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Transplant-Related Malignancies
Over the last 20 years, liver transplantation has become an integral part of the treatment of patients with end-stage liver disease. Every year in the United States alone, more than 6000 such procedures are performed with ever-improving outcomes. Improvements in surgical technique and posttransplant medical care and the development of better immunosuppressants have resulted in 1-year posttransplant survival close to 90% and 5-year survival close to 75% in most transplant centers around the world. Despite these improvements, long-term patient survival (more than 5 years post transplant) has not changed as much over the past 20 years, partly because of increased mortality from cardiovascular disease and malignancies after organ transplantation.
Organ transplant confers a 2- to 4-fold increase in solid organ malignancies and up to a 30-fold increase in lymphoproliferative malignancies compared with the general population. This increased risk seems to be directly related to long-term use of immunosuppression, which can lead to disruptions in normal immune surveillance of malignant cells and also leads to increased risk of oncogenic viral infections, such as Epstein-Barr virus (EBV), human papillomavirus (HPV), and human herpesvirus 8 (HHV8). Another factor is the increasing age of transplant recipients and the presence in these patients of comorbid conditions that increase their cancer risk, such as obesity, alcohol use, and tobacco use. Over the last decade the age of liver transplant recipients has steadily increased. Whereas in 2002, recipients 50 years old or older constituted 58.5% of all liver transplant recipients, they represented 77% of liver transplant recipients in 2011; the proportion of recipients 65 years old or older increased from 7.6% in 2002 to 12.8% in 2011.
According to Israel Penn, founder of the Israel Penn International Transplant Tumor Registry, posttransplant malignancies can be broadly classified into three distinct categories:
- 1.
De novo malignancy: a solid or hematological malignancy that is diagnosed in a posttransplant patient without any history of such malignancy
- 2.
Recurrence of preexisting malignancy: a previous or active malignancy that was treated in the recipient before transplantation and that subsequently recurs after transplantation.
- 3.
Donor-transmitted malignancy: a malignancy with a genetically confirmed donor source that is transferred to a recipient through the donor organ and results in local or metastatic disease.
De Novo Malignancy
Frequency of Malignancy After Solid Organ Transplantation
The increased risk of malignancy after solid organ transplantation is well recognized, with reported frequencies of post–liver transplant malignancies from individual centers varying from 2.6% to 21.7%, generally representing a twofold to fourfold increased risk in comparison to the general population. The vast majority of malignancies diagnosed in the posttransplant period correspond to de novo malignancies, that is, solid and hematological malignancies that are diagnosed in a posttransplant patient without any history of such malignancy.
In a recent study from Indiana University of over 500 liver transplants performed in Indiana residents, the rate of posttransplant malignancy with a mean 6-year follow-up was 13.7%, with 5- and 10-year incidence rates of 11.7% and 24.8%, respectively. These malignancies included solid organ (50%), skin (30%), and hematological (20%) malignancies, with the most common solid malignancies deriving from the aerodigestive tract. Compared with the general population of the state of Indiana, the overall standard incidence ratio (SIR) for all malignancies was 3.1, whereas that for solid organ cancers was 2.7; skin cancer, 5.8; and hematological malignancies, 7.1.
Large registry data have provided a better understanding of the rates of malignancy after solid organ transplant. In a recent cohort study of over 175,000 solid organ transplants, including 38,000 liver transplants, from the U.S. Scientific Registry of Transplant Recipients, Engels et al found that 10,600 patients developed cancer after transplant (16.5%); overall, there was a twofold increased risk for cancer among transplant recipients compared with the general population, corresponding to an excess absolute risk attributable to transplantation of 0.7% per year. The spectrum of posttransplant malignancy was quite broad and included both infection-related (lymphoma, Kaposi’s sarcoma [KS], and cancers of the liver, stomach, oropharynx, and anogenital tract) and infection-unrelated malignancies (lung, kidney, colorectal, urinary, and skin, among others). The risk for prostate and breast cancer was not increased compared with the general population. More than 40% of posttransplant malignancies corresponded to non-Hodgkin's lymphoma (NHL) and kidney, liver, and lung cancer, whereas in the general U.S. population these malignancies combined account for only 21% of overall malignancies. Specifically, in liver transplant recipients the SIR of these cancers compared with the general population was 7.8 for NHL, 1.95 for lung cancer, 43.8 for liver cancer, and 1.8 for kidney cancer.
