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Volume: 13 Issue: 4 August 2015

FULL TEXT

ARTICLE
De Novo Visceral Malignancies in Renal Transplant Recipients: A Single Center Experience of 2054 Recipients for More Than 30 Years

Objectives: We report the incidence and pattern of malignancies in renal transplant recipients from our department.

Materials and Methods: Between March 1983 and August 2013, the records of 2054 renal transplant recipients from our department were retrospectively reviewed with regard to type of neoplasm, age, gender, interval between the transplant and the diagnosis of malignancy, immunosuppressive regimens, graft functional status, and rejection episodes.

Results: Among the 2054 renal transplant recipients, visceral malignancies developed in 74 patients (3.6%). The mean age at transplant was 43.9 years, and the mean age at death was 61.9 years. Sixty eight patients (91.9%) died with a functioning graft. Fifty-four (73%) died during follow-up. The mean time from transplant to malignancy was 96.4 months, and from malignancy to death was 27.5 months. No difference regarding the type of immunosuppression, the type of donor, or the interval between transplant and malignancy was detected when we compared cancers.

Conclusions: Malignancies after a renal transplant display aggressive behavior and occur more frequently several years after the transplant, but they also may occur earlier. The type of immuno-suppression, the type of donor, or the interval between transplant and malignancy do not differ significantly among cancers.


Key words : Immunosuppression, Cancer, Solid organ

Introduction

Renal transplant recipients receiving long-term immunosuppressive therapy have an increased risk of developing malignancies compared with the general population.1,2 Even if the incidence of malignancy is difficult to accurately calculate, a 6% to 11% proportion of de novo malignancies has been reported among transplant recipients in the Western countries2-4; however, it may be higher because there is a steady increase in graft survival, which reflects an approximately 100 times greater-than-normal age-matched population.5,6 Incidence rates for malignancies such as breast, lung, prostate, and colon cancer, are thought to be comparable to those of the general population4,6 because of the fact that the origin of these tumors is not related to immunosuppression.3

However, several cancers that are generally considered uncommon occur more frequently in renal recipients. Skin and lip cancers are the most common malignant tumors among renal transplant recipients. Transplant recipients also carry a significant risk of developing Kaposi sarcoma and other types of sarcomas and lymphomas, as well as carcinomas of the vulva and the perineum.5 The mechanisms that contribute to an increased risk of cancer in immuno­suppressed recipients include impaired immune surveillance for abnormal cells; susceptibility to viral infections with oncogenic potential; and possibly, a direct proneoplastic action of some immuno­suppressive drugs.2,4-6

In this retrospective study, we report the incidence and pattern of malignancies in renal transplant recipients from our center and further analyze the types of visceral malignancies.

Materials and Methods

The records of 2054 patients, who underwent a renal transplant in our department between March 1983 and August 2013, were retrospectively reviewed. Of those patients, 1018 received their transplants from first–, second–, or third–living-related donors and 1036 from deceased donors (including 7 combined kidney-pancreas transplants). Recipients presenting malignancies were evaluated regarding the type of neoplasm, age, sex, ethnic background, posttransplant duration, immunosuppressive regimens, graft functional status, and rejection-return to dialysis episodes. We retrospectively analyzed the incidence and types of posttransplant malignancies, as well as their clinical courses, focusing on visceral cancers. Patients with a history of pre-existing cancers were excluded. Additionally, we evaluated posttransplant de novo malignancies in 3 eras: (1) the azathioprine era from 1983 to late 80s, (2) the cyclosporine era from late 80s to present (in which the calcineurin inhibitors, cyclosporine, and tacrolimus, were the mainstay of recipient immunosuppression), and (3) the mTOR inhibitor era starting in the year 2000. Our study conforms to the Declaration of Helsinki in 2000 and the Declaration of Istanbul in 2008. The study was approved by the Ethical Review Committee of “Laiko” General Hospital.

Statistical analyses
The Shapiro-Wilk test was used to assess the normal distribution of data. The t test or the Mann-Whitney U test was used for 2-group comparisons with quantitative data when values were or were not normally distributed. The comparisons among 3 or more groups with quantitative data were performed using an analysis of variance (ANOVA) with the Bonferroni correction. For qualitative data, the chi-square, and the Fisher exact test were used to compare between 2 groups and the Kruskal-Wallis test was used to compare among 3 groups or more. The results were considered statistically significant if P < .05.

