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Saudi Journal of Kidney Diseases and Transplantation
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RENAL DATA FROM THE ARAB WORLD Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 5  |  Page : 825-830
Cancers after Renal Transplantation: Multicenter Experience


1 Unity of Organ Transplantation, Military Hospital of Tunis, Tunisia
2 Department of Nephrology, Charles Nicolle Hospital Tunis, Tunisia
3 Department of Nephrology, Hedi Chaker Hospital Sfax, Tunisia
4 Department of Nephrology, Fattouma Bourguiba Hospital Monastir, Tunisia
5 Department of Nephrology, Sahloul Hospital Sousse, Tunisia, Tunisia
6 Unity of Hemodialysis, Military Hospital of Tunis, Tunisia

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   Abstract 

Renal transplant recipients are at higher risk of certain tumors such as lymphomas and skin cancers and than the general and dialysis populations. We retrospectively studied the prevalence of tumors in adult renal transplant recipients in four Tunisian centers of transplantation in Tunis, Monsatir and Sfax from January 1986 to January 2005. The study included 36 patients; 19 men and 17 women with a mean age of 34.6 years (range from 18-54 years). The mean time since dialysis to transplantation was 43 months (6-131months). Maintenance therapy was based on calcineurin inhibitors (CNI) in 86 % of cases, on antimetabolites and corticosteroids in 100 % of cases. Anti-thymoglobulin was administered in a mean course of 12.4 days in 78 % of the patients. Acute rejection occurred in 25 cases and was treated with polyclonal or monoclonal antibodies on 40 % of cases. Incidence of cancer among our population was 7 % and occurred after a mean period of 54 months of transplantation (range from 4-160 months). Eighty three percent of the tumors were solid, and the rest were in the skin. Kaposi sarcoma formed 41.6 % and non-Hodgkin or Hodgkin lymphoma 27.7 % of the solid tumors, while spinocellular carcinoma formed 83% and basocellular carcinoma 17% of the skin tumors. Switching CNI to sirolimus in 8.3% cases was associated with a favorable outcome. Mortality was the outcome in 33.3% of the patients with cancer, while partial or complete regression of cancers was observed in 55.5% cases after decreasing the doses of the immunosuppressive medications. We conclude that post renal transplant cancer is mainly characterized by the predominance of Kaposi sarcoma favored by solar exposure and rigorously induced and maintained immunosuppression. Careful follow-up may results in early inter­vention and decrease mortality.

Keywords: Cancer, Renal, Transplantation, Immunosuppression, Tumor

How to cite this article:
Harzallah K, Abderrahim E, Chareffedine K, Yeich S, Belhadj R, Skhiri H, Younsi F, Abdallah TB, Abdelletif A, Hachicha J, Hmida J, El May M, Khedr A, Manaa J. Cancers after Renal Transplantation: Multicenter Experience. Saudi J Kidney Dis Transpl 2008;19:825-30

How to cite this URL:
Harzallah K, Abderrahim E, Chareffedine K, Yeich S, Belhadj R, Skhiri H, Younsi F, Abdallah TB, Abdelletif A, Hachicha J, Hmida J, El May M, Khedr A, Manaa J. Cancers after Renal Transplantation: Multicenter Experience. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2019 Jul 22];19:825-30. Available from: http://www.sjkdt.org/text.asp?2008/19/5/825/42473

   Introduction Top


Renal transplant recipients are slightly more vulnerable to the development of cancers parti­cularly virus-related cancers than the general population. [1]

The etiology of post transplant cancers in­clude environmental and genetic factors, especially the chronic opportunistic infection by oncogenic viruses. [2] Therefore, the principal post renal transplant neoplasms are lympho­proliferative disorders due to Epstein-Barr virus, Kaposi's sarcoma due to human herpes­virus 8 (HHV–8), and skin cancer due to human papillomavirus. [3]

The objective of our study is to determine prevalence of cancer among Tunisian renal transplant patients, to analyze the effect of the modification of the immunosuppressive medi­cations and the outcome of the patients.


