- Email: [email protected]
How can donors with a previous malignancy be evaluated?
Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513
References [1] Weber M, Dindo D, Demartines N, Ambuhl PM, Clavien PA. Kidney transplantation from donors without a heartbeat. N Engl J Med 2002;347:248–255. [2] D’ Alessandro AM, Hoffmann RM, Knechtle SJ, et al. Successful extra-renal transplantation from non-heart-beating donors. Transplantation 1995;59:977–982. [3] Casavilla A, Ramirez C, Shapiro R, et al. Experience with liver and kidney allografts from non-heart-beating donors. Transplantation 1995;59:197–203. [4] A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337–340. [5] Kootstra G, Daemen JH, Oomen AP. Categories of non-heartbeating donors. Transplant Proc 1995;27:2893–2894. [6] Muiesan P, Girlanda R, Jassem W, et al. Single-centre experience with liver transplantation from controlled non-heartbeating donors: a viable source of grafts. Ann Surg 2005;242:732–738. [7] Alvarez J, del Barrio MR, Arias J, et al. Five years of experience with non-heart-beating donors coming from the streets. Transplant Proc 2002;34:2589–2590. [8] Abt PL, Crawford MD, Desai NM, et al. Liver transplantation from controlled non-heart-beating donors: an increased incidence of biliary complications. Transplantation 2003;75:1659–1663. [9] Monbaliu D, Crabbe T, Roskams T, et al. Livers from non-heartbeating donors tolerate short periods of warm ischemia. Transplantation 2005;79:1226–1230. [10] Uchiyama M, Matsuno K, Hama H, et al. Comparison between nonpulsatile and pulsatile machine perfusion preservation in liver transplantation from non-heart-beating donors. Transplant Proc 2001;33:936–938. [11] D’Alessandro AM, Fernandez LA, Chin LT, et al. Donation after cardiac death: the University of Wisconsin experience. Ann Transplant 2004;9:68–71. [12] Abt PL, Desai NM, Crawford MD, et al. Survival following liver transplantation from non-heart-beating donors. Ann Surg 2004;239:87–92.
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[13] Foley DP, Fernandez LA, Leverson G, et al. Donation after cardiac death: the University of Wisconsin experience with liver transplantation. Ann Surg 2005;242:724–731. [14] Manzarbeitia CY, Ortiz JA, Jeon H, et al. Long-term outcome of controlled, non-heart-beating donor liver transplantation. Transplantation 2004;78:211–215. [15] Muiesan P, Jassem W, Girlanda R, et al. Segmental liver transplantation from non-heart beating donors–an early experience with implications for the future. Am J Transplant 2006;6:1012–1016. [16] Nicholson ML, Metcalfe MS, White SA, et al. A comparison of the results of renal transplantation from non-heart-beating, conventional cadaveric, and living donors. Kidney Int 2000;58:2585–2591. [17] Sanchez-Fructuoso AI, de Miguel Marques, Prats D, et al. Nonheart-beating donors: experience from the Hospital Clinico of Madrid. J Nephrol 2003;16:387–392. [18] Alvarez J, del Barrio R, Arias J, et al. Non-heart-beating donors from the streets: an increasing donor pool source. Transplantation 2000;70:314–317. [19] Otero A, Gomez-Gutierrez M, Suarez F, et al. Liver transplantation from Maastricht category 2 non-heart-beating donors: a source to increase the donor pool?. Transplant Proc 2004;36:747–750. [20] Quintela J, Gala B, Baamonde I, et al. Long-term results for liver transplantation from non-heart-beating donors maintained with chest and abdominal compression-decompression. Transplant Proc 2005;37:3857–3858. [21] Reddy S, Greenwood J, Maniakin N, et al. Non-heart-beating donor porcine livers: the adverse effect of cooling. Liver Transpl 2005;11:35–38. [22] Fukunaga K, Takada Y, Taniguchi H, et al. Endothelin antagonist treatment for successful liver transplantation from non-heart-beating donors. Transplantation 1999;67:328–332. [23] Dutkowski P, Graf R, Clavien PA. Rescue of the cold preserved rat liver by hypothermic oxygenated machine perfusion. Am J Transplant 2006;6:903–912. doi:10.1016/j.jhep.2006.07.018
How can donors with a previous malignancy be evaluated? Joseph F. Buell*, Rita R. Alloway, E. Steve Woodle The University of Cincinnati, Division of Transplantation, Cincinnati, OH, USA
1. Introduction Solid organ transplantation has flourished over the last three decades with improvements in surgical technique and modern immunosuppression resulting in * Corresponding author. Tel.: +1 513 558 6010; fax: +1 513 558 3580. E-mail address: [email protected] (J.F. Buell). Abbreviations: OPTN, Organ Procurement and Transplantation Network; UNOS, united network for organ sharing; DCIS, ductal carcinoma in situ.
improved patient outcomes. Traditionally, solid organ transplantation has been limited by organ availability. The principal source of these organs has been cadaveric donation. A steady increase in organ donation was observed in the early 1990s realized through public awareness and education programs [1]. Concurrently several surgical innovations in live donor kidney, pancreas, liver and intestinal transplantation have also contributed to an increase in transplants. However, both efforts have appeared to have achieved a plateau in the last few years.
