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Posttransplant lymphoproliferative disorders in adult kidney transplant recipients: clinical features and relationship to Epstein-Barr virus
Posttransplant Lymphoproliferative Disorders in Adult Kidney Transplant Recipients: Clinical Features and Relationship to EpsteinBarr Virus R. Lauzurica, B. Baye´s, C. Frı´as, A. Herna´ndez, J. Bonet, N. Fontsere´, A. Jimenez, V. Ausina, and R. Romero
P
OSTTRANSPLANT lymphoproliferative disorders (PTLD) are an heterogeneus morphologic group of lymphoid proliferations with diverse degrees of clonality. Their incidence ranges from 1% in kidney transplantation to 9% in heart and lung transplantation.1 In addition to the type of organ transplanted and the degree of immunosuppression, several risk factors have been described, namely Epstein-Barr virus (EBV) seronegativity of the recipient (with subsequent infection), use of antilymphocyte antibodies (particularly their cumulative dose and as therapy for acute rejection), and donor positive and recipient negative cytomegalovirus (CMV) mismatch.1 EBV seems to determine PTLD pathogenesis, especially in early B-cell lymphomas. For T-cell lymphomas that develop at a later time (more than 12 months after transplantation), the role of EBV is less clear,2 although the association has been reported.3 EBV follow up for diagnosis and treatment of PTLD has been the topic of many papers: the assessment of EBV load in saliva4,5 as well as the serological studies have proved to be of little use.6 Nevertheless, when performed on peripheral blood, the assays seems to be a valuable tool.5,7 PATIENTS AND METHODS Three hundred sixty-eight cadaveric kidney transplants were performed at the Kidney Transplantation Unit between October 1985 and August 2002. EBV viral load in blood and saliva was carried out by a semiquantitative PCR method described in previous reports.4,5 EBV DNA detection in tissues has also been described in a previous paper.3
RESULTS
Five episodes of PTLD were diagnosed in four patients (1.3%). The three women and one man, had a mean age of 56 years (range 34 –70). Three received a cadaveric first transplant, and a 65-year-old woman a second transplant. All were both EBV- and CMV-seropositive prior to transplantation. Immunosuppression
Three patients received induction with antilymphocyte antibodies; two, cyclosporine (in both cases associated with
azathioprine); one tacrolimus (associated with mycophenolate mofetil); the fourth, MMF only; all received corticoids. There were no acute rejection episodes. The time of PTLD development in relationship to the time of transplantation was 9, 27, 41, 55, and 117 months; and the last patient experienced two episodes. In two patients the PTLD was a monoclonal primary brain B-cell lymphoma. One woman had monoclonal B-cell multicentric type, involving the retroperitoneally, kidney and graft. In the man, who had a recurrence, the first localization was in the small bowel (T-cell monoclonal lymphoma); 62 months later (117 months after transplantation), a big tumor mass was identified in the amygdalar region and at the tongue base, which was an atypical T- and B-polyclonal PTLD. Therapy consisted of immunosuppression tapering/withdrawal, as well as surgical removal and chemotherapy (bowel T-cell lymphoma) with recovery from this episode; chemotherapy and radiotherapy in one patient. All patients died, including the one with the recurrence; EBV detection was positive in all tissue samples from the five episodes tested. Two of the four patients (brain lymphoma) were included in a prospective EBV follow-up study from the time of transplantation.5 In both cases, EBV viral load in saliva did not change throughout the study. In blood there was a value of 0 –50 EBV DNA copies/75,000 peripheral blood mononuclear cells at the time of transplantation that increased to 500 copies at the time of diagnosis, and decreasing to previous levels when immunosupression was withdrawn. In the other two patients, and although there were no previous samples of follow-up after transplantation, viral load in the blood at the time of diagnosis of the three episodes showed values of 500 –1000 copies. From the Nephrology Department, Kidney Transplant Unit (R.L., B.B., J.B. N.F., R.R.), and Microbiology Department (C.F., A.H., A.J., V.A.), Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Address reprint requests to Dr Ricardo Lauzurica, Kidney Transplant Unit, Hospital Universitari Germans Trias i Pujol, Ctra. Del Canyet, s/n - 08916 Badalona, Spain. E-mail: [email protected]
