|
1
|
Zheng X, Zheng Y, Zhang Y, Xie J, Teng X, Bi K, Sun L, Huang X, Jin M, Zhou X. An exploratory study on the differential diagnostic indicators between adult systemic EBV-positive T-cell lymphoproliferative disorders and angioimmunoblastic T-cell lymphoma with multiple EBV infections. Infect Agent Cancer 2025; 20:3. [PMID: 39844250 PMCID: PMC11756112 DOI: 10.1186/s13027-024-00627-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 12/03/2024] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND The differential diagnosis between adult systemic EBV-positive T-cell lymphoproliferative disorders (EBV+ T-LPD) and angioimmunoblastic T-cell lymphoma (AITL) with multiple EBV infections is difficult, and distinguishing between the two has become a diagnostic challenge for pathologists. Given that the clinical treatment plans are different, an accurate diagnosis is a prerequisite to ensure effective treatment, therefore, it is extremely necessary and meaningful to find effective pathological indicators for distinguishing between two diseases. METHODS We present a retrospective study comparing 7 cases of adult EBV+ T-LPD and 16 cases of AITL with multiple EBV infections diagnosed at our institution from 2017 to 2022. Differences in immunophenotype, type of EBV-infected cells, clonality and gene mutations between the two groups of cases were compared by immunohistochemical staining, double-label staining, TCR gene rearrangement and next-generation sequencing analysis. RESULTS 7 cases of adult EBV+ T-LPD: all cases had no more than 1 T follicular helper (THF) marker was expressed, and there were significantly more EBER+/CD3 + cells than EBER+/CD20 + cells; 5 cases had mutation detection results, in which only 1 had the characteristic KMT2D mutation, 2 had TET2 mutations, and no common mutations such as DDX3X were detected.16 cases of AITL with multiple EBV infections: all cases were found to express at least 2 TFH markers, with 87% of them expressing at least 3 TFH markers., and had significantly more EBER+/CD20 + cells than EBER+/CD3 + cells; 4 cases had mutation test results, with mutated high-frequency genes being TET2 (100%, and all of them had 2 or more TET2 mutations) and RHOA G17V (100%), DNMT3A mutation occurred in 2 cases (50%), and IDH2 R172 mutation occurred in 1 case (25%). CONCLUSIONS We found that the expression pattern of TFH markers, the types of cells predominantly infected by EBV and the different mutations can all be used as effective pathological indicators for distinguishing between two diseases.
Collapse
Affiliation(s)
- Xiaodan Zheng
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yuanyuan Zheng
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yanlin Zhang
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jianlan Xie
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaojing Teng
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Kuo Bi
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lan Sun
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaowen Huang
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Mulan Jin
- Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
| | - Xiaoge Zhou
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
|
2
|
Liu DL, Wang YJ, Qian SY, Ma SS, Ding MJ, Dong M, Zhang JM, Zhang MZ, Chen QJ, Zhang XD. Clinical features and prognosis of chronic natural killer cell lymphoproliferative disorders. Hematology 2024; 29:2307817. [PMID: 38319083 DOI: 10.1080/16078454.2024.2307817] [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: 06/26/2023] [Accepted: 01/15/2024] [Indexed: 02/07/2024] Open
Abstract
OBJECTIVE To analyze the current treatment status and prognostic regression of the chronic NK cell lymphoproliferative disorder (CLPD-NK). METHODS We retrospectively analyzed the clinical features, treatment and prognosis of 18 patients with CLPD-NK who were treated at our Hospital between September 2016 and September 2022. RESULTS Eighteen patients were included: three patients were treated with chemotherapy, five patients underwent immune-related therapy, one patient was treated with glucocorticoids alone, five patients were administered granulocyte colony-stimulating factor, blood transfusion therapy, or anti-infection therapy, followed by observation and follow-up, and four patients were observed without treatment. Fifteen patients survived, including two patients who achieved complete remission (CR) and seven patients who achieved partial remission (PR), of whom one patient progressed to Aggressive NK-cell leukemia (ANKL) and sustained remission after multiple lines of treatment; three patients were not reviewed, of which one patient was still in active disease, three patients developed hemophagocytic syndrome during treatment and eventually died, one of them had positive Epstein-Barr virus (EBV) expression. The 5-years overall survival rate was 83%. CONCLUSION Most patients with CLPD-NK have inert progression and a good prognosis, whereas some patients have a poor prognosis after progressing to ANKL and combined with hemophagocytic syndrome. Abnormal NK cells invading the center suggest a high possibility of ANKL development, and immunosuppressants and hormones are effective treatments for this disease.
Collapse
Affiliation(s)
- Dong-Lin Liu
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Yan-Jie Wang
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Si-Yu Qian
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Shan-Shan Ma
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Meng-Jie Ding
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Meng Dong
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Jie-Ming Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Ming-Zhi Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Qing-Jiang Chen
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Xu-Dong Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| |
Collapse
|
|
3
|
Miranda RN, Amador C, Chan JKC, Guitart J, Rech KL, Medeiros LJ, Naresh KN. Fifth Edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues: Mature T-Cell, NK-Cell, and Stroma-Derived Neoplasms of Lymphoid Tissues. Mod Pathol 2024; 37:100512. [PMID: 38734236 DOI: 10.1016/j.modpat.2024.100512] [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: 12/31/2023] [Revised: 04/14/2024] [Accepted: 05/02/2024] [Indexed: 05/13/2024]
Abstract
This review focuses on mature T cells, natural killer (NK) cells, and stroma-derived neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors, including changes from the revised fourth edition. Overall, information has expanded, primarily due to advancements in genomic understanding. The updated classification adopts a hierarchical format. The updated classification relies on a multidisciplinary approach, incorporating insights from a diverse group of pathologists, clinicians, and geneticists. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, Epstein-Barr virus-positive nodal T- and NK-cell lymphoma, and several stroma-derived neoplasms of lymphoid tissues have been newly introduced or included. The review also provides guidance on how the fifth edition of the World Health Organization classification of hematolymphoid tumors can be applied in routine clinical practice.
