Transplantation Reviews 29 (2015) 38–41
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Transplantation Reviews journal homepage: www.elsevier.com/locate/trre
Management of de novo malignancies after liver transplantation Anjana A. Pillai ⁎ Division of Digestive Diseases, Department of Medicine, Emory Transplant Center, Emory University Hospital/Emory Clinic, USA
a b s t r a c t Due to advances in medical and surgical expertise leading to significant improvements in graft and patient survival, there is an increased recognition of long term complications in survivors such as de novo malignancies, cardiovascular events and infections. Data show solid organ transplant recipients have 2–3 times the increased risk of developing a de novo malignancy compared to an age-matched and sex-matched general population and malignancy is expected to be the number one cause of mortality in long term transplant recipients in the next two decades. Risk factors include an aging transplant population, oncogenic viruses and the long term effects of immunosuppression in the development of carcinogenesis. This review summarizes common de novo malignancies occurring in the post liver transplant population and current strategies for their prevention and management. Unfortunately, due to limited evidence based data, robust screening guidelines for post transplant cancer prevention have yet to be implemented in this population. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Liver transplantation outcomes have improved dramatically with advances in immunosuppression and surgical techniques leading to excellent short term and improved long term survival. Patient and graft loss due to rejection and surgical complications have decreased tremendously and one and five year survival rates are nearing 90% and 75% respectively [1]. However, overall long term survival rates in transplant recipients have remained unchanged [2], largely due to complications such as infection, cardiovascular events and de novo malignancies [3,4]. Solid organ transplant recipients are especially at risk for the development of de novo malignancies largely in part due to the oncogenic effects of long term immunosuppression. It is well-documented that overall cancer incidence in these patients is significantly higher than the general population [5–11] and de novo cancer is the second leading cause of late term mortality after cardiovascular disease [3]. The reported incidence of de novo malignancy after liver transplantation ranges from 2.6% to 26%, depending on the individual center and length of follow-up [6,12–14]. The cumulative risk of de novo cancer after liver transplant increases from 3–5% at 1–3 years to 11–20% at ten years after transplant [13,15]. Consequently, this also translates to more aggressive tumors with inferior treatment response and a higher mortality rate in transplant recipients when compared to the general population [6,16].
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Risk factors for de novo malignancy in this population are multifactorial and include increasing age, alcohol abuse, tobacco use, oncogenic viruses and long term immunosuppression. In fact, studies in renal transplant recipients have shown a positive correlation between the length of exposure and intensity of immunosuppression with the increased incidence of cancer [17]. This is not surprising given that the ideal balance between adequate immunosuppression and increased toxicity is difficult to achieve. In addition, several immunosuppressive drugs including cyclosporine, tacrolimus and azathioprine are believed to have intrinsic oncogenic properties. Both azathioprine and cyclosporine have been implicated in increasing the risk of cutaneous neoplasia [18], and tacrolimus has been shown to increase the risk of internal neoplasia [19]. It is believed that immunosuppressive therapy impairs immune surveillance allowing for a permissive environment for malignant cells to proliferate as well as allowing for increased activity of several oncogenic viruses [20,21]. Oncoviruses act on various cellular signaling pathways, leading to immortalization and proliferation of the infected cells by disrupting the mitotic checkpoint upon infection of the host cell [21,22]. Examples of oncoviruses include human papillomaviruses (HPV) causing cervical and anogenital cancer, Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) and nasopharyngeal carcinoma, human herpes virus (HHV8) triggering Kaposi’s sarcoma, and hepatitis B and C viruses in the development of hepatocellular carcinoma (HCC). Grulich et al confirmed this relationship in a large population based study comparing cancer incidence in solid organ transplant recipients to patients with HIV/AIDS [23]. In this study, both patient populations had a similarly increased risk of malignancy indicating that immune deficiency, rather than other risk factors, was the primary trigger in the development of cancer.
