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Pleural Plaques and Asbestos-associated Malignancy Philip Haxber, MD. MPH; Zab Mohseniiar, MD; Ami Oren, MD; and Myron Lew Pleural plaques are common in asbestos-exposed workers, affecting 15% to 60% of workers.1 The wnriing of a pleural plaque is often a signal of abnor mality and is frequently a cause of fear of additional disorders. However, the significance of these plaques is uncertain; is the plaque simply a "marker of exposure" or does it signify increased risk of disability or death? The large size of the population that has had asbestos exposure makes pleural plaques a frequent health conoera for these workers' families, as well as to their employers and to the medical and legal personnel in volved. Recent increases in public and health profes sional awareness of asbestos effects is increasing the vigor with which plaques are sought diagnostically. Previoui studies of the significance of pleural plaques have yielded conflicting results."4 We have therefore conducted a nested case-control study of a cohort of asbestos-exposed workers to determine whether pleural plaques are a risk factor for development of asbestosassociated malignancy. Methods A total of 1.500 asbestos-exposed workers were ex amined for the detection of asbestos-associated disease between 1979 and 1983 by physicians in the departments of pulmonary and occupational medicine at three Uni versity of California. Los Angeles, medical centers (Cen- Frotn the Department of Medicine. University of California. Los Angelas (Dr Harber. Assistant Professor. Occupational Medicine Branch--Center for Health Sciences and Pulmonary Division: Dr Mohaemfar. Assistant Professor. Cedars-Sinai: and Dr Oren. Assistant Jb'ofeesor. Harber-UCLA Medical Centers). Address correspondence to: Occupational Medicine Branch. De partment of Medicine. UCLA. Los Angeles. CA 90024 (Dr Harber). -1736/87/8908-441*08.000 Copyright S by American Occupational Medical Association ter for Health Sciences, Cedars-Sin&i. and Harbor-UCLA Medical Centers). Most of the workers examined were referred after filing a claim for compensation for asbestos-related lung disease. Each subject was interviewed in a standard manner by a trained nurse and subsequently by a physician. Dates of exposure were determined from information supplied by subjects and employers. Particular care was taken to encourage accurate reporting of exposure and of smoking histories. Radiographic examination of the chest included four views (posteroanterior, lateral, and bilateral obliques) in almost all cases. The radiographs were read by radiologists but were not coded according to the International Labor Office (ILO) system. Most had worked in shipyards, performing both new construc tion and refitting work. The median duration of work with asbestos exposure was 24 years. Industrial hygiene data describing fiber counts are unavailable, but work description suggests that asbestos exposure was heavy. Members of this population were subsequently con tacted to ascertain who had developed asbestos-associ ated malignancies detected after the initial examina tion. Malignant mesothelioma and carcinomas of the larynx, pharynx, trachea-bronchus-lung, kidney, and gastrointestinal tract were considered to be asbestos related based on reports confirming or suggesting such associations.7 The average interval between initial ex amination and follow-up contact was 30 months. Information about cancer status was sought from the subject or family members by telephone and by letter. A trained interviewer called the last known telephone number and administered a short interview if possible. Letters with a brief questionnaire were sent to the last known address. Information about 726 of the potential subjects was obtained. Each patient, defined as a subject known to have developed an asbestos-associated malignancy, was indi vidually matched to a control, a subject known to be free of cancer. Thus, subjects whose cancer status was unknown were ineligible to be a control. Only male Journal of Occupational Medicine/Volume 29 No. 8/August 1987 TX TIMER RMC0086022 641 subjects were included. Each patient was individually matched to a control of the same race, smoking status, and hospital of examination and with similar age. du ration of asbestos exposure, and pack-years of smoking (if an ex-smoker or current smoker). Workers who had stopped smoking at least 6 months before examination were classified as ex-smokera, and persons who had smoked less than 1 pack-year with none for at least 5 years were considered nonsmokers. Although selection of more than one control