In a similar fashion, Sampaio et al reviewed recently reported data on de novo posttransplant malignancy among 193,000 adult recipients of solid organ transplants registered in the U.S. Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database. Of 43,106 liver transplant recipients, 1923 (4.5%) developed a de novo posttransplant malignancy, for an incidence of 11 per 1000 per year. Overall, the mean time from transplantation to cancer diagnosis was 938 days. An early presentation (<800 days) was seen with liver, metastatic liver, uterine, and ovarian cancers, leukemia, and KS. The highest incidence was seen in posttransplantation lymphoproliferative disorder (PTLD) (2.4 per 1000 per year) and lung cancer (2.2 per 1000 per year), although as a group, gastrointestinal cancers (including colorectal and liver cancer) had the highest incidence (2.6 per 1000 per year). In comparison, the age-adjusted incidence of NHL, lung cancer, and combined gastrointestinal cancers was 0.2, 0.7, and 0.86, respectively, per 1000 per year in the U.S. general population. They found that age greater than 39 years, male sex, white race, and use of induction at the time of transplant were independently associated with an increased risk for developing a posttransplant malignancy.
Similar to what has been described in the United States, liver transplant has been linked to increased risk for malignancy compared with the general population in other countries: Canada (SIR, 2.5; Fig. 86-1 ), Finland (SIR, 2.6), Japan (SIR, 1.8 in living donor liver transplants), and Korea (SIR, 7.7 for men and 7.3 for women).
Malignancy and Mortality After Transplantation
In a multicenter study of close to 800 adult liver transplant recipients from the United States who received transplants in the early 1990s and were followed for more than 12 years, Watt et al described a de novo malignancy frequency of 22% (with slightly more than half corresponding to skin malignancies), with 11% developing a solid organ cancer at a median of 10 years’ follow-up. The probability of developing a de novo malignancy after transplant was 12% at 5 years and nearly 22% at 10 years. The most common malignancies included PTLD, gastrointestinal cancer, and lung cancer, similar to data described earlier. As expected, a diagnosis of nonskin posttransplant malignancy was associated with increased mortality after transplant, with 1- and 5-year survival rates of only 55% to 60% and 27% to 45%, respectively. In a follow-up study from this same database, malignancy was the second most common cause of mortality (22%) among recipients living more than 1 year post transplant, preceded only by liver-related causes (28%) and followed in third place by cardiovascular causes (11%). In a recent report from the United Kingdom of close to 4500 adult liver transplant recipients who survived more than 1 year after transplant, the overall mortality was 15% at 10-year follow-up, and the main causes of death were malignancy (31%), multisystem failure (10%), graft failure (10%), infection (10%), and cardiac disease (9%). The overall mortality among these patients was more than twice that expected in the general population, with a death rate of 27.6 per 1000 per year versus 10.5 per 1000 per year. Clearly, the development of de novo malignancy after transplant confers an increased mortality and is among the two most common causes of death among long-term survivors. Development of appropriate screening strategies might improve our ability to diagnose these malignancies at earlier stages and potentially to improve survival among these liver transplant recipients as described further in this chapter.
Mechanisms Involved in Posttransplant Carcinogenesis
Similar to what occurs among the general population, the development of cancer after transplantation is a multifactorial process involving several biological steps. Among the transplant population, the main factors involved in carcinogenesis include age, infection with oncogenic viruses, and, importantly, immunosuppression with its direct and indirect effects on cancer development. Chronic immunosuppression plays a central role in the development of malignancies in all posttransplant patients and leads to an increased rate of malignancy similar to that of other disease states in which immunosuppression is a prominent feature. There is also a direct correlation between the intensity and length of exposure to immunosuppression and posttransplant cancer incidence rates. The high incidence of malignancy after transplant and its generally more aggressive behavior are thought to be strongly associated with impaired immunosurveillance in the transplant recipient. Through the cancer immunoediting phenomenon, the immune system protects the host against non–viral-induced malignancies and helps determine tumor immunogenicity. Under normal circumstances, immunosurveillance works as a tumor suppressor and protects the immunocompetent host from developing cancer. In comparison, the transplant recipient’s acquired immune deficiency from the use of immunosuppression results in defective immunosurveillance, allowing neoplastic cells to proliferate unregulated, which can ultimately lead to cancer development. Another relevant factor that contributes to carcinogenesis in chronically immunosuppressed recipients is their susceptibility to develop a variety of viral infections, some of which are oncogenic: EBV resulting in PTLD; HPV leading to cervical, vaginal, or anal cancer; and HHV8 leading to KS. These and other oncogenic viruses disrupt the normal host cellular signaling pathways, leading to immortalization and uncontrolled proliferation of the infected cells. Once the virus has gained access to the cell, virally encoded gene products can inhibit or degrade many of the host cell’s tumor suppressor proteins. Infected cells can then either be eliminated through cell-mediated apoptosis or survive to establish long-term persistent infections, which can ultimately lead to cancer development. In addition, calcineurin inhibitors (CNIs) can increase the expression of EBV growth and virus-inducing factors (interleukin-1, interleukin-6, and transforming growth factor [TGF]-β), promote EBV replication, and increase immunoresistance by promoting the expression of antiapoptotic genes. Additionally, CNIs seem to have direct pro-oncogenic activities, which include the induction of cancer cell invasiveness; inhibition of DNA repair mechanisms and apoptosis; promotion of the transcription and functional expression of the TGF-β1 gene, leading to malignant cell invasion and metastatic potential; and promotion of tumor angiogenesis via stimulation of vascular endothelial growth factor. The advent of non-CNI immunosuppressants in clinical practice may lead to decreased posttransplant cancer rates in the future and potentially improve late patient survival.
