Asian Journal of Urology 9 (2022) 208e214 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/ajur Review Small renal masses in kidney transplantation: Overview of clinical impact and management in donors and recipients Alberto Piana a,b,*, Iulia Andras c, Pietro Diana a, Paolo Verri a,b, Andrea Gallioli a, Riccardo Campi d,e, Thomas Prudhomme f, Vital Hevia g, Romain Boissier h, Alberto Breda a, Angelo Territo a, on behalf of European Association of Urology (EAU) Young Academic Urologists (YAU) Kidney Transplantation Working Group, Arnhem, Netherlands a Department of Urology, Fundació Puigvert, Autonoma University of Barcelona, Spain b Department of Urology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy c Urology Department, Iuliu Hatieganu University of Medicine and Pharmacy and Municipal Hospital, Cluj-Napoca, Romania d Unit of Urological Robotic Surgery and Renal Transplantation, University of Florence, Careggi Hospital, Florence, Italy e Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy f Department of Urology and Kidney Transplantation, Toulouse University Hospital, Toulouse, France g Hospital Universitario Ramon y Cajal. Alcala University, Instituto Ramon y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain h Aix-Marseille université, service de chirurgie urologique et de transplantation rénale, CHU Conception, AP-HM, Marseille, France Received 8 December 2021; received in revised form 24 March 2022; accepted 19 April 2022 Available online 10 June 2022 KEYWORDS Abstract Kidney transplantation is the best replacement treatment for the end-stage renal Small renal mass; disease. Currently, the imbalance between the number of patients on a transplant list and Renal cancer; the number of organs available constitutes the crucial limitation of this approach. To expand Kidney the pool of organs amenable for transplantation, kidneys coming from older patients have been transplantation; employed; however, the combination of these organs in conjunction with the chronic use of Nephron-sparing immunosuppressive therapy increases the risk of incidence of graft small renal tumors. This treatment narrative review aims to provide the state of the art on the clinical impact and management of incidentally diagnosed small renal tumors in either donors or recipients. According to the * Corresponding author. Department of Urology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy. E-mail address: alb.piana@gmail.com (A. Piana). Peer review under responsibility of Tongji University. https://doi.org/10.1016/j.ajur.2022.06.001 2214-3882/ª 2022 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Asian Journal of Urology 9 (2022) 208e214 most updated evidence, the use of grafts with a small renal mass, after bench table tumor excision, may be considered a safe option for high-risk patients in hemodialysis. On the other hand, an early small renal mass finding on periodic ultrasound-evaluation in the graft should allow to perform a conservative treatment in order to preserve renal function. Finally, in case of a renal tumor in native kidney, a radical nephrectomy is usually recommended. ª 2022 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). 1. Introduction Kidney transplantation (KT) is the best replacement treat- ment for end-stage renal disease (ESRD) and demonstrated solid advantages over hemodialysis in terms of survival and morbidity [1e3]. Currently, the imbalance between the number of patients on a transplant list and the number of organs available constitutes the crucial limitation of this approach. To overcome this limitation, nowadays, most grafts come from deceased donors who are usually over 60-year-old and the most common cause of death is a ce- rebrovascular event. Just in a few cases, when available, a living donor’s graft is employed. The employment of donated kidneys coming from older patients in conjunction with the chronic use of immunosuppressive therapy increases the risk Figure 1 Flowchart of literature search. of incidence of graft tumors [3,4] that, in most of the cases, are diagnosed as asymptomatic incidental small renal tu- approach, minimally-invasive surgical alternatives were mors. Moreover, the incidental finding of a small renal mass introduced. The employment of these techniques led to a (SRM) in a patient candidate for kidney donation constitutes shorter hospital stay and a faster recovery, decreasing the another important issue in the transplantation decision- use of analgesics and providing more satisfactory aesthetic making process. This study aims to provide an overview of results [7,8]; on the other hand, a longer ischemia time the current impact and the clinical management of inci- increases the risk of delayed graft function. To overcome dentally diagnosed de novo SRMs in donors and in recipients. these limitations, new surgical tools were introduced [9]. Secondly, the incidental finding of a SRM or a previous 2. Materials and methods history of renal tumor in either recipients or donors is still a very debated issue and a priority research topic. The spe- This is a narrative mini-review on the state of the art on the cific risk of RCC among transplanted patients is about 5e10 clinical impact and management of small renal incidenta- times increased compared