Will all liver transplantation patients eventually die from cancer?

Journal of Hepatology 44 (2006) 13 38 Special Section Editor and Associate Editor: Pierre-Alain Clavien Will all liver transplantation patients eventually die from cancer? William Sanchez, Jayant A. Talwalkar, Gregory J. Gores* Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55901, USA www.elsevier.com/locate/jhep Cancer occurring after transplantation, either recurrent or de novo malignancy, is a serious complication of liver transplantation and of great concern to transplant physicians and patients. Liver transplant (LT) recipients are at risk of developing cancer after transplantation from a variety of mechanisms. Prior to transplantation, long-term exposure to known carcinogens such as alcohol and tobacco or infection with oncogenic viruses such as HBV and HCV place many patients with advanced liver disease at increased risk. After transplantation, immunosuppressive medications result in decreased immune surveillance against malignant cells and increases the risk of malignancies mediated by viruses such as human papilloma virus, Epstein Barr virus and human herpes virus-6. With the rising incidence of hepatocellular carcinoma (HCC), an increasing number of liver transplantations are being performed for the treatment of hepatic malignancies, which may recur after LT (OPTN Data 2004). Finally, given the demographic shift toward an older population, the majority of patients undergoing LT in the USA are now over the age of 50 (OPTN Data 2004). Given these facts, the question is raised: Will all liver transplant patients eventually die from cancer? Recipients of LT can develop cancer either as the recurrence of a pre-transplantation malignancy (e.g. posttransplantation recurrence of HCC), or a de novo malignancy developing after LT. De novo malignancies include sporadic cancers, malignancies associated with the immunocompromised state (e.g. post-transplantation lymphoproliferative disorder) as well as those cancers associated with the patient s pre-transplantation disease state (e.g. * Corresponding author. Eisenberg Professor of Medicine and Physiology, Chair, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55901 USA. Tel.: C1 507 284 8700; fax: C1 507 284 0762. E-mail address: gores.gregory@mayo.edu (G.J. Gores). Abbreviations: HCC, hepatocellular carcinoma; IBD, inflammatory bowel disease; LT, liver transplant; PTLD, post-transplant lymphoproliferative disorder; PSC, primary sclerosing cholangitis. colorectal carcinoma complicating inflammatory bowel disease in patients with primary sclerosing cholangitis). While the transmission of tumors of donor origin to organ transplant recipients can occur, the incidence is very low. Among a cohort of over 100,000 cadaveric organ transplant recipients from the Organ Procurement and Transplantation Network/United Network for Organ Sharing, the donorrelated tumor rate was 0.017% [1]. In order to ascertain whether LT recipients are more likely to die from cancer we need to understand whether LT recipients are at a higher risk of developing cancer and whether they have increased cancer-related mortality than non-lt patients with cancer. 1. Cancer incidence after liver transplantation Solid organ transplantation and subsequent chronic immunosuppression has been long associated with an increased risk for the development of cancer. Patients are at increased risk for hematologic malignancies as well as solid cancers. Concerning solid malignancies, several studies have demonstrated a higher incidence of both cutaneous and non-cutaneous solid malignancies in LT recipients compared with the general population. The reported rates in various studies range from 3 to 17%. The reported neoplasia rates are likely to be elevated due to the presence of screening bias among this population of patients where close medical surveillance is routine. These studies are also limited due to heterogeneity in terms of many important variables such as cohort size, patient population, indication for LT, era of transplantation, immunosuppressive regimen and length of follow-up. Many of these studies are further limited by inadequate control groups [2 18]. Among the larger published series, Galve et al. reported the cancer prevalence in 1827 Spanish LT recipients. Seventy patients (3.8%) were diagnosed with de novo malignancies after transplantation, including 17 skin 0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.10.007

