Cancers among US organ donors: a comparison of transplant and cancer registry diagnoses.

Transmission of cancer is a life-threatening complication of transplantation. Monitoring transplantation practice requires complete recording of donor cancers. The US Scientific Registry of Transplant Recipients (SRTR) captures cancers in deceased donors (beginning in 1994) and living donors (2004). We linked the SRTR (52,599 donors, 110,762 transplants) with state cancer registries. Cancer registries identified cancers in 519 donors: 373 deceased donors (0.9%) and 146 living donors (1.2%). Among deceased donors, 50.7% of cancers were brain tumors. Among living donors, 54.0% were diagnosed after donation; most were cancers common in the general population (e.g. breast, prostate). There were 1063 deceased donors with cancer diagnosed in the SRTR or cancer registry, and the SRTR lacked a cancer diagnosis for 107 (10.1%) of these. There were 103 living donors with cancer before or at donation, diagnosed in the SRTR or cancer registry, and the SRTR did not have a cancer diagnosis for 43 (41.7%) of these. The SRTR does not record cancers after donation in living donors and so missed 81 cancers documented in cancer registries. In conclusion, donor cancers are uncommon, but lack of documentation of some cases highlights a need for improved ascertainment and reporting by organ procurement organizations and transplant programs.

Donor-transmitted malignancies in organ transplantation: assessment of clinical risk.

The continuing organ shortage requires evaluation of all potential donors, including those with malignant disease. In the United States, no organized approach to assessment of risk of donor tumor transmission exists, and organs from such donors are often discarded. The ad hoc Disease Transmission Advisory Committee (DTAC) of the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) formed an ad hoc Malignancy Subcommittee to advise on this subject. The Subcommittee reviewed the largely anecdotal literature and held discussions to generate a framework to approach risk evaluation in this circumstance. Six levels of risk developed by consensus. Suggested approach to donor utilization is given for each category, recognizing the primacy of individual clinical judgment and often emergent clinical circumstances. Categories are populated with specific tumors based on available data, including active or historical cancer. Benign tumors are considered in relation to risk of malignant transformation. Specific attention is paid to potential use of kidneys harboring small solitary renal cell carcinomas, and to patients with central nervous system tumors. This resource document is tailored to clinical practice in the United States and should aid clinical decision making in the difficult circumstance of an organ donor with potential or proven neoplasia.

An update on donor-derived disease transmission in organ transplantation.

Several recent donor-to-recipient disease transmissions have highlighted the importance of this rare complication of solid organ transplantation. The epidemiology of donor-derived disease transmissions in the United States has been described through reports to the Organ Procurement and Transplant Network (OPTN); these reports are reviewed and categorized by the ad hoc Disease Transmission Advisory Committee (DTAC); additional data comes through the published literature. From these reports, it is possible to estimate that donor-derived disease transmission complicates less than 1% of all transplant procedures but when a transmission occurs, significant morbidity and mortality can result. Only through continued presentation of the available data can continuous quality improvements be made. As the epidemiology of donor-derived disease transmission has become better understood, several groups have been working on methods to further mitigate this risk.

Donor-derived disease transmission events in the United States: data reviewed by the OPTN/UNOS Disease Transmission Advisory Committee.

Donor-derived disease transmission is increasingly recognized as a source of morbidity and mortality among transplant recipients. Policy 4.7 of the Organ Procurement and Transplantation Network (OPTN) currently requires reporting of donor-derived events. All potential donor-derived transmission events (PDDTE) reported to OPTN/UNOS were reviewed by the Disease Transmission Advisory Committee (DTAC). Summary data from January 1, 2005-December 31, 2007, were prepared for presentation. Reports of PDDTE have increased from 7 in 2005, the first full year data were collected, to 60 in 2006 and to 97 in 2007. More detailed information is available for 2007; a classification system for determining likelihood of donor-derived transmission was utilized. In 2007, there were four proven and one possible donor-derived malignancy transmissions and four proven, two probable and six possible donor-derived infectious diseases transmissions. There were nine reported recipient deaths attributable to proven donor transmissions events arising from eight donors during 2007. Although recognized transmission events resulted in significant morbidity and mortality, transmission was reported in only 0.96% of deceased donor donations overall. Improved reporting, through enhanced recognition and communication, will be critical to better estimate the transmission risk of infection and malignancy through organ transplantation.

Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury.

Carbon monoxide (CO), a byproduct of heme catalysis, was shown to have potent cytoprotective and anti-inflammatory effects. In vivo recipient CO inhalation at low concentrations prevented ischemia/reperfusion (I/R) injury associated with small intestinal transplantation (SITx). This study examined whether ex vivo delivery of CO in University of Wisconsin (UW) solution could ameliorate intestinal I/R injury. Orthotopic syngenic SITx was performed in Lewis rats after 6 h cold preservation in control UW or UW that was bubbled with CO gas (0.1-5%) (CO-UW). Recipient survival with intestinal grafts preserved in 5%, but not 0.1%, CO-UW improved to 86.7% (13/15) from 53% (9/17) with control UW. At 3 h after SITx, grafts stored in 5% CO-UW showed improved intestinal barrier function, less mucosal denudation and reduced inflammatory mediator upregulation compared to those in control UW. Preservation in CO-UW associated with reduced vascular resistance (end preservation), increased graft cyclic guanosine monophosphate levels (1 h), and improved graft blood flow (1 h). Protective effects of CO-UW were reversed by ODQ, an inhibitor of soluble guanylyl cyclase. In vitro culture experiment also showed better preservation of vascular endothelial cells with CO-UW. The study suggests that ex vivo CO delivery into UW solution would be a simple and innovative therapeutic strategy to prevent transplant-induced I/R injury.

Recurrent hepatitis C in liver allografts: prospective assessment of diagnostic accuracy, identification of pitfalls, and observations about pathogenesis.

RATIONALE AND DESIGN: The accuracy of a prospective histopathologic diagnosis of rejection and recurrent hepatitis C (HCV) was determined in 48 HCV RNA-positive liver allograft recipients enrolled in an "immunosuppression minimization protocol" between July 29, 2001 and January 24, 2003. Prospective entry of all pertinent treatment, laboratory, and histopathology results into an electronic database enabled a retrospective analysis of the accuracy of histopathologic diagnoses and the pathophysiologic relationship between recurrent HCV and rejection. RESULTS: Time to first onset of acute rejection (AR) (mean, 107 days; median, 83 days; range, 7-329 days) overlapped with the time to first onset of recurrent HCV (mean, 115 days; median, 123 days; range, 22-315 days), making distinction between the two difficult. AR and chronic rejection (CR) with and without co-existent HCV showed overlapping but significantly different liver injury test profiles. One major and two minor errors occurred (positive predictive values for AR = 91%; recurrent HCV = 100%); all involved an overdiagnosis of AR in the context of recurrent HCV. Retrospective analysis of the mistakes showed that major errors can be avoided altogether and the impact of unavoidable minor errors can be minimized by strict adherence to specific histopathologic criteria, close clinicopathologic correlation including examination of HCV RNA levels, and a conservative approach to the use of additional immunosuppression. In addition, histopathologic diagnoses of moderate and severe AR and CR were associated with relatively low HCV RNA levels, whereas relatively high HCV RNA levels were associated with a histopathologic diagnosis of hepatitis alone, particularly the cholestatic variant of HCV. CONCLUSIONS: Liver allograft biopsy interpretation can rapidly and accurately distinguish between recurrent HCV and AR/CR. In addition, the histopathologic observations suggest that the immune mechanism responsible for HCV clearance overlap with those leading to significant rejection.

Immunomodulatory effects of inhaled carbon monoxide on rat syngeneic small bowel graft motility.

