Lymphoproliferative disorders after liver transplantation

Abstract

The last two decades have seen an increase in various types of organ transplantation for the treatment of otherwise incurable organ diseases. Prevention of organ rejection requires long-term immunosuppression, which places recipients at an increased risk of both infections and neoplastic diseases such as Kaposi's sarcoma and posttransplant lymphoproliferative disorders (PTLD). Patients who have received solid-organ transplants (SOT) have a 20- to 120-fold higher incidence of non Hodgkin's lymphoma, depending on the degree and duration of immunosuppression [[1]Menachem Y Safadi R Ashur Y Ilan Y Malignancy after liver transplantation in patients with premalignant conditions.J Clin Gastroenterol. 2003; 36: 436-439Crossref PubMed Scopus (14) Google Scholar]. PTLD are mostly of B-cell origin and are often associated with active infection by Epstein–Barr virus (EBV), an oncogenic herpes virus found in most patients with PTLD. PTLD characteristically shows rapid onset, aggressive behavior, a predilection for extranodal sites and, sometimes, partial or complete regression after reduction or withdrawal of immunosuppressive therapy. The small number of cases in individual centers, and treatment heterogeneity, explain the lack of a therapeutic consensus. The incidence of PTLD is 2–10% in liver transplant recipients, ranging from 2 to 3% in adults [2Zein N.N Perez R.G Wiesner R.H Hepatitis C virus infection and lymphoproliferative disorders.Hepatology. 2000; 31: 808-809Crossref PubMed Scopus (13) Google Scholar, 3Glez-Chamorro A Jimenez C Moreno-Glez E Glez-Pinto I Loinaz C Gomez R et al.Management and outcome of liver recipients with post-transplant lymphoproliferative disease.Hepato-Gastroenterol. 2000; 47: 211-219PubMed Google Scholar, 4Duvoux C Pageaux G.P Vanlemmens C Roudot-Thoraval F Vincens-Rolland A.L Hezode C et al.Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients.Transplantation. 2002; 74: 1103-1109Crossref PubMed Scopus (106) Google Scholar, 5Pageaux G.P Bonnardet A Picot M.C Perrigault P.F Coste V Navarro F et al.Prevalence of immunoglobulins after liver transplantation: relationship with posttransplant lymphoproliferative disorders.Transplantation. 1998; 65: 397-400Crossref PubMed Scopus (39) Google Scholar, 6Lemoine A Pham P Azoulay D Saliba F Emile J.F Saffroy R et al.Detection of gammapathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants.Blood. 2001; 98: 1332-1338Crossref PubMed Scopus (29) Google Scholar, 7Wu L Rappaport D.C Hanbidge A Merchant N Shepherd F.A Greig P.D Lymphoproliferative disorders after liver transplantation: imaging features.Abdom Imaging. 2001; 26: 200-206Crossref PubMed Scopus (38) Google Scholar, 8Jain A Nalesnik M Reyes J Pokharna R Mazariegos G Green M et al.Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience.Ann Surg. 2002; 236: 429-436Crossref PubMed Scopus (191) Google Scholar] to more than 10% in some pediatric series [8Jain A Nalesnik M Reyes J Pokharna R Mazariegos G Green M et al.Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience.Ann Surg. 2002; 236: 429-436Crossref PubMed Scopus (191) Google Scholar, 9Newell K.A Alonso E.M Kelly S.M Rubin C.M Thistlethwaite Jr, J.R Whitington P.F Association between liver transplantation for Langerhans cell histiocytosis, rejection, and development of posttransplant lymphoproliferative disease in children.J Pediatr. 1997; 131: 98-104Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 10Cao S Cox K Esquivel C.O Berquist W Concepcion W Ojogho O et al.Posttransplant lymphoproliferative disorders and gastrointestinal manifestations of Epstein–Barr virus infection in children following liver transplantation.Transplantation. 1998; 66: 851-856Crossref PubMed Scopus (46) Google Scholar, 11Smets F Vajro P Cornu G reding R Otte J.B Sokal E Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation.Transplantation. 