What Is Mesothelioma?
Mesothelioma is a cancer of the smooth lining of the chest, lungs, heart, and abdomen. This skin layer is made up of mesothelial cells, hence the name mesothelioma. Mesothelioma is a diffuse but solid tumor that begins as a result of insult to the tissues caused by asbestos particles. These have penetrated into the pleural cavity of the chest or into the abdomen. Mesothelioma is either called pleural mesothelioma or peritoneal mesothelioma based on where it appears.
Because it occurs in such a small number of patients mesothelioma is often referred to as an orphan disease. Numbers of newly affected individuals in the United States have been reported to be between 2,500 and 3,000 every year. A steady rise in cases is reported in North America, Europe, Australia, and Asia.
In its early stages mesothelioma is difficult to detect as it may start with a thickening of the pleural rind, or fluid which can be associated with many other conditions. This rind is normally thin and smooth in the non diseased state. In time it begins to demonstrate progression forming a more pronounced irregular rind and nodules which coalesce into a crust that compresses and invades into adjacent structures compromising lung and cardiac function. In the abdominal cavity it can invade into the liver and bowel rendering the patient inoperable. Peritoneal mesothelioma it is often found coating the omentum described sometimes as a salt like sand like particles too numerous to count and impossible to remove without sacrificing the entire omentum. Involvement of the ovaries and fallopian tubes is not uncommon in women and often mesothelioma is confused with ovarian cancer. Once vital organs are involved or disease identified outside of the operative field surgery is no longer an option and patients are referred to chemotherapy or clinical trials.
Figure E: Right Pleural Epithelial Mesothelioma on chest wall and lung. Photo courtesy K. Brauch
For the vast majority of patients, as the tumor mass grows, once subtle symptoms will give way to weight loss, cough, respiratory infections, fatigue, shortness of breath, digestive and bowel problems and pain in the chest or abdomen, depending upon whether it is pleural or peritoneal. It may begin to weep fluid into the intracavitary space. In the chest cavity this is called an effusion and it fills the space where the lobes of the lung reside, next to the lining of the chest cavity, and often spreads into the area surrounding the heart creating symptoms similar to those observed in congestive heart failure. In peritoneal patients it is called ascites and it fills the abdomen bathing the visceral organs with this malignant fluid.
Figure F: Epithelial mesothelioma on the diaphragm. Click here. for enlargement. Photo courtesy K. Brauch.
The symptoms gradually become more noticeable prompting the patient to seek a medical consultation. By this time the progression of the disease may already be too advanced as the tumor may have spread to the lymph nodes and/or begun to metastasize to remote organs of the body like the brain, spleen, liver or kidneys. Metastatic mesothelioma is considered late stage and incurable, given the current state of treatments. It is widely reported that only 10-20% of patients with pleural mesothelioma are diagnosed early enough for surgical intervention, the rest are referred on to palliative care No such figures have been reported in peritoneal mesothelioma.
What Causes Mesothelioma?
The exact method by which asbestos causes mesothelioma isn’t known with certainty. Animal models have provided some understanding of the type of damage that asbestos fibers can do, but the exact mechanism hasn’t been found yet. After asbestos became a commercially successful product, it was soon apparent that asbestos workers were an at-risk population.
Starting at the turn of the century, British investigators discovered a relationship between exposure to high levels of asbestos and respiratory disease. These early studies were often suppressed by government at the request of the asbestos industry. By the mid 50’s American medical researchers had joined the chorus of concerned professionals identifying asbestos as hazardous. Much of their work was never published or was suppressed and/or disputed by scientists in the pay of the asbestos lobby.
Figure G: Amphiboles Protruding, Brook T. Mossman, UVM College of Medicine.
Asbestos fibers have been detected in many resected surgical specimens from mesothelioma patients. In pleural mesothelioma, asbestos fibers are found trapped in the tissues from the lower parts of the lung and they are sometimes concentrated into nodules or spots on the parietal pleura, the primary location for mesothelioma in the thoracic cavity. These fibers are found using electron beam microscopy. They are invisible to the naked eye and are not routinely commented upon in a typical pathology report. Although smoking while exposed to asbestos is known to significantly increase lung cancer risks, smoking is not a risk factor in the formation of mesothelioma. It is not uncommon to find pleural plaques in the lungs of patients with primary peritoneal mesothelioma which is indicative of heavy asbestos exposure.
Genetic susceptibility may also contribute to the cause of malignant mesothelioma. Populations of three small villages located in Turkey has been environmentally exposed to a rare asbestos-like fiber called erionite for generations. (Please see erionite on the Understanding Asbestos page for more information.)
