Mesothelioma

Mesothelioma is a form of cancer that is almost always caused by previous exposure to asbestos.[1] In this disease, malignant cells develop in the mesothelium, a protective lining that covers most of the body's internal organs. Its most common site is the pleura (outer lining of the lungs and chest cavity), but it may also occur in the peritoneum (the lining of the abdominal cavity) or the pericardium (a sac that surrounds the heart).

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. Unlike lung cancer, there is no association between mesothelioma and smoking [2].
Signs and symptoms

Symptoms of mesothelioma may not appear until 20 to 50 years after exposure to asbestos. Shortness of breath, cough, and pain in the chest due to an accumulation of fluid in the pleural space are often symptoms of pleural mesothelioma.

Symptoms of peritoneal mesothelioma include weight loss and cachexia, abdominal swelling and pain due to ascites (a buildup of fluid in the abdominal cavity). 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.

Mesothelioma that affects the pleura can cause these signs and symptoms:

* chest wall pain
* pleural effusion, or fluid surrounding the lung
* shortness of breath
* fatigue or anemia
* wheezing, hoarseness, or cough
* blood in the sputum (fluid) coughed up

In severe cases, the person may have many tumor masses. The individual may develop a pneumothorax, or collapse of the lung. The disease may metastasize, or spread, to other parts of the body.

Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage. Symptoms include:

* abdominal pain
* ascites, or an abnormal buildup of fluid in the abdomen
* a mass in the abdomen
* problems with bowel function
* weight loss

In severe cases of the disease, the following signs and symptoms may be present:

* blood clots in the veins, which may cause thrombophlebitis
* disseminated intravascular coagulation, a disorder causing severe bleeding in many body organs
* jaundice, or yellowing of the eyes and skin
* low blood sugar level
* pleural effusion
* pulmonary emboli, or blood clots in the arteries of the lungs
* severe ascites

A mesothelioma does not usually spread to the bone, brain, or adrenal glands. Pleural tumors are usually found only on one side of the lungs.

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. A history of exposure to asbestos may increase clinical suspicion for mesothelioma. A physical examination is performed, followed by chest X-ray and often lung function tests. The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma. A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytology if this fluid is aspirated with a syringe. For pleural fluid this is done by a pleural tap or chest drain, in ascites with an paracentesis or ascitic drain and in a pericardial effusion with pericardiocentesis. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g. tuberculosis, heart failure).

If cytology is positive or a plaque is regarded as suspicious, a biopsy is needed to confirm a diagnosis of mesothelioma. A doctor 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 laparoscopy. To obtain tissue for examination, the doctor makes a small opening in the abdomen and inserts a special instrument into the abdominal cavity. If these procedures do not yield enough tissue, more extensive diagnostic surgery may be necessary.
Typical immunohistochemistry results Positive Negative
EMA (epithelial membrane antigen) in a membranous distribution CEA (carcinoembryonic antigen)
WT1 (Wilms' tumour 1) B72.3
Calretinin MOC-3 1
Mesothelin-1 CD15
Cytokeratin 5/6 Ber-EP4
HBME-1 (human mesothelial cell 1) TTF-1 (thyroid transcription factor-1)

Screening

There is no universally agreed protocol for screening people who have been exposed to asbestos. However some research indicates that the serum osteopontin level might be useful in screening asbestos-exposed people for mesothelioma. The level of soluble mesothelin-related protein is elevated in the serum of about 75% of patients at diagnosis and it has been suggested that it may be useful for screening.[3]

Staging

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 cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers).[4] However, there is now evidence that smaller particles may be more dangerous than the larger fibers.[1][2] They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs. "We probably will find out a lot more about the health aspects of asbestos from [the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of pulmonary and critical-care medicine at North Shore-Long Island Jewish Health System. Dr. Fein has treated several patients for "World Trade Center syndrome" or respiratory ailments from brief exposures of only a day or two near the collapsed buildings.[3]

Mesothelioma 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 mesothelioma. 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 mesothelioma 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 act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.

