Malignant mesothelioma – Introduction and general observations on asbestos and mesothelioma

Malignant mesothelioma – Introduction and general observations on asbestos and mesothelioma

1. 
   Malignant mesothelioma is a cancer of the mesothelial cells that line the serosal membranes of the major body cavities, namely the pleura, the peritoneum, the pericardium and the tunica vaginalis testis; the constituent neoplastic cells characteristically express the phenotype of a recognized pattern of differentiation of the mesothelium, whether epithelioid, sarcomatoid or both (biphasic), as revealed by conventional light microscopy, mucin immunohistochemistry, immunohistochemistry or electron microscopy, or a combination of these techniques [31-33]. Like other forms of cancer, mesothelioma has the capacity for local invasion of tissues such as the chest wall or lung, with confluent serosal spread in most cases but not all, and in some instances distant metastasis [31], with an almost invariably fatal outcome. Mesothelioma is resistant to conventional cancer therapies (e.g. radiotherapy or chemotherapy), but some long-term survivals have been recorded following radical surgery (pleuropneumonectomy) in patients in good physical condition and with early-stage disease [34-43]; radical surgery of this type is not a treatment option for the majority of mesothelioma patients.
   
2. 
   Most mesotheliomas encountered in the 1990s are a consequence of prior occupational exposure to asbestos [24], including bystander exposure. The relationship between asbestos - especially one or more of the amphibole varieties - and mesothelioma is accepted by virtually all authorities as causal. In this respect, asbestos fulfils all The Bradford Hill Criteria for the establishment of causality (e.g. please see Stolley and Lasky [44]).
   
3. 
   The following points about asbestos and mesothelioma are worth emphasis:
   

1. Inhalation of asbestos fibres represents the overwhelming cause of mesothelioma in industrialized societies, so much so that the incidence of mesothelioma is usually considered to be an index of those societies' past usage of asbestos.

4. 
   Boffetta [15] claims that:
   

5. 
   The asbestos exposure may take the following forms: (i) direct or indirect occupational exposure (including bystander exposure); (ii) domestic exposure: e.g. household contacts of asbestos workers, such as wives who washed the asbestos-contaminated work clothes of their husbands [45-47]; (iii) environmental exposure: this category includes those who lived downwind of asbestos industries or in townships contaminated by asbestos [45-47]. For example, ≥ 27 mesotheliomas have been recorded among those who lived at Wittenoom as children (the roads, airstrip and school yards were surfaced with crocidolite tailings from the mine, and children often played in the mine tailings).
   

1. 
   No history of asbestos exposure is obtainable in about 15-25 per cent of mesothelioma cases [31, 48]. Nonetheless, absence of a history of exposure does not equate to absence of exposure, and evidence indicates that many of these mesotheliomas are in reality attributable to asbestos inhalation — e.g. remote, brief or forgotten exposure, or alternatively, the individual may be unaware that he (the male:female ratio is about 8:1) was in fact exposed to asbestos: (i) from my own series of mesotheliomas, 79 per cent of the request forms that accompanied the biopsies on which the diagnosis was made gave a positive history of past asbestos exposure; clinical review of the remaining 21 per cent yielded a history of asbestos exposure in a substantial proportion, including some for whom the original history stated that there was no exposure, so that my estimate of the proportion for whom a positive history of exposure was eventually obtained is ≥ 85-90 per cent. This estimate is in reasonable agreement with figures in the 1999 Report for the Australian Mesothelioma Register [AMR 99], where 85 per cent of mesotheliomas had a history of asbestos exposure; (ii) Leigh et al. [49] found measurable asbestos fibre levels (> 200,000 fibres per gram dry lung tissue) in 81 per cent of the 28 per cent of Australian mesothelioma cases that had no history of occupational or environmental exposure to asbestos.
   

