I recommend also the Oncolink NCI mesothelioma page available on http://oncolink.org/pdq_html/1/engl/101071-3.html

Epidemiology

Mesothelioma is a malignant tumour of the pleural surface, usually beginning on the parietal surface but eventually covering the visceral pleura, trapping the lung. It was not thought that mesothelial surfaces developed malignant tumours till a description in 1947 of a tumour of the pleura comprising mesothelial cells. It soon became apparent that cases of pleural mesothelioma tended to cluster around certain industrial sites, particlarly those where asbestos was frequently used (occupations). The use of asbestos was banned gradually from the mid 1960’s. As there is a lag time of approximately 30-40 years from the time of first exposure till the diagnosis of mesothelioma the incidence can expect to rise for a further 15 years in Westrern Europe, peaking in 2015. Thereafter there should be a gradual decrease in the incidence till only sporadic cases occur.

Ninety per cent of cases are males with the mean age at diagnosis being 64 years. The mean lag time from first asbestos contact to diagnosis is 40 years though it is shorter for insulation workers suggesting a dose-response relationship. However, in contrast to asbestosis and the risk for bronchogenic carcinoma the mesothelioma risk is somewhat idiosyncratic with minor exposure of a few weeks being enough to induce malignant change.

Aetiology:

Long fibre asbestos has been identified as the cause of most cases of mesothelioma. The fibre length is critical to their ability to enter the respiratory tract setting up a florrid reaction in the larynx, trachea, bronchi which can ultimately lead to squamous metaplasia and bronchogenic cancer, particularly in association with tobacco smoke. Passing into the lung parenchyma they cause fibrosis referred to as asbestosis. This fibrosis is pre-malignant for bronchogenic carcinoma. Those fibres long and thin enough pass onto the parietal pleural surface. There they accumulate in anthracotic “black spots” where they are phagocytosed by macrophages which develop a characteristic inflammatory reaction, eventually forming calcified pleural plaques. It is not yet certain whether mesothelioma arise in these plaques or whether they arise in non-plaque mesothelium.

There are different forms of asbestos (types) each causing different pathologies. It is thought that the amphibole fibres cause mesothelioma. However, different types of fibres frequently occur together making it difficult to specifically assign causation to individual fibre types. It would be prudent therefore to treat chrysotile with the same caution as the amphibole forms. Other organic fibres have also been implicated as causes for mesothelioma. Fibrous zeolite (erionite) is a common cause in rural Turkey and Greece.

Evidence of asbestos exposure is found in 80% of mesothelioma cases. However, the history may be difficult to elicit. Unlike asbestosis and lung cancer which are related to the dose of asbestos and length of exposure, MPM can be more idiosyncratic with brief exposure up to 40 years before the diagnosis is made.

The genetic changes include aneuploidy and specific chromosomal changes including deletions, inversions or translocations most commonly found on chromosomes 1, 3 and 9. P53 abnormalities seem to play only a minor role in MPM. The C-sis gene which codes for PDGF, implicated in proliferative mesenchymal disease, is sited on chromosome 22, abnormalities of  which are frequently seen in MPM. Also implicated are the growth promoters IGF-1, TGF-b and EGF, and the cytokines IL-6 and GMCSF.

There have been recent reports of an association of a virus normally found in Himalayan rhesus monkies with pleual mesothelioma (simian Virus 40 - SV40).  In the 1950’s polio vaccine was  produced on the kidneys of rhesus monkeys. A number of batches of vaccine were contaminated with the virus. It is thought that up to 60% of Americans have antibodies to this virus. SV40-like DNA (T antigen expression) has been found in up to 60% of mesothelioma series. When implanted into the pleura of hamsters SV40 induces mesothelioma in virtually all cases. The role of SV40 in the causation of human mesothelioma remains unconfirmed. It is possible that it is a co-carcinogen triggering separate genetic changes to those induced by asbestos allowing progression of mesothelioma.

PREVENTION

Control of exposure to amphibole asbestos will prevent most cases of mesothelioma. Legislation in most countries has reduced the incidence of new exposure. The incidence of new cases of mesothelioma however will continue till at least 2015 as amphibole asbestos was still widely used in many European countries till 1975.

Screening for mesothelioma is impractical as early disease is often not apparent on chest x-ray. Even when early disease is detected there is no treatment proven to change the course of the disease.

