Malignancy in pediatric transplant recipients

Malignancy in pediatric transplant recipients

Seminars in Pediatric Surgery (2006) 15, 179-187 Malignancy in pediatric transplant recipients Joseph F. Buell, MD,a Thomas G. Gross, MD, PhD,b Mark ...

211KB Sizes 1 Downloads 147 Views

Seminars in Pediatric Surgery (2006) 15, 179-187

Malignancy in pediatric transplant recipients Joseph F. Buell, MD,a Thomas G. Gross, MD, PhD,b Mark J. Thomas, MD,a Guy Neff, MD,a Chandar Muthiah,a Rita Alloway, PharmD,a Frederick C. Ryckman, MD,c Gregory M. Tiao, MD,a E. Steve Woodle, MDa From aThe Israel Penn International Transplant Tumor Registry, Division of Transplantation, University of Cincinnati, Cincinnati, Ohio; b Division of Pediatric Hematology Oncology, Columbus Children’s Hospital, Columbus, Ohio and the c Division of Pediatric Surgery, Cincinnati’s Children’s Hospital, Cincinnati, Ohio. INDEX WORDS Pediatric solid organ transplantation; Chronic immunosuppression; Malignancy in transplant recipients; Lymphoproliferative disorder; Epstein–Barr virus; Viral inducement

Malignancy is a well defined complication of chronic immunosuppression. Post transplant malignancies appear to be related to cumulative doses of immunosuppression, and in pediatric patients, acute infection of previously naive patients. The most commonly encountered malignancy in this age population is Post Transplant Lymphoproliferative Disorder (PTLD). PTLD is not a single entity but rather represents a continuum of disease. Treatment of PTLD should be initiated with immunosuppression reduction. Standard dose chemotherapy leads to significant morbidity. With the introduction of anti-CD20 antibody treatment with rituximab, chemotherapy has become second line therapy. The occurrence of solid malignancy appears to be associated with chronic immunosuppression. These cancers include those of skin, gynecologic organs, and the rectum, all of which appear to have the strongest association with viral mediators. Several strategies have been postulated to minimize the occurrence of malignancy. These include ganciclovir prophylaxis for the prevention of PTLD and the use of mychophenolic acid and TOR inhibitor maintenance to diminish the incidence of PTLD and solid malignancies. This leaves transplant physicians with several new and novel immunosuppressive agents with uncertain oncologic potentials that will need to be examined over the next decade. © 2006 Elsevier Inc. All rights reserved.

In the era of modern immunosuppression, the incidence of acute rejection and early septic deaths has decreased, extending the life expectancy of both transplant allografts and transplant recipients.1 Subsequently, with increased survival posttransplant, malignancy has become an important cause of mortality in solid organ transplant recipients. The etiology of posttransplant malignancy is believed to be multi-factorial, including chronic exposure to immunosuppressive agents and viral mediators of tumor oncogenes. Since the early days of transplantation, a high incidence of Address reprint requests and correspondence: Joseph F. Buell, MD, University of Cincinnati, The Israel Penn International Tranpslant Tumor Registry, Division of Transplantation, 231 Albert Sabin Way, Cincinnati, OH 45267. E-mail: [email protected]

1055-8586/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2006.03.005

cancer has been observed. In particular, lymphomas and atypical malignancies have been identified.2-4 Several significant differences are noted between cancers in solid organ recipients and the general population. These include a high incidence of squamous cell carcinoma (SCC), Kaposi’s sarcoma, melanoma, and other rare tumors, such as sarcomas and Merkel cell tumors. Pediatric transplant recipients in particular experience the high incidence of post transplant lymphoproliferative disorder (PTLD). The relationship between viral infection and immunosuppression appears pervasive in posttransplant malignancies. These include associations between Epstein Barr virus and PTLD, human papillomavirus and squamous cell cancer, and human herpes virus 8 and Kaposi’s sarcoma.5-11 The strongest association between viral infection and post-


Seminars in Pediatric Surgery, Vol 15, No 3, August 2006

Figure 1

Reported incidence of de novo malignancy in transplant recipients.

transplant malignancy is seen in pediatric transplant recipients. The extent of immunosuppression, particularly cumulative dose, has been related to the development of PTLD and solid organ tumors.12,13 Initial studies from Dr. I. Penn estimated that transplant recipients incur a 3- to 4-fold increase in risk of malignancy related to chronic immunosuppression; however, the relative risk may increase 100fold for specific cancers in comparison to the general population.2-4 Traditionally the incidence of malignancy has been estimated at 20% after 10 years of chronic immunosuppression (Figure 1).7,8 Recent figures from the Australian New Zealand Registry (ANZ) show this to be a significant underestimation of the problem. This group has identified nearly a 30% incidence of malignancy after 20 years of chronic immunosuppression (Figure 2).