Risk Factors and Predisposing Conditions for Developing Posttransplant Malignancy
Many risk factors are associated with the development of cancer in the general population, some of which have also been proven to be relevant in the development of cancer after liver transplantation. Prominent among them are tobacco and alcohol use, chronic immunosuppression as discussed earlier, recipient age, and recurrence of viral hepatitis C ( Table 86-1 ). As discussed in a recent systematic review detailing the main findings of several studies addressing this issue, three risk factors—tobacco and alcohol, age and gender, and premalignant disease—are thought to contribute to de novo cancer development in the liver transplant population.
TABLE 86-1
Site-Specific Risk Factors for De Novo Malignancy in Adults After Liver Transplantation
Modified with permission from Chak E, Saab S. Risk factors and incidence of de novo malignancy in liver transplant recipients: a systematic review. Liver Int . 2010;30:1247. John Wiley and Sons.
| Site | Risk Factor |
|---|---|
| Skin | Smoking Alcoholic cirrhosis Age > 40 Male gender Cyclosporine use Skin type Sun exposure Primary sclerosing cholangitis |
| Posttransplant lymphoproliferative disorder | Age > 50 Hepatitis C virus infection Alcoholic cirrhosis Transplantation for acute liver failure Rejection therapy with high-dose steroids Use of antilymphocyte antibodies |
| Colorectal | Primary sclerosing cholangitis Inflammatory bowel disease |
| Oropharyngeal | Alcohol use Smoking |
| Lung | Alcohol use Smoking |
Tobacco and Alcohol
Smoking tobacco is the leading cause of premature mortality worldwide and is responsible for an estimated 5 million deaths annually. Although the negative health effects of smoking are well recognized among the general population, the effects of tobacco in the liver transplant setting are not well known, and there are data showing it is associated with increased cardiovascular death and in some studies with an increased rate of de novo malignancy and cancer-related mortality. In a single-center study from the Netherlands, the posttransplant 10-year cumulative rate of malignancy in smokers was 13%, significantly higher than that in nonsmokers (2%), although the authors did not find a significant increase in the incidence of skin cancer or cardiovascular disease in smokers. In a smaller study from the United Kingdom of 136 liver transplant recipients (23% active smokers), tobacco had a significant detrimental effect in all-cause mortality, with estimated 1-, 5-, and 10-year survival rates of 94%, 68%, and 54%, respectively, among active smokers compared with 94%, 83%, and 77% for nonsmokers. Interestingly, the increased mortality among active smokers was seen in cardiovascular and sepsis-related mortality but not in malignancy-related mortality. Ex-smokers, compared with active smokers at the time of transplant evaluation, did not have an increased mortality. In a multicenter long-term follow-up study from the United States of close to 800 liver transplants, smoking history (hazard ratio [HR] 1.72) and alcoholic liver disease as cause of transplant (HR 2.14) were independent risk factors for developing de novo malignancy after liver transplant. Likewise, in a study from Indiana University, tobacco use was independently associated with de novo malignancy with an HR of 2.8. In a single-center study from Spain, there was an almost 20-fold increase in smoking-related malignancies (lung cancer, head and neck and esophageal cancer, as well as kidney and urinary tract cancers) among liver transplant recipients who had a significant smoking history (>20 pack-years) or who were actively smoking after transplantation compared with lifelong nonsmokers or nonsignificant smokers (<20 pack-years or those who had quit smoking >10 years before transplant). Contrary to these findings, smoking during transplant evaluation or after transplantation in a large cohort of chronic liver disease patients from the University of Michigan was not associated with increased mortality at any time point. Nonetheless, most transplant programs encourage smoking cessation in all patients during the evaluation process, both because of the well-documented negative health consequences of tobacco and because of concerns for poor postoperative outcomes, such as hepatic artery thrombosis and pulmonary complications, together with increased posttransplant malignancy risks.
