1.       Introduction

Patients with End-Stage Renal Disease (ESRD) have been recognized to be a high risk for many cancers, including kidney and urinary tract cancers [1]. Previous reports suggested that bilateral renal cell carcinoma (RCC) occurred in 5% to 36% of Hemodialysis (HD) patients [2,3]. In patients undergoing HD, the incidence rates of Acquired Cystic Disease Of The Kidney (ACDK) have ranged from 35% to 79% [4,5]. The main complication of ACDK is frequent development of renal tumors [6]. Patients with bilateral sporadic RCC have a poor prognosis compared to those with unilateral RCC [7]. Although previous reports have suggested that tumor size, performance status, tumor grade, and HD duration before surgery were the prognostic factors for ESRD patients with RCC, bilateral RCC has not been discussed. The purpose of the study was to investigate the influence of bilateral RCC on clinicopathological features and prognosis in hemodialysis patients with ESRD, and to compare the findings with features of patients treated for unilateral RCC. 

2.       Materials and Methods 

This retrospective study was approved by our institutional review board and included consecutive patients from November 1985 to June 2016. ESRD patients with renal tumors who underwent surgical therapy at our institution were identified from our surgical database. ESRD was defined as chronic renal failure treated by HD or peritoneal dialysis. Using abdominal Ultrasonography (US) and Computed Tomography (CT), annual screening for RCC was performed in patients on HD. When RCC was suspected in patients with ACDK because of enlarged cysts after the most recent US and CT, dynamic CT or magnetic resonance imaging was also performed. All ESRD patients with RCC were included after the initiation of dialysis. In the present study, paraffin-embedded tumor specimens were histopathologically evaluated by one pathologist at our institution. The criteria used for the diagnosis of ACDK were in accordance with previous reports [8]. The tumors were classified according to the World Health Organization (2004) classification system. Tumor size was defined as the diameter of the largest tumor if there were multiple cancerous lesions in the same kidney. Information was collected on age, sex, symptoms, duration of dialysis therapy, tumor staging and grading, histological subtype and outcome. The median post-surgical follow-up period was 95 months (range 1-374 months). There were 317 radical nephrectomies performed in 207 patients with unilateral RCC and in 55 patients with bilateral RCC including synchronous RCC in 31 patients and metachronous RCC in 24. The median time between the 1st and 2nd RCC diagnoses was 32 months (range 11-130 months). Statistical analysis was performed using Student’s t-test and the chi-square test. A p-value of less than 0.05 was considered significant. Patient survival was defined as the time between the date of surgery and the date of death. The 5-year cancer specific survival rate was calculated using the Kaplan-Meier method, and significance was determined by the log-rank test. Patients alive after their last follow-up were censored. 

3.       Results 

3.1.  Patients’ Characteristics

We identified 262 patients with ESRD who were surgically treated for RCC at a single institution (Table 1).

Symptomatic RCC was evident in 28 (11%) patients, and gross hematuria was the most frequent complaint (12 patients). RCC was incidentally diagnosed in 237 (91%) patients by US or CT screening. The overall mean age at diagnosis was higher in the unilateral RCC group (57 years vs 52 years, respectively; p=0.001) and the rate of female sex was higher in the unilateral RCC group than in the bilateral RCC group (18% vs 5%; p = 0.019). There were no significant differences with regard to the median duration of dialysis before surgery between the two groups. The median follow-up period was significantly longer in the bilateral RCC group than in the unilateral RCC group (126 months vs 82 months; p<0.001). There were no differences in tumor size between contralateral kidney tumor in bilateral group and primary tumor in unilateral group (2.5 cm vs 2.2 cm; p=0.258). 