Figure 2

Malignancy in the pediatric age group Pediatric malignancies, outside the transplant setting, are clinically, histopathologically, and biologically distinct from adult malignancy. Childhood cancers tend to have short latency periods, with invasive tumors often identified with rapid and aggressive growth. Pediatric malignancies are rarely associated with carcinogenic exposure, whereas often most are responsive to standard therapies. Subsequently, most pediatric malignancies are sporadic with less than 15% of patients with a recognized congenital or familial disorder.14 Transplant-related malignancies appear to differ most from the general population in their association with viral mediation and effect of cumulative dose immunosuppression. This appears to be consistent with those

Reported incidence of de novo malignancy in transplant recipients compared with nonimmunosuppressed patients.

Buell et al. Table 1

Malignancy in Pediatric Transplant Recipients Malignancies observed in non-transplant children

Leukemia (23%) - ALL (18%) - AML (4%) ● CNS tumors (18%) ● Lymphoma (17%) - Hodgkin’s disease (10%) - Non-Hodgkin’s lymphoma (7%) ● Soft tissue sarcoma (7%) - Rhabdomyosarcoma (3%) - Other STS (4%) ● Germ cell tumors (6%) ● Bone tumors (5%) - Osteosarcoma (2.5%) - Ewing’s sarcoma (2.5%) ● Neuroblastoma (5%) ● Wilms’ tumor (4%) ● Thyroid Cancer (3.5%) ● Skin Cancer (3.5% ● Retinoblastoma (1.5%) ● Hepatoblastoma (0.5%) ● Other (11%)

pediatric malignancies identified within the transplant setting, in particular PTLD. PTLD is the most commonly encountered malignancy in pediatric transplant recipients. The most common malignancies identified in the pediatric general population are acute lymphoblastic leukemia (23%), astrocytoma (13%), neuroblastoma (5%), lymphoma (17%), Wilm’s Tumor (4%), Hodgkin’s disease (10%), primitive neuroectodermal tumor (5%), acute myeloid leukemia (4%), retinoblastoma (1.5%), and sarcomas (7%)15 (Table 1). In comparison, the majority of malignancies in pediatric transplant patients were PTLD (52%). Several cases of leukemia, sarcoma, and brain cancer were encountered similar to those observed in the general population. However, few cases of Wilm’s tumor or neuroblastoma were identified. Despite this low incidence, these two malignancies comprised a significant proportion of tumors in pediatric transplant recipients with prior malignancies. The majority of these patients required renal transplantation for chemotherapy-induced renal failure. Consistent with adult transplant experiences, the pediatric patients experienced a high incidence of skin cancer, including melanoma and Kaposi’s sarcoma. Several gynecologic malignancies, including vulvar and cervical cancer, were identified. Both of these malignancies have been associated with human papillomavirus. Thyroid and renal cancers were also identified. Both malignancies are associated with genetic disorders and congenital malignancies.

Malignancy in pediatric transplant recipients Eight hundred and thirteen tumors were reported in pediatric transplant recipients. The majority of these tumors were PTLD (n ⫽ 409; 50%). The remaining tumors were: skin

181 Table 2 Malignancies identified in pediatric transplant recipients Type of Tumor

Number of cases

PTLD Skin Cancer GYN Thyroid Kaposi’s Sarcoma Leukemia Sarcoma Thyroid Melanoma Liver GU Brain Adenocarcinomas PENUT

409 209 25 20 26 14 25 19 11 15 16 7 10 7

malignancies (n ⫽ 209; 26%), genitourinary and gynecologic malignancies (n ⫽ 25; 3%), sarcoma (n ⫽ 25; 3%), thyroid (n ⫽ 19; 2%), and brain (n ⫽ 10; 1%) (Table 2). The majority of skin cancers were squamous cell carcinoma. A 7.4:1 ratio of squamous cell carcinomas to basal cell carcinoma was identified. This ratio is consistent with adult experience where squamous cell carcinomas predominate. A higher incidence of lymph node invasion was also observed with invasive disease present in 9% of patients. Gynecologic malignancies included ovarian, uterine, and vulvar. All thyroid tumors were papillary in histology. PTLD cases most frequently developed in nonrenal allograft recipients, whereas all other malignancies occurred with a higher frequency in renal allograft recipients (P ⬍ 0.001) (Table 3). Significant differences in age at transplantation were noted between the PTLD group and the solid malignancy group (7.9 versus 13.2 yrs; P ⬍ 0.0001). Time from transplant to diagnosis was also significantly less in the PTLD group compared with the solid organ group (60.9 versus 99.2 months; P ⬍ 0.0001).

