© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 211–216 DOI: 10.1111/ctr.12299
Clinical Transplantation
Renal cell carcinoma in patients with end-stage renal disease has favorable overall prognosis Shrewsberry AB, Osunkoya AO, Jiang K, Westby R, Canter D, Pattaras J, Turgeon N, Ogan K. Renal cell carcinoma in patients with end-stage renal disease has favorable overall prognosis. Abstract: Patients with end-stage renal disease (ESRD) demonstrate a greater risk for renal cell carcinoma (RCC) than the general population. This study compared pathological and clinical outcomes in patients with RCC with and without ESRD. Patients with ESRD who underwent nephrectomy and were found to have RCC at our institution since 1999 were identified. The control group was composed of patients from the general population with RCC. The primary outcome was risk of cancer recurrence. The study included 338 RCC patients: 84 with ESRD and 243 without ESRD. In the ESRD group, mean tumor size was smaller, there was decreased prevalence of advanced T category (>3) , and the average Karakiewicz nomogram score was lower. ESRD was associated with decreased tumor recurrence and clear cell pathology. No patients with ESRD had metastatic disease. There was no difference in overall or cancer-specific mortality between the ESRD and control groups. Patients with ESRD who develop RCC have a better prognosis compared to RCC in patients without ESRD, which is likely secondary to favorable histopathologic phenotype as well as the likelihood of early diagnosis. Thus, the delay between nephrectomy and renal transplantation may not be necessary, especially in patients with asymptomatic, low grade tumors.
The prevalence of renal cell carcinoma (RCC) in patients with end-stage renal disease (ESRD) is estimated to be between 2–7% (1–4). It is well established that patients with ESRD demonstrate a significantly greater risk for RCC than the general population. In 1977, Dunnill et al. (5). published a landmark autopsy series describing the relationship between ESRD, acquired renal cystic disease (ARCD), and RCC. While there have been many reports attempting to determine the incidence of RCC in the ESRD population, the actual clinical significance and prognosis of RCC in the ESRD population has not been adequately addressed. Typically, patients undergoing renal transplant evaluation that are found to have a renal tumor are treated with nephrectomy prior to transplantation. It is generally accepted that the immunosuppression mandatory for transplantation favors the growth of existing cancer cells. Therefore, it has become standard practice to issue a waiting period from the time of treatment of a malignancy to
Adam B. Shrewsberrya, Adeboye O. Osunkoyaa,b, Kun Jiangb, Ruth Westbya, Daniel Cantera, John Pattarasa, Nicole Turgeonc, Viraj A. Mastera,d and Kenneth Ogana a
Department of Urology, Emory University, Department of Pathology, Emory University, c Emory Transplant Center, Emory University and dWinship Cancer Institute, Emory University, Atlanta, GA, USA b
Key words: end-stage renal disease – renal cell carcinoma – transplant Corresponding author: Kenneth Ogan, MD, Department of Urology, Emory University, 1365 Clifton Road, Atlanta, GA 30322, USA Tel./fax: 404 778 4615; e-mail: [email protected] Conflicts of interest: None Accepted for publication 17 November 2013
transplantation, excluding patients who would have a recurrence. Clinical practice guidelines published by the American Society for Transplantation recommends a waiting time of at least two yr following definitive treatment of RCC for patients with symptomatic RCC while some large (>5 cm) and/or invasive renal cancers may warrant a five-yr waiting period (6). According to the Cincinnati Transplant Tumor Registry (CTTR), a waiting time of at least two yr eliminates approximately 61% of recurrences (7). Unfortunately, the negative effects of ESRD and dialysis on the patient are numerous and include emotional, physical, and financial burdens. Additionally, increased time on dialysis has been shown to confer worse graft and patient survival (8, 9). In fact, ESRD time is the strongest modifiable risk factor for renal transplant outcomes (10). The purpose of this study was to retrospectively compare pathological and clinical outcomes in a cohort of patients with RCC with and without ESRD. We hypothesize that the prognosis of
211
Shrewsberry et al.
patients with ESRD is better than patients without ESRD. If risks of cancer recurrence are low, then the standard delay prior to renal transplantation may be able to be decreased or even eliminated.