A.A. Pillai / Transplantation Reviews 29 (2015) 38–41
2. Common de novo malignancies in liver transplant recipients The most common de novo malignancies in liver transplant recipients are PTLD, non-melanoma skin cancer, and upper aerodigestive tract and lung cancers [6]. The incidence of PTLD ranges from 2–4% [24,25] in adults and up to 15% in the pediatric population [26]. Solid organ malignancies, unlike PTLD, tend to occur after the first posttransplant year, develop with increasing recipient age and do not tend to affect children. In addition, increased age, history of tobacco use and alcoholic liver disease were associated with an increased risk of developing solid organ malignancies in this population [13]. In a prospective, observational study by Watt et al, 798 liver transplant recipients from the National Institute of Diabetes and Digestive and Kidney disease (NIDDK) database were followed long-term and 12% developed non-cutaneous solid organ malignancies [13]. In addition, patients with primary sclerosing cholangitis (PSC) and alcoholic liver disease were at the highest risk of developing a non-cutaneous malignancy, at 22% and 18% at 10 years, respectively [13]. Similarly, analyzing a UK transplant database, Collett et al demonstrated that the incidence of de novo cancer in solid organ recipients was twice that of the general population, with the incidence of non-melanoma skin cancer being 13 times greater [8]. This study also showed a significant increase in the rates of oral cancer, PTLD, colorectal cancer (CRC), anal cancer and kidney cancer when compared to the general population. 2.1. PTLD Post-transplant lymphoproliferative disorder refers to uncontrolled lymphoproliferation which occurs as a result of iatrogenic immunosuppression in solid organ transplantation. The incidence of PTLD is greatest during the first 12–18 months post transplant and tends to occur earlier in children than adults [24]. EBV is known to play a strong role although the exact pathogenesis is unclear. The vast majority of PTLD cases are related to infection of B lymphocytes with EBV resulting in unrestricted B-cell proliferation. This occurs in the absence of T-cell control secondary to immunosuppression-induced inhibition of EBV-specific cytotoxic T-lymphocytes [27]. The risk factors for PTLD include EBV seronegativity, increased doses of immunosuppression (especially with antilymphocyte antibodies), type of organ transplanted and younger age [24,25,27,28]. PTLD rates are over 70-fold higher in EBV seronegative recipients [28]. PTLD can also occur in the absence of EBV but tends to occur later and is believed to carry a worse prognosis. Clinical manifestations include lymphadenopathy, cytopenias, fevers and abnormalities of the gastrointestinal tract, lungs, spleen and central nervous system [29]. Overall survival rates for liver transplant recipients with PTLD have ranged from 56–85% at 1 year to 41–69% at 5 years with early identification and appropriate treatment [24,25]. A high index of clinical suspicion is needed and tissue is essential for accurate diagnosis. Once the diagnosis of PTLD is established, appropriate staging may include body computed tomography (CT), echocardiogram, bone marrow biopsy and positron emission tomography (PET) scan. The role of monitoring EBV viremia for early diagnosis has not yet proven to be effective [30] and in one study only 50% of patients with elevated EBV viremia on routine screening developed overt PTLD [31]. Therefore, EBV viral levels are not recommended to be used as a screening tool for early detection of PTLD. Treatment for PTLD requires a multidisciplinary approach between the transplant team and hematologists/oncologists. Reduction of immunosuppression is key; however, there is always a significant risk of acute cellular rejection and thus patients have to be monitored very closely. It is believed that a 25–60% reduction in immunosuppression dosing can be quite effective and can cause up to a 90% response rate within 2–4 weeks in patients with favorable prognostic factors [32,33]. In fact, up to 45–70% of patients reportedly respond to reduction in immunosuppression alone [32,33]. Other treatment options such as Rituximab (monoclonal antibody to CD20), conventional chemotherapy, radiation
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and surgical resection are available when reduction of immunosuppression alone is insufficient to induce remission. There is limited role for the use of antiviral therapy in the treatment of PTLD. Knight et al examined 78 patients diagnosed with PTLD at a single center over four decades and determined that two thirds of patients had a complete response when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone–like chemotherapy (either with or without rituximab). The median overall survival was 8 years proving that with adequate treatment, survival was similar to that of the general surveillance, epidemiology, and end results (SEER) population sample [28]. 2.2. Cutaneous neoplasia Cutaneous neoplasia, specifically non-melanomatous skin cancers such as squamous cell (SCC) and basal cell carcinomas (BCC) are the most common de novo malignancies seen in transplant recipients [6]. In a recent study by Herrero et al the 5 and 10 actuarial rates of cutaneous neoplasia in liver transplant recipients were reported to be 14% and 22%, respectively with an overall relative risk of 16.91 (95% confidence interval: 11.78–23.51) when compared to the general population [6]. Additionally, a study by Mithoefer et al indicated that the overall incidence of cutaneous malignancy was 22.5% in liver transplant recipients with SCC being the most commonly seen neoplasm [34]. Although there is an increased rate of morbidity in this population, overall mortality was not affected [6]. Risk factors for skin cancer include increasing age, life time sun exposure, skin type, previous history of neoplasia and immunosuppression regimen [6,13,34]. In liver transplant recipients, data have been variable in regard to the risk of the specific immunosuppression regimen to the development of skin cancer. In a study by Frezza et al there was a significantly lower incidence of skin cancer in tacrolimustreated patients [35], whereas two other studies by Jonas et al [36] and Jain et al [37] did not find any difference between the tacrolimustreated group and the cyclosporine-treated group. More than likely, the risk of skin cancer is related to the cumulative immunosuppressive load rather than the specific medication. All transplant recipients are encouraged to avoid direct sun exposure especially during peak ultraviolet radiation hours and to use adequate sun protection, specifically in regard to sun protective attire (widebrimmed hats, long sleeved tee shirts, long pants and sunglasses). We also recommend judicious use of sunscreen (with a sun protection factor of at least 15 including in lip balms) especially in sun-exposed areas such as behind the ears in men. Patients are also encouraged to perform self skin exams as well as undergo annual dermatological examinations. We recommend that our patients see a transplant dermatologist with an expertise in Moh’s surgery. There should be a low index of suspicion for biopsying or removing any abnormal findings and any positive findings should be monitored closely given that SCC in an immunocompromised host has a greater tendency to recur and metastasize [38,39]. 