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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 22Parasites

, MD.

The intensity of parasitic infection frequently correlates with its prevalence.1 Thus, when relatively uncommon neoplasms are noted with undue frequency in countries with a high prevalence of parasitic diseases, the question of the role of parasites arises. In this respect, the two most intriguing examples are probably the relationships of schistosomiasis to bladder cancer and that of malaria to Burkitt’s lymphoma. Classic references have been presented before.2

Schistosomiasis and Cancer of the Bladder

Epidemiologic Aspects

The data associating schistosomiasis (frequently called bilharzia in Africa) and neoplasia are overwhelming, but explanations for this association remain speculative.3,4 Data published so far have been retrospective and, therefore, have yielded only relative frequencies, with their well-known inherent limitations.


In Africa, squamous cell carcinoma of the bladder is greatly over-represented among the fellaheen of Egypt and the Africans of Mozambique, Zimbabwe, and Zambia (formerly Rhodesia), all countries where Schistosoma haematobium is endemic. An age-standardized mortality rate for bladder cancer of 10.8 per 100,000 males places Egypt at the top of the list of the 54 countries providing data for the 1987 WHO database.5 Observations made in Ghana are only suggestive of an association, however, and none emerges from Tanzania, Uganda, or French-speaking West Africa, where schistosomiasis is endemic but bladder cancer apparently is rare.

No prospective study measuring the risk of developing bladder cancer in infected and uninfected persons is yet available. Although differences in relative frequencies may reflect differences in risk, the interplay of other factors, such as geopolitical variations in case finding, can result in spurious differences and erroneous associations. If the postulated association is correct, one of several conditions must obtain: the worm (1) produces a carcinogen, (2) carries a virus, or (3) is cocarcinogenic to some other insult. In this case, there are many unanswered questions regarding geographic differences in vesical cancer observed where schistosomiasis is endemic. These range from whether there is geographic uniformity in the host’s reaction to infection to whether other environmental variables (such as the bright food coloring used in the candy popular in the Nile delta) interact and are additionally responsible for vesical neoplasia.

Age and Sex

Egyptian data from the Alexandria Cancer Registry disclose a five-fold sex-linked disparity in the annual age-adjusted incidence rate of bladder cancer: 19.2 per 105males and 3.6 per 105 females.5 Bilharzial (i.e., schistosomal) bladder cancer attacks men preferentially and seems to be especially common in those with HLA-B16 and Cw2 antigens.6 In Egyptian hospital series, the mean age of patients is 41 years, about 5 years younger than that of patients with nonbilharzial bladder cancer,5,7 and the sex ratio ranges from 5:1 to 9:1. In Ghana, 5 of 13 males with bladder cancer came to autopsy before age 36 years.8 In Mozambique, too, bilharzial bladder cancer occurs earlier in life, but the sex ratio (M/F 1.75:1) is not as striking as in Egypt.9 Whether this difference from Egypt reflects a greater susceptibility of females in Mozambique, a reduced risk in males, or simply a vagary resulting from under-reporting remains unresolved.

Urban/Rural Distribution

In Egypt, additional support for an association with bilharzial infection can be found in the relative paucity of bladder cancer cases (10 among 33 cancers) reported from hospitals serving the nonparasitized Italian and Greek residents of metropolitan Cairo, compared with the large number observed in hospitals attending Egyptian peasants (45 among 74 cancers).7,8

Frequency and Severity of Infection

The association of bladder cancer with schistosomal infection seems to become stronger with longer-standing and more severe infection.7 In the Nile delta, Schistosoma ova in the urine correlate with bladder status: cytologically benign epithelium, squamous metaplasia, benign tumors, and, finally, cancer.

The severity of infection tends to rise sharply with opportunities for exposure. In Egypt, it is directly related to the extent of perennial irrigation through canals, which creates a constant risk of re-infection, and inversely related to control measures and availability of safe and effective therapy. In Ghana, where different agricultural conditions prevail, schistosomiasis is essentially a prepubertal disease, and only a small proportion of the population is infested, as compared with the extent in Egypt. Comparative studies in these two countries indicate a rather clear and direct relationship between parasitic infection with S. haematobium and frequency of bladder cancer.8 Thus, the peculiar agricultural setting of the Nile valley singles out this region for a dose–response relationship not encountered in other parts of Africa.