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. The most common abnormality is monosomy of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.

Common gene abnormalities in mesothelioma cell lines include deletion of the tumor suppressor genes:

* Neurofibromatosis type 2 at 22q12
* P16INK4A
* P14ARF

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 several possible mechanisms:

* Inactivation of tumor suppressor genes
* Activation of oncogenes
* Activation of proto-oncogenes due to incorporation of foreign DNA containing a promoter region
* Activation of DNA repair enzymes, which may be prone to error
* Activation of telomerase
* Prevention of apoptosis

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 also may 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 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-β (TGF-β) 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. The incidence is approximately one per 1,000,000. For comparison, populations with high levels of smoking can have a lung cancer incidence of over 1,000 per 1,000,000. Incidence of malignant mesothelioma currently ranges from about 7 to 40 per 1,000,000 in industrialized Western nations, depending on the amount of asbestos exposure of the populations during the past several decades.[5]It has been estimated that incidence may have peaked at 15 per 1,000,000 in the United States in 2004. Incidence is expected to continue increasing in other parts of the world. 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. Approximately one fifth to one third of all mesotheliomas are peritoneal.

Between 1940 and 1979, approximately 27.5 million people were occupationally exposed to asbestos in the United States [4]. Between 1973 and 1984, there has been a threefold increase in the diagnosis of pleural mesothelioma in Caucasian males. From 1980 to the late 1990s, the death rate from mesothelioma in the USA increased from 2,000 per year to 3,000, with men four times more likely to acquire it than women. These rates may not be accurate, since it is possible that many cases of mesothelioma are misdiagnosed as adenocarcinoma of the lung, which is difficult to differentiate from mesothelioma.

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. In rare cases, mesothelioma has also been associated with irradiation, intrapleural thorium dioxide (Thorotrast), and inhalation of other fibrous silicates, such as erionite.

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 airways (lung cancer, bronchial carcinoma). 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 modern cigarettes does not appear to increase the risk of mesothelioma.

Some studies suggest that simian virus 40 (SV40) may act as a cofactor in the development of mesothelioma.[6]

Exposure

Asbestos was known in antiquity, but it wasn't mined and widely used commercially until 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 publicly 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, and created guidelines for engineering controls and respirators, protective clothing, exposure monitoring, hygiene facilities and practices, warning signs, labeling, recordkeeping, and medical exams. 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 exist 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.

Occupational

Exposure to asbestos fibres has been recognised as an occupational health hazard since the early 1900s. Several epidemiological studies have associated exposure to asbestos with the development of lesions such as asbestos bodies in the sputum, pleural plaques, diffuse pleural thickening, 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. Cases of mesothelioma have been found in people whose only exposure was breathing the air through ventilation systems. Other cases had very minimal (3 months or less) direct exposure.

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 mesothelioma had occurred by 1985. By 1994, 539 reported deaths due to mesothelioma had been reported in Western Australia.

Paraoccupational Secondary Exposure

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 fibres, asbestos workers are usually required to shower and change their clothing before leaving the workplace.

Asbestos in buildings

Many building materials used in both public and domestic premises prior to the banning of asbestos may contain asbestos. Those performing renovation works or diy activities may expose themselves to asbestos dust. In the UK use of Chrysotile asbestos was banned at the end of 1999. Brown and blue asbestos was banned in the UK around 1985. Buildings built or renovated prior to these dates may contain asbestos materials.

Environmental Exposure

Incidence of mesothelioma had been found to be higher in populations living near Naturally Occurring Asbestos (NOA).

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

Surgery, either by itself or used in combination with pre- and post-operative adjuvant therapies has proved disappointing. A pleurectomy/decortication is the most common surgery, in which the lining of the chest is removed. Less common is an extrapleural pneumonectomy (EPP), in which the lung, lining of the inside of the chest, the hemi-diaphragm and the pericardium are removed. It is not possible to remove the entire mesothelium without killing the patient.

