Diagnosis Of Post-transplant Lymphoproliferative Disorder Research Articles

II. Challenges in the management of post-transplant lymphoproliferative disorder.

II. Challenges in the management of post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder in liver recipients: Characteristics, management, and outcome from a single-centre experience with >1000 liver transplantations.

The literature regarding post-transplant lymphoproliferative disorder (PTLD) in liver transplant recipients (LTRs) is limited. To study the incidence, predictors and outcomes of PTLD after liver transplantation in a single, large-volume centre. The charts of all LTRs (n=1372) in the authors' centre between January 2000 and June 2012 were retrospectively reviewed and those who developed PTLD were identified. Demographic, clinical and treatment data were prospectively collected. Responses to treatment, including complete response, no response, relapse and survival, were recorded. The incidence of PTLD in LTRs was 32 in 1372 (2.3%). Overall, median survival was 37 months (range 0.5 to 195 months), with one-, three- and five-year survival rates of 81%, 74% and 60%, respectively. Epstein-Barr virus (EBV)-negative patients had a better mean (± SD) survival (95±79 months) than EBV-positive patients (41±42 months) (P=0.02). For stage I⁄II PTLD, one-, three- and five-year actuarial survival was 87%, 87% and 75%, compared with 50%, 30% and 0% for stage III⁄IV PTLD, respectively (P=0.001). In patients with complete response, median survival was 58 months (range 10 to 195 months); and one-, three- and five-year actuarial survival was 100%, 94% and 76%, respectively, after diagnosis of PTLD. Changing immunosuppression (IS) from calcineurin inhibitor to sirolimus at the time of diagnosis may have improved survival (seven of seven survivors) compared with only decreasing or stopping IS (14 of 25 survivors) (P=0.07). This series from a single large-volume centre showed excellent short and long-term survival after PTLD in adult LTRs who were EBV negative, had early disease and showed complete response. Consistent with the known in vitro antiproliferative effect of sirolimus, switching IS from calcineurin inhibitor to sirolimus may improve survival.

Post Transplant Lymphoproliferative Disorders (PTLD) after Solid Organ Transplant: Cleveland Clinic Experience

Background: Post transplant lymphoproliferative disorders (PTLD) are rare pathologically and clinically heterogeneous diseases arising in the setting of immunosuppression following hematopoietic stem cell and solid organ transplants (SOT). Our understanding of PTLD is restricted by its low incidence and heterogeneous treatment approaches, resulting in paucity of data. We sought to further describe characteristics and outcomes in PTLD patients who underwent treatment at our institution.Methods and Patients: We performed a retrospective study to describe our institutional experience in a relatively large cohort of PTLD patients after SOT. Patient and disease characteristics were examined and prognostic factors for survival were determined using univariate and multivariate Cox analysis.Results: Between May 1987 to January 2014, 98 patients with a confirmed diagnosis of PTLD underwent treatment at our institution. Median time from SOT to PTLD diagnosis was 60 months with median follow of 68 months from PTLD diagnosis. Baseline characteristics include male gender 77%, ECOG performance status (PS) 0-1 in 61%, and stage III-IV 69% with a median age at diagnosis of 47 years. Most common transplanted organ included heart 30%, lung 24%, kidney 20% and liver 19% and median time from SOT to PTLD diagnosis was 60 months. Most cases had monomorphic histology (81%) and were EBV+ (82%). Graft involvement and rejection were observed in 32% and 43% respectively. Of the 84% with extranodal (EN) involvement, gastrointestinal tract (37%) and lung (27%) were the common sites, while 3.2% had bone marrow (BM) involvement. Central nervous system (CNS) was involved in 11% of the cases. Only 58% received rituximab as part of the initial therapy, as significant part of our cohort was treated prior to rituximab era. Reduction in immunosuppression (73%), chemotherapy (40%), radiation (11%) and surgery (8%) were utilized either as single modality or in combination for treatment. Of the 66 patients with response data, 59% had complete response (CR) and 14% had progressive disease (PD). Relapse occurred in 23% of cases. Median overall survival (OS) from diagnosis of PTLD was 6 years (Figure 1), but in rituximab treated patients it was 8 years. On univariate analysis, higher age at diagnosis (HR 1.19, 95% CI 1.01-1.40, p=0.033), lung transplant (HR 2.42, 95% CI 1.36-4.33, p=0.003), higher IPI (HR 1.83, 95% CI 1.40-2.39, p=<0.001), decreased PS (HR 2.43, 95% CI 1.70-3.48, p=<0.001), and platelet count <200,000 (HR 2.84, 95% CI 1.27-6.33, p=0.011) were associated with lower OS, whereas liver transplant (HR 0.24, 95% CI 0.09-0.68, p=0.007) and GI involvement (HR 0.47, 95% CI 0.24-0.95, p=0.036) predicted better OS. Rituximab treatment (Figure 2) and achieving CR were associated with better OS. Histology, EN involvement, and EBV status were not significant predictors for survival. On multivariate analysis only lung transplant, IPI, and PS were predictive for OS. Lung transplant patients had a higher risk of mortality compared to other SOT (HR 2.63, 95% CI 1.39-4.95, p=0.003). Both higher IPI (HR 1.66, 95% CI 1.18-2.32, p=0.003) and poor PS (HR 1.94, 95% CI 1.27-2.96, p=0.002) were associated with inferior OS.Conclusions: In this large cohort of PTLD patients after SOT, lung transplants, higher IPI and poor PS were identified as poor prognostic factors for OS on both univariate and multivariate analysis. Rituximab treatment was a favorable prognostic factor for OS that resulted in prolonged survival observed in this cohort. [Display omitted] [Display omitted] DisclosuresHill:Millenium: Research Funding; Novartis: Research Funding.