BACKGROUND: Intestinal transplantation provokes an intense inflammatory response within the graft muscularis that causes intestinal ileus. We hypothesised that endogenously produced anti-inflammatory substances could be utilised as novel therapeutics. Therefore, we tested the protective effects of inhaled carbon monoxide (CO) and an endogenous haeme oxygenase 1 (HO-1) anti-inflammatory mediator on transplant induced inflammatory responses and intestinal ileus in the rat. METHODS: Gastrointestinal transit of non-absorbable FITC labelled dextran and in vitro jejunal circular muscle contractions were measured in controls and syngeneic orthotopic transplanted animals with and without CO inhalation (250 ppm for 25 hours). Inflammatory mRNAs for interleukin (IL)-6, IL-1beta, tumour necrosis factor alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide (iNOS), cyclooxygenase 2 (COX-2), and IL-10 were quantified by real time reverse transcriptase-polymerase chain reaction and HO-1 by northern blot. Histochemical stains characterised neutrophil infiltration and enterocyte apoptosis. RESULTS: Transplantation delayed transit and suppressed jejunal circular muscle contractility. Transplantation induced dysmotility was significantly improved by CO inhalation. Transplantation initiated a significant upregulation in IL-6, IL-1beta, TNF-alpha, ICAM-1, iNOS, COX-2, and HO-1 mRNAs with the graft muscularis. CO inhalation significantly decreased expression of IL-6, IL-1beta, iNOS, and COX-2 mRNAs. CO also significantly decreased serum nitrite levels (iNOS activity). CONCLUSIONS: CO inhalation significantly improved post-transplant motility and attenuated the inflammatory cytokine milieu in the syngeneic rat transplant model. Thus clinically providing CO, the end product of the anti-inflammatory HO-1 pathway, may prove to be an effective therapeutic adjunct for clinical small bowel transplantation.

Real-time monitoring of acute liver-allograft rejection using the Banff schema.

BACKGROUND: The Banff schema is the internationally accepted standard for grading acute liver-allograft rejection, but it has not been prospectively tested. METHODS: Complete Banff grading was prospectively applied to 2,038 liver-allograft biopsies from 901 adult tacrolimus-treated primary hepatic allograft recipients between August 1995 and September 2001. Histopathologic data was melded with demographic, clinical, and laboratory data into a database on an ongoing basis using locally developed software. RESULTS: Acute rejection developed in 575 of 901 (64%) patients and the worst grade was mild in 422 of 575 (73%). At least one episode of moderate or severe acute rejection developed in 153 of 901 (17%) patients and most episodes, irrespective of severity, occurred within the first year after transplantation. Patients with moderate or severe acute rejection showed higher alanine aminotransferase (P =0.007) and aspartate aminotransferase ( P=0.07) levels and were more likely to develop perivenular fibrosis on follow-up biopsies (P =0.001) and graft failure from acute or chronic rejection ( P=0.004) than those with mild rejection. Regardless of severity, 80% of patients with acute rejection did not develop significant fibrosis in follow-up biopsies, and graft failure from acute or chronic rejection occurred in only 11 of 901 (1%) allografts. CONCLUSIONS: Most acute-rejection episodes are mild and do not lead to clinically significant architectural sequelae. When tested prospectively under real-life and -time conditions, the Banff schema can be used to identify those few patients who are potentially at risk for more significant problems. Creation, capture, and integration of non-free text, or "digital," pathology data can be used to prospectively conduct outcomes-based research in transplantation.

Clinical significance of elevated alpha-fetoprotein in adults and children.

