Tumors and Transplantation: The 2003 Third Annual ASTS State-of-the-Art Winter Symposium

Abstract

Malignancies in donors, transplant candidates, and transplant recipients is a challenge increasingly faced by the transplant community. The Third Annual American Society of Transplant Surgeons' Winter Symposium, entitled ‘Tumors and Transplantation’ assembled a diverse faculty of physicians, surgeons, and scientists to explore this topic in detail. By bringing together data and expertise, the goals of the Symposium were to review the current status of our knowledge, to assess how this knowledge has been applied to patient care, and to identify areas lacking data that are in need of further study. In an era of critical organ shortage where donor criteria are continuously expanding, the Symposium began by examining donor-transmitted malignancy. Kauffman [United Network for Organ Sharing (UNOS)] reported that the UNOS Tumor Registry data (April 1, 1994 through January 24, 2001) demonstrated extremely low rates of donor cancer transmission through organ transplantation (Table 1; 1). Data on central nervous system (CNS) tumors were discussed by Kauffman and Buell (University of Cincinnati). Despite 13 000 glioma deaths annually in the United States, patients with CNS tumors comprise less than 1% of all organ donors (50–60 annually). There was consensus that certain histologic types such as glioblastoma multiforme, the most aggressive form of glioma, and medulloblastoma along with clinical factors such as ventricular shunting, major craniotomy and/or extensive radiation increase the risk of tumor transmission. The Israel Penn International Transplant Tumor Registry (IPITTR) data identified a 7% rate of CNS tumor transmission in the absence of any risk factors and a 43% transmission rate in the presence of one or more risk factor(s) (2). This high rate of CNS tumor transmission, even in cases without risk factors for transmission, is in stark contrast to two recent reports. The UNOS Tumor Registry reviewed 397 donors with primary CNS tumors from January 1, 1992 through December 31, 1999 (3) and the Australian and New Zealand Organ Donation Registry reviewed 46 donors with primary CNS tumors from January 1989 through December 1996 (4). There were no cases of CNS tumor transmission in either series. The expanded time period of the IPITTR and its historical focus on the collection of index cases most likely explain the discrepant transmission risks reported by the three registries. Holland (Memorial Sloan Kettering Cancer Center) provided insight into the presentation, classification, and biology of gliomas. He presented several lines of molecular evidence supporting the intriguing hypothesis that the malignant nature of gliomas, including its propensity to metastasize widely within the brain, is driven by abnormalities in cellular differentiation status (5). Seventy percent of glioblastoma multiforme tumors exhibit elevated activity of Akt and its downstream component mTOR, the mammalian target of rapamycin. Elevated Akt activity is thought to promote glioma tumor cell survival in inhospitable environments, such as non-CNS environments including the peripheral circulation or transplantable organs. The important problem of renal cell carcinoma (RCC) transmission was discussed by Buell and Jacobs (University of Maryland). IPITTR data showed a RCC tumor transmission rate of 61% (43/70 cases) with a transmission-related mortality of 23.2% (10/43 cases) (6). Interestingly, no transmission occurred after local excision of small (median diameter 2.5 cm, range 2–5 cm) or low Fuhrman grade (I or II) tumors after procurement, but either prior to (14 cases) or after transplantation (three cases). Jacobs confirmed the curative potential of local excision strategies, citing the increasing use of partial nephrectomies as definitive therapy for RCC in the general population, a practice supported by data indicating that tumor-free margins of as little as 5 mm or less were acceptable and safe. Nevertheless, in the general population, small tumors (<2.5 cm) of low or high Fuhrman grade carry a 7–8% lifetime recurrence rate. Adams (University of Virginia) discussed the appropriateness of using organs from donors with a history of either breast or colon cancer. Although these patients contribute only a small number of potential organs to the pool, the increasing tendency for early detection along with the escalating age of our donor population motivate the discussion. Basing his arguments and recommendations on the existing cancer literature, Adams suggested that the low incidence of tumor recurrence and tumor-related mortality in the setting of early stage breast (7) and colon cancer (8) justifies