Urological Cancers And Kidney Transplantation: A Literature Review

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Abstract

Purpose of Review： The aim of this review is to provide an overview of epidemiology, risk factors, and treatment of urological malignancies in renal transplant recipients (RTR). Recent Findings： Although optimal immunosuppressive therapy and cancer management in these patients remains controversial, adherence to general guidelines is recommended. Summary： Kidney transplantation is recognized as the standard of care for the treatment of end-stage renal disease (ESRD) as it offers prolonged survival and better quality of life. In the last decades, survival of RTRs has increased as a result of improved immunosuppressive therapy; nonetheless, the risk of developing cancer is higher among RTRs compared to the general population. Urological malignancies are the second most common after hematological cancer and often have more aggressive behavior and poor prognosis.

Keywords Urological cancer · Kidney transplantation · Immunosuppressive agents

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Introduction

Kidney transplantation is considered the gold standard treatment for ESRD as it notably decreases mortality and improves the quality of life. Nevertheless, as immunosuppressive therapy extends graft survival, malignancy risk is increased among these patients [1, 2]. Urological cancers have a higher incidence among RTRs when compared to non-transplanted patients; hence, the development of new urological malignancies in RTRs decreases overall survival.

Management in RTRs with urological cancer de novo is still controversial and adjustments in immunosuppressive therapy represent a challenge for the specialist [3]. The aim of this review is to provide an overview of epidemiology, risk factors, and treatment of urological malignancies in RTRs.

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Renal Transplantation and Prostate Cancer

Prostate cancer (PCa) is the most frequent non-cutaneous malignant tumor in men, with a trend suggesting an increasing worldwide incidence [4]. Often, men on the waiting list for kidney transplants (KT) are in the same age group of risk for PCa. Since strong recommendations for the early detection of this malignancy in this specific group are lacking, the same principles for the general population are followed [5]. Although RTRs are at higher risk for the development of malignant tumors than the general population, the evidence regarding PCa is less convincing [6]. Recently, Carvalho and colleagues demonstrated a clinical incidence of PCa of 1.1% in patients who underwent KT [7]. On the other hand, Ochoa and colleagues found that only 0.1% out of 1256 RTRs developed PCa [2]. Regarding age, PCa is diagnosed earlier in RTRs when compared to the general population [8], possibly as a consequence of a thorough preoperative clinical evaluation.

The association between carcinogenesis and immuno- suppressive therapy in RTRs is not clear; thus, the long-term risk of developing cancer remains controversial [9]. Cyclosporin A (CYA) did not show any difference in cancer incidence when compared to placebo among RTRs in long-term trials [10]. Moreover, comparisons between CYA and tacrolimus reported no difference in de novo cancer development in RTRs [11]. Azathioprine (AZA) has also not been associated with an increased long-term risk for PCa, with comparable outcomes to CYA [7, 10]. Regarding mycophenolate mofetil (MMF), the Collaborative Transplant Study and Organ Procurement and Transplantation Network/ United Network for Organ Sharing (OPTN/UNOS) prospective database analysis showed no increased risk for the development of lymphoproliferative cancer and other malignancies when compared to non-MMF regimes, with even longer time to diagnosis of malignancy in the MMF group [12]. The mammalian target of rapamycin (mTOR) inhibitor, sirolimus, has been associated with a lower risk of malignancy (HR 0.60, 95% CI 0.39–0.93) with an even greater reduction in patients switching from other regimens to sirolimus [13]. In a recent study, Bratt and colleagues demonstrated that immunosuppressive therapy did not increase the overall risk of PCa in RTRs [14].

Despite recent controversies, risk-adjusted screening for PCa is still recommended for men older than 50 with prostate-specific antigen test (PSA) and digital rectal exam (DRE)-based evaluation [15]. However, this recommendation is questionable in RTRs, as the development of this malignancy is not that high in this group of patients [16, 17]. The American Society of Nephrology states that all RTRs older than 50, having a life expectancy longer than 10 years, should be screened for PCa [18]. As previously mentioned, there is no evidence that immunosuppressive therapy contributes to a higher risk for PCa; thus, careful selection of candidates to undergo screening for PCa is essential [19].

