Introduction

Human schistosomiasis syn. bilharziasis is a parasitic disease caused by trematode flukes of the genus Schistosoma. The World Health Organization conservatively estimates at least 240 million people worldwide who are infected with Schistosoma spp. with severe disease manifestations in estimated 20 million people and an incidence of 280,000 deaths yearly (WHO 2014; Colley et al. 2014). Mobile larvae called cercariae penetrate the skin when the individuals are in contact with contaminated freshwater about two months later the larvae have matured into the adult worms which descend the mesenterial vessels for reaching small peripheral vessels of the intestine, the bladder and/or reproductive organs. Adult schistosome worms colonize the blood vessels for years, successfully evading the immune system while excreting hundreds to thousands of ova daily, which must either leave the body in excreta or become trapped in nearby tissues. Trapped ova induce a chronic granulomatous response that causes local and systemic pathological effects ranging from anaemia, growth stunting, impaired cognition and decreased physical fitness, with largely unknown effects on endocrinologic hormones and their receptors to organ-specific effects such as severe hepatosplenism, portal fibrosis with portal hypertension (Colley et al. 2014). Urogenital involvement may cause in women stigmatization, infertility, vagino-vesical fistulae and negative pregnancy outcomes, and in men infertility and scrotal swellings (Leutscher et al. 2000; Richter 2000; Richter et al. 2002, 2008; Kjetland et al. 2012). Schistosomiasis of the lower reproductive tract seems to constitute a risk factor for transmission of sexually transmitted diseases including HIV (Feldmeier et al. 1994; Kjetland et al. 2012; Ndeffo Mbah et al. 2013, 2014). Of the six species pathogenic to humans, two are endemic in Angola, Schistosoma (S.) mansoni and Schistosoma haematobium (Ministry of Health of Angola 2005; WHO 2014).

Materials and methods

A 56-year-old black man living in Malanje (Angola) was admitted to the Service of External Urology Consultation of the Américo Boavida Hospital in Luanda (Angola) because of diminution of the urinary jet, urine dripping, dysuria, pollakisura, nycturia, urgency for urination and with antecedent episodes of total haematuria and terminal haematuria, as well as haematospermia in adolescence. He recalled his actual urinary symptoms to having been present for at least 3 years. Medical history otherwise was not indicative, including treatments for arterial hypertension, but he did not recall any sexually transmitted infection (STI), trauma of the urethra, previous surgery. The patient admitted moderate consumption of alcohol and did not smoke. He did not know of any significant family antecedents.

Ethical considerations

Before the investigations, the patient was informed in detail on all investigations planned and provided written informed consent according to the protocol approved by the Ethics Committee of the Américo Boavida Hospital of Luanda and the Health Minister of Angola.

Literature research

To know about the frequency of the association of prostate cancer and schistosomiasis, a systematic MEDLINE research was performed with the search term association of “prostate cancer AND schistosomiasis”. Other sources were retrieved from other published articles investigated not listed in these databases or via internet research. MEDLINE data were compared with other arguments to obtain a still approximative but better idea of the relative frequency of hits obtained. These terms included “prostate cancer”, “adenocarcinoma of the prostate”, “squamous prostate cancer”, “schistosomiasis”, “genitourinary schistosomiasis”, “bladder cancer”, “transitional bladder cancer”, “squamous bladder cancer”, “schistosomiasis AND bladder cancer”, “genital schistosomiasis”, “colon cancer AND schistosomiasis”, “uterine cancer AND schistosomiasis”, “uterus cancer AND schistosomiasis”, “cervical cancer AND schistosomiasis”. Although the case series was small and not comparable with other meta-analysis on a large number of trials, transparent data analysis is presented adhering to the spirit of the PRISMA declaration (Moher et al. 2009).

Results

Case report

At physical examination, the patient reported bilateral loin pain. Digital examination of the rectum revealed an enlarged prostate that was hard, irregular in shape, without a groove and with a peripheral nodule. Haematology tests revealed anaemia (7 g/dl) (normal value [n] = 14.0/18.0), with relative eosinophilia 10 % (n ≤ 5 %), serum urea 59 mg/dl n < 55), serum creatinine 1.4 mg/dl (n ≤ 1.0), urine with leucocytes 20/μl (n ≤ 10) and numerous bacteria. Urine culture revealed a superinfection by Escherichia coli, 106/ml which was cured with ciprofloxacine. HIV serology was negative, prostatic specific antigen (PSA) was elevated to >100 ng/ml (n = 0.02-4.0) and chest X-ray was normal.

