Radiation Treatments:

Radiation has proved to be of limited use in abdominal mesothelioma as a primary treatment but has proved useful in preventing malignant seeding of the incision sites. Its use is highly recommended in both pleural and peritoneal mesothelioma to prevent the appearance of mesothelioma in the area of surgical incisions.

Because of the easy access to the peritoneal cavity, some consideration has been given to using photodynamic therapy as an adjuvant treatment for peritoneal mesothelioma. The surface to be treated is bathed in a chemical that is absorbed by both healthy cells and tumor cells. Healthy cells tend to clear this chemical more quickly. The chemical sensitizes cellular tissues to exposure to light, causing apoptosis or cell death. If timed correctly, only the cancer cells self destruct because only they retain the sensitizing chemical. Clinical trials for this have been attempted but the results aren't convincing enough to make this a standard therapy.

Chemotherapy Actions:

Chemotherapy agents can act in two principal ways: disrupting cell reproduction (cell division) or physically destroying cancer cells. The process of cell reproduction is complicated and has several different and distinct stages. The first treatment approach uses chemotherapies that act at several different times during cell replication process. Such drugs are called Alkylating agents.

No matter how it’s done, when a cancer cell is blocked from replicating itself, the tumor stops growing. Unfortunately, many of these agents will have that effect on ANY fast replicating cell. Since we can’t protect our healthy fast replicating cells, sperm, white and red blood cells, we often get nasty side effects such as low blood counts that may interfere with treatment if unresolved.

Recently, research scientists have discovered ways to begin producing chemical agents that only target specific types of cells. In some cases it has been possible to target specific subgroups of cancer cells, known to replicate themselves by using a specific receptor. One day soon, we hope to have unique chemical poisons for each type of tumor. Then we can spare the regular cells from the side effects of the treatment. Such targeted chemotherapies are not yet in standard clinical use but are being investigated in clinical trials.

Chemotherapy Treatments

The principles behind treating cancer with chemotherapy are a bit like a scorched earth strategy, denying the enemy sustenance in the expectation that cancer needs resources more than healthy tissues do.

Most cancer chemotherapy is applied systemically, meaning it is applied to your whole body via the circulatory system. The easiest way to deliver systemic chemotherapy is to ingest it in pill or liquid form via the digestive system. This approach works only for those chemicals that can survive the rigors of being digested in the stomach, and then only if the molecules are small enough to be absorbed into the circulatory system by the intestines.

The molecular structures of many chemotherapy agents are too fragile to allow the drug to be taken this way, or they are too large to be absorbed into the blood stream through the intestines. Therefore, most chemotherapies are given by an injection or an intravenous drip along with saline solution on a specific timetable. Your entire body is therefore exposed to the effects of a systemic poison and not just the cancer in a specific location. This can be an important benefit of a systemic treatment if the cancer has already metastasized and begun to move to secondary areas or other organs. Once in the blood stream, the chemical agents can go wherever your circulatory system can reach.

Since organs like the brain, kidneys, lungs, and liver are also exposed to the toxic effects of these drugs, dosages need to be carefully controlled so as not to kill healthy cells along with the cancer cells. Antidotes can also be given in advance for some chemotherapy agents that are known to carry high risks of morbidity to organs like the kidneys or liver. Since excreting these systemic poisons as quickly as possible is important, having healthy kidneys may dictate whether chemotherapy is an option.

The most effective alternative to systemic application is a regional or localized application where higher doses of the drugs can be administered directly to the affected area or organ. There are two variations to this technique of controlling the application of chemotherapy to specific surfaces. The first method is direct application and the second is intra-cavitary application via a special shunt or tube that is used to feed the chemicals directly into the peritoneal space. Both of these techniques allow much higher doses of chemicals to be used since most of the drug remains outside of the bloodstream, coating only the exposed tissue surfaces.

Some absorption of the chemo into the affected surfaces is necessary for it to work. For chemotherapy given in this manner during surgery, the surgeon will sometimes take tissue samples to analyze how deeply the drug has penetrated the tissue wall. Since penetration of the cell wall implies some entry of chemo into the bloodstream, the use of an antidote is an important precaution.

Which approach is used depends upon the goals of the treatment and the need to control side effects. In any case, the application methods are carefully selected to ensure that more damage happens to the cancer cells than to the healthy cells. Chemotherapy works because the rapid growth of cancer cells makes them more vulnerable to chemicals that block, destroy or interfere with fast growing cells.

