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Journal of Hematology & Oncology Sep 2023Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from... (Observational Study)
Observational Study
Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA to profile PTLD and explore its potential to serve as a screening tool. We included seventeen patients with monomorphic PTLD after solid organ transplantation in this multi-center observational cohort study. We used low-coverage whole genome sequencing (lcWGS) to detect copy number variations (CNVs) and targeted next-generation sequencing (NGS) to identify Epstein-Barr virus (EBV) DNA load and somatic single nucleotide variants (SNVs) in cfDNA from plasma. Seven out of seventeen (41%) patients had EBV-positive tumors, and 13/17 (76%) had stage IV disease. Nine out of seventeen (56%) patients showed CNVs in cfDNA, with more CNVs in EBV-negative cases. Recurrent gains were detected for 3q, 11q, and 18q. Recurrent losses were observed at 6q. The fraction of EBV reads in cfDNA from EBV-positive patients was 3-log higher compared to controls and EBV-negative patients. 289 SNVs were identified, with a median of 19 per sample. SNV burden correlated significantly with lactate dehydrogenase levels. Similar SNV burdens were observed in EBV-negative and EBV-positive PTLD. The most commonly mutated genes were TP53 and KMT2D (41%), followed by SPEN, TET2 (35%), and ARID1A, IGLL5, and PIM1 (29%), indicating DNA damage response, epigenetic regulation, and B-cell signaling/NFkB pathways as drivers of PTLD. Overall, CNVs were more prevalent in EBV-negative lymphoma, while no difference was observed in the number of SNVs. Our data indicated the potential of analyzing cfDNA as a tool for PTLD screening and response monitoring.
Topics: Humans; DNA Copy Number Variations; Epigenesis, Genetic; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Lymphoproliferative Disorders; Cell-Free Nucleic Acids; Genomics
PubMed: 37705050
DOI: 10.1186/s13045-023-01500-x -
American Journal of Transplantation :... Feb 2013Epstein-Barr virus (EBV) is an important pathogen in recipients of solid organ transplants (SOT). Infection with EBV manifests as a spectrum of diseases/malignancies... (Review)
Review
Epstein-Barr virus (EBV) is an important pathogen in recipients of solid organ transplants (SOT). Infection with EBV manifests as a spectrum of diseases/malignancies ranging from asymptomatic viremia through infectious mononucleosis to posttransplant lymphoproliferative disorder (PTLD). EBV disease and its associated PTLD is more frequently seen when primary EBV infection occurs after transplant, a common scenario in pediatric SOT recipients. 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. Other therapies, including the rituximab (anti-CD20 monoclonal antibody) and traditional chemotherapy, are also useful in the treatment of established PTLD. The future development of standards for management based on EBV viral load and routine monitoring of EBV-specific CTL responses promise further improvement in outcomes with EBV and PTLD.
Topics: Adult; Animals; Antibodies, Monoclonal; Antigens, CD20; Antiviral Agents; Child; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Incidence; Interferons; Lymphoproliferative Disorders; Mice; Postoperative Complications; Transplantation; Treatment Outcome; Viral Load
PubMed: 23347213
DOI: 10.1111/ajt.12004 -
The Journal of Dermatology Sep 2021Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a rare cutaneous disease associated with Epstein-Barr virus infection. We retrospectively analyzed the...
Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a rare cutaneous disease associated with Epstein-Barr virus infection. We retrospectively analyzed the clinical presentation, histopathological characteristics, and prognostic study of HV-LPD in 24 Chinese patients. All patients presented with recurrent papulovesicular and necrotic eruptions on the face, neck, and extremities, with 11 showing systemic symptoms. Twenty patients were diagnosed with HV-LPD in childhood (age < 18 years) and four in adulthood (age ≥ 18 years). The median age at diagnosis was 8.5 years old (range, 2-50). Histopathology revealed variably dense lymphocyte infiltration throughout the dermis. All cases were strongly positive for CD3 and Epstein-Barr encoding region based on in situ hybridization. Of 18 cases with a T-cell phenotype, 15 harbored monoclonal rearrangements in T-cell receptor (TCR) genes. Four cases with a natural killer cell phenotype carried polyclonal rearrangements in TCR genes. Among 24 patients, eight (33.3%) received chemotherapy, two (8.3%) allogeneic hematopoietic stem cell transplantation, and both are currently alive without disease. The median follow-up period was 24 months (range, 7-120) and 23 patients were available: 15 (62.5%) were alive, and eight (33.3%) had died. Fourteen cases had a relapse of disease and three developed lymphoma within 24 months of diagnosis. The mean survival time of childhood-onset patients was longer than that of adult-onset patients (36.4 vs. 20.8 months). In summary, the wide clinical course and representative presentation of cases in our center reflect the pedigree characteristics of HV-LPD. Allogeneic hematopoietic stem cell transplantation should be a preferred choice for relapse and refractory patients due to the poor effect of chemotherapy. Adult-onset and high serum EBV DNA loads may indicate an increased risk of aggressive disease in patients with HV-LPD.
Topics: Adolescent; Adult; Child; China; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Hydroa Vacciniforme; Lymphoma; Lymphoproliferative Disorders; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies
PubMed: 33982815
DOI: 10.1111/1346-8138.15944 -
Cancer Letters Jun 2011Two lymphotropic human gamma herpesviruses can cause lymphoproliferative disorders: Epstein Barr virus (EBV, formally designated as human herpesvirus 4) and Kaposi... (Review)
Review
Two lymphotropic human gamma herpesviruses can cause lymphoproliferative disorders: Epstein Barr virus (EBV, formally designated as human herpesvirus 4) and Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus 8). Individuals with inherited or acquired immunodeficiency have a greatly increased risk of developing a malignancy caused by one of these two viruses. Specific types of lymphoproliferations, including malignant lymphomas, occur in individuals with HIV infection, transplant recipients and children with primary immunodeficiency. Some of these diseases, such as Hodgkin's and non-Hodgkin lymphoma resemble those occurring in immunocompetent patients, but the proportion of tumors in which EBV is present is increased. Others, like primary effusion lymphoma and polymorphic post-transplant lymphoproliferative disorder are rarely seen outside the context of a specific immunodeficient state. Understanding the specific viral associations in selected lymphoproliferative disorders, and the insights into the molecular mechanisms of viral oncogenesis, will lead to better treatments for these frequently devastating diseases.
Topics: Acquired Immunodeficiency Syndrome; Castleman Disease; Cell Transformation, Neoplastic; Gammaherpesvirinae; Herpesviridae Infections; Herpesvirus 4, Human; Herpesvirus 8, Human; Humans; Immune System; Immunocompromised Host; Lymphoma; Lymphoma, AIDS-Related; Lymphoproliferative Disorders; Models, Biological; Virus Latency
PubMed: 21493001
DOI: 10.1016/j.canlet.2011.03.003 -
European Journal of Haematology Oct 2022Posttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients has a high mortality and may present early (<2 years) or late (≥2 years)...
OBJECTIVES
Posttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients has a high mortality and may present early (<2 years) or late (≥2 years) posttransplantation. We investigated the clinical characteristics of early and late PTLD among kidney and liver transplant recipients.
METHODS
Recipients, transplanted at Rigshospitalet, with PTLD development as adults from January 2010 to August 2020, were included. Clinical characteristics, laboratory parameters, and pathology of early and late PTLD were compared.
RESULTS
Thirty-one PTLD cases were detected where 10 (32%) were early and 21 (68%) were late PTLD. EBV DNA in plasma was detected in 78% versus 28% in early and late PTLD (p = .037). None of the recipients with early PTLD and nine recipients with late PTLD (47%) had Ann Arbor stage IV at the time of their diagnosis (p = .006). Cyclophosphamid-Hydroxyrubicin-Oncovin-Prednisolon was used for treatment in 10 (48%) recipients with late PTLD (p = 0.032) only. There was no difference in mortality between the two groups.
CONCLUSIONS
Recipients with late PTLD had a lower prevalence of detectable EBV DNA in plasma, were diagnosed with more advanced disease, and were more frequently treated with chemotherapy compared to recipients with early PTLD.
