Because of its effectiveness, its cost, and the quality of life that it ensures, renal transplantation is a primary treatment option for patients who experience terminal renal failure.1 Nonetheless, because of the resulting immunosuppression, renal transplant recipients have a 100-fold-increased risk of malignancy compared with non–transplant recipients.2 The major complication associated with immunosuppression in the medium and long term is the appearance of malignant lesions,3 with skin malignancies and malignant non-Hodgkin lymphomas being the most common. Malignancies of the genitourinary tract make up 15% of all malignant tumors in the Cincinnati Tumor Transplant Register, and carcinoma of the native kidney accounts for up to 5% of all malignancies found in transplant recipients.4 In addition, Doublet et al.5 reported a 100-fold-increased risk of native kidney malignancy among transplant recipients compared with the general population.
The purpose of the current retrospective study is to present and discuss the epidemiologic, clinical, and paraclinical aspects (i.e., radiology and histology) as well as the therapeutic options and prognosis associated with de novo malignancies of the native kidney in renal transplant recipients at our center.
MATERIALS AND METHODS
Between January 1987 and December 2003, 933 consecutive patients underwent renal transplantation at our center. All 933 received conventional quadruple sequential immunosuppressive therapy (induction: polyclonal antibodies, 1 mg/kg corticoids, anticalcineurin, and azathioprin; maintenance: corticoids, anticalcineurin, and azathioprin). During the time period examined, there was no policy of including routine radiologic monitoring of the native kidney as a part of follow-up. Urologic evaluation was indicated when a posttransplantation medical or surgical complication was suspected on nephrologic follow-up.
Of the 933 consecutive renal transplant recipients encountered at our center, those who developed de novo renal cell carcinoma of the native kidney during follow-up were included in the current analysis.
Among the 933 consecutive renal transplant recipients at our center between January 1987 and December 2003, 14 subsequently were diagnosed with de novo tumors of the native kidney. Three of these patients had benign tumors (1 oncocytoma, 1 cystadenoma, and 1 papillary adenoma). The remaining 11 patients (1.2% of the study cohort) had a combined total of 12 de novo malignancies of the native kidney. (One patient had two separate malignancies of the native kidney.)
Among the 11 transplant recipients with renal carcinoma, there were 10 males and 1 female. These 11 patients had a mean age at diagnosis of 49.1 years (standard deviation [SD], 9.9 years; range, 31–63 years), a mean age at transplantation of 42.5 years (SD, 11.1 years; range, 27–59 years), and a mean time from transplantation to diagnosis of malignancy of 70.9 months (SD, 49.4 months; range, 8–156 months).
The initial nephropathy (which was recorded for 10 patients) was chronic glomerulonephritis in 5 cases, nephrosclerosis in 3 cases, chronic interstitial nephritis in 1 case, and polyarteritis nodosa in 1 case; 9 of the 11 patients also had arterial hypertension. With regard to treatment, eight patients received immunosuppressive tritherapy, two received bitherapy, and one underwent transplantectomy and was no longer receiving immunosuppressive therapy at the time of diagnosis.
Eight of 11 patients had normal renal functioning at diagnosis (mean serum creatinine concentration, 180 μM; SD, 63.2 μM). Among the three patients with deteriorated renal functioning, two had experienced chronic rejection and were not receiving dialysis, and the other had undergone transplantectomy and was receiving dialysis. Ten of 12 renal cell carcinomas were diagnosed incidentally (9 radiologically and 1 histologically [in a binephrectomy specimen obtained for arterial hypertension]), and the remaining 2 were symptomatic. One case of metastatic bone pain and one macroscopic hematuria also were encountered.
Renal ultrasonography was performed in 10 patients, yielding 9 true-positive diagnoses (5 Category 3 Bosniak cysts and 4 typical solid lesions) and 1 false-negative diagnosis (bilateral renal atrophy that later was shown to be a typical solid mass on computed tomography [CT]). Renal CT scanning was performed in 10 patients and had a true-positive rate of 100% (5 cystic malignancies and 5 solid lesions). One patient, who had multicystic renal dysplasia, underwent renal angiography to confirm a diagnosis of renal malignancy that was suspected on the basis of ultrasonographic and CT findings. In total, six patients had multicystic renal dysplasia; five of these six were asymptomatic, and the remaining patient had a macroscopic hematuria.
