Urothelial Carcinoma in Renal Transplant Recipients

1. Introduction

The risk of renal transplant recipients to develope malignant disease is significantly higher than these in general population. The incidence of malignancy is estimated to be around 15-20% of renal recipients 10 years after renal transplantation and increases as high as 49.6% after 20 years.(Alberu, 2010; Kapoor, 2008; Penn, 2000; Gaya, et al, 1995). The most common malignancies are skin carcinomas and lymphomas (Lutz & Heemann, 2003). The immunosuppressive agents play an important role in contributing to such happenings. United Network for Organ Sharing (UNOS) registry data demonstrated that mammalian target of rapamycin (mTOR) inhibitors is associated with a reduced incidence of tumors compared to regimens that do not utilize mTOR-inhibitor (Rama & Grinyo, 2010). In UK transplant registry (UKTR) database, 1.9% of patients were reported to have a subsequent urological malignancy after renal transplantation (Besarani & Cranston, 2007).

2. Urothelial carcinoma after kidney transplantation

2.1. Urologic cancer after kidney transplantation

With increasing age of donor and recipient, the risk of post-transplant malignancy including genitourinary cancers is increasing. Urologists have an increasing likelihood of treating these cases. Melchior et al reported 29 urological de novo malignancies [12 renal cell carcinoma, 8 urothelial carcinoma (6 bladder, 2 renal pelvis), 7 carcinoma of the prostate, 2 seminoma] developed in a series of 802 patients after renal transplantation (Melchior et al, 2011). The overall incidence of urological neoplasms varied from 0.38% to 3.1% (Ravaud et al, 2010). Urothelial carcinoma (UC) of the bladder is not common in Western countries (Master et al, 2004) while it is the most common genitourinary tumor following kidney transplantation in China, Iran, Taiwan and Thailand (Einollahi et al, 2009; Ativitavas et al, 2008). Among the Chinese population, urological malignancies, especially UC, are an important complication after renal transplanatation (Zhou et al, 2006). In some areas around the world, the incidence of UC (or “transitional cell carcinoma, TCC”) of the urinary tract in renal transplant recipients is singificantly higher than other parts of world. Majority of previous studies showing increased incidence of UC in renal transplant recipients came from Taiwan where it was attributed to environmental and occupational factors (Husain et al, 2009). Urinary tract UC is the leading de novo malignancy following renal transplantation in Taiwan followed by hepatoma (Wang et al, 2010; Hung et al, 2007; Liao et al, 2004; Kang et al, 2004; Kao et al, 2003; Wang et al, 2002; Yang et al, 1998). This is very different from the Western countries or other Asian countries such as Japan, Korea.

Wu at al from Taiwan reported that as high as 17.5% of renal transplanta recipients developed urinary tract UC at 10 years after transplantation. Compared with the general population in Taiwan, the standardized mortality ratio (SMR) was 398.4 among renal transplant recipients and the SMR was much higher among female patients (875.6). Painless gross hematuria was the cardinal initial symptom in 73.3% of patients (Wu et al, 2004). The male to female ratio is reported to be 1:1.7~3.5. Female predominance among these patients is uniformly found in the reports from Taiwan and China (Liao et al, 2004; Wu et al, 2004; Li et al, 2009; Wang et al, 2010). However, in our early report, although uremic patients were at greater risk of developing urologic cancer, UC was uncommon among the renal transplant recipients (Chen et al, 1995).

2.2. Carcinogenesis of urothelial carcinoma in renal transplant recipients

Among the general population, only 5% of UC arise in the upper urinary tract (UUT) and only 2.5% involved bilaterally. UUT-UC is restricted to the renal pelvis in 58% of cases, 35% in the ureter, especially in the distal ureter. Many environmental factors have been reported to contribute to the development of these cancers. Some are quite similar to bladder cancer-associated factors related to occupational and environmental exposure such as tobacco, industrial dye and certain aromatic amines, etc, while others are more specific to the carcinogenesis of the UC such as analgesic, Balkan endemic nephropathy (BEN), Chinese herb nephropathy (CHN) or association with Blackfoot disease (BFD) (Hall et al, 1998; Colin et al, 2009). In Western countries, analgesic nephropathy (AN) is implicated to contribute to development of UC following renal transplantation. UC occurred more frequently in the AN group (2.8%) than these in the control group (0.49%) (Swindle et al, 1998). In Taiwan, older age at kidney transplantation, female recipient, compound analgesics usage, Chinese herb usage, underground water intake and low educational status were the significant risk factors for the development of de novo UC (Wang et al, 2010; Liao et al, 2004).

