Schistosomiasis and bladder cancer: similarities and ...

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THEMED ARTICLE y Bladder Cancer

Schistosomiasis and bladder cancer: similarities and differences from urothelial cancer Expert Rev. Anticancer Ther. 12(6), 753–763 (2012)

Mohamed S Zaghloul* and Iman Gouda Radiation Oncology and Pathology Departments, Children’s Cancer Hospital and National Cancer Institute, 1 Sekket El Emmam, El Sayeda Zainab, Cairo University, Cairo, Egypt *Author for correspondence: Tel.: +20 225 351 500 (ext. 1192) [email protected]

Through the years, schistosoma-associated bladder cancer was believed to be a unique entity of disease, different from urothelial cancer. As carcinogenesis is a highly complex process resulting from the accumulation of many genetic and epigenetic changes leading to alterations in the cell proliferation and regulation process, confirmation of their minute differences or similarities are extremely difficult. In bladder cancer, many of these carcinogenic cascades were not fully documented in spite of the efforts undertaken. The control of schistosomiasis and the subsequent decrease in the intensity of infestation showed feature changes approaching that of urothelial tumors. However, schistosoma-associated bladder cancer still presents in more advanced stages than schistosoma-non-associated urothelial cancer. Furthermore, many data were collected proving that, upon applying the same treatment protocol and management care, stage-by-stage comparison of the treatment end results were found to be similar in bladder cancer patients with the different etiologies. Keywords : bilharziasis • biology • bladder cancer • chemotherapy • cytogenetics • pathology • radical cystectomy • radiotherapy • schistosomiasis

Bladder cancer (BC) represents a significant worldwide health problem, with an estimated 386,300 new cases and 150,200 deaths in 2008 worldwide. The majority of BC occurs in males, and there is a 14-fold variation in incidence internationally. The highest incidence rates are found in the countries of Europe, North America and Northern Africa [1] . It is estimated that one in every 26 males and one in every 87 females in the USA will develop BC during their life [2] . Smoking and occupational exposures are the major risk factors in Western countries, whereas chronic infection with Schistosoma haematobium (SH) in developing countries, particularly in Africa and the Middle East, accounts for approximately 50% of the total burden. The majority of BCs associated with schistosomiasis are squamous cell carcinomas (SCC). Although the majority of the BC population present with disease confined to the superficial layer of the bladder wall, approximately 20–40% of the patients will present with or subsequently develop invasive cancer. BC is morphologically heterogeneous; more than www.expert-reviews.com

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90% of BC cases are urothelial carcinoma (UC; transitional cell carcinoma [TCC]), whereas primary SCC, adenocarcinoma, small cell carcinoma and other rare tumors are less common [3] . Urothelial cell carcinoma may present mixed with other malignant components. These mixed forms of bladder histologies include squamous differentiation (present in 20–60% of BC cases), adenocarcinoma or glandular differentiation (10%), sarcomatoid (7%), micropapillary (3.7%) and lympho epithelioma-like carcinoma. In many developing countries, life expectancy is much lower than in Western countries, which is one of the reasons why overall BC incidence (not agespecific incidence) is lower in these developing countries [2] . BC is associated with substantial morbidity and mortality. History of tobacco smoking not only increases the incidence of BC, but it can also increase tumor grade, size and number [4] . Chronic schistosomal cystitis was related for a long period to the development of BC in areas endemic for schistosomiasis such as Egypt. In these areas, there are many

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risk factors, including exposure to schistosomiasis, increased smoking rate and exposure to carcinogenic chemicals [5] . Although smoking is recognized as a major risk factor in the etiology of BC, the increasing incidence of BC, despite the reduction in smoking in the USA, suggests that other environmental factors may have a substantial role in the development of this cancer. On the contrary, there was a 5.14% decrease in the death rate due to BC in the USA, upon comparing the death rate in the years 1990 and 2007 [2] , owing to the success in management. Other risk factors, such as positive family history, parents’ consanguinity, exposure to pesticides and chronic cystitis, seem to play roles beside schistosomiasis and smoking in development of this disease in the developing countries such as Egypt [6] . BC formation