Radiation
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For patients with localized disease, and who can tolerate a radical surgery, radiation is often given post-operatively as a consolidative treatment. The entire hemi-thorax is treated with radiation therapy, often given simultaneously with chemotherapy. This approach of using surgery followed by radiation with chemotherapy has been pioneered by the thoracic oncology team at Brigham & Women's Hospital in Boston. [7] Delivering radiation and chemotherapy after a radical surgery has led to extended life expectancy in selected patient populations with some patients surviving more than 5 years. As part of a curative approach to mesothelioma, radiotherapy is also commonly applied to the sites of chest drain insertion, in order to prevent growth of the tumor along the track in the chest wall.

Although mesothelioma is generally resistant to curative treatment with radiotherapy alone, palliative treatment regimens are sometimes used to relieve symptoms arising from tumor growth, such as obstruction of a major blood vessel. Radiation therapy when given alone with curative intent has never been shown to improve survival from mesothelioma. The necessary radiation dose to treat mesothelioma that has not been surgically removed would be very toxic.

Chemotherapy

In February 2004, the United States Food and Drug Administration approved pemetrexed (brand name Alimta) for treatment of malignant pleural mesothelioma. Pemetrexed is given in combination with cisplatin. Folic acid is also used to reduce the side-effects of pemetrexed.

Immunotherapy

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 (while it may benefit patients with bladder cancer). Mesothelioma cells proved susceptible to in vitro lysis by LAK cells following activation by interleukin-2 (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 tumor mass combined with minimal side effects.

Heated Intraoperative Intraperitoneal Chemotherapy

A procedure known as heated intraoperative intraperitoneal chemotherapy was developed by Paul Sugarbaker at the Washington Cancer Institute.[7] The surgeon removes as much of the tumor as possible followed by the direct administration of a chemotherapy agent, heated to between 40 and 48°C, in the abdomen. The fluid is perfused for 60 to 120 minutes and then drained.

This technique permits the administration of high concentrations of selected drugs into the abdominal and pelvic surfaces. Heating the chemotherapy treatment increases the penetration of the drugs into tissues. Also, heating itself damages the malignant cells more than the normal cells.

Prevention & Expectations

What can be done to prevent the disease? Since the 1970s, the Environmental Protection Agency and the Occupational Safety and Health Administration have regulated the asbestos industry in the U.S. In the past, asbestos was used as a fire retardant and an insulator. Other products are now used in its place. The controversy involving exposure to different forms of asbestos continues.

There are two major types of asbestos: chrysotile and amphibole. It is thought that exposure to the amphibole form is more likely to cause mesothelioma. However, chrysotile has been used more frequently, hence many mesotheliomas are caused by chrysotile.

Removal is taking place in schools and other public buildings throughout the U.S. The hope is that these measures will greatly reduce the occurrence of this cancer.

What are the long-term effects of the disease? A mesothelioma is a highly aggressive tumor that is generally deadly. Current treatment of malignant mesothelioma is designed to make the person with cancer comfortable. Although long-term survival cannot usually be expected, the case of famed paleontologist Stephen Jay Gould is a noted exception.

What are the risks to others? Mesothelioma is not contagious and cannot be passed from one person to another. The exposure to the asbestos that caused the cancer occurred many years to several decades before the disease appeared. People who live with asbestos workers have a higher risk of getting this cancer.

What happens once treatment is over? Although mesothelioma is very unpleasant it's still important for person after treatment is over to keep up all follow-up appointments and that's vital because further testing is always needed to check whether cancer is coming back or to examine possible side effects that could be rather unpleasant and what's even worse permanent.

Notable people with mesothelioma

Mesothelioma, though rare, has had a number of notable patients. Australian anti-racism activist Bob Bellear died in 2005. British science fiction writer Michael G. Coney, responsible for nearly 100 works also died in 2005. American film and television actor Paul Gleason, perhaps best known for his portrayal of Principal Richard Vernon in the 1985 film The Breakfast Club, died in 2006. Mickie Most, an English record producer, died of mesothelioma in 2003. Paul Rudolph, an American architect known for his cubist building designs, died in 1997.