Collapse
Affiliation(s)
- Roberto N Miranda
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Catalina Amador
- Department of Pathology, University of Miami, Miami, Florida
| | - John K C Chan
- Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Joan Guitart
- Department of Dermatology, Northwestern University Feinberg Medical School, Chicago, Illinois
| | - Karen L Rech
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - L Jeffrey Medeiros
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kikkeri N Naresh
- Section of Pathology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Laboratory Medicine & Pathology, University of Washington, Seattle, Washington.
| |
Collapse
|
|
4
|
Shen K, Shuai X, Li J, Liu J, Liu T, Niu T, Ma H. Chronic active Epstein-Barr virus infection involving gastrointestinal tract with hemophagocytic lymphohistiocytosis. Ann Hematol 2023; 102:45-53. [PMID: 36534145 DOI: 10.1007/s00277-022-05081-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/04/2022] [Indexed: 12/23/2022]
Abstract
Chronic active EBV infection (CAEBV) is a lymphoproliferative disorder of T- or NK-cell type in Asian countries. CAEBV involving the gastrointestinal tract (GI CAEBV) is a rare condition with poor prognosis that may rapidly progress with hemophagocytic lymphohistiocytosis (HLH) and life-threatening complications such as GI bleeding and/or perforation. The approach to CAEBV with GI tract involvement (GI CAEBV) is still an unmet clinical need. In this case series study, we summarized the clinical features, treatment, and prognosis of seven cases of GI CAEBV with HLH, particularly focusing on its prognosis and the possible salvage therapy combining surgery, novel therapeutic agents, and/or autologous(auto-) hematopoietic stem cell transplantation (HSCT) based on successful cases from our center. GI CAEBV is often misdiagnosed as inflammatory bowel diseases and certain infections. The key to its early recognition is the integrative consideration of its systemic manifestation, serum virology, endoscopic, and imaging findings along with pathology. Surgical intervention should not be hesitated when life-threatening GI complications occur. Resection of the involved bowel segment is an effective way of controlling bleeding and reducing tumor burden. In addition to upfront allogeneic HSCT, new therapeutic modalities including PD-1 antibody and auto-HSCT may be effective in certain patients.
Collapse
Affiliation(s)
- Kai Shen
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Xiao Shuai
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Jianjun Li
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Jiazhuo Liu
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Ting Liu
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Ting Niu
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Hongbing Ma
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
|
5
|
The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 2022; 36:1720-1748. [PMID: 35732829 PMCID: PMC9214472 DOI: 10.1038/s41375-022-01620-2] [Citation(s) in RCA: 1821] [Impact Index Per Article: 607.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/17/2022] [Accepted: 05/26/2022] [Indexed: 02/05/2023]
Abstract
We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.
Collapse
|
|
6
|
Onishi Y, Onodera K, Fukuhara N, Kato H, Ichikawa S, Fujiwara T, Yokoyama H, Yamada-Fujiwara M, Harigae H. Unrelated cord blood transplantation for adult-onset EBV-associated T-cell and NK-cell lymphoproliferative disorders. Int J Hematol 2022; 115:873-881. [PMID: 35274195 DOI: 10.1007/s12185-022-03313-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/15/2022] [Accepted: 02/15/2022] [Indexed: 11/29/2022]
Abstract
Adult-onset EBV-associated T-cell and NK-cell lymphoproliferative disorders (EBV-T/NK-LPDs) often progress rapidly, and require allogeneic stem cell transplantation early in the course of treatment. Unrelated cord blood transplantation (UCBT) is a readily available option for patients without HLA-matched donors. We retrospectively analyzed the outcomes of 12 UCBT in adult patients with chronic active EBV infection (CAEBV, n = 8), EBV-positive hemophagocytic lymphohistiocytosis following primary EBV infection (n = 2), hydroa vacciniforme-like lymphoproliferative disorder (n = 1), and systemic EBV-positive T-cell lymphoma of childhood (STCLC, n = 1). The median age at transplantation was 31.5 years (range 19-58). At the median follow-up time for survivors, which was 6.3 years (range 0.3-11.3), 3-year overall survival (OS) rates in all patients and 8 CAEBV patients were 68.2% (95% CI 28.6-88.9) and 83.3% (95% CI 27.3-97.5), respectively. Graft failure occurred in 4 of 8 CAEBV patients, requiring a second UCBT to achieve neutrophil engraftment. The cumulative incidence of grade II-IV acute GVHD was 33.3% (95% CI 9.1-60.4%). The EBV-DNA load became undetectable or very low after UCBT in all cases. UCBT may be a promising treatment option for adult-onset EBV-T/NK-LPDs.
Collapse
Affiliation(s)
- Yasushi Onishi
- Department of Hematology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
| | - Koichi Onodera
- Department of Hematology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Noriko Fukuhara
- Department of Hematology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Hiroki Kato
- Department of Hematology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Satoshi Ichikawa
- Department of Hematology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Tohru Fujiwara
- Department of Hematology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Hisayuki Yokoyama
- Department of Hematology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Minami Yamada-Fujiwara
- Department of Hematology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Hideo Harigae
- Department of Hematology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| |
Collapse
|
|
7
|
Zanelli M, Sanguedolce F, Palicelli A, Zizzo M, Martino G, Caprera C, Fragliasso V, Soriano A, Gozzi F, Cimino L, Masia F, Moretti M, Foroni M, De Marco L, Pellegrini D, De Raeve H, Ricci S, Tamagnini I, Tafuni A, Cavazza A, Merli F, Pileri SA, Ascani S. EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 3). Cancers (Basel) 2021; 13:6021. [PMID: 34885131 PMCID: PMC8656853 DOI: 10.3390/cancers13236021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 11/27/2021] [Accepted: 11/28/2021] [Indexed: 12/28/2022] Open
Abstract
EBV is the first known oncogenic virus involved in the development of several tumors. The majority of the global population are infected with the virus early in life and the virus persists throughout life, in a latent stage, and usually within B lymphocytes. Despite the worldwide diffusion of EBV infection, EBV-associated diseases develop in only in a small subset of individuals often when conditions of immunosuppression disrupt the balance between the infection and host immune system. EBV-driven lymphoid proliferations are either of B-cell or T/NK-cell origin, and range from disorders with an indolent behavior to aggressive lymphomas. In this review, which is divided in three parts, we provide an update of EBV-associated lymphoid disorders developing in the gastrointestinal tract, often representing a challenging diagnostic and therapeutic issue. Our aim is to provide a practical diagnostic approach to clinicians and pathologists who face this complex spectrum of disorders in their daily practice. In this part of the review, the chronic active EBV infection of T-cell and NK-cell type, its systemic form; extranodal NK/T-cell lymphoma, nasal type and post-transplant lymphoproliferative disorders are discussed.
Collapse
Affiliation(s)
- Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | | | - Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Giovanni Martino
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (D.P.); (S.A.)
| | - Cecilia Caprera
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (D.P.); (S.A.)
| | - Valentina Fragliasso
- Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Alessandra Soriano
- Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Fabrizio Gozzi
- Ocular Immunology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (F.G.); (L.C.)
| | - Luca Cimino
- Ocular Immunology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (F.G.); (L.C.)
| | - Francesco Masia
- Dipartimento di Medicina, Università degli Studi di Perugia, 05100 Terni, Italy; (F.M.); (M.M.)
| | - Marina Moretti
- Dipartimento di Medicina, Università degli Studi di Perugia, 05100 Terni, Italy; (F.M.); (M.M.)
| | - Moira Foroni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Loredana De Marco
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - David Pellegrini
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (D.P.); (S.A.)
| | - Hendrik De Raeve
- Pathology, University Hospital Brussels, 1090 Brussels, Belgium;
- Pathology, O.L.V. Hospital Aalst, 9300 Aalst, Belgium
| | - Stefano Ricci
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Ione Tamagnini
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Alessandro Tafuni
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy;
| | - Alberto Cavazza
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Francesco Merli
- Hematology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Stefano A. Pileri
- Haematopathology Division, European Institute of Oncology-IEO IRCCS Milan, 20141 Milan, Italy;
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (D.P.); (S.A.)
| |
Collapse
|
|
8
|
Annaloro C, Serpenti F, Saporiti G, Galassi G, Cavallaro F, Grifoni F, Goldaniga M, Baldini L, Onida F. Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications. Front Immunol 2021; 11:569381. [PMID: 33552044 PMCID: PMC7854690 DOI: 10.3389/fimmu.2020.569381] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022] Open
Abstract
In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.