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Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513
2. Incidence of donor transmission This year over 98,000 patients are awaiting a solid organ transplant with less than 15,000 donors currently available [1]. This disparity in organs has led to a reevaluation of certain cadaveric donors. This group known as extended criteria donors has included older (>65 or 75 years) patients, patients with a history of (viral) infection or active or treated malignancies. This portion of donors comprises a small but extremely controversial source of all donor organs. This point has been punctuated by several dramatic cases of fatal transmission in multiple recipients from a single donor [2–6]. In 1996 the OPTN began to track donors with a history of treated or active malignancy. During this time period 62,041 donors were utilized, with 1778 (2.9%) having either an active or treated malignancy [7]. Notably during this time period a dramatic rise in cancer donors was observed. During the 60 month period from 2001 to 2005 a 3.2% incidence of cancer donors was identified in comparison to a 2.5% incidence during the prior 48month period (p < 0.0001) [7]. During the last six years UNOS/OPTN has reviewed their experience with reported cancer transmission in donors with a history of malignancy. The first study failed to confirm any cases of cancer transmission from donors with a history of malignancy [8]. The subsequent studies did identify donor cancer transmission in a cohort of recipients from cadaveric and live donors [9– 11]. A similar study was performed through the Danish Cancer Registry [12]. This study also quantified the risk in a population-based register of 1.3% for having a donor with an undetected malignancy and 0.2% risk of getting a transmitted cancer. In the most recent commentary from the UNOS/OPTN a cancer transmission rate of 0.018% was identified utilizing a cadaveric donor
Table 1 Donor transmission rates Tumor type
Cases
Transmission (%)
Recommendation
Skin SCC Melanoma
10 38
0 74
Low risk Excessive risk (avoid)
Brain Grade I/II Grade III/IV RCC Breast Colon Lung
67 33 34 70 9 16 29
25 0 40 61 29 19 43
a
Low risk High riska Intermediate riskb Intermediate riskc Intermediate riskc High risk (avoid)
Transmission is associated with high mortality. Transmission is frequently limited to the graft but higher grade tumors can lead to lethal transmission. c Transmission is associated with high mortality and is related to both tumor stage and interval from diagnosis. b
source [11]. Despite this low incidence reported by UNOS/OPTN the Penn Tumor Registry continued to identify multiple cases of donor cancer transmission [13] Table 1. 3. Distribution of donor malignancies As reported by the first OPTN article, the most common cancer history in an organ donor was skin malignancy [8]. The majority of these organs were utilized in kidney recipients. This was also observed in the 296 organ donors with cancer reported to the Penn Tumor Registry [6]. Organs from donors with a cancer history were also utilized in liver, heart, lung and pancreas recipients. However, a significantly higher transmission rate was observed in the Penn Tumor Registry with 124 cases (42%) of confirmed donor transmission [4]. The incidence of donor malignancy transmission was uniform among allograft recipients, occurring in 45% of renal allograft recipients (99/222), 37% of liver allograft recipients (14/38), and 30% of cardiac allograft recipients (8/27). There was one case (25%) that occurred in the pancreas group and three cases that occurred among the lung recipients (60%). The majority of donors involved in this study were cadaveric (n = 296); there were three living unrelated donors and the remainder were living-related donors. Mean donor age was 37.4 ± 15.0 years of age. Importantly only seventy-six (26%) of the donors had a known history of active or prior malignancy. The mean time from transplantation to presentation of the donor malignancy transmission was 2 months, with a range of 2 days to 38 months [6]. In the UNOS/OPTN report the second most common cancer in donors with a cancer history was brain tumors. This report identified a lack of precise histology in 73% of donor records [8]. In the last summary statement by UNOS/OPTN one transmission in 174 donors utilized in 528 recipients was identified establishing a transmission rate of 0.6% [11]. This report did note that 116 of these donors had potentially high grade cancers with a transmission rate of 0.9%. In the Penn Tumor Registry an overall transmission rate of 23% was observed with all brain tumors. In high grade tumors, donors with extensive crainitomies or ventricular shunts this rate was as high as 43% [4]. In a review of all reported glioblastomas, histologic grading was correlated to donor transmission. This study confirmed no donor transmission in grade I or II glioblastomas. All confirmed donor transmissions occurred in donors with histologically high grades of III or IV (glioblastoma multiforme). In the Penn Tumor experience two donor tumors were noted to have high transmission rates: malignant melanoma and choriocarcinoma [2,4]. Choriocarcinoma, a gynecologic malignancy, had an identified transmission rate of 93%, with a resulting 64% mortality
Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513
rate. The other donor tumor was malignant melanoma. Malignant melanoma has demonstrated a 74% tumor transmission rate with a resulting 58% mortality [6]. Two leading cancers common to both male and female donors are lung and colon. In the United States they comprise 23% of all newly diagnosed cancers [14]. Both cancers are noted to have an increasing probability of invasive cancer with advancing age. In the first 40 years the probability of invasive lung cancer is 0.03% which dramatically increases to 6.3% after age 70 [14]. An equally dramatic rise in probability was noted in colon and rectal cancer with a 0.07% rate at age 40 compared to 4.9% at age 70 [14]. Both cancers are also more prevalent in the African American population. In the Penn Tumor Experience utilization of organs from donors with a treated or active lung malignancy resulted in a 43% tumor transmission rate, with a corresponding 32% percent mortality rate [6]. Limited data are available on utilization of donors with a history of colon cancer. In the Penn Tumor Experience a handful of patients experienced a transmission rate of 19% [2,6]. Recently, during a recent consensus conference of American Society of Transplant Surgeons, Reid Adams, M.D., noted that the incidence of nodal or metastatic disease associated with colon cancer having a primary tumor classification of T1 is less than 1%. With primary tumors classified as T2 or T3, the incidence increases, with overall survival decreasing until a period seven years post-resection [15]. Thus, he concluded that the risks associated with the use of donors with a primary tumor classification of T1/T2 are acceptable in Caucasian males and any race females after a five year disease free interval, while organs from African American or T3 lesions donors should never be considered [15]. 4. Donor pool and associated risks During the last decade both the cadaveric and live donor pool has grown. During this time period the cadaveric pool has increased by 29% while the live donor pool has increased by 45% [1]. This growth has been attributed to public awareness and patient education programs. In recent years the highest per capita donation has been in Barcelona, Spain [16]. This country has routinely utilized older donors with this organ procurement organization accessing donors well above 60 years of age. Currently in the United States donors in 50–64 year group have shown the greatest growth [1]. During the period from 1990 to the first quarter in 2006 cadaveric donors increased from 15% to 27% of the donor pool, while live donors increased from 13% to 23% (p < 0.0001). The percent of donors older than 65 did not increase in the live donor pool while the cadaveric pool realized an 8% growth from 2% to 10%. This increase in donor age will theoretically translate into a higher incidence of donors with a malignancy and