At abdominal ultrasonography, the bladder neck was hyperechogenic, the urinary tract being otherwise normal. Prostate ultrasonography showed a heterogenous structure with an irregular and nodular capsule weighing 75 g by ultrasonographic volumetry (Sukov et al. 1977). Radiography of the pelvis and lumbosacral column showed foci suspicious of bone metastases. A sextant biopsy was made that histologically showed glands covered in epithelial cells showing signs of malignancy indicating a well-differentiated adenocarcinoma. Gleason score was (3 + 3) 6, with presence of S. haematobium ova (Fig. 1).

Fig. 1
figure 1

Histological result of prostatic gland with adenocarcinoma (arrow) with Gleason of 3 + 3 and calcified eggs of Schistosoma haematobium (inside the circle). Haemotoxylin and eosin (H and E) stains. ×40 objective

Full size image

A combined treatment was initiated with s.c. injections of a luteinising hormone-releasing hormone (LHRH) agonist (goserelin acetate, Zoladex®, AstraZeneca, London, UK), and radiotherapy was foreseen. Unfortunately, the patient, who originated from a place 400 km distant from Luanda, did not come back for follow-up examinations.

Database research

The MEDLINE research with the term association “prostate cancer AND schistosomiasis” yielded 39 results of which 9 were case or small case series reports comprising 14 patients. Two other Nigerian publications were retrieved via the Internet (Al Adnani 1985; Tungekar and Al Adnani 1986; Alexis and Domingo 1986; Godec et al. 1992; Cohen et al. 1995; Ma and Srigley 1995; Basílio de Oliveira et al. 2002; Bacelar et al. 2007; Manasseh et al. 2009; Mazigo et al. 2010; Okani et al. 2013) The research process is described in detail in Table 1. Taken all together including our patient, only 17 cases have been described worldwide (Table 2). The median age of the patients including the patient presented was 50 years (range 27–75). In four studies, patient age was not reported. It was lower in patients with prostate cancer associated with S. haematobium infection (27, 29, 29, 41, 50, 56, 63, 75 years) as compared to patients with S. mansoni infection (47, 49, 68, 70 years). In three of the studies retrieved by the research “prostate cancer AND schistosomiasis”, the low frequency of prostate cancer in case series was mentioned; in further 7/13 studies on “bladder cancer AND schistosomiasis”, the absence of prostate involvement was specifically reported (Houston 1968; Powell et al. 1968; Sherif et al. 1980; Osegbe and Amaku 1984; Al Adnani 1986; Ebert 1987; Sharfi and Hassan 1994; Nabeeh et al. 1995; Dawam et al. 2001; Mohammed et al. 2003). For a rough comparison of the perceived importance of the medical problem, other MEDLINE research gave the following figures: the research term “prostate cancer” yielded 118.856, “bladder cancer” 60.888, “schistosomiasis” 22.832, “transitional bladder cancer” 14.945, “adenocarcinoma of the prostate” 13.568, “squamous bladder cancer 3.036, “genitourinary schistosomiasis” 1.642, “squamous prostate cancer” 1.237, “schistosomiaisis AND squamous bladder cancer” 594, “prostatete cancer AND Africa” 442, “schistosomiasis AND HIV” 269, “genital schistosomiasis” 257, “male genital schistosomiasis” 212, “colon cancer AND schistosomiasis” 113, “rectum cancer AND schistosomiasis” 84, “uterine cancer AND schistosomiasis” 60, “uterus cancer AND schistosomiasis” 60, and “cervical cancer AND schistosomiasis” 56, “prostate malignancy AND schistosomiasis” 26, “scrotal schistosomiasis” 17, “testicular carcinoma AND schistosomiasis” 15, and “hydrocele AND schistosomiasis” 7 hits, respectively.