Multiparametric magnetic resonance imaging (mpMRI) is a well-established tool for the detection of suspicious areas prior to prostate biopsy; although this has not been studied in the particular setting of RTRs, mpMRI has become of paramount relevance in the diagnostic pathway [20]. As in the general population, diagnostic procedures to rule out PCa in RTRs include transperineal and/or transrectal ultrasound (TRUS)-guided prostate biopsies as these procedures are well tolerated in patients receiving immunosuppression therapy. Recommended antibiotic prophylaxis for TRUS- guided prostate biopsy in RTRs should be the same for the general population and according to local antimicrobial resistance patterns [15, 21].

Almost every treatment strategy for patients diagnosed with PCa can be recommended to RTRs [22]. Radical prostatectomy (RP) in RTRs involves a unique challenge due to changes in genitourinary/pelvic anatomy (including the distortion of the peritoneum and small bowel in patients with a history of peritoneal dialysis), the possible compromise to graft function, and the risk of surgical site infection, and to the impossibility to perform a complete lymph node dissection (LND) [22]. Despite these issues, it has been demonstrated that RP is a reasonable option for the treatment of localized PCa [23–25]. Carvalho and colleagues reported that, after a median follow-up of 14 years, the overall survival was 65% in RTRs with an initial PSA of 6 ng/mL and Gleason scores mostly of 7 (3 + 4) and 6 (3 + 3), with only 2 patients developing bone metastases [7]. Regarding surgical techniques, retropubic radical prostatectomy (RRP) is the most studied approach in RTRs [26, 27]. Interestingly, it has been described that this group of patients has a higher risk of bacteremia when compared to the control group (15% vs 2.5%) [28]. Perineal radical prostatectomy (PRP) prevents ureteral and graft injury without compromising second access for a re-transplantation. Conversely, LND is not feasible by this approach [29]. When comparing RRP and PRP, both are safe options for the management of localized PCa in RTRs [30]. Minimally invasive techniques, such as laparoscopic radical prostatectomy (LRP) and robotic-assisted radical prostatectomy (RARP), have also been evaluated in the setting of RTRs with PCa. LRP is a safe option, whether it is transperitoneal or extraperitoneal [31]. Robert and colleagues found no differences in oncological outcomes, but a higher incidence of rectal injury when compared to the control group (22.2% vs. 1.8%) [32]. RARP is also a safe and feasible technique among RTRs [33, 34]. Leonard and colleagues reported no difference in terms of postoperative complications and renal graft function between RTRs and the control group; nonetheless, a shorter biochemical recurrence (BCR) free survival in RTRs was observed (HR = 4.29, p < 0.001) [35]. Mistretta and colleagues reported two diferent RARP approaches in RTRs: the Retzius-sparing technique versus the transperitoneal approach, concluding that both techniques are reasonable and safe [36]. When comparing RRP, LRP, and RARP, no difference in postoperative, oncological, and renal graft function outcomes were found among procedures [37].

Radiation therapy (RT) is a feasible alternative for localized PCa using radiation dosages of 74 Gy and 76 Gy, as there are several studies showing no compromise to graft function in RTRs as long as special caution for avoiding upper pelvic areas to prevent graft injury is taken [38–40]. However, there are still concerns about nephritis and strictures, complications described with this modality [41].

In patients with locally advanced or advanced PCa, androgen deprivation therapy (ADT) has high overall and cancer-specific survival rates of 88%. It is suggested to assess cardiovascular risk before starting ADT in RTRs [25, 42]. Since specific recommendations for treating metastatic PCa in RTRs are lacking, general population guidelines should be followed.

