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92 Morris Greenberg and T. A. Lloyd Davies 200 cases which had been diagnosed in Britain in the previous 15 years, with histological confirmation of diagnosis, was in their possession with the help of information resulting from an enquiry (Smithcr, Gilson, and Wagner, 1962). In that year the register was handed over to the Medical Branch of HM Factory Inspectorate (now Employment Medical Advisory Service, Department of Employment). The objects of the register were stated in the Senior Medical Inspector's Advisory Panel Memorandum (1968): i to record the annual number of deaths from mesothelioma of the pleura or peritoneum associated with asbestos exposure; ii to ascertain trends in the prevalence rates; iii to discover, if possible, tumours occurring without any exposure to known or suspected occupational causes; iv to provide part of the evidence on which pre ventive measures should be based. This paper presents the results of investigations into cases notified to the register from England and Wales and from Scotland for the period 1 January 1967 to 31 December 1968. Preliminary results have been published elsewhere (Lloyd Davies, 1970) and the present report relates to information available to May 1972. Plan of investigation The Registrars General for England and Wales and for Scotland forwarded copies of (a) death certifi cates which included a diagnosis of mesothelioma of pleura or peritoneum and (A) Cancer Bureaux registrations with a diagnosis of malignant mesothe lioma. Pneumoconiosis Medical Panels also notified cases of mesothelioma which were subject to claims for benefit under the National Insurance Acts or otherwise came to their notice. Information about other cases was received from chest physicians, surgeons, pathologists, and coroners. The majority of cases were notified from two or more sources. The Central Ethical Committee of the British Medical Association agreed that tracing of cases by medical advisers should take place only after the prior approval of the patient's medical attendant. In the event, approval was given in all cases. Where possible histological slides or blocks of histological material were obtained: these were submitted to the Union International contre le Cancer (UICC) Panel of Pathologists (see Appendix). Diagnostic criteria A definitive diagnosis was made only when histo logical proof was available. Borrowed material was referred to the UICC Panel of Pathologists together with an abstract of occupational and clinical histories and of necropsy findings. The histological and histochemical features of mesothelial tumours have, been discussed by UICC panel pathologists (Wagner, Munday, and Harington, 1962; Hourihane, 1964;McCaughey, 1965; Whitwell and Rawcliffe, 1971) and the criteria employed by the UICC panel to derive a consensus opinion appears in the Appendix^Where material could not be borrowed the reports: of consultant pathologists were examined. Where several pathologists gave varying opinions on a section and it was not possible to refer material tothe UICC panel, the majority decision was taken. The occupational history was often sought after thehistological diagnosis had been made by the non-- panel pathologists. Diagnoses made by these pathologists were allocated to the following groups:: 'Definite', where in the view of the pathologist,, based on adequate histological material supported by the gross appearance at thoracotomy, lapar otomy or necropsy, mesothelioma was the diagnosis of election. 'Undecided', where the material examined and other features while compatible with a diagnosis of mesothelioma did not permit the pathologist to make a firm diagnosis (this corresponds to the category `undecided' finally employed by UICC . pathologists). 'Insufficient histological material', where the pathologist was dissatisfied with the material, or where neither histological nor necropsy material were ever examined. 'Definitely not', where a definite alternative diagnosis was made by the pathologist. When tumour was present in both thorax and abdomen the site stated in the analysis is that given by the pathologist as the primary site. Where the death certificate differed from the necropsy report, the latter was accepted. .ontaining .sorked in dust. `'iissiblc', . uprecise -ii'pieion 1 \tinc'. v ,-tkUpatioi I hknown mi forth c\po->ure txlorc de. I'Uermitte ::eure. I imiiestic e\ I >< -Dicstic e> tl . ^<c home Mined. 1 f.ihliy expo I :.'hby exp i -Mers or ing asb -.'.'.houses. V i"!ibourh V ighbourl pQt- lived \ "^*4ipyurd u "UdZ O''sure. , , 'wJ ilKieimr ocssidec . , "* ulence of necropsv Asbestos exposure history < -N'UIHCATI Where possible living subjects were interviewed, but (. , for deceased subjects the relatives were interviewed J in the first instance. Occupational histories were also - sought from coroners and from former employers and workmates. The initial classification was made. by the investigating medical adviser who may or^ may not have been aware of the interim diagnosis o C.J---------- t*-"1 ICC Pane; and was rarely aware of the final diagnosis. The final classification was made by a second medical adviser in consultation with the first, and often this took 1 ' tier pathc place before the final diagnosis had been received. Occupational exposure Occupational exposure to asbestos was defined as follows: *Definite', where the job involved full-time or intermittent handling of asbestos or asbestos- I..l.d Ml cases ``ee lext fo I BB 000557^1 grins'! Journal of Industrial Medicine, 1974, 31, 91-104 Mesothelioma Register 1967-68 MORRIS GREENBERG and T. A. LLOYD DAVIES Employment Medical Advisory Service, Department