per patient would increase the statistical power of the analysis, it would have required including controls who were less comparable to the patients. The matches were selected according to a prescribed protocol by an individual who had no knowl edge of the subjects' radiographs. The radiographs from the patients' and controls' ini tial examinations were then obtained for review. The readers were unaware of the identity and cancer status for each radiograph. Names and dates were masked to avoid any possible bias. Each radiograph was read in dependently by two readers familiar with the ILO sys tem. one of whom was a certified B reader. The radiographs were read by three systems, which are summarized in Table 1. First, posteroanterior films were interpreted according to ILO guidelines, modified to include four categories of certainty for plaque pres ence: "negative," "probably negative," "probably posi tive." and "positive."6 Second, the ILO guidelines were used to interpret, but were applied to all four views (ILO-4 view). Third, the readers were asked to choose which of a pair of radiographs was most likely to show a plaque or interstitial disease. A forced choice was required for each of these questions, not allowing "nei ther" or "both" as answers. Each pair included a patient and his control; the readers were unaware of the iden tity. All radiographs were read by a single system before proceeding to the next system. The choice of radiographic scoring methods and sta tistical analysis methods was made before collation of TABLE 1 Radiographic Reading Methods* 4 Radiographs interpreted individually PA only |ILO) 4 View (ILO--4 view) Radiographs interpreted in pass Question t 'Which of the pair is more likely to have a plaque?' (Pair-Plaque) Question 2 'Which of the par is more likely to have interstitial disease9' (Pair-Interstitial) results. The interpretations based upon the ILO system were scored with the point system shown in Table 2 to yield a composite plaque score. This was done for both the ILO and ILO-4 view interpretations. The readings by the B reader and the non-B readers were analyzed separately to avoid counting each case-control pair twice. Analyses were performed by the paired t test8 8 and by the sign test (a nonparametric test depending only on the direction rather than magnitude of the casecontrol differences).10 The paired readings for most likely pleural plaque (question 1) and most likely inter stitial disease (question 2) were analyzed by the sign test, approximating the normal distribution. This was performed for both the interpretations of the B reader and of the non-B readers. Also, a 3-point scale was developed for the paired readings; the score is the number of readers (0 to 2) who felt the patient was more likely than the control to be positive. The investi gators realized in advance that performance of multiple analyses increased the likelihood of finding a "statisti cally significant" result. Results Sixteen cases of asbestos-associated malignancy were identified. A total of 13 were bronchogenic carcinoma; other malignancies included colon, kidney, and throat. Age, smoking history, and duration of asbestos exposure were comparable between patients and controls, and pack-years and duration of exposure were similar. Results of the analysis are shown in Table 3. The order of presentation of results for the B reader and the non-B readers has been varied. If a reader indicated that a radiograph was not of high quality, it was ex cluded from analysis, eliminating up to two pairs for some analyses. As shown in the table, there were no statistically significant differences (P < .05). Further more. there is no suggestion of a strong trend toward association of pleural plaque with subsequent malig nancy. Estimates of the power of several of these analyses were performed based upon a conditional sample size of 16 pairs. For the sign test, Fisher exact method showed that there was a 92% probability of finding a difference between patients and referrents (with a 10% chance of type II error) if 80% of the patients' radiographs showed plaque-like findings to a greater degree than the matched controls' radiographs. There was an 81% Composite Score = Plaque Score-Right (0. 1. 2. or 3) TABLE 2 Plaque Score-Left (0, 1.2. or 3) + Profile Width Score-Right (0 or 2) + Profile Width Score-Left (0 or 2) + Calcification Score (0 or 2) Plaque score = 0 if pleural abnormality (localized plaque or diffuse thickening) is definitely absent. 1 if pleural abnormality is probably absent. 2 if pleural abnormality is probably present. 