   Patients and methods Top


We retrospectively studied all adult renal transplant patients affected by a solid or a skin cancer in the 4 active transplantation centers in Tunisia, which include Charles Nicolle Hos­pital of Tunis, Military Hospital of Tunis, Hedi Chaker Hospital of Sfax, and Fattouma Bour­guiba Hospital of Monastir from 1–1–1986 and 1–1–2005.

We adopted the following classification of tumors in our study:

  1. Skin cancers include spinocellular carci­noma (SCC), basocellular carcinoma (BCC), and Bowen's disease.
  2. Solid cancers include post transplant lymphoproliferative disease (PTLD), the melanoma, Kaposi's sarcoma, and Merkel cell carcinoma.
  3. The diagnosis of de novo cancers was restricted to those developing after the first 3 months of transplantation except for the PTLD.


The database included demographic data, recipient initial disease, time on dialysis before transplantation, date of transplantation, Immu­nosuppressive medications, and incidence of acute rejection. Induction immunosuppressive medications included antithymoglobulin serum thymglobuline® (ATG) or lymphoglobuline® (ALG) was prescribed in 78 % of the patients with a mean duration of 12.4 days per course. [8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] On the other hand, maintenance therapy included calcineurin inhibitors (CNI) in 86 % of the patients (Cyclosporine A (CsA): 90 % or Tacrolimus (Tac): 10 %), antimetabolites in 100 % (Azathioprine (AZA): 70 % and myco­phenolate mofetil (MMF): 30 %), and on corti­costeroids in 100 %.


   Results Top


Of 514 renal transplanted patients 36 (7%) developed cancer. All the patients received only one renal graft except one woman who was retransplanted once. The cancer patients included 19 men and 17 women with a mean age of 36 years (range from 18–54 years). The mean time on dialysis before transplantation was 43 months (range from 6–131months).

[Table 1] shows the distribution of the pre­valent cancers in our study. Of the 36 patients with cancer, 83.3% developed solid tumors and 16.7% developed skin cancers. Kaposi's sarcoma was diagnosed in 41.6% of the solid cancer; limited to the skin in 77% and asso­ciated with visceral involvement in 23% with either oral, ocular, or pulmonary lesions. Lym­phoma was diagnosed in 27.7% of the pa­tients; non-Hodgkin lymphoma in 90% and in Hodgkin lymphoma in 10% of the cases. The other solid tumors included cerebral tumors in 3 patients, gastric tumor in 1, breast tumor in 1, and a graft tumor transmitted by the donor in 1. SCC was encountered in 5/6 of our skin cancer patients and BCC in one case.

The median time from transplantation to the development of solid cancers varied according to type of the tumor. Kaposi sarcoma with skin localization and Hodgkin lymphoma occurred earlier with a mean time of 31.1 months and 20 months, respectively in contrast to non­Hodgkin lymphoma (59 months), Kaposi sar­coma with visceral involvement (110 months), and for the gastric tumor (103 months). In addition, the median time was prolonged for the development of skin tumors; 116 months for SCC and 83 months for the BCC.

An acute rejection occurred in 25 cases be­fore the diagnosis of cancers. The patients were treated with methylprednisolone pulses alone in 60 % of the episodes, and combined with monoclonal or polyclonal antibodies in other 24%. Monoclonal antibody OKT3 type (Orthoclone OKT3® ) and polyclonal antibody was administrated alone equally in 8% of the episodes of rejection.

After the diagnosis of cancer, treatment mo­dification was characterized by discontinuation of all the immunosuppressive treatment in 21% of cases, discontinuation or decrease of CNI in 58.3%, and discontinuation of anti­metabolites with decreasing CNI in 21%. We switched CNI to sirulimus in 8.3% cases,which resulted in a favorable outcome. Failure of allografts and return to hemodialysis after modification of the immunosuppressive treat­ment occurred in 22% cases.

