MESOTHELIOMA CANSER INFO

M alignant mesothelioma is a 20th century phenomenon and as we begin a new century it is timely to review the clinical, research, epidemiological and legal aspects of this disease. I t is a canser, and canser is " a slang or slang-like term for any malignant growth or tumor caused by abnormal and uncontrolled cell division". Cancer affects people at all ages with the risk for most types increasing with age. Cancer caused about 13% of all human deaths in 2007 (7.6 million). T umor is derived, via the Old French tumour , from the Latin tumor "swelling". It originally meant an abnormal swelling of the flesh. In contemporary English, tumor is synonymous with solid neoplasm. A tumor may be benign, pre-malignant or malignant. The nature of the tumor is determined by a pathologist after examination of the tumor tissues from a biopsy or a surgical excision specimen. T he epidemic of mesothelioma has been seen throughout the world, not just in Australia. In Europe mesot...

0. Mesothelioma, Bruce W. S. Robinson MD, A. Philippe Chahinian, MARTIN DUNITZ; 2002 1. Wagner, J.C., Sleggs, C.A., Marchand, P. Diffuse pleural mesothelioma and asbestos expo- sure in the North Western Cape Province. Br J Ind Med 1960; 17: 260–271. 2. Hansen, J., Deklerk, N.H., Musk, A.W., Hobbs, M.S.T. Environmental exposure to crocido- lite and mesothelioma – exposure-response relationships. Am J Respir Crit Care Med 1998; 157: 69–75. 3. McDonald, J.C., McDonald, A.D. The epidemiology of mesothelioma in historical context [Review]. Eur Respir J 1996; 9: 1932–1942. 4. Branchaud, R.M., Garant, L.J., Kane, A.B. Pathogenesis of mesothelial reactions to asbes- tos fibres. Monocyte recruitment and macrophage activation. Pathobiology 1993; 61: 154– 163. 5. Owens, M.W., Grimes, S.R. Pleural mesothelial cell response to inflammation: tumor ne- crosis factor-induced mitogenesis and collagen synthesis. Am J Physiol 1993; 265: L382– 388. 6. Davis, J.M. Ultrastructure of human mesotheliomas. J N...

The rise in mesothelioma cases that has occurred since 1950 has been associated with the widespread commercial use of asbestos. However, less than 10% of asbestos workers exposed to high levels of asbestos actually develop the disease, suggesting that additional factors may increase an individual’s susceptibility to the carcinogenic effects of asbestos. In addition, about 20% of mesotheliomas are not associated with asbestos exposure, suggesting that alternative factors may also cause mesothelioma. * The SV40 SV40 is a DNA tumour virus which was introduced into a significant portion of the human population between 1955 and 1963 through polio vaccines and adenovaccines contaminated with the virus. SV40 and human tumours The discovery that SV40 produced tumours in hamsters led to the PCR analysis of human mesotheliomas for the presence of SV40. Our group was the first to investigate whether there was any correlation between Polyomavirus and mesothelioma, and this was accom- plished in tw...

Asbestos fibres continually clear from the lung toward the pleura and lymphatics. Short fibres may make this translocation more readily, but long fibres also move from the lung. The rapidity of fibre translocation can be surprising. In rats, after intratracheal injection of chrysotile asbestos, fibres could be found in the pleura within 7 days and, in 1 of 3 rats after inhalation of asbestos, fibres could be found in the pleural space 1 week after a 2 week exposure. Free fibres or those within macrophages likely move with pleural liquid toward the lymphatic stomata, where liquid and protein are removed from the pleural space. Here, it appears fibres cannot be completely removed and many of the longer ones accumulate and become concentrated in these discrete areas. After inhalation of asbestos in animals, asbestos fibres can be found adjacent to mesothelial cells, in the submesothelial space and occasionally within mesothelial cells themselves. In human subjects exposed to asbestos in w...

