Epstein-Barr virus--determined clonality in posttransplant lymphoproliferative disease

Analysis of the genomic termini of Epstein-Barr virus can provide valuable insight into the cofactor role of EBV in the development of B cell lymphomas and lymphoproliferative disease. We report EBV genomic findings in pathologic specimens from 10 patients who developed lymphoma or lymphoproliferative disease after renal or bone marrow transplantation. Endonuclease restriction patterns of EBV genomic termini are highly variable in size in both the episomal and linear configuration. This variability in fragment size permits direct assessment of tissue clonality in EBV-infected material. Hybridization with terminus-specific probes also reveals configuration of viral genome (circular and latent vs. linear and replicative). Nine of 10 patients had tumors with mono- or biclonal episomal markers, and 4 of 10 had evidence of linear or replicative virus. Analyses of virally determined markers were compared to immunoglobulin gene rearrangement studies, histologic immunophenotyping, cytogenetics, and clinical outcome. These 10 cases represent a spectrum of lymphoproliferative disorders ranging from benign polyclonal to malignant monoclonal disease. The molecular data lend credence to two important aspects of viral pathogenesis: (1) the finding of a homogeneous episomal population in the monoclonal tumors suggests that EBV infection is an early event in tumorigenesis that occurs before clonal expansion; and (2) therapeutic efficacy of acyclovir has been shown only in presence of polyclonal disease but may impact on intermediate stages where linear replicative virus can be found. Finally, the various assessments of tumor clonality were compared, and although heterogeneity was seen among patients and among diagnostic methods, analyses at the molecular level using virus and immunoglobulin gene specific probes were concurrent and provide the more sensitive means for detection of clonality.     

Early posttransplant lymphoproliferative disease in pediatric liver transplant recipients

Among 23 pediatric patients who underwent orthotopic liver transplant (OLT), we report two (11 and 26 months old) with posttransplant lymphoproliferative disease (PTLD) that occurred in the early posttransplantation period. They were Epstein-Barr Virus (EBV)-negative and received graft from EBV-positive donors. The surveillance for EBV viremia using serial EBV polymerase chain reaction determinations in the peripheral blood was positive at 10 and 90 days after OLT concomitant with symptoms of primary infection, both patients were treated with gancyclovir. The patients should progression to a Burkitt's and a non-Hodgkin's lymphoma that appeared 3 months posttransplantation. They were treated by withdrawal of immunosuppression and six courses of cyclophosphamide as well as anti-CD20 monoclonal antibody (Rituximab) every 21 days. One patient experienced acute graft rejection, which resolved with steroids and low doses of tacrolimus, she is free of disease at 24 months after the end of treatment. The other patient relapsed with a cerebral lymphoma, receiving aggressive chemotherapy, but died due to sepsis. In conclusion, PTLD occurred among in 2/23 patients who underwent OLT and appeared in the first quarter post OLT. The risk factors associated with early PTLD were primary EBV infection after OLT, young age, and EBV-negative recipient receiving a transplant from an EBV-positive donor. Antiviral treatment alone was inefficient; withdrawal of immunosuppression and courses of Rituximab and cyclophosphamide were well tolerated and controlled PTLD. The risk of graft rejection was increased by withdrawal of immunosuppression. One patient died.     

成人肝移植后淋巴组织增生性疾病二例

移植术后淋巴组织增生性疾病（posttransplant lymphoproliferative disease,PTLD）是见于各种器官移植术后的一种较为罕见的致命性并发症，预后不佳。据国外单中心大宗病例统计成人肝移植后PTLD发病率约为2.9%，国内尚未见该种病例报道。我中心2005年确诊2例成人肝移植后PTLD，现报告如下。     

EB病毒相关性移植后淋巴组织增生性疾病生物标志物的相关进展

移植后淋巴组织增生性疾病（PTLD）是一系列异质性淋巴增生性疾病,也是儿童实体器官移植术后的严重并发症。超过70%的PTLD与爱泼斯坦-巴尔病毒（EBV）有关,EBV相关性B细胞淋巴瘤也是儿童器官移植术后的主要恶性肿瘤。EBV相关性PTLD在儿童实体器官移植中仍然是一个棘手的问题,主要由移植术后的免疫抑制导致机体免疫功能受损所致,但具体发生机制仍不清楚。近年来,在EBV相关性PTLD的临床诊断和治疗中,开发生物标志物以实现指导诊断和个性化治疗具有极好的应用前景。本文旨在综述实体器官移植EBV相关性PTLD的发生情况及其生物标志物的研究进展,以期为临床诊疗开拓思路。     

The utility of FDG-PET/CT and other imaging techniques in the evaluation of IgG4-related disease