Steve McQueen was diagnosed with peritoneal mesothelioma on December 22, 1979. He was not offered surgery or chemotherapy because doctors felt the cancer was too advanced. McQueen sought alternative treatments from clinics in Mexico. He died of a heart attack on November 7, 1980, in Juárez, Mexico, following cancer surgery. He may have been exposed to asbestos while serving with the US Marines as a young adult—asbestos was then commonly used to insulate ships' piping—or because of its use as an insulating material in car racing suits.[8] (It is also reported that he worked in a shipyard during World War II, where he might have been exposed to asbestos. [citation needed]

United States Congressman Bruce Vento died of mesothelioma in 2000. The Bruce Vento Hopebuilder is awarded yearly by his wife at the MARF symposium to persons or organizations who have done the most to support mesothelioma research and advocacy.

After a long period of untreated illness and pain, rock and roll musician and songwriter Warren Zevon was diagnosed with inoperable mesothelioma in the fall of 2002. Refusing treatments he believed might incapacitate him, Zevon focused his energies on recording his final album The Wind including the song Keep me in your heart which speaks of his failing breath. Zevon died at his home in Los Angeles, California, on September 7, 2003.

Although life expectancy with this disease is typically limited, there are notable survivors. In July 1982, Stephen Jay Gould was diagnosed with peritoneal mesothelioma. After his diagnosis, Gould wrote the "The Median Isn't the Message"[9] for Discover magazine, in which he argued that statistics such as median survival are just useful abstractions, not destiny. Gould lived for another twenty years eventually succumbing to metastatic adenocarcinoma of the lung, not mesothelioma.

Author Paul Kraus was diagnosed with mesothelioma in June 1997 following an umbilical hernia operation. His prognosis was "a few months." He continues to survive using a variety of integrative and complimentary modalities and has written a book about his experience.

Legal issues

Main article: asbestos and the law

The first lawsuits against asbestos manufacturers were in 1929. Since then, many lawsuits have been filed against asbestos manufacturers and employers, for neglecting to implement safety measures after the links between asbestos, asbestosis, and mesothelioma became known (some reports seem to place this as early as 1898). The liability resulting from the sheer number of lawsuits and people affected has reached billions of dollars. The amounts and method of allocating compensation have been the source of many court cases, and government attempts at resolution of existing and future cases.

History

The first lawsuit against asbestos manufacturers was brought in 1929. The parties settled that lawsuit, and as part of the agreement, the attorneys agreed not to pursue further cases. It was not until 1960 that an article published by Wagner et al first officially established mesothelioma as a disease arising from exposure to crocidolite asbestos.[10] The article 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 McNulty reported the first diagnosed case of malignant mesothelioma in an Australian asbestos worker.[11] The worker had worked in the mill at the asbestos mine in Wittenoom from 1948 to 1950.

In the town of Wittenoom, asbestos-containing mine waste was used to cover schoolyards and playgrounds. 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. 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 Wittenoom were issued against CSR and its subsidiary ABA, and the Asbestos Diseases Society was formed to represent the Wittenoom victims.

Mesothelioma

Mesothelioma is a rare cancer of the lining of the chest, the abdomen, or other tissues. It has become increasingly more frequent since 1900, however, paralleling the use of asbestos. Exposure to asbestos is the most common cause of this disease, with the vast majority of cases occurring following exposures that may have taken place decades earlier. Mesotheliomas can be seen ten years after first exposure, but they peak at three to four decades after exposure. The risk is lifelong, and the prognosis is extremely poor, with death often occurring within twelve months of diagnosis, no matter what the treatment. Newer, extensive surgical techniques may alter this historical experience.

All fiber types of asbestos cause this disease, although there is continuing controversy over the differential ability of the different fiber types to do so. The one other recognized cause of this disease in humans is another group of fibrous materials called zeolites. In animal studies, however, a wide variety of other fibers have been known to cause mesotheliomas.

Mesotheliomas appear as several cellular patterns and may be difficult to diagnose. Special panels of experts are available to assist with making these evaluations. The most common lesions with which these may be confused are lung cancers.