3 if pleural abnormality is definitely present. Profile width score = 0 if plaque width in profile <6 mm. 2 if plaque width in profile 26 mm. Calcification Score = 2 if pleural calcification is present in either side, otherwise = 0. Possible scores range from 0-t2. For example, a radiograph with a 3-mm wide calcified probable plaque on nght and a 7-mm calcified definite plaque on left would be scored as 9; plaque score nght = 2. plaque score-left - 3. profile width core-nght = 0, profile width score-left = 2. calcification score = 2 642 Pleural Plaques and Asbestos/Harber et al TX TIMER RMC0088023 Thest order c averag test is chant havie was. paire Varir refer for a. Pow one-i woul 6 poi ence plaq DiSCl A aabe Is ur of a deta the exp< Are or a S wit) per aab* do : add on StU' abs ris) ex; cur sep 1 ter ris) tos J01 TABLE 3 Results of Radograpfuc Interpretation* System Reader Paired 1 test Mean A P WHcoxon P Sign test % positive P ILO ILO-4 view Pair-plaque Pair-interstitial Pair-3 point-plaque 1 2 1 2 1 2 1 2 1 +2 - 10 .07 21 -03 .43 .45 .31 .48 .34 -.31 .50 91 .67 50 0 50 0 50 0 54 .11 47 -.10 40 -.28 50 0 32 -43 ' These statistical analyses test the hypothesis that the patient is more abnormal than the control. No results were statistically significant. The order of readers is varied on the table. ILO and ILO-4 view results are based upon the plaque scoring system described in Table 2. Mean X average case-control difference. % positive, percentage of pairs in which the patient received a higher score than his control. P value for the sign test is based upon a z score approximation. chance of this finding if the true probability of the case having a more abnormal radiograph than the referent was .75. Power estimates for the 12-point scale readings paired differences were also performed for a reader. Variance of the difference between scores for cases and referents was estimated as twice the pooled variance for all readings, conservatively assuming no covariance. Pcwer was then estimated using the t distribution for a one-sided a = 0.05. A mean score difference of 2 points would be detected with 60% likelihood. A difference of 6 points would be detected with 81 % power: this differ ence, for example, corresponds to finding bilateral plaques in the patient and normal pleura in the referent. Discussion Although pleural plaques are a common effect of asbestos exposure.1 2 the medical significance of plaques is uncertain. At the very least, plaques serve as a marker of asbestos exposure, alerting clinicians to take a more detailed occupational history. Albelda et al13 have shown the specificity of bilateral pleural plaques for asbestos exposure. Is there, however, additional significsince? Are asbestos-exposed workers at higher risk of cancer or asbestosis if they have a plaque than if they do not? Several previous studies have suggested that persons with plaques have increased risks of cancer relative to persons who do not have plaques. However, because asbestos causes both plaques and cancer, these studies do not demonstrate whether plaques per se imply any added risk. For example. Edge3 matched on age but not on asbestos exposure. Hillerdal4 also stated that his study did not show that knowledge of the presence or absence of plaques added any information about cancer risk that was independent of the extent of asbestos exposure. Hence, there is a need for studies such as the current one. in which the effect of the plaque per se is separated from that of asbestos exposure. This nested case-control study was performed to de termine whether pleural plaques are an independent risk factor for the subsequent development of an asbes tos-associated malignancy. As shown in Table 3. despite the use of multiple analytic techniques to discern such a relationship, none was found. Thus, although asbestos exposure can cause plaques and can also cause cancer, plaques per se do not appear to be causally related to subsequent cancer development. Any apparent associa tion between plaques and cancer is spurious, being a consequence of their associations with asbestos expo sure. The study design allowed control of confounding foetors, matching each patient individually with a control subject (ie, without cancer) who had similar duration of asbestos exposure, smoking status, extent of smoking, and age. Each of these factors has been shown to lead to increased pleural plaque prevalence rates. Earlier studies have relied upon less certain information about these factors. For example, Wain et al6 relied on occu pational histories gleaned from the medical records of patients who underwent autopsies at a Veterans Admin istration hospital. To assure close