Urothelial tumor is characterized by its multifocality. There have been two theories proposed to explain the frequency of this urothelial tumor multifocality. The monoclonal theory suggests that multiple tumors arise from a single transformed cell that proliferates and spreads throughout the urothelium. The second theory (the field-effect theory) suggests independent transforming genetic alterations in the urothelial lining, at different sites, leading to multiple tumors [7] . This may highlight the existence of different histopathologies in the same specimen. Furthermore, many other theories have been proposed to combine the two mechanisms. It is known that the modern carcinogenesis model suggests that malignancy represents clonal expansion of one cancer stem cell that proliferates and can diversify into heterogeneous cancer cell lineages through uneven differentiation at different carcinogenic steps. This asymmetric differentiation means that following cell division, one daughter cell retains the capacity to divide while the other daughter cell possesses genetic plasticity. Through this, phenotypic variation is allowed in the offspring. A specific set of genomic, epigenomic and/or microenvironment niche alterations is essential for continued clonal expansion. As a result, each chromosomal somatic change and its pro/zaxgency possess a unique set of genetic, epigenetic and phenotypic features. Stromal somatic genetic cell alterations assist chromosomal somatic changes in the niche to promote cancer development and progression [8] . With the establishment of different new methods, detection of meaningful chromosomal changes became more apparent and allowed better understanding of the process of evolution of different kinds of cancer. Each new method widened the recognition of karyotypic changes and increased the resolution of cytogenetic details [9] . Schistosomia haematobium

According to the WHO, schistosomiasis infects 200 million people and is endemic in as many as 76 tropical developing countries. Schistosomes are parasitic blood flukes, which have a mammalian host and an intermediate invertebrate host: freshwater snails [10] . There are four human schistosomes: SH, Schistosoma mansoni, Schistosoma japonicum and Schistosoma mekonji. SH is the one associated with BC. SH, like other 754

schistosomes, is dioecious as the adult female lives in copulo in the gynecophoral canal of the male; and lives in the venules of the human urinary bladder. Eggs laid in the urinary bladder produce irritation and tissue fibrosis that may contribute to the development of human carcinogenicity [11] . All schistosoma infections follow direct contact with fresh water that harbors free-swimming larval forms of the parasite cercariae, which penetrate the skin. The cercariae shed their bifurcated tails, and the resulting schistosomula enter capillaries and lymphatic vessels en route to the lungs. After several days, the worms migrate to the portal venous system, where they mature and unite. Pairs of worms then migrate to the vesical plexus and veins draining the ureters. Egg production starts 4–6 weeks after infection and continues throughout the life of the worm, usually 3–5 years. Eggs pass from the lumen of blood vessels into adjacent tissues, and then they pass through the bladder mucosa to shed in the urine. The life cycle is completed when the eggs hatch, releasing miracidia that, in turn, infect specific freshwater snails (Bulinus species). After two generations – primary and then daughter sporocysts within the snail – cercariae are released [12] . Relation of prevalence of schistosomiasis & BC

Ferguson first linked schistosomiasis to urinary BC in Egypt in 1911 [13] . The incidence of urinary BC in the Middle East and Africa is greater in areas with high rather than low SH prevalence. The overall prevalence of SH infection in Egypt was 37–48%, which decreased due to the antibilharzial campaign to 3% [14] . Urinary BC previously accounted for approximately 31% of the total incidence of cancers in Egypt, but that subsequently decreased to 12% in recent years. However, it is still the most common type of cancer in males and the second most prevalent in females [15] . There are several factors that may contribute to the oncological potential of schistosoma infection. Schistosoma ova deposited in the bladder provoke an intense inflammatory reaction, associated with the production of oxygen-derived free radicals, which may induce genetic mutations or promote the production of carcinogenic compounds (such as N-nitrosamines and polycyclic aromatic hydrocarbons) [16,17] , leading to malignant transformation. Shokeir showed that schistosomiasis is often accompanied by chronic bacterial superinfection, which may in itself predispose to squamous cell neoplasia [18] . Bacteria that usually accompany schistosomiasis can promote the formation of N-nitrosation of amines, adding to those from other sources such as the diet. A 54–81% incidence of SCC was found in cases of BCs in endemic areas, compared with 3–10% in Western countries [19] . The International Agency for Research on Cancer found that the intensity of infection was determined by urinary egg counts and confounded by smoking, a recognized cause of BC in nonendemic countries, and the combination was strongly considered. A positive association between BC and SH infection was detected, with odds ratios ranging from 2 to 14. The more heavily infected individuals were, the more likely they were to develop BC, and at a younger age [20] . Expert Rev. Anticancer Ther. 12(6), (2012)

Schistosomiasis & bladder cancer: similarities & differences from urothelial cancer

