Schistosomiasis and cancer of the bladder

Schistosoma haematobium was first incriminated for a potential role in induction of urinary BC in Egypt in 1911 by Fergusson³; an issue that was finally confirmed by the International Agency of Research on Cancer (IARC) in 1994; which reported the parasite as a carcinogen.⁴ Bilharzial bladder cancer (BBC) is theoretically a preventable malignancy if nationwide preventive strategies, including snail control and mass treatment campaigns, and screening projects could be adopted.⁵

Epidemiologic aspects

The highest incidence rates of BC are found in the countries of Europe, North America, and Northern Africa.⁶ Smoking and occupational exposure are the major risk factors in Western countries; however, the morbidity and mortality due to BC have declined over the past decade owing to changing the habits of cigarette smoking.⁷ Chronic infection with S. haematobium in developing countries, particularly Africa and the Middle East, accounts for about 50% of the total burden,⁸ with Egyptian males having the highest mortality rates (16.3/100,000).⁹ The association between S. haematobium infection and BC is far greater than that for any other parasitic infection,¹⁰ and it was classified as group 1 carcinogen.¹¹ Association between S. haematobium and BC was initially established through case-controlled studies and close correlation of the incidence of BC with the prevalence of parasite. Clinically, the evidence of association was based on the presence of parasite eggs and Schistosoma-induced histopathological changes in cases of BC.¹²

Urinary BC is morphologically heterogeneous. More than 90% of the cancers are of the transitional cell carcinoma type (TCC),¹³ as in case of BC associated with smoking and occupational hazards.¹⁴ In Africa, squamous cell carcinoma (SCC) of the bladder is greatly overrepresented among the fellaheen of Egypt and the Africans of Mozambique, Zimbabwe, and Zambia (formerly Rhodesia), where S. haematobium is endemic.^15–17 However, a shift toward TCC subtype was observed in developing countries owing to shift in risk factors with increased urbanization and industrialization.⁷ In Egypt, following the construction of the High Dam in the 1960s that led to changes in the water flow with direct impact on the intermediate snail host, S. haematobium was gradually replaced by Schistosma mansoni that causes intestinal rather than urinary disease.¹⁸ Furthermore, effective oral treatment campaigns in Egypt since 1977 resulted in significant decrease in urinary schistosomiasis.¹⁹ Strikingly, despite the large decline in S. haematobium infection in Egypt, BC continues to be the most common cancer among males. This is because the decline in BBC is being offset by increase in smoking-associated BC.²⁰ This is evidenced by the shift in the incidence of SCC in Egypt from 78% in the 1980s to 27% in 2005 with a shift to TCC.²¹ Another retrospective study was conducted in Egypt, from 2001 to 2010, on two groups: group 1 included 1002 patients from 2001 to 2005 and group 2 included 930 patients from 2006 to 2010. The authors found that the incidence of BBC decreased from 80% in group 1 to 50% in group 2. Besides, a significant increase in TCC from 20% to 66% was observed with a significant decrease in SCC from 73% to 25% by comparing the two groups.²² Hamed et al.²³ suggested another cause for the general decline in BBC in Egyptian governorates. Tendency toward warming, with high temperature exceeding 45°C, and increased number of hot days all over the year are incriminated in damaging the effectiveness of the snail host and hence schistosomal transmission.

The association of BC with schistosomal infection seems to become stronger with long standing and more severe infection.²⁴ In Egypt, this association is directly related to the extent of perennial irrigation through canals, which creates a constant risk of reinfection, and inversely related to control measures and availability of safe and effective therapy.²⁵ Children of school age are especially at risk because of their daily contact with infected water in rural areas.²⁶ Besides, it was noted that in endemic areas in Iraq, Coastal Kenya, Ghana, Malawi, Mozmbique, Zambia, and Zimbabwe, a high association between S. haematobium and BC is present, whereas it was absent in Nigeria and areas in Southern Africa and Saudi Arabia with moderate to high prevalence of S. haematobium.²⁷ Typically, schistosomiasis is a disease affecting agricultural communities, particularly those dependent upon irrigation to support their agriculture. The problem became much more significant in the nineteenth century, when the combination of new irrigation projects and population increases led to a higher probability of exposure to the parasite.²⁸