Materials and methods Data and patients
This retrospective study was approved by our institutional review board and included patients from 1999 to 2011. Patients with renal tumors and ESRD that underwent nephrectomy at our institution were identified from our surgical database. ESRD was defined as chronic renal failure treated by renal replacement therapy (hemodialysis or peritoneal dialysis). The patients who were found to have RCC while on dialysis made up our study cohort. The following variables were documented: demographics, duration and type of dialysis, Charlson Comorbidity Index (CCI) (11), presence of ARCD, maximum tumor diameter, histologic subtype, Fuhrman grade, TNM staging, Karakiewicz nomogram score (12), tumor recurrence, cancer-specific mortality (CSM), and overall mortality. ARCD was defined by at least five renal cysts per kidney on ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). CSM was determined through the National Death Index, and the Social Security Death Index (SSDI) was employed to determine overall mortality. Tumor recurrence was defined as clinical evidence of disease on follow-up imaging or tissue biopsy. As new ESRD-specific histopathologies were identified after many of the patients had undergone their nephrectomy, all pathologic specimens from the ESRD cohort were independently reviewed and re-classified by a dedicated genitourinary pathologist (AO) according to the new classification scheme (4). All cases of clear cell papillary RCC were confirmed by the classic immunohistochemical profile seen in this subtype (positive CK7 and negative CD10 and AMACR/P504S expression). In a similar fashion to Neuzillet et al. (13), the ESRD cohort was compared to a control group without ESRD-associated RCC that was operated on during the same time frame identified in our surgical database. The primary outcome was defined as risk of tumor recurrence. Secondary outcomes included histological type, Fuhrman grade, pathologic stage, the Karakiewicz nomogram score, and cancer-specific (CSM) and overall mortality. For ESRD patients, surgical treatment of RCC was radical nephrectomy. For patients in the control group, radical nephrectomy or nephronsparing surgery was performed.
212
Statistical analysis
Data analysis was performed with SAS 9.3 (Cary, NC, USA). The primary exposure (ESRD) and other covariates of interest were tabulated via counts and percentages for categorical variables and means and standard deviations for continuous variables by the outcome of cancer recurrence. The crude associations between exposures and the primary outcome of recurrence were evaluated via crude odds ratios (OR) and 95% confidence intervals (CI). The crude associations between the primary exposure and other covariates were evaluated via chi-square tests (or Fisher’s exact tests) for categorical variables or two-sample t-tests for continuous variables. Covariates significantly associated with the outcome of interest and primary exposure in univariate analyses were entered into a multivariate logistic regression model predictive of cancer recurrence to control for confounding. Repeat observations for patients with bilateral RCC in the ESRD group were controlled for by including patient identification in the model as a continuous variable. Effect measure modification was not hypothesized a priori to influence results, and no effect measure modification was observed in post hoc examination for gender or race. Variables entered into the multivariate model were evaluated for co-linearity using condition indices >30 and variance decomposition proportions >0.5 as cutoffs. The multivariate model predictive of recurrence was built with manual backward selection using a p-Value of 0.05 as the cutoff criteria for variable selection. In secondary analyses, the association between the primary exposure and mortality (yes vs. no), cause-specific mortality (RCC vs. other), and histological subtype (clear cell vs. non-clear cell) were evaluated via logistic regression using a similar modeling strategy as described above for the primary outcome. Additionally, ordinal logistic regression was used to evaluate the association between the primary exposure and increasing Fuhrman grade, and the association between the primary exposure and Karakiewicz nomogram score was evaluated via linear regression.