Mortality was the outcome in 33.3% of the patients with cancer, and it was directly attri­butable to cancer in 66.6% of them. Partial or complete regression of cancers was observed in 54.5% of the patients with cancer. Tumor recurrence was observed in 4.5% of the cancer patients with metastases in 13.6% of them.


   Discussion Top


The improvement of graft and patient sur­vival has increased the mean age of recipients by 10 years over the last decade with greater risk for developing malignancy. [4]

Prevalence of skin and solid cancers among our renal transplanted population was esti­mated as 7%. It's close to the Hungarian [5] prevalence, slightly more important than the Kuwaiti [6] and the Italian [7] prevalence and signi­ficantly less important than the French [8] preva­lence, [Table 1]. The elevated prevalence of tumors in the French population is probably due to prolonged history of renal transplan­tation (25 years). After 20 years of transplan­tation, 50%[9] and 70–80% of patients develop at least one skin cancer. [10],[11],[12],[13]

With our young transplant population, it is difficult to evaluate the impact of age and gender on the incidence and prevalence of cancer. However, the Italian registry of organ transplant recipients reported a 9-fold increase of skin cancer in transplanted patients after 50 years in comparison with those transplanted before 30 years and a 2–fold in transplanted men versus woman. [8]

Several studies reported a high risk of cancer associated with a longer time on dialysis before transplantation. This is not supported by Kasiske [3] who considered that abnormalities in the immune system caused by uremia were associated with a lower risk for solid and skin cancer.

Other risk factors for developing cancer after transplantation include history of pretransplant neoplasm. [14] None of our patients had incidence of cancer before transplantation.

The median time to the development of solid tumors was 54 months in our study. Pedotti et al [8] reported an average length between trans­plant and cancer diagnosis at 40 months with an earlier occurrence of Kaposi sarcoma at 18.4 months. In our study, Kaposi's sarcoma occurred earlier in the skin forms (average of 31 months) than the visceral forms (average of 110 months).

In our study, Kaposi sarcoma develops in 41.6%. This is not in agreement with the results of Pedotti [7] (24.2%) and the French registry [8] (2.9%). This could be the effect of a less exposure of the northern Mediterranean population to ultraviolet rays versus the southern Mediterranean population.

SCC was the predominant skin cancer in the Tunisian transplanted population in 5/6 cases followed by BCC in one case. This is in concordance with the results of several studies, which reported a ratio of BCC to SCC reversed in transplant patient when compared with the general population in which the BCC is the most common. [15]

In our study, acute rejection occurred in 25 cases associated with an excessive use of monoclonal or polyclonal antibodies in com­parison with the other series. [16],[17] in addition, the association between prolonged immuno­suppression in transplant recipients and an increased risk of malignant disorders is well established. [18],[19],[20],[21],[22],[23]

Several studies demonstrated a higher inci­dence of cancer with CsA. [19],[24],[25] Guba et al [26] observed a different lymphocyte-independent colon adenocarcinoma tumor-promoting effect of CsA in mice and emphasized that tumor­ bearing mice treated with CsA developed ele­vated expression of the angiogenesis stimu­lator VEGF. A few studies compared TAC with CsA and found similar neoplastic poten­tial. [27] Maluccio [28] suggested that TAC stimu­lation of TGF(31 expression in a murine model. AZA is believed to affect carcinogenesis by intercalation at the DNA level, inhibiting re­pair splicing and eliciting codon misreads. [29]

More appropriate dosing of TAC results in a substantial decline in risk of PTLD. [30] some studies suggested that TAC in combination with MMF was not a risk factor for deve­lopment of PTLD. [3],[30]

In addition to its immunosuppressive effect, MMF may also possess anti-neoplastic quail­ties. [16],[31] Indeed, several studies suggested that it inhibits some tumor cell lines. [30],[31]

Harzallah et al [8] found that the adjusted inci­dence of cancer was higher in transplanted patients before 1999 compared with those transplanted after 1999. Possible explanations include more use of the MMF-TAC combi­nation, better screening for incidence of can­cers, and less dosing or duration of immuno­suppressive therapy as suggested by others. [32],[33]

Early data in randomized studies imply that Sirolimus may lead to less cancer. [34] In our study, 3 patients with visceral Kaposi's sar­ coma were switched from CNI to sirulimus with a favorable outcome. However, larger number of patients and Long-term follow-up are still required to disclose these results.