Comparison of Free Light Chain Assay with Protein Electrophoresis for Screening and Monitoring PTLD

Background: Post-transplant lymphoproliferative disorder (PTLD) is primarily diagnosed histologically using tissue biopsy. Free light chain (FLC) assay and serum protein electrophoresis (SPE) have both been studied as tools to screen and monitor PTLD. However, limited data are available to compare these two assays in a well characterized patient population. It is also not clear what reference ranges should be adopted for the FLC assay in a post-transplant population.Method: Blood samples from 169 patients receiving a variety of solid organ transplants were analyzed for FLCs and screened for gammopathies by SPE/IFE.Results: Compared with non-PTLD patients, PTLD patients had higher mean, median and upper 95 percentile range of both κ and λ FLCs (p ranging from 0.0002 to 0.024). The mean, median and 95 percentile range of κ:λ ratio were similar between the two groups. PTLD patients were more likely to have polyclonal or monoclonal FLC elevations (p = 0.04). They also showed a higher frequency of gammopathy abnormalities (p = 0.0052). Nonetheless, neither FLC assay nor SPE demonstrated a clear association with the timing of PTLD diagnosis. FLC concentrations in non-PTLD recipients were higher than those in the general healthy population (95 percentile range: κ, 0.60-8.33 mg/dL vs. 0.33-1.94 mg/dL; λ, 0.77-7.08 mg/dL vs. 0.571-2.63 mg/dL) but the κ:λ ratio was similar to that of the healthy group (0.26-1.65).Conclusions: Our results suggested that elevated FLC concentrations and gammopathy abnormalities were both associated with PTLD. Therefore, FLC assay and SPE should be used conjunctively for screening PTLD among solid organ transplant recipients. For this application, the data showed that a higher upper limit of κ and λ FLC levels and normal κ:λ ratio should be used as diagnostic reference ranges. Additionally, neither method was clearly associated with the timing of PTLD diagnosis, indicating that they may be unsuitable for monitoring PTLD in the post-transplant population.Table 1Longitudinal measurements of serum/plasma free light chains and SPE/IFE in eight PTLD cases.Type of transplant and type of PTLDSamplesDays from PTLD diagnosisaκ FLC, mg/dLλ FLC, mg/dLκ /λSPE/IFELiver transplant, B-cell PTLD1.1 1.2– 6162.33b1.824.966.010.47 0.303no band –cLiver transplant, B-cell PTLD2.1 2.2 2.3 2.4 2.5-145* -126 84 141 4280.338 0.79 0.335 0.476 2.530.62 1.02 1.06 1.15 1.980.545 0.775 0.316 0.414 1.28no band no band 1 IgG ©µ, 1 IgG λ 1 IgG ©µ, 1 IgG λ no bandLiver transplant, polymorphic hyperplasia3.1 3.2-77 2084.197.185.93.380.71 2.122 IgG ©µ, 2 λ FLC–Liver transplant, B-cell PTLD4.1 4.2 4.361 272 5374.643.257.111.16.6510.960.418 0.489 0.648no band no band no bandLiver transplant, B-cell PTLD5.1 5.2 5.3 5.4 5.59 12 393 429 476305.59570.721 1.01 1.2474.251921.67 1.72 2.564.114.980.432 0.587 0.4841 IgG ©µ, 1 λ FLC 2 IgM ©µ no band no band no bandLiver transplant, B-cell PTLD6.1 6.2 6.3 6.462 153 174 1883.165.583.972.142.923.913.813.371.08 1.43 1.04 0.635– 1 IgG ©µ 1 IgG ©µ 1 IgG ©µKidney transplant, PTLD7.1 7.215 301.4 1.681.58 2.060.89 0.82no band no bandLung transplant, Non-Hodgkin lymphoma8.1-604.284.580.94no banda Positive values indicate time points before PTLD diagnosis, while negative values indicate time points after PTLD diagnosis.b Numbers in bold format indicates values above ULN.c SPE/IFE results not available due to insufficient sample volume. DisclosuresKuhn:The Binding Site, Inc: Employment.

