1. De novo malignancy is one of the leading causes of late mortality after liver transplantation.
2. The risks of skin cancers and lymphoma are more than 10-fold greater than the risks in an age-matched and sex-matched general population.
3. Some types of neoplasia, such as lung, head and neck, and colorectal cancer, are more frequent in liver transplant recipients than in an age-matched and sex-matched population. The risks of other frequent malignancies, such as prostate and breast cancer, do not seem to be increased.
4. The most important risks for posttransplant malignancy are Epstein-Barr virus seronegativity (for lymphoma), sun exposure (for skin cancer), smoking, and increasing age.
Liver transplant recipients are at risk of developing de novo neoplasia through a variety of mechanisms. Immunosuppressive therapy decreases immune surveillance against malignant cells and against a variety of viruses that have oncogenic properties. Moreover, certain immunosuppressive drugs may have intrinsic oncogenic properties. As a result, liver transplant recipients have an increased risk of de novo neoplasia. For instance, in a recently published randomized trial, patients with alcoholic cirrhosis had a higher risk of nonhepatic neoplasia if they were transplanted than if they received standard care (5-year risk of neoplasia: 37% versus 6%).1
Overall, the risk of malignancy is 2 to 4 times higher in transplant recipients than in an age-matched and sex-matched population2–6 (Table 1 and Fig. 1). This increased risk is especially high in neoplasia related to viral infections,7 such as non-Hodgkin lymphoma, Kaposi's sarcoma, and uterine cervical cancer. The risk of skin cancer is also greatly increased.3–6, 8 The incidence of other common malignancies also seems to be increased, but this risk is not so high. Some series have shown that the risk of colorectal,3, 5 lung,9 head and neck,10 urological,3 and hepatocellular carcinomas11 are increased. In some cases, the cause of this increased risk may be a specific association between certain causes of liver disease and risk factors for the development of certain types of neoplasia in the general population. This is very important in 2 circumstances. First, there is the association between primary sclerosing cholangitis and ulcerative colitis, which markedly increases the risk of colorectal cancer. Second, patients with alcoholic liver disease may have an increased risk of neoplasia because a high intake of alcoholic beverages is associated with a higher risk of esophageal cancer and head and neck cancer and also because of the association between high alcohol intake and smoking, which is an important risk factor for some of the most frequently diagnosed tumors in transplant recipients. In fact, this increased risk has not been adjusted for well-known risk factors of neoplasia. Finally, the risk of other common neoplasia types such as prostate and breast cancer does not seem to be increased in liver transplant recipients.9 As a result, the risk of mortality due to neoplasia is significantly higher than that in the general population,2, 3 and de novo neoplasia is one of the most common causes of mortality after transplantation, mainly in the long term.12 In our experience (Fig. 2), more than 30% of late deaths are caused by de novo malignancy, and de novo malignancy is the single most frequent cause of death after liver transplantation.
Table 1. Relative Risks of Neoplasia in Liver Transplant Recipients in Comparison with a Sex-Matched and Age-Matched Population
Type of Neoplasia
NOTE: The data in this table were taken from Herrero et al.,2 Haagsma et al.,3 Sheiner et al.,4 Oo et al.,5 Åberg et al.,6 Fung et al.,9 Herrero et al.,10 and Hoffmann et al.11 Tumors are listed in the order of frequency.
Squamous and basal cell skin cancer
Head and neck cancer
In alcoholic liver disease
In ulcerative colitis
The outcomes after the diagnosis of malignancy in liver transplant recipients seem to be worse than the outcomes in the general population. Unfortunately, there have been no studies that have confirmed whether this is true and whether it results from a more advanced stage at diagnosis, from more aggressive behavior of neoplasia in transplant recipients, or from the presence of comorbidities.
RISK FACTORS OF NEOPLASIA
The intensity of immunosuppressive treatment has been related to the development of neoplasia. For instance, antilymphocyte antiglobulin therapy increases the risk of lymphoproliferative disorders,13 and azathioprine may be related to the development of cutaneous neoplasia.14 In relation to the use of calcineurin inhibitors, cyclosporine has been related to a greater risk of cutaneous neoplasia,14 but tacrolimus has been related to a higher incidence of internal neoplasia.15 The antiproliferative effect of mammalian target of rapamycin (mTOR) inhibitors may be associated with a protective effect against neoplasia. In fact, several retrospective analyses have shown that renal transplant recipients receiving sirolimus-based immunosuppressive therapy have a lower incidence of cutaneous malignancies.16
The incidence of neoplasia according to age has a U shape. In children and young adults, the incidence of neoplasia is high because of the high incidence of lymphoma at these ages. This is because their Epstein-Barr virus (EBV) status before transplantation is frequently negative, and EBV-seronegative patients have the highest risk of lymphoma.13 In young adults, the risk of malignancies is lower, and this risk increases with age, just as in the general population. In fact, the increased risk of malignancy is one of the most important causes of lower survival after the transplantation of older recipients.17 Figure 3 shows the risk of de novo malignancy according to age in our series.