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subsequently cancer transmission. The most concerning issue facing the use of older donors is the fact that the majority of donor transmitted malignancies had no prior history of malignancy. This fact should alert organ procurement agencies and transplant physicians to these potentially fatal transmissions. Both groups should be diligent in donor evaluation both pre-donation as well as intra-operatively. 5. Donor assessment Initial donor evaluations are often extensive but may not uncover a history of an active or treated malignancy. Often a history of a ‘‘tumor’’ will arise. This is valuable but often confusing. Many breast, brain or gynecologic tumors may be benign. In the United States the incidence of non-melanoma skin cancer are not recorded by the American Cancer Society. A history of an excised skin lesion can be a most vexing issue during donor evaluation, since this may be a simple basal cell cancer with almost no chance of donor transmission or an invasive malignant melanoma with a staggering rate of transmission with often fatal outcomes. Obviously pathologic reports are extremely valuable and are the most reliable documents in donor evaluation however these may be unrecoverable due to remote resections or a rapid organ recovery due to patient instability. To minimize the risk of unrecognized melanoma the recovery team should assess the resection site for a prior wide resection or skin graft. Often invasive melanoma patients will have a node sampling or a formal nodal dissection. These incisions will often provide a clue to the histology and invasiveness of a malignancy. The history of prior breast surgery can also lend to uncertainty in donor suitability. Each year in the United States over 214,000 cases of invasive breast cancer are diagnosed [14]. During this same time interval over 60,000 cases of in situ cancer are diagnosed and treated. In situ breast cancer is merely markers of potential synchronous or metachronous cancer. Subsequently in situ cancer by itself is not a contraindication to donor utilization. During donor assessment one should be aware that appropriate management of in situ (DCIS) breast cancer includes surgical re-resection or local radiation. This point is critical because axillary sampling or nodal dissection is not routine and will often provide insight into the diagnosis. In general a significant number of invasive cancers will be treated with systemic chemotherapy and should be cautiously used as a gauge for extent of disease. Colon cancer is another common malignancy in the general population [14]. Despite few reported cases of donor transmission the increasing incidence of colorectal cancer with advancing age is a considerable concern for potential donors [14]. At the age of 65 the incidence of colorectal cancer is nearly 200 per 100,000 for females
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and 300 per 100,000 for males. By age 75 this increases by almost an additional 100 to 200 cases, respectively [14]. Since screening colonoscopy is poorly adhered and intervals between screenings are controversial the incidence of undiagnosed colorectal cancer in donors is uncertain. Brain tumors appear to be the most abundant source of potential donors with active or treated malignancy. Unfortunately, these patients are the most controversial group of potential donors. Transmission of malignant brain tumors from donors to recipients often occurs in the setting of high grade tumors, extensive craniotomies or ventricular shunts. Several other important issues must be examined in these donors: (1) several donor transmissions have occurred in the setting of undiagnosed brain tumors in the setting of acute cerebral hemorrhage, (2) stereotactic brain biopsies can be inaccurate due to sampling errors of inheterogeneous tumors, (3) brain tumors can often change their tumor biology becoming more aggressive and higher grade. All these issues are extremely important in assessing acceptable risk. In a situation of excessive mortality without transplantation a patient and their physicians may accept a significant risk of donor cancer transmission in lieu of certain death. 6. Intra-operative donor evaluation One critical step in donor management involves the intra-operative conduct of the donor operation. A careful examination of donor scars may provide a significant insight into prior treated malignancies and alert the procurement team that further investigation may be necessary. Once the donor is explored a thorough and careful examination of the body cavity should be made. In the thoracic cavity this includes bimanual palpation of the lungs, visual inspection of both the pericardium, and mediastinal lymph nodes. Inspection of the abdominal cavity should include inspection of the liver, stomach, colon, small bowel and pelvis. In women careful attention should be turned to the pelvis with inspection of the ovaries and uterus. In general, careful attention should be given to enlarged lymph nodes particularly in the iliac fossa, mesentery, porta-hepatis, and paraaortic region. A not too uncommon dilemma faced by organ procurement teams is the post-explantation discovery of an incidental renal cell carcinoma. Unfortunately careful inspection of the kidneys is not achieved until well after cross-clamp and explantation. These lesions are often only discovered during back table preparation of the kidneys with small or even large renal cell carcinomas can be uncovered. At this point both heart and lung and often liver teams are returning to their home institutions where the recipient explantation is often near complete. This results in a great dilemma for the recipient team to re-transplant or observe. In
the last six years UNOS established a priority for retransplantation of recipients who have received an organ from a donor with an active malignancy. Despite re-transplantation of five recipients, two suffered metastatic disease and succumbed to donor transmitted malignancy [7,17–19]. One controversial area of donor management that has not been addressed is the presence of atypical cerebral hemorrhage as donor etiology. Several cases of donor transmission have arisen in the setting of a misdiagnosed cerebral hemorrhage which later was diagnosed as a primary brain tumor or metastatic cancers to the brain [20]. This situation is particularly concerning, since the proper diagnosis may require extensive diagnostic testing or a post-donation brain autopsy. Obviously these diagnostic maneuvers are excessive in the evaluation of all cerebral hemorrhage donors, however in those patients that appear atypical for a brain bleed a post-donation autopsy may be a reasonable maneuver to avert further unwanted donor malignancy transmissions. In conclusion, careful evaluation of potential donors can provide some valuable data for the transplant team, unfortunately a significant number of donor transmissions have occurred with no prior history. This may become a more common event as the average donor age increases. In the use of older donors or organs from donors with known malignancies the transplant groups should provide informed consent with a reasonable estimate for donor transmission based on tumor histology and grade. Lastly, rapid identification of donor transmissions with notification to all recipients is critical for utilization of emergent re-transplantation. References [1] 2005 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry for Transplant Recipients: Transplant Data 1004-2005. Department of Health and Human Services, Health Resources and Services Administration, Office of Special Programs. Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, Mich. [2] Penn I. Donor transmitted disease: cancer. Transplant Proc 1991;23:2629–2631. [3] Penn I. Malignancy in transplanted organs. Trans Int 1993;6:1–3. [4] Buell JF, Trofe J, Goss TG, Hanaway MJ, Beebe T, Alloway RR, et al. Donors with central nervous system malignancies: are they truly safe?. Transplantation 2003;75:340–343. [5] Penn I. Transmission of cancer from organ donors. Ann Transplant 1997;2:7–12. [6] Buell JF, Beebe TM, Trofe J, et al. Donor transmitted malignancies. Ann Transplant 2004;9:53–56. [7] UNOS/OPTN Data query. [8] Kauffman HM, McBride MA, Delmonico FL. First report of the United Network for Organ Sharing Transplant Tumor Registry: donors with a history of cancer. Transplantation 2000;70:1747–1751.
Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513 [9] Kauffman HM, McBride MA, Cherikh WS, Spain PC, Mares WH, Roza AM. Transplant Tumor Registry: donor-related malignancies. Transplantation 2002;74:358–362. [10] Kaufman HM, McBride MA, Cherikh WS, et al. Donor-related malignancies. Transplant Rev 2002;16:177–180. [11] Kauffman HM. The United Network for Organ Sharing position on using donors with central nervous system malignancies. Transplantation 2005;79:622–623. [12] Birkeland SA, Strom HH. Risk for tumor and other disease transmission be transplantation. Transplantation 2002;27:1409–1413. [13] Buell JF. United Network for Organ Sharing Publication on Scientific Registry Transplant Recipients Central Nervous System Donor Cancer Transmission Data. Transplantation 2005;79:623. [14] Cancer Facts and Figures 2004. American Cancer Society website. [15] Adams R. The impact of breast or colon cancer. In: Presented at 3rd Annual ASTS Winter Symposium. Miami Beach, Florida. January 24–26, 2003.
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[16] Chang GJ, Mahanty HD, Ascher NL, Roberts JP. Expanding the donor pool: can the Spanish model work in the United States?. Am J Transplant 2003;3:1259–1263. [17] Kreisnel D, Engels FH, Krupnick AS, Szeto WY, Krasinskas AM, Popma SH, et al. Emergent lung retransplantation after discovery of two primary malignancies in the donor. Transplantation 2001;71:1859–1862. [18] Loren AW, Desai S, Gorman RC, Schuchter LM. Retransplantation of a cardiac allograft inadvertently harvested from a donor with metastatic melanoma. Transplantation 2003;76: 741–743. [19] Lipshutz GS, Baxter-Lowe LA, Nguyen T, et al. Death from donor-transmitted malignancy despite emergency liver retransplantation. Liver Transpl 2003;9:1102–1107. [20] Buell JF, Beebe TM, Gross TG, Hanaway MJ, Alloway RR, Trofe J, et al. Donor assessment: is a policy change warranted? Am J Transplant 2004. doi:10.1016/j.jhep.2006.07.019
How should we evaluate organ donors with active or prior infections? Nicolas J. Mueller1,*, Jay A. Fishman2 2
1 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zu¨rich, Switzerland Transplant Infectious Disease and Compromised Host Program, Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
1. Introduction The spectrum of infections that infect the immunocompromised organ transplant recipient is a reflection of the degree of immune deficits of these hosts [1]. Infections that are derived from the donor tissues and activated in the recipient are among the most common and important exposures in transplantation. Some of these are latent while others are the result of bad timing – active infection transmitted at the time of transplantation. The pre-transplant assessment of a potential organ donor is aimed at minimizing the risk of transmission of such infections to the compromised recipient. This is particularly important in liver transplantation, where infections have an important impact on success of transplantation [2]. This summary focuses on the liver donor,
*
Corresponding author. Tel.: +41 44 255 3712; fax: +41 44 255 3291. E-mail address: [email protected] (N.J. Mueller). Abbreviations: CMV, cytomegalovirus; EBV, Epstein Barr virus; HBsAg, hepatitis B surface antigen; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; WNV, West Nile virus; LCMV, lymphocytic choriomeningitis virus.
