|
1
|
Sneyers F, Rocha‐Iraizos A, Vergote VKJ, Dierickx D. Delving deeper into the pathogenesis and genomics of posttransplant diffuse large B-cell lymphoma. Hemasphere 2025; 9:e70123. [PMID: 40236504 PMCID: PMC11997454 DOI: 10.1002/hem3.70123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/13/2025] [Accepted: 03/14/2025] [Indexed: 04/17/2025] Open
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) are a well-known complication of solid organ transplantation and allogeneic hematopoietic stem cell transplantation. The diffuse large B-cell lymphoma subtype (PT-DLBCL) is the most frequent monomorphic PTLD and is associated with poor prognosis. Transplant recipients have an increased risk of abnormal proliferation of lymphoid cells because of diminished immune surveillance. In about 60% of the cases, Epstein-Barr virus infection seems to contribute to the cancer phenotype. Although clinical and research interest in the disorder has increased during the last two decades, the pathology of the disease remains largely elusive. In this review, we summarize current knowledge of PT-DLBCL pathogenesis, and we discuss how a better understanding of PT-DLBCL can lead to improved diagnostics and therapeutic strategies.
Collapse
Affiliation(s)
- Flore Sneyers
- Department of OncologyLaboratory of Experimental HematologyKU LeuvenLeuvenBelgium
- Department of Human GeneticsLaboratory of Molecular Biology of LeukemiaKU LeuvenLeuvenBelgium
- Center for Cancer Biology, VIBLeuvenBelgium
- Leuven Kankerinstituut (LKI), KU Leuven – UZ LeuvenLeuvenBelgium
| | - Ana‐Lucía Rocha‐Iraizos
- Department of OncologyLaboratory of Experimental HematologyKU LeuvenLeuvenBelgium
- Department of Human GeneticsLaboratory of Molecular Biology of LeukemiaKU LeuvenLeuvenBelgium
- Center for Cancer Biology, VIBLeuvenBelgium
- Leuven Kankerinstituut (LKI), KU Leuven – UZ LeuvenLeuvenBelgium
| | - Vibeke K. J. Vergote
- Leuven Kankerinstituut (LKI), KU Leuven – UZ LeuvenLeuvenBelgium
- Department of HematologyUZ LeuvenLeuvenBelgium
| | - Daan Dierickx
- Department of OncologyLaboratory of Experimental HematologyKU LeuvenLeuvenBelgium
- Leuven Kankerinstituut (LKI), KU Leuven – UZ LeuvenLeuvenBelgium
- Department of HematologyUZ LeuvenLeuvenBelgium
| |
Collapse
|
|
2
|
Ivanova VS, Menter T, Cui N, Leary P, Zinner C, Halter JP, Stenner F, Dirnhofer S, Müller A, Tzankov A. Distinct subtypes of post-transplant lymphoproliferative disorders: CHIP-like mutations in early lesions and substantial mutational differences between EBV-positive and EBV-negative diffuse large B-cell lymphomas. Br J Haematol 2025; 206:484-504. [PMID: 39777628 DOI: 10.1111/bjh.19952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025]
Abstract
Post-transplant lymphoproliferative disorders (PTLD) and lymphomas in immunocompromised individuals represent significant clinical challenges, with a limited understanding of their pathogenesis. We investigated a PTLD cohort (n = 50) consisting of 'early lesions' (infectious mononucleosis-like PTLD, plasmacytic and follicular hyperplasias), polymorphic PTLD and post-transplant diffuse large B-cell lymphomas (PT-DLBCL). The study also included 15 DLBCL with autoimmune/immunocompromised backgrounds (IS-DLBCL) and 14 DLBCL, not otherwise specified (DLBCL, NOS), as control. To investigate microarchitectural and genetic changes, immunohistochemistry, multiplex immunofluorescence (mIF), fluorescence in situ hybridisation and high-throughput sequencing were performed. Scarcity of viral infections other than Epstein-Barr virus (EBV) was observed. mIF revealed lower Treg infiltration in PT-DLBCL and high CD8+/PD1+ T cells in IS-DLBCL. MYC rearrangements were most common in PT-DLBCL, followed by IS-DLBCL and DLBCL, NOS, all EBV-negative. TP53 mutations were frequent in EBV-negative PT-DLBCL and DLBCL, NOS but absent in 'early lesions'. NOTCH1 mutations were predominant in PT-DLBCL (N1 DLBCL-subgroup). Gene expression profiling showed a significant overlap between 'early lesions' and polymorphic PTLD. The presence of clonal haematopoiesis of indeterminate potential (CHIP)-like mutations and the absence of immune-escape gene mutations in 'early lesions' suggest these disorders may represent clonal expansions driven by exogenic immunosuppression and/or EBV infection 'substituting' for mutations of the latter group of genes.
Collapse
Affiliation(s)
- Vanesa-Sindi Ivanova
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Thomas Menter
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Ningxuan Cui
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Peter Leary
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Carl Zinner
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Jörg P Halter
- Haematology, University Hospital Basel, Basel, Switzerland
| | - Frank Stenner
- Oncology, University Hospital Basel, Basel, Switzerland
| | - Stefan Dirnhofer
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Anne Müller
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Alexandar Tzankov
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| |
Collapse
|
|
3
|
Williams JF, Lucas FM, Carrasco RD, Lovitch SB, Fisher DC, Kupper TS, Sadigh S. Primary cutaneous EBV+ extranodal NK/T-cell lymphoma of gamma/delta T-cell lineage in the posttransplantation setting. J Cutan Pathol 2024; 51:777-782. [PMID: 38986680 DOI: 10.1111/cup.14677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 06/10/2024] [Accepted: 06/17/2024] [Indexed: 07/12/2024]
Abstract
Posttransplantation primary cutaneous T-cell lymphomas (PT-CTCL) are a rare complication of sustained immunosuppression in the posttransplant setting. When present, PT-CTCLs are typically EBV- and exhibit features of mycosis fungoides/Sézary syndrome or CD30+ lymphoproliferative disorders. We present a case of a 75-year-old individual who developed skin lesions 30 years after liver transplantation. Pathologic evaluation of the skin biopsy revealed involvement by a clonal, EBV+ T-cell population of gamma/delta lineage with no evidence of systemic disease. Comprehensive genomic profiling was performed, confirming focal one-copy loss of 6q23.3, altogether consistent with the extremely rare and unusual diagnosis of primary cutaneous EBV+ extranodal NK/T-cell lymphoma of gamma/delta T-cell lineage in the posttransplantation setting.
Collapse
Affiliation(s)
- Jessica F Williams
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Fabienne M Lucas
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Ruben D Carrasco
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Scott B Lovitch
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - David C Fisher
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Thomas S Kupper
- Department of Dermatology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Sam Sadigh
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
4
|
Carbone A, Chadburn A, Gloghini A, Vaccher E, Bower M. Immune deficiency/dysregulation -associated lymphoproliferative disorders. Revised classification and management. Blood Rev 2024; 64:101167. [PMID: 38195294 DOI: 10.1016/j.blre.2023.101167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 12/13/2023] [Accepted: 12/30/2023] [Indexed: 01/11/2024]
Abstract
Significant advances in the field of lymphoma have resulted in two recent classification proposals, the International Consensus Classification (ICC) and the 5th edition WHO. A few entities are categorized differently in the ICC compared to the WHO. Nowhere is this more apparent than the immunodeficiency lymphoproliferative disorders. The three previous versions of the WHO classification (3rd, 4th and revised 4th editions) and the ICC focused on four clinical settings in which these lesions arise for primary categorization. In contrast the 2023 WHO 5th edition includes pathologic characteristics including morphology and viral status, in addition to clinical setting, as important information for lesion classification. In addition, the 2023 WHO recognizes a broader number of clinical scenarios in which these lesions arise, including not only traditional types of immune deficiency but also immune dysregulation. With this classification it is hoped that new treatment strategies will be developed leading to better patient outcomes.