The mesothelial cells line the serosal cavities of the body, the pleural, peritoneal and pericardial spaces. Geographically, across the serosal surfaces, mesothelial cells canbe seen to have a variety of morphologies between flat or cuboidal and showing few or a dense forest of microvilli. Although their important in vivo functions have not been identified, they have the potential to regulate cell traffic, the balance between coagulation and fibrinolysis, cell proliferation, and fibrogenesis within and around the pleural space. They likely represent the progenitor cell for mesothelioma. In in vitro studies, the mesothelial cell demonstrates a multitude of abilities. Mesothelial cells can produce most of the components of the submesothelial matrix, at amounts comparable to that of fibroblasts. They can also release growth factors such as TGF-beta and insulin-like growth factorI. The cells may regulate the fibrinolytic and procoagulant activities on their cell surface and in the pleural ...

The mesothelial cell appears to be a major target of the asbestos fibre. This cel is the likely progenitor of the tumour, mesothelioma, a tumour strongly associated with asbestos exposure. In addition, the mesothelial cell may play a role in other asbestos-induced pathology, including pleural plaques, benign asbestos pleurisy and pleural fibrosis. After much study of the asbestos fibre and its interaction with the mesothelial cel in vitro, it is still unclear what determines asbestos-induced pleural disease. On the one hand, the uniqueness of this pleural pathology may be dependent on the tendency of asbestos fibres to accumulate in the pleural space by their lodging in the parietal pleura around the draining lymphatic stomata. In fact, with decreases in occupational exposure to asbestos fibres, lung disease is waning in incidence, but pleural disease is rising. One explanation is that, with a lower burden of fibres in the lung, the lung can avoid injury as the fibres gradually clear t...

Because of the misfortune of having the Wittenoom mine located in its far north, Western Australia (WA) has one of the highest per capita rates of mesothelioma in the world. It is not surprising to find that the first claims for damages for contracting mesothelioma were brought in that State. Causation The issue which has most vexed asbestos litigation is, undoubtedly, that of causation. There are three contexts in which the issue of cause potentially arises in asbestos disease claims: 1. Has a particular asbestos exposure ‘caused’ the disease suffered by the claimant? 2. Which one or more of a number of exposures to asbestos give rise to legal culpabil- ity for the disease suffered by a claimant? 3. Has the disease for which legal culpability exists caused the loss and damage suf- fered by the claimant with the disease? These causation issues arise both in statutory workers’ compensation claims where the issue of fault in exposing the worker to asbestos is irrelevant (and so the causa...

Light has been the subject of medical treatments since the ancient Greeks. Raab first prescribed photodynamic therapy (PDT) in 1900 by documenting the death of Paramecia with acridine and light, and skin cancer was treated with eosin and light in 1903. Various chemicals have been examined in efforts to optimise the cytotoxic effect of PDT. Hauseman found that porphyrins, naturally occurring iron- or-magnesium-free respiratory pigments present in the protoplasm of plant and animal cells, promoted photochemically induced cell death. Studies with the complex porphyrin mixture haematoporphyrin derivative (HPD), revealed that this sensitiser concentrates in tumors, and multiple HPD injections and light exposures were used to treat locally recurrent breast cancer. Ensuing studies by Dougherty and others explored the use of PDT in the treatment of a wide variety of animal and human malignancies. PDT is based on the fact that a basic photochemical reaction occurs when a sensitising drug is exp...

In the absence of other reliably effective therapies for malignant mesothelioma, several groups are investigating the evolving technology of gene therapy. There are several characteristics that make mesothelioma an attractive target for gene therapy. First is the absence of any effective standard therapy. Second is its unique accessibility in the pleural space for vector delivery, biopsy, and subsequent analysis of treatment effects. A surgical ‘debulking’ procedure to remove gross disease, followed by gene therapy to remove residual disease would thus be technically feasible. Third, local extension of disease, rather than distant metastases, is responsible for much of the morbidity and mortality associated with this neoplasm. Thus, unlike other more widespread neoplasms, small increments of improvement in local control could engender significant improvements in palliation or survival. Accordingly, a number of gene therapy trials aimed at treating mesothelioma using a wide variety of a...

The treatment of malignant mesothelioma (MM) is a particular challenge for the physician. The diffuse nature of the disease makes it difficult for the surgeon to perform a radical resection. Even if technically possible, such extensive resections are usually not curative. The role of two other treatment modalities, radiotherapy and chemotherapy, will be discussed in this chapter. Radiotherapy In the past, only anecdotal reports provided some insight on the efficacy of radiotherapy for pleural MM. Elmes stated that radiotherapy was avoided because it seemed ‘to cause the tumor to grow more rapidly through the chest wall and to involve the skin’. The first systematic trial of radiotherapy was published in France by Eschwege and Schlienger in 1973. These authors gave a total dose of 3500–7500 cGy delivered by a 23 MeV betatron in individual doses of 330 cGy three times per week in 14 patients with pleural MM. Anterior and posterior portals were used to include the entire hemithorax, the d...