2.3. Upper aerodigestive tract and lung cancer A cohort study using the Scientific Registry of Transplant Recipients (SRTR) from 1987 to 2008 confirmed that liver transplant recipients had a standardized incidence ratio (SIR) for post transplant lung cancer of 1.95 [5]. Patients with alcoholic liver disease have a higher incidence of esophageal and head and neck cancer [40]. In fact, patients with alcoholic liver disease have an almost two-fold higher risk of non-cutaneous cancer compared to patients transplanted for other etiologies of liver disease with the exception of patients with PSC [13]. This is especially accelerated in patients with a history of smoking and alcohol abuse. In fact, a cumulative life time history of smoking is associated with an increased risk of esophageal, head and neck and lung cancer in solid organ transplant recipients [6]. Patients with a smoking history of greater than 20 pack-years and who continue to smoke after transplant had a hazard ratio of 20 for developing smoking-related malignancies [6]. In
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A.A. Pillai / Transplantation Reviews 29 (2015) 38–41
contrast, non-smokers and inactive former smokers had a statistically significant decreased risk. All patients should be counseled on tobacco cessation at each clinic visit and strongly encouraged to remain abstinent from alcohol use. In addition, annual ear, nose, throat (ENT) examinations and annual chest x-rays should be considered in patients with a history of long standing tobacco and alcohol abuse. Although data on preventive screening are limited, patients found to have malignancy during routine screening may have more treatment options and better treatment response than those patients who present symptomatically. 2.4. Colorectal cancer Colorectal cancer is believed to be increased in patients undergoing liver transplantation and this is largely due to the association of PSC and inflammatory bowel disease (IBD), mainly ulcerative colitis (UC) [13,41]. In a recent study by Hanouneh et al, 43 patients with PSC and IBD who underwent liver transplantation were compared to two age and sex matched groups; the first group had PSC and IBD and did not undergo liver transplantation and the second had chronic liver disease other than PSC necessitating liver transplantation [42]. Liver transplant recipients with PSC and IBD had similar rate of CRC as those PSC/IBD patients who did not undergo liver transplantation. However, when compared with patients with other chronic liver disease who underwent liver transplantation, there was a statistically significant risk of colonic neoplasia in the PSC/IBD group (34% vs. 0%) [42]. This study confirms that patients with PSC and IBD should undergo careful monitoring with annual colonoscopies regardless of transplant status. However, the risk of CRC in the non-IBD post liver transplant population is less clear. A case-control study from the US reported a higher prevalence of adenomatous polyps in liver transplant recipients but not an increased risk of CRC when compared to healthy controls undergoing colonoscopy [43]. Similarly, an English study did not show an increased risk of CRC in non-PSC post-transplant patients when compared to an age and sex-matched population and thus concluded that these patients did not need a more intensified surveillance [44]. A third study showed that patients with colon polyps on pre-liver transplant screening are at a higher risk of post-transplant polyps; but overall CRC risk again was not increased in the post liver transplant population [45]. The same study also showed that patients with alcoholic liver disease had a significantly higher rate of adenoma formation than those with other causes of chronic liver disease (50.0% vs. 11.1%) [45]. Finally, a recent meta-analysis examined the risk of colorectal cancer in liver transplant recipients compared to the general population [46] and found that the relative risk was 2.59 for developing CRC for the overall post-transplant patient and 1.8 once PSC patients were excluded. Although there is limited evidence to recommend strict screening guidelines in this cohort, given the small but increased risk for CRC in this population, a five year surveillance interval for colonoscopies can be considered in all post transplant recipients. This protocol should exclude patients with a family or personal history of colorectal cancer or high risk polyps. In the latter individuals, time interval for surveillance colonoscopy should be based on CRC guidelines for high risk groups as recommended by the American College of Gastroenterology. All patients with a diagnosis of PSC and IBD should continue annual surveillance colonoscopies after liver transplant. Further prospective studies are needed before robust guidelines can be made for this population. 2.5. Genitourinary cancer Transplant recipients have an increased risk of anogenital cancers with HPV being the main culprit. The majority of data on genitourinary cancer in transplant recipients stem from the renal transplant experience. Lower genital tract intraepithelial lesions are increased as early as six months post transplantation in female liver and kidney recipients despite negative testing for HPV pre-transplant [47]. HPV has been
found in up to 62% of female renal transplant recipients [48]. HPVpositive women undergoing renal transplantation have a 14-fold increased risk of cervical cancer, 50-fold increased risk of vulvar cancer and 100-fold increased risk of anal cancer [49]. Although limited data exist in the prevention of this cancer in liver transplant recipients, annual Papanicolau smear (for women) and anogenital examination (for women and high risk men) are recommended. 