Mechanisms of Carcinogenesis and Clinical Features of Asbestos-Associated Cancers

Exposure to asbestos, particularly members of the amphibole subgroup (crocidolite, amosite), is associated with the development of malignant mesothelioma and lung cancer. Although management of asbestos in buildings and increased regulation of asbestos in workplace settings are viable approaches to the prevention of disease, the prognosis of asbestos-associated tumors is generally dismal. Moreover, although a vast amount of information is available on the responses of cells and tissues to fibers, understanding the pathogenesis of asbestos-associated malignancies is hampered by the complexity of and differences between various fiber types. Multiple interactions between components of cigarette smoke and asbestos may be important in the development of lung cancer. In this article, the general properties of asbestos fibers will be discussed with an emphasis on chemical and physical features implicated in tumorigenesis. We will then provide a brief overview of the clinical features and treatment of cancers associated with exposure to asbestos. Finally, we will review recent experimental data providing some insight into the cellular and molecular mechanisms of carcinogenesis by asbestos.     

Manganese superoxide dismutase as a diagnostic marker for malignant pleural mesothelioma

Although several immunohistochemical markers are available, differential diagnosis between mesothelioma and metastatic adenocarcinoma of the pleura is difficult. We have found that the immunoreactivity of manganese superoxide dismutase (MnSOD), an important antioxidant enzyme, is high in mesothelioma compared to healthy pleural mesothelium. The aim of the present study was to investigate whether MnSOD can be used in the differential diagnosis of malignant mesothelioma and metastatic adenocarcinoma of the pleura. MnSOD expression was assessed by using immunohistochemistry in biopsies of malignant mesothelioma (n = 35) and metastatic adenocarcinoma of the pleura (n = 21). MnSOD immunoreactivity was assessed semiquantitatively with and without microwave pretreatment. Fifteen of the 35 malignant mesotheliomas showed moderate or strong MnSOD expression without and 23 with microwave pretreatment, the corresponding figures for metastatic adenocarcinoma of the pleura being 1 and 2 out of 21 (P = 0.002 and P < 0.001, respectively by Fisher's exact test). Only mesothelioma biopsies showed strong MnSOD reactivity, and it was never negative in mesothelioma, whereas one-third of the adenocarcinomas showed no MnSOD reactivity. In conclusion, MnSOD immunoreactivity can, combined with other markers, aid the differential diagnosis between malignant mesothelioma and metastatic adenocarcinoma of the pleura.     

Mesotheliomas induced in rats by the fibrous mineral erionite are independent from p53 alterations

The development of human malignant mesothelioma (MM) is strongly associated with occupational or environmental exposure to certain natural mineral fibers, although the genetic mechanisms underlying this malignancy remain unclear. Although the p53 gene is frequently mutated in various tumors, human asbestos-associated MMs appear to develop independently from p53 alterations. The high mesotheliomagenic potency of natural fibrous mineral erionite is well established in humans and rodents, but no data regarding genetic alterations in erionite-associated tumors are currently available. Previous speculations that the oncogenic mechanisms underlying asbestos and erionite carcinogenesis may differ led us to examine whether the p53 gene is targeted in erionite carcinogenesis. Fifteen erionite-induced rat MMs as well as six cell lines derived from asbestos-induced and spontaneous rat MM were analyzed for p53 mutations by direct DNA sequencing and immunohistochemical analysis. Both approaches did not reveal p53 alterations in rat MM samples used in the study indicating that, similar to asbestos carcinogenesis, erionite carcinogenesis does not target the p53 tumor suppressor gene.     