to the general population [10]. lomas in either donors or graft recipients. The research was In about 90% of the cases, it presents in native kidney and restricted to articles published in the English language on rarely in the graft [11]. The use of immunosuppressive PubMed database until September 2021 and largely based drugs in patients undergoing KT increases overall 2e4 fold on the most updated evidence from European Association the risk for cancer compared to the general population, of Urology and the European Society of Medical Oncology especially for ultraviolet radiation-related cancers (i.e., guidelines. Among the keywords, we included “kidney”, skin cancer) and cancer associated to infections (i.e., “tumor”, “cancer”, “renal cell carcinoma (RCC)”, “trans- Epstein-Barr virus induced lymphoma). plant”, “allograft”, and “graft” (Fig. 1). All the articles In the general population, RCC accounts for around 2%e3% were written in English, and tumor staging was defined of all cancer, with the highest incidence in patients aged >60 according to the Union for International Cancer Control years [12,13] with a rising incidence of SRMs, which consist in tumor, node, and metastasis (TNM) 2021 [5]. solid or complex cystic mass 4 cm. These masses are clas- sified as pT1a according to TNM classification [5]. The size of the lesion and the histotype carry out the prognostic impli- 3. Management strategies in different clinical cations and define the treatment strategies according to the scenarios age and clinical conditions of the patients. The most common histotype of renal masses is clear cell RCC, accounting for Although KT constitutes the treatment of choice in case of around 90% of the cases [12]. ESRD [6], some issues are still needed to be considered in In case of a patients neither scheduled for kidney donation order to expand its indication. nor transplantation, the recommended surgical treatment for Firstly, the high complexity and invasiveness of the a cT1a mass is minimally-invasive nephron-sparing surgery procedure leads to major risk for all grade complications. In (NSS), considering its oncological safety and advantages in order to reduce the morbidities linked to the standard open terms of overall survival (OS) over the radical nephrectomy 209 A. Piana, I. Andras, P. Diana et al. [14,15]. Other surgical alternatives are radiofrequency deceased donors diagnosed for SRM during organ retrieval. ablation, microwave ablation, or cryoablation, which are Moreover, similar results were observed among different usually employed in patients with small cortical tumors with histological types [25]. high surgical risk. In this cases, renal biopsy is strongly rec- A recent systematic review from Hevia et al. [22] on the ommended to confirm malignancy and subtype [16,17]. In use of kidneys with small renal tumors excised ex vivo re- case of a frail patients with a short life expectancy and renal ported that five-year OS was 92% and graft survival rates masses of <4 cm holding a previous renal biopsy, active sur- was 95.6%. The authors suggested that although with veillance may be considered as an option [18,19]. low-level evidence, kidneys with excised SRMs are an In case of patient who underwent KT, the epidemiology acceptable source of transplantation without compromising of renal tumor changes. Patients may develop kidney can- oncological outcomes and with similar functional outcomes cer in the native kidney after transplantation or more rarely to other donor kidneys. Their use should be mainly reserved in the transplanted graft. Moreover, another important to patients >60 years with a significant survival advantage issue is related to the incidental finding of SRMs in the living by maximizing their residual renal function [26]. As sug- donor and the possibility and modality of transplantation. gested by Hevia et al. [22], preoperative biopsy may be In these cases, it is important to assess diagnostic and useful to exclude Grade 4 RCC and a bench frozen section therapeutic strategies in order to preserve graft function might be another key diagnostic tool to ensure a complete without compromising patient’s survival. tumor resection. 3.1. SRM in donors 3.2. Kidney transplant recipients with a history of pretransplant SRM KT after ex vivo excision of small tumors has been reported since 1982 [20]. Incidental renal tumors are usually diag- Patients with ESRD and cancer diagnosis before KT are nosed during the surgical work-up prior to transplantation. considered a challenging group, due to the increased risk of Due to the low availability of organs, a careful case-by-case posttransplant malignancies, graft loss, and decreased OS evaluation of donors with SRMs should be performed [27]. Previous history of cancer does not represent a considering the low risk of recurrence of small and low- contraindication to KT. However, the majority of centers grade tumors. This risk should be balanced on the recommend an arbitrary waiting time between no wait-time increased risk of mortality and morbidity for patients and 5 years, depending on the stage at diagnosis, as the risk treated with dialysis in waiting list for transplantation [21]. of recurrence is considered the highest within the first The gold standard surgical