50% of all deaths in these villages was attributable to malignant mesothelioma. All villagers lived in homes built with this mineral and research by Dr. Michele Carbone discovered that those who developed mesothelioma had a genetic predisposition to the disease . Predisposed individuals who lived in villages without erinote were not found to develop mesothelioma. Further research into the residents of these communities has confirmed an autosomal dominant pattern of susceptibility to malignant mesothelioma and disease develops in the presence of asbestos-like fibers.
Some important journal articles pertaining to this section are listed below.
Mechanisms of asbestos-induced carcinogenesis.
A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes.
Mesothelioma due to environmental exposure to erionite in Turkey.
A History of Mesothelioma
The history of the acceptance of mesothelioma as a primary malignancy of the pleura is one of more than 100 years of confusion and frustration. The disease was rare enough that its appearance was only intermittently identified in the medical literature. With less than one case in a thousand being identified as pleural or peritoneal carcinomas, it is little wonder that physicians at first were reluctant to assign it the status of a primary tumor. The medical establishment of the 1800’s was convinced that pleural tumors had to be metastatic cancers from some other primary tumor, regardless of the lack of evidence for this.
In the late 1800’s it was noted that mesothelioma could be found in the lymph nodes and the theory developed that the cancer began in the lymphatic system and spread to the lungs or abdomen. Not until 1891 was consideration given to the opposite theory. As always, research into the nature of mesothelioma was hampered by the lack of a sufficiently large body of evidence. Patients, thankfully, were still few and far between and reaching a consensus with so little clinical data was difficult.
The early 20th century finally brought acceptance that some pleural sarcomas could arise even without a primary cancer elsewhere in the body. From this humble beginning, the realization that the tumor developed from the mesoderm hit home and the term mesothelioma came to be accepted in 1921. Through the ‘30’s and ‘40’s further research and an increasing number of patients established the description of the tumor and began to identify the link to asbestos exposure.
Because of the confusion over whether mesothelioma truly was a separate clinical entity, five different views about causation took hold:
1. The endothelial lining of the lymph nodes was the cause, hence the name endothelioma.
2. Aberrant lung tissue became malignant within the lining of the pleura.
3. The tumor arose in the pleural capillary endothelium.
4. Tumors of epithelial origin always arose from a primary tumor elsewhere. The primary tumors were felt to be too small to be detected in autopsy.
5. The tumor arose from the mesothelial lining of the pleura and peritoneum.
It was Wedler in 1943 who reported a connection too high to be coincidental between asbestosis and pleural malignancy in a population of German asbestos workers. The analysis, which factually reported the connection but made no attempt to stamp the disease with a label, was widely accepted in Germany and ignored in the rest of the world. It wasn’t until the early 1950’s that additional evidence rescued the observations of Wedler and began to build an irrefutable connection between asbestos exposure and mesothelial cancer.
Inhalation- The Primary Path of Exposure
The primary access path for asbestos fibers is the respiratory system. Fibers released into the air are inhaled by the subjects where they are carried into the deepest recesses of the lungs. Asbestos fibers that are locked into heavier particles of plaster, concrete or paint are often expelled through coughing and rarely reach deeply enough into the lungs. From studies conducted in the early to mid-20th century, most of which were post-mortem examinations, it became apparent that pleural asbestos disease tended to accumulate near the bottom lobes of the lungs, in the gutter of the thoracic cavity and on the surface of the diaphragm.
Microscopic examination of biopsy or autopsy tissue samples revealed that in many cases the asbestos fibers were no longer located in the alveoli of the lungs but rather in the intrapleural space or within the mesothelial lining of that space. This was described by many physicians as a “clearing” of the lungs, but despite the benign sounding label, this process held serious and potentially fatal implications for the subject. It has also been hypothesized that asbestos fibers can be swallowed or may enter directly by piercing the skin. It is not known why some patients develop pertitoneal mesothelioma rather than the more common pleural based disease.
The clearing of the lungs is directly connected to the two primary theories about how injury is caused by asbestos. The first theory postulates that the asbestos fibers pierce the tissue walls of the pleural space (and sometimes the peritoneal space via the stomach or the diaphragm) and cause tissue damage which creates an inflammatory immune response. The second theory states that the asbestos fibers are so small that they begin to interact with mesothelial cells at a molecular level, interrupting cell replication and/or damaging the cellular DNA during mitosis, or cell division.
Inflammatory Immune Response
The migration of the asbestos fibers out of the alveoli is a function of the small size of the fibers. This allows them to pierce the cell walls and migrate between cell boundaries into the mesothelial lining of the pleural cavity or even into the intrapleural space. There, they sometimes penetrate the diaphragm and make their way into the abdomen or the testes.