Chemokine (C‐C motif) ligand 3 detection in the serum of persons exposed to asbestos: A patient‐based study

Exposure to asbestos results in serious risk of developing lung and mesothelial diseases. Currently, there are no biomarkers that can be used to diagnose asbestos exposure. The purpose of the present study was to determine whether the levels or detection rate of chemokine (C‐C motif) ligand 3 (CCL3) in the serum are elevated in persons exposed to asbestos. The primary study group consisted of 76 healthy subjects not exposed to asbestos and 172 healthy subjects possibly exposed to asbestos. The secondary study group consisted of 535 subjects possibly exposed to asbestos and diagnosed with pleural plaque (412), benign hydrothorax (10), asbestosis (86), lung cancer (17), and malignant mesothelioma (10). All study subjects who were possibly exposed to asbestos had a certificate of asbestos exposure issued by the Japanese Ministry of Health, Labour and Welfare. For the primary study group, levels of serum CCL3 did not differ between the two groups. However, the detection rate of CCL3 in the serum of healthy subjects possibly exposed to asbestos (30.2%) was significantly higher (P < 0.001) than for the control group (6.6%). The pleural plaque, benign hydrothorax, asbestosis, and lung cancer groups had serum CCL3 levels and detection rates similar to that of healthy subjects possibly exposed to asbestos. The CCL3 chemokine was detected in the serum of 9 of the 10 patients diagnosed with malignant mesothelioma. Three of the patients with malignant mesothelioma had exceptionally high CCL3 levels. Malignant mesothelioma cells from four biopsy cases and an autopsy case were positive for CCL3, possibly identifying the source of the CCL3 in the three malignant mesothelioma patients with exceptionally high serum CCL3 levels. In conclusion, a significantly higher percentage of healthy persons possibly exposed to asbestos had detectable levels of serum CCL3 compared to healthy unexposed control subjects.     

胸膜间皮瘤19例临床分析

目的总结１９例胸膜间皮瘤的诊断经验。方法分析１９例胸膜间皮瘤的临床资料,包括年龄、石棉接触史、临床表现、影像学检查、实验室检查和转移情况。结果１９例患者均无明确石棉接触史;８例（４２．１％）无明显胸痛;９例（４７．４％）单纯右侧胸腔积液;２例（１０．５％）臂丛神经受影响;１例（５．２６％）胸水中查到恶性间皮细胞;９例（４７．４％）Ｂ超检查发现胸膜肥厚或结节;１３例（６８．４％）ＣＴ检查发现胸膜结节状病灶。结论石棉接触史并非胸膜间皮瘤的唯一病因;胸痛并非胸膜间皮瘤诊断的必要条件;Ｂ超和ＣＴ检查对临床发现胸膜间皮瘤有提示作用。     

Malignant mesothelioma in young adults

Ten cases of malignant mesothelioma presenting in patients 40 years old or younger at diagnosis were reviewed. Seven cases had a documented history of asbestos exposure of which five were household exposures. The median age at first exposure to asbestos was 10 years and the median duration of exposure was 120 months. The median latency period (time between initial asbestos exposure and diagnosis of malignant mesothelioma) was 19 years. The median interval from initial symptoms to definitive diagnosis was 5.5 months. The case history of each patient is presented. A significant delay in diagnosis in this age group compared with an age-unrestricted series is noted. The significance of nonoccupational exposure to asbestos is emphasized as a probable causative factor in the development of malignant mesothelioma. In addition, a possible genetic predisposition is briefly discussed.     

Non-occupational malignant mesotheliomas

The mineral content of the lungs from 84 cases of malignant pleural mesothelioma was estimated by electron microscopy and energy-dispersive X-ray analysis. These cases were chosen because the history of asbestos exposure was absent, indirect or ill-defined. The occupational exposures were classified according to the method of Zielhuis, and the results indicated that this classification is unnecessarily complicated. The chrysotile counts in the lungs from these mesothelioma cases were similar to those in controls and in a previous series of mesotheliomas in which the majority had had direct exposure to asbestos. Amphibole counts were intermediate between those in controls and in the previous series of mesotheliomas with direct asbestos exposure. These findings confirm those of previous studies indicating that amphiboles are more important than chrysotile in the causation of malignant mesothelioma. The results confirm that some mesotheliomas develop in the absence of asbestos exposure.     