Imaging occupies a vital role in the diagnosis and treatment of malignant pleural mesothelioma (MPM). In this respect the conventional chest x-ray, although limited in its scope, still remains an important modality. It can suggest or render a diagnosis of exist- ing disease or at least recognise abnormalities affecting the lungs and/or the pleura. More recently, additional imaging modalities such as computed tomography (CT), high resolution tomography and magnetic resonance imaging (MRI) have proven to be not only important adjuncts but more efficient in outlining the features of both asbestosis and mesothelioma. These techniques more readily distinguish pleural disease from normal pleura, accurately stage and determine tumour extent, and easily identify the optimal site for biopsy as well as aid in the biopsy procedure itself. High resolution tomography has been shown to be well in advance in demonstrating fine interstitial disease and plays an important role in distinguishing emphyse...

Distinction between epithelioid mesothelioma and adenocarcinoma has been, and re- mains, the subject of numerous publications dating back over several decades. The current approach, using histochemistry and immunohistochemical panels, facilitates the diagnosis in the vast majority of cases, although there is a subset of difficult cases, in which ultrastructural assessment may still be required. Controversy remains as to which immunohistochemical markers are of greatest value although there is general acceptance that distinction between mesothelioma and adenocarcinoma requires the use of a panel of antibodies rather than reliance on a single immunohistochemical result. The component antibodies included in these panels are undergoing change, with the recent commercial availability of several novel antibodies positive in mesothelioma. Effusion cytology Approximately 60% of mesotheliomas can be diagnosed on morphological grounds in effusion specimens; 20% require additional ancillary studi...

This distinction represents one of the most challenging areas in mesothelioma diagnosis. Cytology Effusion cytology has a minimal role in the differential diagnosis between fibrous pleuritis and desmoplastic mesothelioma. This reflects the minimal shedding of malig- nant cells from these fibrous lesions into effusions. In rare cases atypical spindle cells may be recognised in effusion fluids, although this recognition is often retrospective following diagnosis by another modality, such as core or open biopsy. There may be an absence of mesothelial cells and lymphocytosis in the effusions associated with sarcomatoid/desmoplastic mesothelioma. Histology In biopsy material, the desmoplastic variant of mesothelioma may have large areas that are composed of paucicellular collagenous tissue containing bland spindle cells, which mimic either a pleural plaque or reactive process. Conversely, reactive processes may be highly cellular and mitotically active. Mangano et al. described useful light...

Depending on the type of mesothelioma and the clinical presentation, there are several samples that may independently or collectively be examined to establish a diagnosis of mesothelioma . By optimising sampling procedures, the clinician can greatly influence and enhance the pathologist’s ability to offer a definitive diagnosis. Although thoracoscopic wedge biopsies – and even open biopsy via thoracotomy – are sometimes required to establish a diagnosis of mesothelioma, there are several less invasive forms of sampling which may be diagnostic in some settings. diagnostic pathway. (After Henderson et al., Malignant mesothelioma, Hemisphere, 1992.) MESOTHELIOMA CANSER INFO

Since its first recognition over a century ago, malignant mesothelioma has been the subject of social, epidemiological, legal and scientific interest. From an epidemiological and social viewpoint, this interest has derived largely from the strong association between malignant mesothelioma and exposure to asbestos, often with implications for litigation. For the pathologist, the diagnosis of mesothelioma is challenging, not only because of the histological diversity of this tumour, but also because of the difficulty in distinguishing mesothelioma from both reactive serosal processes and from metastatic disease involving the serosa. There has been controversy in the past, as to whether a diagnosis of mesothe- lioma could be established reliably on cytological examination of serous effusions or fine needle aspiration (FNA) samples – or histological examination of small biopsy specimens and there have been claims that the diagnosis should only be made after a full postmortem examination or...

