B Cell Lymphomas of the GI Tract.

PURPOSE OF THE REVIEW: Primary GI lymphomas of B cell origin are a diverse group of lymphomas. In this article, we provide an overview of the diagnosis, pathologic and molecular features, and management of these varied lymphomas. RECENT FINDINGS: The most common primary GI lymphomas are diffuse large B cell lymphoma (DLBCL) and marginal zone lymphomas (MZL), but follicular lymphomas (FL), mantle cell lymphomas (MCL), post-transplant lymphoproliferative disorders (PTLD), and Burkitt lymphoma of the GI tract also occur. Many features of these lymphomas are similar to their nodal counterparts, but certain clinical and biological aspects are unique. Diagnostic and treatment strategies for these lymphomas continue to evolve over time. There are ongoing discoveries about the unique pathophysiology, molecular characteristics, and complications of primary B cell GI lymphomas that are already leading to improvements in management of this histologically diverse set of lymphomas.

[Clinicopathological features of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract: a report of five cases].

Objective: To investigate the clinicopathological features of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Methods: Five cases of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract from the Affiliated Hospital of Qingdao University from 2016 to 2019 were retrospectively reviewed. The clinical and pathological parameters were analyzed by combining clinical data and reviewing the available literature of 35 cases (34 cases abroad and 1 case in China). Results: There were 4 males and 1 female with a median age of 47 years (18-66 years). All patients had abdominal pain and constitutional symptoms including diarrhea, emaciation, intermittent mucous stool or oral and epiglottic ulcers. Endoscopic manifestations included multiple punctate congestion, erosion and ulcer at the terminal ileum and colorectum. Two cases had congestion and erosion of antrum and angle of stomach, and the lesions did not fuse and form tumors. Histologically, the lamina propria was expanded by a dense, medium to small lymphocyte infiltration, which was monomorphic, with slightly irregular nuclei without prominent nucleolus or lymphoepithelial lesions. There were admixed small amount of plasma cells and eosinophils. In 4 cases, immunohistochemistry showed the lesional cells were positive for CD3, CD8, TIA1, and negative for CD4, CD56, granzyme B and Ki-67 index was ≤10%. In situ hybridization showed that EBER was negative and clonal TCR gene rearrangement was detected. One consultation case was CD3(+), CD5(-) and Ki-67 index of 10%, although other indicators were not done. All five patients were treated with symptomatic support. In follow-up observation for 2 to 25 months, all patients were alive with the disease. Conclusions: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract is a newly classified monoclonal T-cell proliferative disease, with low incidence, clinical inertia and long-term survival. It has unique clinicopathological features but pathologically it is easily misdiagnosed as inflammatory bowel disease or T-cell lymphoma. Correct diagnosis is of great important clinical significance.

Common variable immunodeficiency syndrome with chronic diarrhoea.

Common variable immunodeficiency syndrome (CVID) is a heterogeneous disorder characterised by diminished levels of IgG, IgA and/or IgM, and recurrent bacterial infections. Sinopulmonary infections are most commonly reported followed by gastrointestinal (GI) infections. GI tract represents the largest immune organ with abundance of lymphoid cells, its involvement can manifest variably ranging from asymptomatic involvement to florid symptoms and signs. Diffuse nodular lymphoid hyperplasia (DNLH) of the GI tract is characterised by numerous small polypoid nodules of variable size in the small intestine, large intestine or both. It is commonly seen in association to immunodeficiency states such as CVID, IgA deficiency and chronic infections due to Giardia lamblia and Helicobacter pylori and cryptosporidiosis. Repetitive antigenic stimulation leads to lymphoid hyperplasia. We herein describe a case of DNLH of the intestine and another case of duodenal cytomegalovirus (CMV) infection associated with CVID.

Ixazomib: an investigational drug for the treatment of lymphoproliferative disorders.

INTRODUCTION: Ixazomib is a new, orally administered, reversible proteasome inhibitor which is under investigation for the treatment of refractory/relapsed multiple myeloma (MM), systemic light chain amyloidosis (AL) and Waldenström macroglobulinemia (WM). Areas covered: This article covers the mechanism of action, pharmacology and clinical trial results of ixazomib while under investigation for the treatment of various lymphoproliferative disorders. We examine the findings from several phase 3 clinical trials (i) the pivotal TOURMALINE-MM1 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone; (ii) the TOURMALINE-MM3 study investigating ixazomib versus placebo as a maintenance therapy in newly diagnosed MM following induction therapy and autologous stem cell transplantation; (iii) the TOURMALINE-MM2 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM; and (iv) TOURMALINE-AL1 investigating ixazomib plus dexamethasone in patients with relapsed/refractory AL amyloidosis. Finally, we explore early phase clinical studies of this agent in Waldenström macroglobulinemia. Expert opinion: A key advantage of ixazomib is that it could allow an efficacious treatment approach to MM and other lymphoproliferative disorders through a convenient oral administration route. Ixazomib could soon be used in combination treatment regimens, but more work is necessary to define the place of this agent going forward.