2000; 69: 982-984Crossref PubMed Scopus (62) Google Scholar, 12Guthery S.L Heubi J.E Bucuvalas J.C Gross T.G Ryckman F.C Alons M.H et al.Determination of risk factors for Epstein–Barr virus-associated posttransplant lymphoproliferative disorder in pediatric liver transplant recipients using objective case ascertainment.Transplantation. 2003; 75: 987-993Crossref PubMed Scopus (74) Google Scholar]. The higher frequency of PTLD in children is due to EBV infection of EBV-negative recipients transplanted with EBV-positive donors [8Jain A Nalesnik M Reyes J Pokharna R Mazariegos G Green M et al.Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience.Ann Surg. 2002; 236: 429-436Crossref PubMed Scopus (191) Google Scholar, 10Cao S Cox K Esquivel C.O Berquist W Concepcion W Ojogho O et al.Posttransplant lymphoproliferative disorders and gastrointestinal manifestations of Epstein–Barr virus infection in children following liver transplantation.Transplantation. 1998; 66: 851-856Crossref PubMed Scopus (46) Google Scholar]. Retrospective serological studies show that most children with PTLD acquired primary EBV infection during the 6 months prior to tumor onset; EBV-seronegative pediatric transplant recipients who develop primary EBV infection are reported to have a significantly higher EBV viral load than previously EBV-seropositive recipients, with the highest levels seen in those who develop PTLD [13Smets F Latinne D Bazin H reding R Otte J.B Buts J.P Sokal E.M Ration between Epstein–Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease.Transplantation. 2002; 73: 1603-1610Crossref PubMed Google Scholar, 14Muti G Mancini V Veronese S Poli F Oreste P Baldanti F et al.Donor of recipient origin posttransplant lymphoproliferative disorders in liver transplanted patients: two different clinically relevant patterns of disease.Blood. 2003; 102 (abst 2324): 629aGoogle Scholar]. Tumor onset classically occurs more than 1 year after liver transplantation in adults and within the first year in children, although PTLD can also occur several years after transplant, as most of these patients receive life-long immunosuppression. Jain et al., studying 170 cases of PTLD after liver transplantation, observed a shorter median time to PTLD onset in adults treated with cyclosporin than in those treated with tacrolimus (6.1 months vs 23.6 months), while the opposite was true for children (27 months with cyclosporin and 4.7 months with tacrolimus) [[8]Jain A Nalesnik M Reyes J Pokharna R Mazariegos G Green M et al.Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience.Ann Surg. 2002; 236: 429-436Crossref PubMed Scopus (191) Google Scholar]. Several factors predictive of PTLD onset have been reported. Recipient age and EBV viral load are the most widely accepted. Muti et al. recently found that the serum IL10 level had better predictive value than EBV viral load [[15]Muti G Klersy C Baldanti F Granata S Oreste P Pezzetti L et al.Epstein–Barr virus (EBV) load and interleukin-10 in EBV-positive and EBV-negative post-transplant lymphoproliferative disorders.Br J Haematol. 2003; 122: 927-933Crossref PubMed Scopus (39) Google Scholar]. Stable monoclonal gammopathy also seems to be highly predictive of PTLD [[6]Lemoine A Pham P Azoulay D Saliba F Emile J.F Saffroy R et al.Detection of gammapathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants.Blood. 2001; 98: 1332-1338Crossref PubMed Scopus (29) Google Scholar]. The immunosuppressive regimen has an important role in PTLD, and especially the use of antilymphocytic serum [[4]Duvoux C Pageaux G.P Vanlemmens C Roudot-Thoraval F Vincens-Rolland A.L Hezode C et al.Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients.Transplantation. 2002; 74: 1103-1109Crossref PubMed Scopus (106) Google Scholar] and tacrolimus in children [8Jain A Nalesnik M Reyes J Pokharna R Mazariegos G Green M et al.Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience.Ann Surg. 2002; 236: 429-436Crossref PubMed Scopus (191) Google Scholar, 12Guthery S.L Heubi J.E Bucuvalas J.C Gross T.G Ryckman F.C Alons M.H et al.Determination of risk factors for Epstein–Barr virus-associated posttransplant lymphoproliferative disorder in pediatric liver transplant recipients using objective case ascertainment.Transplantation. 