3. Surveillance strategies and management Because of the aggressive nature of post-transplant malignancies, surveillance programs are vital to lowering the risk of death. However, there is very little evidence based data on prevention and screening of malignancy after liver transplantation. A recent Austrian study examined the utility of an extensive surveillance protocol in improving early diagnosis and survival in liver transplant recipients [15]. This retrospective study examined 779 transplant recipients and noted a statistically significant improvement in cancer detection rate from 4.9% to 13% as well as improvement in non-cutaneous skin cancer survival from 1.2 to 3.3 years with an intensified surveillance method. Of note, surveillance in this population included annual chest and abdominal CT scans as well as colonoscopy every 5 years in all transplant recipients. However, this approach may not be cost-effective or practical to apply to all transplant recipients. Minimization or modification of immunosuppression is likely a key component of cancer prevention as the effect of immunosuppression on carcinogenesis appears to be dose related; however, balancing the risk of rejection with the benefits of cancer prevention needs to be weighed carefully. Both sirolimus and everolimus, inhibitors of mammalian target of rapamycin (mTOR), have potential antiproliferative properties and are believed to suppress tumor growth. However, the literature on their antitumor effects is mixed. Few studies in kidney transplant recipients confirm a decreased frequency of cutaneous malignancies in patients receiving rapamycin versus calcineurin inhibitors [50] while others demonstrate no difference [51]. In addition, their effect on preventing other malignancies has also been variable with some studies illustrating a decrease in malignancies in patients converting from calcineurin inhibitors to mTOR inhibitors [52,53] while others do not [54]. Although data are limited, screening protocols are recommended for the early detection of post transplant malignancies with the goal to improve survival. All liver transplant patients should be counseled on tobacco cessation, alcohol abstinence and sun avoidance as well as the use of adequate sun protection. Annual dermatological exams, pap smears and anogenital exams are encouraged. In patients with PSC and IBD, annual colonoscopies should be mandated; all others should be considered for five year screening intervals. In patients with long-standing alcohol and tobacco use pre-transplant, annual ENT exams and chest x-rays should be considered. Neither prostate cancer nor breast cancer appears to be increased in liver transplant recipients when compared to the general population [3] and thus testing should be in accordance with recommended guidelines for the general population. 4. Conclusion De novo malignancies are a leading cause of long-term morbidity and mortality in liver transplant recipients. Risk factors are multifactorial and include long-term immunosuppression, advanced age, extensive tobacco use, alcoholic liver disease, EBV seronegativity, ulcerative colitis and excessive sun exposure. Although the exact role immunosuppression plays in the development of carcinogenesis is not completely understood, it is believed to be dose related and thus minimization of immunosuppression to the lowest tolerable level is encouraged. The role of mTOR inhibitors in decreasing cancer risk in this population needs to be studied further. Surveillance protocols are key to cancer prevention, however there is limited evidence to support
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that such protocols improve survival in liver transplant recipients and further prospective studies are needed to address this very important subject matter. Conflict of interest The author does not have any conflict of interest in relation to the subject matter or materials discussed in this article. References [1] Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant 2010;10:1420–7. [2] Lodhi SA, Lamb KE, Meier-Kriesche HU. Solid organ allograft survival improvement in the US: the long-term does not mirror the dramatic short-term success. Am J Transplant 2011;11:1226–35. [3] Fung JJ, Jain A, Kwak EJ, Kusne S, Dvorchik I, Eghtesad B. De novo malignancies after liver transplantation: a major cause of late death. Liver Transpl 2001;7:S109–18. [4] Pruthi J, Medkiff KA, Esrason KT, et al. Analysis of causes of death in liver transplant recipients who survived more than 3 years. Liver Transpl 2001;7:811–5. [5] Engles EA, Pfeiffer RM, Fraumeni JF, et al. Spectrum of cancer risk among U.S. solid organ transplant recipients. JAMA 2011;306:1891–901. [6] Herrero JL, Lorenzo M, Quiroga J, et al. De novo neoplasia after liver transplantation: an analysis of risk factors and influence on survival. Liver Transpl 2005;11:89–97. [7] Aberg F, Pukkala E, Hockerstedt K, Sankila R, Isoniemi H. Risk of malignant neoplasms after liver transplantation: a population based study. Liver Transpl 2008;14:1428–36. [8] Collett D, Mumford L, Banner NR, Neuberger J, Watson C. Comparison of the incidence of malignancy in recipients of different types of organ: a UK registry audit. Am J Transplant 2010;10:1889–96. [9] Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation 2005;80:S254–64. [10] Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl 2008;14:1428–36. [11] Adami J, Gabel H, Lindelof B, et al. Cancer riks following organ transplantation: a nationwide cohort study in Sweden. Br J Cancer 2003;89:1221–7. [12] Saigal S, Norris S, Muiesan P, Rela M, Heaton N, O’Grady J. Evidence of differential risk for post-transplantation malignancy based on pre-transplantation cause in patients undergoing liver transplantation. Liver Transpl 2002;8:842–7. [13] Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Sanchez W, Gores GJ. Long term probability of and mortality from de novo malignancy after liver transplantation. Gastroenterology 2009;137:2010–7. [14] Xiol X, Guardiola J, Menendez S, et al. Risk factors for development of de novo neoplasia after liver transplantation. Liver Transpl 2001;7:971–5. [15] Finkenstedt A, Graziadei IW, Oberaigner W, et al. Extensive surveillance promotes early diagnosis and improved survival of de novo malignancies in liver transplant recipients. Am J Transplant 2009;9:2355–61. [16] Haagsma EB, Hagens VE, Schaapveld M, et al. Increased cancer risk after liver transplantation: a population-based study. J Hepatol 2001;34:84–91. [17] Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomized comparison of two cyclosporin regimens. Lancet 1998;351:623–8. [18] Euvrard S, Kanitakis J. Skin cancers after liver transplantation: what to do? J Hepatol 2006;44:27–32. [19] Benlloch S, Berenguer M, Prieto 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. [20] Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004;21:137–48. [21] Butel JS. Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis 2000;21:405–26. [22] Campistol J, Cuervas-Mons V, Manito N, et al. New concepts and best practices for management of pre- and post-transplantation cancer. Transplant Rev 2012;26: 261–79. [23] Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007;370:59–67. [24] Kremers WK, Devarbhavi HC, Wiesner RH. Post-transplant lymphoproliferative disorders following liver transplantation: incidence, risk factors and survival. Am J Transplant 2006;6:1017–24. [25] Jain A, Nalesnik M, Reyes J, et al. Posttransplant lymphoproliferative disorders in liver transplantation: a 20 year experience. Ann Surg 2002;236:429–36.