Table 3 Incidence of common malignancies in renal and extra-renal pediatric transplant recipients


Renal patients number


Non-renal number


PTLD Skin cancer Gyn Sarcoma Liver Thyroid Kaposi’s Sarcoma GU Leukemia

127 165 22 15 14 17 23 14 9

31 89 88 60 93 89 88 88 64

282 17 3 10 1 2 3 2 5

69 11 12 40 7 11 12 12 36


Impact of immunosuppression States of impaired immunity have been linked to the development of malignancy, including inherited disorders of the immune system, immunocompromising infections (eg, Acquired Immunodeficiency Syndrome or AIDS), and chronic immunosuppression.12,13 The two most commonly encountered cancers are lymphoma and Kaposi’s sarcoma. Chronic immunosuppression has long been recognized in the development of skin malignancy. This cancer was most often observed in autoimmune patients chronically treated with azathioprine.16-18 The risk of oncogenesis after transplantation is thought to closely correlate with overall or cumulative exposure to immunosuppression.12,13 The mechanism of oncogenesis is thought to be impairment of antitumor immune surveillance particularly NK cell function and antiviral activity. Chronic antigen stimulation from transplanted organs, repeated infections, or transfusions of blood products may overly stimulate a partially depressed immune system, resulting in the development of a transplant-related lymphoma. Moreover, once this loss of regulation occurs, the defensive capabilities of the immune system are weakened, which may enable other nonlymphoid neoplasia to appear.19 The strongest correlation between immunosuppression and risk of malignancy exists with induction agents. Swinnen first reported an association between murine monoclonal anti-CD3 antibody and PTLD in transplant recipients.20 Subsequently, this association was observed in both adult and pediatric cardiac recipients.21 In a recent study of 38,519 primary kidney recipients, monoclonal antilymphocyte antibody was the only induction agent associated with the development of PTLD22 resulting in a 72% increased risk of PTLD compared with no induction. However, another population study failed to find an association with anti-CD3 monoclonal antibody induction and PTLD prevalence in pediatric renal transplant recipients.23 Despite the association between anti-CD3 monoclonal antibody induction therapy and the development of PTLD, antiCD3 has not been found to be a causative factor in the development of other solid organ malignancies. In data from our own registry, the incidence of antibody usage for either induction or the treatment of rejection was constant at approximately 50%.24 Currently, anti-CD25 monoclonal antibodies (basiliximab and daclizumab) do not appear to be associated with an increased risk of de novo malignancy. Basiliximab (and daclizumab) has the theoretical potential for lymphocyte clonal selection and late proliferation and has been associated with an earlier onset of lymphoplasmacytic hyperplasia, the most indolent form of B lymphocyte clonal expansion in intestinal transplant recipients.25 Although this is concerning, few cases of frank lymphoma have been encountered. Calcineurin inhibitors have long been linked to the development of posttransplant malignancies, including lymphoma and other solid organ cancers. On a molecular level, peripheral blood mononuclear cells from renal transplant

Seminars in Pediatric Surgery, Vol 15, No 3, August 2006 recipients receiving cyclosporine (CYA) have been found to have an impaired ability to repair radiation-induced DNA (DNA) damage.26 In conjunction with cytokine production of transforming growth factor (TGF)-beta and/or vascular endothelial growth factor (VEGF) they may promote carcinogenesis.27-30 Tacrolimus was identified in a single study to cause a fivefold increase in the lymphoproliferative disorder rate in mice persistently infected with a murine herpesvirus.31 Conversely, tacrolimus was found to inhibit intercellular adhesion molecule (ICAM) and therefore prevent angioinvasion in cell culture, an effect that might limit tumor invasion and dissemination.32 Initial concerns regarding the carcinogenic effect of tacrolimus related to an early experience in pediatric liver transplantation at the University of California, Los Angeles where a high incidence of PTLD was observed in tacrolimus-treated recipients. Subsequent analyses from UCLA and the University of Pittsburgh refuted this association and indicated overaggressive dosing resulted in excessive carcinogenesis. Subsequent and more appropriate dosing experiences with tacrolimus led to substantial declines in risk of PTLD.33 The use of azathioprine, has long been recognized as an etiologic factor in the development of neoplasia in particularly nonmelanotic skin cancer.27,34,35 The antimetabolite mycophenolate mofetil is a morpholinoethyl ester pro-drug of mycophenolic acid (MPA). This drug is an inhibitor of inosine monophosphate dehydrogenase (IMPDH)36-38 that is dramatically elevated in leukemias39 and other solid tumors37,40 theoretically resulting in antiproliferative activity.41-43 In contrast to the concerns with azathioprine, a recent population study by The Scientific Registry of Transplant Recipients (SRTR), showed that MMF was clearly associated with the greatest decrease in relative risk for the development of PTLD. Currently the most controversial agent is sirolimus (SRL), a mammalian target of rapamycin inhibitor.44-46 Initially developed as a antineoplastic agent, SRL was abandoned after demonstrating only mildly antineoplastic activity until analysis identified significant antirejection and renal sparing potential.47,48 Antineoplastic properties of SRL include direct inhibition of cancer cell replication,49,50 induction of apoptosis, inhibition of IL-10 production, and inhibition of tumor angiogenesis through downregulation of VEGF. Early clinical trials with SRL-treated renal allograft recipients49 demonstrated that SRL-treated patients displayed a lower incidence of de novo malignancy when compared with a triple immunosuppressive treated patients. Subsequent reporting on 1008 renal transplant patients, Kahan and coworkers51 identified low incidence of commonly encountered transplant related malignancies (0.4% for PTLD, 0.2% for renal cell carcinoma, and 1.9% for skin tumors).