Pathology of schistosomiasis & schistosomiasisassociated BC

Most of the pathological findings of schistosomiasis are mainly due to inflammatory and immunological responses to egg deposition. Granulomatous areas form around the eggs and induce an exudative cellular response consisting of lymphocytes, polymorphonuclear leukocytes and eosinophils. Resultant perioval granulomas, fibrosis and muscular hypertrophy are detected histologically. In the urinary bladder, masses of large granulomatous inflammatory polyp-containing eggs are found at different walls. Polyps may ulcerate and slough, producing hematuria. Hyperplasia of the urothelium was found in 38% of the autopsied SH cases, metaplasia in 31.6% and dysplasia in 27.2%. Schistosomal bladder ulcers and sandy patches, irregularly thickened or atrophic bladder mucosa, fibrosis and granulomas containing calcified or disintegrating eggs were also seen [21] . The inflammatory and fibrotic response to egg deposition could lead to calcification of the urinary bladder, infection and stone disease, and these changes are frequently associated with schistosomaassociated BC (SA-BC) [22] . Moreover, the following sequences of SH-induced events have been suggested: chronic infection leads to schistosoma eggs being trapped in the bladder wall; proliferation of cells in the bladder mucosa results from constant irritation; and frequent inflammation and clones of neoplastic cells develop. These clones were stimulated by N-nitrosamines and other environmental carcinogens such as cigarette smoke and pesticides [23] . The combined urinary retention, from fibrosis and obstruction of the urinary bladder neck, and the prolonged exposure of the bladder mucosa to various exogenous and endogenous carcinogens were suggested as predisposing factors. Schistosomeinduced urinary stasis allows increased absorption of carcinogens, and therefore plays an integral role in carcinogenesis. Recurrent bacterial urinary tract infections are associated with SCC of the urinary bladder, even in the absence of SH infection [24] . Carcinogenesis of chronic schistosomal infection

Carcinogenesis of SH involving an initiating and promoting effect has been described. First, the damage occurs to the DNA template which, unless repaired, leads to irreversible changes in the complementary strand of DNA produced during the S-phase of the cell cycle. Somatic mutation results when the altered strand is used as a template. The promotion phase is followed by the cell proliferation stimulation phase. Efforts have been made to study the specific genes involved in the induction of SA-BC. Cells exposed to SH cell total antigen (warm extract) were found to divide faster than those not exposed to the parasite and died much less. This was probably due to increased levels of BCL2, a protein involved in cancer apoptosis [25] . Mice urothelium exposed to SH total antigen showed dysplasia, low-grade intraurothelial neoplasm and noninvasive malignant flat lesions in 70% of the tested mice. Bladder carcinoma harbors gene mutations that constitutively activate the receptor tyrosine kinase Ras pathway [26] . Botelho et al. suggested that the parasite abstract may possess carcinogenic ability through oncogenic mutation of the KRAS gene [27] . www.expert-reviews.com

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Among the most common genetic changes in BC is the loss of heterozygosity on chromosomes 9p and 9q, which is found regardless of tumor grade end stage [28,29] . A prospective study stated that there was no evident line of demarcation between SA-BC and schistosoma non-associated BC (SNA-BC) in terms of loss of heterozygosity of microsatellite markers on chromosome 9. This suggests that data obtained from SA-BC can be extrapolated to BC induced via a schistosomiasis-independent mechanism [30] . BC is a very heterogeneous disease cytogenetically, which suggests that the pathogenesis of the disease may not be consistent for every case. The heterogeneity of cytogenetic findings in BC hints that there may be different ‘fingerprints’ or accumulations of genetic changes that individually lead to BC. The overexpression of the BCL-2 gene in SA-BC patients was found to be upregulated in squamous but not transitional cell cancers of the urinary bladder. Therefore, this BCL-2 overexpression is consistent with the predominance of SCC in SA-BC. Upregulation of this gene overrides programed cell apoptosis, increasing the risk of genomic instability, and may interact with various proto-oncogenes leading to tumorigenesis. Mutations of TP53 were found in 73% of tumors, BCL-2 expression in 32% and abnormalities of both TP53 and BCL-2 in 13% [31] . Furthermore, COX-2 is overexpressed in SA-BC. The role of COX-2 in the complex multistage process of SA-BC carcinogenesis was proposed: proinflammatory cytokines such as IL-1, TGF-b and TNF-a are generated by activated macrophages in the inflammatory lesions. These growth factors and cytokines are potent inducers of COX-2 production. Additional mutations may be induced: H-RAS, deletion of p16 and p15, increased EGF receptor, c-ERB-2 and TNF-a. Increased prostaglandin production upregulates COX-2, decreases killer T-cell activity and increases BCL-2 and glutathione-S-transferase. These changes increase tumorigenicity by decreasing cell apoptosis and/or creating immunosuppression. Prostaglandin products of COX-2 cause tumor progression and eventual metastasis by downregulating adhesion molecules, increasing the degradation of the extracellular matrix and increasing angiogenesis [32] . Schistosoma-associated BC