of Employment, 1-13 Chepstow Place, London W2 Greenberg, M., and Lloyd Dawes, T. A, (1974). British Journal of Industrial Medicine, 31, 91-104. Mesothelioma Register 1967-68. A register of mesothelioma cases is maintained by the Department of Employment. Medical Services Division (now Employment Medical Advisory Service). This paper describes an investigation of 413 notifications to the Register hr 1967-68 from England and Wales and Scotland. Cases were regarded as `definite' when histological confirmation of diagnosis had been obtained, either by hospital pathologists, or by the UICC Panel of Pathologists, to whom pathological material was submitted whenever possible. Two hundred and forty-six cases were accepted as `definite' and 76 cases were regarded as `definitely not' mesothelioma. The remainder were classified as `undecided' or `insufficient pathological material'. Thirty-five of the 76 cases definitely not mesothelioma had nevertheless been so described on death certifi cates. The investigation carried out covers clinical aspects, survival, and evidence of exposure to asbestos. Twelve per cent of definite mesotheliomata were of peritoneal origin. The age range was 21 to 87 years, but, in general, mesothelioma occurred at an earlier age than 'carcinoma of bronchus and lung' or `all malignant tumours' in the Registrar General's statis tical mortality tables. Concomitant asbestosis and the finding of asbestos bodies or pleural plaques occurred as frequently in those cases classified as definitely not mesothelioma as in confirmed cases. Occupational exposure to asbestos was found in 68 % of definite cases, apparently signifi cantly more frequently than in those definitely not mesothelioma, but there was observer bias. The interval between first exposure and death from mesothelioma exceeded 25 years in 85 % of cases but was only three and a half years in one case. The duration of exposure varied widely: in 12% of cases it was under five years. The type of asbestos could be ascertained in so few cases that it was impossible to assess the role of crocidolite in aetiology. There were 38 definite cases in which no history of any exposure to asbestos could be obtained. Definite mesotheliomata showed marked clustering in areas where there is substantial industrial use of asbestos. Whether this should be interpreted as evidence of causation or an effect of heightened awareness in these areas cannot be deduced from this study. Evidence is quoted suggesting that the observed annual incidence of approximately 120 definite mesothe liomata in England, Scotland, and Wales may considerably understate the true prevalence. Bill use or malignant mesothelioma of the pleura and Marchand, 1960) gave impetus to the enquiry. For Peritoneum, although rare, has been sought for some years the Pneumoconiosis Unit of the Medical incn.asing|y in the past decade. The reported associa- Research Council had recorded cases of mesothel'on y'ith asbestos exposure (Wagner, Sleggs, and Iioma reported to them. By 1966 a register of some 91 Mesothelioma register 1967-63 93 cim[lining compounds, or where the subject vso.ked in an atmosphere contaminated by asbesto' dust. pos\ible', where the job description was too imprecise to be certain, but there was a strong suspicion of exposure to asbestos. Wotic', where, after exhaustive enquiry, no occupational exposure could be presumed. Lnknown', where adequate industrial details were not forthcoming. If possible the duration of exposure was recorded and the length of time he l ore death that exposure ceased. The duration in intermittent exposures is presented as a cumulative figure. Domestic exposure Domestic exposure was considered as positive when a history that members of a subject's family had come home visibly contaminated by asbestos was obtained. Hobby exposure Hobby exposure was recorded in several house holders or smallholders who gave a history of sav mg asbestos sheeting for the construction of outhouses, garages, and chicken houses. Neighbourhood exposure Neighbourhood exposure was recorded when sub ject lived within one mile of an asbestos factory or shipyard using asbestos but had no occupational exposure. Otiier evidence of asbestos exposure Asbestos exposure was presumed in cases showing evidence of asbestosis (either on chest radiograph or at necropsy) and in those in whom asbestos bodies or fibres had been demonstrated by light microscopy in sputum, lung sections, or fluid expressed from the cut surface of the lung. The reported finding of pleural plaques at operation or necropsy, or evidence of plaques on the chest radiograph, was regarded as suggestive of asbestos exposure. Results For the years 1967 and 1968, a total of 413 cases was reported to the mesothelioma register. Of these, 168 were first notified by death certificate as having died in those years and a further 166 were notified in life and died during this period. Seventy-nine subjects notified survived the period of study. Death certificates were the most important source of notification comprising 53-5% of all notifications in 1967 and 77-8% in 1968. In the absence of death certifications, further notifications __ were received from cancer bureaux, 45 (26*5%) in Q 1967 and 33 (13*6%) in 1968. Further groups of cases were reported exclusively by other sources (physicians, surgeons, and pathologists), 31 (18*2%) J--U. in 1967 and 18 (7*4%) in 1968. Three other cases ^ otherwise unreported were reported in each year by *--i_J the Pneumoconiosis Medical Panels. A total of 170 'Z5-~ j""* notifications were made in 1967 and 243 in 1968. '" Pathological diagnosis In Table 1 the notifications are shown categorized according to the