Collapse
Affiliation(s)
- Antonino Carbone
- Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, Aviano, Italy.
| | - Amy Chadburn
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States of America.
| | - Annunziata Gloghini
- Department of Advanced Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Emanuela Vaccher
- Infectious Diseases and Tumors Unit, Department of Medical Oncology, Centro di Riferimento Oncologico (CRO), IRCCS, National Cancer Institute, Aviano, Italy.
| | - Mark Bower
- Department of Oncology and National Centre for HIV Malignancy, Chelsea & Westminster Hospital, London SW109NH, UK.
| |
Collapse
|
|
5
|
Dharnidharka VR, Ruzinova MB, Marks LJ. Post-Transplant Lymphoproliferative Disorders. Semin Nephrol 2024; 44:151503. [PMID: 38519279 PMCID: PMC11213680 DOI: 10.1016/j.semnephrol.2024.151503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2024]
Abstract
Post-transplant lymphoproliferative disorders (PTLDs) are a heterogenous set of unregulated lymphoid cell proliferations after organ or tissue transplant. A majority of cases are associated with the Epstein-Barr virus and higher intensity of pharmacologic immunosuppression. The clinical presentations are numerous. The diagnosis is ideally by histology, except in cases where the tumor is inaccessible to biopsy. While some pre-emptive therapies and treatment strategies are available have reasonable success are available, they do not eliminate the high morbidity and significant mortality after PTLD.
Collapse
Affiliation(s)
- Vikas R Dharnidharka
- Division of Pediatric Nephrology, Hypertension and Apheresis, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
| | - Marianna B Ruzinova
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Lianna J Marks
- Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Stanford University School of Medicine, Palo Alto, CA
| |
Collapse
|
|
6
|
Chadburn A. Post-transplant lymphoproliferative disorders (PTLD) in adolescents and young adults: A category in need of definition. Semin Diagn Pathol 2023; 40:401-407. [PMID: 37596187 DOI: 10.1053/j.semdp.2023.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/16/2023] [Accepted: 07/31/2023] [Indexed: 08/20/2023]
Abstract
Post-transplant lymphoproliferative disorders are a well-recognized complication of solid organ and stem cell transplantation. Much data has accumulated with respect to the pathobiology and clinical behavior of these lesions in the general post-transplant population as well as in the pediatric and adult age groups. However, information as to these lesions in the adolescent and young adult populations, which bridge the pediatric and adult groups, is limited. In this review, the focus is on this unique population of PTLD patients and their proliferations.
Collapse
Affiliation(s)
- Amy Chadburn
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 525 E 68th Street, Starr 709, New York, NY 10065, United States.
| |
Collapse
|
|
7
|
Salehi M, Rehman S, Qutab M, Altheeb R, Prakash R, Jafari HR. Histiocytic sarcoma in renal transplant patients: a literature review. J Med Case Rep 2023; 17:416. [PMID: 37784161 PMCID: PMC10546704 DOI: 10.1186/s13256-023-04140-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/24/2023] [Indexed: 10/04/2023] Open
Abstract
BACKGROUND Histiocytic sarcoma (HS) is defined as neoplasm resembling morphological and immunophenotypic characteristics of mature histiocytes. It is a rare form of lymphoid neoplasms. Despite advances in treatment and diagnosis of histiocytic sarcoma, majority of cases had poor prognosis due to progressive nature of the disease. In the following article, all reported cases of histiocytic sarcoma in renal transplant patients are reviewed. METHODS In our literature review, all relevant reports were collected electronically by entering the necessary keywords. A Boolean approach using Medical Subject Heading (MeSH) keywords was implemented. After establishing the inclusion/exclusion criteria, article titles and abstracts were evaluated by Systematic Reviews and Meta-Analyses (PRISMA) standards for 2020. All cases of histiocytic sarcoma in renal transplant patients were included. RESULT Based on our inclusion and exclusion criteria 4 case reports were yielded in this review. Two were males and 2 were females with the mean age of 42.25 years. Fever was the most common symptom. Although tumor originated from the native kidney on one patient, the site of the primary tumor was thorax, oropharynx, and transplanted kidney in the rest. Metastasis was detected in all cases. Prednisone was used for all cases. EBV was positive in 2 cases and negative in one of them. Histology was diagnostic and similar in all cases. Immunohistochemistry was done for 3 cases. Although chemotherapy was done for 3 patients, all 4 cases ended in mortality. CONCLUSION Despite the fact that neoplasms are post renal transplant complications, histiocytic sarcoma is a scarce and fatal entity in such patients. Histological and immunohistochemistry tests are the corner stone in diagnosis of histiocytic sarcoma.
Collapse
Affiliation(s)
- Mahsa Salehi
- Mazandaran University of Medical Sciences, Mazandaran, Iran.
| | | | - Miraa Qutab
- Lahore Medical and Dental College, Lahore, Pakistan
| | | | - Rashmi Prakash
- Adichunchanagiri Institute of Medical Sciences, Mandya, India
| | | |
Collapse
|
|
8
|
Lee M, Abousaud A, Harkins RA, Marin E, Balasubramani D, Churnetski MC, Peker D, Singh A, Koff JL. Important Considerations in the Diagnosis and Management of Post-transplant Lymphoproliferative Disorder. Curr Oncol Rep 2023; 25:883-895. [PMID: 37162742 PMCID: PMC10390257 DOI: 10.1007/s11912-023-01418-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2023] [Indexed: 05/11/2023]
Abstract
PURPOSE OF REVIEW A relative lack of molecular and clinical studies compared to other lymphoid cancers has historically made it difficult to determine optimal management approaches in post-transplant lymphoproliferative disorder (PTLD). We sought to better define the "state of the science" in PTLD by examining recent advances in risk assessment, genomic profiling, and trials of PTLD-directed therapy. RECENT FINDINGS Several major clinical trials highlight risk-stratified sequential therapy incorporating rituximab with or without chemotherapy as a rational treatment strategy in patients with CD20+ PTLD who do not respond to reduction of immunosuppression alone. Epstein Barr virus (EBV)-targeted cytotoxic lymphocytes are a promising approach in patients with relapsed/refractory EBV+ PTLD, but dedicated clinical trials should determine how autologous chimeric antigen receptor T cell therapy (CAR-T) may be safely administered to PTLD patients. Sequencing studies underscore the important effect of EBV infection on PTLD pathogenesis, but comprehensive genomic and tumor microenvironment profiling are needed to identify biomarkers that predict response to treatment in this clinically heterogeneous disease.