1. Putative or possible factors other than asbestos implicated in the induction of mesothelioma

   1. 
      In the reply to Question 3 from the European Communities, Canada makes the following statements:
      

2. 
   Possible factors other than asbestos implicated as contributory or causative for rare mesotheliomas are tabulated below:
   

other than asbestos

3. 
   There are anecdotal reports of mesothelioma following radiation, including radiotherapy for childhood cancer such as Wilms' tumour [50-56]. In addition, excess rates of mesothelioma have been reported among both Danish and German patients exposed to radioactive thorium dioxide (Thorotrast) for radiological procedures [57, 58], although a similar but smaller Japanese study found no such excess [59]. Neugut et al. [60] investigated women with breast cancer and patients with Hodgkin's disease, many of whom had been treated by radiotherapy (RT):
   

1. 
   I am also aware of at least one mesothelioma in a patient with HIV infection (AIDS) [61]. Other mesotheliomas have occurred many years after chronic inflammatory lesions of the pleura — e.g. chronic empyema or packing of the pleural cavity with leucite spheres as treatment for tuberculosis [62, 63], and there are a few reports of an association between familial Mediterranean fever (FMF) and mesothelioma (about eight cases only; possibly related to recurrent FMF serositis [64-67]). However, cases of this type are exceptional and most cases of "post-inflammatory" mesothelioma with a short interval between inflammation and tumour (e.g. ≤ 2-3 years by analogy with the criteria for the diagnosis of benign asbestos pleuritis [33, 68, 69]), are probably mesotheliomas that presented with a burst of inflammatory activity, followed by a period of quiescence [70].
   
2. 
   In addition, background asbestos exposure represents a confounding factor for some cases associated with radiation and immunodeficiency: (i) in one report on mortality among 260 plutonium workers, all six mesotheliomas occurred in individuals who had also sustained asbestos exposure [71]: "... no apparently elevated causes of death except for six cases of mesothelioma and six cases of astrocytoma glioblastoma multiforme. The mesothelioma cases had a documented occupational exposure to asbestos ..." [extract from abstract]; (ii) in one of my own cases, the patient had been treated for Hodgkin's disease by mantle radiotherapy 10 years before the diagnosis of his primary pericardial mesothelioma, but he also had a background of occupational exposure to asbestos; (iii) in another case — a pleural mesothelioma in a renal transplant recipient — the patient had also sustained earlier occupational exposure to asbestos.
   

1. Erionite and mesothelioma in Turkey

   1. 
      Erionite (a fibrous zeolite) represents a naturally occurring fibrous mineral implicated in the induction of mesothelioma in certain villages (notably Karain and Tuskoy) in the Cappadocian region of Turkey [72, 7 3], and in Turkish emigrants [74]. So far as I am aware this represents a restricted geographic pocket of mesothelioma cases induced by erionite used as stucco or whitewash in buildings, so that the inhabitants were exposed to high concentrations of erionite fibres from birth. Erionite has no relevance to the broader mesothelioma problem in Western Europe, North America, and Australia. Nonetheless, in its physical properties erionite has similarities to the amphibole varieties of asbestos and it has been suggested that its greater mesotheliomagenicity is related to a greater surface area (200 m² per gram) than crocidolite (8-10 m² per gram), due to the presence of pores in the crystal lattice (see Roggli and Brody [75]); such differences in surface topography might correlate with differences in free radical generation at the surface of fibres.
      

2. Simian virus 40 (SV40) and mesothelioma

   1. 
      Recently, a voluminous literature has grown rapidly on the detection of SV40 DNA in up to 60 per cent of human mesotheliomas [76-87] and some other tumours, such as papillary carcinoma of the thyroid [88], osteosarcomas and brain tumours [83, 89-91]. These observations followed an initial finding that SV40 could induce mesothelioma in hamsters when injected into the pleural cavity [92], and the later demonstration that SV40 could inactivate the tumour suppressor genes p53 and the retinoblastoma gene (Rb) via the large T antigen (TAG) [80, 82, 93, 94]. For humans, early poliomyelitis vaccines contaminated with SV40 were a potential source for the SV40 DNA [82-84]. The following points on this interesting association are also worth emphasis:
      

• 
  It has been suggested that the presence of SV40 might explain: (i) why mesothelioma only develops in a relatively small proportion of asbestos-exposed individuals (usually < 10 per cent); and (ii) why no history of asbestos exposure is obtainable on a sizeable minority of mesotheliomas [95]. However, almost all the mesotheliomas in which SV40 DNA has been found were asbestos-associated; to the best of my knowledge, there is no reported case-control analysis of SV40‑associated mesotheliomas where asbestos fibre counts were not elevated above reference values, with the exception of a recent study by Mayall et al. [96] (please see following discussion). Therefore, the existing data do not adequately address either (i) or (ii): there are many other possible explanations for these observations.
  