criteria of diagnosis. The correla tion between histological diagnosis and the diagnosis given on the death certificate was weak. Of the 246 cases accepted as `definite', only 186 were so des cribed on death certificates. On the other hand, of b~~ 76 cases `definitely not mesothelioma' death had * been attributed to mesothelioma on the death LU x.3 CJi TABLE 1 OO Notifications to Mesothelioma Register analysed by Diagnostic Criteria and Site of Tumour Site of tumour t ICC Panel Oilier pathologists Toul All cases - 'Sec text for definition Pleura Peritoneum Pleura Peritoneum Pleura Peritoneum Definite US') >-134 98'| Ul2 4J 216 30 246 Diagnostic category1 Undecided Insufficient material ll8 4J 12'| r13 jJ 26-i |*28 2j 40 6 321 r3z J 44 1 46 45 Definitely not 23') U 7J 421 >46 4J 65 11 76 Total 167 28 198 20 365 48 413 GG ._ 94 Morris Greenberg and T. A. Lloyd Davies certificates in 35 instances. The pathological diagnoses in these 35 cases were: Carcinoma of bronchus .. .. .. 11 Carcinoma, origin unstated .. .. 10 Secondary adenocarcinoma (primary unstated) ...................................... 3 Not mesothelioma (no other diagnosis) 4 Myelomatosis...................................... 1 Transitional carcinoma of bladder .. 1 Adenocarcinoma of thyroid ., .. 1 Retroperitoneal fibroma or chordoma 1 Asbestosis and tuberculosis .. .. 1 Severe anaemia secondary to peptic ulcer 1 Malignant melanoma.......................... 1 As the concordance of diagnoses between the U1CC pathology panel and other pathologists was higher than 74 % and the characteristics of the two groups are so similar for distribution of age at death (Fig. 1), tumour site, sex (Table 2), and survival (Figs 2 to 4), they can be treated as one. In this study % peritoneal tumour represented 12-2% of all con-s* firmed mesotheliomas (Table 2). This compares with^ reported proportions by five authors with a range i 3-7 % (of 80 cases) to 72-7 % (of 22 cases) (Table 3).% From Table 2 it can be seen that the distribution ofist I cases between the sites was similar in the groups^ confirmed by UICC pathologists and by other* pathologists. Sex distribution % Table 2 shows that the ratio of mesothelioma in mea4 and women for both UICC and other pathologists^ was about 5:1, which is similar to that for all:^ malignant neoplasms of the respiratory system i (Registrar General, 1970). The sex difference in f carcinoma of the bronchus in general is thought in ^ part to be due to difference in smoking habits J (Hammond, 1966) but tobacco is not known to play rr a role in the aetiology of mesothelioma. If it is assumed that mesothelioma is related to asbestos 4 y TABLE 2 246 `Definite' Mesotheliomas analysed by Sex and Site of Tumour Pathologists UICC Panel.......................... Other pathologists . All..................................... Site of tumour Pleural Peritoneal Pleural Peritoneal Pleural Peritoneal Males ( X of all mesathelial tumours) 96 14 (12-8 `A) 81 10 (10-9 X) 177 24 (12-0X) Females (X of alt mesothelial tumours) 22 2 (8-3%) 17 4 (190T0 39 6 (13-3 X) Total 118 16 (11-9%) 98 14 (12 JX) 216 30 (122%) . ..cure it wot .;i;n and wo ,vr to assess ne'Otheliorr vat- at death . : distribute ;iresented ir N-enee betwee ;-.itho!ogists , . iu'logists, 6 .,,;ributions f .:',tnoma of .,,,xral, 1970 .th from rr 0 05) th. I neoplasms tier to the i n;d cancers b <he retire ina associa; ;.inogen. t iposuro to t>` Table 4 it c ' (63.;) hi * anun and ij_ij:r at wor: ... J Li- Defini1 Mean c 09 TABLE 3 Prevalence of Peritoneal Mesothelioma reported by Various Authors 7t Authors McEwen et at. (1970) All mesotheliomas 80 Peritoneal mesotheliomas only (total) 3 (3-7 X) Comment 13 males and 7 females; 2 males described as 'both sites' (Scotland) * Yeaa J All me Enqlar Ashcroft and Heppleston (1970) .. SelikofT et al. (1970) Thomson (1970).......................... Newhouse et al, (1972) 23 22 17 11 3 (13-0X) 16 (72-7 X) 3 (17-6X) 5 (45-4 X) Tyneside Male insulation workers (USA) Cape Town Females (London) 49 30 (612 X) Males from the same factory Present study 246 30 (12*2 X) England, Wales and Scotland 1967-68 t -fSToooglii Mesothelioma register 1967-68 95 t-xpv^are it would be necessary to know the numbers of men and women at risk over the past 50 years in order to assess the relative susceptibility of the sexes to mesothelioma. TABLE 4 Notifications to Mesothelioma Register ANALYSED BY ASBESTOS EXPOSURE ':i.M Age at death The distribution of age at death of confirmed cases No. of No. undecided, inadequate material, ,s presented in Fig. 1: there is no significant dif ference between cases diagnosed by the two groups of pathologists (mean age: U1CC, 59-4 0-9; other Asbestos exposure history definite mesotheliomas or definite alternative diagnoses in its ill m pamologists, 60-2 1-3). For comparison the age distributions for all malignant neoplasms and for catcinoma of the bronchus and lung (Registrar General, 1970) are also shown. The mean age at Definite occupational exposure Possible occupational exposure Neighbourhood, 167 16 63 17 in death from mesothelioma is significantly younger domestic or hobby .. 13 in its ip < 0 05) than that for bronchial carcinoma and None ,. a'I neoplasms'. This may be due in part or in whole Not obtained .. 