Peritoneal Treatments

Peritoneal Surgery

While it is the primary tool for treating peritoneal mesothelioma, surgery, by itself, is not considered curative. The abdomen is a complex space, filled with a variety of easily damaged and extremely important organs. A cancer affecting the abdominal lining, or peritoneum (paira-tin-e-um) is therefore a very serious and hard to treat matter.

The peritoneum is made of two parts, the visceral and parietal peritoneum. The visceral peritoneum covers the internal organs and makes up most of the outer layer of the intestinal tract while the parietal peritoneum covers the abdominal cavity.

While both the pleural (chest) and the peritoneal (abdominal) space contain the same lining and suffer from the same cancer, the nature of the two spaces dictates that different treatment strategies must be used. The peritoneum is located in an area of soft tissues, easily accessed and pliable, where the pleura is found inside a rigid space (the rib cage) and is difficult to reach without cutting through bone. Thoracic (chest) surgery to remove the pleura almost always involves the permanent removal of at least one rib.

The peritoneal and pleural mesothelial cells are designed to provide lubricating secretions which allow the organs in each respective space to move freely. When the cells of the mesothelium malfunction due to the cancer's progress, an overproduction of this fluid often results. This is called ascites and causes many of the symptoms discussed earlier in the diagnostic section.

Unique structures inside the abdomen make treating peritoneal mesothelioma both more difficult and, in some ways, easier than pleural mesothelioma. There are two folds of the peritoneum called the greater and the lesser omentum. These structures serve to connect the viscera and provide support for blood vessels.

In most mammals, the great omentum forms a great sac, which is attached to the transverse colon and the stomach. It is loaded with fat, and covers nearly all of the intestines. The lesser omentum connects the stomach and liver and contains the hepatic vessels. There is also a ligament called the gastrosplenic omentum which connects the spleen and stomach. If the omentum is heavily encrusted with mesothelioma it may be necessary to remove it, changing the structure of the abdominal space quite dramatically.

On a comparative basis, therefore, the abdomen has a much larger surface area than the chest to be treated. Using a geographic analogue the chest is like a smooth coastline and the abdomen is like a coast covered with inlets and islands. The latter offers far more miles of coastline than the former. This, together with the complexity of the space and fragility of the organs such as the bowels, leaves little chance for surgically resecting all of the tumor.

The relative ease of access to the abdomen has numerous interesting benefits, however. The stomach wall can easily be entered to allow access to the abdominal space and this means that the area can support multiple debulking surgeries and inspections to keep the tumor in check. It also means that the area can be treated with innovative techniques such as heated chemoperfusion, gene therapy, immunotherapy and photodynamic therapy.

Consequently, a very successful strategy for treating peritoneal mesothelioma has emerged that combines aggressive debulking of the tumor with one or more of the other techniques as adjuvants.

Several treatment centers now offer peritoneal treatment that involves several courses of surgery over a specific interval, with chemotherapy, radiation or other treatments either during or after the surgeries. Success with this approach has been excellent and there are now a number of long term 7+ year survivors of peritoneal mesothelioma as proof of the value of this multimodality approach.

The technique of using heated chemoperfusion to attack the residual mesothelioma tumor in the abdominal space was pioneered by the peritoneal surgeons and then was applied to the pleural mesothelioma environment where the strategy is also meeting with success and extended survival times.

Treatment For Mesothelioma

Introduction To Treatment Options:

There are no treatments for mesothelioma that have repeatedly provided a complete response. Any discussion of treatments, therefore, must include a wide variety of approaches, all of which continue to be considered primarily palliative. We will also deal with the post-treatment issues of recovery and coping with after-effects. Also given consideration will be concerns about recurrence and long term prognoses.

Primary Treatments:

As of early 2006, the state-of-the-art treatment for mesothelioma always includes some form of surgery. Either complete resection (if possible) or surgical debulking is a necessity for adjuvant treatments to be maximally effective. Surgery by itself, is not considered optimal and the practice of combining surgery with either chemotherapy, radiation, or both has gained acceptance as the preferred approach. This combination of methods is called multimodality treatment and has shown the most progress of any approach

Even chemotherapy by itself is now rarely administered as a single agent. Chemo protocols usually involve two or more complementary agents, often with widely different targets for each therapy. Assessments of various clinical trials and experience with treatment outcomes that rarely include stable disease have demonstrated that single protocol treatments are much less effective. Single agent protocols are therefore rapidly falling into disfavor.

