0041-1337/04/7711-1719/0 TRANSPLANTATION Vol. 77, 1719–1725, No. 11, June 15, 2004 Copyright © 2004 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. DE NOVO MALIGNANCIES AFTER INTESTINAL AND MULTIVISCERAL TRANSPLANTATION KAREEM M. ABU-ELMAGD, 1,5 MARSHA ZAK, 1 JUNE M. STAMOS, 1 GEOFF J. BOND, 1 ASHOK JAIN, 4 ADA O. YOUK, 3 MOHAMED EZZELARAB, 1 GUILHERME COSTA, 1 TONG WU, 1 MICHAEL A. NALESNIK, 1 GEORGE V. MAZARIEGOS, 2 RAKESH K. SINDHI, 2 AMADEO MARCOS, 1 ANTHONY J. DEMETRIS, 1 JOHN J. FUNG, 1 AND JORGE D. REYES 2 Background. Maintenance immunosuppression re- quired after organ transplantation creates a permis- sive environment in which cancer cells can proliferate because of lack of natural immunologic surveillance. With more than a decade of clinical experience, this report is the first to address the risk of de novo cancer after intestinal transplantation. Methods. A total of 168 consecutive intestinal trans- plant recipients (86 children and 82 adults) were stud- ied, of whom 52% were male and 91% were white. Sur- veillance, Epidemiology, and End Results data was used to count expected rates of de novo cancers in the general population matched for age, sex, and length of follow-up. Results. With a mean follow-up of 4741 months, 7 (4.2%) patients developed nonlymphoid de novo can- cer, with a cumulative risk of 3% at 5 years and 28% at 10 years. Of these malignancies, one was donor-driven adenocarcinoma. With 0.58 being the expected rate of malignancy for the general population, the risk among intestinal recipients was 8.7 times higher (P0.01). Such morbidity was significantly higher (50 times) among younger patients (<25 years), with a slight male preponderance. Induction immunosuppression was associated with early onset of de novo cancer. Patient survival after diagnosis of de novo cancer was 72% at 1 year, 57% at 2 years, and 29% at 5 years. Conclusion. With conventional immunosuppression, intestinal recipients are at a significantly higher risk of developing de novo cancer when compared with the general population. Thus, a novel tolerogenic immuno- suppressive strategy has been recently implemented to reduce the lifelong need for immunosuppression. Intestinal transplantation has recently evolved to be the standard of care for patients with irreversible intestinal fail- ure who no longer can be maintained on total parenteral nutrition (1, 2). Furthermore, survival outcomes continue to improve, with current rates comparable to thoracic and other abdominal organ transplantation (3, 4). Historically, intesti- nal allografts have been at a higher risk for rejection com- pared with other solid organs, with the subsequent need for heavy immunosuppression (5). As a result, higher incidences of opportunistic infections and posttransplant lymphoprolif- erative disease (PTLD) have been reported (2, 6–8). In addi- tion, conventional immunosuppressive drug therapy pro- vides a permissive environment for the development of de novo cancers (9 –15). Tacrolimus-based immunosuppression was first intro- duced in 1989 for solid abdominal and thoracic organ trans- plantation (16). Soon after the demonstration of its high therapeutic efficacy, in May 1990, a clinical intestinal trans- plantation program was established at our institution. The impact of tacrolimus-based immunosuppression on the inci- dence of de novo malignancies after liver transplantation has been recently reported (15). In this article, we report the risk of such morbidity after intestinal and multivisceral trans- plantation examined in comparison with the rate for the general population matched for age, gender, and length of follow-up using Surveillance, Epidemiology, and End Results (SEER) data (17). In addition, clinical presentation, tumor pathologic findings, recipient management, and survival out- come are fully described. MATERIALS AND METHODS Patient Population Between May 1990 and June 2001, a total of 168 consecutive patients underwent primary intestinal transplantation. Of these, 70 received intestine (2 with pancreas and 1 with kidney), 74 received combined liver-intestinal (9 with pancreas), and 24 received multi- visceral (stomach, duodenum, pancreas, intestine, and liver) grafts. Of the 168 recipients, 86 were children (18 years of age) and 82 were adults, with a mean age of 21.419.2 years (median, 16.9 years). Eighty-eight (52%) recipients were male patients and 153 (91%) were white. The indications for transplantation were nonma- lignant except in one adult patient with abdominal gastrinoma. Short-gut syndrome was the cause of intestinal failure in 81% of the cases. Indications other than the absence of bowel included dysmo- tility syndromes (10%), intestinal neoplasm (6%), and enterocyte failure (3%). Loss of the intestine in children was attributable most commonly to volvulus, gastroschisis, necrotizing enterocolitis, and intestinal atresia, and loss of intestine in adults was attributable most commonly to thrombotic disorders, Crohn’s disease, and trauma. The medical history was significant for colorectal adenocar- cinoma and anal squamous cell carcinoma in another two adult recipients 20 and 3 years before transplantation, respectively. The pretransplant workup failed to document any clinical, biochemical, or radiologic evidence of neoplastic lesions in any of the patients. The serologic studies were also negative for hepatitis C, hepatitis B, and human immunodeficiency virus. All recipients were followed through October 1, 2003, with a mean follow-up of 4741 months (range, 0.03–161 months). All donors were cadaveric, and brain death was primarily caused by trauma and cerebrovascular accidents, with no single example of 1 Thomas E. Starzl Transplantation Institute, Pittsburgh, PA. 2 Children’s Hospital of Pittsburgh, Pittsburgh, PA. 3 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh Medical Center, Pittsburgh, PA. 4 University of Rochester Medical Center, Rochester, NY. 5 Address correspondence to: Kareem Abu-Elmagd, M.D., Ph.D., Thomas E. Starzl Transplantation Institute, Intestinal Rehabilita- tion and Transplant Center, UPMC Montefiore, 7 South, 3459 Fifth Avenue, Pittsburgh, PA 15213. Email: abuelmagdkm@upmc.edu. Received 13 November 2003. Revision requested 16 December 2003. Accepted 4 January 2004. 1719 DOI: 10.1097/01.TP.0000131164.43015.4B