The estimated number of new kidney or renal pelvis cancer diagnosis in the United States for 2008 is 54,390, making it the third most common cancer of the genitourinary system. It is 1 of the 10 most common new cancer diagnoses in both men and women. Furthermore 13,010 men and woman are expected to have died of their disease that year, making renal cancer the 10th most common cause of cancer mortality in men (1). Patients with renal failure, specifically those with acquired cystic kidney disease (ACKD), are at an even greater risk of developing renal cancer. Furthermore, the risk is not ameliorated by renal transplantation (2). Over the past 25 years, the number of renal transplants performed annually has increased dramatically from less than 4000 a year in 1980 to more than 17,000 in 2005 (3). A number of these patients will ultimately develop renal cell carcinoma (RCA). We report our experience in 15 posttransplant patients who underwent nephrectomy for renal masses.
The length of time between transplantation and native nephrectomy ranged from 37 days to more than 14 years; the average time between transplant and nephrectomy was just more than 3 years. Ten of the patients had their transplants performed at our institution. As described in our inclusion criteria, all 15 patients remained on immunosuppression perioperatively. Table 1 summarizes immunosuppressive regimens. However, not all grafts were functioning because two patients had creatinine levels greater than 4.0, with one requiring dialysis before coming under our care. The immunosuppressive regimen at the time of surgery was not available for 2 of the 15 patients. Of the 13 patients for whom the regimen was available, 8 (62%) received 2 drugs and 5 (38%) received 3 drugs. The most commonly encountered agents were prednisone and tacrolimus, while sirolimus and mycophenolic acid were the least common.
A total of 22 renal units were removed from 15 patients, with 18 kidneys removed laparoscopically and 4 via an open approach. Of those 22 kidneys, 17 units (77%) from 13 patients contained RCC. One kidney had two cancers, for a total of 18 cancers (Table 2). RCC histologies were 11 papillary (61%), 4 clear cell (22%), and 3 chromophobe (17%). Fuhrman grade was not available for two of the patients with papillary tumors. Eight of the nine tumors for which Fuhrman grade was determined were grade 2; the ninth tumor was grade 3. Seventy-five percent of the clear cell RCCs were grade 3. All chromophobe tumors were grade 2. Ten patients were stage T1N0M0, two patients were stage T2N0M0, and one was stage T3N0M0. Renal cysts were found in 62% of patients with RCC.
Characteristics of patients diagnosed with RCC are presented in Table 3. The average length of stay for laparoscopic nephrectomy was 95 hr, with a median length of stay of 61 hr (range 33–360 hr). The average length of stay for open nephrectomy was 18 days; of note, both patients undergoing open procedures had bilateral nephrectomies for suspicious masses within polycystic kidneys. Surgical complications (7%) included a delayed extraction site hernia. Two additional patients had medical complications after surgery, including bronchitis and bacteremia. There were no episodes of rejection, new dialysis, or injury to the kidney. One patient has developed pulmonary metastasis, with a mean patient follow-up of 60.6 months; mean metastasis-free survival is 58.4 months.
Patients with renal failure, especially those with ACKD, are at risk for RCC. In their 2007 study, Schwarz et al. evaluated the prevalence of RCC in patients who received renal allografts. They screened a total of 561 patients who received a renal transplant with native renal ultrasounds; 23% of those patients had ACKD, with 8.2% having complex renal cysts. In their study, 1.5% (eight) of the patients were newly diagnosed with RCC, including one cancer in a transplanted kidney; seven of those patients also had ACKD. In their cohort, 19 patients had previous RCC diagnoses, 18 of whom had ACKD. Including the previously identified malignancies, they found a prevalence of 4.8% in all patients. Stratifying patients by presence or absence of ACKD increased RCC prevalence to 19.4%. The prevalence rose even further when only looking at complex cysts to 54.4%. Interestingly, this group's prevalence of ACKD (23%) is lower than the 30% to 90% prevalence described in patients on hemodialysis. They suggest a possible protective effect of the transplant or its immunosuppression on cyst pathogenesis, which would ultimately also protect against the development of RCC (4). Others report rates of RCC from 1.2% in a nonscreened population to 3.2% in a population screened with ultrasound (5–7). The presence of cysts was noted in 62% of our patients, which is lower than that reported in the literature, with no malignancies reported within a cyst. This number is lower than that reported in the literature, potentially representing underreporting of ACKD by our pathologists.