Multimodality treatments that combine several complementary approaches, i.e. surgery together with either radiation or a combination of chemotherapy agents, are complicated treatments and should only be pursued at a mesothelioma center of excellence. Surgeries like extrapleural pneumonectomy can involve significant risks of mortality and morbidity if performed by a surgical and post-surgical nursing team with limited experience. Experienced medical teams can help to prevent or circumvent these issues.

Whether pleural or peritoneal, surgery offers the greatest chance for success but may include serious, even life-threatening side-effects. Such side effects, depending upon whether the surgery is abdominal or thoracic may include hemorrhage, lung infection, empyema, bronchoplenral fistula, heart arrhythmia, chest pain, abdominal pain, digestive problems, constipation, hemoptysis, nerve damage, pulmonary embolism, pneumothorax, or pneumonitis. The surgery itself may introduce malignant seeding at the site of the incisions. Certain chemotherapies may introduce another, entirely different set of morbidity issues such as neuropathy, loss of appetite, tinitus, hair loss, weight loss, nausea and low blood counts of white and red blood cells.

Despite the risks, treatments available today have made significant progress against the disease and with skillful intervention by experienced mesothelioma specialists the benefits of treatment far outweigh the alternatives. This is true, both in terms of improved quality of life, and in median survival times, which keep growing in leaps and bounds.

The choice of a treatment path is very much dependent upon the type of mesothelioma the staging of the disease and the health of the individual. As an example, a comparison of statistics for the various common treatment options for pleural mesothelioma is shown in the table below:

Table A: Treatments and Outcomes For Pleural Meso: Legend: 1=lowest, 5=highest, na=not available. NOTE: Lower can mean both best and worst. Example: Staging of 1 is best, Quality of Life (QOL) of 1 is worst. Table courtesy Meso Foundation 9/11 Asbestos Risk Assessment.


(a) (b) Author’s view based on 130+ patient interviews. (c) Since surgery is not always possible or desirable, patients tend to be segregated into surgical and other treatment groups by stage. Lower stage patients are more likely to be offered surgery. The options on the left represent treatment choices patients may be offered by their primary physician. Not all patients are able or willing to seek treatment at a mesothelioma center of excellence.

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.

Diagnosis

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. Once mesothelioma is suspected, a definitive diagnosis requires a tissue biopsy, a complicated, somewhat risky and expensive process.

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 is first detected and invasive investigations first begin.

Other external examinations offer greater resolution and accuracy than X-Rays. The primary vehicle for external radiological examination is the Computed Tomography scan or CT examination. 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 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 aren't usually 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.

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 diagnosing 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. Despite the progress, such 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.

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. The sample would have to contain discarded tumor cells, something that would take luck to find. A diagnosis of mesothelioma can only be made from pleural fluid in about 33% of cases, so a definitive diagnosis is difficult without invasive surgery and a tissue biopsy.

Needle biopsies are also poor indicators since the mesothelioma tumor can be quite diffuse and thin. Hitting a tumor nodule with the biopsy needle from outside of the chest requires luck as well as skill. The principle means of obtaining a pathology specimen is through surgery and in most cases this involves 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 (scraping of the tumor) procedure and the injection of abrasive material, like talc, for example. The purpose of this is to irritate the site and stimulate the formation of scar tissue which will enclose the tumor and prevent further weeping of fluid into the body cavity. If the fluid accumulation isn’t stopped, it leads to secondary problems such as compression of the lung, 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.

After the thoracotomy, the surgeon will temporarily install 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. This tube may also be used longer term in patients who are receiving chemotherapy and require long term management of the effusion as an alternative to repeated thoracentesis procedures.

In late 2004, a serum test for mesothelioma was released by Fujirebio Diagnostics in Australia and Europe called Mesomark™. This blood test checks for elevated levels of a blood serum marker called Serum Mesothelin Related Protein (SMRP) and with further validation and refinement, this test may prove to be a viable alternative method for identifying the presence of mesothelioma. 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.) Mesomark is not yet available in the United States or Canada.

In the spring of 2005, a research article in the New England Journal of Medicine touted the discovery of another possible mesothelioma serum marker called Osteopontin. Researcher Dr. Harvey Pass felt that the two markers might be complementary to each other and assist with the future diagnosis of mesothelioma. Serum tests will be valuable for allowing non-intrusive tracking of residual tumor or monitoring for recurrence in patients who have been treated for the disease.

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.

Of the three subtypes, epithelial, mixed type, or sarcomatous, the latter two have by far the worst prognosis for survival. Patient groups of sarcomatous subtype, or those with lymph node involvement, tend to have no long term survivors. Two year survival rates for these groups are 0% and median survival time is only 5.5 months. 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.