Whenever these fibers migrate, they leave a trail of damaged or compromised cells behind. The inflammatory response includes the migration of both macrophages and mesothelial cells to the affected area. It has now been described that these cells secrete substances which contribute to cell survival and permit cell division rather than programmed cell death as is the case when damaged cells are detected by the body’s natural surveillance system. These damaged cells now acquire a survival advantage and can transform into malignant mesothelioma. The response to this damage varies by individual and invariably involves the immune system. Evidence for the response is found in the irritation and destruction of cells and the creation of scar tissue at the site of the injury. This process can be quite significant in the case of heavy asbestos exposure and can lead to major impairment of the lungs as a crust or plaque of fibrous scar tissue forms over the affected areas. Microscopic examination of this material has often found asbestos fibers entombed in the nodules and layers of tissue and has been used as prima fascia evidence for the asbestos connection as a cause for the injury.
Selected articles for further reading are listed below.
Differential effects of malignant mesothelioma cells on THP-1 monocytes and macrophages.
Acute injury and regeneration of the mesothelium in response to asbestos fibers.
Genetic Damage During Cell Division:
All living cells have a limited ability to renew themselves. This ability confers a specific life span that appears to be pre-programmed into their chromosomes. When cells divide, the ends of the DNA molecules get shorter, truncating a section of the chromosome called the telomeres. The DNA strands get shorter and shorter until the cell can no longer replicate itself.
Almost all of the cells in our body, including mesothelial skin cells, will grow old and die. The only exceptions are bone marrow cells (making blood cells) and the sperm producing cells of the testes. These cells are called immortal cells since they never lose the ability to reproduce themselves. They are assisted during cell division by an enzyme called telomerase that allows them to keep dividing endlessly without degrading. Before regular cells get old and die they divide, and new cells, (daughter cells) take their place. This process, called mitosis, can be repeated roughly 60 to 100 times during the human lifespan before the cells lose their ability to divide. Once that happens, our tissues and organs begin to fail and we reach the end of our lifespan.
It is during mitosis of respiratory tissue cells that asbestos fibers are thought to do the damage that eventually leads to mesothelioma. During mitosis, the DNA in the parent cell is split into two halves and each half is drawn towards an opposite end of the cell. There, new amino acids replace the missing halves of the DNA by using the original halves as templates. Assuming nothing goes wrong, the cell now contains two identical sets of DNA and a barrier forms that divides the cell into two identical halves.
During mitosis, asbestos fibers that have penetrated the cell are thought to physically interfere with the replication of the DNA. This may break the DNA chains, causing the cell to fail, or damage the functioning of its genes, making it become cancerous. The majority of cells whose genetic machinery is non-functional will die and be cleaned up by the immune system but not all of them will. Some cells whose genetic machinery wasn't fatally damaged will continue to live on in a diminished or damaged state. Those malfunctions which cause a regular cell to reproduce endlessly are termed cancer.
Molecular Details
As cells proceed through mitosis they are monitored by a system of chemical controls that check for DNA damage and look for the inability to perform essential cellular processes. If this system detects damage or errant functions, RNA message molecules are used to cause the cells to stop dividing. These controls cause damaged cells to either repair themselves or self-destruct. The latter process is called apoptosis or programmed cell death.
Participating in cancer development are protein encoding genes referred to as oncogenes. When oncogenes are mutated it will often lead to the transformation of normal cells into cancer cells. With the overexpression of oncogenes, the balance in the normal cell apoptosis program (normal cellular pattern of destruction of abnormal cells) is broken and cell survival and proliferation is largely elevated which results in the growth of tumors. There are five classifications of oncogenes they are (i) growth factors, (ii) growth factor receptors, (iii) signal transducers, (iv) transcription factors, and (v) others, including programed cell death regulators. Many of the drugs in development will target one of these classifications and some drugs will actually target multiple oncogenes.
Current research has repeatedly found abnormalities in mesothelioma cases where deletions of chromosome regions 1p, 3p, 9p, and 6p, and the loss of chromosome 22 have been observed. It is believed that these deletions affect tumor suppressor genes, allowing for the development of mesothelioma.
Selected articles for further reading are listed below:
Cytogenetic and molecular genetic changes in malignant mesothelioma.
Cell Methylation and Cancer:
Recent developments in the field of biology have studied the functional processes of genes at the molecular level. Scientists have known for some time that certain sections of the chromosome, called genes, serve essential functions for the health and welfare of the cell and the host organism. There are large areas of the chromosome that were previously regarded as non-functional or “junk” DNA that are now known to have a role in the control of which genes are active (expressed) and which are not. The process of controlling genes through protein molecule messengers is called methylation.