In vivo intratumoral Epstein–Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications

Post-transplant lymphoproliferative disorders are life-threatening complications following hematopoietic or solid organ transplantation. They represent a spectrum of mostly EBV-driven lymphoplasmacytic proliferations. While the oncogenic effect of EBV is related to latent infection, lytic infection also has a role in lymphomagenesis. In vitro, EBV replication is linked to plasma cell differentiation and XBP1 activation, although this phenomenon has never been addressed in vivo. We analyzed for the first time latent and lytic intratumoral EBV infection in a series of 35 adult patients with a diagnosis of post-transplant lymphoproliferative disorder (26M/9F, median age 54 years). A complete EBV study was performed including the analysis of the latent EBER, latent membrane protein-11, and EBV nuclear antigens as well as the immediate-early BZLF1/ZEBRA and early BMRF1/EADE31 lytic genes. XBP1 activation was assessed by nuclear protein expression. EBV infection was observed in 28 (80%) cases being latency II and III the most frequently observed 22 (79%). Intratumoral EBV replication was detected in 17 (60%) cases. Among these, XBP1 activation was observed in 11/12 evaluable cases associated with strong cytoplasmic immunoglobulin expression consistent with plasma cell differentiation. Intriguingly, the combination of latency III infection and EBV replication identified a high-risk subgroup of patients with significantly shorter survival (overall survival at 1 year 18% vs 48%) and early-onset (median of 7 vs 26 months) post-transplant lymphoproliferative disorder. Moreover, these patients appear to be more heavily immunosuppressed, so they exhibit lower rates of rejection and graft vs host disease but higher rates of cytomegalovirus reactivation. In conclusion, EBV replication is associated with plasma cell differentiation and XBP1 activation with prognostic implications. Both latency III and lytic EBV infection are related to aggressive and early-onset post-transplant lymphoproliferative disorder. These results suggest that immunohistochemical study of latent and lytic EBV genes in the clinical practice may help to select higher-risk patients to new therapies including antiviral treatments.

Early diagnosis and comprehensive treatments of post-transplantation lymphoproliferative disorder after pediatric liver transplantation

To summarize the clinical characteristics, early diagnosis, comprehensive treatment and prognosis of 6 cases of children with post-transplantation lymphoproliferative disorder (PTLD) after liver transplantation. Data of 6 cases with PTLD seen between January 2011 and December 2013 were retrospectively analyzed. The anti-rejection drug dose adjustments, the effect of rituximab, antiviral therapy and comprehensive treatment program after surgery were explored. (1) The diagnosis of PTLD was confirmed by histologic findings. Six cases of PTLD including 3 males and 3 females were diagnosed as congenital biliary atresia and underwent split liver transplantation. The occurrence rate of PTLD was 2.9%. (2) The median time to the development of PTLD was less than 6 months. The initial symptom of PTLD in all patients was fever and clinical manifestations of PTLD were non-specific, depending on the involving organs. Five cases of PTLD developed gastrointestinal symptoms, including diarrhea, abdominal pain, and abdominal distension. One case developed respiratory symptoms, including cough and tachypnea. Three cases had lymph node involvement. In 2 cases pathophysiology involved polymorphic lymphocyte proliferation and in 4 cases B lymphocyte proliferation. (3) Two cases died, in whom EBV DNA was not detected and were diagnosed as PTLD by surgical pathology before death. Four survived cases had high EBV-DNA load and then were diagnosed as PTLD by biopsy pathology. (4) Of the 6 cases of PTLD, 2 cases died and 4 cases survived. The overall mortality was 33%. The dead cases were only treated with laparotomy because of intestinal obstruction or perforation and the survived cases were treated with tacrolimus at reduced doses or discontinuation and rituximab. In 2 cases antiviral therapy (acyclovir) was continued, including 1 cases of intestinal obstruction treated with surgical repair. All the survived patients were followed up for 4 months to 1 year and no evidence has been found. EBV infection is the high risk factor for PTLD after liver transplantation. Close clinical surveillance of EBV DNA for pediatric liver transplantation was important for the early diagnosis of PTLD. Reducing doses of immunosuppressive agents and rituximab is the initial therapy for PTLD. A reduction in the dose of tacrolimus is suggested. Operation therapy can also play a role in the management of local complications.

A 13 year-old boy with post-transplantation lymphoproliferative disorder presenting with obscure gastrointestinal bleeding: a case report.