2.2.1. Chinese herb nephropathy (Aristolochic acid nephropathy)

Chinese herbs nephropathy after taking a slimming regimen including Chinese herbs contaminated with Aristolochia fangchi was reported by Belgium groups. These patients experinced a rapid progression to renal failure compared with other interstitial nephropathies. Many patients developed UC (Vanherweghem et al, 1993; Reginster et al, 1997; Cosyns et al, 1998). Aristolochic acid contained in Chinese herbs has been proved to be nephrotoxic and carcinogenic (Thon et al, 1995). Li et al from China reported a 2-center cohort of 1,612 renal transplant recipients, the patients with aristolochic acid nephropathy (AAN) had significantly higher incidence of UC (52.9% vs 0.46% in the control group) (Li et al, 2009). Among these patienst, 88.9% involved the upper urinary tract (37.5% bilateral, 62.5% unilateral). It was more common to see UC cases in the female patients (male to female ratio of 1:3.5). These are very similar to the happenings in Taiwan, i.e., high incedence of UC in the upper urinary tract and female predominence (Hung et al, 2007; Liao et al, 2004; Kang et al, 2004; Kao et al, 2003). Bilateral nephroureterectomy has been a standard procedure for these patients. Synchronous UC in bilateral upper urinary tracts was confirmed in 36.7% of cases (Wu et al, 2004).Among the patients with bilateral upper tract UC, only 25% had bilateral abnormalities in preoperative image studies (Liao et al, 2004).

High incidence rate of UUT-UC has been described in some rural areas of the Balkans after year 1950, but it has been decreased significantly in recent 20 years (Markovic et al, 2005). Bilateral involvement (8–10%) and female predominance are the unique characterictics in these patients with BEN which are quite similar to the cases with CHN. Several studies have shown the carcinogenic potential of aristolochic acid contained in Aristolochia fangchi (contamination in some Chinese herbs) and Aristolochia clematis (a plant popularly present in the farm field of the Balkans) (Arlt et al, 2007; Laing et al, 2006; Nortier et al, 2000; Consyns et al, 1999). Debelle et al. proposed to combine BEN and CHN under one name, i.e., aristolochic acid nephropathy (Debelle et al, 2008). Chen et al reported an incresed risk for the professional personels working with Chinese herb medicine to develop chronic renal failure and urinary tract cancer. The age-adjusted relative risks of these professional personels to develop urinary tract cancer were 3.81 for male and 5.86~9.32 for female subjects. This finding supports the hypothesis that urinary tract cancer in Chinese herbalists could be related to the long-term exposure of aristolochic acid -containing herbal medicines (Chen et al, 2009; Yang et al, 2009). Lai et al using the reimbursement database of National Health Insurance from Taiwan to study 4594 patients and 174,701 control subjects (Lai et al, 2010). There was a statistically significant linear dose–response relationship between the cumulative dose of aristolochic acid and the risk of developing urinary tract cancer. Consumption of aristolochic acid–containing Chinese herbal medicine was associated with an increased risk of developing cancer of the urinary tract in a dose-dependent manner and it is independent of arsenic exposure.

2.2.2. Arsenic intoxication

An unusually high incidence of UUT-UC has been described in Taiwan. It occurred in the south-west part of Taiwan where the population was particularly susceptible to the development of UUT-UC which represented 20–25% of all UC cases. This area corresponds to the endemic area of Blackfoot disease (BFD), which is known to be a thromboangiitis of lower limbs leading to gangrene. The majority of cases required amputation of lower limbs. Contamination of drinking water with arsenic has been considered to be the reason for this endemic disease. The cases of UUT-UC in the endemic area of BFD are characterized by female predominance (male to female ratio of 1:2) and more ureteral tumors (twice as common as the renal pelvis tumors) (Tan et al, 2008; Yang et al, 2002; Chiou et al 2001, Chiang et al, 1993). The prevalence of UC in the BFD endemic area improved significantly after the government modernized the water supply system. However, for some reasons, the prevalence of UC in this area is still higher than other parts of Taiwan (Yang et al, 2005; Yang et al, 2002). Arsenic exposure is associated with an increased risk of UC. UC patients had a significantly higher sum of measured urinary arsenic species including inorganic arsenic, monomethylarsonic acid and dimethylarsinic acid (Pu et al, 2002; Chung et al, 2008). Arsenic intoxication also involves the formation of DNA adducts and DNA damage (Kato et al, 1994; Schwerdtle et al, 2003). Association between inorganic arsenic and UC risk focused on the total arsenic ingested from drinking water had been reported (Pu et al, 2002). Subjects of low exposure, were still observed to have higher UC risk in subjects with unfavorable urinary arsenic profile, i.e., pooreer function of arsenic methylation. The primary methylation index (PMI) was defined as the ratio between monomethylarsonic acid and inorganic arsenic. Secondary methylation index (SMI) was defined as the ratio between dimethylarsinic acid and monomethylarsonic acid. Unfavorable PMI and SMI levels indicate an increased risk of developing UC, especially in non-smokers although smoking has been well documented to cause carcionogesis of UC (Zeegers et al, 2000). Undetectable or negligible environmental arsenic still plays an important role (Chung et al, 2008). The arsenic levels allowed in drinking water is not greater than 5μg/L. The WHO established the water quality guidelines for drinking water which included the arsenic levels to be undetectable to less than 10μg/L (WHO 1996/1998). Actually, the average arsenic concentration in Taipei City, the capital of Taiwan, is ranged from undetectable level to 4.0 μg/L. Smoking is associated with an increased risk of UC in a dose dependent manner (Kato et al, 1994). Arsenic contamination in drinking water and smoking are synergestic in the carcinogesis of UC (Chung et al, 2008).