Geographical distribution of S. haematobium seems to play an important role in determining the susceptible groups as regards their age and gender. The peak incidence of BC in schistosomiasis-nonendemic areas is in the sixth and seventh decades of life.²⁹ In Egypt, Sudan, Iraq, Zambia, Malawi, and Zimbabwe, the mean age of the highest incidence of BC is between 40 and 49 years.¹⁰ The male : female ratio of BBC incidence in Schistosoma-endemic countries is in average 5 : 1,³⁰ and this could be explained by prolonged contact with infected waters during agricultural activities in rural areas, which are normally done by men rather than women.⁵ Recent observation showed that the relative frequency of BBC was increasing among females during the period 1995–2005 in Egypt. This was explained by increasing migration of male farmers from the Nile Valley and Delta to the Urban and Frontier governorates seeking for jobs. Therefore, the females were expected to take place of their husbands in agricultural work and thus their exposure risk to infection was increased.²³ Another study found that females were more affected by BBC (51.4%) compared to the males in the western part of Tanzania on the shores of Lake Victoria in the period 2000–2010.³¹

Variability in criteria for diagnosing urinary schistosomiasis influences the epidemiological rates for BBC. Ruling out a diagnosis of schistosomiasis because of the absence of ova in the centrifuged urine specimen would be unrealistic in many cases of contracted bladder owing to bilharzial fibrosis, in which the dense scar tissue precludes shedding of ova from the submucosa.²⁵ Thus, by expanding the criteria for diagnosis of bilharzial bladder to include recent imaging and molecular techniques with high sensitivity and specificity, the epidemiological rates for BBC are expected to be more accurate.

Progression of bilharzial bladder cancer

BC cells require the acquisition of certain properties before being able to grow rapidly, invade, and metastasize.⁵

Chronic infection leads to trapping of Schistosoma eggs in the bladder wall. Proliferation of cells in the bladder mucosa results from constant irritation and inflammation.¹² This mucosal damage increases the frequency of urinary tract infection.³² Besides, activated macrophages induced at the sites of inflammation are implicated in the generation of carcinogenic N-nitrosamines and reactive oxygen radicals.³³ Mucosal fibrosis and dysuria associating chronic inflammation and bacterial infection lead to urinary stasis that, in turn, allows prolonged contact of urothelium with these carcinogens.³⁴

Nitrate-reducing bacterial species accompanying urinary schistosmiasis can mediate the N-nitrosation of amines¹⁰ with the liberation of N-nitroso compounds.³⁵ At the molecular level, these compounds are implicated in tumorigenic alkylation of specific bases and DNA sequences,^36–38 leading to mutations in oncogenes, tumor suppressor genes, and genes for cell cycle control.⁵ Molecular events associating BBC include the activation of H-ras gene,³⁹ inactivation of p53,⁴⁰ and inactivation of retinoblastoma (Rb) gene.⁴¹ In 2010, Botelho et al.⁴² suggested that the parasite extract had carcinogenic ability through oncogenic mutation of the K-ras gene. The frequency of p53 mutations varies with the different grades of BBC.⁴³ For BBC in Egypt,⁴⁴ it was reported that about 86% had p53 mutations in exons 5, 6, 8, and 10 and that the in activation of p53 ranged from 0% to 38% at the early stage of the disease, as opposed to 33–86% in the advanced tumor stage.⁴³ On the other hand, habitual smoking in a group of Japanese BC patients did not increase the frequency of p53 mutations, but caused unusual AT : GC mutation patterns.⁴⁴ Mutations observed in p53 gene mostly involve transitions at CpG dinucleotides, which are in excess in cases of BBC. These transitions are explained by the effect of nitric oxide produced by the inflammatory response to Schistosoma eggs. Nitric oxide, released during the inflammatory response, can cause such mutations directly by deamination of 5-methylcytosine or indirectly via its capacity to form endogenous N-nitroso compounds leading to DNA alkylation.⁴⁵ Over representation of the protein encoded by the MDM2 gene found in the majority of the studied cases may account for the frequent inactivation of the p53 gene observed in BBC, and hence the accumulation of DNA damage and the aggressive clinical course.⁴⁶

Cancer development is closely related to uncontrolled cell cycles.⁴⁷ Deletions and mutations in the gene coding for p16^INK4, a cyclin-dependent kinase (CDK) inhibitor, were found in 53% of BBC.⁴⁸ Moreover, deletions in chromosome 9, where the CDKN2 gene is located, were found in 92% of SCC in Egypt.⁴⁹

