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Mesothelioma

Mesothelioma is a form of cancer that is almost always caused by
previous exposure to asbestos. 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 they 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. Unlike lung cancer, there is no
association between mesothelioma and smoking.[1] Compensation via
asbestos funds or lawsuits is an important issue in mesothelioma (see
asbestos and the law).

The symptoms of mesothelioma include shortness of breath due to
pleural effusion (fluid between the lung and the chest wall) or chest
wall pain, and general symptoms such as weight loss. The diagnosis can
be made with chest X-rays and a CT scan, and confirmed with a biopsy
(tissue sample) and microscopic examination. A thoracoscopy (inserting
a tube with a camera into the chest) can be used to take biopsies. It
allows the introduction of substances such as talc to obliterate the
pleural space (called pleurodesis), which prevents more fluid from
accumulating and pressing on the lung. Despite treatment with
chemotherapy, radiation therapy or sometimes surgery, the disease
carries a poor prognosis. Research about screening tests for the early
detection of mesothelioma is ongoing.

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 (hemoptysis)

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
CT scan of a patient with mesothelioma, coronal section (the section
follows the plane the divides the body in a front and a back half).
The mesothelioma is indicated by yellow arrows, the central pleural
effusion (fluid collection) is marked with a yellow star. Red numbers:
(1) right lung, (2) spine, (3) left lung, (4) ribs, (5) descending
part of the aorta, (6) spleen, (7) left kidney, (8) right kidney, (9)
liver.
CT scan of a patient with mesothelioma, coronal section (the section
follows the plane the divides the body in a front and a back half).
The mesothelioma is indicated by yellow arrows, the central pleural
effusion (fluid collection) is marked with a yellow star. Red numbers:
(1) right lung, (2) spine, (3) left lung, (4) ribs, (5) descending
part of the aorta, (6) spleen, (7) left kidney, (8) right kidney, (9)
liver.

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.

Screening

There is no universally agreed protocol for screening people who have
been exposed to asbestos. Screening tests might diagnose mesothelioma
earlier than conventional methods thus improving the survival
prospects for patients. 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.[2] Doctors have begun testing the Mesomark assay
which measures levels of soluble mesothelin-related proteins (SMRPs)
released by diseased mesothelioma cells.[3]

[edit] 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.

[edit] 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.
.