2003; 75: 987-993Crossref PubMed Scopus (74) Google Scholar]. The indication for transplantation is probably also important, as the risk of PTLD in patients transplanted for histiocytosis or sclerosing cholangitis is more than 20% [[9]Newell K.A Alonso E.M Kelly S.M Rubin C.M Thistlethwaite Jr, J.R Whitington P.F Association between liver transplantation for Langerhans cell histiocytosis, rejection, and development of posttransplant lymphoproliferative disease in children.J Pediatr. 1997; 131: 98-104Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]; alcoholic cirrhosis and viral hepatitis are indications associated with an increased incidence of PTLD in adult recipients [4Duvoux C Pageaux G.P Vanlemmens C Roudot-Thoraval F Vincens-Rolland A.L Hezode C et al.Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients.Transplantation. 2002; 74: 1103-1109Crossref PubMed Scopus (106) Google Scholar, 6Lemoine A Pham P Azoulay D Saliba F Emile J.F Saffroy R et al.Detection of gammapathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants.Blood. 2001; 98: 1332-1338Crossref PubMed Scopus (29) Google Scholar] although Zein found no role of HCV [[2]Zein N.N Perez R.G Wiesner R.H Hepatitis C virus infection and lymphoproliferative disorders.Hepatology. 2000; 31: 808-809Crossref PubMed Scopus (13) Google Scholar]. Reported PTLD incidence rates and predictive factors after liver transplantation are shown in Table 1.Table 1Incidence and predictive factors of PTLDReferenceTpt (nb)Period (years)PTLD (nb)Incidence (%)Ped (%)TTD (months)>1 year (%)Mo/Po/EaEBV (%)Predictive factors of PTLDNewell [9]Newell K.A Alonso E.M Kelly S.M Rubin C.M Thistlethwaite Jr, J.R Whitington P.F Association between liver transplantation for Langerhans cell histiocytosis, rejection, and development of posttransplant lymphoproliferative disease in children.J Pediatr. 1997; 131: 98-104Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar29885–95258.4100Histiocytosis (67%) Sclerosing cholangitis (20%)Pageaux [5]Pageaux G.P Bonnardet A Picot M.C Perrigault P.F Coste V Navarro F et al.Prevalence of immunoglobulins after liver transplantation: relationship with posttransplant lymphoproliferative disorders.Transplantation. 1998; 65: 397-400Crossref PubMed Scopus (39) Google Scholar8633.5Monoclonal gammopathyCao (1998)17288–94116.4100Gastrointestinal EBV infection diarrhoea 18.2% gastrointestinal bleeding 70%Zein [2]Zein N.N Perez R.G Wiesner R.H Hepatitis C virus infection and lymphoproliferative disorders.Hepatology. 2000; 31: 808-809Crossref PubMed Scopus (13) Google Scholar66085–96131.90HCV is not predictiveGlez [3]Glez-Chamorro A Jimenez C Moreno-Glez E Glez-Pinto I Loinaz C Gomez R et al.Management and outcome of liver recipients with post-transplant lymphoproliferative disease.Hepato-Gastroenterol. 2000; 47: 211-219PubMed Google Scholar45786–97112.436100Smets [11]Smets F Vajro P Cornu G reding R Otte J.B Sokal E Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation.Transplantation. 2000; 69: 982-984Crossref PubMed Scopus (62) Google Scholar450398.6100Lemoine [6]Lemoine A Pham P Azoulay D Saliba F Emile J.F Saffroy R et al.Detection of gammapathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants.Blood. 2001; 98: 1332-1338Crossref PubMed Scopus (29) Google Scholar91185–99212.33876/19/058Monoclonal gammopathy (R65.3) >1 transplantation (R7.5) Viral cirrhosis (R2.8)Wu [7]Wu L Rappaport D.C Hanbidge A Merchant N Shepherd F.A Greig P.D Lymphoproliferative disorders after liver transplantation: imaging features.Abdom Imaging. 2001; 26: 200-206Crossref PubMed Scopus (38) Google Scholar60585–98203.3014Duvoux [4]Duvoux C Pageaux G.P Vanlemmens C Roudot-Thoraval F Vincens-Rolland A.L Hezode C et al.Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients.Transplantation. 2002; 74: 1103-1109Crossref PubMed Scopus (106) Google Scholar48086–97163.35.5Alcoholic cirrhosis (R9.6) HCV cirrhosis (R8.7) Antilymphocyte serum (R4.2) >50 years (R3.5)Jain [8]Jain A Nalesnik M Reyes J Pokharna R Mazariegos G Green M et al.Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience.Ann Surg. 2002; 236: 429-436Crossref PubMed Scopus (191) Google Scholar400081–981704.3209.71008.1a27 months with cyclosporine, 4.7 months with tacrolimus.29/51/1798Tacrolimus2.9015b6.1 months with cyclosporine, 23.6 months with tacrolimus.54/22/868Smets [13]Smets F Latinne D Bazin H reding R Otte J.B Buts J.P Sokal E.M Ration between Epstein–Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease.Transplantation. 2002; 73: 1603-1610Crossref PubMed Google Scholar457100EBV viral load Decrease in anti-EBV CTLGuthery [12]Guthery S.L Heubi J.E Bucuvalas J.C Gross T.G Ryckman F.C Alons M.H et al.Determination of risk factors for Epstein–Barr virus-associated posttransplant lymphoproliferative disorder in pediatric liver transplant recipients using objective case ascertainment.Transplantation. 2003; 75: 987-993Crossref PubMed Scopus (74) Google Scholar2212310.4100Tacrolimus Age EBV viral load, IL10Tpt, transplantation; period, years during which transplantations were done; PTLD, posttransplant lymphoproliferative disorder; Ped, pediatric cases; TTD, time from transplantation to PTLD; >1 year=PTLD, onset more than 1 year after transplantation; Mo, monomorphic; Po, polymorphic; Ea, early lesions (other types of PTLD are not presented in this table); EBV: Epstein–Barr virus; Nb, number; R, relative risk; HCV, hepatitis C virus; IL10, interleukin 10; CTL, T-cell lymphocyte.a 27 months with cyclosporine, 4.7 months with tacrolimus.b 6.1 months with cyclosporine, 23.6 months with tacrolimus. Open table in a new tab Tpt, transplantation; period, years during which transplantations were done; PTLD, posttransplant lymphoproliferative disorder; Ped, pediatric cases; TTD, time from transplantation to PTLD; >1 year=PTLD, onset more than 1 year after transplantation; Mo, monomorphic; Po, polymorphic; Ea, early lesions (other types of PTLD are not presented in this table); EBV: Epstein–Barr virus; Nb, number; R, relative risk; HCV, hepatitis C virus; IL10, interleukin 10; CTL, T-cell lymphocyte. The oncogenic mechanisms of PTLD differ according to EBV involvement. PTLD is nearly always of B-cell origin (85%) and EBV-positive. EBV is usually a bystander infection, but, in rare cases, the transforming capacities of this virus promote the development of B-cell PTLD. EBV-encoded proteins expressed during latency (EBNA1, EBNA2, LMP1, LMP2A) can act as oncogenic pathways: EBNA1 binds to the replication start site of the EBV episome; EBNA2 is a transactivator that regulates several viral and host genes; and LMP1 inhibits apoptosis by upregulating the anti-apoptotic proteins BCL-2 and A20 and induces an activated cellular phenotype. Most effects of LMP1 are due to activation of nuclear factor-κB. This signaling pathway is similar to that of the CD-40 receptor, which has a key role in B cell activation and differentiation. LMP2A can mimic a B-cell receptor and provides an important survival signal for B cells [[16]Kuppers R B cells under influence: transformation of B cells by Epstein–Barr virus.Nat Rev Immunol. 2003; 3: 801-812Crossref PubMed Scopus (408) Google Scholar]. Post-transplantation immunosuppression allows EBV-transformed B cells to proliferate unchecked, by potently suppressing EBV-specific cytotoxic T cells. However, the development of B-PTLD is probably more complex: recipient B cells recirculating in the graft may be chronically stimulated to proliferate in response to donor antigens, and donor lymphoid tissue itself may carry a high EBV load. Thus, the transplanted organ is a site of antigenic stimulation, and the donor tissue, as well as the tumor itself, can contain a heavy infiltrate of CD4-positive cells which can provide help for EBV-infected B-cells, by secreting growth-promoting cytokines. PTLD can be polyclonal, but many cases are oligoclonal or monoclonal. In the latter situation, some EBV-positive B cells may have acquired additional transforming events, finally leading to outgrowth of a malignant B-cell clone after initially polyclonal or oligoclonal expansion (Fig. 1) . When not associated with EBV, PTLD occurs late after grafting (up to 5 years), and has the same characteristics as lymphomas in immunocompetent patients [14Muti G Mancini V Veronese S Poli F Oreste P Baldanti F et al.Donor of recipient origin posttransplant lymphoproliferative disorders in liver transplanted patients: two different clinically relevant patterns of disease.Blood. 