Table 1 Result of MEDLINE search on publications (search term “prostate cancer AND schistosomiasis”)
Full size table
Table 2 Cases of prostate carcinoma associated with schistosomiasis published
Full size table

Discussion

Schistosomal involvement of the genital organs has been reported mainly in infections due to S. haematobium but may occur also in relation to infections by the other species S. mansoni, S. intercalatum, S. japonicum. In men involvement of testicles, seminal vesicles, epididimus, funiculus spermaticus, testicular, scrotum and the gland have been reported (Oliveira 1951; Chaves and Figueiredo 1965; Zaher and El-Deeb 1971; Abul-Khair et al. 1980; Malik and Ibrahim 1982; Fievet et al. 1985; Omer 1985; Bambirra et al. 1986; Mikhail et al. 1988; Lukács et al. 1989; Elem et al. 1989; Wedel and Jess 1991; Githae 1992; Ihekwaba 1992; Khinev and Ralichkova 1993; Corachan et al. 1994; McKenna et al. 1997; Torresi et al. 1997; Vilana et al. 1997; Whitty et al. 2000; Schwartz et al. 2002; Richter et al. 2002; Al-Saeed et al. 2003; Alves et al. 2004; de Cassio Saito et al. 2004; Mortati Neto et al. 2004; Durand et al. 2004; Leutscher et al. 2005; Dauda and Rafindadi 2006; Pérignon et al. 2007; Lambertucci et al. 2007; Ramarokoto et al. 2008; Pawel et al. 2008; Rambau et al. 2009; Leutscher et al. 2009; Al-Qahtani and Droupy 2010; Hassan et al. 2011; Lopes et al. 2011; Periyasamy et al. 2011; Xue et al. 2011; Badmus et al. 2012; Shebel et al. 2012; Ehsani and Osunkoya 2013; Okani et al. 2013; Yu et al. 2013). Little is known on genital infections due to the less frequent species S. mekongi, S. malayensis and to infection by hybrids between human and zoonotic schistosomes, as well as S. guineensis (Moné et al. 2012). The association between urinary schistosomiasis and squamous bladder cancer is well-documented especially in Egypt although geographic differences and co-factors are not sufficiently elucidated (Honeycutt et al. 2014). Not only chronic inflammation would play a role in the development of bladder cancer but also hormonal factors which may act without the necessity that worm ova are exactly localised in the place where cancer develops (Botelho et al. 2010a, b). The association between other malignancies and schistosomiasis is by far less evident, having been postulated associations between schistosomiasis and colonic or cervical cancer (Richter 2000). Histologically, schistosomiasis-associated bladder cancer is squamous (Botelho et al. 2010a; Honeycutt et al. 2014). In Angola, schistosomiasis-associated squamous bladder cancers have been a frequent cause of death (Lopes 1983; Leitão 1989; Botelho et al. 2010a).