Collapse
Affiliation(s)
| | - Aseala Abousaud
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | | | - Ellen Marin
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | | | - Michael C Churnetski
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Deniz Peker
- Department of Pathology, Emory University, Atlanta, GA, USA
| | - Ankur Singh
- Georgia Institute of Technology, Atlanta, GA, USA
| | - Jean L Koff
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
| |
Collapse
|
|
9
|
Gross TG, Rubinstein JD. Post-transplant lymphoproliferative disease in children, adolescents, and young adults. Hematol Oncol 2023; 41 Suppl 1:48-56. [PMID: 37294957 DOI: 10.1002/hon.3139] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 03/28/2023] [Indexed: 06/11/2023]
Abstract
Post-transplant lymphoproliferative disease (PTLD) remains a major complication of transplantation. PTLD is a rare entity and very heterogenous making consensus on diagnosis and treatment very challenging. The majority are Epstein-Barr virus (EBV) driven, CD20+ B-cell proliferations. PTLD does occur following hematopoietic stem cell transplant (HSCT), but due to the relative short risk period and efficacy of pre-emptive therapy, PTLD following HSCT will not be discussed in this review. This review will focus on the epidemiology, role of EBV, clinical presentation, diagnosis and evaluation and the current and emerging treatment strategies for pediatric PTLD following solid organ transplantation.
Collapse
Affiliation(s)
- Thomas G Gross
- Department of Pediatrics, Children's Hospital of Colorado, Aurora, Colorado, USA
| | - Jeremy D Rubinstein
- Department of Pediatric, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Oncology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
| |
Collapse
|
|
10
|
Rubinstein J, Toner K, Gross T, Wistinghausen B. Diagnosis and management of post-transplant lymphoproliferative disease following solid organ transplantation in children, adolescents, and young adults. Best Pract Res Clin Haematol 2023; 36:101446. [PMID: 36907642 DOI: 10.1016/j.beha.2023.101446] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023]
Abstract
Post-transplant Lymphoproliferative Disease (PTLD) remains a major complication of solid organ transplantation (SOT) in pediatric patients. The majority are Epstein-Barr Virus (EBV) driven CD20+ B-cell proliferations responsive to reduction to immunosuppression and anti-CD20 directed immunotherapy. This review focusses on the epidemiology, role of EBV, clinical presentation, current treatment strategies, adoptive immunotherapy and future research in EBV + PTLD in pediatric patients.
Collapse
Affiliation(s)
- Jeremy Rubinstein
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue MLC 7018, Cincinnati, OH, 45229, USA.
| | - Keri Toner
- Center for Cancer and Blood Disorder, Children's National Hospital, Washington, DC, USA; Center for Cancer and Immunology Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA
| | - Thomas Gross
- Department of Pediatrics, Children's Hospital of Colorado, University of Colorado School of Medicine, Box 115/AP Rm C3404, Aurora, CO, 80045, USA
| | - Birte Wistinghausen
- Center for Cancer and Blood Disorder, Children's National Hospital, Washington, DC, USA; Center for Cancer and Immunology Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA.
| |
Collapse
|
|
11
|
Afify ZAM, Taj MM, Orjuela-Grimm M, Srivatsa K, Miller TP, Edington HJ, Dalal M, Robles J, Ford JB, Ehrhardt MJ, Ureda TJ, Rubinstein JD, McCormack S, Rivers JM, Chisholm KM, Kavanaugh MK, Bukowinski AJ, Friehling ED, Ford MC, Reddy SN, Marks LJ, Smith CM, Mason CC. Multicenter study of pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders. Cancer 2023; 129:780-789. [PMID: 36571557 PMCID: PMC11200327 DOI: 10.1002/cncr.34600] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/21/2022] [Accepted: 11/07/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.
Collapse
Affiliation(s)
- Zeinab A. M. Afify
- Primary Children’s Hospital, University of Utah, Salt Lake City, Utah, USA
| | - Mary M. Taj
- The Royal Marsden Hospital, Sutton, London, UK
| | | | | | - Tamara P. Miller
- Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Holly J. Edington
- Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
- Novant Health Presbyterian Medical Center, Charlotte, North Carolina, USA
| | - Mansi Dalal
- University of Florida Health Science Center, Gainesville, Florida, USA
| | - Joanna Robles
- Duke University School of Medicine, Durham, North Carolina, USA
| | - James B. Ford
- University of Nebraska Medical Center, Omaha, Nebraska, USA
| | | | - Tonya J. Ureda
- St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Jeremy D. Rubinstein
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA
| | - Sarah McCormack
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | | | | | - Madison K. Kavanaugh
- Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Andrew J. Bukowinski
- Department of Pediatrics, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Erika D. Friehling
- Department of Pediatrics, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Maegan C. Ford
- Columbia University Medical Center, New York, New York, USA
| | | | - Lianna J. Marks
- Stanford University School of Medicine, Palo Alto, California, USA
| | | | - Clinton C. Mason
- Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
| |
Collapse
|
|
12
|
Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic Hematopoietic Stem Cell Transplantation: Biology and Treatment Options. J Clin Med 2022; 11:jcm11247542. [PMID: 36556158 PMCID: PMC9784583 DOI: 10.3390/jcm11247542] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/15/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Post-transplant lymphoproliferative disease (PTLD) is a serious complication occurring as a consequence of immunosuppression in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT) or solid organ transplantation (SOT). The majority of PTLD arises from B-cells, and Epstein-Barr virus (EBV) infection is present in 60-80% of the cases, revealing the central role played by the latent infection in the pathogenesis of the disease. Therefore, EBV serological status is considered the most important risk factor associated with PTLDs, together with the depth of T-cell immunosuppression pre- and post-transplant. However, despite the advances in pathogenesis understanding and the introduction of novel treatment options, PTLD arising after alloHSCT remains a particularly challenging disease, and there is a need for consensus on how to treat rituximab-refractory cases. This review aims to explore the pathogenesis, risk factors, and treatment options of PTLD in the alloHSCT setting, finally focusing on adoptive immunotherapy options, namely EBV-specific cytotoxic T-lymphocytes (EBV-CTL) and chimeric antigen receptor T-cells (CAR T).
Collapse
|
|
13
|
Markouli M, Ullah F, Omar N, Apostolopoulou A, Dhillon P, Diamantopoulos P, Dower J, Gurnari C, Ahmed S, Dima D. Recent Advances in Adult Post-Transplant Lymphoproliferative Disorder. Cancers (Basel) 2022; 14:cancers14235949. [PMID: 36497432 PMCID: PMC9740763 DOI: 10.3390/cancers14235949] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 11/24/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
PTLD is a rare but severe complication of hematopoietic or solid organ transplant recipients, with variable incidence and timing of occurrence depending on different patient-, therapy-, and transplant-related factors. The pathogenesis of PTLD is complex, with most cases of early PLTD having a strong association with Epstein-Barr virus (EBV) infection and the iatrogenic, immunosuppression-related decrease in T-cell immune surveillance. Without appropriate T-cell response, EBV-infected B cells persist and proliferate, resulting in malignant transformation. Classification is based on the histologic subtype and ranges from nondestructive hyperplasias to monoclonal aggressive lymphomas, with the most common subtype being diffuse large B-cell lymphoma-like PTLD. Management focuses on prevention of PTLD development, as well as therapy for active disease. Treatment is largely based on the histologic subtype. However, given lack of clinical trials providing evidence-based data on PLTD therapy-related outcomes, there are no specific management guidelines. In this review, we discuss the pathogenesis, histologic classification, and risk factors of PTLD. We further focus on common preventive and frontline treatment modalities, as well as describe the application of novel therapies for PLTD and elaborate on potential challenges in therapy.