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[26] Smets F, Sokal EM. Epstein-Barr virus-related lymphoproliferation in children after liver transplant: role of immunity, diagnosis and management. Pediatr Transplant 2002;6:280–7. [27] Shroff R, Rees L. The post-transplant lymphoproliferative disorder — a literature review. Pediatr Nephrol 2004;19:369–77. [28] Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW. Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center. J Clin Oncol 2009;27:3354–62. [29] Lucey M, Terrault N, Ojo L, et al. Long-Term Management of the Successful Adult Liver Transplant: 2012 Practice Guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl 2013;19:3–26. [30] Yang J, Tao Q, Flinn IW, et al. Characterization of EBV-infected B cells in patients with post-transplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response. Blood 2000;96:4055–63. [31] Wagner HJ, Cheng YC, Huls MH, et al. Prompt versus preemptive intervention for EBV lymphoproliferative disease. Blood 2004;103:3979–81. [32] Reshef R, Vardhanabhuti S, Luskin MR, et al. Reduction of immunosuppresion as initial therapy for PTLD. Am J Transplant 2011;11:336–47. [33] Tsai DE, Hardy CL, Tomaszewski JE, et al. Reduction in immunosuppression as initial therapy for PTLD: analysis of prognostic variables and long-term follow-up of 42 adult patients. Transplantation 2001;71:1076–88. [34] Mithoefer AB, Supran S, Freeman RB. Risk factors associated with the development of skin cancer after liver transplantation. Liver Transpl 2002;8:939–44. [35] Frezza EE, Fung JJ, vanT hiel DH. Non-lymphoid cancer after liver transplantation. Hepatogastroenterology 1997;44:1172–81. 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Transplantation Reviews journal homepage: www.elsevier.com/locate/trre
Management of de novo malignancies after liver transplantation Anjana A. Pillai ⁎ Division of Digestive Diseases, Department of Medicine, Emory Transplant Center, Emory University Hospital/Emory Clinic, USA
a b s t r a c t Due to advances in medical and surgical expertise leading to significant improvements in graft and patient survival, there is an increased recognition of long term complications in survivors such as de novo malignancies, cardiovascular events and infections. Data show solid organ transplant recipients have 2–3 times the increased risk of developing a de novo malignancy compared to an age-matched and sex-matched general population and malignancy is expected to be the number one cause of mortality in long term transplant recipients in the next two decades. Risk factors include an aging transplant population, oncogenic viruses and the long term effects of immunosuppression in the development of carcinogenesis. This review summarizes common de novo malignancies occurring in the post liver transplant population and current strategies for their prevention and management. Unfortunately, due to limited evidence based data, robust screening guidelines for post transplant cancer prevention have yet to be implemented in this population. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Liver transplantation outcomes have improved dramatically with advances in immunosuppression and surgical techniques leading to excellent short term and improved long term survival. Patient and graft loss due to rejection and surgical complications have decreased tremendously and one and five year survival rates are nearing 90% and 75% respectively [1]. However, overall long term survival rates in transplant recipients have remained unchanged [2], largely due to complications such as infection, cardiovascular events and de novo malignancies [3,4]. Solid organ transplant recipients are especially at risk for the development of de novo malignancies largely in part due to the oncogenic effects of long term immunosuppression. It is well-documented that overall cancer incidence in these patients is significantly higher than the general population [5–11] and de novo cancer is the second leading cause of late term mortality after cardiovascular disease [3]. The reported incidence of de novo malignancy after liver transplantation ranges from 2.6% to 26%, depending on the individual center and length of follow-up [6,12–14]. The cumulative risk of de novo cancer after liver transplant increases from 3–5% at 1–3 years to 11–20% at ten years after transplant [13,15]. Consequently, this also translates to more aggressive tumors with inferior treatment response and a higher mortality rate in transplant recipients when compared to the general population [6,16].
⁎ 1365 Clifton Rd NE, Ste B1600, Emory University Hospital, Atlanta, GA 30322, USA. Tel.: +1 786 218 0107; fax: +1 404 778 2350. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.trre.2014.11.002 0955-470X/© 2014 Elsevier Inc. All rights reserved.