Some genes control the replication of, and also the longevity of the cells that contain them. While we haven’t identified all of these genes, we have learned that, when growth regulating genes are blocked from doing their functions, cells can grow without restraint, causing cancer.
We have now discovered some of the proteins that appear to be responsible for interfering with the balanced and normal functions of a wide variety of regulatory genes. The excessive presence of such proteins in blood or urine (called over-expression) can be used as a measure of the presence of cancer. We still don’t know exactly what causes these proteins to be produced in excessive amounts, nor have we uncovered all the connections between the production of these molecules and the genetic damage caused by asbestos.
We are now on the cutting edge of science having identified many of the genes responsible for suppressing or promoting tumor growth. Targeting the repair of tumor suppressor genes or inactivation of promoter genes may lead to more effective treatments. Because it is thought that many genetic events are linked to the formation and support of the cancer cell this remains an area under intense investigation.
Selected articles for further reading are listed below:
Gene methylation in pleural mesothelioma: correlations with clinico-pathological features and patient's follow-up.
Simian Virus SV40
One highly contentious issue is the role of simian virus 40 (SV40) in the development of mesothelioma tumors. Animal experiments have established that SV40 is a potent tumor inducing virus, however, clinical studies still have not conclusively linked SV40 to human mesothelioma cases. Many studies and publications have demonstrated the presence of SV40 in multiple tumors including malignant mesothelioma. .
There is some evidence, however, that the SV40 presence in the samples may be due to pervasive laboratory contamination. The source of this contamination was the original monkey cell cultures used as a medium in which to grow smallpox vaccines. The SV40 remnants were felt to be benign and were therefore ignored by laboratories. it was only later that the tentative connection to cancer was noted.
Animal models and in vitro studies with human mesothelial cells when, exposed to a attenuated strain of SV 40 suggest that they may act as co carcinogens. When exposed to this attenuated strain of SV40 alone no malignant mesothelioma was observed, When exposed to both the attenuated strain and asbestos mesothelioma developed. It therefore it can be assumed that SV 40 is not directly responsible for the development of mesothelioma but might have a synergistic role when coupled with asbestos exposure. Laboratory work in this area continues and the role of SV40 in mesothelioma remains to clearly defined.
Selected articles for further reading are listed below:
Mesothelioma epidemiology, carcinogenesis, and pathogenesis.
Types of Mesothelioma
Mesothelioma can be classified into two major groups, benign and malignant. Malignant mesothelioma is organized into four main categories based on the location of the tumor: Rarely mesothelioma is diagnosed in both the pleural and peritoneal cavity but may be found more often as the disease process progresses.
1. pleural – found in the chest cavity, on the surface of the lung and on the diaphragm,
2. peritoneal – found in the abdomen on the surface of the omentum and visceral organs,
3. pericardial – growing on the exterior surface of the pericardium, or lining of the heart, and
4. testicular – noted as a thickening of the ducts and glands in the testes.
Each of these categories of mesothelioma is further divided into one of three subtypes, epithelial, sarcomatoid or mixed. Among the total spectrum of asbestos patients there are a smaller number of cases with different cancers, such as lung cancer and metastatic cancer of the liver, kidneys, bones and other organs. (m) In addition, sarcomatous varieties have been judged to be extremely aggressive, and can be associated with intracranial metastases – brain tumors. There are also benign mesothelial proliferations and well differentialed papillary mesothelioma that are of low malignant potential. The diagnosis should be confirmed by an experienced pathologist as in many cases a more virulent form of the disease can be mixed in with this seemingly benign process. In most cases these tumors are of low malignant potential and are treated only when they begin to cause symptoms and most often with surgery as a single modality.
Who Gets Meso/Who is At Risk
As explained above, the process of developing mesothelioma from asbestos exposure is a long one. Furthermore, while the development of mesothelioma correlates with asbestos exposure, such exposure isn’t an absolute indicator of who will get the tumor and who won’t. Since there is no national or international mesothelioma registry, statistics for the disease vary widely, depending upon the source. Nevertheless, there is a valid statistical relationship between the amount of exposure to asbestos and the incidence of mesothelioma.