The aim of the current study is to identify underlying pathology associated with elevated serum alpha-fetoprotein (AFP; >20 ng/ml) among patients referred to a tertiary-care academic medical center with emphasis in liver diseases, hepatobiliary surgery, and liver transplantation. From May 1992 to April 1997, 386 patients (320 adults and 66 children) with elevated AFP (>20 ng/ml) were identified from the Medical Archival System (MARS) database at the University of Pittsburgh Medical Center. The medical records from all these patients were retrospectively reviewed. Radiological, pathological, and biochemical profiles were obtained at the time of documented elevated AFP. These patients included: 218 adults with malignancies, 102 adults without malignancies, 18 children and infants with malignancies, and 48 children and infants without malignancies. Thirty-two percent of adults were found to have raised AFP with liver disease and without hepatocellular carcinoma and 78% had some type of malignancy, predominantly hepatocellular carcinoma. Seventy-three percent of infants and children had elevated AFP without malignancy. Based on our findings, we recommend that all patients (adults, infants and children) with raised AFP of >20 ng/ml should undergo thorough evaluation to rule out malignant disease.

Hepatocellular carcinomas in native livers from patients treated with orthotopic liver transplantation: biologic and therapeutic implications.

The gross and histopathologic characteristics of 212 nonfibrolamellar hepatocellular carcinomas (HCCs) discovered in native livers removed at the time of liver transplantation were correlated with features of invasive growth and tumor-free survival. The results show that most HCCs begin as small well-differentiated tumors that have an increased proliferation rate and induce neovascularization, compared with the surrounding liver. But at this stage, they maintain a near-normal apoptosis/mitosis ratio and uncommonly show vascular invasion. As tumors enlarge, foci of dedifferentiation appear within the neoplastic nodules, which have a higher proliferation rate and show more pleomorphism than surrounding better-differentiated areas. Vascular invasion, which is the strongest predictor of disease recurrence, correlates significantly with tumor number and size, tumor giant cells and necrosis, the predominant and worst degree of differentiation, and the apoptosis/mitosis ratio. In the absence of macroscopic or large vessel invasion, largest tumor size (P <.006), apoptosis/mitosis ratio (P <.03), and number of tumors (P <.04) were independent predictors of tumor-free survival and none of 24 patients with tumors having an apoptosis/mitosis ratio greater than 7.2 had recurrence. A minority of HCCs (<15%) quickly develop aggressive features (moderate or poor differentiation, low apoptosis/mitosis ratio, and vascular invasion) while still small, similar to flat carcinomas of the bladder and colon. In conclusion, hepatic carcinogenesis in humans is a multistep and multifocal process. As in experimental animal studies, aggressive biologic behavior (vascular invasion and recurrence) correlates significantly with profound alterations in the apoptosis/mitosis ratio and with architectural and cytologic alterations that suggest a progressive accumulation of multiple genetic abnormalities.

Primary pleural effusion posttransplant lymphoproliferative disorder: Distinction from secondary involvement and effusion lymphoma.

Pleural effusion presentation of posttransplant lymphoproliferative disorder (PTLD) is relatively uncommon. Most examples of effusion-based PTLD have been secondary to widespread solid organ involvement, and are associated with an aggressive clinical course. We report on a case of primary effusion PTLD in a 70-yr-old male liver transplant recipient with a history of hepatitis B infection. Cytomorphologically, the pleural fluid specimen showed a monomorphous population of intermediate to large-sized transformed lymphoid cells, with irregular multilobated nuclear contours and readily identifiable mitotic figures. Flow cytometric immunophenotypic studies revealed a CD5-negative, CD10-negative, lambda immunoglobulin light chain-positive, monoclonal B-lymphocyte (CD19-positive/CD20-positive) population. The immunocytochemical stain for CD30 antigen was negative. In situ hybridization study for Epstein-Barr virus (EBV) early RNA (EBER) and Southern blot analysis for EBV terminal repeat sequences were both positive. Southern blot analysis for human herpes virus-8 (HHV-8) was negative. No solid-organ PTLD was identified, and the cytologic results supported the diagnosis of primary effusion PTLD. Immunosuppression was decreased, and 8 mo following the diagnosis of pleural fluid PTLD, the patient was stable and his pleural effusion had markedly diminished. Recognition of primary effusion PTLD and its distinction from PTLD secondarily involving the body fluids and from other lymphomas is important, since the behavior and prognosis appear different.