38 12 10 57 20 iy either to the greater chance of identifying occupa is tional cancers within the working age compared os with the retired or to earlier death from mesothe lioma associated with occupational exposure to a still 38 (15%) for whom careful enquiry failed to or^nogen. elicit any exposure whatever. In the remaining notifications (`undecided', `inadequate material', `definite alternative diagnosis') nearly one third were In Table 4 it can be seen that of 246 confirmed cases without apparent exposure, and those with definite K>7 (68%) had definite occupational exposure to occupational history formed only 38% of the total. C .3 asbestos and a further 29 were possibly exposed, The differences between these groups are significant ; .j either at work or at home. There were, however, (p < 0 001) but may be affected by bias towards j ^ All malignant neoplasms England 6 Woles 1968 10 " VA TI I II IO IS 40 5 SO SS to 65 IQ IS 60 IS 90 9S ICO Yean 6S f"' 1. Age distributions at death. V~ p--- & <! i ^i IBB~0005577* 96 Morris Greenberg and T. A. Lloyd Davies underdiagnosis in areas without large-scale asbestos known asbestos exposure may have been the result of nlCC panel industry, or to bias on the part of the interviewers who might have been more assiduous in pursuing an asbestos association history in cases of definitive over-diagnosis because of the well-known association of mesothelioma with this occupational history thus introducing a bias in the opposite direction. Numb 1O mesothelioma. Ideally it would have been desirable The individual occupations of confirmed cases Mean to conceal frominterviewersthediagnosisin individual with industrial exposure are shown in Table 5. The cases, but on account of limited manpower the degree of risk associated with these occupations interviewer may have been responsible for identify cannot be computed because the population ing cases and arranging for confirmation of diagnosis. exposed, over a period of 50 years, is unknown and - On the other hand, the number of notifications cannot even be guessed. which were not subsequently fully confirmed but had Table 6 lists those subjects with mesothelioma TABLE 5 Industry or Job Title in 167 `Definite' Mesotheliomas with Definite Occupational Exposure to Asbestos where a history of exposure to asbestos, not occupa tional in origin, was obtained. Of those subjects with neighbourhood exposure, the first four lived near the same asbestos factory in a district wherechest physicians have a high awareness of meso thelioma. The final four subjects listed had exposures o Years Crher oat' Num that might be considered minimal and common Oi Industry nr job Number of mesotheliomas experience. In cases notified to the register by the Registrar Mear Shipworker.. 75 General for England and Wales a control group was - Asbestos factory worker......................... 39 established (from 1 January 1968), the next death Insulation worker (not marine) .. 13 registration matched for age and sex but not for Boiler house worker (not marine) Chemical worker .. Docker .. ,..................................... 5 area being notified to the register for comparison of 3 4 occupation. It was found, however, that as cases of Welding rod manufacture 4 mesothelioma were more commonly referred to Building worker .. Electrician .. Sack clcaner/repairer Wdder/plater ..................................... 3 coroners than were other subjects the job description 3 --^ Yean was frequently qualified to indicate asbestos ex 3 3 posure; for example, `plumber' or `fitter' was further O Vy Defin Battery box manufacture Electricity generating industry .. Gas worker Railway coach/locomotive builder Motor mechanic 2 categorized as `shipyard', whereas no such qualifica L expc ter2 tion appeared in the controls. Even `housewife' and 2 `widow' were recorded as occupations with the 2 1 disease attributed to asbestos exposure. u ^jw^gnized Refuse work ..................................... 1 Ethical considerations prevented the interviewing (^-LEwen, F of control subjects (or their relatives) though it is igures 2, TABLE 6 Non-occupational Asbestos Exposure Histories obtained in Cases of Mesothelioma Case number Duration of exposure Nature of exposure cJO c'S ' asbe C: hough th UT . irs and mificunt c Uj EW 67/70 EW 68/174 EW 68/38 EW 68/86 S 68/71 S 68/31 S 68/23 EW 67/82 EW 67/115 EW 68/19 EW 68/88 EW 68/190 EW 68/186 EW 68/80 25 years 14 years 3 years 22 years Unknown 13 years 30 years Unknown 14 years Unknown 17 years 40 years 2 years Unknown 4 years 3 years 1 day Resident within yards of an asbestos factory; at school nearby Resident close to an asbestos factory; probably went to school nearby; t \ j O both parents worked in asbestos factory ^ ** Worked next door to asbestos factory Resident 1J miles from same asbestos factory Hobby: rehning and refitting clutches and brakes . ^ hGi o Resident 200 yards from an asbestos factory Resident < J mile from a shipyard Resident < j mile from a shipyard Resident J mile from an asbestos using factory Resident < ^ mile from an abestos factory pp 1 / ~r r Resident < 1 mile from asbestos factory 1 1! . | ( Jj i_ Resident < 1 mile from an asbestos factory ^ Husband worked in an asbestos factory Lived in a house largely composed of asbestos cement sheeting Worked on and lived adjacent to chicken farm composed of asbestos cement buildings Intermittent exposure to brother's overalls contaminated with asbestos Sawing up asbestos cement sheets to construct two sheds rvxotileoi r.iutlolite c inosite onl' ri'odohte a Mixed nsbes 1 pc not as." llM.il f. | BB 0005578 | esult of >ciation ry thus 1 cases 5. The pations Nation vn and elioma ccupaubjects r lived where rnesoiosures mmon gistrar ip was death ot for ed to iption 3S exurther llificae' and h the wing it is y; Mesothelioma register 1967-68 97 UICC panel Number of case! 1 0 4 6 3 IO tl It tl 18 14 Meon*37-4 yeori :o- UICC panel 40 -i Number of coses 36 873 13 356224 30- 20 k ,, u ' {f'H O s IO IS 20 23 30 JJ 40 45 50 55 Years Other., cosbologisti Number of cases 00019 798 17 14 3 2 1 Meant38-4 years 3 Years IO IS 20 23 50 53 40 43 30 33 50 53 H' 2. Definite mesotheliomaswith definite occupational j' otos exposure: survival after first exposure. IO xl 0 5 10 IS 20 25 50 55 40 4! 