• 
  In other studies, SV40 or TAG could not be detected within mesotheliomatous tissue [97-99]. Galateau-Sallé et al. [100] found that SV40 was present not only in mesotheliomas but also in benign inflammatory disorders of the pleura and non-neoplastic lung tissue. In an as yet unpublished investigation carried out in collaboration with Prof. Alec Morley in the Department of Haematology-Oncology at the Flinders University, we have also identified SV40 in mesotheliomas, and in non-neoplastic pleural lesions, normal tissues and colon cancers, casting doubt on the specificity of the association.
  
• 
  Two epidemiological studies have shown no increase in the incidence of bone or brain tumours — or mesotheliomas — 30 years after the use of polio vaccines contaminated with SV40 [101, 102], although in a later study using SEER data¹⁴, Fisher et al. [103] reported an increased frequency of these tumours in subjects who had received SV40-contaminated poliomyelitis vaccines.
  
• 
  The evidence so far only points to SV40 as a possible co-factor for asbestos in the genesis of mesothelioma [96]. For example, Mayall et al. [96] detected SV40 sequences in five of seven asbestos-associated mesotheliomas, but none of four mesotheliomas that were not asbestos-related (investigated by fibre burden analysis of lung tissue, using electron microscopy). However, the evidence in favour of SV40 as a co-factor for mesothelioma induction is still inconclusive and non-persuasive, and in humans the SV40 may represent an innocent bystander or passenger: the criteria for causality [44] have not been fulfilled.
  

2. 
   The point of these comments is that the evidence for a role of SV40 in the development of mesothelioma is inconclusive, and most of SV40-associated cases still represent asbestos-associated mesotheliomas. Although the literature contains anecdotal reports of mesothelioma following radiation, some of these cases (e.g. among plutonium workers) are complicated by coexistent asbestos exposure and it is worth emphasizing that these cases are rare: together they add up to only a small fraction of 1 per cent of the total burden of mesotheliomas in industrialized societies, for which asbestos remains the overwhelming cause. As emphasized already, there is general agreement that the incidence of mesothelioma in various nations is a reflection of the past usage of asbestos by those societies.
   
3. 
   Hillerdal [20] comments along similar lines:
   

1. Male: female ratio for mesothelioma

   1. 
      Asbestos-induced mesothelioma affects males more often than females in a ratio of about 8:1, as a reflection of occupational exposure.
      

2. Anatomical distribution of mesothelioma

   1. 
      With the exception of one series in which 44 per cent of mesotheliomas were peritoneal [104], there is general agreement that primary asbestos-induced mesothelioma affects the pleura more often than the peritoneum, in a ratio of at least 3:1 or even up to ≥ 11:1 [31, 33] (see also AMR 99). In Australia, ≥ 91 per cent of mesotheliomas arise in the pleural cavities, whereas about 7 per cent represent primary peritoneal mesotheliomas and ≤ 1 per cent affect the pericardium or tunica vaginalis testis [33]. This predominance of pleural mesotheliomas in comparison to the peritoneum appears to correlate with gender differences in the frequency of occupational exposure to asbestos (the same high ratio of pleural to peritoneal tumours is also encountered in the United States). In females, a smaller proportion of mesotheliomas arises in the pleura, and in one study of Swedish insulation workers, all seven mesotheliomas arose in the peritoneum [105] (please see following discussion).
      
   2. 
      One report [106] that included cases notified to the Australian Mesothelioma Register from 1986 through 1988 gave figures for the anatomical sites affected in men and women: 676 of 723 men had a pleural mesothelioma (93 per cent), whereas 38 were peritoneal tumours (5 per cent) and nine occurred in other sites (1 per cent). In contrast, 84 mesotheliomas in 101 women were pleural in location, whereas 17 per cent had a peritoneal mesothelioma.
      