If we contain this discussion to the subject of pleural mesothelioma, we will find that well over fifty years of published studies have established three primary groups of individuals by virtue of their exposure. These are: -1- individuals with high levels of exposure of a short duration, -2- individuals with high levels of exposure of long duration and -3- individuals with low levels of exposure of long duration. (l)
The majority of studies showed that group -1- exposure sometimes led to gradual impairment of lung function but it didn’t always rise to the level of asbestosis, i.e. there was little evidence of plaque or nodules in the pleural space. Group -1- also had a relatively high incidence of cancer, most of which was later to be called mesothelioma.
The second case, -2-, led to very high levels of impairment with asbestosis and early death from from the effects of the impairment. secondary illnesses with some cases of mesothelioma.
The third case -3- led to gradual impairment with asbestosis and death caused by a broad spectrum of secondary conditions such as pneumonia, emphysema, tuberculosis etc. Asbestosis appeared to greatly reduce the patient’s ability to resist secondary diseases, raising some of these to the level of fatal illnesses. (o)
Mesothelioma was not seen as often in groups two and three. Medical researchers felt that this was because patients either didn't live long enough to develop cancer or weren't genetically at risk. Ironically, only after dust abatement practices were mandated into the workplace did the incidence of mesothelioma become a significant health issue in the literature and in the vernacular of the medical community, lending credence to the theory about group two.
Studies also revealed a clear relationship between the amount of dust inhaled over a lifetime and the development of asbestosis. Trades with a history of working with asbestos tend to dominate the population of mesothelioma patients. The greater the former, the more likely it would be that signs of asbestosis would be observed. Conversely, it was discovered that there was no safe level of asbestos exposure with respect to mesothelioma, since even short exposures could create the cancer, with or without asbestosis symptoms.
Symptoms of Mesothelioma
As the tumor grows and expands, it often produces fluid that fills the chest or the abdomen, depending upon whether it is pleural or peritoneal mesothelioma. This fluid places pressure on vital organs. In the case of pleural mesothelioma, which represents 80% of cases, the fluid compresses the lung, causing intense pain, shortness of breath and overwhelming fatigue. This fuid will eventually enter the pericardial space and patients will have symptoms suggestive of congestive heart failure. ,Sleep disturbance, loses appetite, and pain are common complaints as the fluid and the expanding tumor slowly fills up the chest, compromising lung function. Relieving the fluid pressure can provide short term symptomatic relief. (p)
Pleural mesothelioma patients in five studies presented by P. Chahinian showed the following symptoms in varying degrees:
Dyspnea (shortness of breath) 6-60% of cases
Chest pain 33-71% of cases
Both dyspnea and pain 19-28% of cases
Cough
3-27%
Hemoptysis (spitting blood or bloody sputum) 1-6%
Hoarseness 1-3%
Dysphagia (difficulty swallowing) 1%
Weight Loss
14-29%
Fever
3-33%
Asymptomatic
3-4%
Pleural effusion (fluid in the chest cavity)
74-84%
Pericardial patients reported different clinical symptoms:
Pericardial effusion (fluid in the pericardial space)
Dyspnea
Pain
Constrictive pericarditis (inflammation of the pericardial sac)
Vascular compression
Cardiac tamponade (bleeding into the pericardium)
Pericardial thickening on scans (12% of patients only)
Peritoneal patients present another set of symptoms again:
Abdominal pain
63%
Abdominal mass
40%
Increased abdominal girth
70%
Ascites (fluid in the abdomen)
66%
Digestive disturbances
33%
Fever
20%
Weight loss
44%
Thrombocytosis (increased platelets in the peripheral blood)
23%
Leukocytosis (elevated white blood cell count)
50%
Disease Development And Progression
The latency of mesothelioma has been one of its greatest problems and may partly explain why a connection with asbestos exposure took so long to be accepted as the primary cause. Mesothelioma latency isn’t known exactly since exposure to asbestos doesn’t always equate directly or immediately to an insult to the tissues. Consequently, estimates of latency vary widely with mesothelioma patients being reported in age ranges from early teens to octogenarians. The accepted figure falls somewhere between 15 and 50 years from the date of exposure to asbestos although it’s anyone’s guess as to when the asbestos first triggered the cellular damage that translated into mesothelioma.
Since symptoms are often misdiagnosed or even absent during early stage mesothelioma, the rate of progression of the disease is also a guess. The most commonly available figures pertain to median survival time from the date of diagnosis but many mesothelioma experts believe the tumor may be in existence for quite some time before diagnosis.
Even survival times vary widely with no clear consensus emerging. On the low side, survival times of 4 to 8 months are reflected in the information to be gleaned from obituaries and tributes paid to the afflicted. On the high side, 12 to 18 months is considered the norm, although this number is demonstrating some upward movement and tends to become differentiated when mesothelioma types, categories and treatments are considered as part of the assessment.