The diverse pathology of post-transplant lymphoproliferative disorders: the importance of a standardized approach.

Post-transplant lymphoproliferative disorders (PTLD) are a diverse group of abnormal lymphoid growths that include both hyperplasias and neoplasias. They have been divided into several general pathologic categories that have prognostic significance. These include early or hyperplastic PTLD, polymorphic PTLD, and lymphomatous or monomorphic PTLD. The majority of PTLDs are of B-cell origin and contain Epstein-Barr virus (EBV). However, PTLDs of T- or NK-cell origin have been described, and late-arising EBV-negative lymphoid tumors are becoming more frequently reported in this population. Other lymphoid neoplasms, such as those arising from mucosal-associated lymphoid tissue (MALTomas), have recently been recognized in transplant patients, and their relationship to PTLD is uncertain. Multicentric PTLD may represent either advanced-stage disease or multiple independent primary tumors. Likewise, recurrent PTLD may represent true recurrence or the emergence of a second primary tumor. Transplant patients are also at risk for other opportunistic neoplasms, including EBV-associated leiomyosarcomas that may be seen alone or in conjunction with PTLD. This underscores the necessity for pathologic diagnosis of mass lesions in this patient population. The pathologist should strive to categorize the form of post-transplant lymphoproliferation in accordance with currently accepted criteria. The diagnosis should incorporate the histopathologic appearance, cell phenotype, clonal status, and EB viral status. The pathologist may play a special role in guiding therapy by ascertaining the presence of such markers as CD20 on tumor cells. Specialized techniques, such as molecular analysis of oncogenes/tumor suppressor genes and evaluation of host:donor status of PTLD, may play important roles in diagnostic evaluation in the future.

Suppressed T-cell receptor zeta chain expression and cytokine production in pancreatic cancer patients.

Suppression of various functions of T cells derived from cancer patients has been linked previously to changes in the T-cell receptor (TCR)-associated signal transduction molecules, in particular the zeta chain of the TCR complex. In this study, we have examined the TCRzeta chain expression and cytokine production in vivo and in vitro in T cells of patients with metastatic adenocarcinomas of the pancreas that participated in a Phase I clinical trial of the MUC1 peptide plus bacillus Calmette-Guerin cancer vaccine. A majority of the patients had reduced TCRzeta chain expression and interleukin 4 production by T cells, and all of the patients showed decreased production of IFN-gamma of their peripheral T cells when compared with healthy individuals. Peripheral blood T cells were activated with the phorbol ester phorbol myrisate acetate and ionomycin to show that although aberrant TCRzeta chain expression and decreased cytokine production were often correlated, the reduced cytokine production was not simply a consequence of an impaired TCRzeta chain expression. Rather, these are two separate but parallel defects in signal transduction in T cells, which are potentially modulated by the same mechanisms. Half of the patients showed an improvement for TCRzeta chain or IFN-gamma expression after vaccination.

Comparative genomic hybridization of hepatocellular carcinoma: correlation with fluorescence in situ hybridization in paraffin-embedded tissue.

BACKGROUND: Proto-oncogene MYC, mapped to chromosomal band 8q24 and the genes for hepatocyte growth factor (HGF at 7q21) and its receptor, MET, at chromosomal band 7q31, have an important role in the biology and growth of normal and neoplastic liver. Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) studies have reported frequent abnormalities of chromosomes 1 and 8 in hepatocellular carcinomas (HCCs) of various clinical and pathological stages. Chromosome 7 involvement is reported to be less frequent. MATERIALS AND METHODS: Frozen tissue from 17 HCCs was used for CGH analysis and sections of corresponding formalin-fixed, paraffin-embedded HCC tissue were used for dual-color FISH with locus-specific (LSI-cMYC for chromosome 8q24 and LSI D7S486 for chromosome 7q31) and centromeric probes, CEP8 (8p11.1-q11.2) and CEP7 (7p11.1-q11.2) (Vysis, Inc, Downers Grove, IL). This study intended to determine the pattern of chromosomal aberrations in early-stage (incidental) HCC and large surgically resected HCC, and also compared the efficiency and usefulness of the two cytogenetic methods. RESULTS: CGH showed abnormalities on chromosomes 1q, 5q, 7q, 8q, 9, 10, 13q, 15, 16, 17p, 18q, 19, 20, 21, 22, and X. Gains of 8q were noted in 50% of the HCCs, including five cases of incidental HCCs by CGH. Increase in copy numbers of MYC detected by FISH was noted in 25% of tumors that had shown 8q gains by CGH and in five cases with no chromosome abnormalities noted by CGH. Three cases with 7q31 copy number abnormalities were found by FISH in addition to those detected by CGH. CONCLUSION: Combined use of CGH and FISH may provide important information about early and/or primary genetic changes in the development of HCC.

