T-cell Lymphoproliferative Disease Of Childhood Research Articles

Clinical epidemiology of Epstein-Barr virus-associated Lymphoproliferative Disorders (EBV-LPDs) in hospitalized children: A six-year multi-institutional study in China

BackgroundEpstein-Barr virus-associated lymphoproliferative disorders (EBV-LPDs) are a group of disorders involving lymphoid tissues or lymphocytes. The epidemiology and economic burden of hospitalized children with EBV-LPDs in China have not been well studied. This study aimed to reveal the epidemic characteristics and disease burden of EBV-LPDs among the Chinese hospitalized children, providing strategies for the prevention and management.MethodsThis study was based on the FUTang Updating medical REcords (FUTURE) database of China and collected the medical records from 27 tertiary children’s hospitals between January 2016 and December 2021 in China, counting five types of EBV-LPDs, namely EBV-positive T-cell lymphoproliferative disease, NK/T cell lymphoma, extranodal NK/T-cell lymphoma (nasal type), systemic EBV-positive T-cell lymphoproliferative disease of childhood and posttransplant lymphoproliferative disorders. We conducted a retrospective syhthesis and analysis of the epidemiological characteristics, expenses, length of stay (LOS), as well as complications among hospitalized children diagnosed with five types of EBV-LPDs and compared parameters using appropriate statistical tests.ResultsThe study described 153 children aged 0–18 years hospitalized with EBV-LPDs from 2016 to 2021 in the FUTURE database. The male-to-female ratio was 1.10:1, and more than half of the age distribution was in the 6–12 y group. Among EBV-LPDs cases, EBV+ T-LPD accounted for the largest proportion (65.36%). Complications were presented in 93 children with EBV-LPDs, mainly hemophagocytic lymphohistiocytosis (HLH). The median LOS of NKTL was 26.5 days [interquartile range (IQR) = 3–42], which was the longest among EBV-LPDs. The median hospitalization cost of PTLD was 10 785.74 United States dollars (IQR = 7 329.38–16 531.18), which was the heaviest among EBV-LPDs.ConclusionsCompared with the total number of hospitalized children in China during the same period and in the same age group, the proportion of EBV-LPD is very low. EBV-LPD can develop in all age groups, but it is more common in school-age children. Among 5 EBV-LPDs, the disease with the highest proportion is EBV+ T-LPD. The overall disease burden of EBV-LPD was heavy, especially the economic burden. HLH was one of the most common complications, which could directly affect the burden of patients because of prolonged hospitalization. These data are taken from a very large database, illustrating the epidemiological and economic burden of EBV-LPDs hospitalized children in China, which enriched the existing epidemiological and disease burden content of EBV-LPDs.

Demographic insights in systemic EBV-positive T-cell lymphoproliferative disease of childhood: A comprehensive NCDB analysis.

e19077 Background: Infection with the Epstein-Barr virus can result in lymphoproliferative disorders due to the capability of the virus to infect lymphocytic cells. Systemic EBV-positive T-cell lymphoproliferative disease (LPD) of childhood is a specific lymphoproliferative disorder caused by infection with the Ebstein-Barr virus that is characterized by T cell clonal proliferation that showcases cytotoxic T lymphocytes cells expressing a combination of the glycoproteins CD8 and CD4. The rarity of this lymphoproliferative disorder makes it a great candidate for further analysis of demographic factors impacting the disease. We will employ the National Cancer Database (NCDB) to shed light on the demographic complexities. Methods: A retrospective cohort analysis was conducted to examine all patients within the National Cancer Database (NCDB) who possessed histologically confirmed systemic EBV positive T cell LPD between 2004 and 2020. Descriptive statistical methods were applied to assess demographic factors, and a thorough regression analysis was employed to investigate patterns in the incidence of the disease. Results: The NCDB confirms a total of 91 patients from 2004-2020 having a diagnosis of systemic EBV-positive T-cell LPD of childhood. The average age of diagnosis was 28 years (IQR= 22). The majority of patients did not receive palliative care (98%). Primary treatment that patients received for this disease were chemotherapy (77%), hormone therapy (48%), immunotherapy (27%), and radiation therapy (7%). The two-year survival rate was 49% and the five-year survival rate was 46%. The mean survival time was around 5.6 years with this disease. Males and females were close to equal in numbers (52% and 48%). 69% of patients were white, 13% were black, and 82% were non-Spanish; non-Hispanic. A greater percentage of patients were privately insured (59%) compared to patients insured through Medicare or Medicaid. The primary site was bone marrow (47%) and the NCDB analytic stage group was high at Stage IV (58%). The majority had Charlson-Deyo comorbidity scores of 0 (84%). Conclusions: Following a thorough investigation of existing literature, we conclude this is the first NCDB analysis on systemic EBV-positive T-cell LPD of childhood, bridging a critical knowledge gap in the current research landscape. Socioeconomic factors have yet to be discussed revolving patients with systemic EBV-positive LPD of childhood. Our study showed a higher prevalence of the disease was found in privately insured, white patients with few comorbidities. Considering the mean age of diagnosis and prognosis of this disease, it is imperative that further research be conducted to understand the interaction between socioeconomic and demographic characteristics on the diagnosis, treatments, and survival of patients living with this cancer.

