Therapy and Prognosis of Tumors of the Genitourinary Tract After Kidney Transplantation

Urogenital System

Therapy and Prognosis of Tumors of the Genitourinary Tract After Kidney Transplantation R. Diller, A. Gruber, H. Wolters, N. Senninger, and H-U. Spiegel ABSTRACT There is an increased incidence of tumors of the genitourinary tract among kidney graft recipients. From 1979 to 2001, all patients who received kidney transplants had records of both their underlying diseases and their initial immunosuppression. Patients who developed a genitourinary tract malignancy were evaluated for tumor type, location, stage, tumor therapy and clinical course. During this period, 1804 patients underwent 2068 kidney transplantations. Thirty-four patients had 39 tumors of genitourinary origin. One patient was lost to follow-up. There were 15 patients with 18 renal cell carcinomas (one of them multifocal): six had seven transitional cell carcinomas; six, prostatic carcinoma; six, tumor of the female genital tract (one also had a renal cell carcinoma); and two, a seminoma. Most tumors were diagnosed in their early stages (ⱕpT3, N0, M0; n ⫽ 31 tumors) and thus accessible to curative therapy, achieving good long-term results: 1- and 5-year survival rates of 100% and 91%, which were better than those obtained in advanced stages (N⫹, M⫹; n ⫽ 7 tumors), namely both 1- and 5-year survival rates of 38% (P ⬍ .05). Death was caused by tumor growth in nine patients (27%) and by other causes in three patients (9%). With appropriate treatment genitourinary tumors at early stage show a good prognosis. New immunosuppressants with supposed antiproliferative effects may help to decrease the incidence of malignancies. The most important factor is risk-adapted screening to identify malignancies early and to initiate appropriate therapy.

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RANSPLANT LOSS due to rejection decreases in the early transplant period. Longterm graft function improves when patients receive a well-tailored immunosuppressive regimen. Secondary problems due to immunosuppressants and concomitant diseases, including hypertension and diabetes, are of growing importance. In the long run, an increasing number of grafts are lost because of the patient death. Over the previous decades, malignant neoplasms in transplant recipients have been widely recognized as a factor in morbidity and mortality.1–3 There is an increased

incidence of tumors of the genitourinary tract in kidney graft recipients. Tumors may also occur in the transplanted organ. Various immunosuppressants, especially cyclosporFrom the Department of General Surgery, Muenster University Hospital, Munster, Germany. Address reprint requests to Dr. Ricarda Diller, Muenster University Hospital, Department of General Surgery, Waldeyer Str. 1, Munster, FRG, NRW 48149, Germany. E-mail: [email protected]

© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.061

Transplantation Proceedings, 37, 2089 –2092 (2005)

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DILLER, GRUBER, WOLTERS ET AL

ine (CsA) and ATG/ALG or OKT3, seem to effect tumor development.1,4,5 However, it is not known whether immunosuppressants influence the further course of the disease. The aim of this study was to investigate the incidence and prognosis of genitourinary tract tumors after kidney transplantation and their effect on patient prognosis and transplant function. PATIENTS AND METHODS From 1979 to 2001, all patients who received kidney transplants had records of their underlying diseases and initial immunosuppression. Patients who developed a histologically proven malignancy of the genitourinary tract were also evaluated with regard to tumor type, location, stage, tumor therapy, and further clinical course. The results were expressed as mean values ⫾ standard deviations. Follow-up was terminated either at December 31, 2002, at the time of death, or at last follow-up. Statistical evaluation was performed using the chi-square test for nominal data. Survival analyses used Kaplan-Meyer survival plots with comparisons by the log rank test. P less than .05 was considered significant.

RESULTS

During this period, 1804 patients underwent 2068 kidney transplantations. The male to female ratio of the patients was 3:2. There were 21% second transplants and 3% third transplants. The age at first transplantation was 42 ⫾ 14 years. After transplantation, 130 patients (average age: 54 ⫾ 11 years) developed one or multiple malignant tumors (6.9%). Of these patients seven (5%) had been treated for a malignancy before transplantation. Overall 80 patients (4.3%) developed 87 tumors of solid organs. Thirty-four patients had 39 tumors of genitourinary origin. Patients with urogenital tumors had an average age at the time of first transplantation of 46 ⫾ 11 years. The male to female ratio was 2:1. Data on therapy and further clinical courses were available in 33 patients. Details of the patients are shown in Table 1. Five patients developed a tumor after the second transplant (15%) and one patient after the third transplant (3%) (ns). Analgesic nephropathy was the underlying disease (9.5% resp. 12%) in two of the 21 patients (or 3 of the 25 kidney and urinary tract tumors). This disorder was more frequent in this group compared to its overall incidence of 1.6% in all transplant patients (P ⬍ .05). Polycystic kidney disease was present in 12% (n ⫽ 4) of the 34 patients with posttrans-