In conclusion, our study demonstrated that Kaposi's sarcoma restricted to skin was a predominant post transplant tumor among Tunisian patients. It is necessary to perform careful surveillance to detect all suspicious lesions. An easy access dermatologic consul­tation must be instituted for advice and even­tual biopsy. Modification of immunosuppre­ssive therapy is required in almost all the cases of post transplant tumors.

 
   References Top

1.National Kidney Federation. Cancer after kidney transplantation. Available at: ­http://www.kidney.org.uk/medicalinfo/transplant/txcancer.html.AccessedMay 2003 .  Back to cited text no. 1    
2.Penn I. Cancers in renal transplant recipients. Adv Ren Replace Ther 2000;72(2):147-56.  Back to cited text no. 2    
3.Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4(6):905-13.  Back to cited text no. 3    
4.Gaston RS, Alveranga DY, Becker BV, et al. Kidney and pancreas transplantation. Am J Transplant 2003;3(s4):64.  Back to cited text no. 4    
5.Vegso G, Toth M, Hidvegi M, et al. malignancies Malignancies after renal transplantation during 33 years at a single center. Pathol Oncol Res 2007;13(1):63-9.  Back to cited text no. 5    
6.Samhan M, Al-Mousawi M, Donia F, Fathi T, Nasim J, Nampoory MR. Malignancy in renal recipients. Transplant Proc 2005;37(7):3068-70.  Back to cited text no. 6    
7.Pedotti P, Cardillo M, Rossini G, et al. Incidence of cancer after kidney transplant: Results from the North Italy transplant program. Trans­plantation 2003;76(10):1448-51.  Back to cited text no. 7    
8.Harzallah K, Frimat L, Kessler M, et al. Solid and skin tumors after Kidney transplantation: Which risk factors ? Am J Transplant 2006;6 S2: 65-1061.  Back to cited text no. 8    
9.Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppression and the risk of post­transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004;4(1):87-93.  Back to cited text no. 9    
10.Bouwes Bavinck JN, Hardie DR, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia: A follow­up study. Transplantation 1996;61(5):715-21.  Back to cited text no. 10    
11.Ramsay HM, Fryer AA, Hawley CM, Smith AG, Harden PN. Non-melanoma skin cancer risk in the Queensland renal transplant popu­lation. Br J Dermatol 2002;147(5):950-6.  Back to cited text no. 11    
12.Webb MC, Compton F, Andrews PA, Koffman CG. Skin tumours posttransplantation: A retrospective analysis of 28 years' experience at a single centre. Transplant Proc 1997;29(1- 2):828-30.  Back to cited text no. 12    
13.Kasiske BL, Klinger D. Cigarette smoking in renal transplant recipients. J Am Soc Nephrol 2000;11(4):753-9.  Back to cited text no. 13    
14.Kauffman HM, Cherikh WS, McBride MA, Cheng YA, Delmonico FL, Hanto DW. Transplant recipients with a history of a malignancy: Risk of recurrent and de novo cancers. Transplant Rev 2005;19(1):55-64.  Back to cited text no. 14    
15.Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation 1990;49(3):506-9.  Back to cited text no. 15    
16.Caillard S, Dharnidharka VR, Agodoa L, Bohan E, Abott K. Posttransplant lymphoproliferative disorders after renal transplan-tation in the United states in Era of modern immunosup­pression. Transplantation 2005;80 (8):1233-43.  Back to cited text no. 16    
17.Masood R, Cai J, Zheng T, Smith DL, Naidu Y, Gill PS. Vascular endothelial growth factor­vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. Proc Natl Acad Sci USA 1997;94(3):979-84.  Back to cited text no. 17    
18.Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: Randomised comparison of two cyclosporin regimens. Lancet 1998;351(9103):623-8.  Back to cited text no. 18    