One well recognized and potentially serious complication of chronic immunosuppression in organ transplant recipients is post-transplantation lymphoproliferative disorders (PTLD). This accounts for 20% of all malignancies in transplant recipients, which is four times higher than the general population (1,2). The diagnosis of PTLD is often difficult, due to various manifestations resulting in late diagnosis. We report an unusual presentation of PTLD in a pediatric patient where the diagnosis was achieved only after extensive investigation.

Maintaining calcineurin inhibition after the diagnosis of post-transplant lymphoproliferative disorder improves renal graft survival

Post-transplant lymphoproliferative disorder (PTLD) is an uncontrolled proliferation of transformed lymphocytes fostered by immunosuppression. In addition to chemotherapy, treatment of PTLD includes a reduction of maintenance immunosuppression. Patients with PTLD have an increased risk of graft loss, suggesting that reduced immunosuppression strategy needs to be optimized with regard to graft outcome. Here we retrospectively reviewed 101 cases involving PTLD to identify the risks associated with graft loss. During a median follow-up of 70 months, 39 patients died and 21 lost their graft. Multivariate analysis found that an eGFR under 30 ml/min per 1.73 m(2) at PTLD diagnosis, a biopsy-proven acute rejection episode following reduction of immunosuppression, and the absence of calcineurin inhibition in maintenance immunosuppression are independent risk factors for allograft loss. Neither the type of PTLD nor the chemotherapy regimen was predictive of allograft failure. Histological analysis of graft biopsies showed that maintaining calcineurin inhibition after the diagnosis of PTLD reduced the risk of developing de novo anti-HLA antibodies and humoral rejection. Remarkably, calcineurin inhibitor maintenance was neither associated with higher mortality nor with worse progression-free survival. Thus, maintaining calcineurin inhibition at a reduced dose after the diagnosis of PTLD seems safe and may improve renal graft outcome, possibly through better control of the recipient's humoral immune response.

Immunosuppression (IST) Can Be Safely Ceased During Chemotherapy For Post-Transplant Lymphoproliferative Disorders (PTLD) In Renal Transplant Patients

IntroductionThe optimal reduction of IST in renal transplant patients with PTLD is uncertain. As chemotherapy used to treat PTLD is inherently immunosuppressive, IST may be able to be stopped during this time without compromising graft function. Subsequent long-term reduction of IST is important to reduce PTLD relapse, but may increase long-term risk of graft rejection. MethodsWe performed a retrospective matched cohort study of adult renal transplant patients where IST was ceased during chemotherapy and then resumed at lower dose (calcineurin inhibitor at 50%, prednisolone <6mg daily, no third agent). Outcomes were compared to renal transplant patients without PTLD, matched for creatinine at the equivalent time post-transplant that PTLD was diagnosed in the cases, as well as age, gender, year of transplant and age at transplant. The primary endpoint of time to renal deterioration, defined as the time from PTLD diagnosis (cases) or study entry (controls) to a 25% increase in creatinine, was analysed using competing risk survival analyses. Additional endpoints were time to renal allograft failure requiring dialysis or re-transplant and overall survival. Results24 cases were identified: median age at PTLD diagnosis 45yrs; 75% male; median time to onset of PTLD post-transplant was 9 years. 22 cases received CHOP-like chemotherapy and 2 received primary CNS lymphoma protocols, 7 received concurrent rituximab and 4 had consolidation radiation therapy. 88% attained complete remission. Five patients have relapsed. The 5 yr overall survival for the cases was 71% with a median follow-up of survivors of 11.9 years.The 24 PTLD cases were compared to 84 well matched controls. There were 11 deaths in the cases and 5 in the controls. Three cases recommenced dialysis, compared to 3 controls (HR 2.5, p=0.27). The 5 yr rate of 25% increase in creatinine was 36% in cases and 20% in controls (HR 1.8, p=0.098). Of the 11 cases with ≥25% increase in creatinine, only 1 of these occurred within 6 months of IST cessation in the setting of rapidly progressive PTLD and early death. Only 2 of these 11 cases received rituximab. In contrast 5 of the 7 patients given rituximab did not develop a ≥25% deterioration in renal function. ConclusionsIST can be safely ceased during chemotherapy for PTLD in renal transplant patients. Whilst long-term reduction in IST is necessary to reduce PTLD relapse, this is associated with a trend to increased risk of chronic allograft nephropathy. Prospective trials are needed to address the ideal reduction of IST in PTLD. Disclosures:No relevant conflicts of interest to declare.