Variability in Diagnostic Criteria of Schistosomiasis

Many reports of schistosomal bladder cancer fail to define the diagnostic criteria for infection. 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 due to bilharzial fibrosis, in which the dense scar tissue precludes shedding of ova from the submucosa. Conversely, sound epidemiologic practices require that when evidence of infestation in ova-negative bilharzial patients is sought by rectal scrapings or radiographic studies, the same diagnostic refinements be used in every member of the group studied.

One study conducted in the Nile delta concluded that only 11% of the men and 3% of the women could be considered infected, on the basis of presence of Schistosomal ova in the initial urinalysis. On the basis of this diagnostic criterion, only a suggestive association of infection and cancer of the bladder was demonstrated (p = .04). By expanding the criteria for diagnosis of schistosomiasis to include the presence of ova in any centrifuged urine sample, and other evidence of infection obtained by endoscopic or radiologic procedures, the prevalence of infection was increased threefold. After correcting for age, sex, and residence, the relative risk of developing bladder cancer among the bilharzial patients was double that in the comparison population group. By adopting the expanded definition of schistosomiasis, the probability that the association of infection and cancer occurred by chance was much lower. (p = .002).8

Geographic Variability in Schistosomal Virulence

Within East Africa, a coastal strain of S. haematobium is more virulent than that at Lake Victoria, where infested bladders do not show severe changes.

When Schistosoma mansoni is considered, the Brazilian and Puerto Rican strains are the most virulent, as measured by the production of liver disease in infested mice. Under the same experimental conditions, the Egyptian strain caused the least liver damage and the Tanzanian strain produced the fewest eggs.10 Variability in S. mansoni virulence has been cited to explain the high frequency of liver cancer in Mozambique but not in Egypt, even though schistosomal liver cirrhosis is common in both countries. This type of explanation is, at best, tentative because other, as yet undetected, environmental carcinogenic hazards can be at work.

Role of Urinary Infection

In Egypt, but not in Mozambique, bladder calculi and incrustations of vesical ulcers are frequent complications of schistosomal infection. The experimental work linking some nitroso products of bacterial metabolism to carcinogenesis may perhaps re-invigorate the old carcinogenic hypothesis of the early Egyptian workers who implicated “alkaline urine.” In fact, the urinary excretion of nitrite and N-nitroso compounds is increased in patients with S. haematobium infection.11 The prevalence of urinary nitrites found in symptomatic active bilharzial cystitis increases in patients who also have schistosomal bladder cancer.12 In noncancerous bladders, infection with S. haematobium increases significantly the ability of the vesical bacterial flora to reduce nitrates to the nitrite precursors of N-nitroso compounds.13

Urinary tract infection has been associated with increased chromosomal breakage in the urothelium. The frequency of micronuclei is reduced significantly after antihelminthic treatment.14 Urothelial carcinogenesis in the presence of schistosomiasis seems to proceed along different pathways from those linked to cigarette smoking, which appears to have a significant impact on mutation of the p53 gene with A:T to G:C transitions, that are not observed in bilharzial bladder cancer.15

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 bladder cancer, and for this reason, leukoplakia acquires clinical importance as a precancerous condition. Monosomy 9 may be an early chromosomal change in bilharzialinfected urothelium and a predictor of incipient carcinoma in patients with bilharzial cystitis.16

Site of Origin

In patients in Western countries, bladder cancer frequently arises in the trigone; in patients in Egypt, it usually develops in areas remote from the ureters, mostly in the anterior and posterior bladder walls. This peculiarity tends to strengthen its association with schistosomal infection because the scanty or altogether absent submucosal tissue of the trigone discourages significant deposition of ova (Table 22.1).

Table 22.1. Anatomic Distribution of Vesical Cancer in Egypt and the United States.

Table 22.1

Anatomic Distribution of Vesical Cancer in Egypt and the United States.