PATHOLOGY

Mesothelioma generally arises in the parietal pleura spreading diffusely along the pleura before invading chest wall or diaphragmatic muscle, fissural pleura and lung. Mediastinal node metastasis is late. The tumour gradually “strangles” the lung and eventually encases it. Transdiaphragmatic spread can lead to peritoneal involvement. Contralateral pleura and pericardial encasement are common in advanced cases. Mesothelioma has a propensity to spread along needle tracks, chest drain incisions, thoracoscopic port sites and operative incisions. 

Macroscopically the tumour consists of thickened pleura with nodularity. On microscopy sheets of spindle shaped cells admixed with a fibrotic stroma is the main feature. At times the fibrotic reaction is such that malignant cells are difficult to visualise. Small percutaneous or thoracoscopic biopsies may not be adequate for diagnosis and frozen section is notoriously unreliable. 

Three types of mesothelioma are commonly described: sarcomatous, epithelial and mixed.  Sarcomatous mesothelioma, the less common, is more obviously malignant with a poor prognosis. It can occur as a discrete, but invasive chest wall mass. Microscopically it can be difficult to differentiate from secondary sarcoma elsewhere in the body. The epithelial type resembles adenocarcinoma with complex acinar spaces lined by mesothelial cells, with frond-like papillary projections. Electron microscopy and immunohistochemistry can aid differentiation of mesothelioma from other tumours and pleural conditions.

The important differential diagnoses are, benign pleural fibrosis in which inflammatory cells may give the impression of malignancy, benign pleural mesothelioma and non mesotheliomatous malignancy. Adenocarcinoma metastatic from lung, breast, ovary or gastro-intestinal tract, many of which are responsive to chemotherapy or hormonal therapy, can be difficult to differentiate.

Electron Microscopy

EM ultrastructural evaluation shows multiple long, thin, sinuous microvilli covering the cell surface. In contrast to adenocarcinoma cells, these are not covered by glycocalyx.

Immunohistochemistry

Immuno-histochemical staining has added substantially to the ability to differentiate epithelial MPM from adenocarcinoma and sarcomatous MPM from other sarcomas. All tests must be interpreted with caution in light of the clinical history and the light microscopy findings. The search continues, however, for a gold standard diagnostic instrument for this disease. The majority of epithelial mesotheliomas are CEA, LeuM1, B72.3 and BerEP4 negative. Sarcomatous MPM are usually strongly positive for vimentin and keratin. 

PRESENTATION

The onset of mesothelioma is insidious.  A “herald” effusion may predate the diagnosis by up to five years. [Non mesotheliomatous effusions which do not proceed to mesothelioma also occur in conjunction with benign asbestos related conditions such asbestosis, pleural plaque and asbestos pseudo tumour].

Breathlessness is common due to pleural effusion or entrapment of the lung by tumour. It is important to differentiate from parapneumonic effusion or infected empyema. Pain at this stage is pleuritic making such differentiation difficult. Pulmonary embolism is often suspected. More persistent neuralgia type pain is usually a sign of chest wall invasion and in an asbestos worker is almost pathognomonic of mesothelioma.

Vague symptoms of lethargy, malaise and weight loss are common. Pyrexia and night sweats may be due to infection in an atelectatic lung, secondary empyema after pleural instrumentation, or due to a direct effect of the tumour itself.

EXAMINATION

Decreased chest wall movement is a feature as the thickened pleural crowds the ribs. Dullness to percussion may be due to the thick pleura or the associated effusion. Breath sounds would be decreased on the affected side. Differentiation from a simple effusion may be difficult. The development of tumour nodules at the biopsy or surgical sites is strongly suggestive of mesothelioma. 

DIAGNOSIS

A strong index of suspicion in those who have been exposed to asbestos will expedite the diagnosis. Chest x-ray may show non specific volume loss in the affected hemithorax with pleural effusion and pleural thickening. CT scan, however, will often give more distinct clues, such as nodularity of the pleura and mediastinal pleural thickening which is uncommon in benign pleural conditions. Associated calcified pleural plaques will confirm the asbestos exposure. Pleural fluid may show overt signs of malignancy with blood straining. High viscosity, low pH (,7.0), low glucose (<40 mg/dL), low WBC (<5000 cells/uL) and raised LDH (>1000 IU/dL) are all suggestive of pleural malignancy. The presence of abnormal mesothelial cells is not diagnostic as such cells are shed in many pathological pleural processes.

Cytology may show malignant mesothelioma cells but frequently reactive mesothelial cells are reported. Percutaneous biopsy using an Abrams needle is frequently successful but false, negative biopsies are common. Thoracoscopy not only allows directed biopsies but also enables drainage of fluid, break down of adhesions and loculations and chemical pleurodesis with talc or other agents. Unfortunately even a negative thoracoscopy does not rule out the diagnosis.

