1

What is mesothelioma?

Malignant mesothelioma is a rare and very aggressive tumour of mesothelial cells.

It can occur in any body cavity covered by mesothelial cells, including the pleura, peritoneum and pericardium, with malignant pleural mesothelioma (MPM) being the most common (87%) (Figure 1).

2

What is the pathogenesis for mesothelioma?

Mesothelioma appears when several factors act alone or in synergy to cause malignancy, including:

a)

asbestos exposure;

b)

exposure of other fibrous minerals, including erionite;

c)

viruses – including simian virus 40 (SV 40);

d)

ionizing radiation;

e)

genetic factors.

The mechanism of degeneration from asbestosis to MPM is very complex and still unclear.

Although all types of asbestos can result in MPM, amphibole fibres, including crocidolite (blue asbestos) and amosite (brown asbestos), are the most potent causes. The role of the most commonly used form of asbestos, chrysotile (white asbestos), is debated.

Although approximately 80% of patients in the Western World with MPM have been exposed to asbestos, only a fraction of individuals exposed to asbestos develop mesothelioma.

Occupational exposure was more common in those working in the shipbuilding, railway or asbestos manufacturing industries. Para-occupational exposure, such as by women laundering the clothes of those working with asbestos, has also been shown to be associated with the development of MPM.

Asbestos fibres are insoluble and, when inhaled, induce physical damage, including scratches and chronic inflammation leading to the development of fibrosis and calcified plaques.

Because asbestos fibres neither appear to be metabolised nor directly interact with DNA, they do not seem to act like most chemical carcinogens.

Simian virus 40 (SV 40), a DNA tumour virus that preferentially causes mesothelioma in hamsters, has been detected in several human mesotheliomas. SV 40 infection stimulates the production of growth factors implicated in the autocrine growth of mesothelioma cells and inactivates RASSF1, a gene silenced in MPM.

Asbestos appears to increase SV 40-mediated transformation of human mesothelial cells in vitro, suggesting that asbestos and SV 40 may be co-carcinogens (Figure 2).

Recent studies revealed the existence of a genetic factor in the villages of Karain and Tuzkoy, Turkey, where 50% of deaths are caused by mesothelioma. Erionite, a type of fibrous mineral similar to asbestos, is found naturally in the area.

3

Describe the pathological classification of mesothelioma

Several major histologic types and more than a dozen subtypes of MPM exist, including:

a)

epithelioid (50-70%) – which is the commonest type and has the best survival;

b)

sarcomatoid (7-20%) – which has the worse prognosis;

c)

mixed/biphasic (20-35%);

d)

desmoplastic;

e)

fibrotic;

f)

others, such as malignant fibrous histiocytoma-like, chondroid, osteoblastic and liposarcomatous forms.

4

What is the epidemiology of mesothelioma?

The incidence of mesothelioma in the USA and UK has been rising since 1980, with 2000-3000 new cases diagnosed each year, usually among patients in the 5th-7th decade of life (14 new cases per 1,000,000 for men and three new cases per 1,000,000 for women).

The disease pattern is expected to peak in 2020 as a result of increased awareness and government regulation of asbestos exposure by the 1970s, coupled with the inherent latency period of 30 to 40 years.

Conversely, not all patients with MPM necessarily have a known history of asbestos exposure.

5

What is the pathophysiology of mesothelioma (Figure 3)?

MPM usually begins as discrete parietal pleural plaques that eventually coalesce. The lesions usually develop in the lower part of the chest and may invade the diaphragm, visceral pleura and interlobar fissures.

The tumour may also grow along the chest drain, video-assisted thoracoscopic surgery (VATS) port and thoracotomy tracts.

As the disease progresses, it often extends into the lung parenchyma, chest wall and mediastinum. Subsequent extension may also involve the oesophagus, vertebra, brachial plexus, ribs and superior vena cava.

6

Describe the clinical presentation of a patient with mesothelioma

The clinical latency period between asbestos exposure and the development of mesothelioma is 30-40 years.

Detection of MPM is difficult and often occurs at a late stage, which in part accounts for the poor prognosis of these patients.

Some patients are asymptomatic and present with incidental findings of a pleural effusion or pleural thickening on chest radiograph.

Dyspnoea (associated with a pleural effusion) and non-pleuritic chest pain are the commonest initial presenting symptoms.

Hypercalcaemia, fever and sweating are also very common findings at this stage.

The next stage can bring significant weight loss and severe deterioration of the patient’s general performance status.

The patient’s symptoms may be disproportionately high compared to the radiological findings and treatment with oxygen may not provide much benefit due to pulmonary shunting.

The tumour tends to spread to the chest wall or may invade the mediastinal structures, including the aorta and oesophagus, causing symptoms related to pressure on these structures.

Approximately 33% of patients experience small bowel obstruction due to direct involvement after penetration of the diaphragm.

Patients generally die of respiratory failure or pneumonia, with approximately 10% of patients dying of pericardial or myocardial involvement with mesothelioma.

Physical examination may be normal for a long time but the presence of a pleural effusion (stony dull percussion note and reduced breath sounds) in a patient with a history of exposure to asbestos is highly suggestive of mesothelioma.

Chest wall tenderness may also be present, which is suggestive of chest wall involvement.

7

What are the chest radiological findings in a patient with mesothelioma (Figure 4)?

The most common findings are:

a)

unilateral, concentric, pleural thickening;

b)

calcified pleural plaques, which are usually related to lung asbestosis.