In addition to ACKD increasing the risk of RCC, Maru et al. suggest that end stage renal disease (ESRD) is a negative prognostic indicator. They compared clinicopathologic features of RCC between 16 patients with ESRD and 134 patients without. Although there was no difference between age at diagnosis, stage, grade, or percentage of incidentally discovered lesions, patients with ESRD were more likely to recur (8). While the Maru study found no difference in grade of tumor, other studies have conflicting conclusions concerning tumor grade. In the study by Klatte et al. (9), only 4% of masses were Fuhrman grade 3 or higher, as opposed to the study by Moudouni et al. where 50% of the tumors were high grade. Moudouni et al. (6) additionally quotes the rate of high-grade lesions to be 25%, thus asserting an increased risk of aggressive disease among transplant recipients. In our patient population, 25% of all masses where grade was known were high grade. When stratified by histologic type, 11% of papillary cancers and no chromophobe cancers were high grade, while 75% of clear cell carcinomas were high grade.
In our patient population, papillary RCC was the most common histology, as in patients on hemodialysis. This contrasts with the histology observed in the general population. In their 2007 analysis of the Surveillance Epidemiology and End Results (SEER) database, Aron et al. (10) noted that 85% of men and 88% of women with RCC have clear cell histology. Schwarz's transplant series, while showing a high percentage of papillary tumors (42%), still showed a predominance of clear cell RCC (58%); one patient had both (4). This may be an artifact of the relatively small number of patients in each series. This also may reflect misdiagnosis of cancers including both papillary architecture and clear cell components. In their 2008 study, Gobbo et al. examined immunohistochemical and cytogenetic analyses as ancillary studies to help differentiate between clear cell and papillary RCC. Despite their armamentarium, 14% of their malignancies remained unclassified. The distinction is important, as the prognosis varies between clear cell and papillary RCC (11). In another study, the same group suggests that a distinct variant of RCC be recognized: clear cell papillary RCC. Its immunophenotypic and genetic profiles differ from both classically recognized clear cell and papillary RCC. Furthermore, this variant has been described within ESRD kidneys (12). First described in the study by Tickoo et al. in 2006 as “clear-cell papillary RCC of the end-stage kidneys,” these tumors had a papillary architecture composed of clear cell cytologic changes. The study looked at the pathology of 66 end-stage kidneys removed for suspicion of malignancy. Grossly, 261 tumors were identified within these kidneys. Clear-cell papillary RCC was the dominant mass in 23% of the 66 kidneys, as opposed to clear cell (18%) and papillary (15%) RCCs (13). It may be that tumors both within our own study and others were classified as clear cell or papillary, where this new category may be more appropriate. Further research should be dedicated to ascertain whether the prognosis more closely follows papillary or clear cell RCC. Translocation RCC, another recently recognized RCC subtype, also may be misdiagnosed as papillary or clear cell RCC. Although it is often associated with children and young adults, it is not limited to this population. In a recent Japanese study, approximately 1.5% of 443 RCCs were identified as translocation by cytogenetic analysis or TFE3 immunohistochemistry. If only the 26 patients younger than 45 years were included, 15% of the tumors were translocation RCC (14). Although it has not been described in the ESRD population, it may be that some clear cell or papillary RCCs have been misdiagnosed, especially in younger patients.
Our study has demonstrated that renal transplant recipients with suspicious masses or cancer or both can safely undergo nephrectomy of native kidneys without jeopardizing their grafts by stopping immunosuppression. No patient who was not receiving dialysis preoperatively required dialysis after surgery. Furthermore, our complication rate suggests that stopping immunosuppression may not be necessary for acceptable results. Our overall complication rate was 20%; one patient (7%) had a surgical complication and two patients (13%) had medical complications. The surgical complication, an extraction site hernia, was in a patient who was dialysis dependant before surgery and who received sirolimus (Rapamune) perioperatively. Sirolimus was demonstrated in a prospective, randomized study to increase to the risk of wound complications, including fluid collections, wound infections, and incisional hernias (15). All of our patients are actively followed up by transplant surgeons, nephrologists, and pharmacists, in addition to the operating urology team. The transplant team should guide immunosuppressive regimen changes, if necessary, during the perioperative period. Sirolimus should more than likely be withheld.