The frequency of schistosomal prostate infections as resulting from post-mortem studies exceeds that of diagnosis in vivo by far. In a Zimbabwen study carried out in 1970, seminal vesicles were affected in 70 %, urinary bladder in 65 %, the vas deferens in 42 % and prostate in 21 % of male corpses (Gelfand et al. 1970). In a necropsy study in Zambia on 50 cadavers, the bladder was involved by S. haematobium in 62 %, seminal vesicles in 58 % and the prostate in 50 % of cases (Patil and Elem 1988). In a recent prospective study of prostate glands from 79 post-mortem cases of Nigerian adults who died of non-prostate-related illnesses, three patients (3.8 %) had schistosomiasis with ova of S. haematobium in the prostate. In these three cases, one case of schistosomiasis was associated with adenocarcinoma, one with nodular hyperplasia of the prostate and one was pure schistosomiasis (Okani et al. 2013). An inconstant key symptom for the involvement of the male genital organs is haematospermia (Omer 1985; Corachan et al. 1994; McKenna et al. 1997; Torresi et al. 1997; Whitty et al. 2000; Schwartz et al. 2002; Durand et al. 2004; Leutscher et al. 2005, 2009; Pérignon et al. 2007; Yu et al. 2013). Abnormal semen quality may contribute to infertility, and probably partly because male genital schistosomiasis is associated with haematospermia, it may constitute a factor for the transmission of sexually transmitted diseases (Feldmeier et al. 1994; Ndeffo Mbah et al. 2013, Ndeffo Mbah et al. 2014). The suspicion of genital schistosimiasis is confirmed by microscopy of the ejaculate confirming the presence of schistosome ova. Genital schistosomiasis may cause infertility and endocrine insufficiency in women and men (Rambau et al. 2009; Leutscher et al. 2009; Kjetland et al. 2012; Schanz et al. 2010; Santos et al. 2014). The prostate gland is not seldomly involved where echogenic and calcified foci may be detected (Vilana et al. 1997; Ramarokoto et al. 2008). Since ova are not always excreted in urine, multiple stool examinations are also required. In travelers from non-endemic areas, serology may be also useful (Corachan et al. 1994; McKenna et al. 1997; Torresi et al. 1997; Whitty et al. 2000; Schwartz et al. 2002; Durand et al. 2004; Pérignon et al. 2007). Prostatic lesions are seen most frequently in S. haematobium infections but have also been reported in infections by S. mansoni, S. intercalatum, and S. japonicum (Corachan et al. 1994; Lambertucci et al. 2007; Yu et al. 2013). Increased prevalence of leukocytes and elevated cytokine levels in semen from S. haematobium-infected Madagascan men (Leutscher et al. 2005) and premalignant abnormalities have been described in a prostatic S. japonicum infection (Yu et al. 2013). Considering the high prevalence of schistosomal prostate infections and the chronic inflammatory stimulus produced as well as the well-recognised oncogenicity of S. haematobium regarding squamous bladder cancer, one would expect to find more reports on the association between schistosomiasis and prostate cancer. Looking through the literature, it is striking that, as compared to the literature on schistosomiasis-associated bladder cancer, that there are so few reports on prostate carcinoma associated with schistosomiasis and, interstingly, no report on schistosomaisis associated with testicular carcinoma (in all 15 references found in MEDLINE on testicular malignancy AND schistosomiasis, malignancy was excluded, 12 references indicated schistosomiasis mimicking a testicular malignancy [Elem et al. 1989; Wedel and Jess 1991; Githae 1992; Ihekwaba 1992; Khinev and Ralichkova 1993; de Cassio Saito et al. 2004; Mortati Neto et al. 2004; Dauda and Rafindadi 2006; Rambau et al. 2009; Al-Qahtani and Droupy 2010; Hassan et al. 2011; Periyasamy et al. 2011]).

One hypothesis that one could put forward is that the large majority of schistosomiasis-associated prostate cancers are missed by figures regarding the health care systems in schistosomiasis endemic areas. Usually, these rural areas characterized by poverty and very little access to appropriate health care. Furthermore, people from highly endemic areas who live since generations exposed to S. haematobium may interpret haematuria and hematospermia as signs which are not life-menacing or even as a parallel for sexual maturity similar to menarche in adolescent girls (Amazigo et al. 1997). Men with prostate cancer may not go to seek health care, a way which may take hours or even days of walk. When they die, this may be perceived as “slim disease”, or when a febrile bacterial superinfection occurs, death may be interpreted as a febrile malaria attack. In fact, autopsies are rarely performed in this setting. Where health care centres are available, it is extremely difficult to have histopathology examinations performed (Okesina 2009). Test methods which rose the suspicion of prostate cancer in our patient such as PSA increase or its velocity are even more seldomly available (Bolarin and Badejo 1985; Cohen et al. 1995; Thompson and Ankerst 2007; Ehsani and Osunkoya 2013). Since the advent of less invasive tools namely ultrasonography, schistosomal lesions of the genital tract as well as prostate abnormalities may be more frequently recognised in vivo (Vilana et al. 1997; Richter 2000; Richter et al. 2003; Ramarokoto et al. 2008). But, even ultrasonography is still mostly not available for the poor people of rural environments.