Posttransplant lymphoproliferative disorder PTLD is not a single entity but a spectrum of disease varying from benign EBV driven hypertrophy to frank

Buell et al.

Malignancy in Pediatric Transplant Recipients

12 10 8 6 4 2 0 Intestine Heart/ Lung Figure 3 online.)


Adults Pediatrics



Liver Kidney

Incidence of pediatric to adult cases of de novo malignancy distributed by allograft type. (Color version of figure is available

aggressive lymphoma. The development of PTLD appears to arise from EBV infection, degree of cumulative immunosuppression, and perhaps coinfection with cytomegalovirus (CMV). PTLD can occur in all age groups but children are at higher risk for primary EBV and CMV infection with subsequent development of PTLD. The risk for EBV naïve recipients is thought to result from primary infection either due to transmission of EBV from the donor organ, blood products or community contact.52,53 However, EBV also plays a significant pathogenic role in previously infected recipients via latent virus. Immunosuppressed transplant recipients display higher EBV viral loads than normal healthy subjects in peripheral B cells and increased production of cell free virus in saliva. The exact events that lead up to and trigger subsequent PTLD remain unclear.54 The magnitude of risk of PTLD for an individual recipient depends on the organ transplanted, age of recipient and the cumulative dose of immunosuppression required to maintain these organs (Figure 3). This persists through the first year after transplantation when overall risk of PTLD is greatest and even beyond the first posttransplant year.55 There is a gradation of risk for recipients of kidneys, who may expect an incidence of 2% to 3%, through pancreas, liver, heart, lung (10%), to recipients of intestinal transplants, who have an incidence of PTLD of up to 20% (Table 4). This variation in risk may relate to differences in cumulative dosages of immunosuppressive drugs, and potentially biological differences in the tissue transplanted. Lung and intestine allografts contain a relatively large amount of lymphoid tissue, which may increase donor EBV transmission, whereas disordered tissue integrity and lymphatics may disrupt cytokine and T-cell responses to donor antigen, further disabling normal immunosurveillance.56 There is a suggestion from case series data that PTLD of donor origin has a predilection for the transplanted organ, may occur earlier in the posttransplant period, and may have a better prognosis than PTLD of recipient origin. Registry data suggest that recipients with PTLD localized to the transplanted organ have an improved 5-year survival.57,58

Prophylaxis and preemptive therapy Prophylaxis and preemptive strategies to reduce the incidence of PTLD in solid organ transplant recipients are controversial. Prophylaxis therapies are based on suppression of viral replication. Because antivirals, ie, acyclovir or ganciclovir, do not suppress EBV driven B-cell proliferation, their role in PTLD has been questioned.59 Theoretically, antivirals may play a role is reducing the incidence of PTLD by reducing the number of infected B-cells in high-risk patients, ie, EBV⫹ donor into an EBV⫺ recipient.60 Several antiviral trials have been designed either as prophylaxis or preemptive treating CMV.61 There are several nonrandomized trials of antivirals for CMV prophylaxis that suggest lower incidences of PTLD compared with historical controls. There are other studies detecting no effect of antiviral prophylaxis on the incidence of PTLD. Equally, in randomized trials of prophylactic antivirals, it has been difficult to demonstrate decreased incidence of PTLD. To date, there have been no published randomized trials addressing the efficacy of antiviral therapy for the prevention of PTLD. Attempts to prevent PTLD by acting preemptively at times of increased EBV levels in the peripheral blood posttransplant have reduced the incidence of PTLD compared with historical controls.62,63 Once diagnosed, the intervention most commonly performed to control PTLD is to reduce the dosage of immunosuppression with or without antiviral therapy. As a prognostic indicator, low quantity of EBV-CTL in the peripheral blood is a better predictor of patients who will develop PTLD or relapse after treatment.64,65 Therefore, EBV viral monitoring may serve as a surrogate for immunosuppression dosing. Some have used rituximab preemptively at time of increased EBV viral load63,66; however, there is a poor correlation between reduction of EBV viral load by rituximab and clinical response of the PTLD.67

Systemic chemotherapy Local control with surgery and/or radiotherapy is very effective in curing localized PTLD.68 However, traditional therapeutic approaches to lymphoma such as systemic chemotherapy can be problematic due to end organ damage and


Seminars in Pediatric Surgery, Vol 15, No 3, August 2006

Table 4 Standardized incidence ratios for cancer risk (excluding non-melanocytic skin cancer) experienced by patients undergoing at least one kidney transplant* Site of cancer