Posttransplant Lymphoproliferative Disorder in Pediatric Patients

Transplantation of solid organs and hematopoietic stem cells is accompanied by profound disturbance of immune function mediated by immunosuppressive drugs or delayed immune reconstitution. Disturbed T cell control of Epstein-Barr virus (EBV)-infected B cells leads to posttransplant lymphoproliferative disorder (PTLD) in up to 10% of patients. Children are at a higher risk because they are more often EBV-naïve before transplantation. Patients with PTLD often present with unspecific symptoms (pain and organ/graft dysfunction). Depending on the onset of PTLD, manifestations vary between mainly nodal (late PTLD) and extranodal sites (early PTLD). Histology, immunohistology, EBER in situ hybridization and molecular pathology are required for diagnosis and subclassification of PTLD. The three major types are early lesions (resembling reactive proliferations in immunocompetent patients), polymorphic PTLD (proliferation of B and T cells with effacement of histoarchitecture) and monomorphic PTLD (presenting as malignant lymphomas, mainly high-grade B cell lymphomas). In a subfraction of cases, including monomorphic PTLD, reduction of immunosuppressive medication alone is sufficient to induce remission. Surgical debulking of tumor mass and anti-CD20-antibody treatment with or without chemotherapy (usually at lower dosages than in immunocompetent patients) constitute the basis of additional therapy.

18F-fluorodeoxyglucose positron emission tomography/computed tomography in diagnosis of post-transplant lymphoproliferative disorder

The aim of the present study was to investigate the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the diagnosis of post-transplant lymphoproliferative disorder (PTLD), a serious complication of solid organ and bone marrow transplant. Between January 2004 and January 2012, 40 patients (22 males; median age 52 ± 17.4 years, range 11–77 years) underwent 18F-FDG PET/CT scans in our department for diagnostic evaluation of PTLD. Twenty-three (57.5%) patients had negative 18F-FDG PET/CT and 17 (42.5%) had a positive examination. In five patients PET/CT revealed extranodal disease (adrenal, pleural, spleen, liver, lung, esophagus and bone involvement). On the basis of our results, 18F-FDG PET/CT had a sensitivity of 88.2% (95% confidence interval [CI] 0.62–0.98), a specificity of 91.3% (CI 0.70–0.98), a positive predictive value of 88.2% (CI 0.62–0.98) and a negative predictive value of 91.3% (CI 0.70–0.98). The diagnostic performance of CT in patient-based analysis was: a sensitivity of 87.5% (CI 0.60–0.97), a specificity of 88.8% (CI 0.64-0.98), a positive predictive value of 87.5% (CI 0.60–0.97) and a negative predictive value of 88.8% (CI 0.64–0.98). PET/CT in five cases revealed more findings than CT, upstaging the disease, and revealed three extranodal findings, not visualized in conventional imaging. 18F-FDG PET/CT plays a significant role in the setting of PTLD diagnosis, demonstrating its high accuracy in detecting PTLD.

Response to Rituximab-Based Therapy and Risk Factor Analysis in Epstein Barr Virus–Related Lymphoproliferative Disorder After Hematopoietic Stem Cell Transplant in Children and Adults: A Study From the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting. A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease. One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extralymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0-1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival. More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.

Post‐transplant lymphoproliferative disorder in adult liver transplant recipients: a South American multicenter experience

Post-transplant lymphoproliferative disorder (PTLD) is a major and potentially life-threatening complication after solid-organ transplantation. The aim of this study was to describe the disease characteristics, clinical practices, and survival related to PTLD in adult orthotopic liver transplant (OLT) recipients in South America. We conducted a survey at four different transplant groups from Argentina, Brazil, and Chile. Among 1621 OLT recipients, 27 developed PTLD (1.7%); the mean age at diagnosis was 53.7 (± 14) yr with a mean time of 39.7 (± 35.2) months from OLT to PTLD diagnosis. Initial therapy included reduction in immunosuppression alone in 23.1% of the patients. Either rituximab or chemotherapy was employed as initial or second-line therapy in 76.9% of the patients. PTLD location was frequently extranodal (80.7%) and mostly involving the transplanted liver (59.3%). The overall survival at one and five yr post-PTLD diagnosis was 53.8% and 46.2%, respectively. Significant univariate risk factors for post-PTLD mortality included lactate dehydrogenase ≥ 250 U/L (HR 9.66, p = 0.02), stage III/IV PTLD (HR 5.34, p = 0.004), and HCV infection (HR 7.68, p = 0.01). In conclusion, PTLD in OLT adult recipients is predominantly extranodal, and although mortality is high, long-term survival is possible.