Histologic Classification

Table 22.2 contrasts the over-representation of squamous cell carcinoma of the bladder in countries like Egypt, Kuwait, Mozambique, South Africa (Bantu population),17 and Zimbabwe, where the association with schistosomiasis is considered important, with the Ugandan and Caucasian South African experiences where the reverse applies.

Table 22.2. Histologic Distribution of Bladder Cancer in Africa.

Table 22.2

Histologic Distribution of Bladder Cancer in Africa.

Within the same country, squamous cell carcinoma of the bladder is markedly over-represented only in areas where schistosomiasis is endemic.18,19 Moreover, the more intense the infection, the greater is the proportion of squamous cell cancers with a reciprocal decrease in the frequency of transitional cell neoplasms (Fig. 22.1).20

Figure 22.1. Bilharzial bladder cancer.

Figure 22.1

Bilharzial bladder cancer. Infiltrating well-differentiated squamous cell carcinoma with adjacent calcified S. hematobium eggs. (H & E × 100). (Courtesy of Doctors M. R. Mahran and M. El-Baz, Mansoura University, Egypt).

A rare, though distinct, variant of squamous cell cancer is verrucous carcinoma of the bilharzial bladder (Fig. 22.2). Despite reports to the contrary, a large proportion develop into invasive squamous cell carcinoma, with which they share the same adverse prognosis.21

Figure 22.2. Verrucous carcinoma (noninvasive) of bladder with superficial filamentous elongated surface projections.

Figure 22.2

Verrucous carcinoma (noninvasive) of bladder with superficial filamentous elongated surface projections. (H & E × 40). (Courtesy of Doctors M. R. Mahran and El-Baz, Mansoura University, Egypt.)

Figure 29.1. Immunoperoxidase staining reaction of line 10 guinea pig undifferentiated bile duct carcinoma exposed to a monoclonal antibody specific for fibrin (supplied by Dr.

Figure 29.1

Immunoperoxidase staining reaction of line 10 guinea pig undifferentiated bile duct carcinoma exposed to a monoclonal antibody specific for fibrin (supplied by Dr. Gary Matsueda). Tumor comprises nests of malignant cells interspersed in a stroma that (more...)

Experimental Data

Half a century ago, papillomatous hyperplasia of the vesical wall was observed in African sooty monkeys within 3 months of infection with S. haematobium. More recently, carcinoma of the bladder was diagnosed in a baboon killed 26 weeks after infection.22 In a number of nonhuman primates, infection with S. haematobium resulted in epithelial proliferation, squamous metaplasia, and transitional cell carcinoma of the urinary bladder.23 The American opossum has also been found experimentally suitable for infection with S. haematobium.24 These experimental observations are important because eggs of S. haematobium, lyophilized worms, and urine from bilharzia patients have not been found to be carcinogenic to mice.25,26 Furthermore, Schistosoma ova, alone or in the presence of 3-methylcholanthrene lacked urothelial topical carcinogenicity or cocarcinogenicity in mice.27 However, 2-acetyl-aminofluorene appears to promote malignant and benign bladder neoplasms of mice infested with schistosomes more often than does either agent alone.28 Similarly, N-methyl-N-nitrosourea and S. haematobium caused bladder tumors in 5 of 16 hamsters, whereas no oncogenic effect was seen with either alone. Three S. haematobium infected baboons treated with N-butyl-N-butazolnitrosamine all developed extensive bladder cancer.29

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.30 Similarly, an increased incidence of hepatoma has been described after administration of carcinogen to mice infested with S. mansoni.25 This occurs even though the toxic morphologic alterations occurring in the liver are fewer than those observed in noninfected mice exposed to the same hepatocarcinogen.31

Helminthic Infestations and Viruses

No information seems to be available on the relationship between helminthic parasites and oncogenic viruses, though it is recognized that parasitic diseases exacerbate viral infection. In 1 of 4 capuchin monkeys, C-type virus particles were found in a papillary carcinoma induced by S. haematobium that had not been present earlier in the normal bladder tissue. In mice infected with S. mansoni, the parasitic disease may enhance the acute effect of hepatitis virus, but no evidence has been found as yet that the chronic cirrhosis-like picture results from this.32

Metabolic Observations During Schistosomiasis

Increased urinary excretion of free 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and 2-amino-3-hydroxyacetophenone has been documented in some patients with bladder cancer. These ortho-aminophenol derivatives of tryptophan are generally excreted as conjugates of sulfuric acid or glucuronic acid. They are related to the carcinogenic metabolites of β-naphthylamine and are themselves carcinogenic to mice.