Observed cancer

Expected cancer

Standardized incidence ratio

All Registrable Cancers Head, neck and lip Esophagus Stomach Small intestine Colorectal Liver Gallbladder Pancreas Nasal cavity Larynx Trachea, bronchus and lung Other thoracic organs Bone and articular cartilage Melanoma Mesothelioma Kaposi’s sarcoma Connective and other soft tissue Breast Vulva Vagina Cervix uteri Corpus uteri Ovary Other female genital organs Penis and other male genital organs Prostate Testis Kidney, ureter and urethra Bladder Eye Brain and central nervous system Thyroid gland Other endocrine glands Unknown primary site All lymphomas Immunoproliferative neoplasms Multiple myeloma Leukemia

1545 63 29 15 3 141 19 8 16 5 11 108 6 5 183 4 28 12 87 41 12 46 18 8 0 11 53 0 125 82 4 16 27 4 70 231 3 15 32

495.08 22.77 6.14 12.07 1.49 72.76 3.97 3.21 9.30 0.92 5.54 53.85 0.57 1.01 57.64 2.97 1.06 3.80 69.52 0.90 0.33 6.97 9.75 7.56 0.32 0.62 54.72 4.36 14.73 15.97 1.50 9.59 5.96 0.43 16.74 22.74 0.29 5.62 12.28

3.12 2.77 4.73 1.24 2.01 1.94 4.78 2.49 1.72 5.41 1.99 2.01 10.60 4.94 3.18 1.35 26.44 3.16 1.25 45.60 36.02 6.60 1.85 1.06 0.00 17.81 0.97 0.00 8.49 5.14 2.67 1.67 4.53 9.37 4.18 10.16 10.23 2.67 2.61

95% CI 2.97 2.16 3.28 0.75 0.65 1.64 3.05 1.25 1.05 2.25 1.10 1.66 4.76 2.06 2.75 0.51 18.26 1.79 1.01 33.58 20.46 4.94 1.16 0.53 9.86 0.74 7.12 4.14 1.00 1.02 3.11 3.52 3.31 8.93 3.30 1.61 1.84

3.28 3.54 6.80 2.06 6.23 2.29 7.49 4.98 2.81 13.00 3.59 2.42 23.60 11.87 3.67 3.59 38.29 5.56 1.54 61.93 63.43 8.81 2.93 2.12 32.16 1.27 10.12 6.38 7.12 2.72 6.61 24.97 5.28 11.55 31.73 4.42 3.69

CI, confidence interval. *Analysis of 13,077 patients in Australia and New Zealand 1980 –2003 (110,395 person years), standardized for age, gender, and calendar year with Australian population.

infections. Despite this, chemotherapy remains a generally accepted approach for the treatment of refractory PTLD. In addition to potent cytotoxicity against lymphoproliferation, the concurrent immunosuppressive effect of chemotherapy is usually sufficient to prevent or treat allograft rejection. The utility of chemotherapy in treating PTLD is difficult to determine, because the published literature contains mainly small, single center retrospective experiences and no large, prospective trials using uniform treatment. Results from published studies demonstrate that standard chemotherapy regimens for NHL, eg, CHOP, ProMACE-CytaBOM, ESHAP, etc., are effective for patients with PTLD, with CR achieved in about 60%, whereas both relapses and allograft loss due to rejection are rare events, ie, ⬍5%. However, the 2-year survival remains less than 50%,

with the major problem being therapy-related mortality (TRM), ie, death due to causes other than PTLD while on chemotherapy, ranging from 25% to 70%.69-77 A low-dose chemotherapy regimen of cyclophosphamide and prednisone has been used to treat children with refractory PTLD with very good results, but it remains to be determined whether this regimen will be as effective in adults with PTLD.69

Conclusions The relationship between cumulative immunosuppression exposure and viral cofactors to the development of trans-

Buell et al.

Malignancy in Pediatric Transplant Recipients

plant related malignancies has been firmly established. Pediatric transplant recipients will experience the highest cumulative doses of immunosuppression of any transplant recipient. This is merely a reflection of the recipient age at transplantation and the overall improvement of graft half lives. This series identifies several important points: PTLD prophylaxis can be achieved through ganciclovir therapy in seronegative recipients. Unfortunately there is no consensus on the overall length or dosage required to achieve this decrement in malignancy. PTLD should not be treated as a single entity but more as a spectrum of disease. Initial therapy should emphasize immunosuppression reduction and not systemic chemotherapy. Use of anti CD-20 antibody appears to be an essential therapeutic modality in the treatment of most PTLDs. EBV-negative malignancies appear to be poorly responsive to any therapy and may arise from an alternative mechanism. Development of solid malignancies particularly those virally associated are associated with chronic immunosuppression. Clinical outcomes of solid organ malignancy maybe impacted by either immunosuppression reduction or modification. Several immunosuppressive agents have provided optimism. These include mycophenolic compounds including mycophenolate mofetil and mycophenolate acid sodium. The antineoplastic and antiviral properties of mycophenolic acid compounds appear to represent the soundest strategy for minimizing chronic malignancy. The most promising compound is the TOR inhibitor that has shown promise in malignancy prevention. Agents such as sirolimus must further be investigated to determine the benefits in diminishing new de novo malignancies and inhibiting recurrent malignancy. Uncertain however are the effects of newer immunosuppressive agents and monoclonal antibodies whose primary mechanism relies on clonal selection and trafficking. Further investigation of these drugs is essential in minimizing long-term morbidity and mortality expected in long-term survivors after pediatric transplantation.