2003; 102 (abst 2324): 629aGoogle Scholar, 17Leblond V Davi F Charlotte F Dorent R Bitker M.O Sutton L et al.Posttransplant lymphoproliferative disorders not associated with Epstein–Barr virus: a distinct entity?.J Clin Oncol. 1998; 16: 2052-2059Crossref PubMed Scopus (303) Google Scholar]. PTLD is clinically heterogeneous at presentation, sometimes delaying the diagnosis. A single site of involvement may be found in the central nervous system, gastrointestinal tract, or lung. In a retrospective study of 605 liver transplant recipients, 20 patients developed PTLD: 55% had cervical, abdominal or thoracic lymphadenopathy, 25% had a portal mass, and 15% had a gastrointestinal mass [[18]Wu L Rappaport D.C Hanbidge A Merchant N Shepherd F.A Greig P.D Lymphoproliferative disorders after liver transplantation: imaging features.Abdom Imaging. 2001; 26: 200-206Crossref PubMed Scopus (24) Google Scholar]. Waldeyer's ring is a common site of pediatric PTLD with tonsillar involvement [[19]Koh B.Y Rosenthal P Medeiros L.J Zhou Y Osorio R.W Roberts J.P et al.Posttransplantation lymphoproliferative disorders in Childs undergoing liver transplantation. A clinicopathologic and molecular study.Arch Pathol Lab Med. 2001; 125: 337-343PubMed Google Scholar]. Involvement of the grafted organ can occur in liver transplant recipients, mainly in early-onset forms such as PTLD of the liver hilum with extensive necrosis and compression of the porta hepatis, leading to biliary stricture and portal vein thrombosis, or at sites of previous surgery [20Doria C Marino I.R Scott V.L Jaffe R Minervi M.I Zajko A Nalesnik M.A Posttransplant lymphoproliferative disorders presenting at sites of previous surgical intervention.Transplantation. 2003; 75: 1066-1069Crossref PubMed Scopus (9) Google Scholar, 21Baron P.W Heneghan M.A Suhocki P.V Nuckols J.D Tuttler-Newhall J.E Howell D.N Clavien P.A Biliary stricture secondary to donor B-cell lymphoma after orthotopic liver transplantation.Liver Transpl. 2001; 7: 62-67Crossref PubMed Scopus (20) Google Scholar]. In late-onset PTLD, the disease is often disseminated at diagnosis [[14]Muti G Mancini V Veronese S Poli F Oreste P Baldanti F et al.Donor of recipient origin posttransplant lymphoproliferative disorders in liver transplanted patients: two different clinically relevant patterns of disease.Blood. 2003; 102 (abst 2324): 629aGoogle Scholar]. The lymphoid proliferation arises from B-cells of recipient origin in most cases of late-onset forms, but a few cases involving donor B-cells have been reported; the latter often occur on the graft (liver hilum), within the first year, and can be misinterpreted as graft rejection [14Muti G Mancini V Veronese S Poli F Oreste P Baldanti F et al.Donor of recipient origin posttransplant lymphoproliferative disorders in liver transplanted patients: two different clinically relevant patterns of disease.Blood. 2003; 102 (abst 2324): 629aGoogle Scholar, 21Baron P.W Heneghan M.A Suhocki P.V Nuckols J.D Tuttler-Newhall J.E Howell D.N Clavien P.A Biliary stricture secondary to donor B-cell lymphoma after orthotopic liver transplantation.Liver Transpl. 2001; 7: 62-67Crossref PubMed Scopus (20) Google Scholar]. Correlative morphologic and molecular genetic analyses have identified three distinct categories of PTLD [22Harris N.L Ferry J.A Swerdlow S.H Posttransplant lymphoproliferative disorders: summary of Society for hematopathology Workshop.Semin Diag Pathol. 1997; 14: 8-14PubMed Google Scholar, 23Knowles D.M Cesarman E Chadburn A Frizzera G Chen J Rose E et al.Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders.Blood. 