Objectives: Our objective was to analyze characteristics, risk factors, and incidence of de novo malignancies after liver transplant.
Materials and Methods: The hospital records of 557 patients who underwent liver transplant were analyzed from the point of de novo malignancy development. We evaluated the demographic features and survival of these patients retrospectively.
Results: The research covered 429 patients, 9 (2%) of whom developed de novo malignancy. All of these patients were male (100%), and their mean (SD) age was 51.33 (4.69) years (range, 45-65 y). Indications for transplant included alcohol related in 4 cases, chronic hepatitis B in 2 cases, chronic hepatitis B and C in 1 case, chronic hepatitis B and D in 1 case, and chronic hepatitis C and alcohol-related cirrhosis in 1 case. The mean (SD) time from transplant to cancer diagnosis was 63.41 (37.10) months (range, 17-122 mo). The types of tumors were lung cancer, lymphoma, neuroendocrine tumor of lung, nasopharyngeal cancer, and squamous cell carcinoma of the skin. Seven cases received chemotherapy with or without radiotherapy. Two cases received surgery and radiotherapy. One patient underwent surgical treatment. One patient died before treatment was started.
Conclusions: In recent years, improvements in surgical techniques and immunosuppressive therapies have helped prolong survival of patients who undergo liver transplant. However, this also has led to a rise in the incidence of long-term complications such as de novo malignancy. These patients are more likely to develop de novo malignancy than the general population, for which chronic immunosuppression is identified as a major risk factor. Early diagnosis and treatment of de novo malignancies can help obtain better prognosis and higher survival rates in these patients.
Key words : Cancer, Immunosuppression, Organ transplantation, Survival
Recently, liver transplant has emerged as the best treatment for end-stage liver failure and hepato-cellular carcinoma in selected cases.1 Over the years, development in surgical techniques, progress in immunosuppressive therapies, and improvements in patient follow-up have extended graft and patient survival after liver transplant.
Many transplant centers have reported that the 1-year survival rate after liver transplant is above 90%, whereas 10-year survival is around 60%.2 Naturally, prolongation of survival has also increased the incidence of cardiovascular diseases and de novo malignancies in these patients.3,4 Just like other solid-organ recipients, risk of developing de novo malignancy in liver transplant recipients is 3 to 7 times higher than in the general population due to oncogenic effects s0111-econdary to chronic immunosup-pression.5-7 Collett and associates have reported that the incidence of de novo malignancy development 10 years after liver transplant is 10%.8 In this study, we aimed to determine the incidence of de novo malignancy after liver transplant in our clinic, as well as malignancy types and risk factors.
Materials and Methods
The data of 557 patients who underwent liver transplant at that Dokuz Eylül University Hospital Hepatopancreaticobiliary Surgery and Liver Transplantation Unit between February 1998 and June 2016 were collected prospectively. Patients provided written informed consent for inclusion in the database. Our study included 429 patients who survived more than 3 months after transplant, had 3 months of follow-up, were older than 18 years at the time of transplant, and had no malignancy before transplant. Liver grafts were obtained from deceased and living donors.
After transplant, initial standard immunosup-pressive treatment included calcineurin inhibitors (cyclosporine/tacrolimus), corticosteroids, and myco-phenolate mofetil. Mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) were used immediately after the development of renal toxicity from calcineurin inhibitor use. In patients with hepatocellular carcinoma who underwent transplant, these agents were used within the first year. For patients with high creatinine and serum urea nitrogen levels in the preoperative period, 40 mg of basiliximab was used during liver transplant and on postoperative day 4. After discharge, patients were followed once per week for 2 months in the liver transplant clinic. After this, they were followed every month during the first year and at intervals of 3 to 6 months after year 1.
Patient baseline characteristics are shown as median (range) for continuous data and as number (%) for categoric data. Numeric data are presented as means and SD or as median. Statistical analyses were per-formed with SPSS software (SPSS: An IBM Company, version 19, IBM Corporation, Armonk, NY, USA).
