Mesothelioma

Mesothelioma is a form of cancer, almost always caused by previous exposure to asbestos. In

this disease, malignant (cancerous) 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.



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.




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 histopathologist. 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.




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




Staging

Once the diagnosis is confirmed, the doctor may need to assess the stage to help 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 cause cancer.

Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than

"feathery fibers" (chrysotile or white asbestos fibers)[2]. However, there is now evidence

that smaller particles may be more dangerous than the larger fibers.[3][4] 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.[5]

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 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-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation

of mesothelial cells after injury by asbestos fibres.




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 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 current 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





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

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 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

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. 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 mesothelioma

had been reported in Western Australia.

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.




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 with a 5 year survival rate of less than 10%. 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.




Radiation

Although the tumor is highly resistant to radiotherapy, these regimens are sometimes used to

relieve symptoms arising from tumor growth, such as obstruction of a major blood vessel.

Radiotherapy is commonly applied to the sites of chest drain insertion, in order to prevent

growth of the tumor along the track in the chest wall.




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[10]. 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.