50 55 Years 50 Number of coses 37 7 3 4 1 8 2 5 2 1 40 30 /o 20 GO LU -"-1 (Tv s_u c O nxognized that this would have been desirable 1 McEwen, Finlayson, Mair, and Gibson, 1970). igures 2,3 and 4 illustrate time relationships with Mtown asbestos exposure. In 85% of cases death `'.vjrred more than 25 years after first exposure, ah-ough the shortest period was three and a half ?c^rs and the longest 53 years. There was no ''.M'ficant difference in the distributions of years of 10 - i-- O 3 K3 13 20 2S\ SO 55 40 45 30 33 40 - Yeors t-*' {---- fig. 3. Definite mesotheliomas with definite occupi^ tional asbestos exposure: survival after last exposure. o o TABLE 7 Type of Asbestos involved in Occupational Asbestos Exposure Asbestos type to which exposed occupationally 1 ' 'olife only 1 r 'Jolite only '""'itc only .. 1 ' viJolite and other asbestos '-d asbestos without crocidolite f'f1 not ascertainable To-.i........................................................................ Definite mesothelioma 4 4 0 42 0 117 167 Histological diagnosis Undecided and insufficient material 1 0 0 8 2 25 36 Definitely not mesothelioma 11 rbr' 7 2 15 27 :--ct ~ . Jr~* t 11 V53t- -- i y i | BB 0005579 | Morris Greenberg and T. A. Uoyd Davies UK_ cans! Number of octet 20 13 12 It 9 7 3 b 5 7 fa 1 15 % 10 5 O ,, O 1 10 IS !0 !S SC 35 40 45 50 51 Tears Qlher anlKoloqtiri Number of casej 20 4 9874 to 6654 t5 3 to I s o O 5 to IS 10 35 SO 15 40 45 50 55 Tears fig. 4. Definite pleural mesothelioma: duration of occupational exposure to asbestos. survival after first exposure in the two groups (mean age: UICC, 37-4 years; other pathologists, 38-4 years). The interval between last handling asbestos and death was under one year in about 40% cases but varied up to 52 years (one case). The duration of exposure was more widely spread, ranging from three weeks to over 50 years. Twelve per cent of cases had been exposed for under five years. The man with only three weeks' exposure died over half a century later. Table 7 summarizes information regarding the type of asbestos, but this could be obtained in only a small proportion of subjects. Of the 50 subjects wit^ `definite mesotheliomas', where the types of asbestos- to which they were exposed were known, 45 had- been exposed to crocidolite. Of the group of 12^ subjects diagnosed as `definitely not mesothelioma'* in which types of asbestos to which they had been-; exposed were known, eight had been exposed tos crocidolite. v There is no significant difference between these* two groups. In four cases of definite mesotheliomav no exposure was known other than to chrysotile. A'; history of exposure to talc was obtained in seven-; subjects with definite mesotheliomas, but six of '; them had also been exposed to asbestos. It was not possible to identify the nature of the talc to which - they had been exposed. Other evidence of asbestos exposure It is apparent that a history of occupational exposure to asbestos is frequently associated with the presence > of asbestosis, asbestos fibre bodies, asbestos fibres or pleural plaques observed at necropsy or radiologi- * cally (Table 8). Ashcroft and Heppleston (1973) stress the importance of phase contrast microscopy and electron microscopy in searching for asbestos in tissues. The presence of pleural plaques docs not always" indicate asbestos exposure (Rous and Studeny, 1970), It is not possible, however, to observe a significant difference of asbestos exposure . between subjects with definite pleural mesotheliomas and those subsequently categorized as definitely not pleural mesothelioma. In four `definite pleural mesotheliomas' corrobora tive evidence of asbestos exposure was found in the absence of occupational exposure histories. Of those subjected to `hobby' or `domestic* exposure (six cases) none showed corroborative features. Of those with `neighbourhood' exposure (eight cases), two had asbestos bodies. TABLE 8 Corroborative Evidence of Asbestos Exposure1 related to Occupational Exposure History and Notifications to Mesothelioma Register (Pleural Tumours only) .'itrapl I - v. 9 ..'tt r 'l Kv i:\ir: Si utlvV ;-Ai: rn uviiu ` J ' V.t'1 ' TIO* `Miiidi <V3y>' -- UJ1"' o --1 l" c* LL W1 t s ki Ft*. CV rk* -.1 v A i\v v. .ili. Occupational asbestos exposure history Definite Possible None ascertainable .. Definite pleural mesothelioma Corroborative evidence No corroborative evidence Not reported 100 (69%) 8 (SO*/.) 4 (D*/.) 24 06%) 4 (25%) IS (56%) 22 (15%) 4 (25%) 10 (31%) Definitely not pleural mesothelioma Corroborative evidence No corroborative evidence Not reported 19 (73%) 0 (-) 0 (-) 3 (12%) 3 (60%) 6 (33%) 4 (15%) 2 (40%) 12 (67%) I 1U` M -'Li : ;nj 'Asbestosis, asbestos bodies, asbestos fibres or pleural plaques GG A 7tr i i-lllooisir; ects with asbestos 45 had P of 12 helioma' ad been >osed to ;n these helioma iotile. A n seven six of was not which xposure 'resence ibres or dioloci- -osS -sbestos oes not is and ver, to posure iliomas dy not pborain the ' those e (six those i, two V AND Mesothelioma register 1967-68 99 lifif Geographical distribution Tables 9a and 9b show the distribution and rate/ million per year of mesothelioma notifications and diagnoses in England and Wales and in Scotland. The Registrar General's standard regions are employed for England and Wales. Clydeside includes Dunbartonshire, Renfrewshire, Greenock, Glasgow, Hamilton, and Motherwell. The distributions are by no means related to population density. South uesiern England, with a population of 3 652 thousands, had a total of 22 definite