the utilization of organs from these donors (Table 2). There was consensus that melanoma, choriocarcinoma, and lung cancer are associated with extremely high transmission rates and subsequent mortality and should be absolute contraindications to organ donation. Despite prolonged disease-free intervals even in the general population, melanomas have been known to recur up to 20 years after primary excision. The conference considered the appropriate selection of transplant candidates with a history of cancer. Clearly, the concerns include the immeasurable impact of immunosuppression on the risk of cancer recurrence balanced against the risk of death or ongoing morbidity without transplantation and the critical organ shortage. Woodle (University of Cincinnati), citing IPITTR data and Hariharan (Medical College of Wisconsin), citing UNOS data and the deliberations of a consensus conference (9), categorized the risk posed by various tumors based upon tumor type and stage (Table 3) and suggested recommendations for appropriate waiting periods between diagnosis and definitive cancer treatment and organ transplantation. As the number of transplant recipients with a history of cancer increases, there is a need for better information regarding the risk of recurrence relative to tumor type, stage, treatment, time from original diagnosis to transplantation, and degree of immunosuppression, along with information regarding the treatment responsiveness of post-transplant recurrent tumors and recipient survival. Currently, hepatocellular carcinoma (HCC) is an accepted indication for liver transplantation and outcomes of transplants for HCC meeting the Milan Criteria (10) mirror those of transplants for other indications. Approximately 80% of HCCs arise in cirrhotic livers, typically on a background of hepatitis B or C. Chari (Vanderbilt University) described how the use of transgenic mouse models has helped to elucidate the molecular pathogenesis of HCC in the setting of viral hepatitis (11). Marsh (University of Pittsburgh) presented recent data demonstrating that the molecular signature of HCC – specifically the loss of heterozygosity for informative microsatellite loci located within or near specific tumor suppressor genes of interest – correlates with post-transplant recurrence risk (12). The combination of genetic mutational data with an artificial neural network model predicted outcome for 91 of 103 cases. Of the 81 patients followed for greater than 3 years, outcomes were accurately predicted for all. The ability to accurately predict the risk of recurrence after transplantation may improve organ utilization by avoiding transplantation of patients with incurable disease. The issues of cadaveric liver allocation for candidates with HCC under the new continuous disease severity scoring system (MELD or Model for End-stage Liver Disease) were discussed. The initial HCC MELD exception was crafted based upon the recognition that the urgency of transplantation for candidates for HCC was determined by risk of progression to prohibitive tumor burden rather than the risk of dying. Yao (University of California San Francisco) examined the natural history of HCC in a cohort of 70 consecutive HCC patients to discern patterns and predictors of tumor progression resulting in dropout from the wait list (13). Monthly dropout rates remained low for the first 6 months, exponentially increasing thereafter to >9% per month by 12 months. Significant predictors of dropout included a single tumor >3 cm in diameter or the presence of three lesions at the time of diagnosis. Freeman (Tufts University) reported on transplantation for HCC during the first 6 months of MELD (February 2002–August 2002). After implementation of MELD, greater than 20% of cadaveric transplants have been performed in patients with HCC, a 3.5-fold increase over the same period in 2001. Patients with HCC were more likely to undergo transplantation and more quickly than patients without HCC with equivalent MELD scores. These data, in conjunction with the dropout data, have already led to an adjustment of the MELD HCC exception with a decrease in the MELD scores granted to HCC patients. Additional important issues that need to be studied and resolved include the optimal tumor burden limits for transplantation (14, 15) and the appropriate stratification of HCC candidates whose tumors have been down-staged by ablative therapies. Historically, it is well-recognized that virally induced malignancies, several of which will be individually discussed below, have increased prevalence in transplant recipients. Port [University of Michigan; Scientific Registry of Transplant Recipients (SRTR)], however, presented new and intriguing