however, the principles outlined are also valid for other solid organ donors. 2. Categories of donor-derived infections A number of types of infection merit consideration [3]: (1) Donors who are bacteremic or fungemic at the time of donation – these are often due to nosocomial pathogens, are often line-related, and include vancomycin, linezolid- and quinupristin–dalfopristin-resistant enterococci, methicillin-resistant staphylococci, pneumococus, Salmonella, Pseudomonas, Escherichia coli, fluconazole-resistant Candida species or Aspergillus species. These organisms tend to ‘‘stick’’ to anastomotic sites (vascular, urinary) and colonize fluid collections (e.g., hematomas) to form abscesses or mycotic aneurysms. Also in this group are the common causes of meningitis: meningococcus, pneumococcus and Hemophilus influenzae. (2) Donors that are actively viremic (often asymptomatic) at the time of donation – including HIV, West Nile virus, rabies, herpes simplex virus, respiratory viruses, lymphocytic choriomeningitis virus (LCMV) and hepatitis viruses (A, B, and C, possibly E). (3) Latent viral infections commonly transmitted
References [1] Weber M, Dindo D, Demartines N, Ambuhl PM, Clavien PA. Kidney transplantation from donors without a heartbeat. N Engl J Med 2002;347:248–255. [2] D’ Alessandro AM, Hoffmann RM, Knechtle SJ, et al. Successful extra-renal transplantation from non-heart-beating donors. Transplantation 1995;59:977–982. [3] Casavilla A, Ramirez C, Shapiro R, et al. Experience with liver and kidney allografts from non-heart-beating donors. Transplantation 1995;59:197–203. [4] A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337–340. [5] Kootstra G, Daemen JH, Oomen AP. Categories of non-heartbeating donors. Transplant Proc 1995;27:2893–2894. [6] Muiesan P, Girlanda R, Jassem W, et al. Single-centre experience with liver transplantation from controlled non-heartbeating donors: a viable source of grafts. Ann Surg 2005;242:732–738. [7] Alvarez J, del Barrio MR, Arias J, et al. Five years of experience with non-heart-beating donors coming from the streets. Transplant Proc 2002;34:2589–2590. [8] Abt PL, Crawford MD, Desai NM, et al. Liver transplantation from controlled non-heart-beating donors: an increased incidence of biliary complications. Transplantation 2003;75:1659–1663. [9] Monbaliu D, Crabbe T, Roskams T, et al. Livers from non-heartbeating donors tolerate short periods of warm ischemia. Transplantation 2005;79:1226–1230. [10] Uchiyama M, Matsuno K, Hama H, et al. Comparison between nonpulsatile and pulsatile machine perfusion preservation in liver transplantation from non-heart-beating donors. Transplant Proc 2001;33:936–938. [11] D’Alessandro AM, Fernandez LA, Chin LT, et al. Donation after cardiac death: the University of Wisconsin experience. Ann Transplant 2004;9:68–71. [12] Abt PL, Desai NM, Crawford MD, et al. Survival following liver transplantation from non-heart-beating donors. Ann Surg 2004;239:87–92.
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[13] Foley DP, Fernandez LA, Leverson G, et al. Donation after cardiac death: the University of Wisconsin experience with liver transplantation. Ann Surg 2005;242:724–731. [14] Manzarbeitia CY, Ortiz JA, Jeon H, et al. Long-term outcome of controlled, non-heart-beating donor liver transplantation. Transplantation 2004;78:211–215. [15] Muiesan P, Jassem W, Girlanda R, et al. Segmental liver transplantation from non-heart beating donors–an early experience with implications for the future. Am J Transplant 2006;6:1012–1016. [16] Nicholson ML, Metcalfe MS, White SA, et al. A comparison of the results of renal transplantation from non-heart-beating, conventional cadaveric, and living donors. Kidney Int 2000;58:2585–2591. [17] Sanchez-Fructuoso AI, de Miguel Marques, Prats D, et al. Nonheart-beating donors: experience from the Hospital Clinico of Madrid. J Nephrol 2003;16:387–392. [18] Alvarez J, del Barrio R, Arias J, et al. Non-heart-beating donors from the streets: an increasing donor pool source. Transplantation 2000;70:314–317. [19] Otero A, Gomez-Gutierrez M, Suarez F, et al. Liver transplantation from Maastricht category 2 non-heart-beating donors: a source to increase the donor pool?. Transplant Proc 2004;36:747–750. [20] Quintela J, Gala B, Baamonde I, et al. Long-term results for liver transplantation from non-heart-beating donors maintained with chest and abdominal compression-decompression. Transplant Proc 2005;37:3857–3858. [21] Reddy S, Greenwood J, Maniakin N, et al. Non-heart-beating donor porcine livers: the adverse effect of cooling. Liver Transpl 2005;11:35–38. [22] Fukunaga K, Takada Y, Taniguchi H, et al. Endothelin antagonist treatment for successful liver transplantation from non-heart-beating donors. Transplantation 1999;67:328–332. [23] Dutkowski P, Graf R, Clavien PA. Rescue of the cold preserved rat liver by hypothermic oxygenated machine perfusion. Am J Transplant 2006;6:903–912. doi:10.1016/j.jhep.2006.07.018
How can donors with a previous malignancy be evaluated? Joseph F. Buell*, Rita R. Alloway, E. Steve Woodle The University of Cincinnati, Division of Transplantation, Cincinnati, OH, USA
1. Introduction Solid organ transplantation has flourished over the last three decades with improvements in surgical technique and modern immunosuppression resulting in * Corresponding author. Tel.: +1 513 558 6010; fax: +1 513 558 3580. E-mail address: [email protected] (J.F. Buell). Abbreviations: OPTN, Organ Procurement and Transplantation Network; UNOS, united network for organ sharing; DCIS, ductal carcinoma in situ.
improved patient outcomes. Traditionally, solid organ transplantation has been limited by organ availability. The principal source of these organs has been cadaveric donation. A steady increase in organ donation was observed in the early 1990s realized through public awareness and education programs [1]. Concurrently several surgical innovations in live donor kidney, pancreas, liver and intestinal transplantation have also contributed to an increase in transplants. However, both efforts have appeared to have achieved a plateau in the last few years.