plant genitourinary tumors and in 9.3% of all transplant patients (ns). Thirty-eight patients (2.2%) had their first kidney transplant after therapy for 41 urogenital tumors. After transplantation, four patients (10.5%) developed repeat tumors. In one case the primary lesion recurred, whereas in the other three cases, the malignancy was independent of the primary: there was one thyroid, one skin, and one pancreatic carcinoma. In 55% of patients the initial immunosuppression after transplantation included CsA, azathioprine (Aza), and corticosteroids. During the last few years, 20% of patients received mycophenolate mofetil (MMF) as a substitute for Aza and 9%, tacrolimus instead of CsA. Induction therapy with ATG/ALG or OKT3 was administered to 4%; 16% had an initial calcineurin-free immunosuppression. Seventy-five percent (of the 41 transplantations preceeding tumor development) received initial immunosuppression with CsA, Aza, and corticosteroids, which was a significantly higher rate than in the general transplant population (P ⬍ .05). In 10% the initial immunosuppression included MMF (ns, P ⫽ .09); in 2% tacrolimus (ns); and two patients (6%) had therapy with ATG/ALG or OKT3 (ns). Twelve percent had calcineurin-free immunosuppression at the outset (ns). Transitional Cell Carcinoma

There were six patients with urothelial carcinomas, which developed 7.3 ⫾ 4.9 years after transplantation. In one case a transitional cell carcinoma occurred synchronously in the bladder and the kidney and in one case multifocally in the bladder. The tumor recurred in three cases after 9 months, 2 years, and 4 years. One patient was lost to follow-up. All tumors were surgically removed, and at the first operation there were no distant metastases. One- and 5-year survival rates were 80% and 40%, respectively. Renal Cell Carcinoma

Fifteen patients suffered from 18 renal cell carcinomas. In two patients the tumor was bilateral, and in one patient it appeared 10 years after a cervical carcinoma. The interval between tumor diagnosis and first transplant was 7.7 ⫾ 5 years. One patient died 6 months after transplantation due to blood-borne metastases from a bilateral hypernephroma

Table 1. Details of Patients with Urogenital Tract Tumors

Urothelial Renal Prostate Female genital tract Seminoma Total ⫹

Patients

Tumors

Average Age at Tumor Diagnosis (years)

Tumor Recurrence/ Persistence

Tumor-Caused 5-Year Mortality Rate (%)

6⫹ 15* 6 6* 2 34

7 (1 multifocal) 18 (1 multifocal) 6 6 2 39

52 ⫾ 14 53 ⫾ 9 59 ⫾ 6 46 ⫾ 8 30 ⫾ 1 51 ⫾ 11

3 3 3 1 0 10

60 23 20 17 0 26

One patient was lost to follow up. *One patient is mentioned twice, as she developed renal cell carcinoma and carcinoma of the cervix.

TUMORS OF THE GENITOURINARY TRACT

that had been operated on 30 months before. Two patients had distant metastases at the time of diagnosis; 87% underwent surgical therapy. In two patients renal cell carcinoma arose in the transplanted kidney, once it was locally resected. A second tumor developed 18 months later, requiring transplant nephrectomy; it did not recur with immunosuppression withdrawal. The other tumor manifestation in the transplant kidney was multifocal and locally advanced. It was treated by transplant nephrectomy and parailiac lymphadenectomy. One- and 5-year mortality rates due to tumor were 13% and 23%, respectively. During this period, two patients with no evidence of tumor recurrence died for other reasons. Prostatic Carcinoma

Of six patients who developed prostate carcinoma at 4.4 ⫾ 3 years after transplantation, five were treated surgically. A radical prostatectomy was performed in one case only, and a plastic orchidectomy in another. In three other patients a transurethral prostate resection was performed, with the incidental finding of an early low grade-prostate carcinoma. Two of them were treated with adjuvant radiotherapy, one in combination with hormonal suppression. One had adjuvant hormonal suppression. None of these three had tumor recurrence. The one patient who was treated by medicamentous hormonal suppression alone experienced tumor progress, leading to death more than 5 years later. After percutaneous irradiation, one patient had proctitis and urethral stenosis and therefore required urethral dilation. In another patient ureteral stenosis had to be treated by a stent. One patient had chronic lymphatic leukemia 8 years and a basalioma 13 years after the diagnosis of prostate carcinoma. Among three patients who experienced tumor recurrence/persistence, two died 4 years and more than 5 years after the primary had been diagnosed. One is still alive under hormonal deprivation (by plastic orchidectomy) more than 4 years after the diagnosis of a nonresectable prostate carcinoma. One patient died of cardiovascular disease more than 5 years after the diagnosis. One- and 5-year mortality rates for prostate carcinoma were 0% and 20%. Female Genital Tract