There are three subtypes of mesothelioma epithelial is the most common accounting for approximately 50% of the cases with sarcomatoid, the more aggressive, reported at approximately 16% and mixed (biphasic) 34%. Of the three subtypes, epithelial is thought to be the most responsive to treatment and sarcomatoid has been refractory to chemotherapy and early relapse in surgical series. Biphasic or the mixed type can vary depening upon the percentage of sarcomatoid cells mixed in with the epithelial variant. Patient groups of sarcomatous subtype, or those with lymph node involvement, tend to have no long term survivors. . Epithelial cases without lymph node involvement, and who are younger than 50, have the best chance for long term survival. Median survival numbers for this group are trending up, and vary based on the type of treatment chosen.
In pleural mesothelioma, the tumor tends to appear only in one lung, with a right/left preference of 60% to 40%. Pleural mesothelioma occurs about four times more frequently than peritoneal.Men are five times more likely than women to get pleural mesothelioma and both sexes are equally represented with peritoneal. Though not common mesothelioma can metastasize to the contralateral lung, abdomen, and in rare cases to the brain and spinal cord.
As of this time, there are no medical procedures that are proven to be curative. Most of the leading treatments (covered under the treatment section of this web site) involve experimental procedures, clinical trials of drugs and novel technologies.
Diagnosis of Mesothelioma
Diagnosis of mesothelioma is difficult because the disease often isn’t visible on external scans and the symptoms may be confused with a number of common ailments that misdirect the medical staff and defer more thorough investigations. Mesothelioma is a diagnosis of exclusion, in other words once common ailments are ruled out an investigation into the rare spectrums of illness begins. A definitive diagnosis of mesothelioma requires a tissue biopsy, obtained either through a needle biopsy or an open procedure. Needle biopsy are inconclusive in many cases which leads to a surgical procedure to obtain enough tissue to confirm the diagnosis and identify the cell type.
The process of diagnosis usually begins with some form of radiological investigation. In pleural cases, where respiratory distress is the primary symptom, doctors may fall back on an x-ray to check for pneumonia or shadows on the lung indicative of tuberculosis or lung cancer. It is during this stage that fluid in the pleural cavity or an irregular pleural rind is noted i and more extensive procedures commence. In many developing countries where tuberculois is common when symptoms develop it is considered more cost effective to treat for a suspected tuberculosis. Therapy continues for 6 months and it is only at this time if sympstoms persist that a more extensive diagnostic work up begins. The window of opportunity to treat mesothelioma has often closed as the disease at this point is usually very advanced and refractory to treatment. Insurance will not approve a more costly test unless a patient has had an abnormal X Ray or another test that suggests a CT scan (Computed Tomography scan) is necessary. Computed tomography involves a series of precisely calibrated X-rays to be taken and received by electronic means rather than photographic film. These images are enhanced by the use of contrast medium. Prior to the CT scan the patients is injected with contrast dye and if an abdominal ct is also requested oral contrast is provided. Patients are required to fast prior to an Abdominal CT scan but not for the Pleural CT scan. These images are then reconstructed by computer to offer a highly detailed view of the body in narrow slices, allowing a look inside the body at anatomical details not otherwise visible without surgical examination.
Figure H: PET/CT Fusion showing combined images. The red cross in the human image shows hot spot. The slices show (from left to right) CT scan, PET scan and Combined fusion scan. Click here for enlargement. Photo courtesy K. Brauch.
CT scans are excellent at showing topography but cannot distinguish between scar tissue or tumor. While they can detect pleural or peritoneal thickening, the results are not definitive enough to allow for a mesothelioma diagnosis with CT scan alone.
Another tool of importance in external exams is the Positron Emission Tomography scanner, or PET. PET is a process where radioactive glucose is injected into the bloodstream, where it is consumed in the greatest proportion by the most active parts of the body. This usually means the brain, heart, sex organs and tumors, if present, will consume the largest amount of this isotope, causing hot spots to appear on a scanned image of the body.
Tumors tend to be extremely active and therefore consume large amounts of the sugar isotope. This will cause hot spots to appear where they normally shouldn't, allowing the radiologist to identify possible indications of cancer.