As the disease progresses, the lung fissures become thickened and irregular in contour, followed by encasing of the lung, compression of lung parenchyma, diaphragmatic elevation, intercostal space narrowing and ipsilateral mediastinal shift.

Direct invasion of the lung, lymph nodes, pericardium and heart may also be present with parenchymal nodules and hilar masses.

In the most advanced stages, major tumour invasion can be detected by mechanical distortion of the hemithorax, chest wall masses, periosteal rib reaction, rib breakdown or direct extension of the tumour across the mediastinum into the contralateral hemithorax.

8

What are the computed tomography findings in a patient with mesothelioma (Figure 5)?

Computed tomography (CT) imaging is the mainstay of the radiographic diagnosis and is helpful in determining the diagnosis, extent of the disease and prognosis.

Benign pleural plaques or pleural thickening from asbestos exposure may mimic the appearance of nodular pleural thickening in patients with mesothelioma.

Signs of malignant pleural disease (mesothelioma or metastases) include:

a)

nodular pleural thickening ≥1cm;

b)

involvement of the mediastinal pleural surface;

c)

circumferential pleural thickening.

Further progression of the disease is evidenced by:

a)

extension along the pleural surfaces;

b)

invasion of the mediastinum structures;

c)

invasion of the chest wall, which manifests as obliteration of fat planes or chest wall nodules;

d)

invasion of the diaphragm, ascites and omental caking.

9

What are the magnetic resonance imaging and ultrasound scan findings in a patient with mesothelioma?

Magnetic resonance imaging (MRI) might be superior to CT scanning in demonstrating foci of chest wall invasion, endothoracic fascial involvement and diaphragmatic invasion. It is, however, rarely used in clinical practice.

Fibrous pleural plaques are usually isointense or less intense relative to muscle.

Inflammatory pleural disease may mimic the increased MRI signal intensity of mesothelioma.

Ultrasonography may demonstrate pleural thickening or the presence of pleural effusions. Although it is not typically used to assess the extent of disease, it can be used to guide biopsy procurement.

10

What is the role of positron emission tomography in a patient with mesothelioma?

Positron emission tomography (PET)-CT scanning is very effective in distinguishing MPM from non-malignant asbestosis, with a reported sensitivity of 88.2%, specificity of 92.9% and overall accuracy of 90.3%.

PET-CT scanning, however, cannot distinguish mesothelioma from adenocarcinoma. False-positive findings are also possible with benign inflammatory pleural processes.

Although not used routinely, PET-CT can evaluate the extent of lymph node involvement or distant metastases, and therefore prognosis.

11

What are the staging systems used for mesothelioma?

There is lack of consensus for a single mesothelioma staging system, with several different systems currently used, including:

a)

Butchart staging system;

b)

Union for International Cancer Control (UICC) TNM staging system;

c)

International Mesothelioma Interest Group (IMIG) staging system, which is based on the TNM status;

d)

Brigham and Women’s Hospital (BWH)/Dana-Farber Cancer Institute staging system.

12

What are the principles of the Butchart’s staging system (Table 1)?

The Butchart system was described in 1976 and was the first staging system to be introduced.

Although it is quite simple, the Butchart system fails to provide any prognostic information as any tumour higher than Stage I is considered unresectable.

13

What are the principles of the UICC staging system?

The UICC system was first described in 1990 and was based on the tumour-node-metastasis (TNM) classification system used for non-small cell lung cancer (NSCLC).

It, however, falls short in terms of correlating patient survival with prognosis.

14

What are the principles of the International Mesothelioma Interest Group (IMIG) staging system (Table 2)?

The IMIG staging system was first described in 1994 and attempted to account for the unique features of mesothelioma, whilst working within the accepted TNM stage indicators.

15

What are the principles of the Brigham and Women’s Hospital (BWH)/Dana Farber Cancer Institute staging system (Table 3)?

The BWH classification was introduced in 2010. It offers better prognostic value for patients treated with different modalities and its validity has been confirmed clinically.

This system stratifies patients according to survival and accounts for resectability, tumour histology and nodal status.

16

What are the principles of management in a patient with mesothelioma?

Discussion at a multidisciplinary team meeting.

Confirmation of diagnosis – pleural tap, US- or CT-guided biopsy, or surgical biopsy.

Staging – to determine the extent of tumour spread.

Assessment of fitness for treatment to subcategorise patients into those suitable for radical therapy or palliative therapy (symptom relief, including drainage of pleural effusion or pleurodesis).

17

What are the therapeutic options for a patient with mesothelioma (Table 4)?

The recommended treatment strategies are based on the same principles applied to other solid tumours and include chemotherapy, radiotherapy, surgery and combinations of these modalities.

Single therapies have failed to significantly affect patient survival, especially chemotherapy and radiation without surgery.

Management plans involving multimodality therapies have shown some improvement over single-modality treatments in non-randomised studies, including surgical resection by pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP), in combination with external-beam radiation to the hemithorax and systemic combined chemotherapy.

There are, however, no evidence-based consensus guidelines on the management of MPM.

As MPM has a unique growth pattern, it makes the application of conventional response criteria difficult.

18

What are the surgical options for a patient with mesothelioma?

Palliative procedures – with the goal of reducing disease burden and alleviate symptoms due to pleural or pericardial effusions, including:

a)

partial pleurectomy – which involves the partial removal of the parietal and/or visceral pleura for diagnostic or palliative purposes but leaving gross tumour behind (Figure 6);