The association between SA-BC and SH was established through many studies, mostly case-controlled ones, and through the intimate correlation of the incidence of BC with the prevalence of SH within different geographic areas. This association was based on the frequent presence of parasitic eggs and egg-induced granulomatous pathology in the examined BC tissue materials. The cellular mechanisms linking SH infestation with BC formation are not yet completely determined. Severe metaplasia in bladder urothelium may represent a precancerous transformation, while in others it may be merely an indicator of prolonged inflammation, which is associated with high cancer risk [33] . It is known that keratinizing metaplasia per se has a strong association with carcinogenesis in patients with chronic irritation due to bladder stones, chronic infection or prolonged catheterization as it has with schistosomiasis. A defined characteristic pathology (i.e., SCC, TCC or adenocarcinoma, rather than mainly transitional) was established by 755

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SA-BC. Cellular and molecular biology may differ from SNA-BC. Few studies have analyzed the cytogenetic and molecular genetic abnormalities in SA-BC and some compared DNA copy number changes in SA-BC and SNA-BC [4,5,34,35] . Demonstrated deletion similarities in schistosoma-associated TCC (SA-TCC) and schistosoma-associated squamous cell carcinoma (SA-SCC) [4] were compared with what has been reported by Kallioniemi et al. on SNA-TCC [5] and Tsutsumi et al. on SNA-SCC [34] . Pools of tissue arising from patients having similar pathological types, were used to more accurately determine the change. These pooled DNAs revealed recurrent primary changes and covered the secondary changes that vary from case to case. The pooled specimens of SA-BC tumors showed no schistosomiasis-specific changes, compared with pools of SNA tumors [36] . The comparison between SA-TCC and SNA-TCC and that between SA-SCC and SNA-SCC gave similar results. Furthermore, the DNA copy number profiles of SA adenocarcinoma BC revealed similarities to that of SA-TCC and SA-SCC [37] . Detailed analysis of individual genes revealed a set of genes with the same copy number changes in all bladder carcinomas, including both SA and SNA tumors. Armengol et al. concluded that there are no major cytogenetic differences among different urinary bladder epithelial tumors, regardless of the suspected predisposed carcinogen [36] . All the detected imbalances in SA-BC have been repeatedly reported in SNA-BC, which suggested that the cytogenetic profiles of chemical- and schistosoma-induced carcinoma are largely similar in the reports of Muscheck et al. [4] and Fadl-Elmula et al. [35] . The decreased intensity of schistosomal infestation in Egypt led to a changing pattern of the clinicoepidemiologic features of SA-BC. The reported clinicoepidemiologic differences between SA-BC and SNA-BC are now continuously decreasing, and the features of SA-BC are slowly approaching that of SNA-BC as reported by Koraitim et al. [38] and Zaghloul et al. [39] . If these changes continue, BC in Egypt is expected to become identical in features to that of Western countries in the near future [15,39] . Clinical presentation

Clinical presentations in SA-BC and SNA-BC are similar, with a few minor differences. Hematuria, dysuria and necroturia are the main symptoms in both situations. However, SA-BC patients have usually experienced these symptoms beforehand as a result of simple schistosomal cystitis. This may be the reason of their relatively late presentation. Table 1 shows the postcystectomy pathological staging in large SA-BC and SNA-BC studies. The early stages (Pa, Pis and P1) were fewer in SA-BC than that in SNA-BC (urothelial and nonurothelial). The pelvic nodal involvement was nearly similar in SA-BC (range: 16.7–25.5%), urothelial SNA-BC (range: 16.3–45%) and nonurothelial SNA-BC (range: 21.8–23%). The clinicopathologic differences between SA-BC and SNA-BC were previously summarized as: late presentation; younger median age; and a higher percentage of SCC [40] . Distant metastases are similar in SA-BC and SNA-BC, including the different histopathological variants. In a study including 357 SA-BC patients, the 5-year incidence of distant metastasis was 23%. The 5-year actuarial incidence of distant metastasis varied according 756