Given the association between immunosuppression and malignancy, a number of studies have sought to characterize the relationship for renal transplant recipients. In the study by Navarro et al., 1017 renal transplant patients were entered in a prospective database. This database was then queried to identify de novo malignancies, including lymphoproliferative disorder, nonmelanoma skin cancer, or solid organ malignancies. A total of 10.8% of patients developed cancer. Native kidney RCC and lung cancer were most common solid organ malignancies. Potential risk factors they identified for solid organ malignancies included recipient age, duration of renal transplant, number of renal transplants, and use of tacrolimus. The duration of renal transplant, number of renal transplants, and use of tacrolimus all implicate immunosuppression as a major causative factor (16). The time between transplantation and detection of malignancy varied greatly among patient patients in our population, with the shorted period being 37 days and the longest being 14 years, with an average of approximately 3 years, thus many of our patients were transplanted with unknown malignancies. It may be prudent to perform screening ultrasounds of native kidneys before transplantation. In addition, many authors currently advocate screening transplant recipients with ultrasound every 6 months to 1 year (4–7, 9, 17), and the European best practice guidelines for renal transplantation advocate ultrasound screening, although they do not specify frequency (18).
Although immunosuppression is possibly associated with de novo RCC, it does not seem to diminish the likelihood of cure. Most of the current literature suggests excellent cure rates for transplant patients with localized disease who undergo nephrectomy, with disease specific mortality of 0% to 10% (4–7, 9, 17). However, several of these studies include patients who had their surgery less than 1 year before the study (5, 6, 9, 17), thus it may be premature to assume them cured. Nonetheless, our results suggest acceptable success rates, with 12 of 13 patients free of disease at a mean metastasis-free survival of 58.4 months and a mean follow-up of 60.6 months. The patient with metastatic disease, the only one with gross hematuria, presented with the highest T stage and thus with the most advanced disease. Klatte et al. (9) performed multivariate analysis on their population, and transplantation had no impact on survival. Tollefson et al. (19) recommend against reducing immunosuppression in patients with nonmetastatic disease.
Although acceptable cure rates and minimal complications seem to obviate the need to change immunosuppression to prevent disease progression or surgical morbidity, a change of agents may provide medical benefit. Neuzillet et al. (5) suggest the potential of rapamycin, a mammalian target of rapamycin inhibitor, to treat RCC while providing immunosuppression. In a study of transplant patients with various de novo malignancies after transplantation, calcineurin inhibitors, azathioprine, and mycophenolate mofetil were converted to sirolimus, another mTOR inhibitor. Two patients with large B-cell lymphoma and four patients with Kaposi sarcoma had full regression with no impairment of allograft function (20). The idea of an immunosuppressive regimen that not only prevents rejection but also is an effective chemotherapeutic for RCC is compelling and warrants future research. In the case of metastatic disease in patients who are not surgical candidates, reduction of immunosuppression may be recommended (5, 19).
In conclusion, renal transplant recipients with suspicious masses or cancer or both can safely undergo nephrectomy of native kidneys without jeopardizing their grafts by stopping immunosuppression. Immunosuppression does not seem to promote metastasis or recurrence, although longer follow-up is required. As in patients on hemodialysis, papillary RCC is more common than clear cell carcinoma, although as more subtypes of RCC are defined, this trend may change. Evaluation for masses before transplantation and screening ultrasound of transplant recipients may aid in early identification.
MATERIALS AND METHODS
Since 2004, one surgeon (M.W.P.) has performed nephrectomies on 18 patients who had previously undergone renal transplants. Patients were included for analysis if the nephrectomy was performed for a suspicious mass and if they remained on immunosuppression, regardless of graft function, at the time of nephrectomy. We retrospectively reviewed the charts of the 15 patients meeting the inclusion criteria, including all available discharge summaries, operative reports, pathology reports, consultations, and progress notes to identify date of transplant, date of nephrectomy, pathology, immunosuppression, length of stay, and complications.In addition, we reviewed follow-up visits and films to identify late complications or recurrence.
Age at analysis ranged from 38 to 76 years. The average age was 57 years (median age 58 years). Of the 15 patients, 13 were men and 2 were women. Pathology, complications, length of stay, and current imaging were available for all patients. Immunosuppression regimen at the time of surgery was available for 13 of the 15 patients. Characteristics of patients diagnosed with RCC are presented in Table 3.
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