What is the incidence of bladder cancer in a normal population compared to individuals with an augmented bladder?

The incidence for the development of a bladder neoplasm following ileocystoplasty or colocystoplasty is approximately 1.5% per decade post augmentation. [Husmann and Rathbun, 2008] The risk for cancer following a gastric cystoplasty appears to be elevated above this level at a risk of approximately 2.8% per decade post augmentation [Vemulakonda et al. 2008; Balachandra et al. 2007].

By extrapolation of the current data by the 6th decade of life (>50 yrs of age) the incidence of bladder cancer in patients with an enteric bladder augmention will be 5–6%, and in gastric augments will be 10–12%. Based on US statistics the incidence of bladder cancer in this age range would be 0.7%. These findings suggests patients will have a 7–8 fold increased risk of malignancy following an ileal or colonic augmentation and a 14–15 fold increased risk following gastric augmentation [Ries et al. 2008].

What is the normal incidence of cancer in the augmenting segment?

Patients in the 6th decade of life with colonic bladder augmentations will have a 5–6% risk of developing a cancer, this incidence is identical to the 5–6% risk of developing a colonic adenocarcinoma of the bowel by that age [Husmann and Rathbun, 2008; Ries et al. 2008; Barrington et al. 1997a]. Based on this information it appears that the colon, when used for bladder augmentation, will not be at an increased risk for neoplasia above that of the normal. In contrast, approximately 5–6% of patients with an ileal augmentation will develop a malignancy of the bladder, since the incidence of carcinoma developing in the small bowel is relatively low – approximately 0.1% – this represents a 40–50 fold increased risk [Husmann and Rathbun, 2008; Ries et al. 2008; Barrington et al. 1997a]. Long-term follow-up of gastric bladder augmentations suggests the incidence of malignancy in these augmentations should be 10–12% by 6th decade of life, the risk of gastric neoplasia in the US population in this age range is 0.3%, representing a 30–40 fold increased risk [Ries et al. 2008; Vemulakonda et al. 2008; Balachandra et al. 2007]. The current published data suggests that the segment of bowl used in augmenting the bladder may impact the incidence of subsequent bladder malignancy. This finding is not novel and has been documented for several decades. [Filmer and Spencer, 1990; Husmann and Spence, 1990] Indeed, the physician must be aware that the risk of malignancy in gastrointestinal bladder augmentations will be a composite of all tissues involved.

In our review of the literature we also became concerned that gastrocystoplasty maybe an independent risk factor for the development of bladder cancer. This concern is based on the relatively high incidence of malignancy reported in this patient population during relatively short follow-up intervals [Vemulakonda et al. 2008; Castellan et al. 2007]. The concern is heightened by the frequent finding of gastric atrophy in surgical specimens and biopsies [Vemulakonda et al. 2008; Castellan et al. 2007; Take et al. 2007; Baydar et al. 2005; Ngan et al. 1993]. Gastric atrophy is a known premalignant condition that arises as a consequence of the Correa cascade. The latter phenomena is a multi-step process by which inflammation stimulates the host's immune response, the immunologic response can lead to gastric atrophy, intestinal metaplasia, epithelia dysplasia and eventually the development of invasive carcinoma [Take et al. 2007; Vajda et al. 2005; Qui et al. 2003; Vajda and Kaiser, 2002]. An increased risk of cancer is also of concern in composite gastic enteric bladder augments, this procedure mimics that of Bilroth II procedures where gastroenterotomies (gastric jejunal anastamosis) were performed for benign disease, these procedures were later found to be associated with frequent cancer development [Husmann and Rathbun, 2008; Baydar et al. 2005; Schafer et al. 1983].

Is the bladder we are augmenting at the normal risk for developing cancer or does it have an inherent increased risk for malignancy?