Collapse
Affiliation(s)
- Claudio Annaloro
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Fabio Serpenti
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Giorgia Saporiti
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Giulia Galassi
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Francesca Cavallaro
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Federica Grifoni
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Maria Goldaniga
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Luca Baldini
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Francesco Onida
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| |
Collapse
|
|
9
|
Yu S, Yang Q, Wu J, Zhu M, Ai J, Zhang H, Xu B, Shao L, Zhang W. Clinical application of Epstein-Barr virus DNA loads in Epstein-Barr virus-associated diseases: A cohort study. J Infect 2020; 82:105-111. [PMID: 33248217 DOI: 10.1016/j.jinf.2020.11.027] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 08/06/2020] [Accepted: 11/21/2020] [Indexed: 12/01/2022]
Abstract
OBJECTIVES This study evaluated the diagnostic value of Epstein-Barr virus (EBV) DNA load in blood samples of patients with EBV-associated diseases, and proposed a strategy for the interpretation of positive EBV DNA results. METHODS Derivation and validation cohorts were established to evaluate the clinical significance of EBV DNA loads in the peripheral blood mononuclear cells (PBMCs) and plasma from EBV-infected patients. EBV DNA loads were compared and receiver operating characteristic curves were employed to assess the optimal cutoff values of EBV DNA for identification of EBV-associated diseases. RESULTS The derivation and validation cohorts comprised 135 and 71 subjects, respectively. EBV DNA loads in the PBMCs of the EBV-associated diseases group was significantly higher than that of the EBV non-associated diseases group (5.8 × 104 vs 7.8 × 103 copies/106 cells, P<0.0001). The diagnostic cut-off value of viral load in PBMCs for EBV-associated diseases was determined to be 1.6 × 104 copies/106 cells. The combined EBV DNA load cutoff in PBMCs and positive EBV DNA qualitative detection in plasma (>500 copies/mL) allowed for the differentiation of EBV-associated and non-associated diseases; the sensitivity and specificity were 80.6 and 96.8%, respectively. CONCLUSIONS The strategy of combining EBV DNA loads in PBMCs and plasma will potentially help identify EBV-associated diseases.
Collapse
Affiliation(s)
- Shenglei Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Qingluan Yang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Wu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Mengqi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jingwen Ai
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Haocheng Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Bin Xu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Lingyun Shao
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China; Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai 200040, China.
| | - Wenhong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China; State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai 200438, China; Key Laboratory of Medical Molecular Virology (MOE/MOH) and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai 200040, China.
| |
Collapse
|
|
10
|
Affiliation(s)
- Emmett T. Cunningham
- The Department of Ophthalmology, California Pacific Medical Center, San Francisco, California, USA
- The Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
- The Francis I. Proctor Foundation, UCSF School of Medicine, San Francisco, California, USA
| | - Manfred Zierhut
- Centre for Ophthalmology, University Tuebingen, Tuebingen, Germany
| |
Collapse
|
|
11
|
Zhao Y, Huang J, Su T, Yang Z, Zheng X, Yang L, Zhou X, Yu X, Wang H, Wang S, Liu G, Yang L. Acute Kidney Injury Relevant to Tubulointerstitial Nephritis with Late-Onset Uveitis Superimposed by Thrombotic Microangiopathy: A Case Report and Review of the Literature. KIDNEY DISEASES 2020; 6:414-421. [PMID: 33313062 DOI: 10.1159/000507668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/01/2020] [Indexed: 11/19/2022]
Abstract
Background The syndrome of tubulointerstitial nephritis and uveitis (TINU) is an uncommon and multisystemic autoimmune disorder. This review reports a rare case of TINU being superimposed on thrombotic microangiopathy (TMA) and, by comparing with the available literature, also summarizes the clinical features, associated conditions, treatment, and outcome of patients with TINU. Summary Herein, we report the case of a 37-year-old male patient with acute kidney injury (AKI) clinicopathologically identified as malignant hypertension-induced TMA superimposed by acute tubulointerstitial nephritis, which was suspected to be related to drug hypersensitivity. After treatment with oral prednisone combined with a renin-angiotensin system inhibitor, the patient achieved partial renal recovery and was withdrawn from hemodialysis. Recurrent AKI concomitant with new-onset asymptomatic uveitis was detected during routine clinical follow-up after cessation of prednisone. TINU was then diagnosed, and prednisone followed by cyclophosphamide was prescribed. The patient achieved better renal recovery than in the first round of treatment and maintained stable renal function afterward. By reviewing the literature, 36 cases were reported as TINU superimposed on other conditions, including thyroiditis, osteoarthropathy, and sarcoid-like noncaseating granulomas. Key messages TINU could be complicated by many other conditions, among which TMA is very rare. When presented as AKI, kidney biopsy is important for differential diagnosis. The case also shows that recurrent AKI with concomitant uveitis after prednisone withdrawal strongly suggested the need for long-term follow-up and elongated prednisone therapy for TINU syndrome.
Collapse
Affiliation(s)
- Youlu Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Junwen Huang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Tao Su
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Zhikai Yang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Xizi Zheng
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Liu Yang
- Department of Ophthalmology, Peking University First Hospital, Beijing, China
| | - Xujie Zhou
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Xiaojuan Yu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Hui Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Laboratory of Electron Microscopy, Pathological Centre, Peking University First Hospital, Beijing, China
| | - Suxia Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Laboratory of Electron Microscopy, Pathological Centre, Peking University First Hospital, Beijing, China
| | - Gang Liu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Li Yang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Renal Pathology Center, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| |
Collapse
|
|
12
|
Takahashi H, Takase H, Arai A, Mochizuki M, Ohno-Matsui K. Bilateral granulomatous panuveitis in two patients with T-cell type of chronic active Epstein-Barr virus infection. BMC Ophthalmol 2019; 19:83. [PMID: 30922271 PMCID: PMC6440096 DOI: 10.1186/s12886-019-1090-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 03/22/2019] [Indexed: 11/10/2022] Open
Abstract
Background To report 2 cases of bilateral granulomatous panuveitis accompanied by chronic active Epstein-Barr virus infection (CAEBV). Case presentation Case 1 was a 38-year-old man who had a history of bilateral mild panuveitis who was diagnosed with CAEBV. Fifteen months later, a severe bilateral granulomatous panuveitis developed. White infiltrates covered the optic disc and all the retinal vessels of the right eye, and white nodules were seen along the retinal veins and arteries of the left eye. Case 2 was a 34-year-old man with bilateral panuveitis showing mutton-fat keratic precipitates and diffuse vitreous opacity in both eyes. A snow ball-like vitreous opacity was present in the right eye. Systemic investigations revealed the presence of CAEBV. In both cases, a comprehensive polymerase chain reaction (PCR) analyses of the aqueous humor detected significant copy numbers of EBV-DNA. The intraocular inflammation did not respond to steroid, methotrexate, and other immunosuppressive therapies, but was ameliorated after hematopoietic stem cell transplantation with preceding chemotherapy and low-dose total body irradiation in both cases. Conclusion Granulomatous panuveitis can develop in eyes with CAEBV as a primary symptom. Ophthalmologists should rule out CAEBV when EBV-DNA is positive in the intraocular fluids of steroid-resistant panuveitis.