EBV associated T- and NK-cell lymphoproliferative diseases: A comprehensive overview of clinical manifestations and novel therapeutic insights.

EBV is a ubiquitous virus that infects nearly all people around the world. Most infected people are asymptomatic and do not show serious sequelae, while others may develop Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations characterised by EBV-infected T or NK cells. These disorders are more common in Asian and Latin American people, suggesting genetic predisposition as a contributing factor. The revised WHO classification classifies the lymphoproliferative diseases as: extranodal NK/T-cell lymphoma nasal type (ENKTL), aggressive NK-cell leukemia (ANKL), primary EBV-positive nodal T or NK cell lymphoma (NNKTL), systemic EBV-positive T-cell lymphoproliferative disease of childhood (STCLC), systemic chronic active EBV infection (sys CAEBV), hydroa-vacciniforme (HV) andsevere mosquito bite allergy (SMBA). Recent advances in the molecular pathogenesis of these diseases have led to the development of new therapeutic strategies. Due to the infrequency of the diseases and broad clinicopathological overlap, the diagnosis and classification are challenging for both clinicians and pathologists. In this article, we aim to review the recent pathological findings which can be helpful for designing new drugs, clinical presentations and differential diagnoses, and suggested therapeutic interventions to provide a better understanding of these rare disorders.

Clinicopathological analysis of systemic EB virus-positive T-cell lymphoproliferative disease in childhood

Objective To investigate the clinicopathological and immunophenotypic features of systemic EB virus (EBV)-positive T-cell lymphoproliferative disease of childhood (CSEBV+T-LPD). Methods The clinicopathological features of 11 patients with CSEBV+ T-LPD were reviewed by using immunohistochemistry, fluorescence in situ hybridization, gene rearrangement method. The follow-up data were collected. Results Of the 11 patients, 5 cases were male and 6 cases were female. The median age was 13 years old (3-19 years old) and the disease course was 6 months (3-25 months). 2 male and 2 female patients were diagnosed with lymphoma. The median age was 15 years old, and the median disease course was 4.5 months. The major symptoms included continued fever (10/11), lymphadenectasis (10/11), splenomegaly (7/11), hepatomegaly (4/11). Histopathology: 4 cases of lymphoma showed lymphocyte flaky or diffuse hyperplasia, and cell volume was too large, isolated hyperplasia cells; 7 cases of benign lesions were mixed cells, and proliferation of lymphocytes were scattered with moderate big or much bigger volume.Immunophenotyping: all biopsies exhibited prominent T cell proliferation, as defined by immunohistochemical staining of CD3e. 2 cases of CD8 single positive in 4 lymphoma patients, 1 case of CD8 single positive in 7 cases of benign lesions. T-cell antigen loss was detected in all the patients, while only 1 loss case was found in patients with benign lesions. All cases were positive for EBV-EBER. T-cell receptor (TCR) gene detection: 3 lymphoma patients with TCR gene cloning rearrangement, 1 case of benign lesions with cloned rearrangement. Pathology classification: 4 cases of lymphoma were A3, 1 case of benign lesions was A2, 6 cases of benign lesions were A1. Conclusions CSEBV+T-LPD comprises a wide spectrum of diseases. The diagnosis should combine with clinical features, pathological morphology, immune phenotype, EBV-EBER in situ hybridization and TCR gene detection. Furthermore, elderly patients, with single hyperplasia of cells, diffuse or flake, CD8 single positive, T cell antigen loss especially CD5, high expression of EBV-EBER, TCR clonal rearrangement, A3 pathological grading, may play a key role in differentiating benign and malignant lesions. Key words: Epstein-Barr virus; T-cell lymphoproliferative disorders; Lymphoma, T-cell; In situ hybridization; T-cell receptor gene rearrangements

Prognostic implication of morphology, cyclinE2 and proliferation in EBV-associated T/NK lymphoproliferative disease in non-immunocompromised hosts.