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00668-7
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1720
Transplantation Proceedings, 35, 1720 –1721 (2003)
PTLD AND EBV
1721
DISCUSSION AND CONCLUSIONS
REFERENCES
The incidence PTLD in our series is similar to that reported for adult kidney transplant recipients.1,2,8 Our cases: showed clinical heterogenicity a PTLD widely disseminated, recurred in one patient, as already reported but an uncommon occurrence,9 and two primary brain lymphomas, an unusual localization with a high mortality rate.10 All cases of PTLD were associated with EBV; which was detected during the five episodes and in all histologic samples tested. Furthermore, there was an increase in EBV viral load in blood at the time of PTLD diagnosis, which decreased when immunosuppression was withdrawn. However, the sensitivity and specificity of the EBV load in blood is still an issue of discussion.7
1. Paya A, Freitas L, Pratas J, et al: Nephrol Dial Transplant 13:2968, 1998 2. Dotti G, Fiocchi R, Motta T, et al: Transplantation 74:1095, 2002 3. Frias C, Lauzurica R, Vaquero M, et al: Clin Infect Dis 30:576, 2000 4. Lauzurica R, Frias C, Baye´s B, et al: Trransplant Proc 31:2339, 1999 5. Frias C, Lauzurica R, Baye´s B, et al: Eur J Clin Microbiol Infect Dis 20:892, 2001 6. Lauzurica R, Frias C, Baye´s B, et al: Transplant Proc 34:120, 2002 7. Green M, Webber SA: Am J Transplant 2:894, 2002 8. Franco A, Jimenez L, Aranda I, et al: Nefrologı´a 22:463, 2002 9. Wu T-T, Swerdlow SH, Locker J, et al: Hum Pathol 27:157, 1996 10. Caillard S, Lachat V, Moulin B: Transpl Int 13:S388, 2000
P
OSTTRANSPLANT lymphoproliferative disorders (PTLD) are an heterogeneus morphologic group of lymphoid proliferations with diverse degrees of clonality. Their incidence ranges from 1% in kidney transplantation to 9% in heart and lung transplantation.1 In addition to the type of organ transplanted and the degree of immunosuppression, several risk factors have been described, namely Epstein-Barr virus (EBV) seronegativity of the recipient (with subsequent infection), use of antilymphocyte antibodies (particularly their cumulative dose and as therapy for acute rejection), and donor positive and recipient negative cytomegalovirus (CMV) mismatch.1 EBV seems to determine PTLD pathogenesis, especially in early B-cell lymphomas. For T-cell lymphomas that develop at a later time (more than 12 months after transplantation), the role of EBV is less clear,2 although the association has been reported.3 EBV follow up for diagnosis and treatment of PTLD has been the topic of many papers: the assessment of EBV load in saliva4,5 as well as the serological studies have proved to be of little use.6 Nevertheless, when performed on peripheral blood, the assays seems to be a valuable tool.5,7 PATIENTS AND METHODS Three hundred sixty-eight cadaveric kidney transplants were performed at the Kidney Transplantation Unit between October 1985 and August 2002. EBV viral load in blood and saliva was carried out by a semiquantitative PCR method described in previous reports.4,5 EBV DNA detection in tissues has also been described in a previous paper.3
RESULTS
Five episodes of PTLD were diagnosed in four patients (1.3%). The three women and one man, had a mean age of 56 years (range 34 –70). Three received a cadaveric first transplant, and a 65-year-old woman a second transplant. All were both EBV- and CMV-seropositive prior to transplantation. Immunosuppression