14 cancers, 17 hematologic malignancies and 29 solid tumors including eight upper aerodigestive tract tumors (head, neck and esophageal cancers). Cancer occurred in patients at an average age of 53.5 years. Cancer tended to occur early after transplantation with the mean time to occurrence of 30.7 months. Fifty percent of cancers developed within 2 years of LT [7]. In a series of 1421 US LT recipients, 125 (8.8%) developed de novo malignancies including 41 skin cancers and 35 lymphomas. Fifty-nine patients with de novo malignancies died from tumor related deaths resulting in a 60% mortality for patients with non-cutaneous neoplasms (16). 2. Recurrent malignancies Liver transplantation is considered to be the treatment of choice for patients with hepatocellular carcinoma (HCC) and decompensated cirrhosis [19]. Despite the use of established criteria for selecting LT candidates with the lowest risk of HCC recurrence, HCC has been reported to recur after LT in approximately 10% of patients [20 22]. After the adoption of the model for end-stage liver disease (MELD) score for organ allocation among LT candidates in the USA, the number of patients undergoing LT for HCC tripled during the first year. Subsequently, a number of patients were identified whose diagnosis of HCC could not be rigorously verified and thus a reduction in assigned MELD score was performed. Nonetheless, the proportion of patients undergoing LT who have HCC continues to rise, the number of patients with recurrent HCC is expected to increase (OPTN Data 2004) [21]. The natural history of recurrent HCC is not well established, although given concomitant immunosuppression, recurrent cancer may run a more aggressive course. In a series of 132 LT recipients from three Italian transplant centers, Regalia et al. reported a 15.9% HCC recurrence rate. Ninety percent of patients developed recurrence within 2 years of transplantation. The authors identified tumors greater than 3 cm in diameter, the presence of a peri-tumoral capsule and tumors, which exceeded the Milan criteria for LT as independent risk factors for post-transplantation recurrence. TNM (American Joint Committee on Cancer Tumor, Nodal Involvement and Metastatis classification system) stage, vascular invasion, pre-transplantation chemoembolization and serum alpha-fetoprotein level did not independently predict HCC recurrence in this study [23]. More recently, among a cohort of 67 patients with undergoing LT for HCC complicating HCV-related liver disease at a single US center, 11 patients (16.4%) developed cancer recurrence. Subsequently, eight deaths occurred from recurrent HCC. The majority of patients (81%) had cancer recurrence within 1 year of transplantation. Both patients who had late (O3 years after LT) recurrence presented with lung metastases. TNM staging, vascular invasion and pre-operative tumor diagnosis (as opposed to incidentally discovered tumors) predicted post-operative recurrence of HCC. Survival after transplantation was predicted by lower TMN staging and pre-lt chemoembolization [24]. Roayaie and colleagues reported the outcomes of 311 patients who had HCC at time of LT from a single US center. Recurrent HCC occurred in 57 patients (18.3%) at a median time of 12.3 months after LT. The prognosis of recurrent HCC was poor, with a median survival of only 8.7 months after recurrence. Multivariate analysis identified larger tumor size (greater than 5 cm in diameter), poorly differentiated histology and bony metastases (irrespective of other metastases) as predictors of decreased survival from time of LT. Early recurrence (less than one year after LT) and bony metastases predicted shortened survival from the time of recurrence, while surgical management of recurrent tumors was shown to increase survival from time of recurrence [21]. Together, these studies suggest that the recurrence rate of HCC after LT may be higher than previously reported. While the majority of patients with cancer recurrences have presented early after LT, a minority patients present with cancer recurrence several years after transplantation. Two of the 11 patients in the Shimoda series developed recurrence of HCC more 3 years after transplantation and approximately 10% of patients in the Roayaie series developed recurrence 4 or more years after LT [21,24]. Patients with recurrent liver disease after LT, such as HCV infection, continue to have an oncogenic stimulus which may, in part, account for late recurrence. While patients who developed a HCC early after LT should be considered to have true recurrence, one could speculate that the development of HCC late after LT represents tumors with a different biology or possibly a de novo primary tumor. 