Nine (2%) of the 429 patients developed de novo malignancy after liver transplant. All patients who developed de novo malignancy were male and had a mean (SD) age of 51.33 (4.69) years (range, 45-65 y) at time of transplant. Indications for liver transplant included chronic alcohol use in 4 cases, chronic hepatitis B infection in 2 cases, chronic hepatitis B and C infection in 1 case, chronic hepatitis B and D infection in 1 case, and chronic hepatitis C infection accompanied by alcohol use in 1 case. Five of these 9 patients received livers from deceased donors, with the other 4 receiving livers from living donors. The mean (SD) follow-up of liver transplant patients was 103.4 (40.32) months (range, 47-158 mo). The mean (SD) duration between liver transplant and malig-nancy was 63.41 (37.10) months (range, 17-122 mo).
Regarding types of malignancy, squamous cell lung carcinoma was present in 4 patients (44.4%), with 1 patient having metastatic disease, 1 patient (11.1%) having metastatic lung neuroendocrine tumor, and 1 patient (11.1%) having nasopharyngeal carcinoma. In addition, 1 patient (11.1%) had tongue cancer, and 1 patient (11.1%) had squamous cell carcinoma of the skin on the lips. We also noted retroperitoneal cancer in 1 patient (11.1%).
Of patients with malignancy, only 1 patient (11.1%; lung cancer) received pulse steroid treatment due to acute rejection. Blood immunosuppressive drug levels of all patients were within reference ranges during follow-up. Three patients received chemotherapy and radiotherapy together, 1 patient received only chemotherapy, 1 patient received only radiotherapy, 1 patient received only surgical treatment, 2 patients received surgical treatment and radiotherapy together, and 1 patient died before any treatment was given.
One patient who underwent surgery due to retroperitoneal sarcoma died from postoperative intra-abdominal hemorrhage. Deaths in other patients were as a result of cancer-related organ failure and infection. Median follow-up time after malignancy diagnosis was 6 months (range, 1-66 mo) after malignancy developed. Demographic and clinicopathological data of the patients are sum-marized in Table 1.
Compared with the general population, malignancy occurs more frequently in patients who have undergone liver transplant.9-13 Depending on the transplant center and the duration of follow-up, the incidence of malignancy varies from 2.6% to 26%.14-16 In a recent study, which reported on 722 cases, the incidence of de novo cancer development after liver transplant was 1.94%.1 The incidence of cumulative de novo cancer development is 3% to 5% between 1 and 3 years after liver transplant and 11% to 20% after 10 years.15 The most frequently reported malignancies after liver transplant are skin cancer, lung cancer, lymphoproliferative neoplasms, and Kaposi sarcoma.1 Due to prolonged survival after liver transplant, the most important second mortality after cardiovascular disease has been de novo cancers.4
There are several factors that cause more frequent occurrence of de novo malignancy in patients who have undergone liver transplant. Among major risk factors are advanced age, alcohol use, smoking, oncogenic viruses, overexposure to sunlight, and long-term immunosuppressive treatment.1,5 Im-munosuppressive therapy increases the frequency of de novo malignancy development by reducing the efficacy of the immunosuppression of the immune system and by reducing resistance to certain oncogenic viruses.17-19 A clinical study in patients who underwent renal transplant showed a parallel relation between the development of malignancy and the dose and duration of immunosuppressive therapy.20 In addition, long-term use of azathioprine and cyclosporin has been shown to contribute to skin cancer,21 whereas tacrolimus enhances the risk of malignancy in internal organs.22
It is suggested that sustaining postoperative treatment at minimum doses provided by drug efficacy can help reduce the incidence of malignancy.5 On the other hand, it is argued that mTOR agents such as sirolimus and everolimus have antiproliferative effects and suppress tumor growth. It has been suggested that the development of skin cancer after renal transplant is lower in patients who receive mTOR than in those who receive calcineurin inhibitors.23 However, another study reported no difference.24 Some studies have reported that using mTOR instead of calcineurin inhibitors reduces the incidence of malignancy,25,26 but another study reported no change.27
In our study, the incidence of de novo malignancy was 2%, and the most common de novo malignancy was lung cancer (44%). These findings are consistent with the literature. As reported in a recent review, lung cancer is the most common solid-organ tumor after liver transplant.28 The standardized incidence ratio for lung cancer ranges between 1.4 and 2.29 The mean time to diagnosis can increase 6 to 12 months after transplant and has been shown to peak at year 5 after transplant.6 Similar to the general population, smoking is the most important risk factor.30 In addition, the underlying pathology, such as alcoholic liver disease, may increase the risk of lung cancer development after liver transplant.15
Skin cancer, which is one of the most frequently reported malignancy types occurring after solid-organ transplant, was observed in only 1 patient (11%) in our series. On the other hand, as opposed to the literature, we did not observe any de novo posttransplant lymphoproliferative disorders or Kaposi sarcoma, which have been reported to be frequent after liver transplant.1
In our patient group, the mean age was over 50 years, which is also a potential risk factor for the development of malignancy. Seven of the 9 patients with malignancy (77%) and 3 of the 4 lung cancer patients (75%) were chronic smokers. Chronic alcohol use was present in only 1 patient (11%) who developed skin cancer. As immunosuppression, tacrolimus was used in 8 patients (88%) and cyclosporine in 1 patient (11%). Routine blood immunosuppressive drug level controls indicated no toxic blood levels that would cause hyperim-munosuppression in any of the patients. Only 1 patient who used cyclosporine developed lung cancer, and high-dose steroids were administered due to acute rejection.