Topics: Adult; Epstein-Barr Virus Infections; Humans; Incidence; Kidney; Liver Transplantation; Lymphoproliferative Disorders; Retrospective Studies; Risk Factors; Transplant Recipients
PubMed: 35719018
DOI: 10.1111/ejh.13815 -
Cancer Science Sep 2023Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a troublesome problem in patients receiving MTX for rheumatoid arthritis (RA). However, its...
Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a troublesome problem in patients receiving MTX for rheumatoid arthritis (RA). However, its incidence, prognosis, and risk factors remain unclear. In this retrospective study, we evaluated the actual incidence, prognostic impact, and risk factors of MTX-LPD. Of the 986 patients with RA treated with MTX, 90 patients experienced 95 new malignancies (NMs), with LPD as the most frequent in 26 patients. The cumulative LPD incidences were 1.3% and 4.7% at 5 and 10 years after MTX initiation, respectively. Among the 24 patients who discontinued MTX after developing LPD, 15 showed sustained regression, without difference in overall survival between patients with LPD and without NM. Inflammatory markers and absolute lymphocyte counts were not useful for early LPD development detection, but most of the patients with LPD had persistently elevated erythrocyte sedimentation ratios. Regarding concomitant drugs, tacrolimus increased the risk only if patients were not receiving biological disease-modifying antirheumatic drugs (bDMARDs). bDMARDs did not increase the risk for any of the drugs or the number of classes used. The number of LPD cases was lower in patients with IL-6A even after a long period after MTX, although with no statistically significant difference. Thus, approximately 1 in 20 patients with RA developed MTX-LPD over the 10 years of MTX treatment, but it did not affect the survival of patients with RA. Tacrolimus increased the risk of developing LPD for certain patients and should be used with caution.
Topics: Humans; Methotrexate; Retrospective Studies; Tacrolimus; Arthritis, Rheumatoid; Antirheumatic Agents; Lymphoproliferative Disorders
PubMed: 37365854
DOI: 10.1111/cas.15894 -
Journal of Dermatological Science Aug 2020Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) encompasses a rare group of Epstein-Barr virus (EBV)-associated lymphoproliferative diseases.
BACKGROUND
Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) encompasses a rare group of Epstein-Barr virus (EBV)-associated lymphoproliferative diseases.
OBJECTIVE
To define the clinical and pathologic characteristics of HVLPD and to identify mutant genes that may be related to the development of HVLPD.
METHODS
Clinical data and archived formalin-fixed, paraffin-embedded tissue were obtained from 19 patients. Specimens were analyzed by immunohistochemistry and in situ hybridization to detect EBV-encoded RNA (EBER1/2) and for T cell receptor (TCR) gene rearrangements. Whole-exome sequencing (WES) analysis was also performed in this study.
RESULTS
Thirteen patients survived between 3-58 months (median, 21 months) during the follow-up. Six patients who were almost adults (>15 years old) and died of the disease presented with facial edema. Lactate dehydrogenase (LDH) levels were elevated, and the TCR gene rearrangement test was positive more frequently in the patients who died. Compared with Chinese patients in a similar previous report, our patients had significantly higher proliferation (in all cases, the Ki-67 index was greater than 10 %) and a more aggressive clinical course. Moreover, after WES and Sanger verification, STAT3, IKBKB, ELF3, CHD7, KMT2D, ELK1, RARB and HPGDS were screened out in our patients.
CONCLUSIONS
HVLPD refers to a heterogeneous group of cutaneous lymphoproliferative diseases with different clinical and pathological features that affect patient outcomes. Gene mutations may be correlated with the development of HVLPD, and our study may provide new therapeutic targets for HVLPD.
Topics: Adolescent; Adult; Biomarkers; Cell Proliferation; Child; Child, Preschool; China; DNA Mutational Analysis; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Herpesvirus 4, Human; Humans; Hydroa Vacciniforme; Lymphoproliferative Disorders; Male; Middle Aged; Mutation; Photography; RNA, Viral; Retrospective Studies; Skin; Exome Sequencing; Young Adult
PubMed: 32682634
DOI: 10.1016/j.jdermsci.2020.06.013 -
Scientific Reports Nov 2020Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) is a rare Epstein-Barr virus (EBV)-associated lymphoproliferative disease. The disease course of HVLPD...
Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) is a rare Epstein-Barr virus (EBV)-associated lymphoproliferative disease. The disease course of HVLPD varies from an indolent course to progression to aggressive lymphoma. We investigated the characteristics of HVLPD in Korean patients. HVLPD patients at Seoul National University Hospital between 1988 and 2019 were retrospectively analyzed. This study included 26 HVLPD patients who all presented with recurrent papulovesicular and necrotic eruption on the face, neck, and extremities. EBV was detected from the skin tissues of all patients. HVLPD was diagnosed during childhood (age < 18 years) in seven patients (26.9%) and in adulthood (age ≥ 18 years) in 19 cases (73.1%). The median age at diagnosis was 24.0 years (range 7-70 years). HVLPD has various clinical courses, from an indolent course to progression to systemic lymphoma. Fourteen patients (53.8%) developed lymphoma: systemic EBV-positive T-cell lymphoma (n = 9, 34.6%); extranodal natural killer/T-cell lymphoma, nasal type (n = 3, 11.5%); aggressive natural killer/T-cell leukemia (n = 1, 3.8%); and EBV-positive Hodgkin lymphoma (n = 1, 3.8%). Mortality due to HVLPD occurred in five patients (26.3%) in the adult group, while it was one patient (14.3%) in the child group. As lymphoma progression and mortality occur not only in childhood but also in adulthood, adult-onset cases may need more careful monitoring.
Topics: Adolescent; Adult; Aged; Child; Disease Progression; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Hydroa Vacciniforme; Lymphoma, T-Cell; Lymphoproliferative Disorders; Male; Middle Aged; Necrosis; Republic of Korea; Retrospective Studies; Skin; Skin Neoplasms; Young Adult
PubMed: 33168864
DOI: 10.1038/s41598-020-76345-2 -
American Journal of Hematology Jul 2014
Topics: Aged; Epstein-Barr Virus Infections; Humans; Lymphoproliferative Disorders; Male
PubMed: 24729413
DOI: 10.1002/ajh.23739 -
The American Journal of Surgical... Jun 2017We report 2 cases of Kaposi sarcoma-associated herpesvirus (KSHV)-and Epstein-Barr Virus (EBV) associated germinotropic lymphoproliferative disorder. Both cases arose in... (Review)
Review
We report 2 cases of Kaposi sarcoma-associated herpesvirus (KSHV)-and Epstein-Barr Virus (EBV) associated germinotropic lymphoproliferative disorder. Both cases arose in patients from regions endemic for KSHV, Cape Verde, and the Democratic Republic of the Congo, presenting as localized lymphadenopathy. The affected lymph nodes showed colonization of the follicles by clusters of large atypical plasmablasts, but also showed regressive changes with vascular proliferation and interfollicular plasmacytosis, both reminiscent of human herpesvirus 8 (HHV-8) positive multicentric Castleman disease. The atypical plasmablasts showed dual positivity for HHV-8 and EBV, being positive for LANA and viral interleukin 6, as well as Epstein-Barr virus-encoded small RNA by in situ hybridization. They showed a latency I phenotype, being negative for LMP1, EBNA2, and BZLF-1. The plasmablasts were negative for immunoglobulin light chains, and in 1 case with successful DNA amplification had a polyclonal immunoglobulin rearrangement pattern. Germinotropic lymphoproliferative disorder is a rare disorder, with only 6 cases reported in the literature. We demonstrate for the first time the expression of HHV-8 viral interleukin 6 and provide evidence for latency I phenotype for EBV. In addition, 1 case progressed to an EBV-positive diffuse large B-cell lymphoma, but interestingly was negative for KSHV/HHV-8, likely indicative of tumor derived from an independent clone.
Topics: Aged, 80 and over; Biomarkers; Epstein-Barr Virus Infections; Female; Herpesviridae Infections; Herpesvirus 8, Human; Humans; Lymphoproliferative Disorders; Male; Middle Aged
PubMed: 28248818
DOI: 10.1097/PAS.0000000000000823