Collapse
Affiliation(s)
- Mariam Markouli
- Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Fauzia Ullah
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Najiullah Omar
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Anna Apostolopoulou
- Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Puneet Dhillon
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Panagiotis Diamantopoulos
- Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Joshua Dower
- Department of Hematology and Medical Oncology, Tufts Medical Center, Boston, MA 02111, USA
| | - Carmelo Gurnari
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Sairah Ahmed
- Department of Lymphoma-Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Danai Dima
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland Clinic, Cleveland, OH 44195, USA
- Correspondence:
| |
Collapse
|
|
14
|
Epstein Barr virus-positive B-cell lymphoma is highly vulnerable to MDM2 inhibitors in vivo. Blood Adv 2021; 6:891-901. [PMID: 34861697 PMCID: PMC8945299 DOI: 10.1182/bloodadvances.2021006156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/25/2021] [Indexed: 11/20/2022] Open
Abstract
MDM2 inhibitors have potent in vivo activity against and could be a novel therapy for EBV-positive B-cell lymphoma. EBV positivity or loss of BCL6 expression can be a potential predictive biomarker for response to MDM2 inhibitors in patients with lymphoma Epstein-Barr virus–positive (EBV-positive) B-cell lymphomas are common in immunocompromised patients and remain an unmet medical need. Here we report that MDM2 inhibitors (MDM2is) navtemadlin and idasanutlin have potent in vivo activity in EBV-positive B-cell lymphoma established in immunocompromised mice. Tumor regression was observed in all 5 EBV-positive xenograft–associated B-cell lymphomas treated with navtemadlin or idasanutlin. Molecular characterization showed that treatment with MDM2is resulted in activation of p53 pathways and downregulation of cell cycle effectors in human lymphoma cell lines that were either EBV-positive or had undetectable expression of BCL6, a transcriptional inhibitor of the TP53 gene. Moreover, treatment with navtemadlin resulted in tumor regression and prevented systemic dissemination of EBV-positive lymphoma derived from 2 juvenile patients with posttransplant lymphoproliferative diseases, including 1 whose tumor was resistant to virus-specific T-cell therapy. These results provide proof-of-concept for targeted therapy of EBV-positive lymphoma with MDM2is and the feasibility of using EBV infection or loss of BCL6 expression to identify responders to MDM2is.
Collapse
|
|
15
|
Bauer M, Jasinski-Bergner S, Mandelboim O, Wickenhauser C, Seliger B. Epstein-Barr Virus-Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies. Cancers (Basel) 2021; 13:cancers13205189. [PMID: 34680337 PMCID: PMC8533749 DOI: 10.3390/cancers13205189] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The Epstein–Barr virus, also termed human herpes virus 4, is a human pathogenic double-stranded DNA virus. It is highly prevalent and has been linked to the development of 1–2% of cancers worldwide. EBV-associated malignancies encompass various structural and epigenetic alterations. In addition, EBV-encoded gene products and microRNAs interfere with innate and adaptive immunity and modulate the tumor microenvironment. This review provides an overview of the characteristic features of EBV with a focus on the intrinsic and extrinsic immune evasion strategies, which contribute to EBV-associated malignancies. Abstract The detailed mechanisms of Epstein–Barr virus (EBV) infection in the initiation and progression of EBV-associated malignancies are not yet completely understood. During the last years, new insights into the mechanisms of malignant transformation of EBV-infected cells including somatic mutations and epigenetic modifications, their impact on the microenvironment and resulting unique immune signatures related to immune system functional status and immune escape strategies have been reported. In this context, there exists increasing evidence that EBV-infected tumor cells can influence the tumor microenvironment to their own benefit by establishing an immune-suppressive surrounding. The identified mechanisms include EBV gene integration and latent expression of EBV-infection-triggered cytokines by tumor and/or bystander cells, e.g., cancer-associated fibroblasts with effects on the composition and spatial distribution of the immune cell subpopulations next to the infected cells, stroma constituents and extracellular vesicles. This review summarizes (i) the typical stages of the viral life cycle and EBV-associated transformation, (ii) strategies to detect EBV genome and activity and to differentiate various latency types, (iii) the role of the tumor microenvironment in EBV-associated malignancies, (iv) the different immune escape mechanisms and (v) their clinical relevance. This gained information will enhance the development of therapies against EBV-mediated diseases to improve patient outcome.
Collapse
Affiliation(s)
- Marcus Bauer
- Department of Pathology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany; (M.B.); (C.W.)
| | - Simon Jasinski-Bergner
- Department of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany;
| | - Ofer Mandelboim
- Department of Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, En Kerem, P.O. Box 12271, Jerusalem 91120, Israel;
| | - Claudia Wickenhauser
- Department of Pathology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany; (M.B.); (C.W.)
| | - Barbara Seliger
- Department of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany;
- Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany
- Correspondence: ; Tel.: +49-(345)-557-1357
| |
Collapse
|
|
16
|
Lee C, Vincentelli H, Visuri J, Knight S, Ploeg R. Epstein-Barr Virus-Negative Diffuse Large B-Cell Post-transplant Lymphoma in an Epstein-Barr Virus-Positive Recipient. Cureus 2021; 13:e18134. [PMID: 34567913 PMCID: PMC8454600 DOI: 10.7759/cureus.18134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2021] [Indexed: 11/26/2022] Open
Abstract
Post-transplant lymphoproliferative disease (PTLD) can arise as a complication after solid organ transplantation. Epstein-Barr virus (EBV) infection is a known risk factor and is known to drive disease manifestation. PTLD can occur in EBV-negative recipients and with EBV-negative donor organs, however, EBV-negative PTLD pathogenesis is unknown. Here, we present PTLD presenting as intussusception in a patient with a historic simultaneous pancreas-kidney transplant (SPK). This case study presents the first documented case of EBV-negative post-transplant lymphoproliferative disease in an EBV-seropositive SPK recipient from an EBV-positive donor. Here we describe the diagnosis and management of this patient, discuss the differences between EBV positive and negative driven post-transplant lymphoproliferative disease, and highlight areas of research opportunity in the latter.
Collapse
Affiliation(s)
- Charlotte Lee
- Medical Sciences Division, University of Oxford, Oxford, GBR
| | | | - Jenni Visuri
- Medical Sciences Division, University of Oxford, Oxford, GBR
| | - Simon Knight
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, GBR.,Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, GBR
| | - Rutger Ploeg
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, GBR
| |
Collapse
|
|
17
|
Rubinstein JD, Shah R, Breese EH, Burns KC, Mangino JL, Norris RE, Lee L, Mizukawa B, O'Brien MM, Phillips CL, Perentesis JP, Pommert L, Absalon MJ. Treatment of posttransplant lymphoproliferative disorder with poor prognostic features in children and young adults: Short-course EPOCH regimens are safe and effective. Pediatr Blood Cancer 2021; 68:e29126. [PMID: 34019326 DOI: 10.1002/pbc.29126] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/20/2021] [Accepted: 05/07/2021] [Indexed: 12/30/2022]
Abstract
No guidelines exist for which intensive chemotherapy regimen is best in pediatric or young adult patients with high-risk posttransplant lymphoproliferative disorder (PTLD). We retrospectively reviewed patients with PTLD who received interval-compressed short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (SC-EPOCH) regimens at our institution. Eight patients were included with median age of 12 years. All patients achieved a complete response with a manageable toxicity profile. Two patients developed second, clonally unrelated, EBV-positive PTLD and one patient had recurrence at 6 months off therapy. No graft rejection occurred during therapy. All eight patients are alive with median follow-up of 29 months.