Mesothelioma

Mesothelioma

Definition

Mesothelioma is a rare form of cancer. In mesothelioma, malignant cells are found in the sac lining of the chest (the pleura) or the abdomen (the peritoneum). The majority of people with mesothelioma have a history of jobs that exposed them to asbestos, an insulation material.

Description

In the chest and abdominal cavities, as well as in the cavity around the heart (pericardial sac), there is a layer of specialized cells called mesothelial cells. These cells also surround the outer surface of most internal organs. These cells form tissue called mesothelium.

The mesothelium performs a protective function for the internal organs by producing a lubricating fluid that permits the organs to move around. For example, this fluid makes it easier for the lungs to move inside the chest while a person breathes. The mesothelium of the abdomen is known as the peritoneum, and the mesothelium of the chest is called the pleura. The pericardium refers to the mesothelium of the pericardial cavity.

There are three primary types of malignant mesotheliomas:

* Epithelioid. About 50% to 70% of mesotheliomas are of this type and have the best outlook for survival.
* Sarcomatoid. Approximately 7% to 20% of cases are of this type.
* Mixed/biphasic. From 20% to 35% of mesothelioma cases fall into this category.

Approximately three-fourths of all mesotheliomas begin in the chest cavity and are known as pleural mesotheliomas. Peritoneal mesotheliomas begin in the abdomen, and make up around 10% to 20% of all cases. Mesotheliomas arising in the cavity around the heart are quite rare.

Demographics

Mesothelioma is a fairly rare form of cancer. According to the American Cancer Society, there are an estimated 2,000 to 3,000 new cases per year of the disease in the United States, but this figure seems to be rising. This rising figure is related to the widespread use of asbestos from the 1940s to the end of the 1970s. European researchers studying the disease expect deaths from mesothelioma to peak around the year 2020 and then drop off, because asbestos use has been cut back greatly since the early 1980s.

The average age of a person with mesothelioma is 50 to 70 years old. It affects men three to five times more often than women and is less common in African-Americans than in Caucasian Americans.

Causes and Symptoms

The primary risk factor for developing mesothelioma is asbestos exposure. In the past, asbestos was used as a very effective type of insulation. The use of this material, however, has been declining since the link between asbestos and mesothelioma has become known. It is thought that when the fibers of asbestos are inhaled, some of them reach the ends of the small airways and penetrate into the pleural lining. There the fibers may directly harm mesothelial cells and eventually cause mesothelioma. If the fibers are swallowed, they can reach the abdominal cavity, where they can contribute to the formation of peritoneal mesothelioma.

Exposure to certain types of radiation as well as to a chemical related to asbestos known as zeolite has also been related to incidences of mesothelioma.

The early symptoms of mesothelioma are often ignored, because they may be caused by a variety of ailments. These symptoms include:

* pain in the lower back or at the side of the chest
* shortness of breath
* difficulty swallowing
* cough
* fever
* fatigue
* abdominal pain, weight loss, and nausea and vomiting (symptoms of peritoneal mesothelioma)

Diagnosis

A doctor should be seen if a person experiences shortness of breath, chest pain, or pain or swelling in the abdomen. If these symptoms are present, the doctor may order an x ray of the abdomen or chest. The doctor will do a complete physical examination and take a thorough medical history. Then, one or more of the following methods may be used to ascertain whether mesothelioma is present.