to the tumor cell type. SCC led to a distant metastasis incidence rate of 15% at 5 years, whereas the transitional cell variety led to a distant metastasis incidence of 39. The metastasis rates were 57% for adenocarcinoma. Although this difference was statistically significant on univariate analysis, it was not statistically significant when multivariate analysis was applied [41] . Similarly, the incidence of distant metastasis in urothelial cancer ranged from 12 to 35% [42,43] . Locoregional recurrence with or without distant metastasis was found in 5–31% of the patients treated with radical cystectomy (RC), depending on their clinical and pathological features [44] . Factors associated with local recurrence are generally the same as that determining distant metastasis, namely pathologic tumor stage, grade and regional nodal involvement together with the lymphadenectomy extent. Rates of local recurrence were reported as 6, 18 and 51% in patients with stage pT1, pT2 and pT3, respectively, in a SNA-BC study [44] . The 5-year local recurrence rate increased with higher stage, and it reached 11, 23 and 31% for stages II, III and IV, respectively, as shown in another SNA-BC study [45] . In a third study, the local recurrence rate at 10 years was reported to be 25% for pT3, 51% for pT4 and 49% in nodepositive patients [46] . A fourth study showed that the 10-year recurrence rate was 48.6% [47] . Out of the 444 SNA-BC patients with relapse, 182 (41%) patients experienced local recurrence and 324 (73%) patients developed distant metastasis at the time of first relapse [47] . Furthermore, Gupta et al. reported 145 BC recurrences out of 502 patients (29%) who underwent RC [48] . Of these, 40 (27.6%) patients had local pelvic recurrence while 105 (72.4%) patients developed distant metastasis. Similar results of locoregional recurrences were repeatedly reported in SA-BC [49–53] . Treatment of non-muscle-invasive BC

Treatment of non-muscle-invasive (superficial) BC remains as transurethral resection of the bladder tumor with or without intravesical Bacille Calmette–Guérin or chemotherapy instillation, according to the tumor risk status. Although this treatment type is very popular in urothelial cancer, it is less popular in SA-BC and nonurothelial SNA-BC, probably due to the lower number of noninvasive stages and the prevalence of many precancerous or cancerous lesions in the bladder mucosa. Treatment of muscle-invasive BC Radical cystectomy

Muscle-invasive BC is mostly treated with RC in many parts of the world. The RC procedure includes removal of the bladder, seminal vesicles and prostate together with perivesical fat and peritoneal coverage, in addition to bilateral endopelvic lymphadenectomy (with varying levels of dissection) in male patients. In females, it includes removal of the bladder, its perivesical fat and peritoneal coverage, urethra, uterus, ovary and anterior wall of the vagina (anterior pelvic excentration) [52–54] . A review of recent literature of treatment end-results of different types of BC showed that applying the same treatment yielded nearly the same level of results in the identical pathological stage [51,55] . Similar 5-year overall survival rates were achieved in SA-BC, Expert Rev. Anticancer Ther. 12(6), (2012)