An Uncommon Presentation of Non-Hodgkin’s Lymphoma in a Renal Transplant Recipient

Dear Sirs, Primary cutaneous posttransplantation B-cell lymphoproliferative disorder is rare. Posttransplantation lymphoproliferative disorders (PTLDs) are usually of non-Hodgkin’s lymphoma (NHL), accounting for 93% of lymphomas in the transplant population versus 65% in the general population. We present a rare case of cutaneous manifestation of a NHL in a renal transplant recipient. A 44-year-old woman was referred to our department due to skin lesion recognized on the right arm (level of deltoid muscle) (Fig. 1). She had undergone renal transplantation from a living donor 7 years ago due to end-stage renal disease attributed to immunoglobulin A nephropathy. Her immunosuppressive regimen included azathioprine, corticosteroids, and cyclosporine. Clinically, skin lesion resembled a soft-tissue sarcoma or a squamous cell carcinoma. Skin biopsy demonstrated diffuse large non-Hodgkin’s B-cell lymphoma (DLBCL; centroblastic cells with appearance of medium- to large-sized lymphocytes with scanty cytoplasm). On immunohistochemistry, cells of DLBCL expressed B-cell–associated antigens (CD19, CD20, and CD22). Serologic analysis for Epstein-Barr Virus (EBV) was positive (seroconversion of a previously seronegative patient) and in situ hybridization techniques identified EBV sequences in the nuclei of lymphoid cells within the lesion. Computed tomography scan applied for staging the disease showed large lung, mesothoracic, and inguinal lymph-node blocks. She was diagnosed with EBV-related PTLD. Immunosuppression reduction, chemotherapy with CHOP-R regimen, was administrated, which induced complete remission of the tumor. No surgical intervention was applied. However, the patient succumbed to recurrent disease 18 months later.FIGURE 1: Skin lesion on the right arm (level of deltoid muscle).DISCUSSION Solid organ transplant recipients have elevated cancer risk due to immunosuppression and oncogenic viral infections. Among transplant recipients, NHL represents one extreme of EBV-driven proliferative disease acknowledged as PTLD, which ranges from benign hyperplasia and infectious mononucleosis to lymphoid malignancy (1 ). The most common NHL subtype among transplant recipients is DLBCL and most cases are EBV positive (2 ). In situ hybridization techniques using the EBV-encoded RNA probe for EBV messenger RNA are used to identify EBV sequences in the nuclei of lymphoid cells within the lesion (1 ). A diagnosis of presumed PTLD was based on documentation of EBV seroconversion of a previously seronegative patient or reactivation of immunoglobulin M against EBV viral capsid antigen, along with symptoms such as fever, fatigue, and anorexia and the detection of pulmonary nodules or extrapulmonary masses or both on radiologic evaluation (1 ). PTLD presenting with skin involvement rarely manifests as lesions and such lesions develop slowly, when they occur. Intensity of immunosuppressive therapies also influences the risk for PTLD. The use of EBV viral load monitoring facilitates the diagnosis and management of EBV/PTLD as well as being used to inform preemptive therapy with reduction of immunosuppression, the most effective intervention for prevention of and treatment for PTLD (3, 4 ). Other therapies, including rituximab (anti-CD20 monoclonal antibody) and traditional chemotherapy, are also useful in the treatment of established PTLD (3). These lesions regress after dose reduction or cessation of treatment (4 ). Future perspectives on treatment of PTLD may include adoptive immunotherapy, intravenous immunoglobulin, mammalian target of rapamycin inhibitors, monoclonal antibodies to interleukin-6 and galectin-1, and even EBV vaccination (5). Demetrios Moris 1,3 Spiridon Vernadakis2,3 Vasileios Zavvos1 Georgios Zavos3 1 1st Department of Surgery Athens University School of Medicine “Laikon” General Hospital Athens, Greece 2 Department of General, Visceral and Transplantation Surgery University Hospital Essen Essen, Germany 3 Transplantation Unit “Laikon” General Hospital Athens, Greece

Significance of Persistent EBV Viral Load in Pediatric Heart Transplant Recipients