2.2.3. Role of virus in the carcinogenesis of urothelial carcinoma

Polyoma virus (PV), BK virus (BKV), human papillomavirus may play a role in the pathogesis of UC following renal transplantation. There is lack of data to indicate a definitive association between BKV and human cancers (Noel et al, 1994; Husain et al, 2009; Abend et al, 2009; Wang et al, 2009; Roberts et al, 2008; Chen et al, 2010). Presence of polyoma virus in the biopsy specimen may mimick high grade transitional cell carcinoma (Seftel et al, 1996).

2.2.4. Urothelial carcinoma in hemodialysis patients and renal transplant recipients

In Taiwan, UC is the most common type of urological cancer in patients with end stage renal disease (Chang et al, 2007). The cumulative incidence of UC was between 0.77% to 1.7% in hemodialysis patients and 3.1% to 4.1% in renal transplant recipients. The cases of UC in hemodialysis patients and renal transplant recipients have similar characteristics of BEN, CHN and BFD. As compared with the incidence of UC in the general population of Taiwan (10.09/100,000), the standardized incidence ratio of UC in hemodialysis is very high (48.2). Women and middle-aged patients had a higher risk. Physicians who are taking care of hemodialysis patients and renal transplant recipients should be highly alert with presence of hematuria which warrants detailed study of the entire urinary system and image study of the native and transplanted kidneys (Wang et al, 2010; Tai et al, 2009; Liao et al, 2004). Only 19.4% of patients had history of long-term consumption of Chinese herbs and 3.1% had history of using analgesic compounds (Wang et al, 2011). Contamination of drinking water is considered to be another carcinogenic factor.

3. Treatment of Urothelial carcinoma after kidney transplantation

Patients with upper tract lesions are recommended to undergo bilateral nephroureterectomy and bladder cuff resection in one session or in separate sessions (Glassman et al, 2001; Kao et al, 2004; Zhang et al, 2009). Whether postoperative intravesical instillation of chemotherapeutic agents reduces the incidence of bladder recurrence is debating. Wu et al reported that intravesical instillation of epirubicin or mitomycin C appeared to be effective in preventing bladder recurrence and in prolonging time to first bladder recurrence (Wu et al, 2010). Transurethral resection of the bladder tumor is indicated in patients with concomitant or superficial bladder lesions. Intravesical chemotherapy is started after transurethral resection and immunosuppressants are adjusted (Li et al, 2008). Laparoscopic bilateral nephroureterectomy and bladder cuff excision can be performed safely and gives similar oncologic results in experinced hands (Chen et al, 2003; Liao et al, 2004). Laparoscopic bilateral nephroureterectomy can be performed in a single session without repositioning of the patient if a specially designed inflatable cuff is used (Chueh et al, 2002). Retroperitoneal laparoscopic nephroureterectomy with bladder cuff excision can be safely performed by combining cystoscopic resection with open transperitoneal dissection. This might be a safe and feasible alternative for native UUT-UC ipsilateral to a transplanted kidney (Ye et al, 2010). Lymphovascular invasion was reported to be the only significant predictor of cancer specific survival in the univariate and multivariate analyses (Chung et al, 2009). The benefit of routine lymphadenectomy during nephroureterectomy of UC is debatable. The benefit of conversion from calcineurin inhibitors to mammalian targe of rapamycin (mTOR) inhibitors (proliferation signal inhibitors) is another debating issue. Many patients experinced recurrence of UC after bilateral nephroureterctomy and conversion to mTOR inhibitors (Chung et al, 2008; Wang et al 2008; Hu et al, 2009). Systemic chemotherapy can be performed on these patients safely and effectively (Matzkies et al, 2000; Lin et al, 2006).

4. Conclusion

UC is the leading cause of malignancy in renal transplant recipeints in some Asian countries such as China, Iran, Taiwan, Thailand, etc. It is characterized with female predominance, frequent bilateral upper urinary tract lesions. The pathogenesis of UC in renal transplant recipients is still under investigation. Aristolochic acid, arsenic intoxication, smoking and some virus may play important and complicated roles. Transplant physicians should be very alert with hematuria, hydronephrosis of native urinary tract which frequently implicates presence of UC. Bilateral nephroureterectomy in a single session or in separate sessions is recommended