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pure urothelial and combined urothelial and Table 1. Postcystectomy pathological stages and nodal involvement nonurothelial SNA-BC types (Table 2) . The in pure urothelial and mixed urothelial and nonurothelial results were slightly higher in the Stein et al. schistosoma-non-associated and schistosoma-associated bladder (SNA-BC) [54] and Zaghloul studies (SAcancer in large series. BC) [51] . Both studies reported neoadjuvant Patients PTa,is,1 PT2 PT3 PT4 Nodal Ref. or adjuvant radiotherapy and/or chemo- Study (year) (n) (%) (%) (%) (%) involvement therapy as a part of treatment in more than one-third of their patients. Furthermore, SNA-BC (pure urothelial carcinoma) this conclusion applies for the comparison of Bassi et al. (1999) 338 [82] 32.8 19.8 42.0 19.8 NM disease-free survival, overall survival or local [54] 39.9 23.5 23.5 13.0 23.3 control rates for RC, or even in adjuvant and Stein et al. (2001) 1057 [46] 303 36.1 28.6 25.5 9.9 16.3 neoadjuvant radiotherapy types of treatment Cheng et al. (2000) for SA-BC and SNA-BC [51,55] . The treatment end-results of RC were not affected [83] 958 22.0 35.0 31.0 12.0 23.0 by the association with schistosomiasis, nor Shariat et al. (2006) tumor cell type (urothelial or nonurothelial) in most of the recently published literature SNA-BC (urothelial and nonurothelial) (Table 2) [52,54,56] . Favorable end-results were [58] Rogers et al. 955 21.0 33.0 32.0 14.0 23.0 reported for patients with pathologically (2006) organ-confined disease. These results were [84] Lughezzani et al. 12003 13.4 38.9 28.1 19.6 21.8 constant for both SA-BC (ranged from 47 (2010) to 83%), and SNA-BC (ranged from 50 to [59] 1422 14.8 29.0 29.3 26.8 84%). However, the results were signifi- Scosyrev et al. (2009) cantly worse when reporting upon locally advanced tumors (PT3N0M0, PT4aN0M0 SA-BC (urothelial and nonurothelial) [49] or Any N). Again, worse results were experi- El Said et al. 420 1.0 3.8 70.7 24.5 16.7 (1979) enced by both SA-BC and SNA-BC patients [52,54,56,57] . Despite the old belief that aber- Zaghloul (1996) [41] 357 0.0 33.3 47.9 18.8 24.4 rant differentiation leads to worse results, [85] El-Mekresh et al. 185 7.0 25.0 64.0 7.0 16.0 many authors reported similar results of (1998) these variants to UC when comparing stage [50] 192 3.6 28.1 51.6 16.7 25.5 to stage. Rogers et al. reported a 5-year Zaghloul et al. (1992) progression-free survival rate of 60 ± 2% [53] 2720 10.5 63.9 16.6 9.0 20.4 after RC for UC and 55 ± 11% for SCC Ghoneim et al. (2008) [58] . This difference was statistically insig[39] 5071 1.9 30.1 54.9 13.1 21.9 nificant. Patients with UC or SCC had Zaghloul et al. (2008) statistically significant higher progression[86] free survival rates than non-UC non-SCC Khaled et al. 180 1.2 5.8 14.1 11.5 16.6 (2005) patients, including those with adenocarcinoma. Another study containing a Ali-El-Dein (2009) 180 [87] 10.0 62.8 25.0 2.2 18.3 considerable number of adenocarcinoma NM: Not mentioned; SA-BC: Schistosoma-associated bladder cancer; SNA-BC: Schistosoma-non-associated patients conducted using the Surveillance, bladder cancer. Epidemiology and End Results (SEER) 17 database showed no difference of statistical significance in adeno- treated in The Netherlands during a 12-year period (1995–2006) carcinoma patients who underwent RC than their UC counter- [60] . They concluded that the relative survival of muscle-invasive parts. Another recent study using a similar SEER database dem- adenocarcinoma patients was equal to that of UC patients. For onstrated that SCC was more aggressive than urothelial cancer stage II and III disease, adenocarcinoma patients had even better after adjusting for common prognostic factors, such as stage and outcomes. Muscle-invasive SCC patients showed worse survival grade [59] . Scosyrev et al. concluded that SCC was an indepen- regardless of stage. In SA-BC, Ghoneim et al. demonstrated that dent predictor of mortality among patients with stage III and IV 1345 SCC patients had a 10-year overall survival (OS) rate of disease, and among patients with stage I and II disease who did 53% compared with 48% for pure UC (705 patients) and 51% for not undergo cystectomy as part of their treatment [59] . Therefore, adenocarcinoma (262 patients) [53] . Those patients who had UC squamous histology was not associated with increased mortality with squamous or adenomatous metaplasia (286 patients) showed among patients with stage I and II disease when treated with a lower 10‑year OS of 43%. The lowest 10-year OS was expecystectomy. Moreover, Ploeg et al. studied all invasive BC cases rienced by those patients who had undifferentiated pathology www.expert-reviews.com