PurposeAs most cases of post-transplant lymphoproliferative disorder (PTLD) are driven by EBV, most centers monitor EBV viral load (VL) by quantitative PCR. Optimal treatment for patients (pts) with persistent EBV VL is unknown. Aim: To determine the outcome of reduced immunosuppression (IS) and anti-viral therapy on the frequency of PLTD and acute rejection (AR) in pediatric heart transplant (Tx) recipients.Methods and MaterialsWe reviewed medical records of 113 pts whose EBV serostatus was known at Tx. We ascertained their EBV PCR VL, IS regimen, anti-viral therapy, CT/PET scan and biopsy results, and AR episodes. Whole blood PCR was used for EBV VL monitoring. Pts were divided into 3 groups based on EBV VL: not detected (ND) (<1000), low (1000-10,000) and high (>10,000) copies/ml. Pts who had persistently high VL twice within 2 months underwent whole body CT/PET imaging to exclude PTLD. Diagnosis of PTLD was based on histopathology findings of abnormal lymphoid proliferation and positive in situ hybridization using EBER probe for EBV.ResultsThe findings of this study are shown in Figure. Abnormal CT/PET scan concerning for PTLD was observed in 66% in EBV naïve heart Tx recipients who had high VL. Of 10 pts who had abnormal PET/CT scan, 3 had PTLD on biopsy. Antiviral therapy was initiated in 4 pts who showed only temporary decrease in VL. Reduction in IS in pts with high VL resulted in AR in 3 cases. [figure 1]ConclusionsPediatric heart Tx recipients with high EBV VL are at risk for PTLD despite reduction in IS. We recommend frequent surveillance of the allograft for AR with IS reduction. Multicenter study is needed to focus on strategies not only to prevent PTLD, but also to protect the allograft. As most cases of post-transplant lymphoproliferative disorder (PTLD) are driven by EBV, most centers monitor EBV viral load (VL) by quantitative PCR. Optimal treatment for patients (pts) with persistent EBV VL is unknown. Aim: To determine the outcome of reduced immunosuppression (IS) and anti-viral therapy on the frequency of PLTD and acute rejection (AR) in pediatric heart transplant (Tx) recipients. We reviewed medical records of 113 pts whose EBV serostatus was known at Tx. We ascertained their EBV PCR VL, IS regimen, anti-viral therapy, CT/PET scan and biopsy results, and AR episodes. Whole blood PCR was used for EBV VL monitoring. Pts were divided into 3 groups based on EBV VL: not detected (ND) (<1000), low (1000-10,000) and high (>10,000) copies/ml. Pts who had persistently high VL twice within 2 months underwent whole body CT/PET imaging to exclude PTLD. Diagnosis of PTLD was based on histopathology findings of abnormal lymphoid proliferation and positive in situ hybridization using EBER probe for EBV. The findings of this study are shown in Figure. Abnormal CT/PET scan concerning for PTLD was observed in 66% in EBV naïve heart Tx recipients who had high VL. Of 10 pts who had abnormal PET/CT scan, 3 had PTLD on biopsy. Antiviral therapy was initiated in 4 pts who showed only temporary decrease in VL. Reduction in IS in pts with high VL resulted in AR in 3 cases. [figure 1] Pediatric heart Tx recipients with high EBV VL are at risk for PTLD despite reduction in IS. We recommend frequent surveillance of the allograft for AR with IS reduction. Multicenter study is needed to focus on strategies not only to prevent PTLD, but also to protect the allograft.

Effect of Cytomegalovirus Immunoglobulin on the Incidence of Lymphoproliferative Disease After Lung Transplantation

Posttransplantation lymphoproliferative disorder (PTLD), a complication of lung transplantation with an incidence ranging from as much as 20%, is mainly associated with Epstein-Barr virus (EBV) infection. In renal transplantation, the use of immunoglobulin (Ig) cytomegalovirus (CMV) prophylaxis, which contains anti-EBV antibodies, resulted in a significant lower incidence of PTLD. In this study, we report our experience with PTLD in lung transplantation with CMV Ig prophylaxis. One-thousand one-hundred fifty-seven consecutive patients who underwent lung transplantation at the Medical University of Vienna between November 1989 and December 2011 were included in this retrospective analysis on PTLD. CMV prophylaxis consisted in all patients of antiviral drugs (ganciclovir/valganciclovir) combined with anti-CMV Ig for 4 weeks. A total of 18 patients (1.5%) developed PTLD of B cell origin. Fifteen patients were diagnosed in the first posttransplantation year, and three patients, beyond 1 year. One- and three-year survival after diagnosis of PTLD was 50% and 38%, respectively. The incidence of PTLD in our center is extremely low when compared with the scientific literature. We hypothesize that CMV Ig prophylaxis also protects from EBV-associated PTLD.

Post-transplant lymphoproliferative disorders in liver transplant recipients: a clinicopathological study

Background and aimsComplications after liver transplantation are major factors that determine the prognosis of patients. In this study, we aimed at investigating an important though less frequently occurring complication, post-transplant...

Characteristics of Early and Late PTLD Development in Pediatric Solid Organ Transplant Recipients