Epidemiology of Environmental Exposure and Malignant Mesothelioma

Although the association between exposure to asbestos and malignant mesothelioma (particularly malignant pleural mesothelioma) has been well established, the health impact of environmental exposure (EE) to asbestos has been less studied. This review summarizes the most recent studies on the association between malignant mesothelioma and EE with asbestos to identify features associated with EE and quantify the association with malignant mesothelioma. There were 44 studies from 18 countries that met our selection criteria, with a considerable amount of heterogeneity in their study design, measures of exposure, and health outcomes. The male-to-female ratio was close to or less than 1 and generally lower than the ratio reported when both occupational and environmental exposures were considered. Although recent studies have continued to improve our understanding of environmental exposure to asbestos, challenges remain. We have highlighted a few new research directions, such as a need for reliable matrices to identify common and less recognized types of EE, asbestos biomarker studies specifically focusing on EE, and research on populations and geographic areas that have not been previously studied.     

恶性胸膜间皮瘤19例临床分析

目的 经病理证实的19例恶性胸膜间皮瘤的诊断经验。方法 分析19例恶性胸膜间皮瘤的临床资料,包括石棉接触史、临床表现、影像学检查、特殊检查、胸水检测和转移情况,并对比15例手术结果。结果 7例工种与石棉有关,占恶性胸膜间皮瘤36.8%(7/19),18例（94.7%)有胸痛,其中16例（84.2%)伴胸腔积液,1例出现Homer‘s综合症并影响臂丛神经,3例（15.8%)CT下穿刺找到间皮瘤细胞,2例（10.8%)胸水中找到间皮瘤细胞,1例锁髓上淋巴结穿刺找到间皮瘤细胞,15例CT发现胸膜增厚或胸膜上结节样病灶,占恶性弥漫性胸膜间皮瘤78.9%,15例手术病例中11例胸膜广泛增厚或胸壁上广泛不规则大小不等结节融合成片,侵犯肺组织或纵隔胸膜、横膈胸膜。结论 石棉接触史是恶生胸间皮瘤主要病因,胸痛、胸腔积液是胸膜间瘤的主要临床表现,CT对诊断胸膜间皮瘤有重要参考价值。CT下活检能提高诊断率。     

Intensity of exposure to asbestos in metropolitan Kure City as estimated by autopsied cases.

In this study, the intensity of exposure to asbestos was evaluated in the residents of Kure City, the site of the Japanese naval shipyard, Kure. The number of asbestos bodies was counted in 728 autopsied cases from those treated surgically in Kure Kyosai Hospital. Five grams of lung tissue was lysed, and the number of asbestos bodies was counted with the use of light microscopic examination. By this method, the number of asbestos bodies detected in men was significantly higher than that in women. There was a peak between 60 and 70 years of age. The number of asbestos bodies in exposed cadavers in Kure City exceeded greatly that found in other districts of Japan. By this criterion, 58 of 109 patients with lung cancer had asbestos exposure, and 39 had a high exposure to asbestos. All 13 patients with malignant mesothelioma had a high exposure to asbestos. Excess asbestos exposure also was found in a large proportion of patients with gastric cancer, colon cancer, and acute leukemia. The crocidolite type of asbestos was detected frequently in patients of malignant mesothelioma or leukemia, and the chrysotile form was found in those with lung cancer.     

Asbestos Exposure and Malignant Mesothelioma in Korea

Although importation of asbestos to Korea has decreased, there are growing concerns of its hazardous effects.This paper describes the use and occupational exposure to asbestos, and the incidence and mortality of malignantmesotheliomas in Korea. Asbestos raw material imports from other countries peaked between 1990 and 1995,but importation of asbestos-containing and -processed materials has steadily increased until now. Acomprehensive exposure survey was conducted in Korea between 1995 and 2006. The average airborne asbestosconcentration was lower than from other countries and steadily decreased during the study period. The numberof malignant mesothelioma cases in Korea was 48 in 1998, 39 in 1999, 45 in 2000, 38 in 2001, and 46 in 2002.There were 334 deaths due to malignant mesothelioma and an average of 30.4 deaths per year between 1996 and2006. The number of deaths attributed to malignant mesothelioma ranged from 16 cases in 1999 to 57 cases in2006. The magnitude of asbestos-related health problems in Korea has been underestimated due to underdiagnosis,incomplete reports, and shorter duration of exposure. A nationwide surveillance system for asbestosexposure and malignant mesothelioma should therefore be implemented.     

