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ARTICLE
Posttransplant Malignancies in Adult Renal and Hepatic Transplant Patients

Objectives: The risk of some cancer types increases after organ transplant compared with that shown in the general population; this has been well documented in clinical studies. With patients having longer survival and with the higher number of transplant procedures, cancer is an increasing health concern at high-volume transplant centers. Malignancy has an important effect on short- and long-term graft and patient survival. In this study, we evaluated cancer frequency during transplant patient follow-up.

Materials and Methods: This single-center retrospec­tive study included patients who underwent solid-organ transplant at the Baskent University Medical Faculty Hospital from 1997 to 2017. Renal and hepatic transplant patients older than 16 years at the time of transplant and diagnosed with cancer after transplant were included the study. In total, 1176 of 2018 renal transplant recipients and 274 of 548 hepatic transplant recipients met the inclusion criteria.

Results: We determined that 52 of 1176 renal trans­plant (4.5%) and 9 of 274 hepatic transplant patients (3.3%) developed posttransplant cancer during follow-up. Of 61 total patients with cancer posttransplant, 44 were males (72.1%) and 17 were females (27.9%), with median age at transplant of 39.2 years. Overall, the incidence of cancer in transplant recipients was 4.2%. The most frequent cancers were basal and squamous skin cancers, which were seen in 18 patients (29%), and Kaposi sarcoma, which was seen in 11 patients (18%). Of the 61 patients who developed cancer, 43 (70%) were still alive at the time of this study.

Conclusions: Despite recent positive developments in the use of immunosuppressive drugs, posttransplant malignancy is still a health problem. Fortunately, most cancers in this patient group have good prognosis and can be cured by surgical resection. Transplant physicians should aim for early detection of these diseases.


Key words : Cancer, Kidney transplant, Liver transplant

Introduction

For patients with end-stage organ failure, transplant is an effective and satisfactory treatment choice. The number of solid-organ transplant procedures increases every year, resulting in more immunosup-pressive drug use. The life expectancy of transplant patients has increased with advances in surgical techniques and with reduction of acute rejection episodes after the introduction of more potent immunosuppressive drugs. With increased life expectancy, posttransplant malignancies have become a serious health concern, especially in centers where there are many transplant procedures. General cancer risk is increased in solid-organ recipients, with nonmelanoma skin cancer being the most common of these tumors.1,2 Kaposi sarcoma, lymphoproliferative diseases, including Hodgkin and non-Hodgkin lymphoma, and nasopharyngeal carcinoma are the most life-threatening cancers seen in transplant patients.

Immunosuppression may lead to cancer through a number of mechanisms. Promotion of oncoviral-driven malignancy by long-term immunodeficiency, impaired immunosurveillance of neoplastic cells due to a nonspecific mode of action, and the prooncogenic properties of immunosuppressive drugs can play roles in cancer development.3,4 Cytomegalovirus, hepatitis B virus, hepatitis C virus, and Epstein-Barr virus infections are major factors leading to cancer, and monitoring the viral load is important in transplant patients.5-7 Transplant patients have about a 200-fold increased rate of developing Kaposi sarcoma, 30-fold increased rate of lympho-proliferative diseases, and a 2- to 4-fold increased rate of malignancies versus that shown in the general population.1,8,9 In this study, our aim was to review the cancer incidence, histopathologic characteristics, and oncologic outcomes of renal and hepatic trans-plant patients who developed de novo malignancy.

Materials and Methods

This single-center retrospective study included patients who underwent solid-organ transplant at the Baskent University Medical Faculty Hospital from February 1997 to September 2017. Renal and hepatic transplant patients older than 16 years at the time of transplant who developed cancer posttransplant were included the study. In total, 1176 of 2018 renal transplant recipients and 274 of 548 hepatic transplant recipients met our inclusion criteria. Follow-up duration was time from date of transplant to date of last follow-up visit or death.