Results Baseline characteristics
The study included 327 patients with renal tumors. The ESRD cohort was composed of 84 patients, 11 of which had bilateral RCC. Each case of RCC was treated as an individual data point, which
RCC in ESRD patients has favorable prognosis resulted in a total of 95 cases in the ESRD cohort. Transplant and non-transplant patients accounted for 24 cases (28.6%) and 60 cases (71.4%), respectively, at time of nephrectomy. The control group was composed of 243 cases. Baseline characteristics are included in Table 1. The ESRD group was younger and was an overall less healthy group, as evidenced by higher age-adjusted CCI scores. Racial distribution was different between groups with 76% and 19% of patients being black in the ESRD and non-ESRD groups, respectively. There was no difference in BMI between the two groups (28.1 5.57 vs. 28.62 5.88, p = 0.46). A significantly greater number of patients in the ESRD group endorsed a smoking history compared to the non-ESRD group (61% vs. 47%, p = 0.02). In the ESRD group, 67% had ARCD, 87% were on hemodialysis, and 13% were on peritoneal dialysis. Average time between initiation of dialysis and nephrectomy was 4.49 yr. A slightly higher percentage of patients with ESRD presented without symptoms (69% vs. 57%, p = 0.03). Comparison of RCC groups with and without ESRD
Main comparison data are summarized in Table 1, and the various histological subtypes are shown in Table 2. Mean RCC tumor size was smaller and Table 1. Comparison of clinical and outcome features of ESRD and non-ESRD RCC patients
Variables Age at nephrectomy, yr, mean SD Male gender, no. (%) CCI, mean SD Tumor size, cm, mean SD pT category ≥3, no. (%) Nodal invasion, no. (%) Metastatic disease, no. (%) Fuhrman grade ≥3, no. (%) Karakiewicz nomogram score, mean SD Death from cancer, no. (%) Overall mortality, no. (%)
ESRD + RCC (N = 95)
RCC (N = 243)
56.32 13.22
59.75 12.49
59 (62) 4.68 2.02 3.4 2.8
159 (65) 2.56 1.99 5.8 3.3
9 (9)
65 (27)
0.001
6 (6)
29 (12)
0.12
p-Value* 0.026 0.566
Clin Transplant 2014: 28: 211–216 DOI: 10.1111/ctr.12299
Clinical Transplantation
Renal cell carcinoma in patients with end-stage renal disease has favorable overall prognosis Shrewsberry AB, Osunkoya AO, Jiang K, Westby R, Canter D, Pattaras J, Turgeon N, Ogan K. Renal cell carcinoma in patients with end-stage renal disease has favorable overall prognosis. Abstract: Patients with end-stage renal disease (ESRD) demonstrate a greater risk for renal cell carcinoma (RCC) than the general population. This study compared pathological and clinical outcomes in patients with RCC with and without ESRD. Patients with ESRD who underwent nephrectomy and were found to have RCC at our institution since 1999 were identified. The control group was composed of patients from the general population with RCC. The primary outcome was risk of cancer recurrence. The study included 338 RCC patients: 84 with ESRD and 243 without ESRD. In the ESRD group, mean tumor size was smaller, there was decreased prevalence of advanced T category (>3) , and the average Karakiewicz nomogram score was lower. ESRD was associated with decreased tumor recurrence and clear cell pathology. No patients with ESRD had metastatic disease. There was no difference in overall or cancer-specific mortality between the ESRD and control groups. Patients with ESRD who develop RCC have a better prognosis compared to RCC in patients without ESRD, which is likely secondary to favorable histopathologic phenotype as well as the likelihood of early diagnosis. Thus, the delay between nephrectomy and renal transplantation may not be necessary, especially in patients with asymptomatic, low grade tumors.