Epstein-Barr Virus and Astrocytoma.

Epstein-Barr virus (EBV) is an established pathogen linked to a wide range of lymphoproliferative disorders and solid tumors. Astrocytoma is one of the most frequent brain tumors in children, adolescents, and young adults. Astrocyte proliferation usually occurs after brain tissue aggression, which may be of different types, including viral infection. In particular, it has been suggested that EBV may play a role in astrocytoma pathogenesis. This article presents the summarized results of a systematic review of the literature on the relationship between EBV infection and astrocytoma pathophysiology. Although most studies detect the presence of EBV DNA in subsets of astrocytoma tumors, our conclusion is that currently, except for rare cases, there is no clear evidence that EBV plays a role in the development of astrocytoma.

Impaired Control of Epstein-Barr Virus Infection in B-Cell Expansion with NF-κB and T-Cell Anergy Disease.

B-cell expansion with NF-κB and T-cell anergy (BENTA) disease is a B-cell-specific lymphoproliferative disorder caused by germline gain-of-function mutations in CARD11. These mutations force the CARD11 scaffold into an open conformation capable of stimulating constitutive NF-κB activation in lymphocytes, without requiring antigen receptor engagement. Many BENTA patients also suffer from recurrent infections, with 7 out of 16 patients exhibiting chronic, low-grade Epstein-Barr virus (EBV) viremia. In this mini-review, we discuss EBV infection in the pathogenesis and clinical management of BENTA disease, and speculate on mechanisms that could explain inadequate control of viral infection in BENTA patients.

The utility of flow cytometry in differentiating NK/T cell lymphoma from indolent and reactive NK cell proliferations.

BACKGROUND: The WHO defines three categories of NK cell malignancies; extra nodal NK/T cell lymphoma (NKTCL), aggressive NK cell leukemia, and the provisional entity chronic lymphoproliferative disorder of NK cells (CLPD-NK). Although the flow cytometric (FC) phenotype of CLPD-NK has been described, studies on FC phenotype of NKTCL are limited. To the best of our knowledge ours is the first study to compare the phenotype of NKTCL, CLPD-NK, reactive NK lymphocytosis (RNKL), and normal NK cells using eight color (8C) FC. METHODS: Specimens analyzed using the Euroflow8C NK Lymphoproliferative Disorder (NKLPD) panel between 2011 and 2014 were identified from our database. All samples were analyzed on the FACSCantoII cytometer. NK cells were identified as CD45+, smCD3-, CD19-, CD56+ and normal T-cells served as internal controls. RESULTS: The majority of NKTCL were CD56 bright, CD16 dim, CD57-, and CD94+. CLPD-NK and RNKL were predominantly CD56+ or dim with positive expression of CD16 and CD57 and weak CD94 expression. Antigen based statistical analyses showed robust division of samples along the NKTCL/normal CD56 bright NK cell and CLPD-NK/RNKL/normal CD56 positive NK cell groups. CONCLUSIONS: It was concluded that FC can reliably distinguish NKTCL from CLPD-NK, normal NK cells of CD56+ phenotype, and RNKL. It was proposed that the typical phenotype for NKTCL is: CD56 bright, CD16 dim with positive CD2, CD7, CD94, HLADR, CD25, CD26, and absent CD57. This resembles the phenotype of the CD56 bright immunoregulatory subset of NK cells which we therefore hypothesize is the cell of origin of NKTCL. © 2017 International Clinical Cytometry Society.

Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients.

X-linked lymphoproliferative disease 1 (XLP1) is an inherited immunodeficiency, caused by mutations in SH2D1A encoding Signaling Lymphocyte Activation Molecule (SLAM)-associated protein (SAP). In XLP1, 2B4, upon engagement with CD48, has inhibitory instead of activating function. This causes a selective inability of cytotoxic effectors to kill EBV-infected cells, with dramatic clinical sequelae. Here, we investigated the NK cell education in XLP1, upon characterization of killer Ig-like receptor (KIR)/KIR-L genotype and phenotypic repertoire of self-HLA class I specific inhibitory NK receptors (self-iNKRs). We also analyzed NK-cell cytotoxicity against CD48+ or CD48- KIR-ligand matched or autologous hematopoietic cells in XLP1 patients and healthy controls. XLP1 NK cells may show a defective phenotypic repertoire with substantial proportion of cells lacking self-iNKR. These NK cells are cytotoxic and the inhibitory 2B4/CD48 pathway plays a major role to prevent killing of CD48+ EBV-transformed B cells and M1 macrophages. Importantly, self-iNKR defective NK cells kill CD48- targets, such as mature DCs. Self-iNKR- NK cells in XLP1 patients are functional even in resting conditions, suggesting a role of the inhibitory 2B4/CD48 pathway in the education process during NK-cell maturation. Killing of autologous mature DC by self-iNKR defective XLP1 NK cells may impair adaptive responses, further exacerbating the patients' immune defect.