References 1. Buell JF, Gross TG, Woodle ES. Malignancy and Transplantation. Transplantation 2005;80(2):S254-64. 2. Penn I. Cancers in renal transplant recipients. Adv Ren Replace Ther 2000;7:147-56. 3. Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf 2000;23:101-13. 4. Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. In: Cecka JM, Terasaki PI, eds. Clin Transpl. Los Angeles, CA: UCLA Tissue Typing Laboratory, 1998:147-52. 5. Engels EA, Goedert JJ. Human immunodeficiency virus/acquired immunodeficiency syndrome and cancer: past, present, and future. J Natl Cancer Inst 2005;97:407-9. 6. Muller AM, Ihorst G, Mertelsmann R, Engelhardt M. Epidemiology of non-Hodgkin’s lymphoma (NHL): trends, geographic distribution, and etiology. Ann Hematol 2005;84:1-12.

185 7. Moore PS, Gao SJ, Dominguez G, et al. Primary characterization of a herpesvirus agent associated with Kaposi’s sarcomae. J Virol 1996; 70:549-58. 8. Penn I. Kaposi’s sarcoma in transplant recipients. Transplantation 1997;64-73:669. 9. Woodle ES, Hanaway M, Buell J, et al. Kaposi sarcoma: an analysis of the US and international experiences from the Israel Penn International Transplant Tumor Registry. Transplant Proc 2001;33:3660-1. 10. Meyer T, Arndt R, Nindl I, Ulrich C, Christophers E, Stockfleth E. Association of human papillomavirus infections with cutaneous tumors in immunosuppressed patients. Transpl Int 2003;16:146-53. 11. Euvrard S, Chardonnet Y, Pouteil-Noble C, et al. Association of skin malignancies with various and multiple carcinogenic and noncarcinogenic human papillomaviruses in renal transplant recipients. Cancer 1993;72:2198-206. 12. Diehl V, Hauch P, Harris N. Hodgkin’s disease. In: DeVita VT, Hellman S, Rosenberg S, eds. Cancer Principles and Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins, 2001:233943. 13. Yarchoan R, Little RF. Immunosuppression-related malignancies. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins, 2001:2575-81. 14. Ebb DH, Green DM, Schanberger RC, Tarbell NJ. Solid tumors of childhood. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins, 2001:2169-72. 15. Gurney JG, Bondy ML. Epidemiology of childhood cancer. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology (ed 5). Philadelphia, PA: Lippincott, Williams and Wilkins, 2005:1-13. 16. Guba M, Graeb C, Jauch KW, Geissler EK. Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation 2004;77:1777-82. 17. Taylor L, Hughes RA, McPherson K. The risk of cancer from azathioprine as a treatment for multiple sclerosis. Eur J Neurol 2004;11: 141-7. 18. Beauparlant P, Papp K, Haraoui B. The incidence of cancer associated with the treatment of rheumatoid arthritis. Semin Arthritis Rheu 1999; 29:148-58. 19. 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. 20. Swinnen LJ, Fisher RI. OKT3 monoclonal antibodies induce interleukin-6 and interleukin-10: a possible cause of lymphoproliferative disorders associated with transplantation. Curr Opin Nephrol Hypertens 1993;2:670-8. 21. Lenner R, Padilla ML, Teirstein AS, Gass A, Schilero GJ. Pulmonary complications in cardiac transplant recipients. Chest 2001;120:508-13. 22. Cherikh WS, Kauffman HM, McBride MA, Maghirang J, Swinnen LJ, Hanto DW. Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation. Transplantation 2003;76:1289-93. 23. Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE. Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 2001;71:1065. 24. Buell J, Hanaway M, Thomas M, Rudich S, Woodle E. Malignancies associated with liver transplantation. In: Busuttil RW, Klintmalm GB, eds. Transplantation of the Liver. Philadelphia, PA: W.B. Saunders, 2004. 25. Ruiz P, Soares MF, Garcia M, et al. Lymphoplasmacytic hyperplasia (possibly pre-PTLD) has varied expression and appearance in intestinal transplant recipients receiving Campath immunosuppression. Transplant Proc 2004;36:386-7.