BackgroundEBV-associated T/NK-cell lymphoproliferative diseases (TNKLPD) is a rare spectrum of disease that occurs more commonly in Asia, and Central and South America. It commonly affects children and young adults and is an aggressive disease that is poorly understood with no known biologic markers that can predict prognosis. The systemic form of TNKLPD includes chronic active EBV infection of T/NK type, aggressive NK cell leukemia and systemic EBV + T-cell lymphoproliferative disease of childhood.MethodsIn this study, we analyse the clinicopathologic and genetic features of 22 cases of systemic TNKLPD in non-immunocompromised patients, including chronic active EBV infection of T/NK cell type and systemic EBV + T-cell lymphoproliferative disease of childhood. We also performed gene expression profiling in a subset of cases to identify markers that may be of prognostic relevance and validated our results using immunohistochemistry.ResultsThe median age is 14.9 years and two of our 22 cases occurring in patients older than 30 years. Fifteen of 17 cases (88%) with adequate data were of T-cell origin. Eleven of 22 cases revealed polymorphic cellular infiltrate (P-group) while the rest showed monomorphic lymphoid infiltrate (M-group). We found a significant difference in survival between P-group vs M-group patients with median survival not yet reached in P-group, and 1 month in M-group (p = 0.0001), suggesting a role for morphology in predicting patient outcome. We also performed gene expression profiling in a subset of patients and compared the genes differentially expressed between P-group and M-group cases to identify markers of prognostic value. We identified cyclin E2 gene and protein to be differentially expressed between patients with good outcome (P-group, median expression 8%) and poor outcome (M-group, median expression 42%) (p = 0.0005). In addition, the upregulation of cyclin E2 protein in M-group cases correlated with a higher Ki67 proliferation rate (Pearson correlation r = 0.73, p = 0.0006) detected by immunohistochemistry. High cyclin E2 expression was also significantly associated with shorter survival (p = 0.0002).ConclusionOur data suggests the potential role of monomorphic morphology, high cyclin E2 and Ki67 expression as adverse prognostic factors for TNKLPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0165-x) contains supplementary material, which is available to authorized users.

Lymphoprolifération systémique T liée à l’EBV chez l’enfant

Systemic EBV+ T-cell lymphoproliferative disease of childhood is a recent entity described in the 2008 World Health Organisation tumours of haematopoietic system and lymphoid tissues as a clonal T-cell EBV+ systemic proliferation. It occurs after acute or chronic active EBV infection. We report the case of a caucasian, immunocompetent 12-year-old girl, with no particular history, who presented with hemophagocytic lymphohistiocytosis in the aftermath of an infectious mononucleosis. Main symptoms were multiple organ failure, hepatosplenomegaly and pancytopenia. Histopathology of peripheral lymph node and bone marrow revealed a T-cell, CD8+, EBV+ lymphoproliferation. An elevated viral load was detected in blood by PCR. The patient died within 3 weeks. Since most of the cases have been reported in Asia and South America, few cases still have been described in Europe. Unlike B-cell lymphoproliferation in immunocompromised individuals, T-cell EBV+ lymphoproliferation occurs in immunocompetent patients and seems to be the consequence of a proliferative disorder of EBV-infected T-cells, attributed to a cytotoxic T-cell response deficiency. These T-cell proliferations are more frequently immunoreactive for CD8 than CD4. A key feature of the diagnosis might be EBV viral load.

TEN‐like eruption in setting of EBV positive T‐cell lymphoproliferative disease with HLH, in a child

Haemophagocytic lymphohistiocytosis complicating Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood is a rare and life-threatening entity. We report a child with this condition presenting with a toxic epidermal necrolysis-like eruption.

STAT3 Gene Mutations and the Association with Pure Red Cell Aplasia in Large Granular Lymphocyte Leukemia.

