T-cell Lymphoproliferative Disease Research Articles

Systemic T-Cell Lymphoproliferative Disease Associated with Epstein-Barr Virus: A Literature Review and a Case Report

Epstein-Barr virus (EBV) is ubiquitous, being identified in 90-95 % of adults. Its reactivation in immunodeficiency conditions often leads to clonal transformation of B-lymphocytes and development of B-cell lymphoproliferative diseases (LPD) and B-cell lymphomas. At the same time, in the countries of North-East and East Asia, as well as Latin America, non-immunocompromised patients sometimes demonstrate the development of EBV-associated T-cell lymphoproliferative diseases. The present paper reports a rare case of EBV-associated systemic T-LPD with lymphadenopathy, splenomegaly as well as acute autoimmune hemolytic anemia in a man of Caucasian race. Complex analysis of anamnestic, pathomorphological, and laboratory data allowed to distinguish this disease from T-cell lymphoma and choose the appropriate patient management strategy.

Comparison of Systemic EBV-positive T-Cell and NK-Cell Lymphoproliferative Diseases (LPD) of Childhood Based on Classification Evolution: New Classification, Old Problems.

Comparison of Systemic EBV-positive T-Cell and NK-Cell Lymphoproliferative Diseases (LPD) of Childhood Based on Classification Evolution: New Classification, Old Problems.

Indolent T-Cell Lymphoproliferative Disease of the GI Tract: Insights for Better Diagnosis, Prognosis, and Appropriate Therapy.

Indolent T-cell lymphoproliferative disease of the gastrointestinal tract (indolent GI T-LPD) is a benign neoplasm of CD4+ or CD8+ T cells that form primary tumors in the GI tract. Indolent GI T-LPD has recently been provisionally recognized as a distinct entity by the 2016 revision of the WHO classification of lymphoid neoplasms. Appropriate diagnosis of these cases is challenging as they may be misdiagnosed as T cell lymphoma that has an aggressive clinical course. Consequently, aggressive therapeutic approaches were usually chosen to treat these cases with no obvious benefit for most of the patients and potential side effects. Moreover, inflammatory diseases of the GI tract with similar symptoms may lead to misdiagnosis that leads to delays in administration of proper therapeutics against these cases. Therefore, it is of utmost importance to identify prognostic genetic biomarkers at the time of diagnosis for optimal medical care of these patients. TCR clonality analyses may not be useful for distinguishing these benign neoplasms from aggressive gastrointestinal T cell lymphomas; however, molecular genetic tests may prove useful as recurrent STAT3-JAK2 fusions, which may have diagnostic, prognostic or therapeutic value, have recently been identified. However, there is still lack of comprehensive information on the genetic and epigenetic factors associated with pathogenesis of indolent GI T-LPD. In this mini-review, we focus on the so far reported literature on indolent GI T-LPD cases, and discuss future directions for better differential diagnosis, risk stratification, and therapeutic target discovery with a special focus on the genetic and epigenetic alterations.

The application of CytoDiff for the differential diagnosis of reactive and tumor lymphocytosis.

CytoDiff reagent was developed to optimize the performance of a WBC differential evaluation. It determines the main population of white blood cells by the expression of linear markers. One of the additional possibilities of using CytoDiff is the differential diagnosis of reactive and tumor lymphocytosis. We studied peripheral blood samples of 76 patients of the All-Russian Central Research Center A.M. Nikiforova EMERCOM of Russia with absolute lymphocytosis of more than 3,0x109/l. The control group included 26 practically healthy people. All performed a clinical blood test on a 5Diff hematology analyzer with smear microscopy, and determination of leukocyte populations by phenotype using CytoDiff. Reference intervals were determined for subpopulations of lymphocytes using CytoDiff. An algorithm has been developed for evaluating the results obtained when determining leukocyte populations by phenotype using CytoDiff for differential diagnosis of reactive and tumor lymphoproliferation. To detect B-cell lymphoproliferative diseases, the use of a cut-off value of 13% or more of the number of leukocytes is optimal. At low values of the relative number of B-lymphocytes, it is important to take into account the results of microscopy of blood smears. If atypical mononuclear cells are absent in smears, then additional clinical and laboratory studies are necessary to establish the cause of lymphocytosis, including phenotyping of peripheral blood lymphocytes to exclude T-cell lymphoproliferative diseases. The expediency of using the CytoDiff reagent for the differential diagnosis of the reactive and tumor nature of lymphocytosis is shown. Already at the stage of primary screening studies, the use of CytoDiff makes it possible to efficiently collect blood samples from patients with possible lymphoproliferative diseases, which significantly reduces the time required for a diagnostic search.