management of a kidney 5 years after transplantation. According to the guidelines of with a SRM is, when feasible, an ex vivo tumor excision the Canadian Society of Transplantation, patients with cT1 on the bench table with an oncological margin, a frozen RCC require no waiting period between the tumor treatment section biopsy, subsequent renorrhaphy, and finally, and KT, whereas patients with a history of symptomatic RCC transplantation [22]. should wait at least 2 years and patients with locally- Data of patients with SRM candidate to graft donation advanced disease should wait at least 5 years before KT [28]. come from several case-reports, and a few systematic reviews Post-transplant malignancies most often occur in the and prospective non-randomized trials. Therefore, despite same location as previous cancers, which suggest they may the promising data, only low-grade evidence is available. be in fact recurrences [29]. In kidney transplant recipients, Sener et al. [23] reported their results in 5 (3/5 RCC) the recurrence rate is the highest for kidney cancer of all living donor KTs of grafts with SRMs (<2.3 cm) incidentally malignancies [30]. A retrospective study on 258 kidney detected during donor’s diagnostic workup. The recipients transplant recipients, in whom native nephrectomy was were on dialysis and had a low life-expectancy. The tumor performed at the time of transplantation showed a rate of excision and subsequent renorrhaphy were performed on occult RCC of 4.7%. While the incidence of acute graft the bench table. A portion of the marginal tissue was sent rejection was similar between the both groups (with or for frozen-section analysis to confirm the absence of any without occult RCC), a higher rate of RCC occurrence in the residual tumor before proceeding with transplantation. The remaining native kidney was identified at a median follow-up authors did not observe any tumor recurrence or metas- of 56 months [31]. Recent reports showed that history of tasis, reporting a cancer-specific survival (CSS) of 100% with previous malignancy does not have an additive effect on CSS a median (range) follow-up of 15 (1e41) months [23]. Same of transplant recipients who develop cancer [32]. Moreover, treatment is provided for cT1a benign and malignant le- CSS and OS were reported as being comparable between sions, due to the very low recurrence rate in case of ma- patients with cancer recurrence after transplantation and lignancy of any histotype [21]. patients who developed de novo cancers [33]. In a prospective non-randomized trial from Ogawa et al. To summarize, KT is safe in patients with a history of [24], 10 patients with low-medium surgical complexity SRM. The remaining native kidney should be followed-up, as SRMs according to nephrometry scores were selected for there is an increased risk for RCC occurrence. kidney donation to patients on dialysis and no tumor recurrence was reported at 32e58 months after surgery in 3.3. Post renal transplant SRM either the recipients or the donors. Although the lack of data from large cohorts, no differ- Due to posttransplant immunosuppression, kidney transplant ence in terms of functional or oncological outcomes was recipients are at an increased risk for developing malig- observed between living donors with incidental SRM and nancies [34], accounting as the third cause of mortality in 210 Asian Journal of Urology 9 (2022) 208e214 these patients, with calcineurin inhibitors being considered The most common histology of kidney allograft tumors is the most carcinogenic [35]. De novo renal tumors, either of papillary RCC in up to 50% of cases, followed by clear cell the allograft, or the native kidney, are diagnosed in about carcinoma in about 33% of cases [50]. 4.6% of kidney transplant recipients, with the latter being the NSS of an allograft SRM is the standard treatment, but it most frequent site [36]. However, the majority of the diag- is particularly difficult, as there can be local fibrosis and nosed tumors are reported to be in early stage, low grade, adherences to main renal blood vessels, significantly and no significant difference in the mortality rate has been increasing the complexity of the surgery. Extraperitoneal observed between KT patients with or without RCC [37]. On access can be performed for tumors located on the convex the other hand, graft survival seems to be decreased in pa- edge, while the transperitoneal access is preferred for tients with RCC, most probably due to back scaling of the medially located tumors, allowing easier vascular control immunosuppressive regimen [38]. with possible hilar clamping [51]. In a multicenter analysis In terms of prevention, several studies suggested of 43 NSS for kidney allograft tumors, the oncologic safety that the administration of an immunosuppressive regimen of this approach has been proven, with no recurrences re- containing mammalian target of rapamycin inhibitors ported at a follow-up of 35.2 months. No graft loss has been (mTORisdsirolimus and everolimus) could reduce the reported and no patient returned to dialysis after surgery. occurrence of posttransplant SRM [39], due to their anti- The total rate of postoperative complications was 20.9%, of tumoral effect particularly in RCC. However, a