1995; : 552-565PubMed Google Scholar]. Plasmacytic hyperplasia most commonly arises in the oropharynx or lymph nodes, is nearly always polyclonal, usually contains multiple EBV infection events or a minor cell population infected by a single form of EBV and lacks oncogene and tumor suppressor gene mutations. Plasmacytic hyperplasia corresponds to the ‘early lesion’ in Harris’ classification [[22]Harris N.L Ferry J.A Swerdlow S.H Posttransplant lymphoproliferative disorders: summary of Society for hematopathology Workshop.Semin Diag Pathol. 1997; 14: 8-14PubMed Google Scholar]. Polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma can arise in lymph nodes or various extranodal sites. These latter forms are nearly always monoclonal, usually contain a single form of EBV, and lack oncogene and tumor suppressor gene mutations. Polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma correspond to ‘polymorphic and monomorphic PTLD’ in Harris’ classification. Immunoblastic lymphoma or multiple myeloma is usually widely disseminated at diagnosis. It is monoclonal, contains a single form of EBV (or is not associated with EBV), and contains alterations of one or more oncogenes or tumor suppressor genes (N-ras, P53, or c-myc rearrangement). These entities correspond to ‘monomorphic’ PTLD and ‘other rare PTLD’ (Hodgkin and Hodgkin-like, plasmacytic lymphoma, T-cell lymphoma) in Harris’ classification. Few PTLDs are of T-cell origin (4–15% of PTLD), and have the pathological criteria of peripheral T-cell lymphomas. EBV is associated with T-cell PTLD in 60% of cases (Table 2)Table 2The World Health Organization classification of posttransplant lymphoproliferative disorders, from Harris et al. [22]Harris N.L Ferry J.A Swerdlow S.H Posttransplant lymphoproliferative disorders: summary of Society for hematopathology Workshop.Semin Diag Pathol. 1997; 14: 8-14PubMed Google ScholarCategories of PTLDEBVClonality IgVH or TCR rearrangementsTime from graft to lymphomaOutcomeGene modificationsEarly lesionsReactive plasmacytic hyperplasiaPositivePolyclonalWithin 3 monthsResponse to immunosuppression reductionNo mutationInfectious mononucleosis-likeNo clonalAcyclovir ?PTLD polymorphicPolyclonal (rare)Polyclonal or monoclonalVariableResponse to immunosuppression reductionNo mutationsMonoclonalClonalUse of other treatmentPTLD monomorphicB-cell lymphomas: diffuse large B-cell lymphoma (immunoblastic, centroblastic, anaplastic)Positive or negative If positive: clonalMonoclonal3 months to 12 year (median: 1.3 year)Rare response to immunosuppression reductionBurkitt/Burkitt like lymphomaUse of other treatmentsMutations of ras, p53Plasma cell myelomaMonoclonal3.5–7 yearNo response to immunosuppression reductionT-cell lymphoma: peripheral T-cell lymphoma, not otherwise categorizedSometimes positiveOther typesOther types (rare)Hodgkin and Hodgkin disease-like lesionsPlasmacytoma- like lesionsEBV, Epstein–Barr virus; PTLD, posttransplant lymphoproliferative disorder; IgVH, immunoglobulin V heavy chain; TCR, T-cell receptor. Open table in a new tab EBV, Epstein–Barr virus; PTLD, posttransplant lymphoproliferative disorder; IgVH, immunoglobulin V heavy chain; TCR, T-cell receptor. Lymphoid proliferation is best characterized by using a combination of histopathology, immunophenotyping, and molecular studies of frozen tissue. The diagnosis is based on tumor biopsy with molecular characterization of clonality. It is important to test the tumor for EBV, as the results have diagnostic, prognostic and therapeutic implications. PTLD used to be highly lethal, killing 40–60% of affected solid-organ recipients. The prognosis has improved markedly with the use of new therapeutic approaches such as monoclonal antibodies and T-cell therapy [24Milpied N Vasseur B Parquet N Garnier J.L Antoine C Quartier P et al.Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients.Ann Oncol. 2000; 11: 113S-116SAbstract Full Text PDF PubMed Scopus (351) Google Scholar, 25Choquet S Leblond V Herbrecht R Socie G Stoppa A.M Vandenberghe P et al.Efficacy and safety of Rituximab in B-cell post transplantation lymphoproliferative disorders (B-PTLD): final results of a multicenter, open label, phase II trial (M39037 TRIAL).Blood. 