   3. 
      Presumably, this difference in anatomical distribution between sexes is a reflection of different rates of occupational exposure to asbestos. On theoretical grounds, one would expect mesotheliomas entirely unrelated to asbestos to occur with about equal frequency in the pleura and peritoneum, or more often in the peritoneum because of the greater surface area of the peritoneal cavity.
      
   4. 
      A partial list of the factors that might explain the higher proportion of peritoneal mesotheliomas in some series and in women includes the following [33]:
      

• 
  The high proportion of pleural mesotheliomas in men is presumably a reflection of asbestos exposure, with deposition of asbestos fibres in lung tissue, followed by translocation of the fibres to the pleura; on this basis, asbestos inhalation appears to skew the proportional distribution of mesothelioma towards the pleura in comparison to other sites. In contrast, fibres presumably follow a more circuitous route from the lung to the pleura, across the diaphragm and into the peritoneal cavity, to induce peritoneal mesothelioma; higher inhaled doses of asbestos might be necessary for the requisite number of fibres (whatever that is) to reach the peritoneum via the pleura, in order to induce peritoneal mesothelioma.
  
• 
  The high proportion of peritoneal tumours in some series may be a consequence of patterns of referral for cases that constitute problems in diagnosis, because the diagnosis of peritoneal mesothelioma is, in general, more difficult than for pleural mesotheliomas. This may explain the higher proportion of peritoneal mesotheliomas among cases referred to the US-Canadian Mesothelioma Panel [107], because many of these represented problems in diagnosis, whereas the Australian Mesothelioma Surveillance Program (AMSP) captured all mesotheliomas throughout Australia [48].
  
• 
  Genuine biological differences in the inhaled dose, deposition or transport of different asbestos fibre types in some groups of workers, notably insulation workers [108] and former Wittenoom workers [109] — as a consequence of heavy occupational exposure — and in women [106, 110].
  

5. 
   In answer to questions posed by the European Communities (Question 3, see Annex II), the following comment is made:
   

1. 
   From the preceding discussion on the proportions of mesotheliomas arising in the pleural cavities versus the peritoneum, it is evident that this proposition is not correct: use of the term typical in this context is inappropriate. In reality, pleural mesothelioma is a more typical or usual outcome of asbestos exposure, whereas asbestos-induced peritoneal mesotheliomas are usually associated with more prolonged and heavier exposures than pleural mesotheliomas, so that the proportion of patients with asbestosis is higher than for pleural mesothelioma [111]. It has also been claimed that peritoneal mesotheliomas are almost always a consequence of amphibole exposure (as opposed to chrysotile only) [112]. Nonetheless, although some of the peritoneal mesotheliomas in my own series of cases followed high-dose exposures to asbestos that included one or more of the amphiboles, a few followed lower cumulative exposures, and Neumann et al. [111] have reported peritoneal mesotheliomas as a consequence of exposure in the building trades and metal industries, in addition to asbestos industries; Rogers et al. [3] recorded peritoneal mesotheliomas in whom only chrysotile fibres were detected on lung fibre analysis (see Table 9, paragraph v.3).
   

1. Latency intervals (lag-times)

   1. 
      In all reported studies, mesothelioma is a disease of long latency between exposure to asbestos and the subsequent diagnosis of the mesothelioma. In the AMSP [48], the mean latency interval (lag-time) was 37 years, with a reported range of 4-75 years; the lag-time was reported to be < 10 years in only four of 499 asbestos-associated mesotheliomas (0.8 per cent). Many authorities set a minimum lag-time of 10 years (e.g. The Helsinki Criteria [113]), and for most patients the lag-time is in the range of 20-40 years, When the lag-time is < 10 years, it is likely that the proximate exposure was coincidental, and that there were one or more earlier exposures.
      

3. 
   
   Directory: english -> tratop e -> dispu e
   dispu e -> Annex g list of exhibits submitted by the parties
   dispu e -> World Trade Organization
   dispu e -> World Trade Organization
   
   
   
   Download 1.28 Mb.
   
   Share with your friends: