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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 4  |  Page : 646-651
Post transplant anaplastic large T-cell lymphoma

1 Department of Pediatrics, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Pathology, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of Radiology, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran

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Date of Web Publication8-Jul-2009


Post transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid proliferation that ranges from polyclonal hyperplasia to monoclonal malignant lym計homa. We report a 13-year-old boy who was diagnosed with PTLD in February 2007 after 3 1/2 years of deceased renal transplantation. We treated him with an adapted ACVBP (doxorubicin, cyclo計hosphamide, vincristine, bleomycin and prednisone) regimen. He responded well to the chemo負herapy without deterioration of graft function.

How to cite this article:
Azhir A, Reisi N, Taheri D, Adibi A. Post transplant anaplastic large T-cell lymphoma. Saudi J Kidney Dis Transpl 2009;20:646-51

How to cite this URL:
Azhir A, Reisi N, Taheri D, Adibi A. Post transplant anaplastic large T-cell lymphoma. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2021 Jan 17];20:646-51. Available from: https://www.sjkdt.org/text.asp?2009/20/4/646/53257

   Introduction Top

Post transplant lymphoproliferative disorder (PTLD) is a well recognized complication of the long-term immunosuppression used in solid organ transplantation. [1] The incidence reported in pediatric renal transplant recipients ranges from 1% [2] to 4.5%. [3] The clinical presentations of PTLD include an infectious mononucleosis syn苓rome with or without generalized lymphade要opathy, a localized nodal or extra-nodal tumo訃al form, or a fulminate disease with multivisce訃al dissemination. [4]

Histologically, PTLD can be classified into four categories: early lesions, including reactive plas衫acytic hyperplasia; polymorphic PTLD, in苞luding polyclonal and monoclonal variants; monomorphic PTLD, including B and T cell lymphomas; and a fourth category that encom計asses T-cell rich lesions and Hodgkin's disease. [5] B-cell proliferations, normally of donor origin, make up 86% of PTLD cases. Furthermore, 14% of PTLD cases are of T-cell origin and have the worst prognosis. [6] ,[7]

Risk factors for developing PTLD include Epstein-Barr Virus (EBV) infection and a high level of potent immunosuppression, cytomega衍ovirus (CMV) disease, the number of methyl計rednisolone pulses, acute rejection episodes, and younger age. [8] ,[9] EBV is associated with an 89% of post transplant B-cell PTLD. [1]

The frequency of PTLD is higher in children than in adults, which may be the result of more frequent EBV seronegativity status of children compared with adult recipients at the time of the transplantation and the high prevalence of EBV seropositivity among donors. [10]

Extension to multiple sites, central nervous system (CNS) involvement, T-cell origin, mono苞lonal proliferation, non-detection of EBV in the tumor and poor performance status have been associated with a poor outcome. [11]

Treatment of PTLD is not standardized. Re苓uction in immunosuppressive therapy may lead to remission in early disease. [4] Alternative ap計roaches include antiviral therapy in early EBV計ositive PTLD, surgery or radiotherapy in loca衍ized disease, interferon a, monoclonal antibodies, adoptive T-cell immunotherapy, and chemothe訃apy. [4] Chemotherapy provides satisfactory res計onse rates in extended diseases, but has been associated with either severe toxicity or high relapse rates resulting in poor long-term survival. [4]

We report a case of PTLD that was success苯ully treated with chemotherapy.

   Case Report Top

A 13-year-old boy underwent deceased renal transplantation in October 2003 due to renal failure caused by a congenital posterior ure負hral valve. At the time of transplantation, the patient was CMV and EBV seronegative and immunosuppressive regimen included methyl計rednisolone that was changed to prednisolone on the 4 th day, cyclosporine (CsA), and myco計henolate mofetil (MMF). He had delayed graft function due to prolonged ischemic time, and serum creatinine was 0.9 mg/dL at the 3rd week post transplantation. The serum creatinine was increased slowly during the following few months post transplant due to high grade re苯lux in transplant kidney and recurrent UTI. The patient did not experience any rejection episodes, and his renal function became steady during the next 2 years (serum creatinine 1.31.6 mg/dL). The cyclosporine dosage (in mg/ kg/day) and the plasma trough levels (in 痢/L) during follow-up ranged from 3.5 and 112, after 3 months 3.5 and 41 after 36 months, respectively.