Collapse
Affiliation(s)
- Hiroyuki Takahashi
- Department of Ophthalmology & Visual Science Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Hiroshi Takase
- Department of Ophthalmology & Visual Science Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan.
| | - Ayako Arai
- Department of Molecular Genetics of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Manabu Mochizuki
- Department of Ophthalmology & Visual Science Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Kyoko Ohno-Matsui
- Department of Ophthalmology & Visual Science Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
| |
Collapse
|
|
13
|
Barros MHM, Vera-Lozada G, Segges P, Hassan R, Niedobitek G. Revisiting the Tissue Microenvironment of Infectious Mononucleosis: Identification of EBV Infection in T Cells and Deep Characterization of Immune Profiles. Front Immunol 2019; 10:146. [PMID: 30842768 PMCID: PMC6391352 DOI: 10.3389/fimmu.2019.00146] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 01/17/2019] [Indexed: 12/27/2022] Open
Abstract
To aid understanding of primary EBV infection, we have performed an in depth analysis of EBV-infected cells and of local immune cells in tonsils from infectious mononucleosis (IM) patients. We show that EBV is present in approximately 50% of B-cells showing heterogeneous patterns of latent viral gene expression probably reflecting different stages of infection. While the vast majority of EBV+ cells are B-cells, around 9% express T-cell antigens, with a predominance of CD8+ over CD4+ cells. PD-L1 was expressed by a median of 14% of EBV+ cells. The numbers of EBER+PD-L1+ cells were directly correlated with the numbers of EBER+CD3+ and EBER+CD8+ cells suggesting a possible role for PD-L1 in EBV infection of T-cells. The microenvironment of IM tonsils was characterized by a predominance of M1-polarized macrophages over M2-polarized cells. However, at the T-cell level, a heterogeneous picture emerged with numerous Th1/cytotoxic cells accompanied and sometimes outnumbered by Th2/regulatory T-cells. Further, we observed a direct correlation between the numbers of Th2-like cells and EBV- B-cells. Also, a prevalence of cytotoxic T-cells over Th2-like cells was associated with an increased viral load. These observations point to contribution of B- and Th2-like cells to the control of primary EBV infection. 35% of CD8+ cells were differentiated CD8+TBET+ cells, frequently detected in post-capillary venules. An inverse correlation was observed between the numbers of CD8+TBET+ cells and viral load suggesting a pivotal role for these cells in the control of primary EBV infection. Our results provide the basis for a better understanding of immune reactions in EBV-associated tumors.
Collapse
Affiliation(s)
| | - Gabriela Vera-Lozada
- Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Priscilla Segges
- Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Rocio Hassan
- Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Gerald Niedobitek
- Institute for Pathology, Unfallkrankenhaus Berlin, Berlin, Germany
- Institute for Pathology, Sana Klinikum Lichtenberg, Berlin, Germany
| |
Collapse
|
|
14
|
Kawabe A, Nakano K, Miyata H, Shibuya R, Matsuyama A, Ogoshi T, Tanaka Y. Fatal Chronic Active Epstein-Barr Virus Infection in a Rheumatoid Arthritis Patient Treated with Abatacept. Intern Med 2019; 58:585-591. [PMID: 30210119 PMCID: PMC6421150 DOI: 10.2169/internalmedicine.1280-18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Chronic active Epstein-Barr virus (CAEBV) T-cell type infection, systemic form, is characterized by persistent infectious mononucleosis-like symptoms, high Epstein-Barr virus (EBV) DNA levels in the peripheral blood, organ damage, and a poor prognosis. The association between CAEBV and rheumatoid arthritis (RA) is unclear. We report a case of fatal CAEBV T-cell type infection in an RA patient undergoing treatment with cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin fusion protein (abatacept, ABT). CAEBV can rapidly worsen in RA patients receiving ABT. Thus, we should try to establish an early diagnosis in patients with CAEBV infection.
Collapse
Affiliation(s)
- Akio Kawabe
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan
| | - Kazuhisa Nakano
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan
| | - Hiroko Miyata
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan
| | - Ryo Shibuya
- The Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Japan
| | - Atsuji Matsuyama
- The Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Japan
| | - Takaaki Ogoshi
- The Department of Respiratory Medicine, School of Medicine, University of Occupational and Environmental Health, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan
| |
Collapse
|
|
15
|
Kim WY, Montes-Mojarro IA, Fend F, Quintanilla-Martinez L. Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases. Front Pediatr 2019; 7:71. [PMID: 30931288 PMCID: PMC6428722 DOI: 10.3389/fped.2019.00071] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 02/21/2019] [Indexed: 12/14/2022] Open
Abstract
EBV-associated T and NK-cell lymphoproliferative diseases (EBV-T/NK LPDs) are characterized by the transformation and proliferation of EBV-infected T or NK cells. The 2016 revised World Health Organization classification recognizes the following EBV-positive lymphoproliferative disorders (LPD): chronic active EBV infection (CAEBV) of T- and NK-cell type (cutaneous and systemic forms), systemic EBV-positive T-cell lymphoma of childhood, aggressive NK-cell leukemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity primary EBV-positive nodal T/NK-cell lymphoma. EBV-associated hemophagocytic lymphohistiocytosis (HLH), although not included in the WHO classification because it is a reactive, inflammatory disease, is included in this review because it can be life-threatening and may have overlapping features with other EBV+ T/NK LPDs. EBV+ T/NK LPDs are rare diseases difficult to diagnose and manage properly, because some LPDs have unusual presentations, and discrepancies between clinical and histological findings might be encountered. Furthermore, EBV+ T/NK disorders share some clinico-pathological features, and may evolve into other categories during the clinical course, including malignant transformation of CAEBV. Here, we review the EBV+ T/NK LPDs in terms of their definitions, clinical features, histology, immunophenotype, molecular findings, and pathogenesis. This review aims to increase our understanding and awareness of the differential diagnosis among the different EBV+ T/NK LPDs. New insights into the genetic characteristics of these disorders will also be discussed.