comparability between patients and controls and to overcome limitations of previous studies of the relationship between plaques and cancer, we selected only one control per patient. The nested casecontrol design used provided a unique ability to avoid biases that often affect cancer studies. First, smoking and exposure data were collected from the subject rather than from next of kin. Second, "recall" bias, due to selective remembering of risk factors after establish ment of a diagnosis, was avoided because the information was collected before making the cancer diagnoses. Third, "diagnostic bias" is avoided: because the diag nosis of cancer and the ascertainment of plaques were accomplished independently, the presence of one is un likely to affect the diagnosis of the other. Fourth, pa tients and controls were selected from the same popu lation, enhancing comparability. Inaccurate information about the confounding factors used for case-control matching are unlikely to affect the conclusions found. If anything, such inaccuracies would bias toward showing a spurious association of plaques and cancer. For example, if a subject understated his smoking experience, he would have been inappropriately matched with a subject with a lesser smoking exposure. Journal of Occupational Medicina/Volume 29 No. 8/August 1987 TX TIMER RMC0088024 643 Because cigarette smoking causes both cancer'4 and an increased chance of radiologic abnormality, the "inac curate" subject is more likely than his control to have both a plaque and cancer, thus biasing the study toward finding a positive plaque-cancer association. The sample size for the statistical analysis is rela tively small, although an initial cohort of 1.500 subjects was used for case identification. The limited sample size decreases the statistical power to find a low P value" in hypothesis testing but does not bias the mean result observed. There was no trend toward increased risk due to plaques, suggesting that lack of effect is the most likely true situation. Although precise data about the duration of asbestos exposure were used, information about intensity of ex posure was not available. Industrial hygiene data, de scribing fiber counts based on use of personal sampling pumps worn by the workers throughout the period of exposure, were not collected. The finding of no associa tion is unlikely to be due to lack of exposure intensity data. Any effect, if present, would lead to a spurious association as discussed in the earlier example about smoking information. Furthermore, systematic interreader differences in radiographic interpretation would be unlikely to confound the results. In summary, this study found no association between pleural plaques and asbestos-associated malignancies that were independent of other causative factors such as duration of asbestos exposure, age, and cigarette smoking. Although pleural plaques do indicate exposure, we do not believe their presence or absence should be used to allocate cancer screening resources among sim ilarly exposed asbestos workers. If workers are known to have had significant exposure, it appears unwise to deny them appropriate examinations that they might otherwise receive simply because pleural plaque is not detected. Acknowledgments This work was supported in part by a grant from the University of California Cancer Research Coordinating Committee. The authors thank Debra Craig for preparation of this manuscript and Oil Fine for statistical advice. References 1. Meurman L: Asbestos bodies and pleural plaques in a Finnish series of autopsy cases. Acts Patio! Microbiol Scand I966;181(uppl):l-107. 2. Kiviluto R, Meurman LO, Hakama M: Pleural plaques and neoplasia in Finland. Ann ,VT Acad Sci 1979:390:31-33. 3. Edge JR: Incidence of bronchial carcinoma in shipyard workers with pleural plaques. Ann NY Acad Sci 1979:38089-294. 4. Hillerdal G: Pleural plaques and risks for cancer in the County of Uppsala. Eur JRespir Dia 198CM51(*uppl 10):111-117. 5. Wain SL, Roggli VL. Foster WL: Parietal pleural plaques, asbestos bodies, and neoplasia: A clinical, pathologic and roentgenographic correlation of 23 consecutive cases. Chest 1984:86:707-713. 6. ILOI VC International Classification of Radiographs of Pneu moconiosis, 1971, no. 28 revised. Geneva, Occupational Safety and Health Services, International Labor Office, 1973. 7. Becklake MR: Asbestos-related diseases of the lungs and pleura current clinical issue. Am Rev Respir Dia 1984:126:187-194. 8. HP-85 Baaic Statistic* and Data Manipulation PAC. Corvallis. Ore. Hewlett-Packard. 1981. 9. HP-86 General Statistics PAC. Corvallis. Ore. Hewlett-Pack ard. 1980. 