The prevalence of renal cell carcinoma (RCC) in patients with end-stage renal disease (ESRD) is estimated to be between 2–7% (1–4). It is well established that patients with ESRD demonstrate a significantly greater risk for RCC than the general population. In 1977, Dunnill et al. (5). published a landmark autopsy series describing the relationship between ESRD, acquired renal cystic disease (ARCD), and RCC. While there have been many reports attempting to determine the incidence of RCC in the ESRD population, the actual clinical significance and prognosis of RCC in the ESRD population has not been adequately addressed. Typically, patients undergoing renal transplant evaluation that are found to have a renal tumor are treated with nephrectomy prior to transplantation. It is generally accepted that the immunosuppression mandatory for transplantation favors the growth of existing cancer cells. Therefore, it has become standard practice to issue a waiting period from the time of treatment of a malignancy to
Adam B. Shrewsberrya, Adeboye O. Osunkoyaa,b, Kun Jiangb, Ruth Westbya, Daniel Cantera, John Pattarasa, Nicole Turgeonc, Viraj A. Mastera,d and Kenneth Ogana a
Department of Urology, Emory University, Department of Pathology, Emory University, c Emory Transplant Center, Emory University and dWinship Cancer Institute, Emory University, Atlanta, GA, USA b
Key words: end-stage renal disease – renal cell carcinoma – transplant Corresponding author: Kenneth Ogan, MD, Department of Urology, Emory University, 1365 Clifton Road, Atlanta, GA 30322, USA Tel./fax: 404 778 4615; e-mail: [email protected] Conflicts of interest: None Accepted for publication 17 November 2013
transplantation, excluding patients who would have a recurrence. Clinical practice guidelines published by the American Society for Transplantation recommends a waiting time of at least two yr following definitive treatment of RCC for patients with symptomatic RCC while some large (>5 cm) and/or invasive renal cancers may warrant a five-yr waiting period (6). According to the Cincinnati Transplant Tumor Registry (CTTR), a waiting time of at least two yr eliminates approximately 61% of recurrences (7). Unfortunately, the negative effects of ESRD and dialysis on the patient are numerous and include emotional, physical, and financial burdens. Additionally, increased time on dialysis has been shown to confer worse graft and patient survival (8, 9). In fact, ESRD time is the strongest modifiable risk factor for renal transplant outcomes (10). The purpose of this study was to retrospectively compare pathological and clinical outcomes in a cohort of patients with RCC with and without ESRD. We hypothesize that the prognosis of
211
Shrewsberry et al.
patients with ESRD is better than patients without ESRD. If risks of cancer recurrence are low, then the standard delay prior to renal transplantation may be able to be decreased or even eliminated.
Materials and methods Data and patients
This retrospective study was approved by our institutional review board and included patients from 1999 to 2011. Patients with renal tumors and ESRD that underwent nephrectomy at our institution were identified from our surgical database. ESRD was defined as chronic renal failure treated by renal replacement therapy (hemodialysis or peritoneal dialysis). The patients who were found to have RCC while on dialysis made up our study cohort. The following variables were documented: demographics, duration and type of dialysis, Charlson Comorbidity Index (CCI) (11), presence of ARCD, maximum tumor diameter, histologic subtype, Fuhrman grade, TNM staging, Karakiewicz nomogram score (12), tumor recurrence, cancer-specific mortality (CSM), and overall mortality. ARCD was defined by at least five renal cysts per kidney on ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). CSM was determined through the National Death Index, and the Social Security Death Index (SSDI) was employed to determine overall mortality. Tumor recurrence was defined as clinical evidence of disease on follow-up imaging or tissue biopsy. As new ESRD-specific histopathologies were identified after many of the patients had undergone their nephrectomy, all pathologic specimens from the ESRD cohort were independently reviewed and re-classified by a dedicated genitourinary pathologist (AO) according to the new classification scheme (4). All cases of clear cell papillary RCC were confirmed by the classic immunohistochemical profile seen in this subtype (positive CK7 and negative CD10 and AMACR/P504S expression). In a similar fashion to Neuzillet et al. (13), the ESRD cohort was compared to a control group without ESRD-associated RCC that was operated on during the same time frame identified in our surgical database. The primary outcome was defined as risk of tumor recurrence. Secondary outcomes included histological type, Fuhrman grade, pathologic stage, the Karakiewicz nomogram score, and cancer-specific (CSM) and overall mortality. For ESRD patients, surgical treatment of RCC was radical nephrectomy. For patients in the control group, radical nephrectomy or nephronsparing surgery was performed.
