Mesothelioma
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Mesothelioma is an uncommon form of cancer, usually associated with previous exposure to asbestos, which affects the pleura, a sac which surrounds the lungs, the peritoneum, the lining of the abdominal cavity, or the pericardium, a sac that surrounds the heart.
In this disease, malignant (cancerous) cells are found in the mesothelium, a protective sac that covers most of the body's internal organs. Most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles, or have been exposed to asbestos dust and fibre in other ways, such as by washing the clothes of a family member who worked with asbestos, or by home renovation using asbestos cement products.
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Signs and symptoms
Symptoms of mesothelioma may not appear until 30 to 50 years after exposure to asbestos. Shortness of breath and pain in the chest due to an accumulation of fluid in the pleura are often symptoms of pleural mesothelioma. Symptoms of peritoneal mesothelioma include weight loss and abdominal pain and swelling due to a buildup of fluid in the abdomen. Other symptoms of peritoneal mesothelioma may include bowel obstruction, blood clotting abnormalities, anemia, and fever. If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face.
These symptoms may be caused by mesothelioma or by other, less serious conditions. It is important to see a doctor about any of these symptoms. Only a doctor can make a diagnosis.
Diagnosis
Diagnosing mesothelioma is often difficult, because the symptoms are similar to those of a number of other conditions. Diagnosis begins with a review of the patient's medical history, including any history of asbestos exposure. A complete physical examination may be performed, including x-rays of the chest or abdomen and lung function tests. A CT (or CAT) scan or an MRI may also be useful. A CT scan is a series of detailed pictures of areas inside the body created by a computer linked to an x-ray machine. In an MRI, a powerful magnet linked to a computer is used to make detailed pictures of areas inside the body. These pictures are viewed on a monitor and can also be printed.
A biopsy is needed to confirm a diagnosis of mesothelioma. In a biopsy, a surgeon or a medical oncologist (a doctor who specializes in diagnosing and treating cancer) removes a sample of tissue for examination under a microscope by a pathologist. A biopsy may be done in different ways, depending on where the abnormal area is located. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples. If the cancer is in the abdomen, the doctor may perform a peritoneoscopy. To obtain tissue for examination, the doctor makes a small opening in the abdomen and inserts a special instrument called a peritoneoscope into the abdominal cavity. If these procedures do not yield enough tissue, more extensive diagnostic surgery may be necessary.
If the diagnosis is mesothelioma, the doctor will want to learn the stage (or extent) of the disease. Staging involves more tests in a careful attempt to find out whether the cancer has spread and, if so, to which parts of the body. Knowing the stage of the disease helps the doctor plan treatment.
Mesothelioma is described as localized if the cancer is found only on the membrane surface where it originated. It is classified as advanced if it has spread beyond the original membrane surface to other parts of the body, such as the lymph nodes, lungs, chest wall, or abdominal organs.
Pathophysiology
The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities. Deposition of asbestos fibres in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibres from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibres may be deposited in the gut after ingestion of sputum contaminated with asbestos fibres.
Pleural contamination with asbestos or other mineral fibres, has been shown to induce carcinogenesis. Malignant mesothelioma (MM) development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibres. It has been suggested that in humans, transport of fibres to the pleura is critical to the pathogenesis of MM. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localised lesions of accumulated asbestos fibres in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed and cellular changes within the lesion culminated in a morphologically malignant tumour.
Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of MM occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibres remain unclear despite the demonstration of its oncogenic capabilities. However, complete in vitro transformation of normal human mesothelial cells to malignant phenotype following exposure to asbestos fibres has not yet been achieved. In general, asbestos fibres are thought to exert their carcinogenic effects via direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.
Studies involving intrapleural or intraperitoneal inoculation of rats and mice with different types of asbestos fibre established that long, thin fibres caused a higher incidence of mesothelioma than did short fibres and that cells phagocytose and accumulate longer fibres more effectively than shorter fibres. Similarly, incubation of Syrian hamster cells with fibreglass which had an average length of 9.5µm resulted in cell transformation with an efficiency identical to crocidolite. Grinding these fibres to approximately 2.2µm reduced the transforming ability 10- to 20-fold while further reduction to <1µm completely eliminated the transforming ability of the fibreglass particles.
Analysis of the interactions between asbestos fibres and DNA has shown that phagocytosed fibres are able to make contact with chromosomes, often adhering to the chromatin fibres or becoming entangled within the chromosome. This contact between the asbestos fibre and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. Most commonly observed are chromosomal translocations or deletions, in addition to trisomies and polysomies of chromosomes 5, 7, 11, 12 and 20, and monosomies of chromosomes 1, 3, 4, 9, 14, 15, 18, 19 and 22. Whilst none of the cytogenetic abnormalities have been found to be specific for MM, Tiainen et al. (1989) reported a statistically significant inverse correlation between the number of copies of chromosome 7 p-arms and the survival rate for MM. This latter finding may provide a useful tool in the prognosis of MM.
Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis by four possible mechanisms: i) inactivation of genes responsible for the regulation of normal cell growth, ii) the activation of oncogenes during the transfection process, iii) activation of proto-oncogenes in the host genome due to incorporation of foreign DNA containing a promoter region, and iv) activation of DNA repair enzymes which may be prone to error.
Asbestos fibres have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favour the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.
Asbestos may also possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce lymphokine-activated killer (LAK) cell viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-b (TGF-b) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.
Epidemiology
Incidence
Although reported incidence rates have increased in the past 20 years, mesothelioma is still a relatively rare cancer. About 2,000 new cases of mesothelioma are diagnosed in the United States each year. Mesothelioma occurs more often in men than in women and risk increases with age, but this disease can appear in either men or women at any age.
Commercial asbestos mining at Wittenoom, Western Australia, occurred between 1945 and 1966. A cohort study of miners employed at the mine reported that while no deaths occurred within the first 10 years after crocidolite exposure, 85 deaths attributable to MM had occurred by 1985. It is predicted that the number of cases within this study group will reach in excess of 700 by the year 2020. By 1994, 539 reported deaths due to MM had been reported in Western Australia.
Risk factors
Working with asbestos is the major risk factor for mesothelioma. A history of asbestos exposure exists in almost all cases. However, mesothelioma has been reported in some individuals without any known exposure to asbestos.
Asbestos is the name of a group of minerals that occur naturally as masses of strong, flexible fibers that can be separated into thin threads and woven. Asbestos has been widely used in many industrial products, including cement, brake linings, roof shingles, flooring products, textiles, and insulation. If tiny asbestos particles float in the air, especially during the manufacturing process, they may be inhaled or swallowed, and can cause serious health problems. In addition to mesothelioma, exposure to asbestos increases the risk of lung cancer, asbestosis (a noncancerous, chronic lung ailment), and other cancers, such as those of the larynx and kidney.
The combination of smoking and asbestos exposure significantly increases a person's risk of developing cancer of the air passageways in the lung. The Kent brand of cigarettes used asbestos in its filters for the first few years of production in the 1950s and some cases of mesothelioma have resulted. Smoking current cigarettes does not appear to increase the risk of mesothelioma.
Exposure
Asbestos has been mined and used commercially since the late 1800s. Its use greatly increased during World War II. Since the early 1940s, millions of American workers have been exposed to asbestos dust. Initially, the risks associated with asbestos exposure were not known. However, an increased risk of developing mesothelioma was later found among shipyard workers, people who work in asbestos mines and mills, producers of asbestos products, workers in the heating and construction industries, and other tradespeople. Today, the U.S. Occupational Safety and Health Administration (OSHA) sets limits for acceptable levels of asbestos exposure in the workplace. By contrast, the British Government's Health and Safety executive (HSE) states formally that any threshold for mesothelioma must be at a very low level and it is widely agreed that if any such threshold does exists at all, then it cannot currently be quantified. For practical purposes, therefore, HSE does not assume that any such threshold exists. People who work with asbestos wear personal protective equipment to lower their risk of exposure.
Exposure to asbestos fibres has been recognised as an occupational health hazard since the turn of the century. Several epidemiological studies have associated exposure to asbestos with the development of lesions such as asbestos bodies in the sputum, pleural plaques and diffuse pleural fibrosis, asbestosis, carcinoma of the lung and larynx, gastrointestinal tumours and diffuse mesothelioma of the pleura and peritoneum.
The documented presence of asbestos fibres in water supplies and food products has fostered concerns about the possible impact of long-term and, as yet, unknown exposure of the general population to these fibres. Although many authorities consider brief or transient exposure to asbestos fibres as inconsequential and an unlikely risk factor, some epidemiologists claim that there is no risk threshold.
Family members and others living with asbestos workers have an increased risk of developing mesothelioma, and possibly other asbestos-related diseases. This risk may be the result of exposure to asbestos dust brought home on the clothing and hair of asbestos workers. To reduce the chance of exposing family members to asbestos fibers, asbestos workers are usually required to shower and change their clothing before leaving the workplace.
Treatment
Treatment of MM using conventional therapies has not proved successful and patients have a median survival time of 6 - 12 months after presentation. The clinical behaviour of the malignancy is affected by several factors including the continuous mesothelial surface of the pleural cavity which favours local metastasis via exfoliated cells, invasion to underlying tissue and other organs within the pleural cavity, and the extremely long latency period between asbestos exposure and development of the disease.