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Renal Transplantation and Bladder Cancer

When compared to the general population, the incidence of any cancer in RTRs is 2.8–4.1 times higher [43, 44]; when it comes to urothelial tumors, the incidence is 3.1 to 3.5 times higher [44–47]. The mean age an RTR presents with urothelial cancer (UC) is 56 years old compared to 70 in the general population [48]. Bladder cancer (BC) risk is higher among RTRs; women have a HR of 30.24 (95% CI: 7.34–124.53; p < 0.001) and men a HR of 5.19 (95% CI: 1.27–21.17; p = 0.022). Moreover, people living in eastern countries have a higher risk of BC when compared to western countries [44]. In Europe the HR is 2.00 (95% CI: 1.51–2.65; p < 0.001) as opposed to 14.74 (95% CI: 3.66–59.35; p < 0.001) in Asia [46]. Risk factors that have been identified for developing UC in RTRs are prior treatments with immunosuppressive agents, cyclophosphamide, BK virus nephropathy, analgesic nephropathy, tobacco, occupational exposure, and aristolochic acid (AA) use (a Chinese herbal product employed for the treatment of digestive, chronic renal, inflammatory, and infectious diseases) [49]. Several mechanisms of immunosuppressive medication have been suggested as oncogenic; for example, MMF has been associated with elevated blood arsenic levels (carcinogen of group 1 associated with BC) and decreased levels of selenium in erythrocytes [50]. In RTRs that consume AA the incidence of UC is as high as 49%, with the peculiarity that they tend to present as multi-focal tumors (OR 3.19, 95% CI 1.76–6.69; p = 0.000), more invasive cancer (OR 3.35, 95% CI 1.95–7.62; p = 0.000) and faster evolution of the disease [47]. Another controversial risk factor for UC is BK polyoma-virus infection [51]. The polyomavirus is a family of 13 viruses including BK, JC, and SV40; all of which have been proven to have oncogenic potential [52]. The BK virus can appear in early childhood and have an asymptomatic course. It is found in several parts of the body and is a frequent colonizer of renal epithelial tubular cells and urothelial cells [52, 53]. From 2000 to 2009, there was an increase in the prevalence of BK virus infection, from 7 to 24% in RTRs [52], with an adjusted RR 2.9–8.0 times higher for UC in patients positive to BK virus as opposed to negative ones [52, 54]. BK virus is generally dormant but it is activated in immunocompromised patients such as transplant recipients, people living with AIDS, pregnant women, patients with multiple sclerosis, or those receiving chemotherapy or biological therapy [55]. Liu et al. compared 943 BK positive versus 943 BK negative RTRs and found a strong association between BC and positive replications of BK virus; moreover, in the multivariate analysis, the replication of BK virus and tobacco use favored BC (RR 11.7; p = 0.0013 and RR 5.6; p = 0.0053, respectively) [56]. Conversely, another study looked for SV40 Antigen-T and BK-specific polyomavirus in 37 BC tissue samples and compared them to normal bladder tissue from the same patients. No viral replication was found on the tumor or the surrounding tissue. [51]. Perhaps, the lack of consistency in these results is due to the use of different techniques to detect the virus [54]. The role of time on dialysis, type of immunosuppressive agents, age at transplant, and the association with human papillomavirus (HPV) remain unclear [57, 58]. The mean time to develop UC after renal transplant ranges from 5.2 to 9.5 years [48, 56, 57, 59–61] with urothelial histology being present in 93% of the patients, while squamous and adenocarcinoma differentiation