AbstractAbstract 2668Large granular lymphocyte leukemia (LGL-L) is a proliferative disorder of cytotoxic T cells or NK cells frequently complicated with cytopenia and autoimmune phenomena. In the current WHO classification, T-cell large granular lymphocyte leukemia (T LGL-L), and chronic lymphoproliferative disorders of NK cells (CLPD-NK) are included in this category. Aggressive NK cell leukemia (ANKL) and Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood (EBV-T LPD) are also categorized as entities in the classification based on the clinical characteristics and EBV-positivity, and their morphologies closely resemble LGL. There has been controversy concerning the nature of these diseases, whether they are reactive processes or neoplasms. Recently, recurrent somatic mutations in the src homology (SH) 2 domain of the signal transducer and activator of transcription 3 (STAT3) gene have been found in T LGL-L and CLPD-NK, leading to constitutive activation of STAT3 and dysregulation of genes downstream of STAT3. Since LGL-L consists of various disorders and is suggested to differ based on racial backgrounds, these findings prompted us to investigate mutations in STAT3 in a Japanese cohort of LGL-L.The study included a total of 36 patients (pts) with LGL. Genes of exons 19 to 24 in STAT3 were amplified by PCR and sequenced directly using genomic DNA isolated from peripheral blood mononuclear cells. Since Y604F and D661Y mutations in STAT3 gene were representative and frequently recognized, allele specific PCR (AS-PCR) assays for these mutations were also performed.Pts consisted of 18 with T LGL-L (14 with αβ T cell receptor (TCR) type and 4 with γΔ TCR type), 11 with CLPD-NK, 5 with ANKL, and 2 with EBV-T LPD; one pt with αβ TCR type and 1 with γΔ TCR type, as well as 1 with reactive NK lymphocytosis used as control.By direct sequencing, two mutations, Y640F and D661Y, were identified. Y640F was recognized in 1 pt with αβ T LGL-L and D661Y in 3 pts with CLPD-NK. By AS-PCR, 10 additional pts were found to be positive for mutations of either Y604F or D661Y. A pt with T LGL-L was positive for both mutations by AS-PCR, although no mutations were detected by direct sequencing. A pt with CLPD-NK was positive for Y640F by AS-PCR in addition to D661Y recognized by direct sequencing. All 4 pts positive for the mutations by direct sequencing were confirmed to be positive by AS-PCR. In total, 7 pts with αβ TCR type T LGL-L and three T LGL-L pts with γΔ TCR type were positive for mutations. All these mutations were heterozygous. Mutations in SH2 domains of the STAT3 gene were not found in ANKL or EBV T-LPD pts by either direct sequencing or AS-PCR. Samples from fifty healthy controls were examined by AS-PCR and all were negative for Y604F or D661Y mutations. Reactive NKL lymphocytosis and three cell lines, Jurkat, NKL and NK92, were also negative for the mutations. The frequencies of STAT3 mutations in T LGL-L and CLPD-NK were 55.6% and 27.3%, respectively (P = 0.25). Among the pts with T LGL-L and CLPD-NK, the frequency of pure red cell aplasia (PRCA) was significantly higher in pts with the mutations (8/13) than in those without the mutations (3/16) (P = 0.03). In three T LGL-L pts positive for the mutations examined on subsequent occasions, the mutation became undetectable after cyclosporine A treatment in one pt, and was persistently found at stable amounts in two other pts by quantitative PCR.Our results indicate that mutations in the SH2 domain of the STAT3 gene frequently occur in T LGL-L and CLPD-NK in a Japanese cohort and these mutations are closely associated with PRCA and treatment requirements. STAT3 mutation thus likely contributes to the pathogenesis of T LGL-L and CLPD-NK, while EBV-associated LGL diseases, such as ANKL or EBV T-LPD, might be driven by mechanisms other than STAT3-associated pathways. Disclosures:No relevant conflicts of interest to declare.

Systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood: Report of a case with review of the literature

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (LPD) of childhood is an extremely rare and distinct clinicopathological entity. The majority of these cases occur with an apparent primary EBV infection. In this study, we describe a case of systemic EBV-positive T-cell LPD of childhood in a 23-year-old female with primary EBV infection, and review the clinicopathological features of this disease. A 23-year-old previously healthy female without an immunocompromized status presented with an acute onset of high fever. Laboratory examinations revealed a markedly elevated white blood cell count and liver and renal function. Peripheral blood smears identified a number of atypical lymphocytes with small azurophilic granules in the cytoplasm. Bone marrow aspiration revealed marked proliferation of small-sized lymphocytes with convoluted nuclei, which expressed EBER1, CD3, CD8 and cytotoxic granules. Monoclonal rearrangements of T-cell receptors were also detected. The patient underwent chemotherapy, but succumbed to multiorgan failure 20 weeks after administration. Upon review of 17 cases of this disease, including the one in the present study, we identified that the major clinicopathological features of systemic EBV-positive T-cell LPD of childhood are as follows: i) clonal systemic proliferation of EBV-infected T-cells that appear morphologically innocuous with an activated cytotoxic phenotype; ii) a high prevalence in the Asian population, commonly affecting children and young adults; iii) a predilection for males; iv) most commonly involved sites are the liver, spleen, lymph node and bone marrow, and the main clinical presentations are hepatosplenomegaly, fever and pancytopenia; v) almost all cases have an aggressive clinical course, which results in mortality. Cytological atypia of the neoplastic cells in this disease, as observed in the present case, is minimal. This study revealed that the cytomorphological features of atypical lymphocytes in the peripheral blood are indistinguishable from those of infectious mononucleosis.