more which 11.62% were of high grade [52]. recent study including 300 kidney transplant recipients Less invasive methods have been proposed in these pa- who were randomized to receive cyclosporine or ever- tients as promising alternatives, such as radiofrequency olimus, showed a similar incidence of posttransplant ma- ablation, cryoablation, microwave ablation, or high-intensity lignancy in both groups [40]. focused ultrasound [53]. The possibility to perform ablative therapy in local anesthesia, the low rate of complications, 3.3.1. Graft tumors lack of need for vascular clamping, and minimal impact upon De novo renal tumors of the allograft kidney are rare find- the renal function [54] make it suitable especially for elderly ings, with an incidence below 0.5% [41]. Early diagnosis and and frail patients. A recent systematic review showed that nephron-sparing treatment are of utmost importance to radiofrequency ablation was the most frequent treatment preserve the renal function, to avoid the need of trans- choice after NSS for allograft SRM, followed by cryosurgery. plantectomy and return to dialysis. No specific factor has Complete tumor necrosis after ablative therapies can be been associated with an increased risk of RCC in allograft proven by imaging and no differences in terms of efficiency kidneys [42]. have been identified between any of the ablative therapies. The origin of the allograft tumors may be donor derived Among 100 procedures of ablative treatment in allograft or recipient derived [43]. The time between trans- kidneys, only three treatment failures were reported, with plantation and the diagnosis of an allograft tumor can range the possibility to repeat the ablative treatment [55]. No from 9 to 258 months or even more [44], but no association cancer-related deaths have been reported, but renal allo- can be made between this period of time and tumor origin. graft loss has been identified in five cases. In another cohort In a recent report, Kijima et al. [45] presented the case of a of 20 patients who underwent local ablative therapy of male patient who received a kidney from a female living allograft tumors, no recurrence was identified at a mean donor and developed an allograft tumor 14 years after follow-up of 27.9 months [56]. transplantation. By using the fluorescence in situ hybridi- No clear recommendations exist for the management of zation technique, the authors showed that the tumor immunosuppressive therapy in patients with renal graft originated from the donor, whilst tumor vasculature origi- tumor for which NSS or ablative therapies are performed. In nated from the recipient. On the other hand, de novo RCC the majority of patients, the immunosuppression is main- of recipient originated from an allograft kidney has also tained after minimally-invasive treatment of the graft SRM been reported at 10 years after transplantation and it was [45]. Tollefson et al. [57] showed a low rate of tumor pro- attributed to the migration and homing of recipient-derived gression in patients under efficient immunosuppression, stem cells to the transplanted kidney, potentially second- demonstrating the safety of continuing this treatment in ary to tissue injury such as graft pyelonephritis [46]. the perioperative setting for patients with localized dis- Non-contrast enhanced computed tomography (CT) scan ease. It is suggested that patients receiving azathioprine might easily miss the diagnosis [47], and as such, the recom- should be switched for mycophenolate mofetil, and cyclo- mended diagnostic protocol comprises abdominal ultrasound sporine could be switched for mammalian target of rapa- and contrast-enhanced CT or magnetic resonance imaging in mycin inhibitors in order to avoid the effect on DNA case of any suspicion. Yearly, ultrasound is most commonly synthesis (for azathioprine) or on transforming growth recommended to detect any new small mass in the allograft, factor (for cyclosporine) [42], but evidence is still limited. allowing for a timely minimally-invasive treatment. The To conclude, yearly ultrasound performed after KT en- follow-up should be performed for indefinite time, as there sures the diagnosis of kidney allograft tumors in early have been reports of tumors diagnosed even in non- stages, allowing for a nephron-sparing treatment and functioning grafts 29 years after KT [48]. maximum preservation of the graft function. Rarely, paraneoplastic syndromes, such as Guillain-Barre syndrome, can be associated with the presence of an allo- 3.3.2. Native kidney tumor graft tumor. As such, in any suggestive context, paraneo- RCCs of the native kidney represent up to 5% of the ma- plastic etiology should be excluded in all patients with a lignancies diagnosed in kidney transplant recipients, with history of transplantation [49]. acquired cystic kidney disease and long-term dialysis being 211 A. Piana, I. Andras, P. Diana et al. the main risk factors [58]. Increased risk for developing The general trend in a KT recipient with de novo ma- RCC post-transplant was also reported among older pa- lignancy was to perform back scaling of the immunosup- tients, non-Caucasian recipients, patients with renal fail- pression regimen [38], which increases the risk of graft ure secondary