Collapse
Affiliation(s)
- Jeremy D Rubinstein
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Rachana Shah
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, USA.,Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Erin H Breese
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Karen C Burns
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jennifer L Mangino
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Robin E Norris
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Lynn Lee
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Benjamin Mizukawa
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Maureen M O'Brien
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Christine L Phillips
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - John P Perentesis
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Lauren Pommert
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Michael J Absalon
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| |
Collapse
|
|
18
|
Zhang Y, Mariani R, Gong M, Kirschmann D, Caparelli E, Wallace N, Turner R, Lu X, Gao J, Yap KL, Gong S. Distinctive Clinicopathologic Features of Monomorphic B-cell Post-transplant Lymphoproliferative Disorders in Children. Pediatr Dev Pathol 2021; 24:318-326. [PMID: 33872109 DOI: 10.1177/10935266211007254] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood. METHODS We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years. Clinical data were reviewed. Pathologic data including histologic types and EBV status were analyzed. Additional immunohistochemical stains, FISH studies, and TP53 gene mutational status were performed. RESULTS 4 of 18 cases were EBV-negative. All 4 EBV-negative cases were strikingly confined to the gastrointestinal (GI) tract or abdominal lymph nodes, while tumors in EBV-positive cases were found at various anatomic sites; 2 of 4 EBV-negative cases carried mutations in TP53 gene. Our cohort also included 2 rare types of PTLD, one plasmablastic lymphoma and one high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). CONCLUSION We report that monomorphic B-cell PTLDs in children have distinctive clinical and pathological features. More studies are needed to clarify whether and how much these pediatric PTLDs differ from their adult counterparts.
Collapse
Affiliation(s)
- Yanmin Zhang
- Northwestern Memorial Hospital, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Rachel Mariani
- Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Michelle Gong
- Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Dawn Kirschmann
- Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Edward Caparelli
- Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Nneka Wallace
- Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Rebekah Turner
- Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Xinyan Lu
- Northwestern Memorial Hospital, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Juehua Gao
- Northwestern Memorial Hospital, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Kai Lee Yap
- Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Shunyou Gong
- Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| |
Collapse
|
|
19
|
Davis AR, Stone SL, Oran AR, Sussman RT, Bhattacharyya S, Morrissette JJD, Bagg A. Targeted massively parallel sequencing of mature lymphoid neoplasms: assessment of empirical application and diagnostic utility in routine clinical practice. Mod Pathol 2021; 34:904-921. [PMID: 33311649 DOI: 10.1038/s41379-020-00720-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/21/2022]
Abstract
Massively parallel sequencing (MPS) has become a viable diagnostic tool to interrogate genetic profiles of numerous tumors but has yet to be routinely adopted in the setting of lymphoma. Here, we report the empirical application of a targeted 40-gene panel developed for use in mature lymphoid neoplasms (MLNs) and report our experience on over 500 cases submitted for MPS during the first year of its clinical use. MPS was applied to both fresh and fixed specimens. The most frequent diagnoses were diffuse large B-cell lymphoma (116), chronic lymphocytic leukemia/small lymphocytic lymphoma (60), marginal zone lymphoma (52), and follicular lymphoma (43), followed by a spectrum of mature T-cell neoplasms (40). Of 534 cases submitted, 471 generated reportable results in MLNs, with disease-associated variants (DAVs) detected in 241 cases (51.2%). The most frequent DAVs affected TP53 (30%), CREBBP (14%), MYD88 (14%), TNFRSF14 (10%), TNFAIP3 (10%), B2M (7%), and NOTCH2 (7%). The bulk of our findings confirm what is reported in the scientific literature. While a substantial majority of mutations did not directly impact diagnosis, MPS results were utilized to either change, refine, or facilitate the final diagnosis in ~10.8% of cases with DAVs and 5.5% of cases overall. In addition, we identified preanalytic variables that significantly affect assay performance highlighting items for specimen triage. We demonstrate the technical viability and utility of the judicious use of a targeted MPS panel that may help to establish general guidelines for specimen selection and diagnostic application in MLNs in routine clinical practice.
Collapse
Affiliation(s)
- Adam R Davis
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Sara L Stone
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Amanda R Oran
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Robyn T Sussman
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Siddharth Bhattacharyya
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jennifer J D Morrissette
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Adam Bagg
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
| |
Collapse
|
|
20
|
Sprangers B, Riella LV, Dierickx D. Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review. Am J Kidney Dis 2021; 78:272-281. [PMID: 33774079 DOI: 10.1053/j.ajkd.2021.01.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 01/02/2021] [Indexed: 12/13/2022]
Abstract
Posttransplant lymphoproliferative disorder (PTLD) is one of the most feared complications following kidney transplantation. Over a 10-year period, the risk of PTLD in kidney transplant recipients (KTRs) is 12-fold higher than in a matched nontransplanted population. Given the number of kidney transplants performed, KTRs who experience PTLD outnumber other organ transplant recipients who experience PTLD. Epstein-Barr virus infection is one of the most important risk factors for PTLD, even though 40% of PTLD cases in contemporary series are not Epstein-Barr virus-associated. The overall level of immunosuppression seems to be the most important driver of the increased occurrence of PTLD in solid organ transplant recipients. Reduction in immunosuppression is commonly accepted to prevent and treat PTLD. Although the cornerstone of PTLD treatment had been chemotherapy (typically cyclophosphamide-doxorubicin-vincristinr-prednisone), the availability of rituximab has changed the treatment landscape in the past 2 decades. The outcome of PTLD in KTRs has clearly improved as a result of the introduction of more uniform treatment protocols, improved supportive care, and increased awareness and use of positron emission tomography combined with computed tomography in staging and response monitoring. In this review, we will focus on the most recent data on epidemiology, presentation, risk factors, and management of PTLD in KTRs.
Collapse
Affiliation(s)
- Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Immunology (Rega Institute for Medical Research), KU Leuven; Division of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Leonardo V Riella
- Division of Nephrology and Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Daan Dierickx
- Laboratory of Experimental Hematology, Department of Oncology, KU Leuven; Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
| |
Collapse
|
|
21
|
Post-transplantation lymphoproliferative disorder after haematopoietic stem cell transplantation. Ann Hematol 2021; 100:865-878. [PMID: 33547921 DOI: 10.1007/s00277-021-04433-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 01/18/2021] [Indexed: 12/19/2022]
Abstract
Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication of haematopoietic stem cell transplantation (HSCT), occurring in a setting of immune suppression and dysregulation. The disease is in most cases driven by the reactivation of the Epstein-Barr virus (EBV), which induces B cell proliferation through different pathomechanisms. Beyond EBV, many factors, variably dependent on HSCT-related immunosuppression, contribute to the disease development. PTLDs share several features with primary lymphomas, though clinical manifestations may be different, frequently depending on extranodal involvement. According to the WHO classification, histologic examination is required for diagnosis, allowing also to distinguish among PTLD subtypes. However, in cases of severe and abrupt presentation, a diagnosis based on a combination of imaging studies and EBV-load determination is accepted. Therapies include prophylactic and pre-emptive interventions, aimed at eradicating EBV proliferation before symptoms onset, and targeted treatments. Among them, rituximab has emerged as first-line option, possibly combined with a reduction of immunosuppression, while EBV-specific cytotoxic T lymphocytes are effective and safe alternatives. Though prognosis remains poor, survival has markedly improved following the adoption of the aforementioned treatments. The validation of innovative, combined approaches is the future challenge.