Three patients received induction with antilymphocyte antibodies; two, cyclosporine (in both cases associated with
azathioprine); one tacrolimus (associated with mycophenolate mofetil); the fourth, MMF only; all received corticoids. There were no acute rejection episodes. The time of PTLD development in relationship to the time of transplantation was 9, 27, 41, 55, and 117 months; and the last patient experienced two episodes. In two patients the PTLD was a monoclonal primary brain B-cell lymphoma. One woman had monoclonal B-cell multicentric type, involving the retroperitoneally, kidney and graft. In the man, who had a recurrence, the first localization was in the small bowel (T-cell monoclonal lymphoma); 62 months later (117 months after transplantation), a big tumor mass was identified in the amygdalar region and at the tongue base, which was an atypical T- and B-polyclonal PTLD. Therapy consisted of immunosuppression tapering/withdrawal, as well as surgical removal and chemotherapy (bowel T-cell lymphoma) with recovery from this episode; chemotherapy and radiotherapy in one patient. All patients died, including the one with the recurrence; EBV detection was positive in all tissue samples from the five episodes tested. Two of the four patients (brain lymphoma) were included in a prospective EBV follow-up study from the time of transplantation.5 In both cases, EBV viral load in saliva did not change throughout the study. In blood there was a value of 0 –50 EBV DNA copies/75,000 peripheral blood mononuclear cells at the time of transplantation that increased to 500 copies at the time of diagnosis, and decreasing to previous levels when immunosupression was withdrawn. In the other two patients, and although there were no previous samples of follow-up after transplantation, viral load in the blood at the time of diagnosis of the three episodes showed values of 500 –1000 copies. From the Nephrology Department, Kidney Transplant Unit (R.L., B.B., J.B. N.F., R.R.), and Microbiology Department (C.F., A.H., A.J., V.A.), Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Address reprint requests to Dr Ricardo Lauzurica, Kidney Transplant Unit, Hospital Universitari Germans Trias i Pujol, Ctra. Del Canyet, s/n - 08916 Badalona, Spain. E-mail: [email protected]
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00668-7
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1720
Transplantation Proceedings, 35, 1720 –1721 (2003)
PTLD AND EBV
1721
DISCUSSION AND CONCLUSIONS
REFERENCES
The incidence PTLD in our series is similar to that reported for adult kidney transplant recipients.1,2,8 Our cases: showed clinical heterogenicity a PTLD widely disseminated, recurred in one patient, as already reported but an uncommon occurrence,9 and two primary brain lymphomas, an unusual localization with a high mortality rate.10 All cases of PTLD were associated with EBV; which was detected during the five episodes and in all histologic samples tested. Furthermore, there was an increase in EBV viral load in blood at the time of PTLD diagnosis, which decreased when immunosuppression was withdrawn. However, the sensitivity and specificity of the EBV load in blood is still an issue of discussion.7
1. Paya A, Freitas L, Pratas J, et al: Nephrol Dial Transplant 13:2968, 1998 2. Dotti G, Fiocchi R, Motta T, et al: Transplantation 74:1095, 2002 3. Frias C, Lauzurica R, Vaquero M, et al: Clin Infect Dis 30:576, 2000 4. Lauzurica R, Frias C, Baye´s B, et al: Trransplant Proc 31:2339, 1999 5. Frias C, Lauzurica R, Baye´s B, et al: Eur J Clin Microbiol Infect Dis 20:892, 2001 6. Lauzurica R, Frias C, Baye´s B, et al: Transplant Proc 34:120, 2002 7. Green M, Webber SA: Am J Transplant 2:894, 2002 8. Franco A, Jimenez L, Aranda I, et al: Nefrologı´a 22:463, 2002 9. Wu T-T, Swerdlow SH, Locker J, et al: Hum Pathol 27:157, 1996 10. Caillard S, Lachat V, Moulin B: Transpl Int 13:S388, 2000