Effects on health of non-occupational exposure to airborne mineral fibres

The most prominent potential marker of disease-related non-occupational exposure to mineral fibres is mesothelioma. Although many cases of mesothelioma have resulted from occupational exposure to asbestos, some have been associated with para-occupational domestic and/or neighbourhood exposure and have been reported in case series, case-control studies and a cohort study among non-occupationally exposed subjects. However, little information is available on mesothelioma as a direct consequence of general environmental asbestos exposure. Such cases of mesothelioma related to non-occupational exposure to asbestos as have occurred to date are likely to have resulted from past exposures much higher than those prevailing at the present time (in the developed countries); numbers will therefore probably decrease in the future. Very high rates of mesothelioma have been reported as a result of exposure to erionite. No studies are available on the effects of non-occupational exposure to man-made mineral fibres but, among occupationally exposed workers, a risk of mesothelioma is not apparent. There are suggestions of raised lung cancer rates among household contacts of asbestos workers and among individuals exposed to erionite. Non-malignant parenchymal and pleural abnormalities have been observed in subjects exposed non-occupationally to asbestos and erionite, but these are not necessarily associated with malignant lesions. Quantitative risk estimates of adverse effects on health have not been derived from these studies, essentially because of the absence of fibre exposure measurements.     

Non-asbestos-related malignant mesothelioma. A review

Malignant mesothelioma is an uncommon, but increasingly important, neoplasm. The existing English-language medical literature concerning non-asbestos-related malignant mesotheliomas was reviewed for evidence of other agents associated with the induction of malignant mesothelioma. Both animal and human data were reviewed. In most reviews of malignant mesothelioma, there are a significant proportion of cases without documented asbestos exposure (range, 0% to 87%). Furthermore, there are several fairly well-documented agents other than asbestos that induce malignant mesothelioma in animals, and strong evidence exists that such is the case in man. In reviews of malignant mesothelioma, the percentage of cases with asbestos exposure varies, but a significant number are apparently not asbestos related. It is believed that sufficient evidence exists to suggest that non-asbestos agents can induce malignant mesotheliomas in man, and additional epidemiologic studies in this area are needed.     

Clinical analysis of 19 patients with pleural mesothelioma

Innumber,4173patientswhosufferedfromrespiratorydiseasewerehospitalizedintheDepartmentofRespiratoryMedicinefromJune1992toOctober1997including304patientswithpleuraleffusion.Amongthem,therewere19patientswithpleuralmesotheliloma,whichaccountedfor0.5%ofthetotalor6.2%ofthepatientswithpleuraleffusion.CLINICALDATAGeneraldataAllofthe19caseswerediagnosedwiththoracoscopicbiopsy;13patientsweremales,and6werefemales.Theiragesrangedfrom22to73years,withanaverageof50.8years.Thehistoryoftheirdiseaserang…     

Malignant Mesotheliomas in Kure City, Japan: The Relationship of Asbestos Exposure

Eighteen patients with malignant mesothelioma were seen at Kure Mutual Aid Hospital over a 10-year period. According to occupational history, chest x-ray manifestations, and evidence of asbestos bodies in the tissue, 13 of these cases were definitely thought to be due to exposure to asbestos as a result of two or three of these items testing positive. Kure City is one of the major ship-building cities in Japan since the 1920s. Most of the 18 patients worked in ship building before and during World War II. Malignant mesothelioma appeared about 40 years after their first exposure to asbestos. In western countries, most malignant mesotheliomas are thought to be induced by exposure to asbestos fibers (1,2). Consequently, there has been a serious effort to deal with this problem recently, including lowering rate of exposure. In Japan, however, there have been few reports that asbestos fibers caused malignant mesothelioma (3). This report suggests that an increased incidence of malignant mesotheliomas in a specific area of Japan may also be due to exposure to asbestos fibers.     