Pleural mesothelioma is more frequent than peritoneal mesothelioma, possibly because inhalation is the usual route of entry of the pathogenic fibres and the incidence has risen in recent years and is expected to peak sometime between 1990 and 2010. This disease is refractory to the standard therapeutic options since chemotherapy is only partially effective, radiation therapy simply provides palliation against pain, and surgery, even when performed at a relatively early stage, is controversial. Perhaps because of this poor prognosis, early screening has not elicited great interest. However, this pessimism belies the fact that certain forms have a better prognosis when diagnosed early. To better ascertain prognostic factors, multifactorial studies using the Cox model have been performed. The most favorable factors are age less than 50 years, epithelial histopathological type, good general condition, and stage I disease. Pleuroscopy is an essential procedure for the management of malignan...

The physical signs of malignant pleural mesothelioma are usually those of a pleural effusion or pleural mass (reduced chest expansion, stony dullness to percussion, reduced intensity or absence of breath sounds, etc.). Large effusions or tumour masses can cause mediastinal displacement. The tumour may erode through the chest wall and cause localised tenderness and/or palpable masses. When the tumour has spread within the pleural cavity it is common to see a ‘fixed’ hemithorax, with reduced chest expansion. Mesothelioma masses alone cause dullness to percussion and reduced breath sounds, but occasionally breath sounds are harsh, almost bronchial in the absence of effusions. Signs of compression or invasion of mediastinal structures, particularly the superior vena cava or the phrenic or cervical nerves, may be present. Signs of extrathoracic involvement are uncommon on presentation, occurring in only 11% of patients in one large series. mesothelioma lumps in the axillae of two patients....

Malignant mesothelioma has a number of characteristics with respect to its diagnosis, natural history and management that separates it from other malignancies. Over the past half-century, its diagnosis has frequently been difficult to establish in individual cases. This is because the disease usually already involves the pleural or peritoneal cavity exten- sively when it presents and clinically mimics secondary cancer; because the diagnosis ulti- mately depends on cytological or histological appearances, which are difficult to differen- tiate from reactive pleural diseases on the one hand and secondary cancers (especially adenocarcinoma) on the other; because for many years the sheer existence of the tumour was denied by the world’s most eminent pathologists; and because there are no unique tumour markers, in serum or effusion, to identify it and follow its course. Often it is the clinical and radiological appearances as well as the behaviour of ma- lignant mesothelioma that are as hel...

The focus for the prevention of environmental mesothelioma has to be twofold: the rehabilitation of the areas polluted by asbestos during mining and milling of the mineral and the education of the affected communities about the asbestos hazard. The extent of the problem of environmental pollution by asbestos in the affected regions is enormous. Living for the most part in complete ignorance of the health threat posed by asbestos, many communities have been seriously polluted with asbestos. Although initial remedial efforts by local and Provincial governments were slow and sporadic, a more concerted effort has been made by the Department of Minerals in recent years. The government has spent 44 million rand on this process, and estimates that a further 52 million is needed to complete this task. Companies have contributed less than 5% of the rehabilitation costs. Felix has documented the asbestos pollution of communities in the Northern Province asbestos fields in the proximity of Penge...

In the vast majority of the cases of mesothelioma in South Africa where there was known to have only been environmental exposure to asbestos, this exposure has occurred in the Northern Cape in proximity to mines, mills and dumps. A high proportion of cases of environmental origin (26.6%) is unique to South Africa. The only comparable example is Australia, the only other country to have mined crocidolite in significant amounts. Ferguson et al. found that in 726 cases of mesothelioma registered in Western Australia during 1980–85, 43 cases or 6% had environmental exposure only, and only in six cases ( Webster9 and Solomons12 do not detail the source of environmental exposure to asbestos of the patients in their series but in a later series that included these and other environmental cases totalling 100, Webster gave the following distribution: 93 cases originated from exposures in relation to mining in the Northern Cape; 3 in relation to amosite and Transvaal crocidolite in the Northern ...