3. De novo malignancies 3.1. Skin cancer Cutaneous malignancies are the most commonly occurring cancers after LT. The prevalence of cutaneous malignancies is increased in transplant recipients and varies with the degree of immunosuppression. The majority of cutaneous malignancies are non-melanoma skin cancers such as squamous cell carcinoma and basal cell carcinoma. While basal cell carcinomas are the most common cutaneous malignancy in the general population, squamous cell skin cancer is more common among transplant recipients. The rate of developing squamous cell skin cancer is estimated to be increased over 60-fold in LT recipients compared to the general population. Fortunately, mortality rates from skin cancer in LT recipients are low with melanoma as the major cause of death [9,25]. While the transmission of donor-related tumors is rare, malignant melanoma is the most commonly transmitted tumor. Transplant recipient mortality due to the transmission of

15 donor melanoma to a LT recipient has been reported [26]. LT recipients, particularly those in sunny climates, should be counseled on photoprotection and require cancer surveillance with regular dermatologic examinations. 3.2. Post-transplant lymphoproliferative disorder Post-transplant lymphoproliferative disorders (PTLD) comprises a spectrum of abnormal lymphoid tissue proliferation among in organ transplant recipients. PTLD is associated with chronically immunosuppression and is frequently associated with Ebstein Barr virus (EBV) infected B-lymphocytes. PTLD has been reported to occur with a prevalence of 1.7 4% of LT recipients. While many cases of PTLD respond to a reduction in the level of immunosuppression, PTLD can present as an aggressive B-cell lymphoma [27 29]. PTLD frequently involves the liver allograft with allograft PTLD (accounting for approximately 44%) and carries a mortality rate of approximately 50% despite therapy [13,28]. Among recipients of LT, infection with the hepatitis C virus may represent an additional risk for the development of PTLD. This is of concern given the universal recurrence of HCV after LT. The hepatitis C virus may induce B-cell proliferation either independently or through a synergistic effect with the EBV virus. In one study of 480 consecutive French LT recipients, multivariate analysis identified age (older than 50 years), the use antilymphocyte antibody therapy, and LT for either hepatitis C related cirrhosis or alcoholic cirrhosis as risk factors for the subsequent development of PTLD. The relative risk of developing PTLD among HCV-infected LT recipients was 8.7 (95% CI 1 78.3, PZ0.015) compared to patients transplanted for non-hcv, non-alcoholic liver diseases [30]. A case control study of 57 HCV-infected LT recipients, the odds ratio of developing PTLD was 9.5 (PZ0.02) among HCV-infected patients compared to non-hcv infected LT recipients [31]. In another study of 157 LT recipients, PTLD was more common in HCV-infected patients than in non-infected patients (10.5% vs 1.7%; PZ0.03). Patients undergoing LT for HCV-related ESLD were more likely to have received antithymocyte globulins. However, among patients who received antithymocyte globulins, PTLD seemed to occur more frequently among those HCV-related disease (27.1% vs 6.4%, PZ0.08) [28]. In contrast, PTLD is a relatively uncommon disease, and the studies which find an increased risk among HCVinfected LT recipients are limited by small numbers of patients. In a prospective study of 394 patients with lymphoproliferative disorders (including 164 patients with non-hodgkin s lymphoma), Hausfater and colleagues found a low prevalence rate of HCV infection (2.79 and 1.83%, respectively). While patients with lymphoproliferative disorders did have a higher prevalence of HCV compared to controls (2.79% vs 0.43%), the authors concluded that the low rate of HCV infection suggests that HCV does not play an important role in the pathogenesis of lymphoproliferative disorders [32]. Among 660 patients undergoing LT at Mayo Clinic, Zein et al. found no link between HCV infection and the development of PTLD [33]. Given the small numbers of patients who developed PTLD and the differences in immunosuppressive regimens used at different institutions, the link between HCV infection and PTLD remains unclear [28,33]. 