Collapse
Affiliation(s)
- Wook Youn Kim
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany.,Department of Pathology, Konkuk University School of Medicine, Seoul, South Korea
| | - Ivonne A Montes-Mojarro
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany
| | - Falko Fend
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany
| |
Collapse
|
|
16
|
Extranodal NK/T-cell lymphoma of the nasal cavity developed in a patient with intestinal Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder. Pathol Res Pract 2018; 214:1051-1055. [PMID: 29843925 DOI: 10.1016/j.prp.2018.05.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 05/20/2018] [Accepted: 05/21/2018] [Indexed: 11/24/2022]
Abstract
Extranodal NK/T cell lymphoma, nasal type (ENKL) developed in a patient with intestinal Epstein-Barr virus (EBV)-positive T/NK-cell lymphoproliferative disorder (LPD). The patient was a 46-year-old Chinese man who complained of diarrhea and abdominal pain without immune-deficiency. Endoscopy demonstrated ileum ulcers like Crohn's disease, without histological granulomas. His symptoms continued waxing and waning for 3 years until he developed overt lymphoma (ENKL) in the nasal cavity. The ileum lesions exacerbated into a large deep ulcer, and the biopsy specimens from the ileum, including the one 3 years ago, showed infiltration of small lymphocytes containing many EBV-positive T/NK cells without atypia. Thus, the patient illness of intestine was revealed as intestinal EBV-positive T/NK-cell LPD, which might be closely associated with development of ENKL in this patient. In cases of inflammatory bowel disease without typical clinical courses and histological findings, check-up of EBV in the biopsy might help correct diagnosis.
Collapse
|
|
17
|
Abstract
The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored.
Collapse
|
|
18
|
Abstract
Aggressive NK cell leukemia (ANKL) is a rare malignant lymphoproliferative disorder of mature NK cells closely associated with Epstein-Barr virus (EBV) and more common in East Asia than in other areas. Significant variations exist in the morphology of ANKL tumor cells, from typical large granular lymphocyte morphology to highly atypical features with basophilic cytoplasm containing azurophilc granules. The main involved sites are hepatosplenic lesions, bone marrow and peripheral blood, and nasal or skin lesions are infrequent. A fever and liver dysfunction with an often rapidly progressive course are the main clinical symptoms, including hemophagocytic syndrome and disseminated intravascular coagulation. Although the outcome had been dismal for decades, with a median survival of less than three months, the introduction of combined chemotherapy including L-asparaginase and allogeneic hematopoietic cell transplantation has helped achieve a complete response and potential cure for some patients. With the advent of next-generation sequencing technologies, molecular alterations of ANKL have been elucidated, and dysfunctions in several signaling pathways, including the JAK/STAT pathway, have been identified. Novel target approaches to managing these abnormalities might help improve the prognosis of patients with ANKL.
Collapse
Affiliation(s)
- Fumihiro Ishida
- Department of Biomedical Laboratory Sciences, Shinshu University School of Medicine, Matsumoto, Japan
| |
Collapse
|
|
19
|
Zhang X, Liu XS, Zhao C, Lai YM, Zhang MF. Ocular manifestations as first signs of systemic T cell lymphoma in two cases. BMC Ophthalmol 2017. [PMID: 28645328 PMCID: PMC5481994 DOI: 10.1186/s12886-017-0494-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Intraocular involvement of systemic T-cell lymphomas are uncommon and have been broadly regarded as markers of poor prognosis. We reported two cases of uveitis patients finally diagnosed as systemic T cell lymphoma. CASE PRESENTATION Case one is a 19-year-old female presented with fever and liver dysfunction, and was diagnosed as EBV-associated chronic active hepatitis. Fourteen months later, she suffered from recurrent granulomatous anterior uveitis in both eyes, which failed to respond to steroid and immunosuppressant therapy. A mass on the left side of pharynx was found and the final diagnosis was pharynx T cell non-Hodgkin's lymphoma. After 13 cycles of chemotherapy, her systematic symptoms and uveitis relieved a lot, and eye condition is stable after cataract surgery. Case two is a 37-year-old male complaining bilateral blurred vision and recurrent abdominal pain. Panuveitis was diagnosed and anterior inflammation did not release after topical steroid. During the following days, the patient complained intermittent abdominal pain and fever, with rapidly progressive bilateral visual decrease. Final diagnosis was gallbladder type II enteropathy-associated T-cell lymphoma. The patient died of multiple organ failure 4 days after operation that was only 26 days after presenting to our hospital. CONCLUSIONS Ocular manifestations as first signs of systemic T cell lymphoma were rare. Diagnosis of lymphoma has to be suspected when patients have systemic manifestations including fever, fatigue, abdominal pain, EBV-associated liver disease, et al., and uveitis fails to respond to steroid therapy.
Collapse
Affiliation(s)
- Xiao Zhang
- Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xin-Shu Liu
- Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Chan Zhao
- Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Ya-Min Lai
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Mei-Fen Zhang
- Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| |
Collapse
|
|
20
|
Hu LM, Takata K, Miyata-Takata T, Asano N, Takahashi E, Furukawa K, Miyoshi H, Satou A, Kohno K, Kosugi H, Kinoshita T, Hirooka Y, Goto H, Nakamura S, Kato S. Clinicopathological analysis of 12 patients with Epstein-Barr virus-positive primary intestinal T/natural killer-cell lymphoma (EBV + ITNKL). Histopathology 2017; 70:1052-1063. [PMID: 28120384 DOI: 10.1111/his.13172] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 11/25/2016] [Accepted: 01/22/2017] [Indexed: 12/19/2022]
Abstract
AIMS Epstein-Barr virus-positive (EBV+ ) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL. METHODS AND RESULTS We enrolled 12 patients with EBV+ ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL (PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection (CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression (P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR-γ rearrangement was found in six patients (50%). Interestingly, EBV+ intra-epithelial lymphocytosis was observed in one case with a background of CAEBV. CONCLUSIONS This study is the first to shed light on the significant heterogeneity of EBV+ ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice.
Collapse
Affiliation(s)
- Lei-Ming Hu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Katsuyoshi Takata
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tomoko Miyata-Takata
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Naoko Asano
- Department of Molecular Diagnostics, Nagano Prefectural Suzaka Hospital, Suzaka, Japan
| | - Emiko Takahashi
- Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan
| | - Katsuya Furukawa
- Department of Hematology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hiroaki Miyoshi
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Akira Satou
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.,Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan
| | - Kei Kohno
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Hiroshi Kosugi
- Department of Hematology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Tomohiro Kinoshita
- Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shigeo Nakamura
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Seiichi Kato
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| |
Collapse
|
|
21
|
Shi PF, Xie YP, Xu Y, Qian SX, Chen K, Gao DQ, Huang XL. [Clinical analysis of 13 patients with EB virus-positive T-cell lymphoproliferative disorders in adults]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2017; 38:243-246. [PMID: 28395451 PMCID: PMC7348377 DOI: 10.3760/cma.j.issn.0253-2727.2017.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Indexed: 12/03/2022]
Affiliation(s)
- P F Shi
- Department of Hematology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Detection of Felis catus gammaherpesvirus 1 (FcaGHV1) in peripheral blood B- and T-lymphocytes in asymptomatic, naturally-infected domestic cats. Virology 2016; 497:211-216. [PMID: 27497183 DOI: 10.1016/j.virol.2016.07.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 07/14/2016] [Accepted: 07/19/2016] [Indexed: 11/24/2022]
Abstract
The domestic cat is natural host to both feline immunodeficiency virus and Felis catus gammaherpesvirus 1 (FcaGHV1). Comparative data suggest that these agents might act as synergistic copathogens in feline AIDS-related lymphoma. To identify leucocyte subsets harbouring gammaherpesvirus DNA, whole blood from 5 healthy, FcaGHV1-infected cats was labelled with monoclonal antibodies to feline CD21, CD4, CD8 and CD14 for 4-way fluorescence-activated cell sorting. FcaGHV1gB qPCR was performed on DNA extracted from purified fractions and whole blood longitudinally. FcaGHV1 DNA was detected in CD21+, CD4+, CD8+, but not CD14+ cells. Variation in whole blood load, up to 19,788 copies/10(6)cells, was detected in individual cats over time. FcaGHV1 DNA was undetectable in one cat on one occasion highlighting that qPCR of whole blood from a single time point will not detect all cases of FcaGHV1 infection. Further investigation of the role of FcaGHV1 in feline lymphoid malignancies is warranted.