Assessment of cell-mediated immunity to malignant mesothelioma by microcytotoxicity tests.

Cell cultures were established from pleural effusions of patients with pleural mesothelioma, and peripheral mononuclear effector cells were tested for cytotoxicity against these cells by means of microcytotoxicity assay. Effector cells were obtained from normal healthy donors and from persons exposed occupationally to asbestos, including apparently healthy persons, patients with benign pleural conditions and patients with malignant mesothelioma. The overall incidence of cytotoxicity was low, and there was no evidence of increased cytotoxicity in mesothelioma patients or other asbestos-exposed donors. It is concluded that little or no tumour-directed cell-mediated immunity is detectable against malignant mesothelioma by microcytotoxicity methods.     

Case-control study of diet and mesothelioma in Louisiana

Data were analyzed from a case-control interview study of malignant mesothelioma in Louisiana, which gathered information on usual diet and on lifetime occupational exposure to asbestos. Thirty-seven patients with malignant mesothelioma of the pleura (n = 32) or peritoneum (n = 5) were matched to controls according to age, sex, race, and factors related to case ascertainment (hospital and date of diagnosis, or parish and date of death). Twenty-one of the 37 cases were judged by masked occupational review to have been exposed to asbestos (57%), compared to seven of 37 controls (19%). Seven additional cases and 10 additional controls had occupational histories suggestive of asbestos exposure. With regard to usual diet before illness, cases reported less frequent consumption of homegrown produce (p = 0.005), cruciferous vegetables (p = 0.005), and all vegetables combined (p = 0.09) than did the controls. An estimate of usual carotene intake was also significantly lower in cases (p = 0.03). Dose-dependent reductions in risk were seen with increasing consumption of vegetables, especially cruciferous vegetables (p for trend = 0.013). These associations were not explained by differences in asbestos exposure as measured by the occupational review. The results indicate that consumption of vegetables or some vegetable-related constituent may have a protective effect on developing mesothelioma.     

Chromosomal abnormalities and their correlations with asbestos exposure and survival in patients with mesothelioma

Cytogenetic findings of our 30 previously reported and eight new patients with malignant pleural mesothelioma were summarised and correlated with asbestos fibre burden in lung tissue and survival. Successful cytogenetic analyses were performed on cells obtained from the tumours and/or pleural effusions of 34 of the 38 patients. Clonal chromosomal abnormalities were detected in 25 patients, 19 of them studied before treatment. Nine patients, seven of them studied before treatment, had normal karyotypes and/or non-clonal chromosomal abnormalities. Most of the karyotypic findings in the patients with clonal abnormalities were complex and heterogeneous, and no chromosome aberration specific to mesothelioma could be demonstrated. The following numerical abnormalities in decreasing order of frequency were preferentially present in karyotypic changes: -22, +7, -1, -3, -9, +11 and -14 (-/+ denoting partial or total loss or gain). Translocations and deletions involving a breakpoint at 1p11-p22 were the most frequent structural aberrations. Statistically significant correlations were found between high content of asbestos fibres in lung tissue and partial or total losses of chromosomes 1 and 4, and a breakpoint at 1p11-p22 (P = 0.0001, P = 0.003, P = 0.009, respectively). The number of copies of chromosome 7 short arms was inversely correlated with survival (P = 0.02). In this study no diagnostic cytogenetic markers of mesothelioma were found, instead the copy number of chromosome 7 short arms turned out to be a possible prognostic factor in malignant mesothelioma.