Although PET scans can show activity, they are rather indistinct and cannot clearly identify the exact location of the activity. Simply put, CT scans can tell where a growth is located and PET scans can tell if there is excessive biological activity. The latest technology combines both the CT scan and the PET scan into a single computer image. Therefore, taken together, the PET/CT fusion scan produces a much more accurate image of activities inside the body. If an area of thickening is actively consuming sugar it may be cancerous. If the activity level is low or normal, it may simply be inflammatory response to injury, healing or other benign activity. PET scans are used as part of the initial work-up for surgery. It helps to identify areas of activity that might not be imaged well on CT scan. This may prompt a biopsy to rule out disease that is outside of the operative field. There are false positives whereas a PET may be positive but the biopsy reveals benign non malignant process but the opposite is also true. A negative PET scan does not always reflect accurately the extent of disease. It is not uncommon to discover more advanced disease during the planned operative procedure leading to technically unresectable disease.
Figure I: PET/CT slice showing tiny central hot spot and presence of EPP (removed lung) in left of image. For Enlargement click here. Photo courtesy K. Brauch
Magnetic Resonance Imaging (MRI) and Ultrasound are both soft tissue scanning tools that are generally little used in the imaging mesothelioma. MRI is sometimes used to determine if mesothelioma has penetrated through the diaphragm into the abdomen. In most cases, the images are considered too indistinct to be of much clinical value. Ultrasound simply doesn't penetrate deeply enough to be a good clinical tool in this setting. Ultrasound is useful in quantifying the amount of effusion present and is often used prior to a thoracentesis. Despite the progress, external tests aren't yet definitive enough to allow diagnosis without biopsy. Even if a tumor is detected, it must be examined by a pathologist to determine what kind of tumor it is and whether it is mesothelioma or some other type of cancer.
Selected articles for futher reading are listed below:
Prognostic Value of (18)F-FDG PET/CT in Patients with Malignant Pleural Mesothelioma.
One of the first physical examinations to be conducted is the examination of fluid from the chest or abdomen. Fluid extractions from the chest via needle (thoracentesis) are performed for two reasons, to relieve the buildup of fluid and to provide a sample for a cytological examination. Unfortunately, examinations of the pleural effusion or abdominal ascites are only rarely conclusive. A negative result is inconclusive as enough viable cells may not have been extracted a positive results will define a malignant process but further examination is warranted.
Needle biopsies are also poor indicators since the mesothelioma tumor can be quite diffuse and thin. The biopsy is usually obtained under CT quidance. An experienced radiologist perfoms this procedure. Some of the problems associated with this technique are too little material to sample, sampling a small area will not allow a discussion of the type of mesothelioma or percentage of more virulent cells which aide the oncologist or surgeon in formulating a treatment plan. . The principle means of obtaining a pathology specimen is through surgery and in most cases this involves a VATS procedure ( video assisted surgery). For pleural mesos the surgery itself is called a thoracotomy (chest incision) followed by a thoracoscopy (fiber optic exam of the chest). For abdominal biopsies the surgery is called a laparotomy and laparoscopy (fiber optic exam of the abdomen). These procedures are in themselves difficult surgeries that are only offered in the event a serious illness is suspected. Since the symptoms of mesothelioma are often confused with other, more benign, illnesses, many people either don’t receive them or receive them only after long delays, affecting the prognosis of their cancer.
In an attempt to improve diagnosis of lymph node involvement, some institutions will require a mediastinoscopy to biopsy the lymph nodes in the chest. This procedure is day surgery and a finding of positive lymph nodes might influence a decision not to offer surgery since the surgical staging would be at least stage 3.
Diagnostic examinations may or may not involve rudimentary treatment attempts. In pleural cases, many surgeons opt to perform a pleurodesis. . The purpose of this is to irritate the site and stimulate the formation of scar tissue which wall off the space thus preventing reacumulation of fluid. If the fluid accumulation isn’t stopped, it leads to secondary problems such as pneumonia, or compression of key blood vessels and arteries. Untreated, the fluid accumulation may lead to serious and life threatening complications long before the tumor itself is fatal. It is recommended that this procedure not be performed prior to a consult with a pleural mesothelioma specialist, unless it is deemed absolutely necessary, as it may preclude some innovative treatment options that are being offered at mesothelioma treatment centers. Further discussion can be found in the section labeled chemotherapy.
After the thoracotomy, the surgeon will temporarily insert a tube , placed in the opening and sewn air-tight to the skin, to allow the remaining fluid and blood from the surgery to drain. An alternative to a pleurodesis would be the placement of a pleurex catheter which permits drainage of pleural fluid and can be managed at home or in the hospital setting. This is used as a palliative procedure to manage effusions and ascites. Chest tubes or chest ports are inserted and used for instillation of intra pleural chemotherapy. .
Selected articles for further reading are listed below:
The comparative accuracy of different pleural biopsy techniques in the diagnosis of malignant mesothelioma.