Tacrolimus-based immunosuppression was administrated to liver transplant recipients, with blood levels maintained between 10 and 15 ng/mL during the first month and between 5 and 10 ng/mL thereafter. Methylprednisolone, administered intra-operatively at 10 mg/kg, was continued post-operatively at 10 mg/kg, then tapered to 0.1 mL/kg at the end of the first month, and stopped at the end of the third month. After de novo malignancies were diagnosed, tacrolimus therapy was switched to sirolimus in all recipients. For renal transplant recipients, the immunosuppressive protocol from 1975 to 1987 included prednisone and azathioprine. After 1987, low-dose cyclosporine was added to the regimen. Since 1998, the maintenance immuno-suppressive regimen has consisted of cyclosporine or tacrolimus and mycophenolate mofetil plus prednisone. We used induction therapy with daclizumab or basiliximab in high-risk patients. High-risk status was defined as retransplant or transplant from a deceased donor, unrelated donor, or maternal donor.

Results

Of the 1176 kidney and 274 liver transplant patients, 61 patients developed de novo malignancy during our follow-up period: 52 renal transplant recipients (4.5%) and 9 liver transplant recipients (3.3%).

The mean follow-up time was 10.6 years (range, 1.6-21.3 y). The mean interval between transplant and diagnosis of de novo malignancy was 72.5 months (range, 3.4-220.6 mo).

Of the 61 patients who developed cancer, 44 were males (72.1%) and 17 were females (27.9%), with a median age at transplant of 39.2 years (range, 16-64 y). Forty-six patients (75.4%) received organs from living donors, and 15 received organs from deceased donors. The cumulative incidence of de novo malignancy among living-donor transplant recipients was significantly higher than that shown among deceased-donor transplant recipients. Overall, the incidence of cancer in transplant recipients was 4.2%. The most frequent cancers were basal and squamous skin cancers, seen in 18 patients (29%), and Kaposi sarcoma, seen in 11 patients (18%). Lymphoma and renal cell carcinoma were the next most common cancers in our population. Table 1 and Figure 1 present the distribution of malignancies. Of the 61 patients who developed cancer, 43 patients (70%) were still alive at the time of the study. Four of the 11 Kaposi sarcoma patients and 3 of the squamous cell skin cancer patients had died during the follow-up period. Only 2 patients with Kaposi sarcoma died from cancer dissemination.

Discussion

The incidence of cancer in organ transplant recipients is higher than shown in the normal population. Skin malignancies and lymphoproliferative disease are the most known cancers that are increased in transplant patients. These cancers cause mortality and morbidity in immunosuppressed individuals, including affecting allograft survival. The use of immunosuppressive drugs and their appropriate selection are important in the development and management of de novo malignancies in organ transplant patients. High-volume organ transplant centers are especially vulnerable to these cancers during follow-up care of organ transplant recipients. Advances in posttransplant immunosuppression and surgical techniques have resulted in better survival and quality of life of transplant recipients. However, prolonged survival has also resulted in increased cancer incidence. We found that the overall incidence of cancer at our center was 4.2% in adult kidney and liver transplant recipients.

In this study, we retrospectively analyzed 1450 adult kidney and liver transplant patients. The most common cancer type was squamous and basal cell carcinoma of the skin, with the second most common being Kaposi sarcoma. In our analyzed patient group, 18 (1.2%) developed skin cancer and 11 (0.8%) developed Kaposi sarcoma. Except for 3 patients with skin cancer and 4 with Kaposi sarcoma, the remaining patients with these cancers were still alive at the time of study. Two Kaposi sarcoma patients died of cancer dissemination, and all skin cancer patients died from causes other than cancer. All skin cancer patients were successfully treated with surgery.