reach 3.4% each [61]. Hematuria is the most frequent clinical presentation (36.4–42.5%) [49, 61, 62]; however, some studies report incidental diagnosis in up to 50% of RTRs [61, 62]. In RTRs up to 66.6% of UC are diagnosed in more advanced stages (i.e., ≥T2 stage) with higher progression rates (RR 10.53; p = 0.0481) [59], in comparison to controls [48, 60]. This aggressive behavior is due to a higher presence of carcinoma in situ (65%) [62, 63] and tumor multifocality [63]. Furthermore, the chemokine ligand 18 (CCL18), also known as dendritic cell chemokine, is overexpressed in urothelial tumors of RTRs, as opposed to non-transplant patients; CCL18 up-regulates migration and invasion of cancer cells [64]. As the number of kidney transplants continues to rise and survival of RTRs improves, the number of UC patients has been also increasing [59]. Intravesical Bacillus of Calmette- Guerin (BCG) instillations have been successfully used in RTRs with non-muscle-invasive BC (NMIBC), with few reported side effects [57, 61, 65, 66] and reduced recurrence rates in comparison to patients not receiving intra- vesical BCG (p = 0.043) [61]. Although this therapy is safe in RTRs, long-term sepsis due to Mycobacteria has been reported [67]. The surgical approach varies from one institution to another [68]. The standard of care for NMIBC is complete transurethral resection of bladder tumor (TURBT) with or without intravesical therapy. If radical cystectomy is indicated (i.e., early cystectomy for BCG failure in NMIBC; stage ≥T2) performing the surgery by experienced surgeons is advised to avoid graft injury; moreover, LND may be challenging on the graft side. Nevertheless, surgical outcomes are acceptable regardless of urinary diversion used (ileal conduit or orthotopic neobladder) or surgical approach (open or minimally invasive) [61, 68–71]. For patients with previous urinary diversions, kidney transplant is not contraindicated since graft survival is not affected, with asymptomatic bacteriuria being the most frequent complication [72]. Moreover, RT appears not to affect graft survival, rendering conventional BC therapeutic options useful for RTRs [57]. If graft UC is diagnosed prompting for graft nephroureterectomy, the time in which another KT can be performed has not been clearly established; however, waiting for 2 years in low-grade upper tract UC and 5 years for high-grade upper tract UC is advised [49]. Once UC is diagnosed, it is recommended to change immunosuppression to mTOR inhibitors, given that they significantly reduce the risk of recurrence (HR 0.24; 95% CI 0.053–0.997; p = 0.049) [61]. If systemic chemotherapy is indicated, the decision is made after careful evaluation of renal function and immunosuppressive therapy. If tumor aggressiveness is an issue, graft nephroureterectomy with subsequent hemodialysis is an alternative for RTRs [58]. One- and 5-year overall survival ranges from 60 to 100% and 36 to 59%, respectively [48, 62], and depends on initial stage as well as BC aggressiveness; when comparing outcomes with non-transplant patients, no survival differences were found (p = 0.1186) [48, 60]. However, there are reports of poor 1-year survival rates when patients have a progression from non-invasive disease to muscle-invasive UC [62]. When comparing patients with ESRD and RTRs, the latter has a higher and earlier recurrence rate of NMIBC (p = 0.019) [73]. In RTRs, the meantime to the first recurrence is 10.9 months, with 30% recurring at 1 year and 40% at 5 years [62]. Annual screening with graft and native kidneys ultrasound to rule out urothelial tumors is advised [74].