504
Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513
2. Incidence of donor transmission This year over 98,000 patients are awaiting a solid organ transplant with less than 15,000 donors currently available [1]. This disparity in organs has led to a reevaluation of certain cadaveric donors. This group known as extended criteria donors has included older (>65 or 75 years) patients, patients with a history of (viral) infection or active or treated malignancies. This portion of donors comprises a small but extremely controversial source of all donor organs. This point has been punctuated by several dramatic cases of fatal transmission in multiple recipients from a single donor [2–6]. In 1996 the OPTN began to track donors with a history of treated or active malignancy. During this time period 62,041 donors were utilized, with 1778 (2.9%) having either an active or treated malignancy [7]. Notably during this time period a dramatic rise in cancer donors was observed. During the 60 month period from 2001 to 2005 a 3.2% incidence of cancer donors was identified in comparison to a 2.5% incidence during the prior 48month period (p < 0.0001) [7]. During the last six years UNOS/OPTN has reviewed their experience with reported cancer transmission in donors with a history of malignancy. The first study failed to confirm any cases of cancer transmission from donors with a history of malignancy [8]. The subsequent studies did identify donor cancer transmission in a cohort of recipients from cadaveric and live donors [9– 11]. A similar study was performed through the Danish Cancer Registry [12]. This study also quantified the risk in a population-based register of 1.3% for having a donor with an undetected malignancy and 0.2% risk of getting a transmitted cancer. In the most recent commentary from the UNOS/OPTN a cancer transmission rate of 0.018% was identified utilizing a cadaveric donor
Table 1 Donor transmission rates Tumor type
Cases
Transmission (%)
Recommendation
Skin SCC Melanoma
10 38
0 74
Low risk Excessive risk (avoid)
Brain Grade I/II Grade III/IV RCC Breast Colon Lung
67 33 34 70 9 16 29
25 0 40 61 29 19 43
a
Low risk High riska Intermediate riskb Intermediate riskc Intermediate riskc High risk (avoid)
Transmission is associated with high mortality. Transmission is frequently limited to the graft but higher grade tumors can lead to lethal transmission. c Transmission is associated with high mortality and is related to both tumor stage and interval from diagnosis. b
source [11]. Despite this low incidence reported by UNOS/OPTN the Penn Tumor Registry continued to identify multiple cases of donor cancer transmission [13] Table 1. 3. Distribution of donor malignancies As reported by the first OPTN article, the most common cancer history in an organ donor was skin malignancy [8]. The majority of these organs were utilized in kidney recipients. This was also observed in the 296 organ donors with cancer reported to the Penn Tumor Registry [6]. Organs from donors with a cancer history were also utilized in liver, heart, lung and pancreas recipients. However, a significantly higher transmission rate was observed in the Penn Tumor Registry with 124 cases (42%) of confirmed donor transmission [4]. The incidence of donor malignancy transmission was uniform among allograft recipients, occurring in 45% of renal allograft recipients (99/222), 37% of liver allograft recipients (14/38), and 30% of cardiac allograft recipients (8/27). There was one case (25%) that occurred in the pancreas group and three cases that occurred among the lung recipients (60%). The majority of donors involved in this study were cadaveric (n = 296); there were three living unrelated donors and the remainder were living-related donors. Mean donor age was 37.4 ± 15.0 years of age. Importantly only seventy-six (26%) of the donors had a known history of active or prior malignancy. The mean time from transplantation to presentation of the donor malignancy transmission was 2 months, with a range of 2 days to 38 months [6]. In the UNOS/OPTN report the second most common cancer in donors with a cancer history was brain tumors. This report identified a lack of precise histology in 73% of donor records [8]. In the last summary statement by UNOS/OPTN one transmission in 174 donors utilized in 528 recipients was identified establishing a transmission rate of 0.6% [11]. This report did note that 116 of these donors had potentially high grade cancers with a transmission rate of 0.9%. In the Penn Tumor Registry an overall transmission rate of 23% was observed with all brain tumors. In high grade tumors, donors with extensive crainitomies or ventricular shunts this rate was as high as 43% [4]. In a review of all reported glioblastomas, histologic grading was correlated to donor transmission. This study confirmed no donor transmission in grade I or II glioblastomas. All confirmed donor transmissions occurred in donors with histologically high grades of III or IV (glioblastoma multiforme). In the Penn Tumor experience two donor tumors were noted to have high transmission rates: malignant melanoma and choriocarcinoma [2,4]. Choriocarcinoma, a gynecologic malignancy, had an identified transmission rate of 93%, with a resulting 64% mortality
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rate. The other donor tumor was malignant melanoma. Malignant melanoma has demonstrated a 74% tumor transmission rate with a resulting 58% mortality [6]. Two leading cancers common to both male and female donors are lung and colon. In the United States they comprise 23% of all newly diagnosed cancers [14]. Both cancers are noted to have an increasing probability of invasive cancer with advancing age. In the first 40 years the probability of invasive lung cancer is 0.03% which dramatically increases to 6.3% after age 70 [14]. An equally dramatic rise in probability was noted in colon and rectal cancer with a 0.07% rate at age 40 compared to 4.9% at age 70 [14]. Both cancers are also more prevalent in the African American population. In the Penn Tumor Experience utilization of organs from donors with a treated or active lung malignancy resulted in a 43% tumor transmission rate, with a corresponding 32% percent mortality rate [6]. Limited data are available on utilization of donors with a history of colon cancer. In the Penn Tumor Experience a handful of patients experienced a transmission rate of 19% [2,6]. Recently, during a recent consensus conference of American Society of Transplant Surgeons, Reid Adams, M.D., noted that the incidence of nodal or metastatic disease associated with colon cancer having a primary tumor classification of T1 is less than 1%. With primary tumors classified as T2 or T3, the incidence increases, with overall survival decreasing until a period seven years post-resection [15]. Thus, he concluded that the risks associated with the use of donors with a primary tumor classification of T1/T2 are acceptable in Caucasian males and any race females after a five year disease free interval, while organs from African American or T3 lesions donors should never be considered [15]. 4. Donor pool and associated risks During the last decade both the cadaveric and live donor pool has grown. During this time period the cadaveric pool has increased by 29% while the live donor pool has increased by 45% [1]. This growth has been attributed to public awareness and patient education programs. In recent years the highest per capita donation has been in Barcelona, Spain [16]. This country has routinely utilized older donors with this organ procurement organization accessing donors well above 60 years of age. Currently in the United States donors in 50–64 year group have shown the greatest growth [1]. During the period from 1990 to the first quarter in 2006 cadaveric donors increased from 15% to 27% of the donor pool, while live donors increased from 13% to 23% (p < 0.0001). The percent of donors older than 65 did not increase in the live donor pool while the cadaveric pool realized an 8% growth from 2% to 10%. This increase in donor age will theoretically translate into a higher incidence of donors with a malignancy and