Collapse
|
|
22
|
Montanari F, Orjuela-Grimm M. Joining Efforts for PTLD: Lessons Learned from Comparing the Approach and Treatment Strategies Across the Pediatric and Adult Age Spectra. Curr Hematol Malig Rep 2021; 16:52-60. [PMID: 33544319 DOI: 10.1007/s11899-021-00606-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 12/28/2022]
Abstract
PURPOSE OF REVIEW Post-transplant lymphoproliferative disorders are a rare and heterogeneous group of diseases, where large prospective studies have been difficult to perform and treatment paradigms are often based on retrospective studies. Here, we critically analyze and present the clinical algorithms commonly used for this disease, with a special focus on the challenges and differences of the approaches in the adult and pediatric populations. RECENT FINDINGS Clinical trials exploring combinations of immunochemotherapies with a sequential and risk-stratified strategy have demonstrated exciting results, but are hampered from specialty and age-determined silos. Approaches introducing novel-targeted therapies and cellular therapies are currently being explored with a goal of joining efforts across the pediatric and adult age spectra. We propose that future therapeutic approaches would benefit from combining pediatric and adult PTLD efforts, gaining from the experience garnered from the age- and subtype-specific tailored strategies, with the aim of limiting treatment-related toxicities while maximizing the efficacy. Joining of efforts holds enormous potential for accelerating access to novel therapeutic strategies for PTLD in the near future.
Collapse
Affiliation(s)
- Francesca Montanari
- Department of Hematology, Yale Cancer Center, Smilow Cancer Hospital, New Haven, USA
| | - Manuela Orjuela-Grimm
- Division of Pediatric Hematology, Oncology, and Stem Cell Transplant, Departments of Pediatrics and Epidemiology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Mailman School of Public Health, 722 West 168th street, Room 730, New York, NY, 10032, USA.
| |
Collapse
|
|
23
|
Song H, Guja KE, Iagaru A. 18F-FDG PET/CT for Evaluation of Post-Transplant Lymphoproliferative Disorder (PTLD). Semin Nucl Med 2021; 51:392-403. [PMID: 33455722 DOI: 10.1053/j.semnuclmed.2020.12.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Post-transplant lymphoproliferative disorders (PTLD) are a spectrum of heterogeneous lymphoproliferative conditions that are serious and possibly fatal complications after solid organ or allogenic hematopoietic stem cell transplantation. Most PTLD are attributed to Epstein-Barr virus reactivation in B-cells in the setting of immunosuppression after transplantation. Early diagnosis, accurate staging, and timely treatment are of vital importance to reduce morbidity and mortality. Given the often nonspecific clinical presentation and disease heterogeneity of PTLD, tissue biopsy and histopathological analysis are essential to establish diagnosis and most importantly, determine the subtype of PTLD, which guides treatment options. Advanced imaging modalities such as 18F-FDG PET/CT have played an increasingly important role and have shown high sensitivity and specificity in detection, staging, and assessing treatment response in multiple clinical studies over the last two decades. However, larger multicenter prospective validation is still needed to further establish the clinical utility of PET imaging in the management of PTLD. Significantly, new hybrid imaging modalities such as PET/MR may help reduce radiation exposure, which is especially important in pediatric transplant patients.
Collapse
Affiliation(s)
- Hong Song
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Dr, H2200, Stanford, 94305, USA
| | - Kip E Guja
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Dr, H2200, Stanford, 94305, USA
| | - Andrei Iagaru
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Dr, H2200, Stanford, 94305, USA.
| |
Collapse
|
|
24
|
Leeman-Neill RJ, Soderquist CR, Montanari F, Raciti P, Park D, Radeski D, Mansukhani MM, Murty VV, Hsiao S, Alobeid B, Bhagat G. Phenogenomic heterogeneity of post-transplant plasmablastic lymphomas. Haematologica 2020; 107:201-210. [PMID: 33297669 PMCID: PMC8719101 DOI: 10.3324/haematol.2020.267294] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Indexed: 11/14/2022] Open
Abstract
Plasmablastic lymphoma (PBL) is a rare and clinically aggressive neoplasm that typically occurs in immunocompromised individuals, including those infected with human immunodeficiency virus (HIV) and solid organ allograft recipients. Most prior studies have focused on delineating the clinico-pathological features and genetic attributes of HIVrelated PBL, in which MYC deregulation, Epstein-Barr virus (EBV) infection and, more recently, mutations in JAK/STAT, MAP kinase, and NOTCH pathway genes have been implicated in disease pathogenesis. The phenotypic spectrum of post-transplant (PT)-PBL is not well characterized and data on underlying genetic alterations are limited. This led us to perform comprehensive histopathological and immunophenotypic evaluation and targeted sequencing of 18 samples from 11 patients (8 males, 3 females; age range, 12-76 years) with PT-PBL; eight de novo and three preceded by other types of post-transplant lymphoproliferative disorders. Post-transplant PBL displayed morphological and immunophenotypic heterogeneity and some features overlapped those of plasmablastic myeloma. Six (55%) cases were EBV positive and five (45%) showed MYC rearrangement by fluorescence in situ hybridization. Recurrent mutations in epigenetic regulators (KMT2/MLL family, TET2) and DNA damage repair and response (TP53, mismatch repair genes, FANCA, ATRX), MAP kinase (KRAS, NRAS, HRAS, BRAF), JAK/STAT (STAT3, STAT6, SOCS1), NOTCH (NOTCH1, NOTCH3, SPEN), and immune surveillance (FAS, CD58) pathway genes were observed, with the mutational profiles of EBV+ and EBV– cases exhibiting both similarities and differences. Clinical outcomes also varied, with survival ranging from 0-15.9 years after diagnosis. Besides uncovering the biological heterogeneity of PT-PBL, our study highlights similarities and distinctions between PT-PBL and PBL occurring in other settings and reveals potentially targetable oncogenic pathways in subsets of the disease.
Collapse
Affiliation(s)
| | | | - Francesca Montanari
- Division of Hematology/Oncology, Columbia University Irving Medical Center, NY Presbyterian Hospital, New York, NY
| | | | | | - Dejan Radeski
- Department of Haematology, Sir Charles Gairdner Hospital, Perth
| | | | - Vundavalli V Murty
- Department of Medicine, Division of Cytogenetics, Columbia University Irving Medical Center, NY Presbyterian Hospital, New York, NY
| | | | | | | |
Collapse
|
|
25
|
Abstract
While our understanding of the biology of CD30 in lymphoma continues to evolve, our need to detect and measure its expression at the protein level remains critically important for diagnosis and patient care. In addition to its diagnostic and prognostic utility, CD30 has emerged as a vehicle for drug targeting through the antibody-drug conjugate brentuximab-vedotin (BV). Given the numerous ways that CD30 is utilized and its emergence as a predictive/prognostic biomarker, pathologists must come to a general consensus on the best reporting structure and methodology to ensure appropriate patient care. In this manuscript, we review the indications for testing, various modalities for testing, technical challenges, pitfalls, and potential standards of reporting. The following questions will try to be addressed in the current review article: What defines a "POSITIVE" level of CD30 expression?; How do we evaluate and report CD30 expression?; What are the caveats in the evaluation of CD30 expression?