On CT, the mean tumor size was determined to be 43 mm (SD, 32.2 mm; median, 40 mm; range, 10–70 mm). Four tumors were located in the right kidney, and seven tumors were found in the left kidney. In the remaining case, the malignancy was bilateral and metastasized to bone. One patient had two separate malignancies of the left kidney.
Nine radical nephrectomies (including seven with adrenal gland conservation) and one binephrectomy were performed. For the patient with metastatic bilateral renal carcinoma, a percutaneous tumor biopsy was performed, interleukin (IL)-2-based immunotherapy and palliative bone radiotherapy were administered, and the intensity of immunosuppressive therapy was reduced.
In surgical specimens, the mean tumor size was found to be 37 mm (SD, 26.4 mm; median, 39 mm; range, 10–90 mm). All malignant tumors in the current analysis were renal cell carcinomas. There were 7 conventional renal cell carcinomas (58%), 3 basophilic papillary renal cell carcinomas (25%), and 2 chromophobic renal cell carcinomas. There were one, five, and six Furhman nuclear Grade 1, 2, and 3 tumors, respectively. Six lesions were classified as pT1aN0M0, four as pT1bN0M0, one as pT3aN0M0, and one as pTxNxM1 (2003 TNM staging system).
Immunosuppressive therapy was modified for only one transplant recipient. This patient, who had bilateral conventional renal cell carcinoma with bone metastases, received cyclosporin A alone after the diagnosis of malignant disease.
The mean follow-up duration for the 11 patients in the current analysis was 39 months (SD, 41 months; median, 22 months; range, 2–129 months). Two of these 11 patients died, one due to pulmonary tuberculosis and the other due to the progression of metastases 2 months after diagnosis. (The latter patient had metastatic disease at diagnosis.) The remaining 9 patients (82%) were alive with no evidence of disease at the time of the current report.
Epidemiology and Risk Factors
Compared with the general population, renal transplant recipients have an increased risk of native kidney malignancies (unpublished data).6, 7 The prevalence of such malignancies among renal transplant recipients ranges from 0.34%8 to 3.9%,5 depending on whether echographic screening is performed. Denton et al.,9 who performed systematic nephrectomy of the ipsilateral native kidney at the time of renal transplantation, reported a 4.2% prevalence of renal cell carcinoma before transplantation. In the current series, in which radiologic screening for native kidney malignancies was not performed, the rate of de novo malignancy of the native kidney was 1.2%. The estimated rate of renal carcinoma in the general population is 0.12%.10 De novo malignancies of the native kidney account for 4.8% of all malignant tumors found in transplant recipients,4 compared with 2.5% in the general population.10
Unlike at other locations, in the native kidney, it appears that immunosuppression does not increase the risk of developing malignant disease, as is suggested by the identical rates of renal carcinoma incidence in cardiac transplant recipients and the general population.11
According to Doublet et al.,5 acquired multicystic dysplasia is significantly associated with the risk of native kidney malignancy in renal transplant recipients. In contrast, there is no significant relation between patient age (mean, 49 years in the current series), time receiving dialysis (mean, 24 months), time since transplantation (mean, 70.9 months), or type of immunosuppressive therapy and native kidney malignancy risk in transplant recipients. Furthermore, neither acquired renal polycystic dysplasia nor simple renal cysts are clearly associated with renal carcinoma risk.10 Nonetheless, it does appear that immunosuppression may be associated with increased tumoral aggressiveness.12–14 In the current series, 50% of all renal malignancies were of high grade, whereas the majority of malignant renal tumors encountered were early-stage lesions.
The diagnosis of native kidney malignancies in renal transplant recipients typically is incidental, because these tumors generally are small and asymptomatic. Hoshida et al.,15 in a retrospective study of 218 renal malignancies, including 22 native kidney malignancies, found in transplant recipients, reported a median native kidney tumor size of 2 cm (pathologic T classification: 12 pT1, 3 pT2, and 7 pT3). Doublet et al.,5 in a prospective study in which systematic native kidney echography was performed for 129 renal transplant recipients, diagnosed 5 tumors, which had a mean size of 2.5 cm; all 5 of these tumors were pT1 lesions. As in those two series, the majority of tumors found in the current series (mean tumor size, 3.7 cm; pT1 disease in 83% of all cases) were asymptomatic (10 of 12).
