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T 43. Neoplasms of the Pleura 559 Cha in a Jthethat ;nant neoaterit titled ough logic case sbesmost not a d five d had ig the nlogic imarv firms, leural sually circunoval. aleura urface ologic i 1940 irted a bestos umors >ma in plasms sented >rt of a was in aathoiesotheelioma rted in ihe German literature in 1953 and 1954,36,17 and in 1960 Keal18 reported the association of peritoneal mesothelio mas and asbestos exposure. Also in 1960 Wagner et al.19 reported 33 cases of diffuse pleural mesothelioma in the North Western Cape Province of South Africa. Of these 33 patients, 32 had exposure to asbestos. Wagner20,21 recounted his experience with the discovery of mesothe liomas in South Africa, and further suggested that all pleural mesotheliomas in the United States were caused by crocidolite asbestos, a suggestion with which we strongly disagree and which is not supported in the medical literature.22,22 Smither et al.24 and McCaughey et al.25 recorded additional cases of asbestos-related meso thelioma in 1962, and for some of those cases the expo sure appeared to have been minimal. In the same year, Wagner et al.26,27 published studies on the mucin histo chemistry of mesothelioma and on the induction of malignant mesothelioma (MM) in experimental animals )y asbestos. In 1964 and 1965 Selikoff and colleagues28,29 linked mesotheliomas to asbestos exposure by finding that 10 of 307 consecutive deaths in asbestos insulation workers were caused by diffuse mesothelioma. Also in 1965 Newhouse and Thompson"10'31 recorded the occurrence of mesotheliomas as a consequence of domestic (household contact) asbestos exposure among those who shook out and laundered the asbestos-contaminated work clothes of their partners, and from neighborhood exposure acquired by residence in the vicinity of an asbestos factory. Most MMs reported since 1970 have been diffuse; the localized form is rare.38,32 By the late 1990s, the incidence of MM in some indus trialized nations was comparable to that of cancer of the larynx,33 with a death rate similar to that of rena! cell carcinoma in males and uterine cancer in females.33-37 Apart from lung cancer,38 MM is now the most important occupational cancer among industrial workers, because of its prevalence, resistance to conventional cancer treat ments, and its lethality. The history of the medical-legal aspects of asbestosrelated lung disease was discussed in detail by Motley39 and Brodeur.40,41 Information presented by these authors suggested that serious deleterious health effects of asbes tos were known long before they were reported in the medical literature. Incidence and Epidemiology Mesotheliomas encountered in the early 21st century are most often a consequence of prior occupational exposure to asbestos from the 1940s through the 1970s, including end-uses of asbestos-containingmaterials and "bystander" (indirect) exposures.36,42-44 The relationship between inha lation of asbestos fibers--especially one or more of the amphibole varieties--and MM is accepted by virtually all authorities as causal.42 Because of the constancy and specificity of the asbestos-MM relationship, the incidence of mesothelioma is usually considered to reflect a soci ety's past per capita usage of asbestos,45^8 after allowance for a suitable latency interval between first exposure to asbestos and the subsequent rise in incidence of MM (Fig. 43.1 and Table 43.1).47,49 220000 hX -*OoS 200000-j Crocidolite warn Amosite HEc Ui 180000 f Chrysotile Exposure index j ^**'""**. \ 2200 2000 1j 1800 rtOai 160000 140000 Nl .....