In February 2007, the patient complained of fever. He was febrile and a large lymph node (30 50 mm) at the right supra-clavicular re茆ion and multiple smaller one on the other side of neck were found on physical exami要ation. In addition, the breath sounds were decreased in right hemithorax and spleen was palpable. At that time, the patient's immuno貞uppressive medications included: CsA (50 mg/bid), prednisone (5 mg/QOD), and MMF (500 mg/bid).

Computed tomography scans of chest, and abdomen demonstrated a large lobulated hilar mass indicating lymphadenopathy with obvious pressure effect on right upper lobe bronchus causing right upper lobe infiltration, multiple mediastinal lymphadenophathies, and an en衍arged spleen, [Figure 1], [Figure 2], [Figure 3].There was not any evidence of central nervous system or bone marrow involvement.

Hepatitis B surface antigen (HBS Ag)/HIV/ Hepatitis C serology were all negative. Cyto衫egalovirus and EBV IgG and IgM antibodies were positive. A positive polychain reaction (PCR) for CMV-RNA (sensitivity: 5 10 2 co計ies/mL) in the blood was detected. EBV DNA PCR in plasma was negative.

Biopsy of the cervical mass was performed. Microscopically, the lymph node showed di苯fuse lymphoid infiltrates consisting of a mix負ure of small mature lymphocytes and large cells resembling immunoblasts with several mitoses. As determined by immunohistoche衫istry, these cells expressed CD30, and Ki67 in 60% of nuclei but CD15, EMA, CD20 and AKL1 were negative [Figure 4]. EBV enco苓ed RNA was positive in the biopsy specimen. Based on these features; the diagnosis of di苯fuse, large T-cell lymphoma consistent with PTLD was established.

Gancyclovir was started intravenously with the dose modified according to creatinine clea訃ance and continued for 4 weeks; at that point CMV-DNA was not detectable. Additionally, the immunosuppressive therapy was changed as follows: MMF treatment was stopped, the cyclosporine dose was decreased to 2.5 mg/kg /day (plasma trough level < 100 痢/L) and prednisolone dosage was increased to 0.5 mg/ kg/day. The patient received adriamycin (50 mg/m 2 on day 1), cyclophosphamide (1 g/m 2 on day 1), vindesine (2 mg/m 2 on day 1), bleo衫ycin (15 mg on day 1) and prednisone (60 mg/m 2 on days 1-5). The cyclophosphamide dose was adjusted and reduced by 10% accor苓ing to the patient's creatinine clearance. A planned total of 6 monthly cycles of chemo負herapy were administered. A platelet count of at least 100 10 9 /L and a neutrophil count above 1 10 9 /L were required to start subse訂uent cycles. Prophylactic use of granulocyte colony stimulating factor (G-CSF) and cotri衫oxazole was considered to reduce the rate of fatal infection. The patient tolerated chemo負herapy well with excellent response. At that point, cyclosporine was changed to sirolimus (1 mg bid) and renal function was preserved well (creatinine 1.4-1.2 mg/dL) after 11 months of follow-up.

   Discussion Top

There are at least three major risk factors for the development of PTLD: allograft type, EBV infection or reactivation, and immunosuppre貞sive regimens. [12] Primary EBV infection after transplantation carries the highest risk of di貞ease development and also the most severe di貞ease course. [13] Only 40% of cases of T-cell PTLD are EBV positive. Concomitant CMV infection appears to further increase the risk for PTLD in patients who are EBV sero negative at the time of transplantation. [14]

Outcome and survival in patients with PTLD depend on the type of organ transplant and overall mortality is around 30%. In a subset of patients who require chemotherapy to control the disease, mortality can reach 80%. [15] The im衫unoblastic or monomorphic form of PTLD carries the highest risk for mortality and like衍ihood of progression. [12] In studies by Armitage et al [16] and Leblond et al, [7] Late onset PTLD (more than 1 year) was associated with 66% mortality, whereas early onset disease was asso苞iated with 38% mortality.

Compared with B-cell PTLD, T-cell lympho衫as tend to occur late following transplanta負ion. [17] The incidence of PTLD (90% B-cell) is increased in the first year of transplantation when the degree of immunosuppression is the highest. [18] The majority of T-cell lymphoma presents after 5 years, with less than 10% in the first year; [17] there is no significant association with latent EBV infection as has been esta苑lished in B-cell malignancy. Another possible viral agent is HTLV-1. [19] Anaplastic large cell lymphoma is even rarer and these lymphomas are positive for CD30, which is considered to be a lymphocyte activation-associated antigen. [20]

Treatment of PTLD is difficult and often re訂uires multiple methods of therapy. The accep負ed initial therapeutic approach to PTLD is the reduction in immunosuppressive therapy. This may be sufficient to obtain a favorable response but exposes the graft to the risk of rejection. Patients with the immunoblastic or monomor計hic form of the disease are at very high risk of death and of further complications from decrea貞ing immunosuppression. [12] Localized lesions can be excised surgically or can be treated with ra苓iation therapy. [12] Chemotherapy is a therapeu負ic option but causes further immunosuppre貞sion and complications in severely ill patients. [12] Gross et al [21] treated 39 children with PTLD with low-dose chemotherapy combining cyclo計hosphamide and prednisone. They reported a high response rate (83%) and a very encou訃aging 2-year survival rate (73%). Two-thirds of the cases were early PTLD and all were EBV positive; these two characteristics in addition to the young age of the patients are associated with a better prognosis and may explain the excellent results. Fohrer et al demonstrated that a dose-adjustment of ACVBP regimen in 33 patients with PTLD favorably impacted on long負erm survival. The mean age at onset of PTLD was 47 years (19-66); only 2 patients had T-cell lymphoma and one of them had a favorable res計onse rate. [4]

Novel methods, such as monoclonal antibody preparations (rituximab) directed at B-cell sur苯ace proteins, infusion of recombinant interfe訃on, and immunoglobulin, have demonstrated remissions in some cases. [7] ,[22] Adjunctive anti赳iral measures, such as acyclovir and gancyclo赳ir, are used with limited success in polyclonal disease [23]

Early diagnosis of T-cell PTLD is essential even though the prognosis is poor. Attention also is being focused on prevention of this disease. The two factors that appear to be the most critical are the degree of immunosuppre貞sion and presence of EBV infection. The use of antiviral agents as a preventative measure in EBV seropositive transplant recipients is being evaluated.

In our patient, immunosuppression was redu苞ed by stopping MMF and decreasing the cy苞losporine dose by 50%. He received a similar chemotherapy regimen that was derived from the ACVBP regimen originally designed for ag茆ressive non-Hodgkin lymphoma in adults. [24] Adaptation of the cyclophosphamide dose to re要al function and prophylactic use of G-CSF and co-trimoxazole certainly helped to reduce the rate of fatal infection. Renal function remained stable throughout the reduction of immunosup計ression. Whether this regimen provides a po負entially curative approach for treatment of post transplant T-cell lymphoma needs further study.

In summary, post transplant T-cell lymphoma is a rare disease and tends to present late fol衍owing transplantation with a poor prognosis. Early diagnosis and intervention are essential to improve survival. Attention should be focused on prevention of this fatal disease.