Officially, even in 1962, there was not sufficient evidence to implicate crocidolite as a major factor in the development of mesotheliomas. It was puzzling that unlike other industrial hazards, even the environmental exposure could be extremely short, in some cases only a few months. Then there was a long latent period, as with exposure to radioactive substances, but there was no evidence of radioactivity in this situation. The majority of patients with mesothelioma had worked or lived in the north-west Cape, but a few people, working elsewhere with the Cape blue, had also developed the tumour. Experimental work with rats given various types of dust had produced a few pleural tumours, but most of the animals had died too early from rat bronchiectasis. Further evidence was required that this was an occupational hazard, and most worrying of all was the evidence of environmental exposure, which differed so much from carcinoma in asbestos workers. The answer was to undertake an investi- ga...

Incidence rates are periodically calculated on cases notified to the program. An annual report series is produced (NOHSC, 1989–2000). Cases accepted by the pathology panel in the program as definite, probable or possible are included. Because of delays in definitive diagnosis being received, incidence rates have been calculated up to end 1996 only, because of the up to two year delay in notification experienced while awaiting confirmed diagnosis and reconciliation with the state cancer registries. Mesothelioma notifications in Australia, 1980–99 Australian age-specific crude incidence of mesothelioma per million persons, by age and sex, 1996. specific incidence rates of malignant mesothelioma in Australian women, 1986-1996. Trends in Australian incidence of mesothelioma per million persons, by State Cases of mesothelioma in Australia, 1994–96, by site of primary lesion MESOTHELIOMA CANSER INFO

The Australian Mesothelioma Surveillance Program (the program), as it finally became known, endeavoured to correct most of the weaknesses identified in the 1960s and 1970s in other such schemes throughout the world, viz, under-reporting of cases, uncertain diagnosis, poor elucidation of the role of occupational and environmental asbestos exposure and less than comprehensive coverage. The program began on 1 January 1980 after preliminary work from 1977. Formal voluntary notification of cases was actively sought from a network of respiratory physicians, pathologists, general and thoracic surgeons, medical superintendents, medical records administrators, State and Territory departments of occupational health, cancer registries, compensation authorities or any other source. Notifications from other than the diagnosing physician were confirmed with him or her. After gaining the appropriate consents a full occupational and environmental history was obtained for each case, from either the pat...

Two series of results, which are less discussed in public, are certainly more important. The first concerns the estimated lifetime probabilities of dying from mesothelioma in recent generations, compared with the older ones. For instance, we found that, in France, these lifetime probabilities were increasing in the new generations (we estimated a lifetime risk of 0.8% for men born in 1965–68), while these lifetime probabilities were found to be decreasing in UK and US studies. This might be explained by the different patterns of asbestos consumption in these three countries. The second concerns the analysis of mortality in women. We did not find any trend in the mortality in females, which is in line with the results of Price in USA (Peto did not study women’s mortality). This is certainly reassuring, as the opposite would be expected if environmental exposures to asbestos played a significant part in the mortality from mesothelioma. MESOTHELIOMA CANSER INFO

Numerous epidemiological studies, discussed at length in HEI-AR, have compared the incidence of lung cancer and mesothelioma in various situations. Moreover, the ratio of mesothelioma/lung cancer numbers has been compared according to fibre types. However, the observed discrepancies between cohorts may be due to the fact that it was retrospectively difficult to know exactly what types of asbestos have been used in these plants. McDonald et al. had the opportunity to evaluate the incidence of mesothelioma deaths in different contrasted cohorts: i) workers exposed only to crocidolite during gas mask manufacture; ii) miners exposed to pure chrysotile; iii) workers in a textile manufacture exposed to a mixture of chrysotile, amosite and crocidolite. The proportional mortality due to mesothelioma (per 1000) increased from pure chrysotile to pure crocidolite, being intermediate for the mixed fibres. We can deduce from comparing different cohorts that those where workers had been exposed to ...

Mesothelioma as a real pathologic entity Klemperer and Rabin used the word ‘mesothelioma’ for the first time in 1931. In this early period, the biphasic pattern of this tumour, epithelial and mesenchymatous, had been demonstrated by different pathologists. Thereafter, we have to wait until the 1950s to find case reports of ‘primary diffuse pleural mesotheliomas’ described by different authors in Europe and in North America. Finally, in the 1960s, the pioneer work of European and North American pathologists reached a consensus for considering that diffuse malignant mesothelioma, located mainly in the pleura and less frequently in the peritoneum, was a primary neoplasmarising from the pluripotential mesothelial cells. The pathological diagnosis of mesothelioma appeared difficult, so that, in most serious epidemiological studies, the diagnosis was ascertained by a panel of national or supranational expert pathologists. At present, most European countries have a mesothelioma panel of train...