--PO--rbe-sdei--crvt-ee-dd-dm-ee-ast-ho-sth-e-lio-m--a-d-e-at-h-s 1~T.r\ i .120000 '3 ---ti 1 | j1 1 | t 'f f \ \ \ 1600 i 1400 i 1200 If) 100000 1000 >iOaxa> 80000 tofi *w If) 40000 X) j.ff--.If) < 20000 0 , L__ L 1 i x 1i/ t 17 i \/ I1 ISiPMFIPClK \ \ \ V 800 600 400 200 0 Year Figure 43.1. Observed and predicted deaths from mesotheli oma in the United Kingdom, versus asbestos imports and esti mated exposure indices, for men aged 20 to 89, for the years 1900 to 2050. (Modified from Health and Safety Executive [HSE], Mesothelioma mortality in Great Britain: estimating the future burden, December 2003, with permission of the HSE.) 560 S.P. Hammar et ai. Table 43.1. Mesothelioma incidence for some countries rela tive to their historical per capita use of asbestos Country Mesothelioma Use of asbestos in incidence cases/HP/yr kg/capita (year) Australia (1995) Netherlands (1995) United Kingdom (1991) Italy (1993) France (1996) Finland (1.995) Germany (1997) Sweden (1995) United States (2000) Norway (1995) 33 27 23 22 17 15 15 15 15 14 4.4 (1968) 3.4 (1976) 2.7 (1970) 2.5 (1975) 2.6 (1970) 2.2 (1970) 3.0 (1975) 2.4 (1970) 2.3 (1975) 1.9 (1970) Source: Modified from Tossavainen.47 Because mesotheliomas are rare neoplasms, their exact incidence is unknown and varies among populations sur veyed (Table 43.2).50-59 The highest incidence in the world is currently in Australia.58 The incidence of mesothelioma in autopsy series is considerably lower. McDonald and McDonald7'9 summa rized the incidence in six series from eight cities between 1950 and 1.970. They tabulated 165 cases in 69,302 autop sies (0.24%). Several studies54-1'07 documented an apparent increased incidence of MM, especially in men, during the last several decades. Hughes and Weill60 estimated that 1500 new cases of mesothelioma were diagnosed in the United States in 1986. The increased incidence of MM is proba bly related to the delayed effects of an increase in occu pational exposure to asbestos. Selikoff et al.28 reported that 8% of 1.7,800 workers in the heat and frost insulation industry who were followed prospectively between January 1, 1967, and December 31, 1976, died of diffuse MM.61 According to Huncharek,62 the incidence of meso thelioma is increasing at a rate of about 10% per year for U.S. males. The authors' experience has also suggested an increased incidence of MM that, in part, may reflect an increased awareness by pathologists of mesothelioma and of more accurate diagnostic methods such as electron microscopy and immunohistochemistry. In addition, many cases of mesothelioma in the United States come to litigation, which has made the general public more aware of meso thelioma and, in turn, has caused heightened physician awareness. According to the Environmental Working Group,63 there is an asbestos epidemic in America. This group reports that asbestos-related disease is responsible for the death of one in 125 American men over the age of 50, and that 10,000 Americans die each year--30 per day--from asbestos-caused diseases. At this time, the death toll is rising in nine of the 10 states with the highest number of mesotheliomas and asbestosis deaths. Between 1979 and 2001, more than 43,000 Americans died from MM. According to Price,64 there are approximately 2500 new cases of MM annually in the U.S., 80% of which occur in men.65 According to Price, the incidence of meso thelioma appears to be rising in men aged 45 years or older, with a maximum lifetime risk in the 1925 to 1929 cohort. The incidence of MM in women and in men less than 75 years of age is claimed to have been stable since 198364 (but see later discussion). Peto et al.66 predicted MM deaths would continue to increase for at least 15, and more likely 25, years. In the most affected cohort, men born in the 1940s, MM would Table 43.2. Incidence of mesotheliomas3 Reference Years surveyed McDonald et ai.50 1959-mid-1968 Theriault and Grand-Bois 5i 1969-1972 Biava et al.'2 Greenberg and Lloyd-Davies53 1967-1968 McDonald and McDonald54 Cutler and Young" 1960-1975 1972 1969-1971 Bruckman et ai.56 1970-1972 Churg57 1982 McDonald and McDonald-''9 1950-1970 Location of population surveyed Canada Quebec Italy England, Wales, Scotland Canada United States Metropolitan area1. Connecticut (U.S.) British Columbia Eight cities Number of cases/million population/year 0.65 (males) 0.35 (females) 1.56 (males) 0.74 (females) 21.4 (males) 1.88 (males) 0.42 (females) 2.8 (males) 0.7 (females) 1.5 (males) 0.7 (females) 1.7 (males) 0.9 (females) 17 (males) 1.9 (females) 0.24% ol 69,302 autopsies '`Incidence includes both pleural and peritonea! mesotheliomas, and in some instances mesotheliomas arising in ovary and male genital system. ''Atlanta, Birmingham, Dallas-Ft. Worth, Detroit. Pittsburgh, San Francisco-Oakland, Denver (U.S.). 