3.3. Solid organ malignancies Multiple studies have reported an increased risk for developing solid organ malignancy after LT. Data from the International Transplant Tumor Registry (formerly the Cincinnati Transplant Tumor Registry) demonstrates a significantly increased risk of cancers such as skin cancer, Kaposi s sarcoma, cervical, vulvar and anal squamous cell carcinomas among organ transplant recipients compared to the general population. Among liver transplant recipients, 324 patients developed 329 cancers after LT. When compared to a cohort of 7200 renal transplant recipients with cancer, LT recipients had a higher rate of lymphoma (57% vs 12% of cancers). In LT recipients both solid tumors (27 vs 72 months) and lymphomas (15 vs 46 months) occurred earlier in the post-transplant course compared to renal transplant recipients. The higher proportion of pediatric LT recipients and the longer follow-up of renal transplant recipients may explain the observed differences [13]. A population-based study of 174 transplant recipients from the Netherlands who survived more than 1 year from LT revealed an increased relative risk of developing solid organ malignancy compared to expected rates in the Dutch population. The relative risk of developing any noncutaneous, solid organ malignancy was 2.7, with the relative risk being highest for colon and renal cell carcinomas (12.5 and 30.0, respectively). Of note, renal cell carcinoma was noted incidentally in two of three cases and none of the three patients who developed colorectal neoplasia had underlying PSC or IBD. Age greater than 40 years was identified as an important risk factor for post-transplant cancer [8]. Based on center-specific practices, a number of LT recipients may be evaluated longitudinally to ensure stable allograft function and for the prevention of immunosuppression-related medical complications. However, the use of cancer surveillance methods in this setting does not appear to guarantee the prospect of early detection time based on annual visits or problem-specific issues. Herrero and colleagues reported a retrospective review of 187 Spanish LT recipients who survived beyond 3 months after transplantation. Despite an aggressive pre- and post-lt cancer screening protocol (including upper and lower GI endoscopy, thoracic and abdominal computed tomography, magnetic resonance neuroimaging and otorhinolaryngology evaluation for smokers), 27 patients developed 28 noncutaneous malignancies (including nine PTLD and one

16 Kaposi s sarcoma). The majority of solid organ malignancies were diagnosed at advanced stages (50% of upper aerodigestive tract tumors diagnosed at stage IV, 66% of non-small cell lung cancers and 71% of abdominal and genitourinary tract tumors diagnosed at stages III IV). Multivariate analysis identified only age, and a history of smoking or history of alcohol abuse as risk factors for post- LT non-cutaneous malignancy [9]. 3.4. Colorectal neoplasia Primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD) with 60 80% of patients with PSC having concurrent IBD. Patients with IBD are at risk for developing colorectal carcinoma (CRC) and coexisting PSC may be an additional cancer risk, although this association remains controversial [34]. Studies have also examined the continued risk for CRC in patients undergoing LT for PSC in the setting of inflammatory bowel disease. Vera et al. reviewed 100 patients with PSC and IBD who underwent transplantation at a single center in the UK. Among 83 patients with intact colons after LT, five patients subsequently developed dysplasia requiring colectomy and an additional eight patients developed CRC. Among patients developing CRC, three were diagnosed with stage I disease, one with stage II disease, three with stage III disease and two patients had metastatic (stage IV) disease at diagnosis. Patients with CRC had a decreased 5-year survival compared to other LT recipients with PSC and IBD (53% vs 73%); four patients with CRC died during the study period [35]. In contrast, data from the Mayo Clinic found no survival difference among patients who developed CRC complicating LT for PSC. Among 108 patients undergoing LT for PSC with coexisting IBD in 81 patients, the cumulative risk for CRC was 4% at 5 years. While there was a higher incidence of colorectal neoplasia (dysplasia and carcinoma) among LT recipients compared to historical controls, there was no excess mortality attributed to CRC in this study [36]. Routine surveillance for neoplasia and subsequent colectomy for dysplasia may account for the low mortality from CRC in LT patients with IBD [8]. 