186 26. Herman M, Weinstein T, Korzets A, et al. Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients. J Lab Clin Med 2001;137:14-20. 27. Guba M, Graeb C, Jauch KW, Geissler EK. Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation 2004;77:1777-82. 28. Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999;397:530-5. 29. Shihab FS, Bennett WM, Isaac J, Yi H, Andoh TF. Nitric oxide modulates vascular endothelial growth factor and receptors in chronic cyclosporine nephrotoxicity. Kidney Int 2003;63:522-33. 30. Reichenspurner H. Overview of tacrolimus-based immunosuppression after heart or lung transplantation. J Heart Lung Transplant 2005;24: 119-24. 31. Mistrikova J, Mrmusova M, Durmanova V, Rajcani J. Increased neoplasm development due to immunosuppressive treatment with FK-506 in BALB/C mice persistently infected with the mouse herpesvirus (MHV-72). Viral Immunol 1999;12:237-47. 32. Sakai M, Miyake H, Tashiro S, Okumura Y, Kido H. Inhibitory effect of FK506 and cyclosporine A on the growth and invasion of human liver cancer cells. J Med Invest 2004;51:63-8. 33. Jain A, Nalesnik M, Reyes J, et al. Posttransplant lymphoproliferative disorders in live transplantation: A 20-year experience. Ann Surg 2002;236(4):429-37. 34. Taylor L, Hughes RA, McPherson K. The risk of cancer from azathioprine as a treatment for multiple sclerosis. Eur J Neurol 2004;11: 141-7. 35. Beauparlant P, Papp K, Haraoui B. The incidence of cancer associated with the treatment of rheumatoid arthritis. Semin Arthritis Rheum 1999;29:148-58. 36. Tressler RJ, Garvin LJ, Slate DL. Anti-tumor activity of mycophenolate mofetil against human and mouse tumors in vivo. Int J Cancer 1994;57:568-73. 37. Weber G, Hager JC, Lui MS, et al. Biochemical programs of slowly and rapidly growing human colon carcinoma xenografts. Cancer Res 1981;41:854-59. 38. Natsumeda Y, Prajda N, Donohue JP, Glover JL, Weber G. Enzymic capacities of purine de Novo and salvage pathways for nucleotide synthesis in normal and neoplastic tissues. Cancer Res 1984;44:247580. 39. Nagai M, Natsumeda Y, Konno Y, Hoffman R, Irino S, Weber G. Selective up-regulation of type II inosine 5=-monophosphate dehydrogenase messenger RNA expression in human leukemias. Cancer Res 1991;51:3886-90. 40. Jackson RC, Weber G, Morris HP. IMP dehydrogenase, an enzyme linked with proliferation and malignancy. Nature 1975;256:331-6. 41. Yu J, Lemas V, Page T, Connor JD, Yu AL. Induction of erythroid differentiation in K562 cells by inhibitors of inosine monophosphate dehydrogenase. Cancer Res 1989;49:5555-60. 42. Ohsugi Y, Suzuki S, Takagaki Y. Antitumor and immunosuppressive effects of mycophenolic acid derivatives. Cancer Res 1976;36:292327. 43. Carter SB, Franklin TJ, Jones DF, et al. Mycophenolic acid: an anticancer compound with unusual properties. Nature 1969;223:848-52. 44. Buell J, Hanaway M, Thomas M, Rudich S, Woodle E. Malignancies associated with liver transplantation. In: Busuttil RW, Klintmalm GB, eds. Transplantation of the Liver. Philadelphia, PA: W.B. Saunders, 2004. 45. Buell J, Gross T, Beebe T, et al. Cancer after renal transplantation. In: Cohen EP, ed. Cancer and the Kidney. New York, NY: Oxford University Press, 2004. 46. Trofe J, Beebe TM, Buell JF, et al. Posttransplant malignancy. Prog Transplant 2004;14:193-204. 47. Yakupoglu Y, Knight R, Katz S. Low incidence of malignancy among sirolimus-cyclosporine treated transplant recipients. Am J Transplant 2004;3:187(suppl 5). 48. Trotter JF. Sirolimus in liver transplantation. Transplant Proc 2003; 35:193-200S.