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sterilize microscopic extensions in the perivesical tissues. Only six randomized trials addressed the issue of adding preoperative radiotherapy to RC in the English litStudy (year) Patients PT1 PT2 PT3 PT4 Nodal Ref. erature. Two of these six studies were on (n) (%) (%) (%) (%) involvement SA-BC patients [61,62] . Only one out of the six trials showed a benefit for adding SNA-BC (pure urothelial carcinoma) [46] preoperative radiotherapy [61] . Most of the Cheng et al. (2000) 218 50 28 17 11 other five studies showed that the benefi[54] cial effect was restricted to high-stage and Stein et al. (2001) 1054 74 81/68† 47 44 35 [88] high-grade tumors, with no difference in Madersbacher et al. 507 76 62 40 49 26 (2003) early cases. Meta-analysis of these random[57] ized studies showed a corrected odds ratio Takahashi et al. (2004) 466 81 74 47 38 50 of 0.94, indicating no benefit for adding [89] Dhar et al. (2006) 385 63 19 NM 9 preoperative radiotherapy in BC [63] . [90] Ho et al. (2009) 148 77 68 65 11 37 Postoperative radiotherapy (PORT) has [91] the advantage of dealing with microscopic Manoharan et al. 432 79 60 43 17 22 cells that are easier to sterilize. It allows (2009) better identification of the group of patients SNA-BC (urothelial and nonurothelial) that may benefit from this adjuvant ther[92] Nishiyama et al. 1113 82 84/69† 59 43 35 apy. One large prospective randomized (2004) trial proved the benefit of PORT in locally [93] Niu et al. (2008) 356 73/44† 22 0 8 advanced SA-BC. The 5-year disease-free survival rate was 49 and 44% for hyper † [48] Gupta et al. (2008) 502 90 78 70/58 46 NM fractionated (HF) and conventional fracSA-BC (urothelial and nonurothelial) tionation (CF) PORT, respectively, com[52] pared with 25% for cystectomy-alone Ghoneim et al. (1997) 1026 73 66 47/31† 19 23 [85] patients [50] . This effect was constant across El-Mekresh et al. 185 83 41 21 all tumor cell types, all muscle-invasive (1998) [86] stages and grades in SA-BC. Similar results Khaled et al. (2005) 180 55 12 6 were replicated in a nonrandomized, pro[50] Zaghloul et al. (1992) 192 100 100/47 40 44 31 spective, controlled Radiation Therapy [94] Zaghloul et al. (2007) 216 100 51 40 30 31 Oncology Group trial on SNA-BC [64] . [53] The results of the two studies were nearly Ghoneim et al. (2008) 2720 82 75/53 40 30 27 identical when compared stage by stage † a/b. NM: Not mentioned; SA-BC: Schistosoma-associated bladder cancer; SNA-BC: Schistosoma-non-associated [40] . The only difference was that the bladder cancer. Radiation Therapy Oncology Group trial (122 patients), with a 10-year OS of 34%. It is clear from this reported a high gastrointestinal tract (GIT) late complication large-number, single-institution study that the OS rates of SCC, rate [64] . Intestinal obstruction was reported in 37% (15 out of UC and adenocarcinoma were similar and had the same profile as 40 patients) after PORT. Nine of these 15 patients required surthat of SNA-BC. They demonstrated that although the univariate gery and three died. On the contrary, Zaghloul et al. reported analysis was significant (undifferentiated carcinoma had much 5 and 18% all grades of late GIT complications for the HF and lower OS), the multivariate analysis proved that tumor cell type CF groups, respectively [50] . Only 4 and 5% of the HF and CF is not an independent working factor determining OS. Many groups, respectively, necessitated surgical interference. Similar authors cautiously concluded that RC treatment end-results low levels of late GIT complications were experienced by other were not affected by tumor histology or etiology but affected by retrospective studies reported on SA-BC and SNA-BC [65–67] . other prognostic factors such as stage, grade, nodal involvement, The differences between late GIT complications were related lymphovascular invasion, angiogenesis, P53, P21, retinoblastoma to the difference in radiation volume in different studies and genes and other biological factors. These prognostic and predictor not to association with schistosomiasis [55] . factors were shown in many SA-BC and SNA-BC studies with In a prospective, randomized trial, El-Moneim et al. comvarying weight effects [53,55,59,60] . pared preoperative and postoperative radiotherapy in SA-BC [68] . They administered the same dose of 50 Gy in 5 weeks to Preoperative & postoperative radiotherapy both groups. The study reported both similar treatment endThe rationale of preoperative radiotherapy is to prevent intra- results and late complication rates for pre- and post-operative operative seeding of tumor cells in the operative field and to radiotherapy. Table 2. The 5-year survival of each pathological stage in schistosoma-non-associated and schistosoma-associated bladder cancer patients in large series of radical cystectomy.

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Neoadjuvant & adjuvant chemotherapy

Neoadjuvant and adjuvant chemotherapy have been utilized in BC, in an attempt to improve the outcomes for patients with high-risk muscle-invasive disease. Several meta-analyses of prospective, randomized trials indicated that patients who underwent neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin prior to cystectomy have an approximate 5.0–6.5% survival advantage over those who underwent surgery alone [69,70] . However, some investigators continue to argue that this neoadjuvant advantage is small and chemotherapy may be better targeted to those at highest risk of relapse after surgery. Furthermore, many elderly patients or those who have comorbidities will not tolerate methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy. Therefore, many investigators tried adjuvant chemotherapy in a supposedly more favorable situation. In reality, adjuvant chemotherapy yielded a modest, statistically significant improvement in survival of SNA-BC patients over cystectomy alone [71,72] . The Egyptian Bladder Cancer Cooperative Group compared neoadjuvant chemotherapy using a gemcitabine–cisplatin regimen to cystectomy alone in 109 SA-BC patients in a prospective, controlled, randomized study. The 1-year survival rate was 54% for the cystectomy-alone patients compared with 69% for the neoadjuvant chemotherapy patients [73] . However, this difference did not rank to the level of significance. Bladder preservation trimodality treatment