STAGING

Relevance of a staging system is questionable in a disease that has a long gestation period, is characterised by long periods of non progressive disease, but is also invariably fatal. Therapeutic interventions are usually decided on the patients performance status more than the pathology disease stage. Staging does however given useful information as to expected median survival. There is currently no accepted staging system for malignant pleural mesothelioma, with at least six attempts in the last twenty years. The International Mesothelioma Interest Group has suggested a staging system in the based on a TNM classification [International Mesothelioma Interest Group (IMIG): A proposed new international TNM staging system for malignant pleural mesothelioma. Chest 108(4): 1122-1128, 1995]. This system has yet to be tested clinically. It is heavily surgically orientated with lung parenchymal invasion and chest wall invasion usually only being apparent after surgical resection. Mediastinoscopy rarely changes the therapeutic approach but there is a case to be made for it before any attempt at surgical resection.

CT scan will show the extent of local intrathoracic and mediastinal disease as well as showing the extent of any peritoneal disease. MRI has as yet not shown much advantage over CT, except that chest wall invasion may be more accurately diagnosed. 

TREATMENT

As yet no therapeutic intervention has been shown to change survival in malignant pleural mesothelioma. Therefore, all patients should be considered for clinical trials.

Surgery

The effectiveness of radical surgical (extra-pleural pneumonectomy or pleuro-pneumonectomy) intervention is questionable. Mortality approaches 20% and there are only a small number of long-term survivors reported. These data must be compared to a series of lesser interventions and less supportive care, many of which have anecdotal evidence of survivors greater than 5 years. 

Less radical, but nevertheless extensive surgery, considering the aim is palliation, consists of parietal pleurectomy and decortication of the lung. Good symptomatic relief can be obtained with a mortality of less than 5%.

For those not fit for major surgery a thoracoscopic biopsy and talc pleurodesis is effective in preventing recurrent of effusion. However, failure of the lung to re-expand can lead to an infected, discharging empyema cavity. This is probably more prominent when the effusion has been drained by tube thoracostomy and a talc instilled as a slurry through the chest drain. Some authorities advocate insertion of a pleuro-peritoneal shunt, a procedure possible under local anaesthetic, when it can be predicted that the lung is unlikely to expand and pleurodesis is thus not possible.

Radiotherapy

Mesothelial cells are at least radio sensitive as non small cell lung cancer. However, because of the large volumes which need to be treated, namely all pleural surfaces, diaphragm, mediastinum with a boost to surgical incision sites, it is not possible to deliver tumoricidal doses. More recent techniques involving three dimensional, conformational planning may allow better radiation delivery in malignant mesothelioma, especially in conjunction with tumour reduction surgery or induction chemotherapy.

An established role for radiotherapy is in the prophylactic treatment of needle aspiration, chest drain, thoracoscopic and thoracotomy incisions to prevent the well recognised propensity for mesothelioma to crack through some sites causing painful subcutaneous masses. 

Chemotherapy

Mesothelioma has recently been regarded as a chemo-resistant tumour. However recent studies have shown that up to 20% of these tumours are sensitive to Platinum based chemotherapy. Like non small cell lung cancer the response rates are better when used in conjunction with other drugs. Both MVP and MIC have been used with some success. Newer drugs such as the Thymidine Synthetase inhibitors such as MTA have shown improved efficacy in early trials.

As the incidences of malignant mesothelioma is continuing to rise and will not plateau till early in the new Millennium there is increased interest in developing effective multi-disciplinary approaches to this disease. Hopefully a co-ordinated approach of cyto-reductive surgery, conformal radiotherapy and chemotherapy will lead to an improvement in the long term survival of patients with this devastating disease. Eventually it is hoped that a cure may be obtained for this disease.

Some non-conventional treatments which have been tried for this tumour include photo-dynamic therapy and gene therapy using adenovirus vectors.

Prognosis

The natural history of mesothelioma varies greatly from patient to patient. Mean survival is 18 months from first symptoms and 12 months from diagnosis regardless of therapy. However all series, be they radical surgery or best supportive care, report five year survivors. Such variability in the natural course of the disease makes conclusions difficult when assessing therapeutic options.

(Driscoll et al Clinical aspects of malignant mesothelioma in Australia: Aust N Z J Med (1993 Feb) 23(1):19-25)