The relative resistance of the trigone to schistosomal bladder cancer would make less tenable an etiologic hypothesis predicated on the topical action of an endogenous urinary carcinogen, were it not for the increased activity of urinary β-glucuronidase in vesical infections, including schistosomiasis. Under these circumstances the enzymatic release of the active carcinogen from its glucuronide could well become a significant biologic factor that determines the anatomic localization of the neoplasm. In the study of bilharzial cancer, the metabolism of tryptophan along the formylkynurenine pathway leading to nicotinic acid has elicited considerable interest.33 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 squamous bladder cancer 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.

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.34,35 Similar differences attributable to dietary habits have been found between bilharzial patients in Mozambique and in South Africa. Egyptian peasants are not plantain-eaters but subsist mostly on beans, lentils, and rice. Those with bilharzial cancer metabolize tryptophan in a manner reminiscent of the pattern seen in many patients with spontaneous bladder cancer, with increased excretion of 3-hydroxyanthranilic acid, anthranilic acid, 5-hydroxyindoleacetic acid, and kynurenine. The excretion of these metabolites is enhanced by a loading dose of tryptophan.

Schistosomiasis should not be considered the only causal factor in the associated excretion of abnormal tryptophan metabolites because, with or without cancer, vesical schistosomiasis is almost universally accompanied by urinary tract infection. The bacterial flora may, thus, contribute to a spurious accumulation of some metabolites of tryptophan. Moreover, untreated pellagra is associated with increased urinary excretion of anthranilic acid, acetylkynurenine, and 5-hydroxyindoleacetic acid.

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, lesser amounts of potential carcinogenic metabolites might be formed owing to lack of hepatic enzymes or cofactors. No mutagens were detected by the Ames test in the urine of patients suffering from bilharzial bladder cancer36 or in soluble extracts of eggs and adult Schistosoma japonicum worms.37 A weak promoting activity was noted for S. japonicum soluble egg antigen, which resulted in the recovery of Epstein-Barr virus (EBV) from cultured human lymphoid cells that harbored the viral genome.37

The hepatic drug-metabolizing capacity of mice infected with S. mansoni is markedly reduced.38 The mutagen inactivating potential of S. japonicum-infected mouse liver is similiarly reduced.39 This results in longer persistence of the mutagen in the animal body.40 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.41 This would explain, at least in part, the over-representation of deeply invasive squamous cell cancers in the bilharzial urinary bladder.41 The significant excess of transitions at CpG dinucleotides in the p53 gene in bilharzial bladder cancer has been attributed to the endogenous production of nitric oxide provoked by the inflammatory response to schistosomal ova.42

A study of the frequency of mutant active ras oncogenes in bilharzial bladder cancer concluded that it was not higher than in nonbilharzial cancer.43 In view of its isolation from direct exposure to putative carcinogens present in the urine, a defunctionalized bilharzial bladder might seem an unlikely site for the development of neoplastic changes. Nonetheless, adenocarcinoma has been reported in a defunctionalized bladder showing extensive metaplasia.44 Quantitative estimates of infection with S. haematobium have shown, however, that its overall severity is unlikely to be the sole factor in the pathogenesis of endemic vesical cancer.45

Schistosomiasis and Cancer of Other Sites

Large Intestine

While acknowledging the frequency of benign schistosomal polyposis, Egyptian data tend to discount any association of S. mansoni or S. haematobium with cancer of the large intestine. On the other hand, in Asia, intestinal infestation with S.japonicum is considered a significant contributory factor to the development of cancer of the colon and rectum. S. japonicum lays a very large number of eggs (2,000 per day per pair of worms) while S. mansoni’s eggs are considerably fewer and, thus, cause fewer pathologic problems.46