Results

Among the 2054 patients who received renal transplants at our center during the last 30 years, posttransplant skin cancers developed in 75 patients (3.7%), visceral malignancies in 74 patients (3.6%), lymphomas in 26 patients (1.3%) and Kaposi sarcoma in 24 patients (1.2%). Thus, out of the 199 patients (9.7%) who developed posttransplant malignancies, skin cancers correspond to a percentage of 37.7%, visceral cancers to 37.2%, lymphomas to 13.1%, and Kaposi sarcoma to 12.1%. Concerning the ethnic background of the renal transplant recipients in our center, 1981 were Greek (96.4%), whereas the remaining 73 patients (3.6%) came from other countries (58 were Albanian [2.8%], 8 were Russian [0.4%], 5 were Arabic [0.2%], 1 was Philippine [0.05%], and 1 was Argentinean [0.05%]). Of the 199 patients who developed posttransplant malignancies, 194 were Greek (97.5%) (73 with skin cancer, 73 with visceral malignancies, 25 with lymphomas, and 23 with Kaposi sarcoma); the other 5 were Albanian (2.5%) (2 with skin cancer, 1 with small intestine adeno­carcinoma, 1 with gastric lymphoma, and 1 with Kaposi sarcoma).

Regarding visceral malignancies, there were 43 men (58.1%) and 31 women (41.9%); their characteristics are shown in Table 1. 39 patients received a graft from a deceased donor, and 35 from a living donor. The mean age at transplant was 43.9 years (range, 23-70 y) and the mean age at death was 61.9 years (range, 52-75 y). 68 of 74 patients (91.9%) had a functioning renal graft at the end of surveillance or when they died. 54 of 74 died (73%), and 20 (27%) are under follow-up and oncologic surveillance. The mean time from transplant to diagnosis of malignancy was 96.4 months (range, 3-398 mo), whereas the mean time from diagnosis of malignancy to death was 27.5 months (range, 1-163 mo). The most common cause of death was metastatic disease and generalized carcinomatosis (34/54, 63%). Disease-related mortality rate reached 45.9% (34/74). Other causes of mortality were sepsis-multiorgan dysfunction syndrome, hepatic failure, end-stage renal disease, pulmonary embolism, and hemorrhage.

Lung cancer was the most common cancer in general and in males, (14/74; 18.9% 11/43; 25.6%), followed by colorectal adenocarcinoma in 8 patients (7 colon and 1 rectal; 10.8%), and gastric adeno-carcinoma in 7 patients (9.5%). The most common visceral cancer in women was breast cancer (6/31; 19.4%). Additionally, 6 patients presented prostate adenocarcinoma (6/43; 14%), 3 hepatocellular carcinoma (3/74; 4.1%), 5 renal cancer (5/74; 6.8%),2 bladder cancer, 2/74; 2.7%), 4 vulvar tumors (4/31; 12.9%), 3 sarcomas (1 ovarian carcinosarcoma, 1 liposarcoma, 1 osteosarcoma; 3/74; 4.1%), 3 pancreatic adenocarcinomas (3/74; 4.1%), 2 thyroid cancers (2/74; 2.7%), 1 cholangiocarcinoma (1/74; 1.4%), 4 endometrial cancers (4/31; 12.9%), 1 ovarian cancer (1/31; 3.2%), 1 squamous cell pharyngeal carcinoma (1/74; 1.4%), 1 testicular germ cell tumor (1/43; 2.3%), and 1 multiforme glioblastoma (1/74; 1.4%). Five patients presented with concomitant skin cancer.

33 patients (44.6%) received azathio-prine, a calcineurin inhibitor, and corticosteroid, and 33 patients (44.6%) received mycophenolate, a calcineurin inhibitor and corticosteroid, whereas 8 patients (10.8%) received other regimens. In 11 patients (14.9%), the immunosuppression regimen changed to mTOR inhibitor after the diagnosis of malignancy. We did not find any statistical significant differences regarding the interval between transplant and diagnosis of malignancy (P = .798), the type of immunosuppressive treatment (P = .539), or the type of donor (living or deceased) (P = .429) when comparing different malignancies.

Discussion

Improved technology and immunosuppressive therapy have contributed to the success of the kidney transplant with currently 95% and 90% 1-year patient and graft survivals.7 Conversely, long-term fate remains relatively unchanged,8 with a life expectancy worse compared with the general population.8,9 Posttransplant malignancy was the leading cause of death accounting for 32% of all deaths.8 Also, cancers tend to occur earlier, grow more rapidly, and metastasize more widely than they do in the general population.9 In kidney transplant patients, the incidence of cancer is increased 2- to 4-fold,9 constituting a major cause of morbidity.