data from the merged databases of the SRTR and the Surveillance Epidemiology and End Results (SEER) Registry (an NCI-funded registry required to capture >98% of all malignancies excluding nonmelanoma skin cancer), which indicate a generalized increase in the incidence of de novo solid tumors in transplant recipients. The standardized incidence ratio (SIR) – the number of observed cases divided by the number of expected cases based upon age-matched controls – for de novo solid tumors in all recipients residing in a three county area of south-east Michigan (2525 patients) was 1.98 [95% confidence interval (CI) 1.6–2.4]. Most notably, the SIR for colon cancer was significantly elevated at 2.5 (CI 1.1–5.0). The SIR for RCC (including native and transplanted kidneys) was 7.1 (CI 3.4–13.0) in transplant recipients and 8.5 (CI 3.6–16.7) in kidney transplant recipients. Interestingly, as the SIR for RCC in dialysis patients is also elevated at 5.0, the increased incidence attributable to kidney transplantation alone did not reach statistical significance. The SIR for other common cancer sites such as lung (SIR 1.4), prostate (SIR 1.1) and breast (SIR 1.6) also did not reach statistical significance. Lung cancer, the leading cause of cancer death in the United States, was a topic of additional discussion. DiMaio (University of Texas Southwestern) reported that recent studies in the general population have demonstrated the efficacy of lung cancer screening protocols in high-risk groups. Low-dose helical computed tomography (CT) scans identified early stage lesions amenable to curative resection (16). According to the Cardiac Transplant Research Database, malignancy becomes the leading cause of death 5 years after heart transplantation. Lung cancers comprise 7% of de novo malignancy in heart transplant recipients, typically resulting rapidly in recipient death. DiMaio therefore urged centres to adopt aggressive surveillance strategy using low-dose CT for high-risk post-transplant patients (>10 pack/year smoking history) to facilitate early detection and thereby improve patient survival (17). Skin cancer, discussed by Otley (Mayo Clinic) and Salasche (University of Arizona), is the most common post-transplant malignancy affecting up to 70% of recipients within 20 years after transplantation, resulting in substantial morbidity and even mortality (18). Risk factors for skin cancer in transplant patients are the same as in the general population: ultraviolet (UV) radiation, genetic susceptibility, and possibly human papillomavirus (HPV) infection. It is suspected that immunosuppression compromises immune surveillance, leading to accelerated carcinogenesis from UV radiation and possibly HPV as well. In transplant recipients, skin cancers occur at an earlier age, occur more frequently, are multiple, and tend to be more aggressive than in the general population (19, 20). Squamous cell carcinomas (SCCs) far outnumber basal cell carcinomas in transplant recipients – the opposite of the predominance of basal cell carcinoma in the general population. Emphasis should be placed upon patient education. particularly regarding modifiable risk factors such as UV exposure, aggressive surveillance by physical examination, early identification and intervention, aggressive surgical margin control, and consideration of chemoprophylaxis for high-risk recipients. Although HPV is strongly linked to the pathogenesis of cervical and other anogenital cancers whose incidence are clearly increased in transplant recipients, its role in the development of nonmelanoma skin cancer is less well-established as discussed by Sligh (Vanderbilt University). Dermatologists identified, greater than 80 years ago, a rare HPV-associated disease in patients with an inherited immune defect characterized by the early onset (<6 years of age) of widespread warts which evolve to SCC typically by the fourth decade. Transplant recipients are known to have a greatly increased incidence of warts with 15–50% affected within 1 year and 50–90% affected by 5 years after transplantation. Warts typically precede the development of SCC in transplant recipients (21), again suggesting the role of HPV infection in skin cancer development. However, advances in genetic technologies enabling exquisitely sensitive HPV detection have resulted in conflicting reports as to whether skin cancers in transplant recipients have a higher incidence of HPV than in nontransplant patients (22, 23). The term PTLD encompasses an entire spectrum of diseases characterized by lymphoproliferation occurring in the post-transplant immunosuppressed setting. Nalesnik (University of Pittsburgh) opened the session by outlining the 2-year evolution of PTLD classification