ObjectivesThis study aimed to evaluate the utility of imaging techniques, including 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), in immunoglobulin (IgG)4-related disease (IgG4-RD).MethodsWe reviewed eight IgG4-RD patients who were referred to our hospital between August 2006 and April 2012. All cases underwent FDG-PET/CT and brain magnetic resonance imaging (MRI) and endobronchial ultrasonography (EBUS) were also performed in five cases and one case, respectively.ResultsAlthough nearly all patients with IgG4-RD in this study were negative for CRP (mean 0.22 mg/dL), various organ involvement sites were detected by FDG-PET/CT. In the active phase in two autoimmune pancreatitis (AIP) cases, FDG-PET/CT showed longitudinal and heterogeneous FDG accumulation in the pancreas with FDG uptake in the hilar or mediastinal lymph nodes. Follow-up FDG-PET/CT after therapy in one case revealed that the abnormal FDG uptake in all affected lesions had completely disappeared. In two cases, brain MRI revealed asymptomatic hypertrophic pachymeningitis. In one case, EBUS imaging of mediastinal lymph node swelling was consistent with tortuous vessels with high Doppler signals and hyperechoic strands between lymph nodes.ConclusionsWhen FDG-PET/CT shows FDG accumulation, characteristic of IgG4-RD in organs, without evidence of an associated inflammatory reaction, a diagnosis of IgG4-RD can be made. Treatment effects can be assessed by the disappearance of FDG uptake. A routine brain MRI is useful for detecting asymptomatic hypertrophic pachymeningitis. EBUS may also be useful for differentiating among the etiologies of lymphadenopathy with characteristic sonographic imaging findings.     

Epstein-Barr virus serology and posttransplant lymphoproliferative disease in lung transplantation.

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is now a widely recognized complication of lung transplantation. In the current study, we present our experience with PTLD over a 15-year period, which includes the incidence rates in 242 lung allografts and the relative risk of developing PTLD in 146 patients with known pretransplantation Epstein-Barr virus (EBV) status. METHODS: Inpatient and outpatient charts of 300 consecutive lung transplant recipients between 1984 and 1999 were retrospectively reviewed. RESULTS: Twelve cases of PTLD were observed for a total incidence rate of 5.0%. Ten of these patients had pretransplantation EBV testing, and the consequent increase in relative risk for patients who were EBV negative was 6.8-fold. The mean time between organ transplantation and tissue diagnosis of PTLD was 17.6 months. Total 1-year survival rate from the time of diagnosis for the cohort was 58%, whereas 2-year survival rate was 50%. Median survival for the six patients who died was 4.5 months. CONCLUSIONS: These data suggest that although EBV seronegativity does carry a 6.8-fold increase in the relative risk of developing PTLD, long-term survival despite the development of PTLD can be achieved, and thus EBV seronegativity by itself should not be considered a contraindication to lung transplantation.     

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

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

Majocchi's granuloma and posttransplant lymphoproliferative disease in a renal transplant recipient

Renal transplant recipients are predisposed to infection and malignancy because of underlying long-term immunosuppressive therapy. In this case report, a renal transplant patient with coexisting Trichophyton rubrum granuloma (Majocchi's granuloma) and posttransplant lymphoproliferative disease (PTLD) is presented, showing the undesirable effects of heavy immunosuppression. Majocchi's granuloma was probably associated with PTLD as a reflection of overimmunosuppression. © 2001 by the National Kidney Foundation, Inc.     

CT scan in the management of acute appendicitis

BACKGROUND: Recent studies demonstrate a 98% accuracy of a CT scan in the diagnosis of acute appendicitis. We aimed to determine the accuracy and clinical value of CT scans in patients suspected of having acute appendicitis. PATIENTS AND MATERIALS: We reviewed outcomes of 125 patients over a 5-month period who had CT scans for the initial diagnosis of acute appendicitis. CT scan interpretations were correlated with surgical and pathologic findings. Follow-up was attempted in all patients who did not undergo appendectomy. RESULTS: CT scans and clinical courses were complete in 110 patients (88%); 14 patients were lost to follow-up and 1 was excluded. One patient had two CT scans. Thus, there were 111 CT scans available for review. Radiologic interpretation of these CT scans yielded 36 positive (33%), 67 negative (60%), and 8 indeterminate (7%), resulting in a sensitivity of 90%, a specificity of 89%, a PPV of 78%, and a NPV of 96%. CONCLUSIONS: CT scan may be useful in the diagnosis of acute appendicitis, but the reported high accuracy rate was not reproduced at our institution. CT scan was not clinically useful in 21% of patients. We conclude that a CT scan may be beneficial in the diagnosis of appendicitis with selected patients who have equivocal findings. Thus, at our institution, the accuracy of a CT scan does not justify its routine use in patients with clinical findings of appendicitis.     

Unusual manifestation of posttransplant lymphoproliferative disorder in the esophagus

Early manifestations of posttransplant lymphoproliferative disorders (PTLD) are mainly associated with a primary Epstein-Barr virus (EBV) infection. Rapid increases in peripheral blood EBV DNA load are supposed to reliably predict PTLD. We report a boy who 6 months after living-related kidney transplantation presented with an extranodal esophageal manifestation of PTLD. Despite a primary EBV infection with tonsillitis, the peripheral blood EBV DNA remained low, hiding the progression to PTLD.     