2003; 102: 277aGoogle Scholar, 26Rooney C.M Heslop H.E Brenner M.K EBV specific CTL: a model for immune therapy.Vox Sanguinis. 1998; 74: 497-498Crossref PubMed Scopus (31) Google Scholar]. Late mortality after liver transplantation in childhood remains low, at 0.32% per year. The most common causes of death were infection (60%), including PTLD-related disease (20%) [[27]Fridell J.A Jain A Reyes J Biederman R Green M Sindhi R et al.Causes of mortality beyond 1 year after primary pediatric liver transplant under tacrolimus.Transplantation. 2002; 74: 1721-1724Crossref PubMed Scopus (53) Google Scholar]. However, the overall survival of patients with PTLD was better in children than in adults, with 65% of survival rate at 15 years in children compared to 39% for adults, and 55% at 10 years in 170 liver transplant adult and pediatric recipients with PTLD [[28]Jain A Mazariegos G Kashyap R Kosmach-Park B Starzl T.E Fung J et al.Pediatric liver transplantation: a single center experience spanning 20 years.Transplantation. 2002; 73: 941-947Crossref PubMed Scopus (114) Google Scholar]. Prognostic factors associated with survival after solid organ transplantation are controversial, and include time from grafting to tumor onset, clonality, the number of involved sites, the LDH level, performance status, EBV negativity, and CNS involvement [29Leblond V Dhedin N Mamzer Bruneel M.F Choquet S Hermine O Porcher R et al.Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders.J Clin Oncol. 2001; 19: 772-778PubMed Google Scholar, 30Ghobrial I.M Habermann T.M Maurer M.J Geyer S.M Macon W Ristaw K Proposed prognostic model for survival in solid organ transplant recipients with posttransplant lymphoproliferative disorders (PTLD).Blood. 2003; 102 (abst 1423): 392aGoogle Scholar]. Among 170 patients with PTLD occurring after liver transplantation, Jain et al. found that survival was better among children, patients transplanted after the advent of tacrolimus immunosuppression, patients with polymorphic PTLD, and patients with limited disease. Larger series with homogeneous treatments are needed for better prognostication in PTLD (Table 3) .Table 3Treatment and predictive factors for response and survival (only studies using homogeneous treatments are presented)ReferencesPTLD/liver (nb/nb)Ped (%)>1 year (%)Mo/Po (%)EBV (%)TtOR (%)Survival (%)PF responsePF survivalNalesnik [43]Nalesnik M.A Rao A.S Furukawa H Pham S Zeevi A Fung J.J Autologous lymphokine-activated killer cell therapy of Epstein–Barr virus-positive and -negative lymphoproliferative disorders arising in organ transplant recipients.Transplantation. 1997; 63: 1200-1205Crossref PubMed Scopus (92) Google Scholar7/357Auto LAK57Benkerrou [39]Benkerrou M Jais J.P Leblond V Durandy A Sutton L Bordigoni P et al.Anti-B-cell monoclonal antibody treatment of severe posttransplant B-lymphoproliferative disorder: prognostic factors and long-term outcome.Blood. 1998; 92: 3137-3147PubMed Google Scholar58/352Anti CD21, CD246246 at T 12 m4 sites>4 sites>1 yearCNSCacciarelli [36]Cacciarelli T.V Green M Jaffe R Mazariegos G.V Jain A Fung J.J et al.Management of posttransplant lymphoproliferative disease in pediatric liver transplant recipients receiving primary tacrolimus (FK506) therapy.Transplantation. 1998; 66: 1047-1052Crossref PubMed Scopus (90) Google Scholar4/4100INF α50Haddad [38]Haddad E Paczesny S Leblond V Seigneurin J.M Stern M Achkar A et al.Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase1–2 clinical trial.Blood. 2001; 97: 1590-1597Crossref PubMed Scopus (112) Google Scholar12/3175025/75100anti IL667>1 yearGross [35]Gross T.G Park J Bucuvalas J Langnas A Kaufman S McDonald R et al.Low-dose chemotherapy for refractory EBV associated post-transplant lymphoproliferative disease (PTLD) following solid organ transplant (SOT) in children.Blood. 2002; 100 (abst 598): 159aCrossref PubMed Scopus (86) Google Scholar36/171005aMedian time from transplantation to PTLD (in months)