The effects of alcohol use on the risk for posttransplant malignancy are not well known, although there are data suggesting that heavy tobacco and/or alcohol use before transplant results in a significantly increased risk for developing upper respiratory tract and lung cancer after liver transplant. In a single-center study from Spain, the rate of upper respiratory tract and lung cancer was 8% among patients transplanted for alcoholic cirrhosis versus 0.8% in those with other causes of liver disease; also of note, the majority of these patients were heavy drinkers (75%) and/or heavy smokers (70%) before transplant. The 3-year survival in patients who underwent surgical resection of the cancer was 20%. In a follow-up study focusing only on de novo lung cancer, the same group diagnosed 17 of 700 recipients with said cancer (2%), including 12 (1.7%) with alcoholic cirrhosis versus 3 (0.4%) with nonalcoholic cirrhosis. Not surprisingly, the prognosis was very poor, because most patients were deemed unresectable at diagnosis and all patients died, with a mean survival of 5 months after diagnosis. Other groups have also found a twofold to threefold increased rate of posttransplant malignancy in patients with alcoholic cirrhosis compared with nonalcoholics.
Age and Gender
There does not appear to be a significant difference in the risk for de novo malignancy after liver transplant between men and women, although in a single-center study male sex was an independent risk factor for developing skin cancer. Similarly, male sex was found to be an independent predictor of posttransplant malignancy in a review of a large transplant database in the United States, resulting in an almost 25% increased risk.
There are robust data supporting the impact of age on the development of posttransplant malignancy. As expected, as recipients grow older, their risk for cancer increases, so compared with younger recipients (age 20 to 29), older patients had anywhere from a 24% increase (age 30 to 39) to a 4.5-fold increase (age 60 to 69) in the incidence of posttransplant malignancy. Findings from others have also supported the impact of age on the development of de novo malignancy after liver transplant. ∗
∗ References .
Premalignant Disease
With our current understanding of the role the immune system plays in surveillance of malignant cells, it is plausible to think that liver transplant recipients on chronic immunosuppression with premalignant conditions would be at an increased risk for developing posttransplant malignancies. One such example is the report of patients developing esophageal adenocarcinoma arising in the setting of previously diagnosed Barrett’s esophagus. Information on the risk for developing cancer after liver transplantation in the setting of a known premalignant condition is scant. In a single-center retrospective study, Menachem et al assessed 175 transplant recipients, 13 of whom developed posttransplant malignancies (7.5%): 5 with NHL and 8 with solid organ malignancies. Five of these 8 patients had a premalignant condition before transplant: 2 patients with ulcerative colitis and colonic polyp went on to develop colon cancer; 1 patient with Barrett’s esophagus developed esophageal adenocarcinoma; 1 patient with cervical atypia went on to develop cervical cancer; and 1 patient with Caroli’s disease developed cholangiocarcinoma. The study authors concluded that patients identified as having premalignant conditions during their pretransplant evaluation should be closely monitored and undergo adequate surveillance in an effort to prevent cancer or to diagnose it at an early stage.
As discussed previously, the frequency of de novo malignancy after transplantation is increased compared with the nontransplant population. Common malignancies, like breast and prostate cancer, seem to be equally frequent in transplant and nontransplant populations, whereas other types of cancer are more frequent among transplant recipients, including nonmelanoma skin cancer, PTLD and lymphoma, KS, lung cancer, head and neck cancer, as well as cervical, vaginal, and vulvar malignancies and certain gastrointestinal tumors such as esophageal cancer and colorectal cancer. Specifically in the liver transplant population, nonmelanoma skin cancer, PTLD, and lung and colorectal cancer seem to be the most common de novo posttransplant malignancies, as described later.
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