schemes culminating in the current 2001 World Health Organization system (Table 4; 24), while Hanto (Harvard Medical School) offered an alternative classification scheme encompassing pathogenesis and treatment implications (Table 4; 25). Both agreed that a complete clinicopathologic characterization of each PTLD case should include clinical presentation, histologic characteristics, tumor staging, phenotypic analysis to determine cell-type origin including CD20 expression, virologic analysis for EBV, and clonality studies based upon light-chain expression and immunoglobulin gene rearrangements. Unfortunately, as one turns to the questions of prevention and/or treatment of PTLD, it is clear that the literature is hampered by the heterogeneous nature of PTLD and a lack of large, randomized, multicentre clinical trials as discussed by Webber (University of Pittsburgh). Preventative interventions have emerged concomitant with the identification of risk factors and the ability to quantify peripheral blood EBV titres (26). Although those with high peripheral viral loads are at increased risk of developing disease, the optimal response to this ‘predisease state’– continued monitoring, reduction of immunosuppression, initiation of antiviral therapy, use of anti-CD20 monoclonal antibody, or possibly even cellular immunotherapy – remains to be determined. Treatment modalities for established PTLD have evolved into a hierarchical organization which reflects upon the nature of the disease (27). Historically, first-line therapies – reducing or stopping immunosuppression with or without initiation of antiviral therapy – are typically used for polymorphic and monomorphic PTLD. Risks of immunomodulation include rebound rejection, which can produce significant organ dysfunction. Second-line therapy – chemotherapy – while frequently used upfront for monomorphic PTLD, has been consistently applied to refractory or progressive disease or stable disease with concurrent rejection. The treatment-related complications associated with conventional, high-dose chemotherapy have motivated a multiinstitutional prospective study of a low-dose chemotherapy regimen sufficient to control lymphoproliferation while preventing graft rejection and minimizing treatment-related mortality in children with refractory PTLD. Gross (Ohio State University) reported that the protocol, entitled ‘CHOP-Lite’ (Cyclophosphamide and prednisone), has produced an impressive 77% complete remission rate with a 67% 2-year event-free survival and 91% allograft survival (28). There has been limited experience with the recently available anti-CD20 monoclonal antibody (MAb), reported predominantly in single-center case reports. Anti-CD20 MAb has assumed an intermediate position in the treatment hierarchy since its high tolerability and low toxicity profiles have led to its suggested use as first or second line therapy in CD20-positive PTLD. Although there has been an encouraging 2/3 overall response rate in both adults and children, the durability of the response and the implications of profound and prolonged B-cell depletion remain to be determined (29). The final modality – cellular immunotherapy (a strategy discussed in detail later) – while widely applied in bone marrow transplant recipients, has had limited utilization in solid organ transplant recipients, and therefore its position in the hierarchy remains to be defined. Brenner (Baylor College of Medicine) reported that indeed it is possible to generate autologous, HLA-restricted EBV-specific cytotoxic T lymphocytes (CTLs) from solid organ transplant recipients although it takes 10–14 weeks. Based upon the experience in stem-cell transplant recipients, he advocated aggressive monitoring of peripheral EBV titres and initiation of therapy, perhaps with anti-CD20 MAb, for persistently high viral loads (two or more measurement of >4000 copies/µg peripheral blood mononuclear cell DNA), which accurately predicts the future development of PTLD. Cytotoxic T lymphocytes can then be generated and, if peripheral viral loads relapse and/or PTLD develops, administered as a therapy with efficacy and durability. Although the Symposium was predominantly devoted to discussing tumors within the context of clinical transplantation, interwoven presentations exploring the basic science underpinnings – the interplay of immunosuppression and malignancy – formed a tangible thematic thread. Rooney (Baylor College of Medicine) and Ganem (University of California San Francisco) outlined the basic biology of two herpes viruses, focusing on their oncogenic mechanisms in the setting of immunosuppression. Immunosuppression in transplant recipients, by compromising or eliminating virus-specific