EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: The incidence of malignancy is higher in solid-organ transplant recipients compared with the general population. In the present study, we present our experience with de novo malignancies encountered after both deceased-donor and living-donor liver transplants.

Materials and Methods: We retrospectively reviewed the medical records of 335 patients who underwent an orthotopic liver transplant at our institution between September 2001 and December 2012 to identify subjects with de novo malignancies.

Results: Fourteen patients (4.1%) developed de novo malignancies after liver transplant. De novo malignancies included lymphoproliferative disorders after liver transplant in 7 patients (treated with chemotherapy), thyroid papillary carcinoma in 1 patient (treated with total thyroidectomy and radioactive iodine therapy), squamous cell carcinoma in 2 patients (treated with surgical resection), gastric stromal tumor in 1 patient (treated with surgical resection), ovarian carcinomas in 1 patient (treated with radical surgical resection and chemotherapy, who died within 1 year of diagnosis), lung cancer in 1 patient (treated with chemotherapy, but he had bone metastasis and died within 1 year of diagnosis), and neuroblastoma in 1 patient (treated with chemotherapy). In all patients, immunosuppression was changed to sirolimus.

Conclusions: Transplant recipients generally have advanced stage cancers at the time of diagnosis with a poor prognosis. Because some neoplasms are common, early detection of cancer is important to decrease cancer-related mortality and morbidity.

Key words : Posttransplant lymphoproliferative disorder (PTLD), Thyroid papillary carcinoma, Liver failure

The only potentially life-saving intervention for acute liver failure or end-stage liver disease is a liver transplant (LT). The survival of the patients has increased owing to successful immunosuppressive therapies. A significant complication of immuno-suppressive therapy for liver transplant is neoplasia. Immunosuppression inhibits immune surveillance against malignant cells and several viruses with oncogenic potential.¹ The risk of malignancy is 2 to 4 times greater in liver transplant recipients than it is in the age-matched and sex-matched general population.² The overall incidence of malignancy in transplant recipients is estimated as being as high as 20% in the 10 years after a transplant.

It is especially high (greater than 10-fold) for skin cancer,³ non-Hodgkin lymphoma,⁴ Kaposi sarcoma,⁵ and uterine cervical cancer.⁵ Most of these tumors are related to viral infections such as Epstein-Barr virus. The risk of some common malignancies, such as breast and prostate adenocarcinomas does not increase,⁶ while the risk of others (such as head and neck cancer, lung, urologic, or colorectal carcinomas) only moderately increases.⁷

This study presents our experience with de novo malignancies encountered after deceased-donor and living-donor liver transplants.

Materials and Methods

We retrospectively reviewed the records of 335 patients who underwent an orthotopic liver transplant at our institution between September 2001 and December 2012 to identify subjects with de novo malignancy in orthotopic liver transplant recipients. All liver transplants were performed from an ABO-compatible donor. The study was approved by the Ethical Review Committee of the institute. All protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration.

All recipients received tacrolimus-based immuno-suppression with blood levels maintained between 10 and 15 ng/mL during the first month, and between 5 and 10 ng/mL thereafter. Methylprednisolone (10 mg/kg), administered intraoperatively, was continued postoperatively from 10 mg/kg, tapered to 0.1 mL/kg at the end of the first month, and stopped at the end of the third month. After the diagnosis of de novo malignancies, tacrolimus therapy was switched to sirolimus in all recipients. All patients received antifungal, antiviral, and antipneumocystis prophylaxis for 6 months after surgery. After a liver transplant, recipients were followed-up every 3 months. At each follow-up, we analyzed the results of lung radiographs, abdominal ultrasonography, and liver function tests. If any lesions were detected, the recipient was further analyzed by computed tomography scanning of the chest and abdomen.

No protocol liver biopsy specimens were obtained, and biopsies were performed only to investigate biochemical abnormalities (elevated serum transaminase or bilirubin levels). Acute rejection was documented by liver histology and treated with methylprednisolone boluses.

Fourteen patients (4.1%) developed de novo malignancies after a liver transplant. The demo-graphic characteristics of the patients are given in Table 1.

The causes of liver failure of these patients include hepatitis B virus (n=3, two of them also have hepatocellular carcinoma and alcohol use), progressive familial intrahepatic cholestasis (n=3), cryptogenic cirrhosis (n=1), primary biliary cirrhosis (n=1), autoimmune hepatitis (n=1), hepatoblastoma (n=1), congenital hepatic fibrosis (n=1), biliary atresia (n=1), fulminant Wilson disease (n=1), and Kasabach–Merritt syndrome (n=1).