cases (a rate of 2 47 cases/million per year) yet Plymouth, with a population of 250 000,1 had 13 cases, all with hotories of occupational exposure to asbestos. The remainder of the region, with nearly 3 million population, produced nine mesotheliomas of which or.ly four had a history of occupational exposure to j'bestos (a rate of 1-5 cases/million per year). turning that Plymouth hospitals serve a population of tw.ae that number, the rate would be 26 casts,'million per Merseyside, Clydeside, Tyneside, the South East Lancashire conurbation, and Greater London had an incidence of mesothelioma markedly greater than the national rate with deficits in the remainder of these regions. They have in common the presence of heavy asbestos-using industries. The geographical distributions of cases, and of cases with occupational exposure, are shown in Figures 5 and 6. Discussion The recognition of diffuse mesothelioma depends on awareness and acceptance of the tumour as a pathological entity. The macroscopic appearance of a typical mesothelioma, resulting from its propensity to infiltrate serosal membranes, is best characterized by the well-developed pleural mesothelioma with permeation of visceral and parietal surfaces by a continuous layer of tumour. However, metastatic tumour in the pleura, usually from a primary adeno- (V TABLE 9 (a) . Ciidgraphical Distribution of Numbers and Dates of Notifications and Confirmations of Meso thelioma 1967-68 CO LU --J CD Xk ;Xw t : vt ! --Mi! t *** Vs i :P 5 ! 1 o, j*+ i > ] 4, "is :i Region1 u-. :'.er London k.,-of SE England M Lancashire conurbation H.rseyside conurbation K,. of NW England.......................... 7 iitside .. F . -I of N England ) orkshire conurbation k... of Yorks & Humberside N W ales hi Wales.. 1 \nglia .. f` Jeside* k -i of Scotland hngland 1 Mid]an(is Midlands conurbation of W Midlands......................... f r .Land, Wales & Scotland .. 1967 population (millions) 7-9 9-3 2-3 14 2-9 08 2-5 1-7 3-0 0-8 1-9 1-6 1-7 3-3 3-7 3-3 2-4 2-6 33-6 Notifications to Register 1967-68 No. Rale/million Ill 40 21 33 13 14 13 17 5 3 14 6 43 18 30 9 11 11 412* 7-03 204 4-20 11-79 2-24 8-75 2-60 500 0-83 1-88 3-68 1-88 12-65 2-57 405 1-36 2-29 2-12 3-84 Definite mesothcliomasl 1967-68 No. RatelmiUion year 58 3-67 18 0-97 16 3 20 25 8-93 8 1-38 9 5-63 9 1-80 12 3-53 3 0 50 3 1-88 10 2-63 3 0-94 28 8-24 6 0-86 22 2-97 3 0-45 6 1-25 6 1-15 245* 2-29 : .'<i 'S;.indard regions of Registrar General England & Wales, except Clydeside `Uanbartonshire, Renfrewshire, Greenock, Glasgow, Hamilton, Motherwell `One subject who died in Australia not included 100 Morris Greenberg and T. A. Lloyd Davies TABLE 9 (b) Geographical Distribution of Mesotheliomas associated with Occupational Asbestos Exposure and the Proportion of These Cases to all Cases of Mesothelioma Region1 Greater London Rest of SE England SE Lancashire conurbation Merseyside conurbation Rest of NW England .. Tyneside Rest of N England W Yorkshire conurbation Rest of Yorks & Humberside N Wales.. SE Wales E Anglia Clydeside* Rest of Scotland SW England E Midlands W Midlands conurbation Rest of W Midlands .. England, Wales &. Scotland Mesotheliomas with definite occupational asbestos C* exposure No. Percentage of all ii- mesotheliomas v r .18 82 167 68 `Standard regions of Registrar General England & Wales, except Clydeside Dunbartonshire, Renfrewshire, Greenock, Glasgow, Hamilton, Motherwell carcinoma, can produce widespread sheet-like growth resembling late diffuse pleural mesothelioma. Histologically the cellular and intercellular charac teristics can be highly equivocal. The UICC patholo gists' panel criteria for reaching a decision were modified in the course of the survey (see Appendix) and have not finally been decided (McCaughey and Oldham, 1974). Willis (1952) cautioned against accepting the diagnosis of mesothelioma until, by careful search, an alternative primary neoplasm had been excluded. In a series of 3 771 necropsies Cameron, Litton, and Lyon (1961) found a prevalence of primary carcinoma multiplex of 1-2%. In the present series there were three with additional primary neoplasms in the 246 `definite' cases (one with carcinoma of the stomach, another with carcinoma of the bronchus, and the third with myelogenous leukaemia). This represents a prevalence of carcinoma multiplex of 1*2%. Sections referred to the UICC pathologists had previously been studied by other pathologists who had not necessarily made a diagnosis of mesothe lioma. In 182 cases where adequate histological 1 material had been studied by UICC pathologists - they made a diagnosis of mesothelioma in 134 (74%), were undecided in 10%, and made an alternative diagnosis on 30 occasions(16%).Theconcordanceof > diagnosis between UICC and other pathologists is * greater in view of the fact that a number of sections were referred to the UICC panelists for a second opinion when the other pathologists had said the . condition was not mesothelioma but an asbestos . occupation history had been obtained by the clinicians. In those cases with adequate histological material, not referred to the UICC panel (186 cases), a pathological diagnosis of definite mesothelioma was * made in 112 (60%). The submission of sections to the UICC panel ; varied in different parts of the country. In Greater ( London 77 out of 111 cases were referred (69%). compared with only 12 out of 61 cases in Scotland t (20%). i GThe number of cases diagnosed is unlikely to be .i 1 BB 0005592 | MWJ all at Mesothelioma register 1967-68 101 n * T ir-N ii& llU itU t i logical ologists (74%), rnative lance of )gists is sections second aid the isbestos by the laterial, ises), a ms was T panel Greater (6* co. I y to be i? f fig. 5. Geographical distribution of notifications and confirmations of mesothelioma 1967-68 (standard regions employed by Registrar General except Clydeside which in cludes Dunbartonshire, Renfrewshire, Greenock, Glasgow, Hamilton and Motherwell): D = definite mesothelioma--UlCC Panel; O = definite mesothelioma--other patho logists; V = other diagnoses. C-G I W | BB 0005593 | A.