Although it is clear that asbestos causes mesothelioma, other factors also play a role. It is not clear why only a relatively small proportion of people exposed to asbestos develop mesothelioma, or why anywhere from 20 to 60 per cent of people with me sothelioma in different studies lack a known history of asbestos exposure. There may be as-yet unidentified cofactors that act as cocarcinogens with asbestos in the induction of mesothelioma. Evidence that not all cases of mesothelioma are caused by asbestos is threefold. First, we have evidence that a background rate of mesothelioma does exist. Historically, primary malignant tumours of the pleura were recognised by pathologists the late nineteenth century, before the industrial use of asbestos could have been responsible, and without any link to occupation. Epidemiological evidence from mortality statistics for mesothelioma over the past 50 years in the United States and Canada also support a background rate of mesothelioma. Many stud...

The adverse effects of asbestos were first observed in the early 1900s and the relation ship to mesothelioma was suggested in the 1940s. One of the earliest reports linking mesothelioma to occupational asbestos exposure came out of the medical clinic at an asbestos mine in Canada. At a scientific meeting in 1952 Cartier, then in charge of the industrial medical clinic at Thetford Mines, Quebec, reported eight cases of respiratory cancer, two of which he described as pleural tumors. He declared that two such rare cancers in a small series of only eight cases suggested an occupational origin. By 1960 the scientific community generally recognised asbestos as a cause of mesothelioma. However, the issue was far from settled. In a national survey of mesothelioma in Canada from 1960 to 1968, McDonald a history of asbestos contact in a relatively small proportion of cases – mostly in insulation and allied trades rather than in the asbestos-producing industry. They surveyed pathologists across ...

In 1890 Biggs reported a case of ‘endothelioma’ of the pleura. This report may have been the first recognised case of malignant mesothelioma in North America. Since then the incidence of mesothelioma in North America and the world has steadily climbed. Studies of the incidence of mesothelioma in North America have been hampered by a paucity of data. Before 1988, the United States did not even have a specific code for mesothelioma, so many cases were misclassified on death certificates as lung cancers or abdominal cancers. In the United States, the best estimates of mesothelioma incidence are derived from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute. The SEER database2 includes about 9.5 per cent of the United States population. It covers 10 regional areas, in five states (Connecticut, Iowa, New Mexico, Utah and Hawaii), and five major urban areas – San Francisco–Oakland, New Orleans, Seattle, Atlanta, and Detroit. Although the SEER regi...

Detailed study of mesothelioma is important not only in its own right but for a number of other reasons. Firstly, it is an example of an occupational lung disease which has frightening rather than nuisance consequences. In that regard the social and medico-legal aspects of the disease are important to discuss. For every patient who develops mesothelioma, thousands of patients live in fear that the ‘sword of Damocles’ will fall upon them; i.e. the morbidity extends beyond those individuals who get the disease. In fact some patients suffer profound anxiety and depression knowing that they have been exposed to asbestos and may develop malignancy at some time in the future. In Australia we have been fortunate to have a dedicated group of individuals who have formed a society which not only supports the individuals who are at risk of the disease or who have developed the disease but also act as advo- cates for these individuals medically and legally. Secondly, malignant mesothelioma has...

Malignant mesothelioma is a 20th century phenomenon and as we begin a new cen- tury it is timely to review the clinical, research, epidemiological and legal aspects of this disease. As a medical student studying pathology around 1970 I can recall only minimal attention being given to mesothelioma. In fact I once reviewed my medical student lecture notes and there were only about three lines of notes on mesothelioma This was the case despite the fact that we were already beginning to see mesothelioma cases in Western Australian following widespread exposure to blue asbestos from the Wittenoom Mine. The situation has changed dramatically since then. Now, all our medical students are aware of the disease mesothelioma the high frequency of the disease in our clinical departments means that students are exposed to many patients suffering from mesothelioma. Indeed when a patient presents with a pleural effusion and chest wall pain, mesothelioma is often assumed to be the diagnosis unti...