43. Neoplasms of the Pleura 561 account for around 1% of all deaths. In 2005 Hodgson et al.67 stated there were 1848 mesothelioma deaths in Great Britain in 2001 and mesothelioma deaths were predicted to peak at around 1950 to 2450 per year between the years 2011 and 2015 (Fig. 43.1). The Health and Safety Executive Data68 suggested the peak wouid occur earlier than originally predicted and the maximum would be approximately 2000 deaths in or around the year 2010. According to Treasure et al.,69 one in every 100 men born in the 1940s will die of malignant pleural mesothelioma.... For a man first exposed as a teenager, who remained in a high-risk occupation such as insulation throughout his working life, the lifetime risk of mesothelioma can be as high as 1 in 5. ...The disease is increasing in frequency.... We will see many more mesotheliomas in the next 25 years. In the developed world alone, 100,000 people alive will now die from it. in Australia, mortality from MM was stated to have been increasing since 1975. Mesothelioma incidence rates are among the highest in the world, and the Australian Mesothelioma Registry received 6129 mesothelioma notifications between 1986 and 2000. Of the mesotheli oma cases with past asbestos exposure, close to 89% were work-related, about 3 % were not work-related, and about 8% could not be classified. Of the persons who developed work-related MM, one in three worked in the construc tion industry and one in five worked in the manufacturing industry. In contrast, Roggli,70 based on his experience, suggests that a mesothelioma epidemic was beginning to wane in the U.S. Lemen,75 using Surveillance Epidemiology and End Results (SEER) data and International Classifica tion of Diseases (ICD-10-TEM) coding that went into effect in 1999, stated the accuracy for reporting mesothe lioma was about 80% effective, which would mean that in the U.S. there were over 6000 cases of mesothelioma per year. Etiology Asbestos The association of asbestos exposure and the develop ment of mesothelioma has been reviewed in detail.72-74 The chronology of asbestos is shown in Box 43.1 (Figs. 43.2 and 43.3). Asbestos is the single most im portant causative agent of mesothelioma. Numerous Box 43.1. The History of Asbestos 4000 BCE 2000-3000 BCE 2500 BCE 800-900 AD 1000 1300-1400 Early 1700s 1724 1828 1853 1866 1896 1900 1913 1919 1939-1945 1945-1975 1990s Asbestos was used for wicks in lamps and candles. '`Asbestos" means inextinguishable or unquenchable. Embalmed bodies of Egyptian pharaohs were wrapped in asbestos cloths to offset the ravages of time. Used in Finland to strengthen clay pots. Anecdotal evidence of Charlemagne's tablecloth made from woven asbestos. Mediterranean people used chrysotile from Cyprus and tremolite from upper Italy for the fabrication of cremation clothes, mats, and wicks for temple lamps. Marco Polo visited an asbestos mine in China in the latter half of the 13th century. He concluded that asbestos was a stone and lay to rest the myth that asbestos was the hair of a wooljy lizard. Asbestos papers and boards were made in Italy. Benjamin Franklin brought a purse made of asbestos to England. The purse is now in the Natural History Museum. United States patent issued for asbestos insulating material used in steam engines. Asbestos helmet and jackets worn by Parisian Fire Brigade. Molded lagging material made from water, glass, and asbestos. First asbestos brake linings were made by Ferodo Ltd., in England. High pressure asbestos gaskets made by Klinger in Austria. First asbestos pipes developed in Italy. Standard corrugated sheet asbestos introduced in Australia by Hardies. Wartime use included fireproof suits and parachute flares. In the film The Wizard of Oz in 1939, the Wicked Witch of the West appeared on a broom made of asbestos. Postwar construction projects relied heavily on the use of asbestos, reaching an all-time high in 1973. The solid fuel boosters of the space shuttle are insulated with asbestos, one of the few remaining current uses.