Systemic Epstein-Barr Virus–Positive T-Cell Lymphoproliferative Disease of Childhood

Systemic Epstein-Barr Virus–Positive T-Cell Lymphoproliferative Disease of Childhood

Epstein-Barr virus-positive systemic NK/T-cell lymphomas in children: report of six cases

The World Health Organization lymphoma classification recognizes two different Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders of childhood: systemic EBV-positive T-cell lymphoproliferative disease of childhood, and hydroa vacciniforme-like lymphoma, which is more prevalent in Asia and Latin America. The aim of this study was to characterize six cases of paediatric EBV-positive peripheral T-cell lymphoma with distinct features. All cases were male, with a median patient age of 9 years (range: 5-17 years). Most of them presented suddenly with fever, weight loss, hepatosplenomegaly, peripheral lymphadenopathy, and high lactate dehydrogenase (LDH) levels. Moreover, gut, lung or soft tissues of the abdominal wall were also affected in four cases. Partial to total replacement of the lymph node by pleomorphic infiltration of atypical neoplastic cells was found in all cases. Vasculitis and geographical areas of necrosis were seen in three and four cases, respectively. Neoplastic cells showed expression of EBV-encoded RNA, T-cell markers (CD2 and CD3), and cytotoxic markers (TIA1, granzyme-B, and perforin). CD56 and T-cell receptor -γ were expressed in one case each. TCR-BF1, CD4, CD8 and anaplastic lymphoma kinase were negative. In all cases, the disease progressed rapidly, causing death of the patient, with a median survival of 7.1 months (range: 1-13 months). These cases probably represent a solid form of systemic EBV-positive T-cell lymphoproliferative disease of childhood, which requires identification and the development of appropriate therapy.

Clinicopathologic features of systemic EBV-positive T-cell lymphoproliferative disease of childhood

To study the clinicopathologic features, diagnosis and differential diagnosis of systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood (CSEBV(+)T-LPD). Thirty cases of CSEBV(+)T-LPD were retrospectively studied by light microscopy, immunohistochemistry and in-situ hybridization for EBV-encoded RNA (EBER). The clinical information and follow-up data were analyzed. Nineteen of the 30 patients were males and 11 females. The median age of disease onset was 9 years (range = 1.5 to 32 years). The average duration between disease onset and diagnosis was 14 months. The major clinical manifestations were fever (96.7%), lymphadenopathy (83.3%) and hepatosplenomegaly (66.7%). Cutaneous manifestations were not uncommon, which included hypersensitivity to mosquito bite (13.3%) and skin rash (20.0%). Six of the 20 patients died on follow up. Histologically, the lymph nodes showed expansion of T zone, with diminished or effaced lymphoid follicles. The lymphoid cells were of small to medium size. Scattered large lymphoid cells were also identified in the expanded T zone. Furthermore, the liver and spleen showed mild to marked sinusoidal infiltration. In some cases, various degrees of sinus histiocytosis with erythrophagocytosis were present. Skin biopsies showed mild to marked degree of lymphocytes infiltration in dermis. Immunohistochemical study and in-situ hybridization showed that the EBER-positive cells were of T lineage and CD3 positive. They also expressed cytotoxic molecules granzyme B and TIA-1. Seven of the 8 cases examined were CD8 positive, while the remaining case was mainly CD4 positive. Thirteen of 15 cases were shown to be CD56 negative. The number of EBER-positive cells ranged from 5 to more than 500 per high-power field. These cells included small to large lymphoid cells located mostly in the expanded T zone and sometimes in the germinal centers. Nine of the 30 cases, which consisted mainly of medium to large-sized lymphoid cells, were also EBER positive. Systemic EBV-positive T-cell lymphoproliferative disease of childhood occurs most often in children and young adults, with a median age of 9 years. It has a subacute or chronic clinical course. Most of the patients have evidence of systemic disease, often with lymph node, liver, spleen and skin involvement. It carries a poor clinical outcome and can be life-threatening. The disease is characterized by a clonal proliferation of EBV-infected T cells with cytotoxic immunophenotype. Definitive diagnosis requires correlation between clinical, pathologic and ancillary investigation findings.