Schistosomal carcinogenesis may therefore be summarized as follows (Fig. 1):

1. The presence of S. haematobium eggs in the mucosal layers of the bladder results in metaplasia as well as reparative hyperplasia of the epithelium, leading to an increased cell turnover that may escape growth control mechanisms. It may also enhance already existing minute foci of intra-epithelial neoplasia.

2. As bacterial infection, notably mixed, forms part of the pathology of schistosomal bladders, the effect of naturally occurring carcinogens may be enhanced by accelerated nitrosation of precursor substrates through nitrate reductase activity.

3. Hydrolytic enzymes such as P-glucuronidase, originating from many sources, split nontoxic glucuronide conjugates into active carcinogenic moities.

4. Altered metabolism of vitamins, and/or deficiencies may enhance carcinogenesis especially through the action of kynurenine metabolites, in themselves carcinogenic. The protective role of certain vitamins such as A and B6 will be absent, either through diet deficiencies or liver and intestinal disease.

5. Differences in diet with a resultant different intake of a variety of naturally occurring carcinogens (although still illusive) may explain focal differences of tumor incidence in endemic schistosomiasis areas.

6. Changes in the stroma underlying and surrounding mucosal lesions may well promote the development of infiltrative lesions; alternatively, interactions between stroma and epithelium may be impaired. Stromal proliferation caused by excess of proline in the vicinity of viable schistosome eggs may possibly have a counterpart in epithelial proliferation.

7. Aberrations of chromosome 9 and 17 have been implicated in the development and progression of transitional cell carcinoma of the urinary bladder. Similar aberrations may occur in chronically inflamed and metaplastic mucosa with bilharzial cystitis and in carcinoma in situ. Bilharzial-associated bladder cancer in Egypt and sporadic cases of bladder cancer in the United States may develop through the same genetic mechanisms.

8. The molecular changes involving H-ras and p53 occurring in schistosomiasis related squamous cell carcinoma are different from those recorded in transitional cell carcinoma in the Western countries. Multiple mutations found at thep53 locus in schistoso-miasis related bladder tumors is consistent with the involvement of a specific etiologic agent, possibly nitrosamine(s), responsible for the neoplastic progression in bilharzial bladder cancer.

Bilharzial Cystitis Pathogenesis
Fig. 1. Proposed pathogenetic pathway of neoplastic progression for squamous cell carcino-genesis associated with schistosomiasis.

9. Molecular changes occurring in the H-ras and p53 genes in squamous cell carcinomas of the bladder associated with schistosomiasis are different from those not infected with the parasite. The H-ras gene is unaltered in the absence of bilharzial infection and may therefore not be directly involved in the tumorogenesis of squamous cell carcinoma of the bladder. Multiple mutations and transitional base changes are a common occurrence in squamous cell carcinoma of the bladder, particularly in the South African population. However, the interaction of the carcinogenic agents in the presence of the parasite produces mutations in the p53 tumor suppressor gene that are different in profile from those seen in the absence of schistosomiasis infection.

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