A recent analysis that estimated the excess risk for cancer in these patients showed that female kidney transplant recipients experience a 3-fold greater incidence of cancer than do women in the general population; for men, the risk is 2.5 fold. Furthermore, this excess relative risk was not constant, but inversely related to age; younger recipients showed 10- to 20-fold higher rates than did the general population, whereas older recipients had a 2-fold higher incidence rate.10 It is noteworthy that not all cancers are equally increased in the transplant population. Information from the USRDS database showed that compared with the age-matched general population, the relative risk of common mali-gnancies, such as colon, lung, prostate, breast, ovarian, or gastric cancer, was approximately 2-fold higher after renal transplant and 3- to 5-fold higher for testicular, bladder, cutaneous melanoma, leukemia, liver, and gynecologic tumors.11 At our transplant unit, 9.7% of renal transplant recipients develop a malignant disease, with skin cancers being the most-frequent and visceral malignancies next.

Regarding the role of immunosuppression, it seems that the intensity of immunosuppression and the types of immunosuppressive agents may be linked to higher tumor risk. In addition, com-binations of immunosuppressive agents (double vs triple therapy), are reportedly associated with a higher tumor incidence. However, when combination therapy is used, it is difficult to determine the effect of each individual agent on cancer development. Therefore, the effect of particular immuno-suppressive drugs on posttransplant cancer development is disputed.12 Several studies have demonstrated a higher incidence of cancer development in patients treated with cyclosporine.13 Other studies that compare tacrolimus with cyclosporine found that the 2 therapies either had similar neoplastic potential or they found a higher incidence of malignancies in patients treated with calcineurin inhibitors compared with conventional therapies.14 However, we found no statistically significant differences regarding the type of immunosuppressive treatment, when we compared the different types of malignancies in our study population.

One recent study showed that there is no statistical difference between patients treated with a cyclosporine-based regimen and those treated with a non–cyclosporin-based regimen regarding elapsed time from renal transplant until detection of non-skin cancer. Similarly, the authors found no difference in tumor-specific survival between the 2 groups, although there was a tendency toward an improved survival for the cyclosporine group.15 A 5-year prospective study showed that low-dose cyclosporine regimens are associated with a lower incidence of tumors than is standard therapy.12 Furthermore, cyclosporine enhances angiogenesis and tumor growth,16 promoting the invasive characteristics of adenocarcinoma cells through a transforming growth factor-βeta-dependent mechanism.17 Another study demonstrated that tacrolimus also induces transforming growth factor-βeta production and promotes tumor progression in murine models of lung metastases by renal cell neoplasms.18 Additionally, the population analysis performed using the Scientific Registry of Transplant Recipients and UNOS database showed a significantly reduced incidence of any cancer, even solid cancers with mycophenolate mofetil compared with azathioprine.19 While both cyclosporine and tacrolimus are associated with an increased risk of cancer via aberrant production of cytokines that regulate the processes promoting cancer growth, metastasis, and angiogenesis, there are some data to suggest that tacrolimus prevents vascular invasion in cell culture models and induce apoptosis in transgenic murine model.20

Clinical studies such as the European and US multicenter trials comparing maintenance immuno-suppression with cyclosporine versus tacrolimus were equivocal, showing no significant difference in cancer incidence between these 2 drugs.21 These studies were not adequately powered to address this question. A study from OPTN and UNOS database in a cohort of 62 896 renal transplants performed during 1998 and 2003 revealed an unadjusted incidence of any cancer, non-skin, nonlymphoid solid cancer, and nonmelanoma skin cancer to be significantly lower in recipients discharged on tacrolimus compared with a cyclosporine regimen.22 This may be secondary to concomitant myco-phenolate mofetil use; however, and lower acute rejection rates.