10. Snedecor GW. Cochran WO: Statistical Motboda. ed 7. Ames: Iowa State University Press. 1980. 11. Hollander M. Wolfs DA. Nonparametric Statistical Methods. New York. John Wllsy * Sons. 1973. pp 269-263. 12. Rublno GF. Scenes HG, Pirs E. et al: Pleural plaques and lung asbestos bodies in tbs gsneral population: An autophical and clinicalradiological survey, in Wagner JC, and Davis W (eds) IARC Scientific Publication. Lyon. France. International Agency for Research on Cancer, 1980. vol 2: Biological Effects of Minsral Fibers, pp 645-661. 13. Albelda SM. Epstsin DM. Gefter WB. et al: Pleural thickening: Its significance and relationship to asbestos dust exposure. Am Rev Respir Dia 1982: 128:621-624. 14. Selikoff IJ. Hammond EC: Asbestos and smoking. JAMA 1979:242:468-469. Hazards of Early Pregnancy The Director-General of WHO (World Health Organization) reminds us of something we know but tend to forget: that the inner-city teenager with two children by her 16th birthday has risked her own future health, has markedly reduced her chances of ever functioning effectively in our complex society, and has placed the babies themselves at risk of premature death. Early fertility in many subgroups of women in the United States is as much a barrier to the solution of our social problems as early fertility in undeveloped countries is to those countries' advancement into the modern world. --From Annals of Internal Medicine 1986;104(2):264. 644 Pleural Plaques and Asbestos/Harber et al TXTINER RMC0086025 Th Vc Pr< Stev Mid Fn oootr mmsi aahMrtf and c to Ait epiao. oo th 868% more than retec aocia prott nevei and mult type etfec life c prod follow if re ideal Fr Niam Dcp* Chau MAI P< ttona Ai ud I ton.' 0096- OOPJT Jou August 1987, Volume 29, No. 8 ISSN 0096 1736 Journal oi Oecupa tional Medicine PLEURAL PLAQUES AND ASBESTOS-ASSOCIATED MALIGNANCY The presence of pleural plaques indlcatss a history of exposure to asbestos but is not an independent risk factor for the development of asbestos-associated malignant disease. THE PROSPECTIVE IMPACT OP PSYCHOSOCIAL VARIABLES ON RATES OP ILLNESS AND INJURY IN PROFESSIONAL EMPLOYEES. In a study of air traffic controllers, high psychosocial risk scores were predictive of future aocidents and future total morbidity. Coworker-related amicability eras protective against these outcome variables. THE EFFECT OF TIME IN A NEW JOB ON HOSPITALIZATION RATES FOR ACCIDENTS AND INJURIES IN THE U.S. NAVY, 1977 THROUGH 1983 For personnel assigned to shore duty, but not sea duty, the highest incidence of injury occurred during the first few weeks at the new job. Among shore-based personnel, the leading causes of injury included athletics and motor vehicle accidents. CHARACTERISTICS OF THE FREQUENT VISITOR TO THE INDUS TRIAL MEDICAL DEPARTMENT AND IMPLICATIONS FOR HEALTH PROMOTION In-house clinic usage, absenteeism, and tardiness were studied among 1606 employees at an automobile assembly plant. Less than lfi per cent of the workforce accounted for over SO percent of the medical visits and more abeenee and tardiness, compared to the rest of the plant population. TXTINER RMC0086026 WM. KEITH C. MORGAN, M.D. (Sheffield), F.R.C.P. (Ed.) Professor ot Medicine and Head. Division of Pulmonary Diseases. West V'iraima L'mversitv Medical Center. Morgantown. W'est Ciramia. Formerlv Director. Appalachian Laboratory tor Occupational Respiratory' Diseases. National Institute ot Occupational Safety and Health ANTHONY SEATON, M.D. (Cantab.), M.R.C.P. (London) Consultant Phvsician SulIv and Llandouah Hospitals. Penarth. and L'mversilv Hospital ot W'ales. Cardiff. South W'ales OCCUPATIONAL LUNG DISEASES 1975 W. B. SAUNDERS COMPANY Philadelphia. London. Toronto TX TIMER RMC0089027 flow S per icitv for or 1 HISTORICAL AND LEGAL ASPECTS OF INDUSTRIAL DISEASE................................................................................... . \V. Keith C. Morgan I 2 PULMONARY PHYSIOLOGY-Its Application to the Determination of Respiratory Impairment and Disability in Industrial Lung Disease........................................ W. Keith C. Alorgan 5 :} THE DEPOSITION AND CLEARANCE OF DUST FROM THE LUNGS................................................................. W\ Keith C. Morgan 20 * EPIDEMIOLOGY AND OCCUPATIONAL LUNG DISEASE................................................................................... \V\ Keith C. Morgan 29 5 PATHOLOGICAL REACTIONS OF THE LUNG TO DUST ........................................................................................ R. M. E. Seal mid J. C Wagner 19 6 IMMUNOLOGY OFOCCUPATIONAL LUNG DISEASES Robert Burrell 65 xi txtiner RMC0088028 TX TIMER RMC0086031