Immunosuppression-induced clonal T-cell lymphoproliferative disease causing severe diarrhoea mimicking coeliac disease following renal transplantation: a case report

BackgroundPost-transplant lymphoproliferative disease is a recognized complication following solid organ transplantation. This is usually a B cell disease and frequently associated with Epstein Barr virus infection, although T cell PTLD can occur. T cell PTLD is usually a monomorphic, lymphomatous disease associated with an adverse prognosis.Case reportWe report a 52 year old male pre-emptive renal transplant recipient who developed severe diarrhea with weight loss following intensification of his immunosuppression due to antibody mediated rejection 3 years after transplantation. Duodenal biopsy demonstrated monoclonal CD8+ T cell duodenitis leading to increased intraepithlieal lymphocytes and sub-total villous atrophy mimicking coeliac disease. Coeliac disease was excluded by negative anti-tissue transglutaminase antibody, HLA-DQ2 and HLA-DQ8 testing. There was no evidence of lymphoma either on biopsy or CT enterography and no FDG avid disease on PET. Symptoms did not improve with reduction of immunosuppression, but resolved fully on complete withdrawal of treatment. The transplant failed and he was established on dialysis. The diagnosis was early PTLD.ConclusionsOesophagogastroduodenoscopy with small bowel biopsies is a useful investigation for determining the cause of diarrhoea in renal transplant patients when more common causes have been excluded. This is the first report that we are aware of clonal T cell PTLD mimicking coeliac disease which only resolved after complete withdrawal of immunosuppression. As treatments for lymphoma are aggressive they are only initiated in the malignant phase and management of early stage PTLD is to minimise risk of progression by reducing immunosuppression. Any plans to retransplant will have to take into consideration the possibility that PTLD will recur.

NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study

ObjectivesPrimary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like...

Successful experience of combined immunochemotherapy at refractory course of primary cutaneous peripheral T-cell lymphoma, unspecified

Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of T-cell lymphoproliferative diseases that involve mainly the skin and are characterized by features of their diagnosis, clinical course and therapeutic approach. They include mainly fungal mycosis and CD30 + lymphoproliferative skin diseases (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis) which account for >50% of CTCL and primary cutaneous peripheral T-cell lymphoma, unspecified/ /not otherwise specified (PTL NOS) which occurs extremely rare. Activation antigen CD30 is a cell membrane glycoprotein that belongs to tumor necrosis factor (TNF) superfamily. Tumor cells in primary skin CD30-positive skin lymphomas express CD30 in more than 75%; in other nosological units it also can be detected but to a lesser extent. Most patients with cutaneous CD30 + lymphoproliferative diseases have an indolent the disease course of the disease with a favorable prognosis. Refractory course occurs in approximately 30% patients, and in 8% of cases lymphoma results in deaths. Recently monoclonal antibodies have been included in clinical practice for the treatment of T-cell lymphomas, one of which is brentuximab vedotin, a CD30 monoclonal antibody conjugated to monomethyl auristatin E. This article provides the clinical case of a patient with a refractory form of PTL NOS.

Systemic Epstein–Barr Virus-Positive T/NK Lymphoproliferative Diseases With SH2D1A/XIAP Hypomorphic Gene Variants