cytolytic responses, facilitates substantial expansion of EBV virus-infected cells through either primary viral infection or reactivation of latent infection. It has been clearly shown that the enhanced proliferation and survival of EBV-transformed, immortalized cells can lead directly to tumorigenesis. HHV-8, the etiologic agent of Kaposi sarcoma (KS), however, has a starkly different oncogenic causality (30). Kaposi sarcoma in immunocompromized individuals typically reflects reactivation of previous HHV-8 infection. Unlike EBV, however, latent HHV-8 infection does not transform or immortalize cells. The HHV-8 genome is actually lost as infected cells proliferate. It has been shown that KS development critically depends upon the viral lytic program which recruits previously uninfected nearby cells thereby perpetuating infection. The actively infected cells secrete critical factors which act in a paracrine fashion to promote the angiogenic and inflammatory components of the KS tumor. Immunosuppression presumably facilitates re-emergence of the viral lytic cycle. This model of HHV-8 oncogenesis is strongly supported by the efficacy of systemic ganciclovir, an antiviral agent that interrupts the lytic cycle of herpes viruses, in preventing KS in individuals infected with human immunodeficiency virus. The sophisticated understanding of the interrelationships of viral infection, oncogenesis and immunosuppression has suggested logical strategies to prevent and/or treat tumors in transplant patients. As T-cell function is considered the primary immunologic deficit in transplant recipients, Greenberg (University of Washington) presented the general principles of the adoptive transfer strategy to augment specific T-cell responses. This strategy involves isolating T cells of desired specificity, expanding them in vitro, and reinfusing them. Clinical studies performed in human stem cell transplant recipients have shown that adoptive transfer of CMV-specific CD8+ cells can prevent CMV reactivation and CMV disease (31). Concurrent transfer of CMV-specific CD4+ clones was required for long-term survival of the transferred cells and maintenance of the anti-CMV response. Similarly, studies in melanoma patients have demonstrated that CD8+ tumor-specific T cells require exogenous IL-2 for persistence which, in turn, was required for tumor elimination. The outgrowth of antigen escape variants – cells with alterations in the targeted antigen – resulted in treatment failure. Therefore the choice of target antigen – ideally an immutable antigen essential for proliferation and/or survival of tumor cells – appears critical to the ultimate success of this therapy. These initial studies have motivated efforts to optimize adoptive transfer therapies using molecular engineering and retroviral gene transfer strategies which are outlined in Table 5. Not all immunosuppression is necessarily tumorigenic. Rapamycin, a macrolide fungicide, is known to inhibit mTOR, a central player in multiple signaling pathways, several of which critically couple growth stimuli to cell-cycle progression. As many tumor cells (including gliomas as discussed by Holland) harbour mutations that activate signal transduction pathways involving mTOR, rapamycin and its analogs can exert a direct, antiproliferative effect on tumor cells (32) and are undergoing clinical trials as anticancer therapy. Geissler (University of Regensburg), however, presented in vivo studies demonstrating that immunosuppressive doses of rapamycin inhibit tumor angiogenesis, resulting in small, stunted, and disconnected tumor vessels and a smaller tumor than in saline-treated controls (33), providing an alternative mechanism for the antitumor effects of rapamycin. Rapamycin might be an alternative to standard calcineurin inhibitor-based immunosuppression for transplant recipients at particular risk for tumor development and/or recurrence. In summary, the ASTS ‘Tumors and Transplantation’ Symposium signaled the realization that malignancy is an increasingly common and difficult issue affecting organ donors, transplant candidates, and transplant recipients. Although there are some well-founded practice patterns to which many of us adhere, the broad range of experts highlighted many areas where we lack adequate information to guide clinical decision-making. These gaps in knowledge will hopefully motivate not only research studies to define the risks of cancer transmission through transplantation and the impact of immunosuppression on cancer recurrence or incidence, progression, and responsiveness to treatment but also studies to understand the role of molecular strategies for cancer diagnosis, prognosis, and therapy in our varied patient populations.