-'.iatet ....ainloginerdiag li-cse au a - i*P of 'le'Otb p.itaolOgi >- s four I he Qb :i Hus sC :: . rcusor ierstat I iie prt .1 `\sIOS j.i.-ted b: eraph .`neil t . 'stanti. 's dclin: upani _ e wc iiuirs) i i this - wtOs ,, c u. Ci - H'liia -i1 sate. 1 nder ... .! Wa ? . uloli % be d. I iMine. ..'I the :'l.>>rv a af 't.mec Keias -!. I IN et s ;; ' d, w! vCs . hers .* s(an nmrs) ` M irriiK lo .! othe Fto. 6. Geographical distribution of definite rnesotheliomas and associated occupa tional asbestos exposure: D = definite mesothelioma--UlCC Panel; O = definite mesothelioma--other pathologists; = definite occupational exposure. 'is n A KL iber ' M. ' `1 iM*f\ ' I >r ' c W'lL ..ertiv : t> e 1 NN . 11 !) K Me* I BZb -2!252prj Mesothelioma register 1967-68 103 NOTE: THIS DOCUMENT DID NOTCOME FROMPPGFILES ow.-niated by the inclusion of diagnoses by other pathologists as the tumour in general tends to be underdiagnosed (Newhouse and Wagner, 1969). Those authors reviewed the causes of death in a jiroup of workers at an asbestos factory and found ; 9 mjsothelial tumours in 84 cases in which adequate pathological material was available, but of which only tour cases had previously been recognized. The observed incidence of definite mesothelioma ,n this series was approximately 120 per year. For the reasons stated above this figure may considerably understate the true incidence. The proportion of mesothelial tumours in which u>be>tos exposure cannot be implicated has been quoted by Wagner et al. (1971) as 10 to 15%. The eeoaraphical distribution in the present series showed that in Greater London, where there are substantial asbestos-using industries, 29 (50%) of 58 definite mesotheliomas had no ascertainable occupational asbestos exposure. Overall in the study ihere were 38 cases (15-0% of all mesothelial tumours) lacking evidence of asbestos exposure. In ibis study the briefest occupational exposure to asbestos associated with a mesothelial tumour was three weeks, but if asbestos was a cause of meso thelioma it cannot be assumed that lesser exposures are safe. U nder industrial conditions prevailing in England and. Wales and in Scotland the significance of erocidolite in the aetiology of mesothelioma could n.v be determined. Punning, administration, and field work were carried out nv all the members of the Medical Services Division (now Imployment Medical Advisory Service) of the Depart ment of Employment between 1967 and 1971. The ".ounce of the following is gratefully acknowledged: ; he Registrars General for England and Wales and Scothir.d: HM coroners and their officers: hospital records oiliL'crs and the staff of the Pneumoconiosis Medical I'j.'.ds who provided information and leads as to further M'urces of information; the pathologists (including the members of the British panel of U1CC pathologists for the standardization of the diagnosis of mesothelial Himours); Dr. K. F. W. Hinson and members of his department at the Brompton Hospital who circulated 'hdes to the panel; Dr. J. C. Gilson, Dr. J. C. Wagner, u J other members of the staff of the MRC Pneumoco- (jnit, Pcnarth; Professor P. C. Elmes and Professor " R. Lee who read the draft manuscript and made a number of helpful suggestions; Mr. R. V. Hayball and 'h. M. T. E. Houghton of the Employment Medical Aihisory Service for their meticulous record keeping; the 'Jio Dr. D. C. Lindars who assisted with the final draft. Hie following members of the Medical Services Division undertook the laborious yet delicate work of tracing: 1 D. Bell, E. S. Blackadder, M. J. Catton, H. J. Davies, T W. Davies, A. T, Doig, K. J. Dunlop, L. E. Euinton, D. Kipling, G. L. Ritchie, G. F. Smith, J. B. L. r>vnbleson, D. G. Trott, J. G. S. West, and R. Whitelaw. References ' Ashcroft. T. and Heppleston, A. G. (1970). Mesothelioma and asbestos on Tyneside--a pathological and social study. In Proceedings of the International Conference on Pneumoconiosis, Johannesburg, 1969, edited by H. A. Shapiro, pp. 177-179. Oxford University Press, Cape Town. ------ ------ (1973). The optical and electron microscopic determination of pulmonary asbestos fibre concentration and its relation to the human pathological reaction. Journal of Clinical Pathology, 26, 224-234. Cameron, J. M., Litton, A., and Lyon, D. S. (1961). Primary carcinoma multiplex. Journal of Clinical Pathology, 14, 574-577. Hammond. E. C. (1966). Smoking in relation to the death rates of one million men and women. In Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases, edited by W. Haenszel, p. 127. National Cancer Institute Monograph, No. 19. National Cancer Institute, Bethesda. Maryland, U.S.A. Hourihane, D. O'B. (1964). The pathology of mesotheliomata and an analysis of their association with asbestos expo sure. Thorax, 19, 268-278. Lloyd Davies, T. A. (1970). Annual Report of H.M. Chief Inspector ofFactories 1969, p. 57, Cmmd 4461. H.M.S.O., London. McCaughey, W. T. E. (1965). Criteria for diagnosis of diffuse mesothelial tumours. Annals of the New York Academy of Sciences, 132, 603-613. ------ and Oidham. P. D. (1974). Diffuse mesotheliomas morbid anatomical and histological criteria, including observer variation in histological diagnosis. Proceedings of the Working Group to review the Biological Effects of Asbestos. International Agency