X-linked lymphoproliferative disease (XLP) is one of the X-linked primary immunodeficiency diseases (PIDs) with defective immune response to Epstein–Barr virus (EBV) infection. Chronic active EBV infection (CAEBV) and EBV-hemophagocytic lymphohistiocytosis (HLH) are recognized as systemic EBV-positive T-cell and natural killer (NK)-cell lymphoproliferative diseases (LPDs) arising from the clonal proliferations of EBV-infected T cells and NK cells. A high incidence of CAEBV in East Asia implies the unknown genetic predisposition. In patients with XLP, EBV-infected cells are generally B cells. No mutation of SH2D1A/XIAP genes has ever been identified in patients with systemic EBV-positive T-cell and NK-cell LPD. We report herewith a male case of NK-cell type CAEBV with SH2D1A hypomorphic mutation (c.7G > T, p.Ala3Ser), two male cases of CAEBV/EBV-HLH with XIAP hypomorphic variant (c.1045_1047delGAG, p.Glu349del), and another female case of CD4+CAEBV with the same XIAP variant. The female underwent bone marrow transplantation from an HLA-matched sister with the XIAP variant and obtained a complete donor chimerism and a cure of laryngeal LPD lesion, but then suffered from donor-derived CD4+ T cell EBV-LPD. These observations demonstrated that SH2D1A and XIAP genes are critical for the complete regulation of EBV-positive T/NK cell LPD. X-linked lymphoproliferative disease (XLP) is one of the X-linked primary immunodeficiency diseases (PIDs) reported to have a defective immune response to Epstein–Barr virus (EBV) infection. Mutations in SH2D1A and XIAP genes cause XLP. Systemic EBV-positive T-cell and natural killer (NK)-cell lymphoproliferative diseases (LPDs) consist of three major types: EBV-positive hemophagocytic lymphohistiocytosis (HLH), chronic active EBV infection (CAEBV), and EBV-positive T-cell/NK-cell lymphoma. CAEBV is recognized as a poor prognostic disease of EBV-associated T-cell and NK-cell LPD arising from the clonal proliferation of EBV-infected T cells (CD4+, CD8+, and TCRγδ+) and/or NK cells. The majority of cases with CAEBV were reported from East Asia and South America. In Caucasian patients with CAEBV disease, the target of infection is exclusively B cells. These imply a genetic predisposition to EBV-positive T/NK cell LPD according to ethnicity. In reported cases with XLP, EBV-infected cells are B cells. On the other hand, no mutation of SH2D1A/XIAP genes have been determined in patients with T/NK-cell-type (Asian type) CAEBV. We here describe, for the first time, four case series of CAEBV/EBV-HLH patients who carried the hypomorphic variants of XLP-related genes. These cases included a male patient with CAEBV carrying SH2D1A hypomorphic mutation (c.7G > T, p.Ala3Ser) and two male patients with CAEBV/EBV-HLH carrying the XIAP hypomorphic variant (c.1045_1047delGAG, p.Glu349del), along with another female patient with CAEBV carrying the same XIAP variant. The female case underwent bone marrow transplantation from a healthy HLA-matched sister having the same XIAP variant. Although a complete donor chimerism was achieved with the resolution of laryngeal LPD lesions, systemic donor-derived CD4+ T-cell EBV-LPD developed during the control phase of intractable graft- vs. -host-disease. These observations demonstrated that SH2D1A and XIAP genes are critical for the complete regulation of systemic EBV-positive T/NK-cell LPD.

CNS atypical T-cell lymphoproliferative disease following treatment with alemtuzumab

Autoimmune disease is a well-recognized complication of alemtuzumab therapy in MS; however, the risk of subsequent malignancy is another important consideration in this highly efficacious therapy. Here, we report a fatal atypical T-cell hematologic disorder.

Targeting Phosphorylation of p21-activated Kinase 1 at Thr423 Induces Cell Cycle Arrest and Apoptosis in Cutaneous T-cell Lymphoma Cells.

Cutaneous T-cell lymphoma (CTCL) represents a rare group of extranodal T-cell lymphoproliferative diseases. Due to poor clinical outcome of CTCL, there is an urgent need for new and improved therapies. A small molecule, IPA-3, which inhibits p21-activated kinase 1 (PAK1), has shown therapeutic potential in various types of malignancies. In the present study, the anti-tumor effect of IPA-3 and its underlying molecular mechanism was evaluated. High expression of phosphorylated-PAK1 (pho-PAK1) was seen in CTCL lesional skin compared to benign inflammatory dermatoses. IPA-3 could significantly inhibit the proliferation of 3 CTCL lines in a dose- and time-dependent manner. The percentage of apoptotic cells was higher in the treatment group. Further, IPA-3 treatment caused increased EGR1 protein levels and decreased apoptosis-related BCL-2 and pho-BAD protein levels. In summary, inhibition of pho-PAK1 has significant anti-tumor effects in CTCL cells and it can be explored as a future therapeutic option.