212
Statistical analysis
Data analysis was performed with SAS 9.3 (Cary, NC, USA). The primary exposure (ESRD) and other covariates of interest were tabulated via counts and percentages for categorical variables and means and standard deviations for continuous variables by the outcome of cancer recurrence. The crude associations between exposures and the primary outcome of recurrence were evaluated via crude odds ratios (OR) and 95% confidence intervals (CI). The crude associations between the primary exposure and other covariates were evaluated via chi-square tests (or Fisher’s exact tests) for categorical variables or two-sample t-tests for continuous variables. Covariates significantly associated with the outcome of interest and primary exposure in univariate analyses were entered into a multivariate logistic regression model predictive of cancer recurrence to control for confounding. Repeat observations for patients with bilateral RCC in the ESRD group were controlled for by including patient identification in the model as a continuous variable. Effect measure modification was not hypothesized a priori to influence results, and no effect measure modification was observed in post hoc examination for gender or race. Variables entered into the multivariate model were evaluated for co-linearity using condition indices >30 and variance decomposition proportions >0.5 as cutoffs. The multivariate model predictive of recurrence was built with manual backward selection using a p-Value of 0.05 as the cutoff criteria for variable selection. In secondary analyses, the association between the primary exposure and mortality (yes vs. no), cause-specific mortality (RCC vs. other), and histological subtype (clear cell vs. non-clear cell) were evaluated via logistic regression using a similar modeling strategy as described above for the primary outcome. Additionally, ordinal logistic regression was used to evaluate the association between the primary exposure and increasing Fuhrman grade, and the association between the primary exposure and Karakiewicz nomogram score was evaluated via linear regression.
Results Baseline characteristics
The study included 327 patients with renal tumors. The ESRD cohort was composed of 84 patients, 11 of which had bilateral RCC. Each case of RCC was treated as an individual data point, which
RCC in ESRD patients has favorable prognosis resulted in a total of 95 cases in the ESRD cohort. Transplant and non-transplant patients accounted for 24 cases (28.6%) and 60 cases (71.4%), respectively, at time of nephrectomy. The control group was composed of 243 cases. Baseline characteristics are included in Table 1. The ESRD group was younger and was an overall less healthy group, as evidenced by higher age-adjusted CCI scores. Racial distribution was different between groups with 76% and 19% of patients being black in the ESRD and non-ESRD groups, respectively. There was no difference in BMI between the two groups (28.1 5.57 vs. 28.62 5.88, p = 0.46). A significantly greater number of patients in the ESRD group endorsed a smoking history compared to the non-ESRD group (61% vs. 47%, p = 0.02). In the ESRD group, 67% had ARCD, 87% were on hemodialysis, and 13% were on peritoneal dialysis. Average time between initiation of dialysis and nephrectomy was 4.49 yr. A slightly higher percentage of patients with ESRD presented without symptoms (69% vs. 57%, p = 0.03). Comparison of RCC groups with and without ESRD
Main comparison data are summarized in Table 1, and the various histological subtypes are shown in Table 2. Mean RCC tumor size was smaller and Table 1. Comparison of clinical and outcome features of ESRD and non-ESRD RCC patients
Variables Age at nephrectomy, yr, mean SD Male gender, no. (%) CCI, mean SD Tumor size, cm, mean SD pT category ≥3, no. (%) Nodal invasion, no. (%) Metastatic disease, no. (%) Fuhrman grade ≥3, no. (%) Karakiewicz nomogram score, mean SD Death from cancer, no. (%) Overall mortality, no. (%)
ESRD + RCC (N = 95)
RCC (N = 243)
56.32 13.22
59.75 12.49
59 (62) 4.68 2.02 3.4 2.8
159 (65) 2.56 1.99 5.8 3.3
9 (9)
65 (27)
0.001
6 (6)
29 (12)
0.12
p-Value* 0.026 0.566