De novo malignancies included post-LT lymphoproliferative disorders (PTLD) (n=7; 50%), thyroid papillary carcinoma (n=1; 7%), squamous cell carcinoma (n=2; 15%), gastric stromal tumor (n=1; 7%), ovarian carcinoma (n=1; 7%), lung cancer (n=1; 7%), and neuroblastoma (n=1; 7%). The characteristic of these malignancies are presented in Table 2.

In PTLD group, at the time of diagnosis, 1 recipient a large mediastinal mass and cough; the remaining 6 patients were asymptomatic. During routine radiologic screening, generalized lymph-adenopathy was shown in 3 recipients, multiple liver masses in 1, a large portal mass in 1, multiple stomach ulcers in 1, and a large mediastinal mass in 1. The endocrinology team was consulted for a patient with thyroid papillary carcinoma, which was diagnosed as a thyroid mass; a biopsy was performed. The dermatology team saw 1 patient with squamous cell carcinoma, which was diagnosed as skin nevus; a punch biopsy was performed. The ophthalmology team was consulted for the other patient owing to a conjunctiva lesion. A gastric stromal tumor was revealed during endoscopy that was performed for dyspeptic problems, and ovarian carcinomas and neuroblastoma were shown on routine radiologic screening. The patient with lung cancer was consulted by the department of chest diseases owing to hemoptysis; after which, a flexible bronchoscopy was performed, which showed lung cancer.

In the PTLD group, 5 patients were treated with chemotherapy and 2 patients were treated with anti-CD20 monoclonal antibodies; thyroid papillary carcinoma was treated with total thyroidectomy and radioactive iodine therapy; squamous cell carcinomas were treated with surgical resection; gastric stromal tumor was treated with surgical resection; ovarian carcinomas was treated with radical surgical resection and chemotherapy but the patient died within 1 year of diagnosis; lung cancer was treated with chemotherapy, but the patient died within 1 year of diagnosis owing to bone metastases; and neuroblastoma was treated with chemotherapy.

During the early 1990s, the risk of de novo malignancies after transplant was controversial. During that time, Penn reported the frequency of tumors in the general population was not increased among transplant recipients; these included lung, prostate, breast, colon, and invasive carcinomas of the uterine cervix.⁸

However, it is now known that there is an increased cancer risk after liver transplant. De novo malignancies may occur at any time after a solid-organ transplant.⁹ Most of reports show the incidence of de novo malignancy ranges from 3% to 26%, and it is a statistically significant increase compared with the general population.¹⁰ Schrem and associates reported that cancer incidence rates for liver transplant recipients were almost twice as high as those for an age-matched and sex-matched general population.¹¹ In another study from the United States, the authors showed a statistically significant increased risk for oropharyngeal cancer when they looked at several cancer types and compared them with the general population.⁹

Recent studies have shown that at all tumor groups, especially skin cancers and lymphomas have a 10-fold increased risk when compared with the age-matched and sex-matched general population.² Penn has shown in a series from the Cincinnati Transplant Tumor Registry, 329 tumors in 324 liver transplant patients. Fifteen percent were skin and lip cancer, and 57% were lymphomas.⁹ Similar to this study, Jonas and associates stated that the cumulative incidence 5 years after a liver transplant, of de novo neoplasia is 14.6%. Skin cancer and lymphoma accounted for about 20% of these cases.9 Many of our patients developed de novo malignancies, which were diagnosed at various tumor stages. Similar to the literature, in our series, PTLD was seen more than the other malignancies. Fifty percent were lymphomas and 15% were squamous cell carcinoma. We diagnosed PTLD in 3 patients during the first year after liver transplant, and 4 patients of PTLD thereafter. In our series of liver transplant recipients, the incidence of PTLD was 2%, which is comparable to most other series. In our series, other malignancies were rare. We believe that mortality can be reduced by early diagnosis.

In conclusion, de novo malignancy is a leading cause of late mortality after a liver transplant. Some types of neoplasia, such as PTLD, lung, head and neck, and colorectal cancer, are more frequent in liver transplant recipients than they are in an age-matched and sex-matched population. Despite close observation of patients during the postoperative phase, clinical signs of de novo malignancies may go undetected. Intensive screening programs may detect malignancies early enough to allow for curative treatment. Clinicians working on a transplant team must bear in mind the possibility of de novo malignancies.

Volume: 12 Issue: 1 March 2014 - Supplement - 1

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