There were six patients with gynecological tumors, three endometrial carcinomas of the uterus, two carcinomas of the uterine cervix, and one advanced metastasizing ovarian carcinoma. All but one patient were treated surgically, one additionally with adjuvant radiotherapy. One patient with pT1 endometrium carcinoma of the uterus had also a pT3 rectal carcinoma, and one patient with carcinoma of the cervix developed a hypernephroma 10 years later. The tumors were diagnosed at 5.2 ⫾ 3.3 years after transplantation. One- and 5-year survival rates after tumor diagnosis were both 83%.

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Seminoma

Two patients aged 30 ⫾ 1 years who developed seminomas were both treated by operation with one also receiving adjuvant chemotherapy. Seminoma developed 0.7 ⫾ 0.4 years after transplantation. One patient was treated by orchidectomy; the other with positive lymph nodes also underwent chemotherapy. Due to the toxicity of the therapy, he lost his graft. Survival rate at 5 years was 100%. Most tumors were diagnosed at earlier stages and were thus amenable to curative therapy, achieving good longterm results. In earlier tumor stages (ⱕpT3, N0; n ⫽ 31 tumors) 1- and 5-year survival rates were 100% and 91%, respectively; which was higher than that in advanced stages (N⫹, M⫹; n ⫽ 7 tumors) with 1- and 5-year survival rates of 38% each (P ⬍ .05). Death was caused by tumor growth in nine patients (27%) and by other causes in three patients (9%). Graft loss was inevitable in the two patients who had transplant nephrectomy for tumor in the transplant. Deterioration of transplant function was observed in eight patients (24%) including one in whom it was permanent, resulting in renal insufficiency due to tumor progression and in another one due to chemotherapy toxicity. In two cases the decrease was reversible and was due to mechanical obstruction. It was treated by urethral dilation in one and ureteral splinting in another, resulting in stable graft function. A rejection episode that responded successfully to corticosteroid bolus therapy was observed in three patients (9%), and three patients suffered chronic transplant loss (9%). Fifty-seven percent had no change in transplant function. Three patients lost their transplant before the tumor was diagnosed. Two to 9 years after tumor diagnosis, four patients had a retransplantation after completion of tumor therapy. DISCUSSION

Tumorigenesis in the genitourinary tract comprises a considerable proportion (45%) of solid organ tumors after kidney transplantation and carries a tumor-induced 5-year mortality of up to 60%. Risk-adapted screening examinations, and if necessary preventive operations (eg, autogenous nephrectomy at the time of transplantation), aim at early tumor detection. In the native urinary tract of renal transplant recipients there is an increased risk of tumor development. The risk for malignancies of the bladder, native kidneys, and ureter is estimated to be twofold to fivefold above that in the normal population.6 – 8 Particularly in those patients with an established premalignant condition such as analgesic nephropathy, urinary tract tumors are to be expected. Moreover, the association of polyoma virus infection with malignoma in the urinary tract has been observed as has the association of human papilloma virus with carcinomas of the cervix.6,9 Given an interval of at least 2 years between the manifestation of an urothelial cell carcinoma and transplanta-