to hypertension or glomerular disease, rejection. In this context, more recent reports showed that cyclosporine-based immunosuppression protocols, longer the immunosuppressive therapy can be continued safely in prednisone treatment, and current smokers [59,60]. In this the perioperative period for patients with localized disease context, bilateral or multifocal tumors are frequently and timely resection [37]. Conversion of the immunosup- diagnosed, as opposed to sporadic tumors [37]. Goh and pressive regimen to a proliferation signal inhibitor combi- Vathsala [61] proposed a screening schedule starting at 1 nation has been shown in preliminary studies to potentially month after transplantation, followed by repeat ultra- improve patient survival in case of RCC [72], by inhibition of sound at 2 years for patients with cysts and at 5 years for mTOR and the antiproliferative effects, but long-term re- patients without cysts. Other authors proposed yearly sults are awaited. abdominal ultrasound to ensure an early diagnosis and SRMs in native kidneys of transplant recipients are more favorable prognosis [62]. frequently diagnosed in the context of acquired cystic The time between KT and native nephrectomy for renal disease or previous long-term dialysis. High-risk patients mass has been reported to be between 1 month and 14 should be regularly followed-up by ultrasonography. years, with an average of 3 years [58]. Klatte and Marberger Radical nephrectomy is the standard treatment with good [63] suggested that a tumor can be considered as de novo if postoperative prognosis. it has occurred at least 6 months after transplantation. The short interval to detection of RCC in some patients suggests 4. Conclusion that a proportion of these tumors were present before transplantation, as such pretransplant assessment should be The increasing demand of kidney grafts for patients with improved. Imaging should be routinely performed in patients ESRD points out the need to expand the organ pool for KT. on renal transplant waiting list to avoid transplantation in The use of graft with SRM may be considered a safe option case of advanced malignancy. The 2020 Kidney Disease after bench table tumor excision in both living and deceased Improving Global Outcomes (KDIGO) Clinical Practice guide- donors. In case of a SRM detected in the graft after KT on lines recommend screening of renal transplant candidates periodic US-evaluation, NSS is the recommended treatment specifically in high-risk setting: more than 3 years on dialysis, in order to preserve renal function. Ablative therapies can family history of RCC, acquired cystic disease, or analgesic be considered in elderly and frail patients. In case of SMR nephropathy [64]. However, imaging performed immediately finding in the native kidneys after KT, radical nephrectomy is prior to the transplant might not always be possible, given recommended. Finally, immunosuppressive therapy can be that a significant proportion of kidney transplants come from safely administered despite the presence of SRM in either deceased donors and not from planned procedures [65]. the native kidney or in the graft. Clear cell and papillary RCC are the two most frequent histopathological types, but renal oncocytoma has been also reported in rare cases [66]. Author contributions The diagnostic workup comprises abdominal ultrasound and contrast-enhanced CT. Contrast-enhanced ultrasound Protocol/project development: Alberto Piana, Angelo Ter- can be considered as a valuable imaging method, therefore, rito, Alberto Breda. an alternative to CT to assess the morphology and vascu- Data collection: Alberto Piana, Iulia Andras, Riccardo larization of renal masses, with no risk of nephrotoxicity Campi, Thomas Prudhomme, Vital Hevia, Roman Boissier. [67]. Moreover, contrast-enhanced ultrasound and mag- Manuscript writing/editing: Alberto Piana, Iulia Andras, netic resonance imaging might be superior for cystic mass Angelo Territo, Pietro Diana, Paolo Verri, Andrea Gallioli. classification [68]. Supervision: Angelo Territo, Alberto Piana. The standard treatment of SRM is radical nephrectomy, given the incidence of multifocal tumors and the fact that native kidneys in transplant recipients are non-functional Conflicts of interest [69]. The laparoscopic approach is feasible, with low rate of perioperative complications. Recent reports showed that The authors declare no conflict of interest. laparoscopic native nephrectomy and simultaneous living donor KT is a feasible approach in selected patients with References suspicion SRMs [70]. Following curative surgery for localized disease, 5-year CSS rates are greater than 80% [63]. Similarly, Sultan et al. [1] Johnson DW, Herzig K, Purdie D, Brown AM, Rigby RJ, Nicol DL, [70] reported no recurrences at 4 years follow-up in a group et al. A comparison of the effects of dialysis and renal of 10 patients with pathologically confirmed RCC who un- transplantation on the survival of older uremic patients. Transplantation 2000;69:794e9. derwent simultaneous native nephrectomy for SRM at the [2] Heldal K, Hartmann A, Grootendorst DC, de Jager DJ, time of transplantation. However, Ryosaka et al. [71] Leivestad T, Foss A, et al. 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