* Imaging tests. These tests may include x rays, computed tomography (CT scans), or magnetic resonance imaging (MRI) to allow the doctor to visualize the area in question. These studies will help determine the location, size, and extent of the cancer.
* Pleural biopsy. Diagnosing mesothelioma requires an adequate biopsy specimen. However, because mesothelioma usually arises from the lower part of the diaphragmatic and/or parietal pleura, obtaining enough tissue may be difficult. A simple, or closed, pleural biopsy involves the insertion of a needle into the chest cavity to obtain tissue from the pleural membrane for analysis. This technique is minimally invasive and normally requires only local anesthesia. This technique, however, may not provide adequate material for the necessary stains of the tissue to make a diagnosis of mesothelioma. Moreover, since the biopsy is not done under direct vision, the sample may not be exactly in the area of the tumor. If the diagnosis cannot be made with this relatively noninvasive technique, an adequate tissue sample usually can be obtained via an open pleural biopsy. In this approach, a surgeon makes an incision on the patient's side and goes into the pleural space. This method allows maximum exploration of the pleural membranes as well. However, the technique requires general anesthesia.
* Thoracoscopy. A thoracoscopy, which is a relatively new technique, allows the doctor to look directly into the chest (pleural) cavity at the tumor and during the same operation to also take a tissue sample for laboratory analysis. The thoracoscopy is performed by making a small incision into the chest and using a tiny video camera to inspect the region. The doctor can then use forceps to obtain a tissue biopsy. A laparoscopy, a similar operation, is used to obtain a biopsy of a peritoneal tumor.
* Bronchoscopy. A bronchoscopy, which examines the airways, or a mediastinoscopy, which looks at the lymph nodes in the chest, allows the doctor to look at the area using a lighted tube. Samples may be taken with a needle and sent to the lab to find out if cancer cells are present. However, bronchoscopy and mediastinoscopy are not that effective for diagnosing mesothelioma, as the disease is seldom found within the airways or the lymph nodes.
* Surgery. This lets the doctor obtain a larger tumor sample or, on occasion, the entire tumor.

Diagnosing mesothelioma is often difficult, even with tissue biopsies. Microscopically, mesothelioma is often difficult to distinguish from several other forms of cancer. For this reason, certain laboratory tests are performed to help correctly diagnose mesothelioma. Some of these tests involve using antibodies to distinguish lung cancer from mesothelioma. Sometimes the tissue samples must be viewed under an electron microscope in order to get the correct diagnosis.

Treatment Team

A person with symptoms of mesothelioma will most likely seek help from a primary physician initially. During the diagnostic phase, various technicians will perform the imaging studies. A specially trained physician—a thoracic surgeon or, rarely, a pulmonologist—performs other diagnostic tests like pleural biopsy and thoracoscopy. A pathologist will view the tissue samples and make the tissue diagnosis. Following diagnosis, the patient will be offered some form of treatment, which may entail surgery, radiation therapy, chemotherapy, or a combination of these. The patient may receive care from a thoracic surgeon, an anesthesiologist, medical and radiation oncologists, and specially trained nurses who administer chemotherapy.

Clinical Staging, Treatments, and Prognosis

The treatment and outlook for those with mesothelioma depends a great deal on the stage of their cancer. Because the most frequently occurring type of mesothelioma is pleural, and it is also the one most studied, it is the only type for which a staging system exists. The following stages are based on a system known as the Butchart system, which divides mesothelioma into four stages:

* Stage I: Mesothelioma is found within the right or the left pleura and may also involve the lung, the pericardium, or the diaphragm on the same side.
* Stage II: In this stage, mesothelioma has spread to the chest wall or involves the esophagus, the heart, or the pleura on both sides. The lymph nodes in the chest may be involved as well.
* Stage III: Mesothelioma has gone through the diaphragm and into the lining of the abdominal cavity. Additional lymph nodes besides those in the chest may be involved.
* Stage IV: There is evidence that mesothelioma has spread through the bloodstream to distant organs or tissues.

Another system of staging mesothelioma is based on a TNM system (T=tumor, N=spread to lymph nodes, and M=metastasis). There are minor differences between this and the Butchart system. It is more detailed and precise, but the original Butchart system is still the one most often used to describe pleural mesotheliomas.

There are treatments available for all patients with malignant mesothelioma. The three kinds of treatment used are surgery, radiation therapy, and chemotherapy.