The effect of immunosuppression on posttransplant lymphoproliferative disease in pediatric liver transplant patients

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a serious complication associated with the use of chronic immunosuppression for solid organ transplantation. This study represents a retrospective analysis of UCLA's experience with PTLD in all pediatric liver transplant recipients between 1984-1997. We assessed the clinical presentation, risk factors, incidence density, immunological characteristics, management, and outcome of patients who developed PTLD when receiving either primary cyclosporin A (CsA) or tacrolimus. METHODS: A total of 251 children received primary CsA therapy of which 70 required OKT3 for steroid resistant rejection and 29 required tacrolimus rescue for OKT3 resistance and/or chronic rejection. One hundred forty one children received tacrolimus as primary therapy. Sixty patients who survived for less than 6 months after transplantation were excluded from the study. RESULTS: The total incidence density (ID) rate of PTLD was 1.8+/-0.4 per 100 patient-years (30/392). The overall ID rate of PTLD in the CsA group was 0.93+/-0.2 per 100 patient-years (15/251). Within this group of primary CsA-treated patients, the ID rate of PTLD was 0.49+/-0.1 without OKT3 or tacrolimus, 0.67+/-0.2 with OKT3, and 6.42+/-1.1 with tacrolimus rescue. The overall PTLD ID rate in the primary tacrolimus-treated patients was 4.86+/-1.2 per 100 person-years (15/141). There was a 5-fold increase in the ID rate of PTLD in the primary tacrolimus group when compared to the comparable, primary CsA group (P<0.001). The mean time to PTLD was 5-fold longer (49.7+/-20.7 months) in the CsA group when compared to the CsA/tacrolimus rescue group (9.8+/-3 months, P<0.05) or the tacrolimus primary group (12.6+/-5.1 months, P<0.05). Five patients had monoclonal disease in the CsA group, but only one in the tacrolimus group (P<0.05). Clinical presentations with enlarged lymph nodes, fevers, malaise, anorexia, weight loss, hypoalbuminemia, and gastrointestinal blood loss were common. Mortality was 20%, three patients died in each group. CONCLUSION: The use of primary tacrolimus therapy was associated with a significant 5-fold higher rate of PTLD when compared to those treated with primary cyclosporine. Early diagnosis, decrease and/or discontinuation of potent immunosuppressive agents may contribute to decrease morbidity and mortality of this entity.     

Successful treatment of posttransplant lymphoproliferative disease with prolonged rituximab treatment in intestinal transplant recipients

BACKGROUND: Posttransplant Epstein-Barr virus-associated B-cell lymphoproliferative disease (PTLD) has a higher incidence after intestinal transplantation than after transplantation of other solid organs and is associated with a high mortality. A new anti-CD20 monoclonal antibody, rituximab, has shown efficiency in the treatment of B-cell lymphoma, including PTLD, but its use has not yet been reported in intestinal transplant recipients. METHODS: We retrospectively reviewed five patients who were diagnosed with PTLD from March 1999 to August 2001, after intestinal transplantation. These patients were primarily managed with rituximab, associated with reduction or interruption of immunosuppression and antiviral therapy with ganciclovir and cytomegalovirus immune globulin. Rituximab was administered at weekly doses of 375 mg/m until full remission was ascertained, and the interval between doses was then increased. No patient received chemotherapy. RESULTS: One patient had nonmalignant lymphoproliferation, and four had malignant PTLD, as assessed by histopathology and monoclonality of the tumor. Two pediatric patients had severe generalized disease. All patients had received OKT3 as treatment of rejection before developing PTLD. All tumors showed proliferation of CD20 cells and were positive for Epstein-Barr virus by in situ hybridization. All patients responded to rituximab therapy and have achieved full remission with a follow-up of 3 to 30 (median, 8) months. CONCLUSION: Prolonged rituximab treatment, in association with reduction of immunosuppression and antiviral therapy, is highly efficient as part of the first-line treatment of CD20 B-cell PTLD after intestinal transplantation.     

Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation

Among 39 posttransplant lymphoproliferative diseases (PTLD) in a cohort of 450 pediatric liver transplant recipients, 3 had a malignant lymphoma, unresponsive to arrest of immunosuppression and to gancyclovir, interferon, and anti-interleukin 6 antibodies. Lymphoma appeared 20, 46, and 96 months posttransplantation and 16, 43, and 90 months after primary Epstein-Barr virus infection. In one case, the patient had histological progression from plasmacytic hyperplasia PTLD, concomitant with symptomatic primary infection, to Burkitt-like lymphoma 43 months later. These three patients received five courses of chemotherapy, after a cyclophosphamide, doxorubicin, vincristine, and prednisone regimen for Burkitt-like or LH 89 scheme for Hodgkin-like PTLDs. Chemotherapy was well tolerated, and all three were free of disease and without immunosuppression 19, 14, and 4 months after chemotherapy. In Burkitt-like or Hodgkin-like PTLDs, immunomodulatory or antiviral drugs were inefficient. Chemotherapy is indicated and can be safely and successfully used. Long-term arrest of immunosuppression seems feasible without graft rejection.