Nonspecific laboratory findings in patients with malignant mesothelioma can include an elevation in the white blood count, number of platelets, erythrocyte sedimentation rate and a decrease in red blood cells (anemia). Elevations of CA125 and hyaluronic acid are also noted in many cases of mesothelioma. All of these findings are nonspecific and are not reliable for making the diagnosis of mesothelioma nor following response to therapy.
Pathology; once a biopsy is obtained special stains are necessary to confirm the diagnosis of mesothelioma. Positive staining for Calretinin, WT1 and cytokeratin is desired, as well as negativity for CEA, CD15, TTF-1 and B72.3. The utility of these stains assists in distinguishing mesothelioma from other cancers that present in similar fashion for example lung cancer. Despite advances in making a pathological diagnosis rare subtypes, poorly differentiated mesotheliomas, and sarcomatoid continue to present diagnostic challenges. Electron microscopy can be employed to look for specific characterists of the cell in some of these more challenging cases.
[A comparative evaluation of immunohistochemical markers for the differential diagnosis between malignant mesothelioma, non-small cell carcinoma involving the pleura, and benign reactive mesothelial cell proliferation][Article in Polish]
Significance of combining detection of E-cadherin, carcinoembryonic antigen, and calretinin in cytological differential diagnosis of serous effusion][Article in Chinese]
Serum Markers
Serum Mesothelin-related protein (SRMP) and Osteopontin have been identified as promising new serum markers to identify and follow response to therapy in patients with malignant mesothelioma. Studies demonstrated that SRMP has value as both a surveillance and prognostic marker for malignant mesothelioma. Mesomark a serum test for SRMP was released in late 2004 by Fujjirebio Diagnostics. It has been approved to follow response to therapy and track changes in disease status in patients with malignant mesothelioma. Studies are underway to validate it’s utility in diagnosing mesothelioma in it’s earliest stages in high risk individuals.
SMRP was the subject of a Meso Foundation grant to investigate its validity in a study of the residents of Libby Montana. (See Meso Foundation press release and press release about European distribution of the test.).
Selected articles for futher reading are listed below.
Osteopontin is a glycoprotein that is overexpresssed in several cancers. In mesothelioma osteopontin are upregulated in asbestos exposed individuals with mesothelioma. Osteopontin might help to distinguish benign pleural changes resulting from asbestos exposure as opposed to malignant tranformaion in asbestos exposed individuals. It has been resported that osteopontin can also predict survival and recurrence patterns. Osteopontin remains under intense investigation to ascertain where it can best be utilized as seen in the clinical setting. Please refer to abstract below for additional information.
Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma.
Asbestos exposure, pleural mesothelioma, and serum osteopontin levels.
Staging And Outcomes
Assuming a diagnosis of mesothelioma is confirmed, staging of the disease remains extremely difficult and is an obstacle to effective treatment. Staging techniques require knowledge about where the tumor is located, how extensive it is and whether it is still locally contained or whether it has metastasized to organs or adjacent tissues.
Since staging is essential to selecting the appropriate treatment, much effort has been invested in developing an accurate pre-operative staging technique. Because of the difficulty of imaging the extent of mesothelioma and its presence or absence in the lymph nodes, staging pre-operatively remains a fairly imprecise process. Several recent attempts have been made to establish a standard process. (t)
Both the International Mesothelioma Interest Group and Brigham & Women's Hospital have developed staging systems based upon a common set of variables. These are:
* T or tumor staging - what is the size and location of the tumor in relation to nearby organs and structures?
* N or nodal staging - are lymph nodes positive or negative for meso?
* M or metastatic staging - is there evidence of metastasis?
Each variable above is expressed as a number and the final combination is compared to a table to establish staging. Negative nodes and metastasis is represented as N0 and M0 Regardless of the staging system used, patients with stage 3 or higher disease are almost always only considered for chemotherapy. This is because stage 3 implies that the tumor is no longer locally contained and cannot be removed (resected) by surgical means.
Recent studies with genomics have added an additional set of considerations to outcome. An assay of the markers of genetic damage in a population of patients seems to co-relate certain genotypes to a better prognosis or outcome. While most of this material is just now being published, it may soon be possible to examine mesothelioma cells for DNA markers that can forecast whether the patient would benefit from aggressive surgical treatment or not.
Stage 1 and 2 patients tend to be surgical candidates, while stage 3 and stage 4 patients are generally offered chemotherapy in combination therapies. (q) (r) (s) Radiation is rarely offered as a primary treatment since it has little effect on its own. Staging, therefore, has a pivotal role in choosing treatment options and determining the prognosis for mesothelioma patients. Treatment options and outcomes are discussed in detail under the treatment section of this web site.