The semiology and the ultrasonographic techniques used to diagnose renal carcinoma are the same for all patients, regardless of whether they are kidney transplant recipients.16 At our center, renal ultrasonography was not performed systematically as a part of follow-up for transplant recipients. When ultrasonography was performed, it yielded one false-negative diagnosis and 9 true-positive diagnoses (five Category 3 Bosniak cystic lesions and four typical solid lesions). These results are similar to those published elsewhere in the literature (positive predictive value, 100%5; negative predictive value, 92%17).
In the detection of renal malignancies, CT scan semiology is similar for transplant recipients and members of the general population; however, acquired multicystic renal dysplasia decreases the diagnostic performance of CT. Among dialysis or transplant recipients, Terasawa et al.19 reported a renal carcinoma detection rate of only 67%, and Sasagawa et al.19 reported a detection rate of only 71%. Thus, it should be emphasized that renal ultrasonography is the only tool confirmed to possess value in the screening (i.e., noninvasive and inexpensive assessment20) and diagnosis of renal carcinoma in kidney transplant recipients.16
There are no specific clinical features associated with renal carcinoma in transplant recipients. The most common clinical symptom of renal carcinoma is macroscopic hematuria, although other symptoms (urologic, general, or metastatic) can also arise.14, 21
The standard surgical treatment for native kidney malignancies is radical nephrectomy.16 This procedure was performed for nine patients in the current series.
Is there a role for synchronous binephrectomy in the treatment of these malignancies? We performed binephrectomy in one case, in which the initial indication was antihypertensive tritherapy for severe arterial hypertension. Histologic examination incidentally revealed a unilateral pT1, Grade 2 papillary renal cell carcinoma (size, 1.5 cm). Levine and Gburek22 were the first to describe bilateral renal cell carcinoma of the native kidney after transplantation; in that case, a binephrectomy was indicated and subsequently performed. Nonetheless, due to the rarity of such cases, those authors concluded that binephrectomy with prophylactic nephrectomy of the kidney opposite the tumor should not constitute a therapeutic standard.
To our knowledge, there are no reports in the literature regarding prophylactic contralateral nephrectomy. We believe that this procedure must be discussed with regard to malignancies such as papillary renal cell carcinoma (i.e., those that carry a high risk of bilaterality).23 In the current series, two patients had basophilic papillary renal cell carcinoma, one in the right kidney and the other in the left. Systematic radical nephrectomy was performed on the kidney opposite the tumor in both of these patients, and no malignancy was diagnosed in either case.
Role of medical treatment
The indication of antitumoral immunotherapy for metastatic native renal cell carcinoma arose in one patient in the current series. This patient had bilateral Furhman Grade 3 clear cell renal carcinoma, which was diagnosed due to the presence of diffuse bone metastases; the diagnosis was confirmed on percutaneous biopsy of the renal tumor. The patient; whose therapeutic strategy was based on maximal reduction of the antirejection regimen, IL-2/interferon-containing immunotherapy, and antalgic treatment; died of metastatic progression 2 months later. This case represents a clinical situation that is rarely found in the literature (unpublished data).
In the treatment of metastatic renal cell carcinoma, antitumoral immunotherapy plays a role only after maximal surgical reduction of the tumor (via radical nephrectomy and, if possible, excision of metastases). Furthermore, in transplant recipients, reduction or even interruption of antirejection treatment under nephrologic surveillance is likely to be mandatory. In cases with a favorable prognosis, this strategy results in a 15% objective response rate (unpublished data).
Antitumoral immunotherapy is theoretically contraindicated for patients receiving immunosuppressive treatment; however, some investigators have reported the safe use of interferon alpha in the treatment of hepatitis C in transplant recipients.24 Nakamoto illustrated the effectiveness of this therapeutic strategy (antalgic effects and lesion regression on radiologic controls) in patients with bone metastases who did not have objective signs of rejection (unpublished data). Nonetheless, the use of such a strategy in patients with metastatic disease is controversial, and additional validation studies are necessary.
Role of immunosuppressive treatment reduction
Upon diagnosis of de novo native kidney malignancy after renal transplantation, we modified the immunosuppressive treatment regimen for one patient, who had bilateral metastatic renal cell carcinoma. Only cyclosporin A treatment was maintained for this patient.