Surgery is a common treatment for mesothelioma. It is not an option unless the cancer is limited to one place and unless the person can withstand the surgery. During surgery, the physician may remove a portion of the lining of the chest (pleurectomy) or abdomen (peritonectomy) and some of the tissue surrounding it. Depending on the extent the disease has spread, a lung may also require removal (extrapleural pneumonectomy). Occasionally, a portion of the diaphragm is taken out as well. If treatment is not possible, other less invasive measures can be used to relieve the patient's symptoms. For example, a needle placed into the chest cavity (thoracentesis) can remove excess fluid in the chest. If recurrence of fluid causes symptoms, a nonsurgical or surgical method can be used to scar the lining of lung cavity and cause it to adhere to the lung. The procedure obliterates the pleural space and thus prevents the fluid from reaccumulating. (This procedure is called sclerosis or sclerotherapy.) These methods are called palliative, for they are not meant to cure the cancer but to improve symptoms.

Radiation therapy uses high-energy x rays to kill cancer cells and cause tumor shrinkage. It is rarely used as the primary treatment for pleural mesothelioma in those patients for whom surgery is not an option. It may also be used as an adjunct to surgery or as a method of alleviating various symptoms like trouble with swallowing, pain, and shortness of breath.

Chemotherapy involves the use of drugs to kill cancer cells. The most commonly used drugs are doxorubicin, cisplatin, and methotrexate. The medicines are delivered into a vein or taken by mouth. In the treatment of mesothelioma, they may also be injected directly into the chest or abdominal cavity. Chemotherapy may be given as the main treatment or may be an addition to surgery, depending on the type and stage of the cancer.

A new treatment being studied for early stages of mesothelioma confined to the chest is called intraoperative photodynamic therapy. This treatment uses special drugs that make cancer cells more sensitive to killing by a laser light. The drugs are given several days before surgery. During surgery, the special light is used to shine on the pleura.

By the time symptoms show up and mesothelioma is diagnosed, the disease is often advanced. The average survival period after diagnosis is about one year. If the cancer is found before it has spread and it is treated aggressively, about half of the patients will live two years, and approximately 20% will survive five years.

Alternative and Complementary Therapies

There are no proven effective alternative therapies for mesothelioma. Because the prognosis is often poor, many patients may be interested in trying other avenues of treatment. Patients should first consult with their physicians prior to trying any of these methods. There are many well-studied complementary treatments that may increase a patient's comfort and sense of well-being. These may include meditation to aid in relaxation, massage to decrease pain, and guided imagery to help prevent nausea.

Coping With Cancer Treatment

Coping with cancer treatment can be difficult and exhausting. It can be very helpful for the patient receiving therapy for mesothelioma to find a group of family and friends who can aid with household responsibilities, provide transportation, and give psychological support. The patient should not feel a need to rush back to normal activities after treatment is completed.

Clinical Trials

A great deal of research is being performed in the area of mesothelioma. Much of the research is focused on finding out how asbestos changes the mesothelial cells to cause these cancers. In addition, new combinations of treatments are being tested, along with gene therapy. A variety of clinical trials are testing new chemotherapy drugs and immunotherapy. Some of these treatments use hormonelike substances called interleukins and interferons that activate the immune system.

Prevention

The best method of preventing mesothelioma is to avoid or limit exposure to asbestos. People who might experience asbestos exposure at work include miners, insulation manufacturers, construction workers, ship builders, and factory workers.

Questions to Ask the Doctor

* What type of mesothelioma do I have?
* Has my cancer spread beyond the primary site?
* What stage is my cancer in? What treatment options are there?
* What is my prognosis?
* Are there experimental therapies I may benefit from? Where are they being performed?

Special Concerns

Mesothelioma is a serious disease with a poor long-term prognosis. Patients with this cancer should communicate their wishes regarding treatment to their family and physicians.

Resources

Periodicals

Apgar, Barbara. "Diagnosis of Malignant Pleural Mesothelioma." American Family Physician January 15, 2000: 536.

Organizations

American Cancer Society. (800) ACS-2345. .

National Cancer Institute. Building 31, Room 10A31, 31 Center Drive, MSC 2580, Bethesda, MD 20892-2580. (800) 4-CANCER. .