In one report from China, where in endemic areas the prevalence of schistosomiasis may reach 44 per 100,000 persons, 48% of colectomy specimens for colorectal carcinoma obtained from 1951 to 1974 were associated with S. japonicum infestation. Associated inflammatory changes, pseudopolyps, and transitional mucosal changes of schistosomal granulomatous disease progressing to mucosal atypia and to carcinoma were reminiscent of bowel carcinoma in patients with ulcerative colitis, save for the ova deposited in all layers of the bowel.47 Nonetheless, 92% of cancers were well differentiated, compared with 69% in the group without schistosomiasis. An ecologic study of 49 Chinese rural counties indicates that both schistosomal infestation and dietary factors contribute to the remarkable geographic variation of colon cancer in China.48

In Shanghai, patients with intestinal schistosomiasis and cancer of the large intestine are, on average, 6 years younger than patients with spontaneous intestinal cancer.49,50 However, Chinese patients whose history of schistosomiasis entailed an elevated relative risk (RR) of rectal cancer (RR 8.3; CI 3.1 to 22.6) did not show a parallel increase in their RR for cancer of the colon.51


In Egyptian hospital material, the male-to-female breast cancer ratio is substantially greater than in the West. If corroborated by incidence studies, this observation would be a valuable epidemiologic observation worthy of further investigation. Hyperestrogenism secondary to bilharzial liver fibrosis has been invoked as one possible cause.


Conflicting observations on the association of schistosomiasis and hepatic cancer are difficult to reconcile without further data. In Egypt5 and Mozambique,9 bilharzial liver cirrhosis is very common; carcinoma of the liver, however, is prevalent only in Mozambique, where it is the most common cancer among males. The association of cirrhosis from S. japonicum with hepatoma has been reported only infrequently and appears, thus, not to be causal.

In Japan, liver cancer correlated highly with three factors: HBsAg (OR = 10.0), history of schistosomiasis (OR = 9.5), and daily intake of alcohol (OR = 3.2) with the combination of hazards acting multiplicatively or at least synergistically.52,53 In experimental animals, infection with S. japonicum, alone54 or in combination with N-2-fluorenyl acetamide, induced or accelerated the occurrence of liver tumors.55

Remnants of schistosomal eggs were found in the severe granulomatous reaction present in a well-differentiated hepatocellular carcinoma that had developed in a chimpanzee devoid of hepatitis B or C markers.56


Eight cases of solitary follicular lymphoma of the spleen were found among 863 spleens removed from patients with hepatosplenic schistosomiasis. The rarity of an isolated tumor at this site and of this type suggests a causal link, possibly mediated by cycles of follicular hyperplasia and involution occurring in the spleen in the course of advanced schistosomiasis.57 In a Nigerian series, lymphoreticular tumors were over-represented in infected individuals (16%) as compared with uninfested ones.58

Other Organs

Immunohistochemically confirmed invasive squamous cell carcinoma of the prostate was diagnosed in two prostatic schistosomiasis patients coming from a population where prostatic cancer is uncommon.59 On the other hand, the Egyptian cases indicate no relationship between bilharziasis and cancer of the lungs, pancreas, prostate, seminal vesicles, urethra, vulva, vagina, cervix uteri, body of the uterus, or ovaries.5 As would be expected, surgical or autopsy material in countries with high schistosomal endemicity from time to time shows the presence of Schistosoma ova in various tissues, including cancerous ones. The literature contains a number of isolated reports of such coincidences. Moreover, in areas where infestation is endemic, schistosomal tissue reaction may be so intense and proliferative as to be mistaken clinically for cancer of the large intestine60 or the cervix.61

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); infection with S. japonicum is possibly carcinogenic to humans (group 2B).63

East Asian Distomiasis

Liver and Pancreas

Clonorchis sinensis is endemic in parts of Japan, Korea, and China; a similar species, Opisthorchis viverrini, causes distomiasis in Thailand. Liver fluke infections have been associated with multi-focal intrahepatic bile duct adenocarcinoma in those areas of Asia where distomiasis is endemic: Thailand, where 70 to 90% of the population of the northeast part of the country are infected with O. viverrini, has the highest recorded incidence of cholangiocarcinoma in the world. In Indonesia, Taipei, and Taiwan, where distomiasis is considered uncommon, cholangiocarcinoma is infrequent. Imported cases of distomiasis are seen in the United States, and since the parasite can live up to 30 years, it represents a long-term hazard to infected persons.64