In series dealing with native kidney malignancies arising posttransplantation, data related to immunosuppressive treatment reduction are scarce. To our knowledge, there are no specific recommendations in the literature concerning the management of antirejection therapy for patients with de novo malignancies of the native kidney. Posttransplantation cervical and skin malignancies could serve as useful models with regard to this issue. According to Sheil et al.,8 immunosuppressive therapy could continue unmodified after the treatment of localized or locally advanced nonmetastatic cervical malignancies; however, those investigators also found that the appearance of metastases necessitated the interruption of immunosuppressive therapy, with transplantectomy in the event of rejection. In patients with skin malignancies, metastatic disease and early recurrence were identified as indications for interruptions, reductions, or changes in immunosuppressive treatment. Nonetheless, when changes were made in the immunosuppressive agents used, nonconventional agents (chlorambucil and cyclophosphamide) were associated with an increased risk of immunologic graft loss. It also was found that in general, it is better to tailor the intensity of immunosuppression to the severity of the tumor.8
This strategy for dealing with cervical and skin malignancies could also be used for the management of native kidney malignancies. Thus, it appears to be reasonable to treat a de novo native kidney malignancy without modifying immunosuppressive therapy, provided that the malignancy is of low stage and low grade. In contrast, it is prudent and logical to modify or halt immunosuppressive therapy in patients with aggressive or metastatic tumors. Nonetheless, objective criteria regarding the adaptation of the extent of immunosuppression to tumor prognosis have yet to be defined.
Rapamycin is an immunosuppressive agent that inhibits the mTOR protein kinase. This protein is involved in proliferation and cell cycle progression, and its unregulated activity is often associated with a PTEN antioncogene mutation resulting in proliferation and invasive behavior by tumor cells. Objective responses to an analog of rapamycin have been reported in patients with renal malignancies.25 The switch from a standard immunosuppressive regimen to a rapamycin-based regimen could be an option for patients who develop de novo native renal malignancies after transplantation.
In published series, the reported sizes of de novo native kidney malignancies are relatively small. Hoshida et al.15 reported a median tumor size of 2 cm, and Doublet et al.5 reported a median size of 2.5 cm. In the current series, the mean tumor size was 47 mm, and 71% of all malignant tumors were pT1 lesions. This discrepancy in tumor sizes could be attributable to the lack of systematic renal follow-up in the current series.
With regard to histologic type, a distribution including 75% renal cell carcinomas and 15% transitional cell tumors has been reported in the literature.22 The current series of de novo malignancies consisted entirely of renal cell carcinomas (12 of 12); there were no transitional cell carcinomas, as no transplant recipient experienced analgesic nephropathy. Fifty-eight percent of all malignancies encountered were clear cell carcinomas, and another 25% were papillary renal carcinomas. All papillary renal carcinomas were basophilic tumors (i.e., type 1 in the Delahunt classification23). Our results regarding the distribution of papillary and nonpapillary renal cell carcinomas are similar to those reported in the literature. The incidence of renal papillary tumors is significantly higher in dialysis and transplant populations compared with the general population,26 and this risk is also increased in patients with acquired multicystic renal dysplasia.10 Papillary renal tumors account for only 10% of all renal cell carcinomas in the general population in Europe, whereas clear cell tumors account for 75%. Hoshida et al.15 reported the presence of 36% papillary renal carcinomas (8 of 22) and 60% clear cell carcinomas in their series. Likewise, Ishikawa et al.26 reported a 40% prevalence of papillary renal cell carcinoma, compared with a 60% prevalence of clear cell disease.
Among dialysis recipients, the histologic distribution of renal tumors is identical to that found in the general population.26
Malignant lesions typically are more aggressive in transplant recipients compared with the general population12 and with the population of patients receiving dialysis.14, 27 This aggressiveness is related to the immunosuppressed state of transplant recipients. In addition, Hoshida et al.15 state that cyclosporin specifically promotes tumor growth. This translates to a higher rate of poorly differentiated and invasive lesions that exhibit multifocal and metastatic evolution, resulting in a more rapid progression to death. Based on their findings in patients with skin malignancies, Barrett et al.12 confirmed the more aggressive evolution of tumors in the transplant population.
In the current series, we reported a high prevalence of high-grade tumors (50% [6 of 12], compared with 29% in the general population).10 In addition, 1 of 11 patients had M1 disease at diagnosis (9%, compared with 6% in the general population), and that patient died 2 months after beginning treatment. Pope et al.27 and Wiesel et al.16 reported the presence of metastatic evolution in 50% and 71% of all transplant recipients, respectively, compared with 8% of patients receiving dialysis. In addition, Katai et al.7 reported on a case of renal cell carcinoma with metastases to liver and bone. These data suggest that de novo native kidney malignancies may exhibit particularly aggressive behavior in transplant recipients.