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subsequently cancer transmission. The most concerning issue facing the use of older donors is the fact that the majority of donor transmitted malignancies had no prior history of malignancy. This fact should alert organ procurement agencies and transplant physicians to these potentially fatal transmissions. Both groups should be diligent in donor evaluation both pre-donation as well as intra-operatively. 5. Donor assessment Initial donor evaluations are often extensive but may not uncover a history of an active or treated malignancy. Often a history of a ‘‘tumor’’ will arise. This is valuable but often confusing. Many breast, brain or gynecologic tumors may be benign. In the United States the incidence of non-melanoma skin cancer are not recorded by the American Cancer Society. A history of an excised skin lesion can be a most vexing issue during donor evaluation, since this may be a simple basal cell cancer with almost no chance of donor transmission or an invasive malignant melanoma with a staggering rate of transmission with often fatal outcomes. Obviously pathologic reports are extremely valuable and are the most reliable documents in donor evaluation however these may be unrecoverable due to remote resections or a rapid organ recovery due to patient instability. To minimize the risk of unrecognized melanoma the recovery team should assess the resection site for a prior wide resection or skin graft. Often invasive melanoma patients will have a node sampling or a formal nodal dissection. These incisions will often provide a clue to the histology and invasiveness of a malignancy. The history of prior breast surgery can also lend to uncertainty in donor suitability. Each year in the United States over 214,000 cases of invasive breast cancer are diagnosed [14]. During this same time interval over 60,000 cases of in situ cancer are diagnosed and treated. In situ breast cancer is merely markers of potential synchronous or metachronous cancer. Subsequently in situ cancer by itself is not a contraindication to donor utilization. During donor assessment one should be aware that appropriate management of in situ (DCIS) breast cancer includes surgical re-resection or local radiation. This point is critical because axillary sampling or nodal dissection is not routine and will often provide insight into the diagnosis. In general a significant number of invasive cancers will be treated with systemic chemotherapy and should be cautiously used as a gauge for extent of disease. Colon cancer is another common malignancy in the general population [14]. Despite few reported cases of donor transmission the increasing incidence of colorectal cancer with advancing age is a considerable concern for potential donors [14]. At the age of 65 the incidence of colorectal cancer is nearly 200 per 100,000 for females
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and 300 per 100,000 for males. By age 75 this increases by almost an additional 100 to 200 cases, respectively [14]. Since screening colonoscopy is poorly adhered and intervals between screenings are controversial the incidence of undiagnosed colorectal cancer in donors is uncertain. Brain tumors appear to be the most abundant source of potential donors with active or treated malignancy. Unfortunately, these patients are the most controversial group of potential donors. Transmission of malignant brain tumors from donors to recipients often occurs in the setting of high grade tumors, extensive craniotomies or ventricular shunts. Several other important issues must be examined in these donors: (1) several donor transmissions have occurred in the setting of undiagnosed brain tumors in the setting of acute cerebral hemorrhage, (2) stereotactic brain biopsies can be inaccurate due to sampling errors of inheterogeneous tumors, (3) brain tumors can often change their tumor biology becoming more aggressive and higher grade. All these issues are extremely important in assessing acceptable risk. In a situation of excessive mortality without transplantation a patient and their physicians may accept a significant risk of donor cancer transmission in lieu of certain death. 6. Intra-operative donor evaluation One critical step in donor management involves the intra-operative conduct of the donor operation. A careful examination of donor scars may provide a significant insight into prior treated malignancies and alert the procurement team that further investigation may be necessary. Once the donor is explored a thorough and careful examination of the body cavity should be made. In the thoracic cavity this includes bimanual palpation of the lungs, visual inspection of both the pericardium, and mediastinal lymph nodes. Inspection of the abdominal cavity should include inspection of the liver, stomach, colon, small bowel and pelvis. In women careful attention should be turned to the pelvis with inspection of the ovaries and uterus. In general, careful attention should be given to enlarged lymph nodes particularly in the iliac fossa, mesentery, porta-hepatis, and paraaortic region. A not too uncommon dilemma faced by organ procurement teams is the post-explantation discovery of an incidental renal cell carcinoma. Unfortunately careful inspection of the kidneys is not achieved until well after cross-clamp and explantation. These lesions are often only discovered during back table preparation of the kidneys with small or even large renal cell carcinomas can be uncovered. At this point both heart and lung and often liver teams are returning to their home institutions where the recipient explantation is often near complete. This results in a great dilemma for the recipient team to re-transplant or observe. In
the last six years UNOS established a priority for retransplantation of recipients who have received an organ from a donor with an active malignancy. Despite re-transplantation of five recipients, two suffered metastatic disease and succumbed to donor transmitted malignancy [7,17–19]. One controversial area of donor management that has not been addressed is the presence of atypical cerebral hemorrhage as donor etiology. Several cases of donor transmission have arisen in the setting of a misdiagnosed cerebral hemorrhage which later was diagnosed as a primary brain tumor or metastatic cancers to the brain [20]. This situation is particularly concerning, since the proper diagnosis may require extensive diagnostic testing or a post-donation brain autopsy. Obviously these diagnostic maneuvers are excessive in the evaluation of all cerebral hemorrhage donors, however in those patients that appear atypical for a brain bleed a post-donation autopsy may be a reasonable maneuver to avert further unwanted donor malignancy transmissions. In conclusion, careful evaluation of potential donors can provide some valuable data for the transplant team, unfortunately a significant number of donor transmissions have occurred with no prior history. This may become a more common event as the average donor age increases. In the use of older donors or organs from donors with known malignancies the transplant groups should provide informed consent with a reasonable estimate for donor transmission based on tumor histology and grade. Lastly, rapid identification of donor transmissions with notification to all recipients is critical for utilization of emergent re-transplantation. References [1] 2005 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry for Transplant Recipients: Transplant Data 1004-2005. Department of Health and Human Services, Health Resources and Services Administration, Office of Special Programs. Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, Mich. [2] Penn I. Donor transmitted disease: cancer. Transplant Proc 1991;23:2629–2631. [3] Penn I. Malignancy in transplanted organs. Trans Int 1993;6:1–3. [4] Buell JF, Trofe J, Goss TG, Hanaway MJ, Beebe T, Alloway RR, et al. Donors with central nervous system malignancies: are they truly safe?. Transplantation 2003;75:340–343. [5] Penn I. Transmission of cancer from organ donors. Ann Transplant 1997;2:7–12. [6] Buell JF, Beebe TM, Trofe J, et al. Donor transmitted malignancies. Ann Transplant 2004;9:53–56. [7] UNOS/OPTN Data query. [8] Kauffman HM, McBride MA, Delmonico FL. First report of the United Network for Organ Sharing Transplant Tumor Registry: donors with a history of cancer. Transplantation 2000;70:1747–1751.
Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483–513 [9] Kauffman HM, McBride MA, Cherikh WS, Spain PC, Mares WH, Roza AM. Transplant Tumor Registry: donor-related malignancies. Transplantation 2002;74:358–362. [10] Kaufman HM, McBride MA, Cherikh WS, et al. Donor-related malignancies. Transplant Rev 2002;16:177–180. [11] Kauffman HM. The United Network for Organ Sharing position on using donors with central nervous system malignancies. Transplantation 2005;79:622–623. [12] Birkeland SA, Strom HH. Risk for tumor and other disease transmission be transplantation. Transplantation 2002;27:1409–1413. [13] Buell JF. United Network for Organ Sharing Publication on Scientific Registry Transplant Recipients Central Nervous System Donor Cancer Transmission Data. Transplantation 2005;79:623. [14] Cancer Facts and Figures 2004. American Cancer Society website. [15] Adams R. The impact of breast or colon cancer. In: Presented at 3rd Annual ASTS Winter Symposium. Miami Beach, Florida. January 24–26, 2003.
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[16] Chang GJ, Mahanty HD, Ascher NL, Roberts JP. Expanding the donor pool: can the Spanish model work in the United States?. Am J Transplant 2003;3:1259–1263. [17] Kreisnel D, Engels FH, Krupnick AS, Szeto WY, Krasinskas AM, Popma SH, et al. Emergent lung retransplantation after discovery of two primary malignancies in the donor. Transplantation 2001;71:1859–1862. [18] Loren AW, Desai S, Gorman RC, Schuchter LM. Retransplantation of a cardiac allograft inadvertently harvested from a donor with metastatic melanoma. Transplantation 2003;76: 741–743. [19] Lipshutz GS, Baxter-Lowe LA, Nguyen T, et al. Death from donor-transmitted malignancy despite emergency liver retransplantation. Liver Transpl 2003;9:1102–1107. [20] Buell JF, Beebe TM, Gross TG, Hanaway MJ, Alloway RR, Trofe J, et al. Donor assessment: is a policy change warranted? Am J Transplant 2004. doi:10.1016/j.jhep.2006.07.019
How should we evaluate organ donors with active or prior infections? Nicolas J. Mueller1,*, Jay A. Fishman2 2
1 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zu¨rich, Switzerland Transplant Infectious Disease and Compromised Host Program, Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
1. Introduction The spectrum of infections that infect the immunocompromised organ transplant recipient is a reflection of the degree of immune deficits of these hosts [1]. Infections that are derived from the donor tissues and activated in the recipient are among the most common and important exposures in transplantation. Some of these are latent while others are the result of bad timing – active infection transmitted at the time of transplantation. The pre-transplant assessment of a potential organ donor is aimed at minimizing the risk of transmission of such infections to the compromised recipient. This is particularly important in liver transplantation, where infections have an important impact on success of transplantation [2]. This summary focuses on the liver donor,
*
Corresponding author. Tel.: +41 44 255 3712; fax: +41 44 255 3291. E-mail address: [email protected] (N.J. Mueller). Abbreviations: CMV, cytomegalovirus; EBV, Epstein Barr virus; HBsAg, hepatitis B surface antigen; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; WNV, West Nile virus; LCMV, lymphocytic choriomeningitis virus.
however, the principles outlined are also valid for other solid organ donors. 2. Categories of donor-derived infections A number of types of infection merit consideration [3]: (1) Donors who are bacteremic or fungemic at the time of donation – these are often due to nosocomial pathogens, are often line-related, and include vancomycin, linezolid- and quinupristin–dalfopristin-resistant enterococci, methicillin-resistant staphylococci, pneumococus, Salmonella, Pseudomonas, Escherichia coli, fluconazole-resistant Candida species or Aspergillus species. These organisms tend to ‘‘stick’’ to anastomotic sites (vascular, urinary) and colonize fluid collections (e.g., hematomas) to form abscesses or mycotic aneurysms. Also in this group are the common causes of meningitis: meningococcus, pneumococcus and Hemophilus influenzae. (2) Donors that are actively viremic (often asymptomatic) at the time of donation – including HIV, West Nile virus, rabies, herpes simplex virus, respiratory viruses, lymphocytic choriomeningitis virus (LCMV) and hepatitis viruses (A, B, and C, possibly E). (3) Latent viral infections commonly transmitted