3.5. Upper aerodigestive tract malignancies Upper aerodigestive tract malignancies, such as oral, laryngeal and esophageal carcinoma, have been reported to be more common in patients after LT. In an analysis of 1000 consecutive LT patients treated with a tacrolimus-based immunosuppressive regimen, the incidence of oropharyngeal cancer was dramatically increased compared to SEER (Surveillance Epidemiology End Result) data (standardized incidence ratio 7.6; P!0.01). Among the seven cases of oropharyngeal cancer, four patients were smokers and five patients underwent transplantation for alcoholic liver disease [10]. Among 772 Spanish patients who underwent LT, upper aerodigestive cancers were the most commonly occurring malignancy after skin cancers. A prior history of alcohol use was noted to be an independent risk factor for the development of cancer [2]. Similar findings were noted in a smaller study of LT recipients in France. All five patients who developed upper aerodigestive tract cancers had been transplanted for alcoholic liver disease and had a higher incidence of tobacco abuse [4]. 3.6. Effect of immunosuppressive therapy In general, the immunocompromised host is at risk for the development of certain malignancies. The degree of intensity with immunosuppression is commonly related to developing PTLD in susceptible hosts. With increasingly powerful immunosuppressive therapy, including a growing array of biologic agents, available studies have examined their effects on cancer incidence among LT recipients. In a study of 500 German LT recipients enrolled in various immunosuppressive protocols, there was no difference in the development of de novo malignancy noted over a median follow-up of 50 months. Thirty-three patients developed cancer including seven lymphomas. Only degree of immunosuppression as measured by a low CD4C/CD8C lymphocyte regimen and a positive T-cell crossmatch were associated with an increased relative risk of malignancy [12]. In a more recent study of 772 LT recipients, the use of azathioprine (RR 3.8, 95% CI 1.67 8.6, PZ0.004) and a history of rejection (RR 2.0, 95% CI 1 3.97, PZ0.04) were identified as independent risk factors for the development of de novo malignancies. Additionally, the authors noted a trend toward more frequent and earlier tumors among the cohort of patients transplanted during the tacrolimus era. Their conclusion was that more profound immunosuppression may further increase the risk of cancer [2]. Population-based data has identified the use of pre-lt immunosuppressive therapy for greater than 1 year in association with a significantly higher rate of de novo malignancy after LT (RR 2.93, PZ0.018). While there was only one patient who developed PTLD, approximately half of patients who were treated with immunosuppressives prior to LT subsequently developed cancer [8]. 4. Causes of death after liver transplantation While infection and surgical complications are prominent causes of mortality in the peri-operative and early posttransplantation period, malignancy has emerged as an important late cause of death in LT recipients. In a series of 4000 consecutive patients who underwent LT between February 1981 and April 1998 at the University of Pittsburgh, 219 died from recurrent or de novo malignancy (including PTLD). Ninety-one cancer-related deaths (42%)

17 Table 1 De novo cancer-related mortality among liver transplant recipients Reference Year published Country Dates included Number of LT recipients analyzed % ALD Cancer incidence a (%) Cancerrelated deaths Cancerrelated mortality rate (%) Peyregne et al. [14] 1998 France 1985 1997 251 27.5 3.2 6 2.4 Galve et al. [7] 1999 Spain 1984 1996 1827 2.9 24 1.3 Duvoux et al. [4] 1999 France 1989 1995 90 33.3 11.1 2 2.2 Jain et al. [37] 2000 USA 1981 1998 4000 14.2 7.5 219 5.5 Sheiner et al. [17] 2000 USA Through 1991 139 b 18.10 11.5 6 4.3 Haagsma et al. [8] 2001 Netherlands 1979 1996 174 c!46 6.3 6 3.4 Pruthi et al. [38] 2001 USA/Canada 1984 1997 299 d 12.37 9 3.0 (4.3%) e Catena et al. [3] 2001 Italy Through 1997 353 3.1 2 0.6 Jimenez et al [11] 2002 Spain 1986 2000 636 38.2 9.1 20 3.1 Benlloch et al. [2] 2004 Spain 1991 2001 772 24.74 5.3 21 2.7 Herrero