Mesothelioma-

        Aetiology and Pathogenesis

                         Dr Sampurna Roy MD

The term Mesothelioma refers to a malignant tumour arising from the mesothelium of the serous cavities of the body.

Link between mesothelioma and asbestos was first reported in 1960 by Wagner et al. who demonstrated a high incidence of the tumour among asbestos workers in Cape Province of South Africa. (Diffuse pleural mesotheliomas and asbestos exposure in the north western Cape Province. Br J Ind Med 1960; 17:260-271 ; The discovery of the association between blue asbestos and mesotheliomas and the aftermath. Br J Ind Med 1991; 48:399-403.)

Since then several publications have reported mesothelioma in various occupational  groups( Eg-  Shipyard workers ; insulation workers ; asbestos cement workers & gas mask manufacturers ).

The main sources of environmental, non-occupational exposure to asbestos or asbestiform fibres are: a) industrial plants in which asbestos was used in the production process; b) asbestos "in place" (mainly in buildings); c) contaminated soils.

Site: The pleura is most frequently involved, then the peritoneum, the pericardial sac and the lining of a hydrocele sac (the tunica vaginalis of the testes) in order of decreasing frequency. 

Age and Sex:  Mesothelioma is a tumour of adult life that mainly affects persons older than 50 and occurs more commonly in men than in women.

Clinical features : General malaise ; weight loss ; pain chest ; shortness of breath ; a haemorrhagic effusion ; usually unilateral ; on enquiry, a history of asbestos exposure.

Aetiology and pathogenesis: i) Asbestos induced mesothelioma ;  ii) Non asbestos associated mesothelioma.

 Asbestos induced mesothelioma:

Asbestos fibres- Physical properties:

Asbestos includes heterogeneous group of hydrated fibrous silicates.

The two main varieties are Serpentine and Amphibole.

Serpentine:  Crysotile or white asbestos belongs to Serpentine family.

Amphibole:  Crocidolite or blue asbestosis ; amosite ; anthropylite; tremolite ; actinolite. 

All forms are fire resistant and insulating. 

Asbestos is used in the following products: Paints ; plastics ; textile; brakes; clutch lining ; pipes ; sheet; vinyl-asbestos tiles.

Asbestos fibres:

Serpentine (crysotile) fibres: Curved large fibres which tend to be deposited in the upper airways.

Amphibole (crocidolite ) fibres:  Smaller straight fibres which penetrate into the lower respiratory tract. The fibres are up to 30 micron in length and 0.5 micron in diameter.

Ferruginous bodies: Coated fibres with protein and iron precipated on the surface. They appear golden brown, drumstick shaped, up to 30 micron in length and 6 micron in diameter.

Asbestos bodies (curious bodies) were first reported in 1924 in African asbestos miners.  

Asbestos related mesotheliomas usually have long latency periods (time calculated from first exposure to asbestos, to death from the disease).

Studies have indicated that mesothelioma risk increases with dose and exposure to amphibole asbestos fibres.

Fibre dimension may be related to the risk of mesothelioma formation. Chrysotile and amphibole fibres have been identified in the visceral and parietal pleura.

Greater the biopersistence of the asbestos fibre, greater the time it has to cause damaging changes in the body.  Amphibole may persist for many years after exposure and play an important role in causing mesothelioma.

Active oxygen free- radicals are considered to play an important role in both asbestos-induced lung disease and formation of mesothelioma. Crocidolite has greater surface area and higher ferrous iron content compared to Chrysotile . It is biologically more active in the generation of oxygen free radicals.

 

Factors related to asbestos fibres that may determine the risk of mesothelioma : 1. Fibre type;   2. Time of exposure;  3. Cumulative exposure;  4. Fibre dimension;   5. Fibre  biopersistence;   6. Fibre surface properties.

Pathogenesis of asbestos related mesothelioma:

Asbestos appears to act as a complete carcinogen. 

Oxygen free-radicals are regarded as important mediators in asbestos induced neoplasia and may cause genotoxic or cytotoxic change within the mesothelial cells.

These radicals are generated by direct or indirect mechanism.

Direct mechanism:  Involves iron-catalyzed reaction on the surface of the fibre.

Indirect mechanism:  There is physical interaction with phagocytic cells. Oxygen-free radicals are released by macrophages and neutrophils. Active oxygen radicals may interact with chromosomal material causing mutational change.

Some authors have suggested that autocrine growth factors (platelet growth factor, epidermal growth factor and insulin like growth factors) may act as a stimulus for mesothelial cells.

CD44H is considered to play a role in tumour cell invasion and metastasis.

Non-asbestos associated mesothelioma:

Causes:

1.Non-asbestiform fibres - Eronite ;Organic fibres- mesothelioma has been recorded in sugar cane workers.

2. Radiation - It has been suggested that combined exposure to atomic radiation and asbestos is associated with an increased incidence of malignant mesothelioma. 

3.Viruses - Association of simian virus 40 (SV40) with malignant mesothelioma has been reported, suggesting that SV40 plays an important role in the origin of a subset of these tumors.

4. Chronic inflammation-

5. Heavy metals -nickel and beryllium ;

6. Chemical agents - Diethylstilboestrol.

            

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