3.2.  Pathological Findings and Outcomes 

(Table 1) shows the pathological characteristics between the unilateral and bilateral RCC groups. The mean maximum tumor size was 2.45 cm (range 0.5-19 cm). Organ-confined cancer was pathologically proven after radical nephrectomy in 98% of the patients, including 86% of those with pT1 (tumors < 7 cm). Only four patients had advanced RCC (pT3). There were no significant differences between the two groups with regard to mean tumor size, pathological tumor stage, and tumor grade. The patients in the bilateral RCC group were more likely to show more multifocal tumors than the patients in the unilateral RCC group (69% vs 26%, p < 0.001). With regard to the histological subtypes, RCC in the bilateral RCC group was more frequently ACDK-associated RCC (30% vs. 14%), and was comprised less frequently of clear cell RCC than in the unilateral RCC (40% vs 62%, p < 0.001). (Table 2) shows the histology of both kidneys in the patients with bilateral occurrence. Twenty-eight of 55 patients had the same pathological findings in both kidneys.

3.3.  Comparison of Survival Between the Unilateral And Bilateral RCC Cases 

In survival analysis, overall survival at 5 years was significantly higher in the bilateral RCC group than in the unilateral RCC group (P=0.011) (Figure 1A). However, the 5-year cancer-specific survival rate was more than 90% in both groups, which was not significantly different between the two groups (P=0.162) (Figure 1B).

Overall ten patients out of 207 (4.8%) with a unilateral occurrence and two patients out of 55 (3.6%) with a bilateral occurrence died from kidney cancer in the follow-up period. On Multivariate Cox Regression Analysis, advanced stage was positively associated with death from cancer. Age, the duration of HD before surgery, tumor size, pathological results, and bilateral occurrence did not affect the likelihood of death from cancer (Table 3).

4.       Discussion 

Among the study patients, there were a very small proportion of patients with advanced disease (1.5%). The present findings are in line with the report by Gigante, et al. [9], who found that RCC in ESRD patients demonstrated favorable clinical, pathological, and outcome features compared with RCC patients in the general population. Specifically, these investigators found that in the ESRD group, tumors were smaller, clear cell histology occurred less frequently, the tumors were discovered incidentally more frequently, the tumors had less advanced T category (less than T3) and produced less nodal invasion, and the patients experienced less metastatic disease. The risk and pathogenesis of RCC may differ in patients on dialysis compared to the general population. The kidney of ESRD shows tubular atrophy, interstitial inflammation and fibrosis, and arterial, arterior and glomerular sclerosis, resulting in acquired cysts due to the loss of structural integrity [10]. Regular screening of patients on dialysis may increase survival by encouraging radical treatment for kidney cancer at an earlier tumor stage. Moreover, in Japan, most patients with ESRD are treated with long-term dialysis which accelerates the development of ACDK and then RCC [1,3,11]. This might be attributed to the common application of dialysis therapy. Thus, regular screening of patients on dialysis contributes to improving survival rates for RCC at earlier tumor stages. 

In the present study, bilateral RCC showed favorable prognosis with a representative 5-year overall survival rate of 97%. Some reports showed that the prognosis of bilateral RCC was comparable to that of unilateral RCC [12-14]. Several factors have been reported to cause RCC occurrence in HD patients with ACDK. In previous ESRD studies, the frequency of ACDK-associated RCC ranged from 23% to 50% [15,16]. This suggests that molecular pathways distinct from the von Hippel-Lindau tumor suppressor protein/hypoxia-inducible factor/ vascular endothelial growth factor pathways are involved in ESRD patients with ACDK. Among the types of histopathological degeneration, ACDK alone has been implicated as the risk factor for malignant transformation [17]. Recent studies have reported that most ESRD-associated RCCs are classic histological types [18]. The first and most common of these is designated ACDK-associated RCC, and the other subtype is clear cell papillary RCC of ESRD [19]. The first subtype occurs only in kidneys with ACDK, while the second subtype occurs in non-cystic ESRD and in patients with ACDK. ACDK has been reported as being associated with a particular histological subtype of RCC: the clear-cell papillary RCC of ESRD. This subtype is known to behave less aggressively than conventional RCC [20]. These features are probably a combination of being on the whole biologically less aggressive biologically as well as the constant medical surveillance of these patients at an early stage. ACDK in patients treated with dialysis is frequently complicated by RCC, either multiple or bilateral [21]. In our study, the patients with bilateral RCC had a higher incidence of ACDK and papillary RCC than the patients with unilateral RCC, indicating favorable overall survival rate.