Risk factors for de novo malignancy in this population are multifactorial and include increasing age, alcohol abuse, tobacco use, oncogenic viruses and long term immunosuppression. In fact, studies in renal transplant recipients have shown a positive correlation between the length of exposure and intensity of immunosuppression with the increased incidence of cancer [17]. This is not surprising given that the ideal balance between adequate immunosuppression and increased toxicity is difficult to achieve. In addition, several immunosuppressive drugs including cyclosporine, tacrolimus and azathioprine are believed to have intrinsic oncogenic properties. Both azathioprine and cyclosporine have been implicated in increasing the risk of cutaneous neoplasia [18], and tacrolimus has been shown to increase the risk of internal neoplasia [19]. It is believed that immunosuppressive therapy impairs immune surveillance allowing for a permissive environment for malignant cells to proliferate as well as allowing for increased activity of several oncogenic viruses [20,21]. Oncoviruses act on various cellular signaling pathways, leading to immortalization and proliferation of the infected cells by disrupting the mitotic checkpoint upon infection of the host cell [21,22]. Examples of oncoviruses include human papillomaviruses (HPV) causing cervical and anogenital cancer, Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) and nasopharyngeal carcinoma, human herpes virus (HHV8) triggering Kaposi’s sarcoma, and hepatitis B and C viruses in the development of hepatocellular carcinoma (HCC). Grulich et al confirmed this relationship in a large population based study comparing cancer incidence in solid organ transplant recipients to patients with HIV/AIDS [23]. In this study, both patient populations had a similarly increased risk of malignancy indicating that immune deficiency, rather than other risk factors, was the primary trigger in the development of cancer.
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2. Common de novo malignancies in liver transplant recipients The most common de novo malignancies in liver transplant recipients are PTLD, non-melanoma skin cancer, and upper aerodigestive tract and lung cancers [6]. The incidence of PTLD ranges from 2–4% [24,25] in adults and up to 15% in the pediatric population [26]. Solid organ malignancies, unlike PTLD, tend to occur after the first posttransplant year, develop with increasing recipient age and do not tend to affect children. In addition, increased age, history of tobacco use and alcoholic liver disease were associated with an increased risk of developing solid organ malignancies in this population [13]. In a prospective, observational study by Watt et al, 798 liver transplant recipients from the National Institute of Diabetes and Digestive and Kidney disease (NIDDK) database were followed long-term and 12% developed non-cutaneous solid organ malignancies [13]. In addition, patients with primary sclerosing cholangitis (PSC) and alcoholic liver disease were at the highest risk of developing a non-cutaneous malignancy, at 22% and 18% at 10 years, respectively [13]. Similarly, analyzing a UK transplant database, Collett et al demonstrated that the incidence of de novo cancer in solid organ recipients was twice that of the general population, with the incidence of non-melanoma skin cancer being 13 times greater [8]. This study also showed a significant increase in the rates of oral cancer, PTLD, colorectal cancer (CRC), anal cancer and kidney cancer when compared to the general population. 2.1. PTLD Post-transplant lymphoproliferative disorder refers to uncontrolled lymphoproliferation which occurs as a result of iatrogenic immunosuppression in solid organ transplantation. The incidence of PTLD is greatest during the first 12–18 months post transplant and tends to occur earlier in children than adults [24]. EBV is known to play a strong role although the exact pathogenesis is unclear. The vast majority of PTLD cases are related to infection of B lymphocytes with EBV resulting in unrestricted B-cell proliferation. This occurs in the absence of T-cell control secondary to immunosuppression-induced inhibition of EBV-specific cytotoxic T-lymphocytes [27]. The risk factors for PTLD include EBV seronegativity, increased doses of immunosuppression (especially with antilymphocyte antibodies), type of organ transplanted and younger age [24,25,27,28]. PTLD rates are over 70-fold higher in EBV seronegative recipients [28]. PTLD can also occur in the absence of EBV but tends to occur later and is believed to carry a worse prognosis. Clinical manifestations include lymphadenopathy, cytopenias, fevers and abnormalities of the gastrointestinal tract, lungs, spleen and central nervous system [29]. Overall survival rates for liver transplant recipients with PTLD have ranged from 56–85% at 1 year to 41–69% at 5 years with early identification and appropriate treatment [24,25]. A high index of clinical suspicion is needed and tissue is essential for accurate diagnosis. Once the diagnosis of PTLD is established, appropriate staging may include body computed tomography (CT), echocardiogram, bone marrow biopsy and positron emission tomography (PET) scan. The role of monitoring EBV viremia for early diagnosis has not yet proven to be effective [30] and in one study only 50% of patients with elevated EBV viremia on routine screening developed overt PTLD [31]. Therefore, EBV viral levels are not recommended to be used as a screening tool for early detection of PTLD. Treatment for PTLD requires a multidisciplinary approach between the transplant team and hematologists/oncologists. Reduction of immunosuppression is key; however, there is always a significant risk of acute cellular rejection and thus patients have to be monitored very closely. It is believed that a 25–60% reduction in immunosuppression dosing can be quite effective and can cause up to a 90% response rate within 2–4 weeks in patients with favorable prognostic factors [32,33]. In fact, up to 45–70% of patients reportedly respond to reduction in immunosuppression alone [32,33]. Other treatment options such as Rituximab (monoclonal antibody to CD20), conventional chemotherapy, radiation
