Asbestos-associated cancers: Clinical spectrum and pathogenic mechanisms

We have summarized the clinical manifestations and the pathogenic mechanisms underlying asbestos-associated malignancies. The available evidence suggests that asbestos-induced bronchogenic carcinoma and malignant mesothelioma remain formidable challenges facing occupationally exposed individuals, especially in view of the very long latency period between initial exposure and disease presentation. There are several controversial areas regarding asbestos-associated malignancieson which further studies should focus, including: (1) determining whether there is a threshold level of asbestos exposure that is not associated with an increased risk of malignancy (eg, is the current OSHA 0.1 fibers/mL PEL level appropriate?); (2) clarifying the criteria that are necessary for attributing bronchogenic carcinoma to asbestos in patients without asbestosis; (3) characterizing the role of spiral CT for detecting malignancies in asbestos-exposed workers; (4) defining the role of recently described staging systems in the management of patients with mesothelioma; and (5) determining whether any of the recently developed multimodality therapies offer any advantage over palliative care. Studies addressing these issues will need to use a combination of sophisticated epidemiologic techniques involving large numbers of patients and, in many instances, data derived from basic science studies. The combined use of epidemiologic and basic science approaches will be particularly important in assessing the effects of low-dose asbestos exposure and determining asbestos causality in patients with lung cancer without asbestosis. The pathogenesis of asbestos-induced diseases probably derives from the long-term interplay between persistent free radical production and the expression of cytokines, growth factors, and other inflammatory cell products. The precise mechanisms by which asbestos- and inflammation-induced free radicals activate specific genes in pulmonary cells are not firmly established, however. Studies investigating the molecular basis of asbestos-mediated diseases are crucial for at least two reasons. First, effective diagnostic, prevention, and management strategies are predicated on a firm understanding of the fundamental pathways involved. Second, the asbestos paradigm is very useful for exploring the mechanisms underlying the production of inflammation, fibrosis, and malignant transformation that are relevant to more common diseases such as lung cancer and pulmonary fibrosis, both associated with a number of causal factors.