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Renal Transplantation and Renal Cancer

The incidence of renal cell carcinoma (RCC) has increased in the United States in the few last decades [75]. In 2018, kidney cancer accounted for 5.5% of all cancer diagnoses globally [76, 77]. Among RTRs, the incidence of RCC has been reported to be around 0.58–0.93% with a 5- to ten-fold increase when compared to the general population. RCC in RTRs occur predominantly in the native kidneys, probably due to malignant transformation of acquired cystic kidney disease (ACKD) [78, 79] with clear-cell RCC and papillary RCC (RCC) being the most frequent subtypes reported (32% and 28%, respectively) [2, 80–82]. Karami and colleagues reported that male sex (HR 1.79), increasing age (HR 6.59), long-term dialysis (2.23), transplant in recent years (HR 2.23), glomerular (HR 1.24) and hypertensive nephrosclerosis (HR 1.55), and vascular diseases (HR 1.53) as etiology of ESRD are risk factors for RCC in RTRs with a marked higher risk for pRCC (HR 13.3, CI 11.5–15.3) [80]. Additionally, there is no clear evidence that immunosuppression is related to de novo RCC in RTRs, as several studies have shown no increased risk in immuno- compromised patients or with diferent immunosuppression regimens [9, 10, 81, 83]. Despite being diagnosed earlier, RTRs tend to have more aggressive RCC when compared to patients with ESRD on dialysis probably because of closer follow-up [79, 84]. Treatment of RCC in RTRs should be tailored according to tumor stage and location. For native kidney RCC, laparoscopic radical nephrectomy is recommended [85–87]. Routine contralateral native nephrectomy is not routinely required in the absence of suspicious contralateral tumors [86]. Radiofrequency ablation (RFA) or cryotherapy have not been evaluated in this specific population [87]. Active surveillance (AS) is an option for non-transplant patients with small renal masses (SRM; < 3 cm) [88–90]. Nonetheless, there are no available prospective studies that support this option in the setting of RTRs. Thus, AS could be an alternative depending on comorbidities and frailty, always on the basis of multidisciplinary consensus and patient counseling. For the RCC of kidney graft, nephron-sparing surgery is feasible with acceptable functional and oncological outcomes [91–93]. Alternative non-invasive techniques such as RFA or cryotherapy have shown adequate long-term outcomes [94, 95]. For advanced RCC in RTRs, the role of immune checkpoint inhibitors such as anti-programmed cell death protein-1 (PD-1) or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents is controversial [96]. diary and colleagues addressed 83 transplanted patients with different oncological diagnoses receiving anti-PD-1 (73.5%), anti-CTLA-4 (15.7%), or a combination of both (10.8%); almost 40% developed graft rejection and only 19.3% were cancer-progression and allograft rejection-free [97]. Venkatachalam reported 6 RTRs with metastatic cancer receiving anti-PD-1 alone or in combination with anti-CTLA-4, with 3 experiencing acute rejection and 5 with cancer progression [98]. Patients should be evaluated individually to balance risks of continuing immunosuppression versus initiation of immunotherapy, as allograft rejection risk is higher and poor oncological outcomes are common [99]. Optimal management of immunosuppression in RTRs with RCC remains unclear. Reducing or modifying immunosuppressive therapy may contribute to reducing the incidence of RCC [100] as well as slowing tumor progression, without compromising graft function [3, 101]. Kleine-Döpke and colleagues demonstrated an increased risk in RCC incidence among patients using CYA and MMF (HR 2.8,95% CI 1.009–9.97; HR 5.39, 95% CI 1.54–18.83, respectively) [102]. Hope and colleagues reported 87 RTRs with de novo cancer diagnosis, in which 36 patients had dose reduction or interruptions of AZT, CYA, and tacrolimus; of note, they reported no impairment of graft function, although no change in cancer-free survival was documented in solid organ cancers [103]. Additionally, in RTRs with recent RCC diagnosis, switching from calcineurin inhibitors (CNI) to mTOR inhibitors such as sirolimus or everolimus is recommended, as better oncological and functional outcomes have been reported in several studies [3, 13, 101, 104]. As aforementioned, caution should be taken when deciding which therapy adjustments are better for this specific population, as evidence is still scarce. Although some studies suggest that screening in RTRs can be useful to detect early-stage RCC [105–107] it is not recommended, as cost-effectiveness has not been observed and no clinical trials report improved survival to exist [5, 82, 108–110]. Therefore, there is no strong evidence to support routine RCC screening.