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and surgical resection are available when reduction of immunosuppression alone is insufficient to induce remission. There is limited role for the use of antiviral therapy in the treatment of PTLD. Knight et al examined 78 patients diagnosed with PTLD at a single center over four decades and determined that two thirds of patients had a complete response when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone–like chemotherapy (either with or without rituximab). The median overall survival was 8 years proving that with adequate treatment, survival was similar to that of the general surveillance, epidemiology, and end results (SEER) population sample [28]. 2.2. Cutaneous neoplasia Cutaneous neoplasia, specifically non-melanomatous skin cancers such as squamous cell (SCC) and basal cell carcinomas (BCC) are the most common de novo malignancies seen in transplant recipients [6]. In a recent study by Herrero et al the 5 and 10 actuarial rates of cutaneous neoplasia in liver transplant recipients were reported to be 14% and 22%, respectively with an overall relative risk of 16.91 (95% confidence interval: 11.78–23.51) when compared to the general population [6]. Additionally, a study by Mithoefer et al indicated that the overall incidence of cutaneous malignancy was 22.5% in liver transplant recipients with SCC being the most commonly seen neoplasm [34]. Although there is an increased rate of morbidity in this population, overall mortality was not affected [6]. Risk factors for skin cancer include increasing age, life time sun exposure, skin type, previous history of neoplasia and immunosuppression regimen [6,13,34]. In liver transplant recipients, data have been variable in regard to the risk of the specific immunosuppression regimen to the development of skin cancer. In a study by Frezza et al there was a significantly lower incidence of skin cancer in tacrolimustreated patients [35], whereas two other studies by Jonas et al [36] and Jain et al [37] did not find any difference between the tacrolimustreated group and the cyclosporine-treated group. More than likely, the risk of skin cancer is related to the cumulative immunosuppressive load rather than the specific medication. All transplant recipients are encouraged to avoid direct sun exposure especially during peak ultraviolet radiation hours and to use adequate sun protection, specifically in regard to sun protective attire (widebrimmed hats, long sleeved tee shirts, long pants and sunglasses). We also recommend judicious use of sunscreen (with a sun protection factor of at least 15 including in lip balms) especially in sun-exposed areas such as behind the ears in men. Patients are also encouraged to perform self skin exams as well as undergo annual dermatological examinations. We recommend that our patients see a transplant dermatologist with an expertise in Moh’s surgery. There should be a low index of suspicion for biopsying or removing any abnormal findings and any positive findings should be monitored closely given that SCC in an immunocompromised host has a greater tendency to recur and metastasize [38,39]. 2.3. Upper aerodigestive tract and lung cancer A cohort study using the Scientific Registry of Transplant Recipients (SRTR) from 1987 to 2008 confirmed that liver transplant recipients had a standardized incidence ratio (SIR) for post transplant lung cancer of 1.95 [5]. Patients with alcoholic liver disease have a higher incidence of esophageal and head and neck cancer [40]. In fact, patients with alcoholic liver disease have an almost two-fold higher risk of non-cutaneous cancer compared to patients transplanted for other etiologies of liver disease with the exception of patients with PSC [13]. This is especially accelerated in patients with a history of smoking and alcohol abuse. In fact, a cumulative life time history of smoking is associated with an increased risk of esophageal, head and neck and lung cancer in solid organ transplant recipients [6]. Patients with a smoking history of greater than 20 pack-years and who continue to smoke after transplant had a hazard ratio of 20 for developing smoking-related malignancies [6]. In
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contrast, non-smokers and inactive former smokers had a statistically significant decreased risk. All patients should be counseled on tobacco cessation at each clinic visit and strongly encouraged to remain abstinent from alcohol use. In addition, annual ear, nose, throat (ENT) examinations and annual chest x-rays should be considered in patients with a history of long standing tobacco and alcohol abuse. Although data on preventive screening are limited, patients found to have malignancy during routine screening may have more treatment options and better treatment response than those patients who present symptomatically. 2.4. Colorectal cancer Colorectal cancer is believed to be increased in patients undergoing liver transplantation and this is largely due to the association of PSC and inflammatory bowel disease (IBD), mainly ulcerative colitis (UC) [13,41]. In a recent study by Hanouneh et al, 43 patients with PSC and IBD who underwent liver transplantation were compared to two age and sex matched groups; the first group had PSC and IBD and did not undergo liver transplantation and the second had chronic liver disease other than PSC necessitating liver transplantation [42]. Liver transplant recipients with PSC and IBD had similar rate of CRC as those PSC/IBD patients who did not undergo liver transplantation. However, when compared with patients with other chronic liver disease who underwent liver transplantation, there was a statistically significant risk of colonic neoplasia in the PSC/IBD group (34% vs. 0%) [42]. This study confirms that patients with PSC and IBD should undergo careful monitoring with annual colonoscopies regardless of transplant status. However, the risk of CRC in the non-IBD post liver transplant population is less clear. A case-control study from the US reported a higher prevalence of adenomatous polyps in liver transplant recipients but not an increased risk of CRC when compared to healthy controls undergoing colonoscopy [43]. Similarly, an