   References Top

1.Pasquale MA, Weppler D, Smith J, et al. Burkitt's Lymphoma Variant of Post transplant Lympho計roliferative Disease (PTLD). Pathol Oncol Res 2002;8(2):105-8.  Back to cited text no. 1    
2.Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE. Risk factors for post transplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 2001;71(8):1065-8.  Back to cited text no. 2    
3.Funch DP, Brady J, Ko HH, Dreyer NA, Walker AM. Methods and objectives of a large US multicenter case control study of post transplant lymphoproliferative disorder in renal transplant patients. Recent Results Cancer Res 2002;159: 81-8.  Back to cited text no. 3  [PUBMED]  
4.Fohrer C, Caillard S, Koumarianou A, et al. Long term survival in post-transplant lymphoproli苯erative disorders with a dose-adjusted ACVBP regimen. Br J Haematol 2006;134(6):602-12.  Back to cited text no. 4    
5.Harris NL, Ferry JA, Swerdlow SH. Post trans計lant lymphoproliferative disorders: summary of Society for Hematopathology Work shop. Semin Diagn Pathol 1997;14(1):8-14.  Back to cited text no. 5    
6.Penn I. Cancers complicating organ transplan負ation. N Engl J Med 1990;323(25):1767-9.  Back to cited text no. 6    
7.Leblond V, Sutton L, Dorent R, et al. Lympho計roliferative disorders after organ transplanta負ion: a report of 24 cases observed in a single center. J Clin Oncol 1995;13(4):961-8.  Back to cited text no. 7    
8.Licht C, Hell K, Eifinger F, Hoppe B, Querfeld U. Posttransplant lymphoproliferative disease in a child: clinical and molecular characterization. Pediatr Nephrol 2002;17(2):79-84.  Back to cited text no. 8    
9.Pickhardt PJ, Siegel MJ, Hayashi RJ, Kelly M. Posttransplantation lymphoproliferative disorder in children: clinical, histopathologic, and imaging features. Radiology 2000;217(1):16-25.  Back to cited text no. 9    
10.Johnson J, Kerecuk L, Harrison M, Taylor JO, Odell E. Epstein Barr virus associated lympho計roliferative disease in oral cavity in a renal transplant recipient: a case report. Pediatr Transplant 2007;11(3):340-4.  Back to cited text no. 10    
11.Leblond V, Dhedin N, Mamzer Bruneel MF, et al. Identification of prognostic factors in 61 patients with posttransplantation lymphoprolife訃ative disorders. J Clin Oncol 2001;19(3):772-8.  Back to cited text no. 11    
12.Nalesnik MA .Clinical and pathological features of post-transplant lymphoproliferative disorders (PTLD). Springer Semin Immunopathol 1998; 20(3-4):325-42.  Back to cited text no. 12    
13.Douglas RS, Goldstein SM, Katowitz JA, et al. Orbital presentation of posttransplantation lym計hoproliferative disorder: a small case series. Ophthalmology 2002;109(12):2351-5.  Back to cited text no. 13    
14.Mafez R, Breinig MC, Linden P, et al. Post負ransplant lymphoproliferative disease in pri衫ary Epstein-Barr virus infection after liver transplantation: the role of cytomegalovirus disease. J Infect Dis 1997;176(6):1462-7.  Back to cited text no. 14    
15.Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RL. Epstein-Barr virus, immunodefi苞iency, and B-cell lymphoproliferation. Trans計lantation 1985;39(5):461-72.  Back to cited text no. 15    
16.Armitage JM, Kormos RL, Stuart RS, et al. Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 1991;10(6):877-86.  Back to cited text no. 16    
17.Rajakariar R, Bhattacharyya M, Norton A, et al. Post transplant T-cell lymphoma: a case series of four patients from a single unit and review of the literature. Am J Transplant 2004;4(9):15348.  Back to cited text no. 17    
18.Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant re苞ipients. Lancet 1993;342(8886-8887):1514-6.  Back to cited text no. 18    
19.Hoshida Y, Li T, Dong Z, et al. Lymphopro衍iferative disorders in renal transplant patients in Japan. Int J Cancer 2001;91(6):869-75.  Back to cited text no. 19    
20.Stein H, Foss HD, Diirkop H, et al. CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 2000;96(12):3681-95.  Back to cited text no. 20    
21.Gross TG, Bucuvalas JC, Park JR, et al. Low苓ose chemotherapy for Epstein-Barr virus計ositive post-transplantation Lymphoproliferative disease in children after solid organ trans計lantation. J Clin Oncol 2005;23(27):6481-8.  Back to cited text no. 21    
22.Shapiro RS, Chauvenet A, McGuire W, et al. Treatment of B-cell lymphoproliferative disorders with interferon alpha and intravenous gamma globulin. N Engl J Med 1988;318(20):1334.  Back to cited text no. 22    
23.Pirsch JD, Stratta RJ, Sollinger HW, et al. Treatment of severe Epstein Barr virus induced lymphoproliferative syndrome with ganciclovir: two cases after solid organ transplantation. Am J Med 1989;86(2):241-4.  Back to cited text no. 23    
24.Coiffier B, Gisselbrecht C, Herbrecht R, Tilly H, Bosly A, Brousse N. LNH-84 regimen: a multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lym計homa. J Clin Oncol 1989;7(8):1018-26.  Back to cited text no. 24    

Correspondence Address:
Afshin Azhir
Pediatric Nephrologist, Department of Pediatrics, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan
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