Our ability to assess if bladder augmentation is an independent risk factor for developing a malignancy is severely impact by inadequate information regarding the inherent risk of malignancy that may exist in the congenitally aberrant bladders [Woodhouse et al. 2006; Smeulders and Woodhouse, 2001; Shapiro et al. 1998]. Our assumptions are that the bladders we are augmenting are at normal risk for developing a malignancy; the increased frequency of malignancy following a bladder augment would then be attributed to the performance of the bladder augmentation. This assumption appears to be invalid. Indeed it is well-documented that the exstrophic bladder and, it is strongly suggested, the neurogenic bladder are at a significantly increased risk for developing bladder cancer [Austin et al. 2007; Michaud, 2007; Woodhouse et al. 2006; Smeulders and Woodhouse, 2001]. Additional problems exist in the calculating the risk for the development of cancer due to failure of reporting authors to report on multiple associated factors that may have played a role in cancer development. Specifically, genetic predisposition to the development of cancer, tobacco/immunosuppressive usage, exposure to of the patient to environmental toxins, the incidence of chronic bacteriuria, and recurrent bladder calculi may all impact the incidence of bladder cancer. Unfortunately the published studies rarely, if ever, report on the presence of these independent risk factors [Jankovic and Radosavljevic, 2007; Michaud, 2007; Pelucchi et al. 2006]. In essence, published data is unable to determine if gastrointestinal augmentation is an independent risk factor for cancer over the inherent risk of cancer arising from a congenitally abnormal bladder.

Etiology of cancer in bladder augmentations

It is believed that cancer arises within the augmented bladder due to either one or a combination of several of the following. (1) Chronic bacteriuria inducing nitrosamines and producing toxic oxygen radicals, both of which can induce DNA mutagenesis. (2) A direct toxic effect of the urine on the enteric epithelium. (3) The removal of the enteric epithelium from a intraluminal nutritional supplies (diversion enteritis or starvation enteritis). (4) Aberrant intercellular cell signaling mechanisms arising from mesenchymal-epithelial interactions of the disparate intestinal and urothelial tissues [Husmann and Rathbun, 2008; Dyer et al. 2005; Ali-El-Dein et al. 2002].

In general it is believed that a chronic infection is the primary stimulus for the development of bladder cancer. This hypothesis is based on the high incidence of chronic bacteriuria, found within this patient population [Husmann and Rathbun 2008]. In fact, it was originally hypothesized that gastrocystoplasties would be more resistant to malignant transformation than enteric cystoplasties due to the relative absence of chronic bacteriuria, 13% versus 55% respectively [Husmann and Rathbun, 2008; Baydar et al. 2005; Vajda et al. 2005]. Unfortunately as noted previously, this has not been found to be true. Also refuting the hypothesis that chronic bacteriuria is the etiology of cancer is the finding that there is no significant correlation between chronic bacteriuria and cancer development. Specifically, in patients undergoing a enteric augmentation where no cancer developed 56% of all urine cultures were positive, in comparison in the patients where cancer developed bacteriuria was noted on 54% of the urine cultures which shows no significant difference between the two patient populations [Husmann and Rathbun, 2008]. Further supporting the fact that bacteriuria may not play a major role in cancer development and also aiding in the substantiation that an inherent bladder abnormality within dysfunctional bladders could possibly be leading to a malignancy is an excellent study by Barrington and associates [Barrington et al. 1997a]. This paper investigates the hypothesis that enterocystoplasty would be associated with cancer development due to the deficiency in intracellular antioxidant activity. This antioxidant deficiency would lead to increased toxic oxygen radical production and thereby increased DNA mutagenesis. These authors investigated 3 patient populations’ neuropathic bladders with and without augmentation and normal controls. This study found significant antioxidant deficiencies of equal nature in patients following enterocystoplasty and in the non augmented neuropathic bladders compared to normal controls, (p<0.001) [Barrington et al. 1997b]. This data certainly supports the concept that patients with congenital bladder dysfunction are at high risk for mutagensis whether or not an enterocystoplasty is present.