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tion, no tumor recurrence was observed, confirming that the proposed interval is sufficient to reduce the risk of developing an urothelial carcinoma to the same level as the average transplant patient.7 We observed one tumor recurrence, namely an advanced renal cell carcinoma, which had been operated on 2 years before the transplantation. Although at the time of transplantation no metastases were evident; the interval may have been too short for this advanced tumor. We would suggest an interval of up to 5 years for such advanced tumor stages. None of the other pretransplant urogenital tumors recurred after transplantation. Tumorigenesis may be due to the duration and type of immunosuppression. Induction therapy with ATG/ALG or OKT3 may increase tumor incidence.5,10 In the group described here no significant influence on tumor incidence was observed from induction therapy with ATG/ALG or OKT3, due to the relatively small numbers in both groups. Possibly the increased tumor rate is limited to virus-induced tumors, such as PTLD or Kaposi’s sarcoma,10 –12 or possibly this increase cannot be uniformly reproduced.13 There was a significantly higher proportion of patients who had CsA, Aza and corticosteroids as initial therapy; however, neither immunosuppression with MMF (instead of Aza) nor calcineurin-free immunosuppression were represented in a significantly lower proportion of affected cases. In the MMF group there was a tendency to a lower tumor incidence, which has been noted for PTLD in another study.13 CsA may act as tumor growth stimulator via TGF-␤14 because there is a lower percentage of tumors with calcineurin-free or calcineurin-reduced immunosuppression.1,4,15 Local resection for renal cell carcinoma in the transplanted kidney has been described, but these tumors may be multifocal,16,17 as was clear in both these cases. Thus in the event of recurrence or multifocal appearance, transplant nephrectomy should be advised. There is no significant increased risk of ovarian and prostate cancer in transplant patients compared to the general population.6,18 Since there is a generally higher prevalence of prostate cancer in the elderly population, they require screening examinations (eg, digital rectal examination and PSA-determination). The therapeutic approaches to prostate cancer have to take into account the nature of the tumor. Even under immunosuppression, curative treatment can be achieved either by radical prostatectomy or radiation therapy.18 Polycystic kidney disease was not associated with an increased tumor formation in the genitourinary tract, though it was observed to coincide with an increased malignancy rate after transplantation.19 There were two seminomas diagnosed early after transplantation; probably the tumors originated before transplantation. Autopsy studies support the idea that some tumors are already present at the time of transplantation, contributing to the tumors putatively developing after transplantation, especially among those observed in the early posttransplantation course.20

DILLER, GRUBER, WOLTERS ET AL

With appropriate treatment, tumors in early stages have a good prognosis. The operative procedure did not differ from patients who had not been transplanted. Surgical tumor therapy, chemotherapy, or radiation therapy occasionally lead to decrease transplant function. If there was a rejection episode, depending on the individual situation and the patient’s decision, antirejection therapy was given to maintain kidney function and life quality. In this period it was best treated with corticosteroids. ATG/OKT3 is alleged to carry an increased tumorigenesis risk, so these substances were not used in this situation. As regards immunosuppressive therapy after tumor diagnosis, immunosuppression was reduced, especially for those with metastasized tumors or under chemotherapy. Perhaps other immunosuppressive regimens—sirolimus or mycophenolate mofetil, which are said to have antiproliferative effects that are not proved—might help to decrease the incidence of rejection and malignancies in highrisk patients. They may even offer an alternative treatment for rejection in such a case, for the switch to sirolimus may reverse rejection episodes.21 The most important factor remains a risk-adapted screening to identify early low-grade malignancies and to initiate appropriate therapy. REFERENCES 1. Marcén R, Pascual J, Tato AM, et al: Transplant Proc 35:1714, 2003 2. Howard RJ, Patton PR, Reed AI, et al: Transplantation 73:1923, 2002 3. Penn I: Transplant Proc 31:1260, 1999 4. Dantal J, Hourmant M, Cantarovich D, et al: Lancet 351:623, 1998 5. Meier-Kriesche HU, Arndorfer JA, Kaplan BJ: Am Soc Nephrol 13:769, 2002 6. Sheil AGR: Transplant Proc 31:1263, 1999 7. Dreikorn K, Heicapell R, Heynemann H, et al: Urologe 40:493, 2001 8. Adami J, Gäbel H, Lindelöf B, et al: Br J Canc 89:1221, 2003 9. Geetha D, Tong BC, Racusen L, et al: Transplantation 73:1933, 2002 10. Cherikh WS, Kauffman HM, McBride MA, et al: Transplantation 76:1289, 2003 11. Pedotti P, Cardillo M, Rossini G, et al: Transplantation 76:1448, 2003 12. Haberal M, Karakayali H, Emirog˘lu R, et al: Artificial Organs 26:778, 2002 13. Birkeland SA, Hamilton-Dutoit S: Transplantation 76:984, 2003 14. Hojo M, Morimoto T, Maluccio M, et al: Nature 397:530, 1999 15. Tremblay F, Fernandes M, Habbab F, et al: Ann Surg Oncol 9:785, 2002 16. Krishnamurthi V, Novick AC: Urology 50:132, 1997 17. Ghasemian SR, Guleria AS, Light JA, et al: Transplantation 64:1205, 1997 18. Cormier L, Lechevallier E, Barrou B, et al: Transplantation 75:237, 2003 19. Errasti P, Manrique J, Lavilla J, et al: Transplant Proc 35:1717, 2003 20. Torbenson MS, Wang J, Nichols L, et al: Transplantation 71:64, 2001 21. Rogers J, Ashcraft EE, Baliga PK, et al: Transplant Proc 36:1058, 2004