Collapse
|
|
23
|
Jung KS, Cho SH, Kim SJ, Ko YH, Kim WS. Clinical features and treatment outcome of Epstein-Barr virus-positive nodal T-cell lymphoma. Int J Hematol 2016; 104:591-595. [PMID: 27456462 DOI: 10.1007/s12185-016-2068-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 07/14/2016] [Accepted: 07/19/2016] [Indexed: 12/12/2022]
Abstract
The classification of mature NK-/T-cell lymphoma mainly originating from the T-cell lineage with predominantly nodal involvement and Epstein-Barr virus (EBV) positivity in a majority of tumor cells is unresolved. We analyzed the clinical features and treatment outcomes of such patients. Five patients with EBV-positive nodal T-cell lymphoma were surveyed during follow-up period. The median age was 53 years (range 33-88 years), and all patients showed nodal involvement. The patients mostly presented advanced clinical features, such as stage III or IV disease, elevated lactate dehydrogenase, and hemophagocytosis. Four patients received cyclophosphamide-containing chemotherapy at the time of diagnosis. However, three patients (75 %) showed disease progression during the early cycles of initial treatment. The median overall survival was 1.5 months (95 % CI 0.0-3.4 months). Patients with EBV-positive nodal T-cell lymphoma mainly show lymph node involvement, but also show aggressive clinical features and poor treatment outcomes, such as aggressive NK-cell leukemia. Therefore, we should consider EBV-positive nodal T-cell lymphoma to be a unique disease entity distinct from peripheral T-cell lymphoma not otherwise specified.
Collapse
Affiliation(s)
- Ki Sun Jung
- Division of Hematology-Oncology, Departments of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea.,Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Su-Hee Cho
- Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Seok Jin Kim
- Division of Hematology-Oncology, Departments of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea
| | - Young Hyeh Ko
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Seog Kim
- Division of Hematology-Oncology, Departments of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea.
| |
Collapse
|
|
24
|
McKelvie PA, Climent F, Krings G, Hasserjian RP, Abramson JS, Pilch BZ, Harris NL, Ferry JA, Zukerberg LR, Sohani AR. Small-cell predominant extranodal NK/T cell lymphoma, nasal type: clinicopathological analysis of a series of cases diagnosed in a Western population. Histopathology 2016; 69:667-79. [DOI: 10.1111/his.12990] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 05/01/2016] [Indexed: 11/30/2022]
Affiliation(s)
- Penelope A McKelvie
- The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology; Harvard Medical School; Boston MA USA
- Department of Anatomical Pathology; St Vincent's Hospital; Melbourne Australia
| | - Fina Climent
- Department of Pathology; University Hospital of Bellvitge-IDIBELL; Barcelona Spain
| | - Gregor Krings
- Department of Pathology; University of California San Francisco School of Medicine; San Francisco CA USA
| | - Robert P Hasserjian
- The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology; Harvard Medical School; Boston MA USA
| | - Jeremy S Abramson
- Center for Lymphoma; Massachusetts General Hospital Cancer Center and Department of Medicine; Harvard Medical School; Boston MA USA
| | - Ben Z Pilch
- The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology; Harvard Medical School; Boston MA USA
| | - Nancy Lee Harris
- The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology; Harvard Medical School; Boston MA USA
| | - Judith A Ferry
- The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology; Harvard Medical School; Boston MA USA
| | - Lawrence R Zukerberg
- The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology; Harvard Medical School; Boston MA USA
| | - Aliyah R Sohani
- The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology; Harvard Medical School; Boston MA USA
| |
Collapse
|
|
25
|
Al-Riyami AZ, Al-Farsi K, Al-Khabori M, Al-Huneini M, Al-Hadabbi I. Unusual Indolent Course of a Chronic Active Epstein-Barr Virus-Associated Natural Killer Cell Lymphoproliferative Disorder. Sultan Qaboos Univ Med J 2016; 16:e230-3. [PMID: 27226916 DOI: 10.18295/squmj.2016.16.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 12/24/2015] [Accepted: 01/21/2016] [Indexed: 11/16/2022] Open
Abstract
Natural killer (NK) cell lymphoproliferative disorders are uncommon and the Epstein-Barr virus (EBV) plays an important aetiological role in their pathogenesis. We report a 20-year-old male with a chronic active EBV infection associated with a NK cell lymphoproliferative disorder which had an unusual indolent course. He presented to the Sultan Qaboos University Hospital in Muscat, Oman, in December 2011 with a history of intermittent fever and coughing. Examinations revealed generalised lymphadenopathy, hepatosplenomegaly, leukocytosis, transaminitis, diffuse bilateral lung infiltrates and bone marrow lymphocyte involvement. A polymerase chain reaction (PCR) test revealed a high EBV viral load in the peripheral blood cells. The patient received a course of piperacillin-tazobactam for Klebsiella pneumoniae, but no active treatment for the lymphoproliferative disorder. However, his lymphocyte count, serum lactate dehydrogenase and liver enzymes dropped spontaneously. In addition, EBV PCR copies fluctuated and then decreased significantly. He remained clinically asymptomatic over the following four years.
Collapse
Affiliation(s)
- Arwa Z Al-Riyami
- Departments of Haematology, Sultan Qaboos University Hospital, Muscat, Oman
| | - Khalil Al-Farsi
- Departments of Haematology, Sultan Qaboos University Hospital, Muscat, Oman
| | | | | | | |
Collapse
|
|
26
|
McEachron TA, Kirov I, Wungwattana M, Cortes D, Zabokrtsky KB, Sassoon A, Craig D, Carpten JD, Sender LS. Successful Treatment of Genetically Profiled Pediatric Extranodal NK/T-Cell Lymphoma Targeting Oncogenic STAT3 Mutation. Pediatr Blood Cancer 2016; 63:727-30. [PMID: 26727971 PMCID: PMC7510171 DOI: 10.1002/pbc.25854] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 11/03/2015] [Indexed: 11/06/2022]
Abstract
Extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) is a distinct type of non-Hodgkin lymphoma predominantly observed in Asian and Latin American adult males. A 12-year-old Hispanic female diagnosed with ENKTCL was enrolled in our genomic profiling research protocol. We identified specific somatic alterations consistent with diagnosis of ENKTCL as well as oncogenic mutations in MAP2K1 and STAT3. To our knowledge, this is the first report of an immunophenotypically confirmed and genetically profiled case of ENKTCL in a female pediatric patient in the United States, including its unique treatment and favorable outcome.