Human papilloma virus

The possibility of association between HPV and BBC remained open for long.⁵⁰ A study done by Khaled et al.⁵¹ showed that the virus was present in 23 out of 40 cases of BBC. Recently, a study using the Mass ARRAY technology showed all BBC blood-tested samples to be associated with HPV-16 DNA.⁵²

Metabolic observations during schistosomiasis

In the study of BBC, the metabolism of tryptophan along the formylkynurenine pathway leading to nicotinic acid has elicited considerable interest.⁵³ The justification for this interest originally stemmed from industrial oncology; however, epidemiologic support is also derived from the high prevalence of classic pellagra that used to be observed in Egypt but not in other parts of Africa where SCC is infrequently reported despite endemic schistosomiasis. In pellagra, exaggeration of the pathway from tryptophan to nicotinic acid occurs, producing larger amounts of tryptophan intermediates along the formylkynurenine pathway.²⁵

Our understanding of the role played by Schistosoma infection in disturbed tryptophan metabolism is complicated by geographic variations of dietary habits. In fact, serotonin metabolites such as 5-hydroxyindoleacetic acid, which are excreted in large amounts by plantain-eating Africans, are low in Africans on other diets.⁵⁴ Similar differences attributable to dietary habits have been found between bilharzial patients in Mozambique and South Africa. Egyptian peasants are not plantain eaters but subsist mostly on beans, lentils, and rice. Those with bilharzial cancer metabolize tryptophan into 3-hydroxyanthranilic acid, anthranilic acid, 5-hydroxyindoleacetic acid, and kynurenine. The excretion of these metabolites is enhanced by a loading dose of tryptophan. Therefore, schistosomiasis should not be considered the only causal factor in the associated excretion of abnormal tryptophan metabolites because, with or without cancer, urinary schistosomiasis is almost universally accompanied by urinary tract infection. The bacterial flora may, thus, contribute to a spurious accumulation of some metabolites of tryptophan.²⁵

Potentially carcinogenic metabolites of tryptophan, which may be the true oncogenic agent in the presence of bilharzial bladder inflammation, are principally determined by hepatic metabolic patterns. Factors that bear on this are coincident infestation of the liver by S. mansoni, pyridoxine deficiency, and chronic protein starvation. In the presence of advanced abnormalities in any of these factors, certain amounts of potential carcinogenic metabolites might be formed owing to lack of hepatic enzymes or cofactors.^{55, 56} The hepatic drug-metabolizing capacity of mice infected with S. mansoni is markedly reduced.⁵⁷ The mutagen-inactivating potential of S. japonicum-infected mouse liver is similarly reduced,⁵⁸ which results in longer persistence of the mutagen in the host body.⁵⁹ It seems likely that the carcinogen dose is a determining factor in the aggressiveness of a bladder tumor, and that a low-grade carcinoma can be converted into a high-grade one if exposed continuously to low doses of N-nitroso compounds. This would explain, at least in part, the overrepresentation of deeply invasive SCC in the bilharzial urinary bladder.⁶⁰

Apoptosis in schistosomal bladder cancer

One negative impact of the several cytogenetic changes that happen in the course of chronic schistosomiais is decreasing cell apoptosis and thus enhanced oncogenesis.¹² In 2009, Botelho et al.⁶¹ showed that cells exposed to S. haematobium total antigen (worm extract) were found to divide faster than those not exposed to the antigen, and died much less. This was explained by increased level of Bcl-2, which is one gene that can contribute to oncogenesis by suppressing apoptosis.⁵ The overexpression of the Bcl-2 gene in BBC patients was found to be upregulated in SCC but not TCC.⁶²

Pathology of benign and preneoplastic schistosomal bladder lesions

An intense, delayed-sensitivity reaction is elicited by viable Schistosoma eggs plugging the vesical venules leading to tubercules, nodules, or polyps. In bilharzial cystitis, the papilloma, covered as it is by one or two layers of flattened cells, which merge with the transitional epithelium at its base, is essentially a granuloma and not a precancerous lesion. With recurrent inflammation and fibrosis, some transitional epithelial cells become sequestered in the vesical submucosa and acquire a globular arrangement around a central cavity. When they open into the bladder cavity, the cystic formations become pseudoglandular. These structures, as part of cystitis glandularis, are at times precancerous; an adenocarcinoma may arise from the columnar epithelium, into which their lining has differentiated. In patients with schistosomiasis, squamous metaplasia is frequently encountered because it is a common concomitant of chronic inflammation. This type of metaplasia is a nearly consistent precursor of BC, and for this reason, leukoplakia acquires clinical importance as a precancerous condition.²⁵