Allograft liver biopsy in patients with Epstein-Barr virus-associated posttransplant lymphoproliferative disease.

Allograft liver biopsy specimens (n = 24) obtained in the clinical setting of primarily extrahepatic posttransplant lymphoproliferative disease (PTLD) were studied for histopathology, lymphocyte subsets, and Epstein-Barr virus (EBV)-encoded EBER RNA. Acute rejection was found in 20 (83.3%) of 24 biopsy specimens and graded as indeterminate in 7 (35%) of 20 (35%), mild in 3 (15%) of 20, and moderate in 10 (50%) of 20 cases. EBV hepatitis was the primary diagnosis in two biopsy specimens and a secondary finding in six others. Four biopsy specimens showed nonspecific reactive hepatitis, and five showed recurrence of primary liver disease. Immunoperoxidase staining showed primarily T cells. EBER RNA was detected in 14 (58.3%) of 24 biopsy specimens: 12 (60%) of 20 with and 2 (50%) of 4 without acute rejection. Antirejection therapy resulted in complete or partial response in 4 (36.3%) of 11 and 7 (63.7%) of 11 treated cases, respectively, despite the presence of EBV-infected cells in some tissues. Subsequent follow-up showed early or late chronic rejection in 6 (25%) of 24 patients. Gamma glutamyl transferase, a marker for early or late chronic rejection, was greater than five times the upper limit of normal in 9 (37.5%) of 24 patients. In conclusion, liver biopsy specimens in patients with PTLD show a spectrum of pathologic changes. Rejection may be treated even if EBV is concurrently present. Long-term graft is suboptimal, because low immunosuppression results in a tendency to develop chronic rejection.

Occult nonhematopoietic malignancies present at autopsy in solid organ transplant patients who died within 100 days.

BACKGROUND: Patients are at an increased risk for developing malignancies after transplantation. Lymphomas, skin malignancies, Kaposi's sarcomas, and cervical/vulvar neoplasms are the most common, but visceral malignancies are also well documented, with a reported frequency ranging from 1% to 6%. These visceral tumors represent a mix of neoplasms that were clinically occult at the time of transplantation and those that arise de novo after transplantation. Little information, however, is available on the frequency of clinically occult malignancies at the time of transplantation and their contribution to the number of posttransplant malignancies. METHODS: A retrospective study was performed of all patients who received an organ transplant from January 1981 to June 1997 and died within 100 days, a time interval in which epithelial malignancies found at autopsy were presumed to have been present, but clinically occult, at the time of transplantation. RESULTS: A total of 375 patients were studied who received the following organ transplants: 231 liver, 52 heart, 26 heart and lung, 32 lung, and 34 kidney. Eleven malignancies were identified for an overall frequency of 2.9% and included three thyroid carcinomas, three carcinoids of the small bowel, two lung carcinomas, one laryngeal carcinoma, one renal cell carcinoma, and one seminoma. CONCLUSION: The 2.9% frequency of malignancies seen in this study suggests that a small, but significant, number of patients have occult malignancies at the time of transplantation and that these occult tumors contribute substantially to the number of malignancies that present clinically after transplantation.