RENAL DATA FROM THE ARAB WORLD
Year : 2008 | Volume
: 19 | Issue : 5 | Page : 825--830
Cancers after Renal Transplantation: Multicenter Experience
Kais Harzallah1, Ezzedine Abderrahim2, Khaled Chareffedine3, Soumaya Yeich3, Raoudha Belhadj1, Habib Skhiri4, Fethi Younsi2, Taeib Ben Abdallah2, Achour Abdelletif5, Jamil Hachicha3, Jalel Hmida6, Mezri El May4, Adel Khedr2, Jamel Manaa1,
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
Unity of Organ Transplantation, Military Hospital of Tunis
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.
|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;19:825-830
|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 2021 Oct 23 ];19:825-830
Available from: https://www.sjkdt.org/text.asp?2008/19/5/825/42473
Renal transplant recipients are slightly more vulnerable to the development of cancers particularly virus-related cancers than the general population. 
The etiology of post transplant cancers include environmental and genetic factors, especially the chronic opportunistic infection by oncogenic viruses.  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. 
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
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:
Skin cancers include spinocellular carcinoma (SCC), basocellular carcinoma (BCC), and Bowen's disease.Solid cancers include post transplant lymphoproliferative disease (PTLD), the melanoma, Kaposi's sarcoma, and Merkel cell carcinoma.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. ,,,,,,,,,, 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 %.
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.
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. 
Prevalence of skin and solid cancers among our renal transplanted population was estimated as 7%. It's close to the Hungarian  prevalence, slightly more important than the Kuwaiti  and the Italian  prevalence and significantly less important than the French  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% and 70–80% of patients develop at least one skin cancer. ,,,
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. 
Several studies reported a high risk of cancer associated with a longer time on dialysis before transplantation. This is not supported by Kasiske  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.  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  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  (24.2%) and the French registry  (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. 
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. , in addition, the association between prolonged immunosuppression in transplant recipients and an increased risk of malignant disorders is well established. ,,,,,
Several studies demonstrated a higher incidence of cancer with CsA. ,, Guba et al  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.  Maluccio  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. 
More appropriate dosing of TAC results in a substantial decline in risk of PTLD.  some studies suggested that TAC in combination with MMF was not a risk factor for development of PTLD. ,
In addition to its immunosuppressive effect, MMF may also possess anti-neoplastic quailties. , Indeed, several studies suggested that it inhibits some tumor cell lines. ,
Harzallah et al  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. ,
Early data in randomized studies imply that Sirolimus may lead to less cancer.  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.
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