Mesothelioma patients of all subtypes rarely survive long enough for medical science to establish conclusively whether or not mesothelioma actively metastasizes or not. As median survival times lengthen, we may find that mesothelioma is no different from other cancers in this respect.

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, with peritoneal being on the decline and pleural on the upswing. Men are five times more likely than women to get pleural mesothelioma and both sexes are equally represented with peritoneal.

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.

Symptoms of Mesothelioma

The symptoms of mesothelioma are cruel and painful. 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. The mesothelioma sufferer cannot sleep comfortably, loses appetite, and endures excruciating pain as the fluid and the expanding tumor slowly fills up the chest, crushing the lung. Relieving the fluid pressure is only 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%

Who Gets Mesothelioma/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.

Rare malignancies associated with mesothelioma.

In addition to the above, rare kinds of mesothelioma have been identified such as: small cell mesothelioma and lymphohistiocytoid mesothelioma. (c) Due to their rarity, testicular and pericardial mesothelioma could also be classified in this category. As well, in the peritoneal category, there are mesos such as: benign/low grade proliferations, well differentiated papillary tumors, and peritoneal inclusion cysts. (n)

The human genital tracts have also been found to contain adenomatoid tumors, which were originally thought to be endothelial. Recent research has reclassified these as a benign form of mesothelioma. From time to time, such incidental tumors have been discovered in the pleural cavities during lung resections for other reasons. There source and clinical development of these tumors remains unknown.

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:

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.

While the rarest of the mesos, testicular mesothelioma is the second most common type of testicular cancer after soft tissue tumors.

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 are often associated with intracranial metastases – brain tumors.

Simian Virus SV40

One new and 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 human mesothelioma tissue samples.

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.

It is also interesting that the presence of SV40 in pathology samples is statistically indicative of a poor outcome, suggesting that asbestos and SV40 may interact in the spread and aggressiveness of mesothelioma tumors. More research is necessary before we can claim to have a causal link between SV40 and human 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.

However, studies of this area would seem to imply that damage to a cell isn’t automatically a cause for cancer and that other factors come into play.

Molecular Details Mesothelioma

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.

Recent research has uncovered a protein, called p53, (ad) which identifies chemical messages caused by genetic damage to the cellular DNA. P53 is produced by a gene that oversees tumor suppression. Once activated, p53 then stimulates the production of proteins that stop the DNA replication process. Without this valuable intervention, damage in the genetic machinery of the cell can accumulate unchecked. A direct consequence of failure to produce p53 is that damaged cells progress into a cancerous state. Today, defects in the functioning of p53 are associated with a variety of cancers, including some breast and colon cancers. A more detailed explanation of gene activation and suppression is provided below.

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 haves 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.

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 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.

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.

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.

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.

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. (k) 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. Although smoking while exposed to asbestos is known to significantly increase lung cancer risks, smoking does not appear to be implicated in the formation of mesothelioma.

Genetic susceptibility may also contribute to the cause of malignant mesothelioma. Two population of two 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.)

In an initial study, 50% of the men in one village contracted malignant mesothelioma while the other village had only one case. This was a woman who was originally from the first village. Further research into the residents of these two communities has confirmed an inheritable genetic predisposition to malignant mesothelioma in the presence of asbestos-like fibers.

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. The mechanism for genetic suppression of tumor development is discussed below.

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.

In its early stages mesothelioma has few symptoms, but given sufficient time it will grow thicker. Eventually it forms bumps and nodules which coalesce into a crust that compresses the organs of the space within which it grows. Over time, pleural mesothelioma may penetrate through the pleura into the chest wall or through the diaphragm into the abdomen. In Peritoneal mesothelioma it may attach itself onto the omentum or penetrate the abdominal wall. In either case it may begin to invade organs like the lungs, heart, stomach, and liver as it spreads. It may even attach itself to key blood vessels, the esophagus or bowels, making it hard or even impossible to remove surgically.

Figure E: Right Pleural Epithelial Mesothelioma on chest wall and lung. Click here. for enlargement. 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 belly, depending upon whether it is pleural or peritoneal. It may begin to weep fluid into the intracavitary space. For pleural patients 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. In peritoneal patients it is called ascites and it fills the abdomen with fluid that surrounds the visceral organs.

Figure F: Epithelial mesothelioma on the diaphragm. Click here. for enlargement. Photo courtesy K. Brauch.

The symptoms gradually become more noticeable until the patient seeks medical help. By this time the progression of the disease may already be too advanced since 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.