Seminars in Pediatric Surgery, Vol 15, No 3, August 2006 49. Luan FL, Ding R, Sharma VK, Chon WJ, Lagman M, Suthanthiran M. Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 2003;63:917-26. 50. Nepomuceno RR, Balatoni CE, Natkunam Y, Snow AL, Krams SM, Martinez OM. Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res 2003;63:4472-80. 51. Kahan B, Knight R, Schoenberg L, et al. Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience. Transplant Proc 2003;35:25-7S. 52. Haque T, Thomas JA, Falk KI, Parratt R, Hunt BJ, Yacoub M, et al. Transmission of donor Epstein-Barr virus (EBV) in transplanted organs causes lymphoproliferative disease in EBV-seronegative recipients. J Gen Virol 1996;77:1169-72. 53. Alfieri CTJ, Carpentier L, Perpete C, Savoie A, Paradis K, Delage G, Joncas J. Epstein-Barr virus transmission from a blood donor to an organ transplant recipient with recovery of the same virus strain from the recipient’s blood and oropharynx. Blood 1996;87:812-7. 54. Hopwood PA, Brooks L, Parratt R, Hunt BJ, Bokhari M, Thomas JA, et al. Persistent Epstein-Barr virus infection: unrestricted latent and lytic viral gene expression in healthy immunosuppressed transplant recipients. Transplantation 2004;74:194-202. 55. Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 1993;342:1514-16. 56. Cockfield SM. Identifying the patient at risk for post-transplant lymphoproliferative disorder. Transplant Infect Dis 2001;3:70-8. 57. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4:222-30. 58. Petit B, Le Meur Y, Jaccard A, Paraf F, Robert CL, Bordessoule D, et al. Influence of host-recipient origin on clinical aspects of posttransplantation lymphoproliferative disorders in kidney transplantation. Transplantation 2002;73:265-71. 59. Paya CVFJJ, Nalesnik MA, Kieff E, Green M, Gores G, Habermann TM, et al. Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. Transplantation 1999;68:1517-25. 60. Green MMMG, Webber SA, Rowe D, Reyes J. The management of Epstein-Barr virus associated post-transplant lymphoproliferative disorders in pediatric solid-organ transplant recipients. Pediatr Transpl 1999;3:271-81. 61. Davis CL. The antiviral prophylaxis of post-transplant lymphoproliferative disease. Springer Semin Immunopathol 1998;20:437-53. 62. McDiarmid SV, Jordan S, et al. Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients. Transplantation 1998;66:1604-11. 63. Lee TCSB, Rooney CM, Heslop HE, Gee AP, Caldwell Y, Barshes NR, et al. Quantitative EBV viral loads and immunosuppression alterations can decrease PTLD incidence in pediatric liver transplant recipients. Am J Transpl 2005;5:2222-8. 64. Smets FLD, Bazin H, Reding R, Otte J-B, Buts J-P, Sokal EM. Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation 2002;73:1603-10. 65. Dotti GR, Fiocchi, et al. Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome. Transplantation 2002;74:1095-102. 66. Ghobrial IMHTM, Ristow KM, Ansell SM, Macon W, Geyer SM, McGregor CG. Prognostic factors in patients with post-transplant lymphoproliferative disorders (PTLD) in the rituximab era. Leuk Lymph 2005;46:191-6. 67. Yang JVM, Lemas, et al. Application of the ELISPOT assay to the characterization of CD8(⫹) responses to Epstein-Barr virus antigens. Blood 2000;95:241-8. 68. Trofe JBJ, Beebe TM, Hanaway MJ, First MR, Alloway RR, Gross TG, Woodle ES. The Israel Penn International Transplant Tumor Registry 32 year experience with 402 renal transplant recipients with post transplant lymphoproliferative disease: multivariate analysis of risk factors that influence survival. Am J Transplant 2005;5:775-80.

Buell et al.

Malignancy in Pediatric Transplant Recipients

69. Gross TGBJ, Park J, Greiner TC, Hinrich SH, Kaufman S, Langnas A, et al. Low dose chemotherapy for the treatment of refractory posttransplant lymphoproliferative disease in children. J Clin Oncol 2005; 23:6481-88. 70. Ghobrial IM, Habermann TM, Macon WR, et al. Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: are they two different diseases? Transplantation 2005;79:244-7. 71. Leblond VN, Dhedin, et al. Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol 2002;19:772-8. 72. Buell JFGT, Hanaway MJ, Trofe J, Muthiak C, First RM, Alloway RR, Woodle ES. Chemotherapy for PTLD: The Israel Penn International Transplant Tumor Registry Experience. Transplant Proc 2005;37: 956-7.

187 73. Hayashi RJ, Kraus MD, et al. Posttransplant lymphoproliferative disease in children: correlation of histology to clinical behavior. J Pediatr Hematol Oncol 2001;23:14-8. 74. Aull MJ, Buell JF, et al. MALToma: a Helicobacter pylori-associated malignancy in transplant patients: a report from the Israel Penn International Transplant Tumor Registry with a review of published literature. Transplantation 2003;75:225-8. 75. Swinnen LJ, LeBlanc M, et al. Phase II study of sequential reduction in immunosuppression, interferon alpha-2b, and ProMACE-CytaBOM chemotherapy for post-transplant lymphoproliferative disorder (PTLD) (SWOG/ECOGS9239). Blood 2003;102:403a. 76. Swinnen LJ, Mullen GM, et al. Aggressive treatment for postcardiac transplant lymphoproliferation. Blood 1995;86:3333-40. 77. Penn I. De novo malignancies in Pediatric Organ Transplant Recipients. Pediatr Transplant 1998;2:56-63.