for Research on Cancer, W.H.O., Lyon (in press). McEwen, J., Finlayson, A.. Mair, A., and Gibson. A. A. M. (1970). Mesothelioma in Scotland. British Medical Journal, 4, 575-578. Newhouse, Muriel L-, Berry, G,, Wagner, J. C., and Turok, Mary, E. (1972). A study of the mortality of female asbestos workers. British Journal of Industrial Medicine, 29, 134-141. ------ , and Wagner. J. C. (1969). Validation of death certifi cates in asbestos workers, British Journal of Industrial Medicine, 26, 302-307. Registrar General (1970). Statistical Review of England and Walesfor the Year 1968, Part l. Medical, p. 124. H.M.S.O., London. Rous, V. and Studcny, J. (1970). Aetiology of pleural plaques. Thorax, 25, 270-284. Selikoff, 1. J., Hammond, E. C., and Churg. J. (1970). Mortality experience of asbestos insulation workers. In Proceedings of the International Conference on Pneumo coniosis, Johannesburg U969), edited by H. A. Shapiro, pp. 180-186. Oxford University Press, Cape Town- Senior Medical Inspector's Advisory Panel Memorandum (1968). Problems arising from the Use of Asbestos. H.M.S.O.. London. Smithcr, W. J., Gilson, 5. C., and Wagner, J. C. (1962), Mesotheliomas and asbestos dust (letter). British Medical Journal. 2, 1194-1195. Thomson, J. G. (1970). The pathological diagnosis of malig nant mesothelioma of the pleura and peritoneum. In Proceedings of the International Conference on Pneumo coniosis, Johannesburg (1969), edited by H. A. Shapiro, pp. 150-154, Oxford University Press, Cape Town. Wagner, J C., Gilson, J. C., Berry, M. A., and Timbrell, V. (1971). Epidemiology of asbestos cancers. British Medical Bulletin, 27. 71-76. ------ , Munday, D. E,, and Harington. J. S. (1962). Histochemical demonstration of hyaluronic acid in pleural f_BB 0Q0S585 f 104 Morris Greenberg and T. A. Lloyd Davies mesotheliomas. Journal of Pathology and Bacteriology, 84, 73-77. ------ , Sleggs, C- A., and Marchand, P. (I960). Diffuse pleural mesothelioma and asbestos exposure in North Western Cape Province. British Journal of Industrial Medicine, 17, 260-271. Whitwell, F. and Rawcliffe, Rachel M. (1971). Diffuse malignant pleura] mesothelioma and asbestos exposure. Thorax, 26, 6-22. WiJlis, R. A- (1952), The Spread of Tumours in the Human Body, 2nd ed., p. 55. Butter-worths, London. Received for publication May 17. 1973 Accepted for publication July 20, 1973 A '* V If the two opinions lead to a blank entry above their the specimen should be sent to the two other readers and a combined diagnosis made on the basis- of four readings. There are many possibilities from four readings but the combined diagnosis should follow the majority if there is a clear one and other wise be undecided. The following rule is sufficient to determine all cases of four readings: score a definite as 1 point, probable as , possible as 0, not as -1; then add up the four scores and if the total is greater than or equal to 1 the diagnosis is Definite, between -- 1 and +1 inclusive it is Undecided, less than or" equal to -1 is Not a mesothelioma. J APPENDIX The UICC Panel of Pathologists and diagnostic criteria A British panel of pathologists specializing in the diagnosis of mesothelial tumours was formed unofficially in 1963 and consisted of Dr. K. F. W. Hinson, Dr. F. Whitwell, Professor W. F. E, McCaughey, and Dr. J. C. Wagner. From 1963 to 1967 all cases were examined by all members of the panel and a majority opinion was arrived at. Subsequently the panel was constituted as a UICC panel. From 1967 panellists decided whether the diagnosis was definitely mesothelioma, definitely not mesothelioma or whether there was insufficient histological material, only referring material to another member or members of the panel in case of doubt. After mid-1968 the policy was adopted that all cases referred to the panel should be seen by at least two members and that if there was a difference of opinion a third opinion should be sought. In mid-1971 the following protocol was designed for combined panel diagnosis. Two opinions are necessary for diagnosis and these two opinions should be combined as below: Addendum The Mesothelioma Register, which in 1967 and 1968 recorded cases from all available sources, has since continued with notifications of deceased casesonly. The following table gives details of notifications (subject to confirmation) for the years up to 1971, figures for the years 1967 and 1968 being included on a similar basis for comparison. Notifications to the Mesothelioma Register (Death Cases) 1967-71 Sources of notification Death certificate Cancer Registry* Industrial injury data* Other Total 1967 9t 39 3 30 163 1968 189 28 3 13 233 1969 126 20 6 5 157 1970 165 11 3 3 184 1971 124 11 -- 3 138. 'Not so certified at death Not on death certificate or cancer registration In the short period studied it is not possible to observe a significant trend. The large number of cases notified in 1968 may have resulted from the publicity and vigilance generated by the survey. If the impression of a falling off in notifications is con firmed then whether this will be due to a change in the prevalence of the disease or to a change in vigilance will require to be evaluated. First opinion Definite mesothelioma Probable mesothelioma Possible mesothelioma Not a mesothelioma Definite Definite Definite Second opinion Probable Possible Definite Undecided Undecided Undecided Undecided Not Hot Not Not -t Jo* Mor popi mine L O.IV O'.'pnrtmf C.mcer F ^ - P Lit LiJ 'CJ3 r'S M 31 IT3 O o -- Ol IV du ' *>> m - f-w- ol U.j o r 'Ml If /a 5- C\ at I** bcv fMrmt front ' otui o s 11 cm ' n odv ' '- ^tI\C s K.iir, * *). Ci ' POSM ''ii Mir cstOb ' *- world *:cronct * ` i' mi* i (uni ''C or av j"BB~000556