Renal Transplantation and Penile Cancer

Penile cancer (PeC) is a rare type of urological malignancy with an adjusted incidence of less than 1.0/100,000 in the USA and 1.7/100,000 in Europe in contrast to 6.8/100,000 in low-income regions such as Africa, Asia, and South America [75, 111, 112]. In RTRs the age-adjusted incidence is 0.04%, with a cumulative incidence of 0.07% in 10 years [57, 113]. However, as life expectancy increases among RTRs, malignant lesions have become a more frequent problem in this population. Identified risk factors for PeC are inflammatory skin diseases such as lichen planus, phimosis, paraphimosis/adherent prepuce, balanitis, genital warts, and immunosuppressive therapy (OR 5.0, 95% CI 2.5–9.8), including those with organ transplantation (OR 7.0, 95% CI 2.4–20.8) [114]. HPV, a sexually transmitted disease, is associated with premalignant genital conditions such as erythroplasia of Queyrat and Bowen’s disease. Around 50% of PeC is associated with HPV types 16, 18, 31, and 33 [115, 116], with squamous cell carcinoma (SCC) being the most frequent histological subtype among RTRs [2]. In terms of clinical characteristics, RTRs have more frequent recurrences and multifocal lesions. [117]. In addition, grade 2–3 penile intraepithelial neoplasia (PeIN) and penile cancer are more frequent (HR 21.9, CI 11.1–43.5; HR 9.6, CI 4.1–22.4, respectively) in comparison to non-transplanted patients [115]. Grulich and colleagues reported in a meta-analysis that immunodeficiency is an important risk factor for de novo appearance of HPV-related malignancies such as PeC in RTRs (OR 15.79, CI 5.79–34.4) [83]. Dysregulated cell-mediated immunity in RTRs results in a shortcoming host response to eradicate HPV infection [118]. Therefore, immunosuppressive therapy may have an important role in the setting of premalignant lesions and PeC in RTRs. Regarding treatment, immunosuppressive therapy reduction seems helpful in refractory disease, although Hope and colleagues reported no difference in cancer-free survival among patients with > 50% reduction [103]. The effect of mTOR inhibitor, sirolimus, has been addressed in RTRs and malignancy, reporting a risk reduction [13]; thus, changing from a CNI to mTOR inhibitor may have a role in malignant lesions among RTRs [119]. Surgical resection and chemotherapy are cornerstone strategies for treating PeC. Depending on HPV status, chemoradiotherapy may be effective as well [120]; however, this has not been analyzed in RTRs. Patients with cT0-T2 tumors are candidates for surgical resection with organ sparing techniques and wide local excision or glossectomy. Tumors involving corpora cavernosa or adjacent structures (cT3-T4) require a more aggressive approach from partial to total penectomy [121, 122]. Since PeC has an increased affinity for lymphatics, adequate surgical staging including inguinal and pelvic lymph nodes is mandatory. Neoadjuvant and adjuvant therapy has an important role in N2-N3 cases [123]. Although limited data regarding the prevention of PeC in RTRs, there are reports of quadrivalent HPV vaccine administered in this group of patients. Kumar and colleagues reported adequate response 4 weeks after transplant in 63.2% and 52.6% for HPV 16 and 18, respectively. Nonetheless, the suboptimal immune response was also reported after 12 months with a reduction of antibody titers [124]. It is exhorted that RTRs should complete vaccination before transplant in order to achieve a higher antibody response [125, 126].

Renal Transplantation and Testicular Cancer

Globally, testicular cancer represents around 1% of malignancies in men, affecting a predominantly young population between 15 and 35 years [75, 127], with an increasing worldwide incidence of 1.8/100,000 [77]. RTRs have an overall risk of around 0.4% a three-fold increased risk to develop testicular cancer after transplantation [128, 129], with an incidence of 21.3/100,000 in the first year after transplant. Seminomatous germ cell tumor (GCT) is the predominant histological type in the majority of series [128, 130, 131] including patients with immunosuppressive conditions (HR 1.9, CI 1.6–2.2) [132]. The evidence regarding non-seminomatous GCT in the setting of RTRs is scarce and limited to case reports [133]. In these cases, treatment should not be different from that recommended for the general population.

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Conclusions

Urological malignancies represent a high proportion of cancers among RTRs. Since immunosuppression may have a major role in the pathophysiology of malignancy, timely diagnosis and treatment should be offered. In most cases, management of urological malignancies does not differ from that recommended for the general population. The additional challenge of preserving graft function and avoiding toxicity should be considered.

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Compliance with Ethical Standards

Conflict of Interest None.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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