Histologic classification

Significant changes in the pathological types of schistosomiasis-associated bladder tumors have been found over the past decades.¹⁰ Comparing the periods 1962–1967 and 1987–1992, there was a decrease in the incidence of nodular tumors (83.4% to 58.7%) and of SCC (65.8% to 54.0%) but an increase in the incidence of papillary tumors (4.3% to 34.8%) and TCC (31.0% to 42.0%).^63–65 Similar results were proved by comparing the periods 2001–2005 and 2006–2010 as was fore-mentioned.²² The extent of Schistosoma infection apparently plays a significant role in the induction of different types of carcinoma; SCC is usually associated with moderate and/or high worm burdens, whereas TCC occurs more commonly in areas associated with lower degrees of infection^63–65 (Figure 1). Adenocarcinoma of the bilharzial bladder is particularly aggressive owing to its proneness to develop gross chromosomal aberrations combined with high cell proliferation.⁶⁶ Another rare, though distinct, variant of SCC is verrucous carcinoma of the bilharzial bladder (Figure 2). Despite reports to the contrary, a large proportion develop into invasive SCC, with which they share the same adverse prognosis.⁶⁷

Experimental data for BBC

In a number of nonhuman primates, infection with S. haematobium resulted in epithelial proliferation, squamous metaplasia, and TCC of the urinary bladder.⁶⁸ These types of carcinoma were morphologically similar to those observed in human bladders,⁶⁹ and such observations suggest that there is an association between S. haematobium and BC. These early experimental observations were important because eggs of S. haematobium, lyophilized worms, and urine from bilharzia patients have not been found to be carcinogenic to mice.^{70, 71} However, 2-acetyl-aminofluorene appears to promote malignant and benign bladder neoplasms of mice infested with schistosomes more often than does either agent alone.⁷² Cancer development was thought to have been accelerated by schistosomal infection, presumably acting as a late-stage cocarcinogen by virtue of its direct proliferative effect on the urothelium.⁷³

Schistosomiasis and cancer of other sites

Evaluation of carcinogenicity of schistosomiasis

According to accepted international criteria, infection with S. haematobium is carcinogenic to humans (group 1); infection with S. mansoni is not classifiable as to its carcinogenicity to humans (group 3); and infection with S. japonicum is possibly carcinogenic to humans (group 2B).⁹⁰

East Asian distomiasis

Malaria

The geographic distribution of BL in the classic malarial belt initially suggested the possible role of an arthropod vector in oncogenesis.^{101, 102} BL is a highly aggressive B-cell non-Hodgkin’s lymphoma and is the fastest growing human tumor.¹⁰³ Two major epidemiological clues to the pathogenesis of BL are early infection by Epstein–Barr virus (EBV) and the geographical association with malaria. Both agents cause B-cell hyperplasia, which is almost certainly an essential component of lymphomagenesis in BL. Recent figures suggest that the incidence in children in equatorial Africa is similar to that of acute lymphoblastic lymphoma (ALL) in high-income countries—probably of the order of 3–6 per 100,000 in children aged 0–14 per year, accounting for 30–50% of all childhood cancers in equatorial Africa. This correlates with the high frequency and intensity of malaria in young children.¹⁰⁴ Incidence figures from other parts of the world, though limited, are considerably lower than those in equatorial Africa.¹⁰⁵ These data give the disease its name in Africa, endemic Burkitt lymphoma (eBL).

The possibility that drugs taken for malaria prophylaxis could have contributed to the development of BL^{106, 107} was considered unlikely because no increase (and indeed a decrease) in eBL was observed in the Malagasy Republic¹⁰⁸ and in Imesi, West Africa,¹⁰⁹ where intensive antimalarial prophylaxis was practiced. Interestingly, recent studies showed that chloroquine could play a role in cancer prevention.^{110, 111} Within endemic areas, the peak incidence of BL follows closely the incidence of severe Plasmodium falciparum malaria, and malarial prophylaxis reduces the incidence of the lymphorna.^{108, 109}