Collapse
|
|
26
|
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant 2020; 10:29-46. [PMID: 32226769 PMCID: PMC7093305 DOI: 10.5500/wjt.v10.i2.29] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/21/2019] [Accepted: 12/14/2019] [Indexed: 02/05/2023] Open
Abstract
Transplant recipients are vulnerable to a higher risk of malignancy after solid organ transplantation and allogeneic hematopoietic stem-cell transplant. Post-transplant lymphoproliferative disorders (PTLD) include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissues to frank malignancy with aggressive behavior. Two main risk factors of PTLD are: Firstly, the cumulative immunosuppressive burden, and secondly, the oncogenic impact of the Epstein-Barr virus. The latter is a key pathognomonic driver of PTLD evolution. Over the last two decades, a considerable progress has been made in diagnosis and therapy of PTLD. The treatment of PTLD includes reduction of immunosuppression, rituximab therapy, either isolated or in combination with other chemotherapeutic agents, adoptive therapy, surgical intervention, antiviral therapy and radiotherapy. In this review we shall discuss the prevalence, clinical clues, prophylactic measures as well as the current and future therapeutic strategies of this devastating disorder.
Collapse
Affiliation(s)
- Fedaey Abbas
- Nephrology Department, Jaber El Ahmed Military Hospital, Safat 13005, Kuwait
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
| | - Mohsen El Kossi
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Ihab Sakr Shaheen
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Paediatric Nephrology, Royal Hospital for Children, Glasgow G51 4TF, United Kingdom
| | - Ajay Sharma
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Transplant Surgery, Royal Liverpool University Hospitals, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Transplantation, Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
| |
Collapse
|
|
27
|
Kim HB, Hong R, Na YS, Choi WY, Park SG, Lee HJ. Isolated peritoneal lymphomatosis defined as post-transplant lymphoproliferative disorder after a liver transplant: A case report. World J Clin Cases 2019; 7:4299-4306. [PMID: 31911911 PMCID: PMC6940333 DOI: 10.12998/wjcc.v7.i24.4299] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/31/2019] [Accepted: 11/15/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a fatal complication of solid organ transplantation or allogenic hematopoietic stem cell transplantation that is associated with immunosuppressive therapy. Potential manifestations are diverse, ranging from reactive lymphoid hyperplasia to high-grade lymphoma. PTLD is usually of B-cell origin and associated with Epstein-Barr virus (EBV) infection. Herein, we describe a case of PTLD involving the peritoneal omentum. There has been only case of PTLD as a diffuse large B-cell lymphoma (DLBCL) in the peritoneum.
CASE SUMMARY The patient was a 62-year-old man who had been receiving immunosuppressive therapy with tacrolimus since undergoing a liver transplant 15 years prior. He reported that he had experienced abdominal discomfort and anorexia 1 month prior to the current admission. Abdominal pelvic computed tomography (CT) revealed peritoneal and omental mass-like lesions without bowel obstruction. Ultrasonography-guided biopsy was performed, and he was histologically diagnosed with EBV-negative DLBCL. Positron emission tomography (PET)-CT depicted peritoneum and omentum involvement only, without any lymphadenopathy or organ masses, including in the gastrointestinal tract. Six cycles of chemotherapy with a “R-CHOP“ regimen (rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone) were administered, and PET-CT performed thereafter indicated complete remission.
CONCLUSION This is the first report of isolated peritoneal lymphomatosis defined as PTLD in a liver transplant recipient.
Collapse
Affiliation(s)
- Hong Beum Kim
- Department of Premedical Course, Chosun University School of Medicine, Gwangju 501-717, South Korea
| | - Ran Hong
- Department of Pathology, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju 501-717, South Korea
| | - Yung Sub Na
- Department of Internal Medicine, Pulomonology, Chosun University Hospital, Gwangju 501-717, South Korea
| | - Woo Young Choi
- Department of Plastic and Reconstructive Surgery, Chosun University Hospital, Gwangju 501-717, South Korea
| | - Sang Gon Park
- Department of Internal Medicine, Hemato-oncology, Chosun University Hospital, Gwangju 501-717, South Korea
| | - Hee Jeong Lee
- Department of Internal Medicine, Hemato-oncology, Chosun University Hospital, Gwangju 501-717, South Korea
- MD, PhD, Department of HematoOncology, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju 501-717, South Korea
| |
Collapse
|
|
28
|
Jiao XL, Wang YQ, Ai H, Wang Q, Zhou H, Fu YW, Wei XD, Song YP. [Post-transplantation lymphoproliferative disorder accompanies acquired hemophilia after haploid hematopoietic stem cell transplantation in a pediatric AML patient: a case report and literature review]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 40:691-693. [PMID: 31495141 PMCID: PMC7342870 DOI: 10.3760/cma.j.issn.0253-2727.2019.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Indexed: 11/23/2022]
Affiliation(s)
- X L Jiao
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
DeStefano CB, Desai SH, Shenoy AG, Catlett JP. Management of post-transplant lymphoproliferative disorders. Br J Haematol 2018; 182:330-343. [DOI: 10.1111/bjh.15263] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
| | - Sanjal H. Desai
- Department of Hematology; MedStar Washington Hospital Center; Washington DC USA
| | - Aarthi G. Shenoy
- Department of Hematology; MedStar Washington Hospital Center; Washington DC USA
| | - Joseph P. Catlett
- Department of Hematology; MedStar Washington Hospital Center; Washington DC USA
| |
Collapse
|
|
30
|
Guidry JT, Birdwell CE, Scott RS. Epstein-Barr virus in the pathogenesis of oral cancers. Oral Dis 2018; 24:497-508. [PMID: 28190296 PMCID: PMC5554094 DOI: 10.1111/odi.12656] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 01/30/2017] [Accepted: 01/31/2017] [Indexed: 12/28/2022]
Abstract
Epstein-Barr virus (EBV) is a ubiquitous gamma-herpesvirus that establishes a lifelong persistent infection in the oral cavity and is intermittently shed in the saliva. EBV exhibits a biphasic life cycle, supported by its dual tropism for B lymphocytes and epithelial cells, which allows the virus to be transmitted within oral lymphoid tissues. While infection is often benign, EBV is associated with a number of lymphomas and carcinomas that arise in the oral cavity and at other anatomical sites. Incomplete association of EBV in cancer has questioned if EBV is merely a passenger or a driver of the tumorigenic process. However, the ability of EBV to immortalize B cells and its prevalence in a subset of cancers has implicated EBV as a carcinogenic cofactor in cellular contexts where the viral life cycle is altered. In many cases, EBV likely acts as an agent of tumor progression rather than tumor initiation, conferring malignant phenotypes observed in EBV-positive cancers. Given that the oral cavity serves as the main site of EBV residence and transmission, here we review the prevalence of EBV in oral malignancies and the mechanisms by which EBV acts as an agent of tumor progression.