Surgery, either by itself or used in combination with pre- and post-operative adjuvant therapies has proved disappointing with a 5 year survival rate of less than 10%. Although the tumour is highly resistant to radiotherapy and chemotherapy, these regimens are sometimes used to relieve symptoms arising from tumour metastases such as obstruction of a major blood vessel.
Treatment regimens involving immunotherapy have yielded variable results. For example, intrapleural inoculation of Bacillus Calmette-Guérin (BCG) in an attempt to boost the immune response, was found to be of no benefit to the patient. Mesothelioma cells proved susceptible to in vitro lysis by LAK cells following activation by interleukin (IL)-2, but patients undergoing this particular therapy experienced major side effects. Indeed, this trial was suspended in view of the unacceptably high levels of IL-2 toxicity and the severity of side effects such as fever and cachexia. Nonetheless, other trials involving interferon alpha have proved more encouraging with 20% of patients experiencing a greater than 50% reduction in tumour mass combined with minimal side effects.
The failure of conventional therapies in combating this aggressive tumour has initiated great interest in the development of alternative forms of therapy, especially those capable of specifically destroying diseased cells but not surrounding healthy tissue.
Research
Because mesothelioma is very hard to control, the U.S. National Cancer Institute (NCI) is sponsoring clinical trials (research studies with people) that are designed to find new treatments and better ways to use current treatments. Before any new treatment can be recommended for general use, doctors conduct clinical trials to find out whether the treatment is safe for patients and effective against the disease. Participation in clinical trials is an important treatment option for many patients with mesothelioma.
Legal issues
See also asbestos and the law
In the United States, the average mesothelioma-related settlement was $1 million; for cases that go to trial awards averaged $6 million, according to a study by the RAND Corporation. Only a small fraction of the thousands of asbestos-related lawsuits in the United States every year are related to mesothelioma. In 2004, a bill in the United States Senate aimed a asbestos litigation reform failed to reach a floor vote. In January of 2005, Senate Judiciary Committee Chairman Arlen Specter announced he would again try to pass an asbestos litigation reform bill.
A separate bill introduced on March 17, 2005, the Fairness in Asbestos Injury Resolution Act of 2005 (FAIR act of 2005), seeks to ensure a set amount of compensation dependent on the symptoms of the victim. The range is from Medical Monitoring for victims with Asbestosis or Pleural Disease to $35,000 for victims with Mixed Disease With Impairment all the way to over $1,000,000 for Mesothelioma victims and nonsmoking Lung Cancer victims. Template:Web reference
History
An article by Wagner, published in the British Journal of Industrial Medicine in 1960, first established mesothelioma as a disease arising from exposure to crocidolite asbestos. The article ("Diffused Pleural Mesothelioma and Asbestos Exposure in the North Western Cape Province") referred to over 30 case studies of people who had suffered from mesothelioma in South Africa. Some exposures were transient and some were mine workers.
In 1962 Dr McNulty reported the first diagnosed case of malignant mesothelioma in an Australian asbestos worker in the Medical Journal of Australia. The worker had worked in the mill at the asbestos mine in Wittenoom from 1948 to 1950.
In 1965 an article in the British Journal of Industrial Medicine established that people who lived in the neighbourhoods of asbestos factories and mines, but did not work in them, had contracted mesothelioma.
Despite proof that the dust associated with asbestos mining and milling causes asbestos related disease, mining began at Wittenoom in 1943 and continued until 1966. It is difficult to understand why the mine and mill was allowed to initially open and operate without adequate risk control measures; and why nothing was done to force the owner (CSR) to clean them up, adopt safer work practices or close down their operations.
In 1974 the first public warnings of the dangers of blue asbestos were published in a cover story called "Is this Killer in Your Home?" in Australia's Bulletin magazine. In 1978 the Western Australian Government decided to phase out the town of Wittenoom, following the publication of a Health Dept. booklet, "The Health Hazard at Wittenoom", containing the results of air sampling and an appraisal of worldwide medical information.
By 1979 the first writs for negligence related to Witternoom were issued against CSR and its subsidiary ABA, and the Asbestos Diseases Society was formed to represent the Wittenoom victims.
Source: Worksafe, Western Australia (http://www.safetyline.wa.gov.au/institute/level2/course21/lecture95/l95_04.asp)
External links
- Medlineplus: Mesothelioma (http://www.nlm.nih.gov/medlineplus/mesothelioma.html)
- Mesothelioma: Questions and Answers (http://cis.nci.nih.gov/fact/6_36.htm) from the National Cancer Institute (http://cancer.gov/).
- American Cancer Society (http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=29)
Sources
The first version of this article was adapted from a public domain U.S. National Cancer Institute fact sheet at http://cis.nci.nih.gov/fact/6_36.htm