Of considerable interest are studies on the frequency of sickle-cell trait in eBL patients and controls. Persons with sickle trait are protected against the lethal effect of overwhelming P. falciparum malaria in early childhood and from the intense reticuloendothelial stimulation that sometimes progresses to hyper-reactive malarial splenomegaly.¹¹² Sickle cells exposed to low oxygen tension do not support the growth of parasites in vitro. A similar phenomenon may explain why children with the sickle-cell trait have a lower P. falciparum parasitemia. As a result, a lower mortality rate, lower IgM levels, and reduced lymphoproliferation (as measured by spleen size) are found among individuals with hemoglobin AS genotype. However, most studies attempting to relate eBL to AS hemoglobinopathy have failed to reach statistical significance.^{113, 114} Other hemoglobinopathies, such as hereditary ovalocytosis, also protect against malaria. If eBL turns out to be underrepresented in populations where both ovalocytosis is prevalent, as in Papua, New Guinea,¹¹⁵ such information would provide strong supporting evidence for malaria as a cofactor in the genesis of eBL.¹¹³

One way of explaining the observation that the malaria patient harboring a multitude of parasite-derived antigens becomes a host susceptible to eBL is the suggestion that malaria patients produce so many nonspecific and “useless” antibodies that they are unable to recognize and respond to the threat posed by a small clone of malignant lymphoid cells.¹¹⁶

Recent evidences

Several studies demonstrated the relationship between several parasites and oncogenesis, for example, the relation between cryptosporidiosis and intestinal cancer.^{135, 136} The study done by Certad et al.¹³⁵ was the first to record that a human-derived Cryptosporidium parvum isolate can induce cancer in mice. Another protozoan Trichomonas vaginalis was incriminated. Although the latter has a possible role in cancer of the cervix, its role in prostatic cancer is still arguable.¹³⁷ Neurocysticercosis was also incriminated in hematological malignancies.¹³⁸ Parasite-induced immunomodulation, DNA damage, and nitric oxide release due to chronic inflammation were the mechanisms proposed.¹³⁹ The relationship of the nematode Strongyloides stercoralis to hepatobiliary cancer¹⁴⁰ and Kaposi sarcoma¹⁴¹ was studied, as well as the role of Toxoplasma gondii in brain cancer^{142, 143} and lymphoma.¹⁴⁴ These parasites and others were incriminated in cancer development; however, clues are not yet sufficient to include them in the IARC roster.¹³⁷

In view of recent revaluation of the role of parasites, it was found that infectious agents and their products can orchestrate a wide range of host immune responses, through which they may positively or negatively modulate cancer development and/or progression. Interestingly, certain types of pathogens, including parasites, can decrease the risk of tumorigenesis or lead to cancer regression.¹⁴⁵ Trypanosoma cruzi was found to decrease the incidence of experimentally induced rodent colon cancer.¹⁴⁶ The nematode Trichuris suis was investigated clinically and experimentally for its ability to alleviate diseases, such as inflammatory bowel disease (ulcerative colitis, Crohn disease), multiple sclerosis, and allergy.^{147, 148} The applicability of this to cancer pathology, and more specifically to tumors of the gastrointestinal system, is a question open to future investigations.¹⁴⁵

Summary

When uncommon neoplasms are noted with undue frequency in countries with a high prevalence of parasitic diseases, parasites become incriminated. Many parasites were studied for a possible role in oncogenesis; however, not all of them were registered as true carcinogens by the IARC. Chronic inflammation, immunomodulation, overexpression of certain carcinogens, DNA mutations, and suppression of apoptosis are the frequent well-common mechanisms for parasite-induced oncogenesis. Besides, concomitant presence of other infectious agents is proved to be an enhancing factor in many situations. Epidemiological, cytogenetic, and animal studies were used to prove the relationship between parasites and cancer. In this view, S. haematobium was proved to play an important role in developing urinary BC due to chronic irritation by submucosal egg deposition, constant high levels of N-nitroso compounds that lead to DNA mutations, suppression of apoptosis, and, hence, histopathological changes in the urinary epithelium. Human papilloma virus is still suspected to play an assistant role in this sequence. Other Schistosoma species S. japonicum is classified as a colorectal carcinogen especially in the Far East. Other helminthes Clonorchis and Opisthorchis are proved to induce hepatobiliary cancer. In Africa, a strong correlation between BL and EBV infection is present, with an evident enhancing role for P. falciparum. These and more can be viewed as possible human carcinogens in respect of chronic inflammatory process associating several parasitic infections. However, strong evidences, especially cytogenetic, are usually required. Strikingly, despite the above-mentioned data, it seemed that certain parasites can modulate the host immune response in a manner that could lead to cancer regression or prevention. This is in the prospect of revaluation of the clinical importance of infectious agents; an issue that requires future concern.

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