Collapse
Affiliation(s)
- Troy A. McEachron
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona,Hyundai Cancer Genomics Center, Children’s Hospital of Orange County, Orange, California
| | - Ivan Kirov
- Division of Oncology, Hyundai Cancer Institute, Children’s Hospital of Orange County, Orange, California
| | - Minkkwan Wungwattana
- Pediatric Hematology/Oncology Residency Program, School of Medicine, University of California-Irvine/Children’s Hospital of Orange County, Orange, California
| | - Daisy Cortes
- Pediatric Hematology/Oncology Fellowship Program, School of Medicine, University of California-Irvine/Children’s Hospital of Orange County, Orange, California
| | - Keri B. Zabokrtsky
- Hyundai Cancer Genomics Center, Children’s Hospital of Orange County, Orange, California,Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of California-Irvine, Orange, California
| | - Aaron Sassoon
- Department of Pathology, Children’s Hospital of Orange County, Orange, California
| | - David Craig
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona
| | - John D. Carpten
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona
| | - Leonard S. Sender
- Hyundai Cancer Genomics Center, Children’s Hospital of Orange County, Orange, California,Division of Oncology, Hyundai Cancer Institute, Children’s Hospital of Orange County, Orange, California,Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of California-Irvine, Orange, California,Department of Pediatrics, School of Medicine, University of California-Irvine, Orange, California,Correspondence to: Leonard S. Sender, Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of California-Irvine, 101 The City Drive South, Building 23, 4th Floor, Orange, CA 92868.
| |
Collapse
|
|
27
|
Saburi M, Ogata M, Satou T, Yoshida N, Nagamatsu K, Nashimoto Y, Moroga Y, Takano K, Kohno K, Shirao K. Successful Cord Blood Stem Cell Transplantation for an Adult Case of Chronic Active Epstein-Barr Virus Infection. Intern Med 2016; 55:3499-3504. [PMID: 27904117 PMCID: PMC5216151 DOI: 10.2169/internalmedicine.55.7432] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
A 41-year-old man was referred to our hospital for treatment of anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Chronic active Epstein-Barr virus (CAEBV) was diagnosed based on the findings of elevated EBV antibody titers and positive EBV-DNA in the peripheral blood, and cord blood stem cell transplantation (CBT) was performed. The EBV-DNA levels in the blood fell below the limit of detection. His lymphoma relapsed on Day 165 with the appearance of eruptions, which disappeared after the withdrawal of tacrolimus. One year after transplantation, there were no signs of recurrence. This encouraging result suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations.
Collapse
Affiliation(s)
- Masuho Saburi
- Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Ng SB, Ohshima K, Selvarajan V, Huang G, Choo SN, Miyoshi H, Shimizu N, Reghunathan R, Chua HC, Yeoh AEJ, Quah TC, Koh LP, Tan PL, Chng WJ. Epstein–Barr virus-associated T/natural killer-cell lymphoproliferative disorder in children and young adults has similar molecular signature to extranodal nasal natural killer/T-cell lymphoma but shows distinctive stem cell-like phenotype. Leuk Lymphoma 2015; 56:2408-15. [DOI: 10.3109/10428194.2014.983099] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
|
|
29
|
In situ hybridisation for Epstein-Barr virus as a differential diagnostic tool for T- and natural killer/T-cell lymphomas in non-immunocompromised patients. Pathology 2014; 46:581-91. [DOI: 10.1097/pat.0000000000000161] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
|
|
30
|
Rickinson AB. Co-infections, inflammation and oncogenesis: future directions for EBV research. Semin Cancer Biol 2014; 26:99-115. [PMID: 24751797 DOI: 10.1016/j.semcancer.2014.04.004] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 04/04/2014] [Indexed: 12/24/2022]
Abstract
Epstein-Barr virus (EBV) is aetiologically linked to a wide range of human tumours. Some arise as accidents of the virus' lifestyle in its natural niche, the B lymphoid system; these include B-lymphoproliferative disease of the immunocompromised, Hodgkin Lymphoma, Burkitt Lymphoma and particular forms of diffuse large B cell lymphoma. Interestingly, HIV infection increases the incidence of each of these B cell malignancies, though by different degrees and for different reasons. Other EBV-associated tumours arise through rare viral entry into unnatural target tissues; these include all cases of nasal T/NK cell lymphoma and of undifferentiated nasopharyngeal carcinoma plus a small but significant subset of gastric carcinomas, a tumour type more generally associated with chronic Helicobacter pylori infection. Understanding EBV's involvement in the pathogenesis of these different malignancies is an important long-term goal. This article focuses on two overlapping, but relatively neglected, areas of research that could contribute to that goal. The first addresses the mechanisms whereby coincident infections with other pathogens increase the risk of EBV-positive malignancies, and takes as its paradigm the actions of holoendemic malaria and HIV infections as co-factors in Burkitt lymphomagenesis. The second widens the argument to include both infectious and non-infectious sources of chronic inflammation in the pathogenesis of EBV-positive tumours such as T/NK cell lymphoma, nasopharyngeal carcinoma and gastric carcinoma.
Collapse
Affiliation(s)
- A B Rickinson
- School of Cancer Sciences, University of Birmingham, Birmingham, UK.
| |
Collapse
|
|
31
|
Fujiwara S, Kimura H, Imadome KI, Arai A, Kodama E, Morio T, Shimizu N, Wakiguchi H. Current research on chronic active Epstein-Barr virus infection in Japan. Pediatr Int 2014; 56:159-66. [PMID: 24528553 DOI: 10.1111/ped.12314] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Accepted: 01/23/2014] [Indexed: 12/15/2022]
Abstract
Epstein-Barr virus (EBV) infection is usually asymptomatic and persists lifelong. Although EBV-infected B cells have the potential for unlimited proliferation, they are effectively removed by the virus-specific cytotoxic T cells, and EBV-associated lymphoproliferative disease develops only in immunocompromised hosts. Rarely, however, individuals without apparent immunodeficiency develop chronic EBV infection with persistent infectious mononucleosis-like symptoms. These patients have high EBV-DNA load in the peripheral blood and systemic clonal expansion of EBV-infected T cells or natural killer (NK) cells. Their prognosis is poor with life-threatening complications including hemophagocytic lymphohistiocytosis, organ failure, and malignant lymphomas. The term "chronic active EBV infection" (CAEBV) is now generally used for this disease. The geographical distribution of CAEBV is markedly uneven and most cases have been reported from Japan and other East Asian countries. Here we summarize the current understanding of CAEBV and describe the recent progress of CAEBV research in Japan.