According to the Turkish Ministry of Health data, the incidence of total cancer was 0.22% in Turkey.31 As expected, in our study, the incidence of de novo malignancy in liver transplant patients was much higher than in the general population in our country (2% vs 0.22%). Lung cancer incidence for male patients in the general population is 0.51%. We calculated the standardized incidence ratio for lung cancer for male patients between 45 and 65 years old according to data obtained from our study and the Turkish Ministry of Health. Our calculation showed that the person-year prevalence during follow-up for male patients who were between 45 and 65 years old was 7.25 years. In addition, the standardized incidence ratio for lung cancer for male patients was 3.8. The high incidence of lung cancer in our study group could be because most of the patients were chronic smokers and older males. It is clearly known that smoking is the most important risk factor for lung cancer. In addition, 2 of 4 patients who developed lung cancer had alcoholic liver disease, which is also a risk factor for lung cancer.
We observed that the earliest de novo malignancy in our study developed 17 months after liver transplant. When we considered the frequency of de novo malignancy development in patients who lived longer than 17 months, the rate was 2.3% and tended to increase. For this reason, studies on the incidence of malignancy after transplant can be more accurate if they include patients with long-term survival rates after liver transplant. This may reveal that the incidence is higher than mentioned in the literature.
Similar to other solid-organ transplant recipients, compared with the general population, patients with liver transplant have a higher risk of developing malignancy and can develop more aggressive malignancies. As in our series, malignancies are usually advanced at the time of admission and the treatment chance is severely reduced. Therefore, patients should be informed about the development of cancer after transplant. Moreover, these patients should receive support to quit smoking and to practice alcohol abstinence; long-term exposure to sunlight and other cancer risk factors should be avoided.
For liver transplant patients, cancer screening programs are of utmost importance for early diagnosis and increased survival. Because skin, head and neck, lung, and lymphatic system-derived cancers are frequently observed after transplant, these patients might benefit from more frequent screening of cancer types to allow earlier diagnosis. However, the application of frequent screening protocols for uncommon cancer types after transplant may be useless and lead to unnecessary costs. For example, the incidence of prostate cancer and breast cancer in liver transplant patients are not increased compared with the general population.4 For this reason, screening protocols for these cancers should follow those used in the general population. Moreover, according to our study results, male and smoking patients require more attention after transplant, especially because of greater possibility for development of lung cancer.
Volume : 17
Issue : 1
Pages : 74 - 78
DOI : 10.6002/ect.2017.0111
From the 1Department of General Surgery, Liver Transplantation and
Hepatopancreaticobiliary Surgery Unit, the 2Department of Internal Medicine, and
the 3Department of Public Health, Dokuz Eylul University School of Medicine,
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Tufan Egeli, Dokuz Eylul University School of Medicine, Department of General Surgery, Liver Transplantation and Hepatopancreaticobiliary Surgery Unit, Izmir, Turkey
Phone: +90 232 412 2901
Table 1. Demographic and Clinical Pathologic Features of Patients With De Novo Malignancy