Indeterminate Cell Histiocytosis and Mycosis Fungoides. A Hitherto Unreported Association

Indeterminate Cell Histiocytosis and Mycosis Fungoides. A Hitherto Unreported Association

CUTANEOUS MANIFESTATIONS OF ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA

Background: Angioimmunoblast T-cell lymphoma (AITL) is a rare T-cell lymphoproliferative disease that is accompanied by generalized lymphadenopathy, hepatosplenomegaly, intoxication symptoms and extranodal lesions. The extranodal manifestations of the disease frequently involve various skin changes. One of the first such manifestations is maculopapular rashes observed in about half of AITL patients and usually preceding the appearance of lymphadenopathy. Other forms of skin lesions accompany the disease considerably less frequently.Aim: To characterize the range of skin changes in patients suffering from AITL, to establish a correspondence between the nature of skin changes and their histological picture.Materials and methods: 54 AITL patients were being treated at the National Research Centre for Hematology from 2000 to 2017, with the male/female ratio being 30/24. The median age was 61 (29–81) years.Results: Changes in the skin were observed in 24 (44.4 %) of 54 AITL patients, out of whom 18 (75 %) and 6 (25 %) were male and female patients, respectively. Maculopapular rash was observed in 22 (91.7 %) out of 24 patients. The morphological and molecular investigations of skin biopsy specimens exhibiting maculopapular rash demonstrated nonspecific reactive changes. Patients with maculopapular rash demonstrated an increase in the level of total (polyclonal) IgE. Specific skin lesions detected in 8 (14.8 %) cases were represented by a ‘livedo reticularis’, focal skin hyperpigmentation, erythroderma, left eyelid tumour and tumour in 3, 2, 1, 1 and 1 cases, respectively.Conclusion: Maculopapular rash frequently observed in AITL patients is a reactive process not associated with a specific skin lesion. Specific skin lesions in AITL are much less common and can be represented by various forms. In some AITL cases, skin changes of the reactive and tumour nature can be simultaneously observed.

Revision of EB virus-positive T-cell and NK-cell lymphoproliferative diseases of childhood in updated WHO classification

Revision of EB virus-positive T-cell and NK-cell lymphoproliferative diseases of childhood in updated WHO classification

REACTIVE PLASMACYTOSIS AT THE ONSET OF ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA. CASE REPORT

Angioimmunoblastic T-cell lymphoma is a rare T-cell lymphoproliferative disease with generalized lymphadenopathy, hepatosplenomegaly, intoxication and polyclonal hypergammaglobulinemia. The persistence of plasma cells in peripheral blood can be a manifestation of both tumor and reactive processes. In our article, we described the case of angioimmunoblastic T-cell lymphoma with an increase in the number of peripheral blood plasma cells to 28 %, and in bone marrow to 9 %. The complex diagnostics, including plasma cells immunophenotyping, morphology of the lymph node biopsy and bone marrow samples, made it possible to verify the diagnosis of angioimmunoblastic T-cell lymphoma with polyclonal plasmacytosis.

Primary Cutaneous CD4+ Small/Medium T-cell Lymphoproliferative Disease: A Case Report

Primary cutaneous lymphoma is a heterogeneous group of diseases. Primary cutaneous CD4+ small/medium Tcell lymphoma (CD4+ SMTCL) is one of the rare subtypes; representing only 2-3% of all cutaneous lymphomas. It was recently described as lymphoproliferative disorder because of its indolent clinical behavior and many similarities with cutaneous pseudolymphoma. This disease is a provisional entity according to latest World Health Organization (WHO) classification of hematolymphoid tumors. CD4+ SMTCL has a n excellent 5-year survival of 60-85%. CD4+ SMTCL usually present with a solitary skin lesion of the head and neck region, and most of reported cases were treated with local managements only. The common clinical presentations and histological features are still not well understood, and no optimal therapy is established. We report a case of primary cutaneous CD4+ small/medium Tcell lymphoma, our patient presented with a facial skin lesion that was treated with excision only.

CD30 Is Dispensable for T-Cell Responses to Influenza Virus and Lymphocytic Choriomeningitis Virus Clone 13 but Contributes to Age-Associated T-Cell Expansion in Mice.