Collapse
Affiliation(s)
- Shigeyoshi Fujiwara
- Department of Infectious Diseases, National Research Institute for Child Health and Development, Tokyo, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Manso R, Rodríguez-Pinilla SM, Lombardia L, Ruiz de Garibay G, del Mar López M, Requena L, Sánchez L, Sánchez-Beato M, Piris MÁ. An A91V SNP in the perforin gene is frequently found in NK/T-cell lymphomas. PLoS One 2014; 9:e91521. [PMID: 24632576 PMCID: PMC3954696 DOI: 10.1371/journal.pone.0091521] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 02/12/2014] [Indexed: 12/24/2022] Open
Abstract
NK/T-cell lymphoma (NKTCL) is the most frequent EBV-related NK/T-cell disease. Its clinical manifestations overlap with those of familial haemophagocytic lymphohistiocytosis (FHLH). Since PERFORIN (PRF1) mutations are present in FHLH, we analysed its role in a series of 12 nasal and 12 extranasal-NKTCLs. 12.5% of the tumours and 25% of the nasal-origin cases had the well-known g.272C>T(p.Ala91Val) pathogenic SNP, which confers a poor prognosis. Two of these cases had a double-CD4/CD8-positive immunophenotype, although no correlation was found with perforin protein expression. p53 was overexpressed in 20% of the tumoral samples, 80% of which were of extranasal origin, while none showed PRF1 SNVs. These results suggest that nasal and extranasal NKTCLs have different biological backgrounds, although this requires validation.
Collapse
Affiliation(s)
- Rebeca Manso
- Pathology Department, Fundación Jiménez Díaz, Madrid, Spain
| | - Socorro María Rodríguez-Pinilla
- Pathology Department, Fundación Jiménez Díaz, Madrid, Spain
- Molecular Pathology Programme, Lymphoma Group, CNIO, Madrid, Spain
- * E-mail:
| | - Luis Lombardia
- Clinical Research Programme, Molecular Diagnostics Clinical Research Unit, CNIO, Madrid, Spain
| | - Gorka Ruiz de Garibay
- Molecular Pathology Programme, Lymphoma Group, CNIO, Madrid, Spain
- Clinical Immunology Department, Hospital Clínico de San Carlos, Madrid, Spain
| | - Maria del Mar López
- Molecular Pathology Programme, Lymphoma Group, CNIO, Madrid, Spain
- Biotechnology Programme, Monoclonal Antibodies Unit, CNIO, Madrid, Spain
| | - Luis Requena
- Dermatology Department, Fundación Jimenez Díaz, Madrid, Spain
| | - Lydia Sánchez
- Biotechnology Programme, Immunohistochemistry Unit, CNIO, Madrid, Spain
| | - Margarita Sánchez-Beato
- Molecular Pathology Programme, Lymphoma Group, CNIO, Madrid, Spain
- Oncology-Haematology Area, Instituto Investigación Sanitaria, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Miguel Ángel Piris
- Molecular Pathology Programme, Lymphoma Group, CNIO, Madrid, Spain
- Pathology Department, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, IFIMAV, Santander, Spain
| |
Collapse
|
|
33
|
|
|
34
|
Avanzi S, Alvisi G, Ripalti A. How virus persistence can initiate the tumorigenesis process. World J Virol 2013; 2:102-9. [PMID: 24175234 PMCID: PMC3785046 DOI: 10.5501/wjv.v2.i2.102] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 04/04/2013] [Accepted: 04/10/2013] [Indexed: 02/05/2023] Open
Abstract
Human oncogenic viruses are defined as necessary but not sufficient to initiate cancer. Experimental evidence suggests that the oncogenic potential of a virus is effective in cells that have already accumulated a number of genetic mutations leading to cell cycle deregulation. Current models for viral driven oncogenesis cannot explain why tumor development in carriers of tumorigenic viruses is a very rare event, occurring decades after virus infection. Considering that viruses are mutagenic agents per se and human oncogenic viruses additionally establish latent and persistent infections, we attempt here to provide a general mechanism of tumor initiation both for RNA and DNA viruses, suggesting viruses could be both necessary and sufficient in triggering human tumorigenesis initiation. Upon reviewing emerging evidence on the ability of viruses to induce DNA damage while subverting the DNA damage response and inducing epigenetic disturbance in the infected cell, we hypothesize a general, albeit inefficient hit and rest mechanism by which viruses may produce a limited reservoir of cells harboring permanent damage that would be initiated when the virus first hits the cell, before latency is established. Cells surviving virus generated damage would consequently become more sensitive to further damage mediated by the otherwise insufficient transforming activity of virus products expressed in latency, or upon episodic reactivations (viral persistence). Cells with a combination of genetic and epigenetic damage leading to a cancerous phenotype would emerge very rarely, as the probability of such an occurrence would be dependent on severity and frequency of consecutive hit and rest cycles due to viral reinfections and reactivations.
Collapse
|
|
35
|
Hong M, Ko YH, Yoo KH, Koo HH, Kim SJ, Kim WS, Park H. EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood. KOREAN JOURNAL OF PATHOLOGY 2013; 47:137-47. [PMID: 23667373 PMCID: PMC3647126 DOI: 10.4132/koreanjpathol.2013.47.2.137] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 03/19/2013] [Accepted: 03/20/2013] [Indexed: 12/01/2022]
Abstract
Background Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality. Methods Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed. Results STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis. Conclusions EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment.
Collapse
Affiliation(s)
- Mineui Hong
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | | | | | | | | | | |
Collapse
|
|
36
|
Isobe Y, Hamano Y, Ito Y, Kimura H, Tsukada N, Sugimoto K, Komatsu N. A monoclonal expansion of Epstein-Barr virus-infected natural killer cells after allogeneic peripheral blood stem cell transplantation. J Clin Virol 2012. [PMID: 23194777 DOI: 10.1016/j.jcv.2012.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Here, we describe a Japanese woman showing a monoclonal expansion of EBV-infected natural killer (NK) cells after receiving allogeneic peripheral blood stem cell transplantation (PBSCT). The patient initially had T-cell-type chronic active EBV disease (CAEBV) and subsequently developed liver T-cell lymphoma. L-Asparaginase-containing chemotherapy led to a favorable lymphoma response. To eradicate CAEBV and the lymphoma, she further received allogeneic PBSCT from a human leukocyte antigen-matched sibling donor. After the PBSCT, the patient presented with transient lymphocytosis of NK cells, which were infected with a monoclonal EBV strain other than previously detected ones. These NK cells seemed to have been transmitted from the healthy donor to the recipient. The patient and donor remain well in spite of carrying these NK cells. This is the first report of an asymptomatic Japanese carrier harboring monoclonal EBV-infected NK cells.
Collapse
Affiliation(s)
- Yasushi Isobe
- Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan.
| | | | | | | | | | | | | |
Collapse
|