Risk Factors Specific for Different Types of Neoplasia
As previously mentioned, the most important risk factor for lymphoproliferative disease is EBV infection (more frequently when the recipient is EBV-negative). Other potential risk factors are the use of OKT3 and antithymocyte globulins, hepatitis C virus infection, and cytomegalovirus infection.
Kaposi's sarcoma is closely associated with human herpesvirus 8 infection. The main risk factors for squamous cell and basal cell carcinomas are skin type and sun radiation8; other potential risk factors are infection by human papillomavirus, hepatocellular carcinoma, primary sclerosing cholangitis, and the immunosuppression received,14 but the role of these factors is less clear.
Upper Aerodigestive Tract and Lung Cancer
As in the general population, smoking is associated with a higher risk of esophageal, head and neck, and lung cancer. It is also probably associated with a higher risk of urological (other than prostate) neoplasia. In fact, smoking is an independent risk factor for noncutaneous malignancy after liver transplantation2 (Fig. 4). Alcohol seems to also be an important risk factor for the development of head and neck cancer and esophageal cancer.18
Patients with ulcerative colitis associated with primary sclerosing cholangitis have a high risk of developing colorectal cancer5 if they have an intact colon. It is not clear whether this risk is due only to long-term ulcerative colitis or also to immunosuppressive therapy.
EBV, Epstein-Barr virus; mTOR, mammalian target of rapamycin.
PREVENTION AND EARLY DIAGNOSIS
Survival after the diagnosis of de novo malignancy is low. If skin cancers are excluded, median survival after neoplasia diagnosis is lower than 3 years (Fig. 5). Therefore, a program of neoplasia surveillance could have a positive impact on survival.
Some of the neoplasia screening programs in general populations have insufficient evidence to be recommended.19 Similarly, none of the recommendations for the prevention and early detection of malignancy after liver transplantation are based on scientific evidence.
The first recommendation is to avoid overimmunosuppression, as it has been suggested that intense regimens of immunosuppression are associated with a higher frequency of malignancy.15 The use of mTOR inhibitors could be associated with a lower incidence of neoplasia, but this benefit has been shown only in retrospective studies in renal transplant patients, and it is nearly restricted to skin cancer, which infrequently leads to death.16 Other potential measures are related to specific types of neoplasia.
It has been shown that patients who develop posttransplant lymphoproliferative disease have higher levels of EBV DNA than those who do not develop it.13 Thus, monitoring of the EBV DNA load has been suggested to be of value in the early diagnosis of lymphoma. Unfortunately, there is no clear threshold value predictive for lymphoproliferative disease. Therefore, it has been proposed that the evolution of the EBV viral load or the combination of the EBV DNA load and EBV-specific cytotoxic T lymphocyte responses may be more useful. Two approaches have been suggested for patients with a high risk of posttransplant lymphoproliferative disease according to the EBV DNA load: antiviral therapy20 and a gradual decrease in immunosuppressive therapy.21
As skin cancer is the most frequent cancer after transplantation, some authors have suggested that transplant recipients should be evaluated every year by a dermatology specialist. With this approach, skin cancer can be diagnosed during early stages, and this would allow curative resections in all cases8 (in transplant recipients, skin cancer with an aggressive course and metastatic spread has been reported). Protection against sunlight seems a logical recommendation for transplant recipients, mainly for patients with a fair skin type. Unfortunately, it is possible that the decades of cumulative sun exposure before transplantation are more important than the few years of exposure after it. Finally, in patients with recurrent skin malignancies, conversion to mTOR inhibitors may have a protective effect against the development of new skin cancers.16
As smoking is a very significant risk factor for the development of neoplasia, smoking cessation should be recommended to avoid the development of de novo malignancies. Once again, it is possible that cumulative lifelong smoking is more important than active smoking. In fact, active smokers did not have a higher risk of malignancy than exsmokers.22 The relevance of avoiding risk factors must be stressed in patients transplanted for alcoholic liver disease, not only because of the association between alcohol and smoking but also because alcohol consumption is a risk factor for neoplasia in the general population.23
As de novo neoplasia is one of the most frequent causes of long-term mortality in liver transplant recipients, some authors have suggested different surveillance protocols. In our experience, the use of a strict protocol has allowed us to diagnose neoplasia in some patients at an early and potentially curative stage.10 This protocol has evolved over the years and includes yearly urinanalysis, abdominal ultrasound, chest X-ray film, prostate specific antigen determination (for elderly males), and ear-nose-throat examination and low-radiation chest computed tomography scan (for smokers); it also includes mammography every 2 years and colonoscopy every 7 to 10 years (or more frequently in the case of previous colonic adenomas and every year for patients with long-term ulcerative colitis).
De novo neoplasia is a frequent complication in liver transplant recipients. It is one of the most frequent causes of death in the long term. The main risk factors for its development are EBV seronegativity (for lymphoma), ulcerative colitis (for colorectal cancer), sun radiation (for skin cancer), smoking (for lung, head and neck, and urological cancer), and increasing age. The role of each immunosuppressive protocol in the risk of cancer remains controversial. Unfortunately, preventive measures and programs for the early diagnosis of neoplasia cannot be widely recommended until the evidence of their usefulness become stronger.