In recent years, mammalian target of rapamycin (mTOR) inhibitors have demonstrated potential role as immunosuppressive and anticancer agents.16,23 Rapamycin inhibited metastatic tumor growth and angiogenesis using in vivo mouse models. This antiangiogenic property was shown to be linked to decreased production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to VEGF stimulation.24 However, the potential anticancer mechanism of rapamycin is not limited to its antiangiogenic effects. Other intracellular signaling pathways via Akt-mTOR participate as well.25

Mammalian target of rapamycin inhibitors allow withdrawal of calcineurin inhibitors in post-transplant patients with cancer.23 Mammalian target of rapamycin inhibitor use causes regression of solid-tumor metastasis and should be introduced rapidly in these patients.26,27 Potential wound healing issues, especially in obese patients with diabetes mellitus, should be given serious consideration when starting these medications. Rapid taper of calcineurin inhibitors also is recommended. The dosage of azathioprine/mycophenolate may be tapered slowly if clinically warranted, and it is recommended that steroid therapy be maintained.27 Dosage regimens for mTOR in renal recipients have been well described before patients develop a posttransplant malignancy and these dosages may be used while other immunosuppressive drugs are reduced or stopped.28 Mammalian target of rapamycin inhibitors should not be expected to yield complete remissions in all cases. They prolong survival in some patients, and clinicians should keep a careful watch for adverse events.27 It recently has been shown that sirolimus does not significantly affect survival among subjects who had de novo malignancies.29 Long-term evaluation of treatment regimens that minimize malignancy is important. As the life expectancy of transplant patients increases, there is greater mortality among those with functioning grafts. Strategies to reduce the long-term risk of malignancy will therefore become crucial in the future.

Apart from the kind of immunosuppressive treatment, ethnic background also affects the manifestation of malignancies in renal transplant recipients. For example, recipients of European origin are more likely to develop skin cancer than non-white recipients such as Africans, Arabs, and Japanese.30-33 Furthermore, Kaposi sarcoma has a higher incidence in recipients of Greek, Italian, Jewish, Arabic, and African origin, whereas it is rare among Japanese recipients.30-32 Moreover, lymphomas appear more frequently in North America than they do in Europe.30 However, their incidence is low in Japan.31 Many examples also may be given regarding visceral malignancies after renal transplant. Hepatocellular carcinoma is frequent in Southeast Asia, and gastric, colorectal, and liver cancers are among the most frequent posttransplant malignancies in Japan.31,32 Conversely, lung cancer, renal cell carcinoma, and cancers of the alimentary tract often develop in recipients from the United Kingdom, whereas anal cancer and malignancies of the genital system are common in recipients from Saudi Arabia.31 Concerning our study, no conclusions can be reached regarding the influence of ethnic background on type and incidence of malignancies because of the high ethnic homogeneity of our renal transplant recipients, because 96.4% of them are Greek.

A significant proportion of de novo post­transplant malignancies include several visceral malignancies. These cases are treated in similar fashion with the general population with or without modification of the immunosuppression. In conclusion, de novo malignancies, which occur frequently after renal transplant, display a different pattern of appearance, more aggressive behavior, and a worse prognosis than do tumors in the general population. More concern should be addressed not only toward survival of the graft, but also toward optimal monitoring of immunosuppression to diminish the risk of acquired malignancy. The main goal in posttransplant health care should be to save the patient’s life. Once a cancer is diagnosed, a realistic management plan including surgery, chemotherapy, radiotherapy, and modification of the patient’s immunosuppressive regimen should be discussed by a team of physicians. Consideration of patients’ personal wishes, type of cancer, and its prognosis, risk of death from cancer or its treatment, and the risk of graft loss must be made. Immunosuppression is generally reduced, but in some cases, we must abandon efforts when appropriate to salvage the renal graft by stopping immunosuppressive therapy and switching to hemodialysis.

In conclusion, although de novo malignancies occur more frequently several years after a kidney transplant, our experience demonstrates that they can occur earlier in the posttransplant follow-up. Skin malignancies have the best prognosis, probably because of early detection and treatment. De novo malignancies in solid organs often are more aggressive than in the normal population, and the life expectancy of these recipients is low. Careful long-term screening protocols are needed to detect malignancies at an early stage.


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Volume : 13
Issue : 4
Pages : 313 - 318
DOI : 10.6002/ect.2014.0297


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From the Transplant Unit, “Laiko” General Hospital, 17 Agiou Thoma Street, 11527, Athens, Greece
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare. Georgios Zavos and Demetrios Moris contributed equally to this work.
Corresponding author: Ioannis D. Kostakis, MD, 27 Achridos Street, Kato Patissia, 11144 Athens, Greece
Phone: +30 210 223 0855
Fax: +30 210 381 3822
E-mail: i.d.kostakis@gmail.com