CD30 is a tumor necrosis factor receptor (TNFR) family member whose expression is associated with Hodgkin’s disease, anaplastic large cell lymphomas, and other T and B lymphoproliferative disorders in humans. A limited number of studies have assessed the physiological role of CD30/CD30 ligand interactions in control of infection in mice. Here, we assess the role of CD30 in T-cell immunity to acute influenza and chronic lymphocytic choriomeningitis virus (LCMV) clone 13 infection, two viral infections in which other members of the TNFR superfamily are important for T-cell responses. We show that CD30 is expressed on activated but not resting CD4 and CD8 T cells in vitro, as well as on regulatory T cells and marginally on T helper 1 cells in vivo during influenza infection. Despite this, CD4 and CD8 T-cell expansion in response to influenza virus was comparable in CD30+/+ and CD30−/− littermates, with no discernable role for the pathway in the outcome of influenza infection. Similarly, during persistent infection with LCMV clone 13, CD30 plays no obvious role in CD4 or CD8 T-cell responses, the level of T-cell exhaustion or viral control. In contrast, in the steady state, we observed increased numbers of total CD4 and CD8 T cells as well as increased numbers of regulatory T cells in unimmunized older (~8 months) CD30+/+ but not in CD30−/− age-matched littermates. Naive T-cell numbers were unchanged in the aged CD30+/+ mice compared to their CD30−/− littermate controls, rather the T-cell expansions were explained by an increase in CD4+ and CD8+ CD44mid-hiCD62L− effector memory cells, with a similar trend in the central memory T-cell compartment. In contrast, CD30 did not impact the numbers of T cells in young mice. These data suggest a role for CD30 in the homeostatic regulation of T cells during aging, contributing to memory T-cell expansions, which may have relevance for CD30 expression in human T-cell lymphoproliferative diseases.

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

EBV-Associated T-Cell Lymphoproliferative Diseases in Young Adults with Unusual Histopathological and Immunophenotypic Features

EBV-associated T-cell lymphoproliferative diseases (EBV T-cell LPDs) in non-immunocompromised hosts are a heterogenous syndrome which is challengeable for both diagnosis and treatment. Here, we report four young patients of EBV T-cell LPDs with unusual histopathological and immunophenotypic features. They presented with intermittent high fever (4/4), multiple lymphadenopathy (4/4), hepatosplenomegaly (4/4), hematochezia (2/4) and high blood EBV antibodies titer (4/4) for seven months to one year. The enteroscopic examination revealed multiple ileocecus ulcers in three of four cases. Histologically, three cases showed similar dense infiltration of polymorphic composition including variable reactive components such as plasma cells and histiocytes as well as atypical lymphocytes and one case was characterized by proliferation of monomorphic atypical lymphocytes. The infiltrating lymphocytes were medium-sized with hyperchromatic nuclei and showed mild cytologic atypia. Abundant eosinophils infiltration and formation of eosinophilic abscess were seen in all cases. Multiple foci of necrosis with granuloma were observed in lymph nodes of all cases, but hemophagocytosis was absent. The immunohistochemical staining showed that infiltrative lymphocytes were CD2 TIA1 CD56﹣, suggesting cytotoxic T-cells origin, but loss of pan-T markers CD3 (2/4), CD5 (4/4) and CD7 (2/4) were frequently observed. Negativity for both CD4 and CD8 (4/4) and silent T-cell receptor (TCR) expression (3/3) were detected. EBV positivity in numerous T-cells was identified by double staining of CD3 and EBER. Three patients died within one year and one patient is alive six months after initial presentation. These unusual pathologic findings prompt us being aware of EBV T-cell LPDs and add to the understanding of this rare disease.

Childhood systemic Epstein-Barr virus positive T-cell lymphoproliferative disease: report of one case

Childhood systemic Epstein-Barr virus positive T-cell lymphoproliferative disease: report of one case

Epigenetics in cutaneous T-cell lymphoma

Epigenetics means heritable changes in gene expressions without alterations in DNA sequence, and mainly involves DNA methylation, histone modification and non-coding RNA regulation. Cutaneous T-cell lymphoma is a class of malignant T-cell lymphoproliferative diseases originated from the skin. Mycosis fungoides and Sezary syndrome are the most common cutaneous T-cell lymphoma. Recent studies have shown that epigenetics not only plays an important role in the occurrence and development of cutaneous T-cell lymphoma, but also provides insights into the treatment of cutaneous T-cell lymphoma. Key words: Lymphoma, T-cell, cutaneous; Epigenesis, genetic; Mycosis fungoides; Sezary syndrome; DNA methylation