An alternative hypothesis to explain the rarity of prostate cancer associated with schistosomiasis might be that this association is in fact very rare and is even more rare than the one to be expected by the mere coincidence of two frequent disease conditions. Interestingly, prostate cancer was deemed to be rare in Africa, an argument which was put forward against a genetic predisposition for prostate cancer in Africans and African descendents (Houston 1968; Sherif et al. 1980; Peters and Armstrong 2005). Many reports on haematuria in endemic areas report squamous bladder cancer and specifically mention that the prostate was not involved (Powell et al. 1968; Osegbe and Amaku 1984; Al Adnani 1986; Ebert 1987; Sharfi and Hassan 1994; Nabeeh et al. 1995; Dawam et al. 2001; Mohammed et al. 2003). Moreover, in emerging countries, the decrease of schistosomiasis infections seems to be paralleled by an increase of prostate carcinoma (Magoha 2007; Parkin et al. 2008; Tindall et al. 2013). A meta-analysis of studies performed worldwide showed significant differences of incidence and outcomes of prostate cancers between rural and urban settings (Obertova et al. 2012). Former Egyptian studies indicated that although schistosomiasis was highly prevalent and incidence of squamous bladder cancer was high, prostate cancer was rare (Sherif et al. 1980). In a recent Egyptian study, i.e. a study performed in a country of high prevalence of schistosomiasis in rural settings, the incidence of prostate cancer was found to be almost five times higher in men living in urban settings which are usually free of schistosomiasis (Dey et al. 2011). Epidemiological studies have yielded evidence that actually prostate cancer is frequent in Africa (Magoha 2007; Parkin et al. 2008; Ogunbiyi 2011; Tindall et al. 2013; Laryea et al. 2014; Hsing et al. 2014; Wabinga et al. 2014; Saeed et al. 2014). Especially in emerging nations such as Egypt, Ghana, Nigeria or Brazil, increase of life expectancy and improvement of health care is to be expected to coincide with an increase of the diagnosis of prostate cancer, as it has already been observed in cancer registries of Nigeria, Ghana, Sudan and Uganda which cover mainly urban populations (Ogunbiyi 2011; Hsing et al. 2014; Laryea et al. 2014; Wabinga et al. 2014; Saeed et al. 2014). Risk factors suspected in the Western world such as sedentary life and fatty food would also affect these populations. These observations must be taken into account when interpreting statistics on the incidence of prostate cancer in schistosomiasis endemic countries.

The development of malignancies is multifactorial, and the identification of risk factors is difficult. Furthermore, not necessarily all histologic types of prostate cancer are due to the same factors. In analogy with bladder cancer, one would expect that especially squamous prostate cancer is related to schistosomiasis, whereas the most frequent type of prostate cancer described in association with schistosomiasis is adenocarcinoma (see Table 2). Interestingly, an Egyptian study observed that carcinoembryonic antigen was increased in patients with S. haematobium infection whether associated with squamous bladder carcinoma or not but not in patients with prostate cancer (Alsabti and Kamel 1979). The species most frequently described in association with prostate cancer is S. haematobium. Models to explain carcinogenesis in bladder cancer may possibly be applicable only to squamous prostate carcinoma but not to adenocarcinoma. For example, in Egypt, transitional cell bladder carcinoma has supplanted squamous cell bladder carcinoma following the decline in the prevalence of S. haematobium infection (Felix et al. 2008). It is also conceivable that human populations in co-evolution for hundreds to thousands of years with S. haematobium involving frequently the prostate gland have developed a certain immune tolerance. Individually, the severity of organ pathology is not strictly correlated to the worm burden, which means that individual genetic factors influence the inflammatory and immune response phaenotype and thus the outcome of the infection as it has been shown in S. mansoni-related liver fibrosis (King et al. 2004; Chevillard et al. 2003). Therefore, it is possible that the immune response to schistosome antigens in single patients triggers carcinogenesis, an observation that explains why some of the patients described develop their prostate cancer at a very young age below 30 years.

Conclusions

There are only very few reports on the association between schistosomiasis and prostate cancer, mainly case reports, if one considers the high prevalence of schistosomiasis in endemic areas and the high incidence of prostate cancer worldwide. The total number of patients with such a disease association published amounts to 17 cases. This scarcity of reports is partly due to the diagnostic difficulties in patients of rural endemic areas with limited access to health care and financial constraints. However, since other conditions affecting the same patient groups such as squamous bladder cancer and genital schistosomiasis are much better documented, prostate cancer related to schistosomiasis is probably rare. In individual patients with a particular genetic background and immunological phenotype schistosomiasis may contribute to the development of prostate cancer at a young age. In future, the incidence or prostate cancer must be expected to increase in Africa. The decrease of the prevalence of schistosomiasis will be statistically more than counterbalanced by the increased chance of reaching a higher age, of being diagnosed in a less resource-poor environment and by the increasing risk associated with an urban lifestyle.