Human infection results from eating raw or undercooked parasitized freshwater fish. In humans, the ingested parasites excyst in the duodenum and ascend the bile ducts and canaliculi, where they mature, causing biliary epithelial hyperplasia and fibrosis. Similarities between the histopathologic responses in infected humans and experimental animals have been documented, including the development of cholangiocarcinoma in dogs and cats experimentally infected with Clonorchis. Hamsters administered dimethylnitrosamine for 10 weeks after infection with Opisthorchis developed mucin-secreting cholangiocarcinomas, whereas noninfected animal controls failed to develop tumors. This observation is in keeping with experimental evidence pointing to infection as a promoter of N-nitrosodimethylamine. In the Far East, nitrosamines are commonly found in such traditional Chinese preserved foods as salted fish, dried shrimp, and sausage.65 Precursors of nitroso compounds have been identified in the body fluid of men infested with O. viverrini.66

Pancreatic ducts may also be infected with C. sinensis; this frequently results in squamous metaplasia and mucous gland hyperplasia. In one instance in the United States, an immigrant with C. sinensis in the common bile duct developed a well-differentiated ductal adenocarcinoma of the pancreas.67

Evaluation of Carcinogenicity of Distomiasis

Infection with O. viverrini is carcinogenic to humans (group 1); infection with O. felineus is not classifiable as to its carcinogenicity to humans (group 3); infection with C. sinensis is probably carcinogenic to humans (group 2A).68


The geographic distribution of Burkitt’s lymphoma in the classic malarial belt initially suggested the possible role of an arthropod vector in oncogenesis.69,70 The notion that drugs taken for malaria prophylaxis contribute to the development of Burkitt’s lymphoma71,72 was considered unlikely because no increase (and indeed a decrease) in endemic Burkitt’s lymphoma (eBL) was observed in the Malagasy Republic73 and in Imesi, West Africa,74 where intensive antimalarial prophylaxis was practiced; moreover, cases occur in Africa,63 Israel,75 and elsewhere among persons who are not receiving malaria prophylaxis.

More significant are the epidemiologic observations that have linked eBL to the combined effect of malaria and infection with the EBV.76 Endemic BL is only found in areas where malaria is holoendemic or hyperendemic; within these areas, it is absent in malaria-free pockets, such as urban centers. Within endemic areas, the peak incidence of eBL follows closely the incidence of severe Plasmodium falciparum malaria, and malarial prophylaxis reduces the incidence of the lymphoma.73,74

Vigorous cellular and serologic responses occur during malarial infection.77 This renders plausible the argument that persistent reticuloendothelial stimulation experienced among malarial populations conditions the EBV-infected African patient to develop a neoplasm rather than a self-limited disease, such as infectious mononucleosis.78 This view finds support in the observation that each one of the erythrocytic, exoerythrocytic, and sexual forms of the parasite is structurally differentiated and probably contains a multitude of biologically active antigenic constituents.79,80 In this respect, it is interesting to note that in endemic malarial areas, the distribution of hyper-reactive malarial splenomegaly parallels the distribution of eBL, and that the peak age incidence of eBL follows closely the peak age incidence of severe P. falciparum malaria.76

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.81 This view is supported by experimental data. In mice, antigenic stimulation and immune suppression often result in an increased incidence of lymphomas. Mice repeatedly injected with Plasmodium berghei sometimes develop malignant lymphoma that is morphologically similar to Burkitt’s lymphoma and sometimes develop persistent antigenic stimulation without significant tumorigenesis.82–84 Lymphomas are frequently induced by Moloney leukemogenic virus in mice infected with P. berghei but rarely occur in mice given either plasmodium or virus alone.85 Acute malaria, which increases B-cell proliferation, also impairs EBV-specific T-cell responses.70,86 This results in a larger pool of EBV-infected cells with increased likelihood for chromosomal translocation and lymphomagenesis.87 In children, the risk of developing Burkitt’s lymphoma is related to antibody titers against EBV capsid antigens.88 The clinical manifestations probably are promoted by other environmental factor(s), such as holoendemic malaria89 and phorbol exposure.90