Collapse
Affiliation(s)
- Joseph T. Guidry
- Department of Microbiology and Immunology, Center for Tumor and Molecular Virology, and Feist-Weiller Cancer Center. Louisiana State University Health Sciences Center-Shreveport. Shreveport, LA 71103
| | - Christine E. Birdwell
- Department of Microbiology and Immunology, Center for Tumor and Molecular Virology, and Feist-Weiller Cancer Center. Louisiana State University Health Sciences Center-Shreveport. Shreveport, LA 71103
| | - Rona S. Scott
- Department of Microbiology and Immunology, Center for Tumor and Molecular Virology, and Feist-Weiller Cancer Center. Louisiana State University Health Sciences Center-Shreveport. Shreveport, LA 71103
| |
Collapse
|
|
31
|
Danylesko I, Shimoni A. Second Malignancies after Hematopoietic Stem Cell Transplantation. Curr Treat Options Oncol 2018; 19:9. [PMID: 29423555 DOI: 10.1007/s11864-018-0528-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OPINION STATEMENT Second malignancies are a rare but well-defined late complication after autologous and allogeneic hematopoietic stem-cell transplantation (SCT). Solid malignancies occur in up to 15% of patients 15 years after SCT with myeloablative conditioning, with no plateau in the incidence rates. They are responsible for 5-10% of late deaths after SCT. The incidence is increased with advanced age at SCT. The major risk factors are the use of total body irradiation, which is associated with adenocarcinomas and with chronic graft-versus-host disease which is associated with squamous cell cancers. There is less data on the incidence of second malignancies after reduced-intensity conditioning, but it may not be lower. The types of solid tumors reported in excess include melanoma and other skin cancers; cancers of the oral cavity and head and neck, brain, liver, uterine cervix, thyroid, breast, lung; and possibly gastrointestinal cancers. Therapy-related myeloid neoplasms (t-MN) are more common after autologous SCT and may be related mostly to pre-transplant therapies. Post-transplant lymphoproliferative disease is donor-cell-derived lymphoma that is more common after allogeneic SCT with T-cell depletion or intensive immune-suppression state. Second malignancies are most often treated similarly to the standard therapy for similar malignancies. Lifelong cancer screening and prevention interventions are required for all transplantation survivors.
Collapse
Affiliation(s)
- Ivetta Danylesko
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel.,Sacker school of medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Avichai Shimoni
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel. .,Sacker school of medicine, Tel-Aviv University, Tel-Aviv, Israel.
| |
Collapse
|
|
32
|
Affiliation(s)
- Daan Dierickx
- From the Department of Hematology, University Hospitals Leuven, and the Laboratory for Experimental Hematology, Department of Oncology, University of Leuven, Leuven, Belgium (D.D.); and the Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN (T.M.H.)
| | - Thomas M Habermann
- From the Department of Hematology, University Hospitals Leuven, and the Laboratory for Experimental Hematology, Department of Oncology, University of Leuven, Leuven, Belgium (D.D.); and the Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN (T.M.H.)
| |
Collapse
|
|
33
|
Menter T, Juskevicius D, Alikian M, Steiger J, Dirnhofer S, Tzankov A, Naresh KN. Mutational landscape of B-cell post-transplant lymphoproliferative disorders. Br J Haematol 2017; 178:48-56. [PMID: 28419429 DOI: 10.1111/bjh.14633] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 12/31/2016] [Indexed: 12/14/2022]
Abstract
It is currently unclear whether post-transplant diffuse large B-cell lymphomas (PT-DLBCL) display a similar genomic landscape as DLBCL in immunocompetent patients (IC-DLBCL). We investigated 50 post-transplant lymphoproliferative disorders (PTLDs) including 37 PT-DLBCL samples for somatic mutations frequently observed in IC-DLBCL. Targeted Next Generation Sequencing (NGS) using the Ion Torrent platform and a customized panel of 68 genes was performed on genomic DNA. Non-tumoural tissue was sequenced to exclude germline variants in cases where available. A control cohort of 76 IC-DLBCL was available for comparative analyses. In comparison to IC-DLBCLs, PT-DLBCL showed more frequent mutations of TP53 (P = 0·004), and absence of ATM and B2M mutations (P = 0·004 and P = 0·016, respectively). In comparison to IC-DLBCLs, Epstein-Barr virus (EBV)+ PT-DLBCL had fewer mutated genes (P = 0·007) and particularly fewer mutations in nuclear factor-κB pathway-related genes (P = 0·044). TP53 mutations were more frequent in EBV- PT-DLBCL as compared to IC-DLBCL (P = 0·001). Germinal centre B cell (GCB) subtype of PT-DLBCL had fewer mutations and mutated genes than GCB-IC-DLBCLs (P = 0·048 and 0·04 respectively). Polymorphic PTLD displayed fewer mutations as compared to PT-DLBCL (P = 0·001). PT-DLBCL differs from IC-DLBCL with respect to mutations in genes related to DNA damage control and immune-surveillance, and EBV association is likely to have a bearing on the mutational pattern.
Collapse
Affiliation(s)
- Thomas Menter
- Department of Cellular and Molecular Pathology, Hammersmith Hospital Campus, Imperial College Healthcare NHS Trust, London, UK.,Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | | | - Mary Alikian
- Department of Cellular and Molecular Pathology, Hammersmith Hospital Campus, Imperial College Healthcare NHS Trust, London, UK
| | - Juerg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Stephan Dirnhofer
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Alexandar Tzankov
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Kikkeri N Naresh
- Department of Cellular and Molecular Pathology, Hammersmith Hospital Campus, Imperial College Healthcare NHS Trust, London, UK
| |
Collapse
|
|
34
|
EBV-Negative Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder with Marked Morphologic Pleomorphism and Pathogenic Mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53. Case Rep Hematol 2017; 2017:5083463. [PMID: 28487787 PMCID: PMC5402239 DOI: 10.1155/2017/5083463] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 02/18/2017] [Accepted: 03/19/2017] [Indexed: 01/05/2023] Open
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) are a diverse group of lymphoid or plasmacytic proliferations frequently driven by Epstein-Barr virus (EBV). EBV-negative PTLDs appear to represent a distinct entity. This report describes an unusual case of a 33-year-old woman that developed a monomorphic EBV-negative PTLD consistent with diffuse large B-cell lymphoma (DLBCL) 13 years after heart-lung transplant. Histological examination revealed marked pleomorphism of the malignant cells including nodular areas reminiscent of classical Hodgkin lymphoma (cHL) with abundant large, bizarre Hodgkin-like cells. By immunostaining, the malignant cells were immunoreactive for CD45, CD20, CD79a, PAX5, BCL6, MUM1, and p53 and negative for CD15, CD30, latent membrane protein 1 (LMP1), and EBV-encoded RNA (EBER). Flow cytometry demonstrated lambda light chain restricted CD5 and CD10 negative B-cells. Fluorescence in situ hybridization studies (FISH) were negative for cMYC, BCL2, and BCL6 rearrangements but showed deletion of TP53 and monosomy of chromosome 17. Next-generation sequencing studies (NGS) revealed numerous genetic alterations including 6 pathogenic mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53(x2) genes and 30 variants of unknown significance (VOUS) in ABL1, ASXL1, ATM, BCOR, BCORL1, BRNIP3, CDH2, CDKN2A, DNMT3A, ETV6, EZH2, FBXW7, KIT, NF1, RUNX1, SETPB1, SF1, SMC1A, STAG2, TET2, TP53, and U2AF2.
Collapse
|
|
35
|
Sundin A, Grzywacz BJ, Yohe S, Linden MA, Courville EL. B-cell posttransplant lymphoproliferative disorder isolated to the central nervous system is Epstein-Barr virus positive and lacks p53 and Myc expression by immunohistochemistry. Hum Pathol 2017; 61:140-147. [DOI: 10.1016/j.humpath.2016.12.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 11/15/2016] [Accepted: 12/01/2016] [Indexed: 01/14/2023]
|