English study did not show an increased risk of CRC in non-PSC post-transplant patients when compared to an age and sex-matched population and thus concluded that these patients did not need a more intensified surveillance [44]. A third study showed that patients with colon polyps on pre-liver transplant screening are at a higher risk of post-transplant polyps; but overall CRC risk again was not increased in the post liver transplant population [45]. The same study also showed that patients with alcoholic liver disease had a significantly higher rate of adenoma formation than those with other causes of chronic liver disease (50.0% vs. 11.1%) [45]. Finally, a recent meta-analysis examined the risk of colorectal cancer in liver transplant recipients compared to the general population [46] and found that the relative risk was 2.59 for developing CRC for the overall post-transplant patient and 1.8 once PSC patients were excluded. Although there is limited evidence to recommend strict screening guidelines in this cohort, given the small but increased risk for CRC in this population, a five year surveillance interval for colonoscopies can be considered in all post transplant recipients. This protocol should exclude patients with a family or personal history of colorectal cancer or high risk polyps. In the latter individuals, time interval for surveillance colonoscopy should be based on CRC guidelines for high risk groups as recommended by the American College of Gastroenterology. All patients with a diagnosis of PSC and IBD should continue annual surveillance colonoscopies after liver transplant. Further prospective studies are needed before robust guidelines can be made for this population. 2.5. Genitourinary cancer Transplant recipients have an increased risk of anogenital cancers with HPV being the main culprit. The majority of data on genitourinary cancer in transplant recipients stem from the renal transplant experience. Lower genital tract intraepithelial lesions are increased as early as six months post transplantation in female liver and kidney recipients despite negative testing for HPV pre-transplant [47]. HPV has been
found in up to 62% of female renal transplant recipients [48]. HPVpositive women undergoing renal transplantation have a 14-fold increased risk of cervical cancer, 50-fold increased risk of vulvar cancer and 100-fold increased risk of anal cancer [49]. Although limited data exist in the prevention of this cancer in liver transplant recipients, annual Papanicolau smear (for women) and anogenital examination (for women and high risk men) are recommended. 3. Surveillance strategies and management Because of the aggressive nature of post-transplant malignancies, surveillance programs are vital to lowering the risk of death. However, there is very little evidence based data on prevention and screening of malignancy after liver transplantation. A recent Austrian study examined the utility of an extensive surveillance protocol in improving early diagnosis and survival in liver transplant recipients [15]. This retrospective study examined 779 transplant recipients and noted a statistically significant improvement in cancer detection rate from 4.9% to 13% as well as improvement in non-cutaneous skin cancer survival from 1.2 to 3.3 years with an intensified surveillance method. Of note, surveillance in this population included annual chest and abdominal CT scans as well as colonoscopy every 5 years in all transplant recipients. However, this approach may not be cost-effective or practical to apply to all transplant recipients. Minimization or modification of immunosuppression is likely a key component of cancer prevention as the effect of immunosuppression on carcinogenesis appears to be dose related; however, balancing the risk of rejection with the benefits of cancer prevention needs to be weighed carefully. Both sirolimus and everolimus, inhibitors of mammalian target of rapamycin (mTOR), have potential antiproliferative properties and are believed to suppress tumor growth. However, the literature on their antitumor effects is mixed. Few studies in kidney transplant recipients confirm a decreased frequency of cutaneous malignancies in patients receiving rapamycin versus calcineurin inhibitors [50] while others demonstrate no difference [51]. In addition, their effect on preventing other malignancies has also been variable with some studies illustrating a decrease in malignancies in patients converting from calcineurin inhibitors to mTOR inhibitors [52,53] while others do not [54]. Although data are limited, screening protocols are recommended for the early detection of post transplant malignancies with the goal to improve survival. All liver transplant patients should be counseled on tobacco cessation, alcohol abstinence and sun avoidance as well as the use of adequate sun protection. Annual dermatological exams, pap smears and anogenital exams are encouraged. In patients with PSC and IBD, annual colonoscopies should be mandated; all others should be considered for five year screening intervals. In patients with long-standing alcohol and tobacco use pre-transplant, annual ENT exams and chest x-rays should be considered. Neither prostate cancer nor breast cancer appears to be increased in liver transplant recipients when compared to the general population [3] and thus testing should be in accordance with recommended guidelines for the general population. 4. Conclusion De novo malignancies are a leading cause of long-term morbidity and mortality in liver transplant recipients. Risk factors are multifactorial and include long-term immunosuppression, advanced age, extensive tobacco use, alcoholic liver disease, EBV seronegativity, ulcerative colitis and excessive sun exposure. Although the exact role immunosuppression plays in the development of carcinogenesis is not completely understood, it is believed to be dose related and thus minimization of immunosuppression to the lowest tolerable level is encouraged. The role of mTOR inhibitors in decreasing cancer risk in this population needs to be studied further. Surveillance protocols are key to cancer prevention, however there is limited evidence to support
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