Of considerable interest are studies on the frequency of sickle-cell trait in eBL patients and controls. Persons with sickle trait are not protected from being bitten by mosquitoes or from malarial infection, but they 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.91 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. Most studies attempting to relate eBL to AS hemoglobinopathy have failed to reach statistical significance, however.86 Other hemoglobinopathies, such as hereditary ovalocytosis, also protect against malaria. If eBL turns out to be under-represented in populations where both ovalocytosis and malaria are prevalent, as in Papua, New Guinea,92 such information would provide strong supporting evidence for malaria as a cofactor in the genesis of eBL.86 In this event, the observation that in Uganda malarial endemicity also correlates with non–Burkitt’s non–Hodgkin’s lymphoma, would acquire added significance.93

The small differences in titers of malarial antibodies observed in Burkitt’s lymphoma patients and controls94 were attributed to the fact that many in the experimental group had received several courses of antimalarial drugs, which may have lowered the level of malaria-specific antibodies.77 A probable role of malaria emerges also from the following considerations. African children with eBL develop autoantibodies, the elevated titers of which show no linear correlation with EBV titers for viral capsid antigen (VCA) or Epstein-Barr nuclear antigen (EBNA),95 suggesting that a factor independent of EBV causes an immunologic imbalance and autoantibody production. The notion that this could be due to malaria is supported by the observation that Caucasians suffering from acute P. falciparum malaria develop autoantibodies,96,97 and that experiments in vitro demonstrated that normal human lymphocytes can produce autoantibodies as a response to malarial antigens.98

In the genesis of eBL, regardless of whether malaria is considered the initiator and EBV the promoter or vice versa, neither hypothesis accounts for the fact that in vitro infection of B cells with EBV and stimulation with malaria antigens has yet to produce a cell that carries the chromosomal tumorigenic translocations found in both sporadic and endemic BL.87 Thus, it seems likely that other unidentified factors (genetic, nutritional, or environmental) play a significant role in tumorigenesis.

American Burkitt’s Lymphoma

By the early 1970s, approximately 100 cases of Burkitt’s lymphoma had been confirmed by the American Burkitt’s Lymphoma Registry.99 Space-time clustering is suggested by the American data.100,101 Although malaria is associated with Burkitt’s lymphoma in Africa, the relative rarity of the tumor in relation to the holoendemic nature of malaria indicates that a combination of genetic factors plus specific environmental factors may be operative. Host and environmental factors other than malaria are probably important in North American cases.99

Cancer in Animals

Observations made by Fibiger102 on gastric cancer in rats infested with a nematode are now all but discredited. A question that remains to be evaluated is whether the nematode helped localize some unidentified carcinogens in the diet, similar to the induction of sarcomas at the site of subcutaneous injection of sodium chloride in rats being fed 3-methylcholanthrene.

Sarcoma is an almost inevitable complication of infection of the liver or the subcutaneous tissues of rats with Cysticercus fasciolaris, the larval form of the common tapeworm of the cat, Taenia taeniaformis. Washed, ground-up C. fasciolaris produced peritoneal sarcomas in half the injected rats, the proportion reaching 91% if the animals were genetically related to the parasitized host. The active agent appears to be associated with the calcium carbonate corpuscles of the parasite, but the mechanism is not clear.103 Although not directly implicated in vesical carcinogenesis, there is suggestive evidence that infestation with another nematode, Trichosomoides crassicauda, increases the incidence of tumors in the bladders of rats receiving 2-acetyl-aminofluorine.104

Another nematode, Spirocerca lupi, has been associated with the development of esophageal sarcoma in dogs. Here the reported association seems to be described only in the southern United States, thereby adding a possible geographic dimension to the problem.

Some neoplastic responses to parasitic infestation are a kind of cecidiosis and may represent the end of a hypothesized evolutionary sequence by which parasite secretions stimulate the host to form protective structures (cecidia) that benefit the parasite.


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