increase the risk of developing MM [malignant mesothelioma] or lung cancer”.
Ameille et al. (2011)	“Among asbestos-exposed individuals, those having radiographic evidence of pleural plaques are at increased risk for lung cancer and pleural mesothelioma, compared to the general population. However, there is no evidence that pleural plaques confer an increased risk of lung cancer or pleural mesothelioma within a population of individuals having the same cumulative exposure”.
Dalphin (2011)	“There is no effective treatment for asbestos-related benign pleural diseases but these are markers of exposure. The presence of pleural plaques has not been shown to be an aetiological factor for thoracic cancers”.
Ameille (2012)	“On the basis of radiological studies, pleural plaques are associated with an increased risk of lung cancer and mesothelioma. For identical levels of total asbestos exposure, it has not been established that the presence of pleural plaques increases the risk of developing thoracic cancer”.
Schaer & Michel (2012)	“Pleural plaques do not appear to increase the risk of cancer associated with asbestos and, thus, do not modify post-exposure follow-up. Incidental finding of pleural thickening remains a gray zone that opens the door to new studies”.
Pairon et al. (2013b)	“Conclusion: after 7.7 years of follow-up, the presence of pleural plaques is associated with a non-significantly increased risk of lung cancer in this cohort”.

Certain features of the Weiss (1993) review have been challenged (Nurminen & Tossavainen, 1994a,b).

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