et al. [9] 2005 Spain 1990 2001 187 36.0 14.4 15 8.0 a Excluding cutaneous malignacies. b Recipients surviving O5 years. c Recipients surviving O1 year. d Recipients surviving O3 years. e Includes deaths that occurred outside study period. occurred more than 3 years after LT. Cancer was the second most common cause of death after infection and surpassed cardiovascular disease as a cause of death among LT recipients [37]. Another single-center study of 138 patients undergoing LT prior to 1991 demonstrated that malignancy was an important cause of late and overall post-lt death. De novo or recurrent malignancy caused six of 49 (12.3%) deaths. Malignancy was the most common cause of death among those who survived more than 5 years beyond the time of LT [17]. Similar findings were noted in a group of 299 North American LT recipients who survived more than 3 years after transplantation. Among 38 deaths during the 13-year study period, nine patients died of non-lymphoid related malignancies. Other significant causes of death included cardiovascular disease (eight deaths), recurrent primary liver disease (eight deaths), and chronic allograft rejection (seven deaths) [38] (see Table 1). Will all liver transplant patients eventually die from cancer? In conclusion, the answer is no. However, available data suggests that malignancy continues to be an important cause of long-term mortality in LT recipients. In some series, malignancy accounts for more deaths than cardiovascular disease [21,37,38] despite chronic immunosuppression leading to hypertension, diabetes mellitus, and dyslipidemia. This discrepancy can be explained by the fact that LT recipients have a low baseline risk of cardiovascular death prior to surgery. Those patients with end-stage liver disease and coexisting cardiovascular disease are often ineligible for LT. In selected centers with long-term management protocols, there is no evidence to date that cancer surveillance methods lead to early detection and improved survival from malignancy in affected patients. Liver transplantation for the treatment of hepatocellular carcinoma remains a life-saving therapy for many patients. The implementation of stringent eligibility criteria has reduced mortality from recurrent HCC. Recurrence is still a problem with nearly all deaths from extrahepatic HCC. It remains to be seen whether deaths from recurrent HCC will increase in the future. Physicians caring for LT recipients should be vigilant to look for malignancy based on recommended guidelines. Secondary interventions remain important for reducing cancer risk if possible. Modifying or eliminating high-risk behaviors such as smoking, alcohol use, and excess sun exposure are critical. Certain risk factors among LT recipients may not be modifiable. A common finding among several studies has been that increasing recipient age is an independent risk factor for malignancy [8,9]. This is clinically important as organ transplantation is being performed in an increasingly older population. Additionally, with the excellent expected survival after LT, many recipients are now surviving into advanced age. Likewise, alcohol and tobacco abuse that occurred prior to transplantation has been identified as a risk factor for cancer development, particularly cancers of the upper aerodigestive tract [4,9,37]. How long this increased risk for cancer may persist despite abstinence after transplantation is unknown. References [1] Myron Kauffman H, McBride MA, Cherikh WS, Spain PC, Marks WH, Roza AM. Transplant tumor registry: donor related malignancies. Transplantation 2002;74:358 362. [2] Benlloch S, Berenguer M, Prieto M, Moreno R, San Juan F, Rayon M, et al. De novo internal neoplasms after liver transplantation: increased risk and aggressive behavior in recent years? Am J Transplant 2004;4: 596 604.

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[36] Loftus Jr EV, Aguilar HI, Sandborn WJ, Tremaine WJ, Krom RA, Zinsmeister AR, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology 1998;27:685 690. [37] Jain A, Reyes J, Kashyap R, Dodson SF, Demetris AJ, Ruppert K, et al. Long-term survival after liver transplantation in 4,000 consecutive patients at a single center. Ann Surg 2000;232:490 500. [38] Pruthi J, Medkiff KA, Esrason KT, Donovan JA, Yoshida EM, Erb SR, et al. Analysis of causes of death in liver transplant recipients who survived more than 3 years. Liver Transpl 2001;7:811 815. doi:10.1016/j.jhep.2005.10.007