In contrast to these findings, Doublet et al.,5 Ishikawa et al.,26 and Hoshida et al.15 all reported a higher or similar prevalence of low-stage tumors (100%, 90%, and 70% pT1–2 tumors, respectively) in transplant recipients compared with the general population (75%). In addition, none of these investigators observed any pejorative postoperative disease evolution. In our series, 10 of the 12 malignant tumors encountered (83%) were pT1–2 lesions, and all 10 had favorable outcomes at the time of the current report.
Ishikawa and Kovacs28 reported a 10% mortality rate in association with de novo malignancies of the native kidney. In the current series (mean follow-up, 39 months), the disease-specific mortality rate was 8.3% (1 of 12). These results suggest a favorable short-term prognosis, even for transplant recipients with high-grade tumors, when radical nephrectomy is performed; however, longer follow-up is necessary to confirm this finding.
In general, Ishikawa et al.6 state that despite the possible increase in tumor aggressiveness due to prolonged immunosuppression, patients who develop de novo malignancies of the native kidney after transplantation have a favorable prognosis.
At our center, systematic radiologic screening of the native kidneys was not performed during dialysis or after transplantation. Nonetheless, because of the possible premalignant state of renal multicystic dysplasia, Brennan et al.29 recommend systematic screening of the kidneys for patients with this condition. Those investigators suggest yearly renal ultrasonography beginning in the third year of dialysis, after an initial ultrasound image is acquired as a reference. They state that radical nephrectomy is indicated when ultrasonographic changes, suspicious cysts, cystic malignancies, or solid masses are detected; however, intracystic bleeding is not considered a tumoral symptom, and in cases of complicated evolution, nephrectomy is indicated on a purely symptomatic basis. This strategy becomes controversial if acquired multicystic renal dysplasia is considered a premalignant lesion.30, 31 Levine32 reported that echographic monitoring of the native kidneys was not useful, as it did not affect patient outcome. Nonetheless, we recommend annual renal echographic monitoring, with a cystic growth rate of less than 1 cm per year being considered normal.5
The currently recognized indications for pretransplantation binephrectomy3 are arterial hypertension not controlled by a medical treatment, Goodpasture syndrome, obstructive or stone-complicated chronic pyelonephritis, and symptomatic or complicated polycystic kidney. Glassman et al.33 have demonstrated that binephrectomy with concomitant renal transplantation in patients with polycystic kidneys is an effective and safe procedure, with a lower complication rate and a higher patient satisfaction rate compared with asynchronous surgeries. Using this strategy, prophylactic binephrectomy for acquired multicystic renal dysplasia is possible only if simultaneous renal transplantation is also possible.
Pretransplantation renal carcinoma
Uncontrolled malignancies are contraindications for renal transplantation.1 In patients being treated for renal carcinoma, a delay in pretransplantation follow-up is required so that progressive disease can be eliminated.3 A period of at least 2 years without evidence of disease is recommended, as 58% of all recurrences occur within this time frame. (Eighty-five percent of all recurrences occur within 3 years, and 92% occur within 5 years.2, 13) Pathologic stage10 and other prognostic factors, such as tumor grade and size, can be used to select patients for transplant receipt within the optimal delay period. Penn34 states that such a waiting period is not necessary for patients with incidental asymptomatic pT1 renal carcinoma but recommends 2 and 5 years of monitoring, respectively, for symptomatic pT1 and pT2 or higher tumors.
The results of the current study suggest that the incidence of de novo native kidney malignancies is higher among transplant recipients compared with the general population even when patients in the former group do not undergo planned radiologic screening. Most of the malignancies encountered in the current study were diagnosed incidentally using radiologic methods. Renal ultrasonography plays a key role in the early diagnosis of de novo malignancies of the native kidney after transplantation. The increased prevalence of papillary tumors is an essential characteristic of renal malignancy arising in transplant recipients. In addition, the elevated proportion of high-grade tumors reflects the potential aggressiveness of native kidney malignancies. For patients with low-stage malignancies who undergo radical nephrectomy and whose immunosuppressive treatment remains unchanged, outcomes (with regard to both the malignancy and the transplantation) are favorable. In general, we recommend a prolonged, systematic course of annual echographic monitoring of the native kidney in renal transplant recipients.