Posttransplantation lymphoproliferative disorders (PTLD) present a major cause of mortality and morbidity after solid organ transplantation. The purpose of this study was to identify the factors associated with the development of early- and late-onset PTLD in pediatric solid organ transplant recipients. We examined the medical history, laboratory parameters, and pathology of 127 children with PTLD who were registered in the German multicenter pediatric PTLD registry. Data were collected retrospectively from 1991 to 2003 and prospectively from 2004 onward. We compared early (<1 year) and late (>1 year) PTLD using survival analysis. The median time to PTLD was 3.00 (95% confidence interval, 2.12-3.26) years. Forty-two patients developed PTLD within the first year after transplantation (early PTLD) and 85 patients developed PTLD after 1 year (late PTLD). Early PTLD development was associated with younger age (P=0.0016), extranodal disease (P=0.019), graft organ involvement (P=0.0065), and immunosuppressive regimens including tacrolimus (P=0.001) or mycophenolate (P=0.0025). Most early PTLD patients experienced graft rejection before PTLD diagnosis (P=0.0081). Early PTLD was often of B-cell lymphoma histology (P=0.024) and tended to be Epstein-Barr virus positive (P=0.052). In contrast, Burkitt's lymphoma (P=0.0047) and Hodgkin's disease (P=0.016) were only observed in late PTLDs, which are more likely to present with nodal disease (P=0.019). Overall survival and event-free survival were not significantly different between early and late PTLD. Early and late childhood PTLD have distinct characteristics. Whereas early PTLD appears mainly as an Epstein-Barr virus-driven disease especially favored by insufficient immunosurveillance, late PTLD often resembles tumors with distinct pathogenetic alterations and nodal appearance.

Spectrum of lymphoproliferative disorders following renal transplantation in North India

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized, but uncommon complication of organ transplantation. This study was a retrospective analysis of 2000 patients who underwent renal transplantation over a period of 30 years (1980-2010). Forty malignancies were diagnosed in 36 patients. Of these, 29 patients (1.45%) had PTLD (7 females, 22 males) accounting for 72.5% of all malignancies after transplantation. Twenty-two (75.8%) developed non-Hodgkin lymphoma and seven patients (24.2%) had myeloma. Diagnosis was made by biopsy of the involved organ in 21 patients (72.4%) and aspiration cytology in five patients (17.2%). In three patients, the diagnosis was made only at autopsy. Mean age at the time of diagnosis of PTLD was 41.9 years (range 21-69 years). Time interval from transplantation to the diagnosis of PTLD ranged from 3 months to 144 months with a median of 48 months. Only five patients (17.2%) developed PTLD within a year of transplantation. Twelve patients developed PTLD 1-5 years and 12 patients 5-10 years after transplantation. Organ involvement was extra nodal in 18 patients (82%). Thirteen (59%) patients had disseminated disease and nine (41%) had localized involvement of a single organ (brain-3, liver-1, allograft-1, perigraft node-1, retroperitoneal lymph nodes-3). Infiltration of the graft was noted in two patients. Patients with myeloma presented with backache, pathological fracture, unexplained anemia or graft dysfunction. PTLD was of B cell origin in 20 cases (70%). CD 20 staining was performed in 10 recent cases, of which 8 stained positive. Of the 26 patients diagnosed during life, 20 (69%) died within 1 year of diagnosis despite therapy. In conclusion, PTLD is encountered late after renal transplantation in the majority of our patients and is associated with a dismal outcome. The late onset in the majority of patients suggests that it is unlikely to be Epstein Barr virus related.

Clinicopathologic spectrum and EBV status of post-transplant lymphoproliferative disorders after allogeneic hematopoietic stem cell transplantation

Post-transplant lymphoproliferative disorders (PTLDs) are serious, life-threatening complications of solid-organ transplantation (SOT) and bone marrow transplantation, and are associated with high mortality. PTLDs represent a heterogeneous group of lymphoproliferative diseases, which show a spectrum of clinical, morphologic, and molecular genetic features ranging from reactive polyclonal lesions to frank lymphomas. We describe clinicopathologic features of 17 cases of PTLD after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which were analyzed by in situ hybridization for EBV and a panel of antibodies directed against numerous antigens, including CD20, PAX5, CD3, bcl-6, CD10, MUM-1/IRF4, CD138, Kappa, Lambda, CD30, CD15, and Ki67. The cases included 13 males and 4 females with a median age of 31years (range 9-49years) and the PTLDs developed 1.5-19months post-transplant (mean 4.7months). The histological types indicated five cases of early lesions, two of plasmacytic hyperplasia and three of infectious mononucleosis-like PTLD. Eight cases were polymorphic PTLD, and four were monomorphic PTLD, including three of diffuse large B cell lymphoma, and one of plasmablastic lymphoma. Foci and sheets of necrosis were observed in five cases. The infected ratio of EBV was 88.2%. Some cases were treated by reduction of immunosuppression, antiviral therapy, donor lymphocyte infusion, or anti-CD20 monoclonal rituximab. Eight cases died. The first half year after allo-HSCT is very important for the development of PTLD. The diagnosis of PTLD relies on morphology and immunohistochemistry, and EBV plays an important role in the pathogenesis of PTLD. The prognosis of PTLD is poor, and, notably, PTLD after allo-HSCT exhibits some features different from those of PTLD after SOT.