Since the late 1980s, many centers investigated the bladder preservation strategy as an alternative to RC. The rationale of this strategy depends on three goals: first, eradication of the local disease; second, elimination of potential micrometastasis; and third, maintenance of the best possible quality of life through organ preservation [74] . Several treatment protocols were carried out by different investigators. However, they all comprised three essential procedures, with varying timing and varying minute details. The first main procedure is maximal transurethral resection of the bladder tumor. This is to be followed by the second procedure: neoadjuvant chemotherapy or radiochemotherapy followed by cystoscopic assessment. The

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third procedure is either radical radiotherapy or consolidation radiochemotherapy for the complete responders. Cystoscopic assessment will segregate the complete responder (CR) for bladder-conserving management and those showing less than CR to undergo salvage cystectomy [75] . The 5-year OS rates ranged between 39 and 58%, and the 5-year survival with native bladder preservation ranged from 36 to 43% [76–80] . Sabaa et al. reported similar results for UC (SA-BC and SNA-BC) in Egypt using a trimodality treatment [81] . Complete remission was achieved in 79% of cases after initial radiochemotherapy using a gemcitabine–cisplatin regimen. The 5-year OS rate for patients with initial CR was 68%, which is comparable to the results in SNA-BC in Western countries treated with trimodality therapy. Moreover, Sabaa et al. found that the association with schistosomiasis had no significant impact on the results of therapy for the patient [81] . Expert commentary & five-year view

Schistosomiasis that prevails in many countries has a documented association with SA-BC. This disease represented a major health problem in these countries. For a long time, SA-BC was considered a completely different entity, with very few features in common with urothelial cancer. Many investigators considered the state-of-the-art recommendations for urothelial cancer not applicable for SA-BC, and vice versa. The carcinogenic, cytogenetic and epigenetic techniques are sensitive and complex procedures. Therefore extreme caution in performing and interpretation is needed when searching for common criteria that identify certain disease. Minor deviation in the technique may lead to a major defect in the results. Closer and more careful consideration of the biological, genetic, cytogenetic and histopathological characteristics of SA-BC showed great similarity to urothelial cancer in many aspects. With the continuous advancement in healthcare in schistosoma-endemic areas, the management of SA-BC followed, to a great extent, the recommendations for urothelial tumors. The reported treatment end-results for different modalities (surgery, neoadjuvant, adjuvant radiotherapy or chemotherapy and trimodality treatments, among others) showed similar results

Key issues • Muscle-invasive cancer represents 20–40% of urothelial cancer and a higher percentage of nonurothelial variants, particularly in schistosoma-associated bladder cancer (SA-BC). • Bladder cancer is characterized by its multiplicity. Some of the foci may show heterogeneous dysplastic or metaplastic differentiation and may appear as a variant histopathology. • Schistosoma infection produces inflammatory, immunological and fibrotic tissue responses that may be carcinogenic, especially in combination with other factors such as smoking, pesticides and other chemical exposure. • Exposure to Schistosoma haematobium total antigen resulted in the development of bladder cancer in experimental animal urothelium. • Although no entirely specific cytogenetic aberrations have been identified for bladder cancer, various nonrandom deletions, gains of chromosomes, polyploidization and formation of isochromosomes have been observed. These observations depend upon the applied technique. • There are no documented significant differences in clinical presentation or the natural history of SA-BC and schistosoma-non-associated bladder cancer. • The radical cystectomy, adjuvant or neoadjuvant radiotherapy or chemotherapy treatment end-results did not differ in SA-BC from that of schistosoma-non-associated bladder cancer after controlling for stage, grade and nodal involvement.

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to that of urothelial cancer. Similarities between SA-BC and SNA-BC with its urothelial and nonurothelial entities are now evident, although not reaching level 1 evidence-base level. There is no direct randomized trial comparing any of the recommended treatment modalities in SA-BC and urothelial or nonurothelial SNA-BC. The coming years may allow prospective, randomized, multicentric trials comparing SA-BC and SNA-BC that will serve patients in both categories. The application of evidence-base recommendations in the treatment of BC regardless of its etiology may improve the treatment end-results, including quality of life. The availability of large References

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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