19.Dong C, Hemminki K. Second primary neo­plasms in 633,964 cancer patients in Sweden, 1958-1996. Int J Cancer 2001;93(2): 155-61.  Back to cited text no. 19    
20.Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999; 40(2 Pt 1):177-86.  Back to cited text no. 20    
21.Sheil AG. Skin cancer in renal transplant recipients. Transplant Sci 1994;(1):42-5.  Back to cited text no. 21    
22.Ducloux D, Kazory A, Challier B, et al. Long­term toxicity of antithymocyte globulin induc­tion may vary with choice of agent: A-single center retrospective study. Transplantation 2004;77(7):1029-33.  Back to cited text no. 22    
23.Cherikh WS, KauffmanHM, McBride MA, Maghirang J, Swinnen LJ, Hanto DW. Asso­ciation of the type of induction immuno­suppression with posttransplant lymphopro­liferative disorder, graft survival and patient survival after primary kidney transplantation. Transplantation 2003;76(9):1289-93.  Back to cited text no. 23    
24.Tremblay F, Fernandes M, Habbab F, et al. Malignancy after renal transplantation: Inci­dence and role of type of immunosuppression. Ann Surg Oncol 2002;9(8):785-8.  Back to cited text no. 24    
25.Vivarelli M, Bellusci R, Cucchetti A, et al. Low recurrence rate of hepatocellular carcinoma after liver transplantation: Better patient selection or lower immunosuppression? Transplantation 2002;74(12):1746-51.  Back to cited text no. 25    
26.Guba M, Graeb C, Jauch KW, Geissler EK. Pro- and anti-cancer effects of immunosuppre­ssive agents used in organ transplantation. Transplantation 2004;77(12):1777-82.  Back to cited text no. 26    
27.Jonas S, Rayes N, Neumann U, et al. De novo malignancies after liver transplantation using Tacrolimus-based protocols or cyclosporine­based quadruple immunosuppression with an interleukin-2 receptor antibody or anti­thymocyte globulin. Cancer 2003;80:1141.  Back to cited text no. 27    
28.Maluccio M, Sharma V, Lagman M, et al. Tacro­limus enhances transforming growth factor­beta1 expression and promotes tumor prog­ression. Transplantation 2003;76(3):597-602.  Back to cited text no. 28    
29.Swann PF, Waters TR, Moulton DC, et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 1996;273(5278):1109-11.  Back to cited text no. 29    
30.Dharnidharka VR, Ho PL, Stablein DM, Harmon WE, Tejani AH. Mycophenolate, tacrolimus and post-transplant lymphoprolife­rative disorder: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 2002;6(5):396-8.  Back to cited text no. 30    
31.Robson R. Risk of PTLD and other malign­nancies in renal transplant patients treated with MMF: a prospective observational cohort study [Abstract]. Paper presented at: American Transplant Congress; May 31-June 1, 2003;Washington, DC.  Back to cited text no. 31    
32.Mihalov ML, Gattuso P, Abraham K, Holmes EW, Reddy V. Incidence of post-transplant malignancy among 674 solid-organ-transplant recipients at a single center. Clin Transplant 1996;10(3):248-55.  Back to cited text no. 32    
33.Barrett WL, First MR, Aron BS, Penn I. Cli­nical course of malignancies in renal transplant recipients. Cancer 1993;72(7):2186-9.  Back to cited text no. 33    
34.Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal­transplant recipients. N Engl J Med 2005;352 (13):1317-23.  Back to cited text no. 34    

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Correspondence Address:
Kais Harzallah
Unity of Organ Transplantation, Military Hospital of Tunis
Tunisia
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PMID: 18711309

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    Tables

  [Table 1]

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