Haberal and associates previously reported that Kaposi sarcoma is the most frequent cancer after transplant in pediatric and adult patient groups.10 They found that all Kaposi sarcoma patients were renal transplant recipients, compatible with the results of our present study. Squamous cell carcinoma and basal cell carcinoma mostly develop in sun-exposed areas.11 Protection from sunlight exposure is the leading method for skin cancer prevention, and transplant recipients should be informed carefully about sunscreen use and potential risks of sunlight.12

Lymphoproliferative diseases developed in 10 (0.7%) of our transplant recipients (8 with B-cell and 2 with T-cell lymphoma). Sampaio and associates2 reported an incidence of lymphoproliferative disease of 1.58% in their general transplant population, which was the leading one reported among all cancers. In our study, lymphoproliferative diseases were the third most common cancer. Indeed, the frequency of lymphoproliferative disease in the study from Sampaio and associates was 2 times that of ours. The mean age was 39.2 years in our study, and cancer incidence is higher in those who are 55 to 59 years old; therefore, age differences may have caused the different results. Epstein-Barr virus infections seem to be associated with lympho-proliferative diseases; however, association of hepatitis B virus infections with liver cancer, human papilloma virus infections with cervical and skin cancer, human herpes 8 virus infections with Kaposi sarcoma, and human T-cell lymphotropic virus infection with leukemia have been previously reported.13,14 Immunosuppression may have an effect on these viral infections in transplant recipients. Chemotherapy is the cornerstone of treatment in lymphoproliferative diseases; however, drug-drug interactions and the additive effects of immuno-suppression are the most important problems.

All renal cell cancers (7 patients) and other genitourinary cancers (testicular, gynecologic, and urothelial cancers; 7 patients) were observed in renal transplant patients, which is similar to that shown in previous studies in which patients with end-stage renal disease had a higher risk of developing genitourinary cancers.15,16 Mammalian target of rapamycin inhibitory drugs, which are used for both renal cell carcinoma and immunosuppression in renal transplant recipients, have beneficial effects on malignancy. After occurrence of de novo malignancy, mammalian target of rapamycin inhibitors can be used for dual mechanisms of action. After kidney transplant, the incidence of renal cell carcinoma is about 0.5%. Renal cell carcinoma is more likely to develop in the native kidneys of a transplant recipient, and from 5% to 16% of posttransplant malignancies are renal cell carcinomas.14

In their analyses of 335 liver transplant patients, Akdur and associates reported that 14 patients developed de novo malignancy after liver transplant. Seven patients developed lymphoproliferative disorders, and 1 patient developed neuroblastoma.18 In our study, only 3 liver transplant patients developed lymphoproliferative disease. The percen-tage of de novo cancer after liver transplant in our study was 3%, whereas it was 4% in the study from Akdur and colleagues. In our study, we only included adult patients. The fact that childhood cancers have different characteristics may have caused this discrepancy. Although a previous study reported an incidence of cancer of 6.8% after renal transplant,19 our finding was merely 4.4%. That study also found skin cancer to be the most prevalent in their patient group, similar to the results of our study.

Conclusions

De novo malignancy after organ transplant is a life-threatening health problem among transplant recipients. For long-term survival of solid-organ transplant recipients, close follow-up is necessary to detect posttransplant malignancy, which is one of the complications posttransplant. Aggressive treatments, including chemotherapy, radiation therapy, and cancer surgery, should be given to all appropriate candidates. Drug-drug interactions may be a challenge and a point of concern for health care providers. Transplant physicians must pay attention to early detection of these diseases as early detection is the most effective way to successfully treat post-transplant cancers. In addition, attention should be paid to the proper selection of immunosup-pressive drugs.


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DOI : 10.6002/ect.2018.0177


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From the 1Department of Medical Oncology and the 2Department of General Surgery, Baskent University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Samed Rahatli, Baskent University Faculty of Medicine, Department of Medical Oncology, Baskent University Hospital, Mareşal Fevzi Çakmak Caddesi 53, Sokak No. 48, Ankara, Turkey
Phone: +90 312 2122912
E-mail: samedrahatli@hotmail.com