Favorable outcome of Epstein-Barr virus-associated B-cell lymphoproliferative disorder complicated by immunoglobulin G4-related disease treated with rituximab-based therapy: a case report.

BACKGROUND: After acute infection of Epstein-Barr virus, Epstein-Barr virus-infected B cells survive but usually do not show clonal proliferation. However, Epstein-Barr virus-infected B cells occasionally acquire a proliferative capacity that provokes clonal lymphoproliferative disorders. We herein present a case with Epstein-Barr virus-infected CD30+ B cell and immunoglobulin G4+ plasmacytoid cell proliferation in the lymph nodes, suggesting a pathological and clinical interaction between Epstein-Barr virus-associated B-cell lymphoproliferative disorders and immunoglobulin G4-related disease. Immunoglobulin G4-related disease has been recognized as a benign disease with proliferation of IgG4-related disease+ plasmacytoid cells. Several studies have recently reported the coexistence of immunoglobulin G4-related disease+ plasmacytoid cells with Epstein-Barr virus-infected B cells in lymph nodes in some immunoglobulin G4-related disease cases. However, the pathogenic role of the clonal proliferation of Epstein-Barr virus-infected B cells in immunoglobulin G4-related disease, as well as the treatments for patients with both Epstein-Barr virus-infected B cells and immunoglobulin G4-related disease, have never been discussed. CASE PRESENTATION: A 50-year-old Japanese man was referred to us for persistent fatigue and lymphadenopathy. His blood examination showed elevated IgG4, and detected high levels of Epstein-Barr virus DNA. A lymph node biopsy revealed IgG4+ plasmacytoid cells and infiltration of large lymphoid cells, which were positive for CD20, CD30, Epstein-Barr virus-related late membrane protein 1, and Epstein-Barr virus-encoded RNA, and were negative for IgG4. Based on the diagnosis of both Epstein-Barr virus-associated B-cell lymphoproliferative disorder and IgG4-related disease, the patient received eight cycles of rituximab combined with cyclophosphamide and prednisolone, which resulted in the complete disappearance of lymphadenopathy. Moreover, his serum IgG4 level was significantly reduced, and plasma Epstein-Barr virus DNA became undetectable. Although prednisolone was transiently administered in each cycle of immunochemotherapy, the therapeutic effect has persisted for Epstein-Barr virus-associated B-cell lymphoproliferative disorder and IgG4-related disease as of 1 year after finishing treatment. CONCLUSIONS: In the present case, clinical presentation and pathological findings revealed that Epstein-Barr virus-associated B-cell lymphoproliferative disorder coexisted with IgG4-related disease. Although several studies have described the relationship between Epstein-Barr virus-infected B cells and IgG4-related disease, this is the first report of a patient whose plasma Epstein-Barr virus DNA level, which correlated with the disease statuses of both diseases, was monitored. Moreover, rituximab-based immunochemotherapy was highly effective for both diseases. Our findings are suggestive for establishing a novel treatment strategy for IgG4-related disorders associated with chronic Epstein-Barr virus infection.

Variable clinical phenotypes of X-linked lymphoproliferative syndrome in China: Report of five cases with three novel mutations and review of the literature.

BACKGROUND: X-linked lymphoproliferative disease (XLP) is a rare life-threatening syndrome. Rapid recognition and definitive diagnosis are critical to improve the prognosis and survival of patients with XLP. Nowadays, little is known about patients with XLP in China. METHODS: We report the characterization of five Chinese XLP patients with three novel mutations and review the literature related to this syndrome. Male patients with fulminant infectious mononucleosis (FIM), Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) or persistent EBV viraemia were enrolled in this study. The patients' clinical features were assessed by retrieval of data from medical records. Immunological function included analysis of lymphocyte subsets and the detection of immunoglobulins G, A, M and/or E were evaluated by flow cytometry and nephelometry. Direct sequencing was used to detect SH2D1A/XIAP gene mutations. RESULTS: Twenty-two male patients with FIM, EBV-associated HLH or persistent EBV viraemia were evaluated among 421 PID patients in our centre. Four patients had SH2D1A mutations, and one patient had an XIAP mutation. The onset age of the 5 patients range from 1month to 4years which was earlier than that in the western world. The diagnosis age was between 16months and 9years with a long diagnosis lag (1-97months). Two of them had positive family history. The clinical phenotypes varied in different patients among which two patients with FHLH and hypogammaglobulinaemia, one with hypogammaglobulinaemia, lymphoma and aplastic anaemia (AA) which is the first case with AA in China, one with hypogammaglobulinaemia only and the other one with FHLH. For immunological function, three exhibited reduced CD4/CD8 ratios. Arg55stop mutations as well as splice mutation in intron 1 were most frequently found and exon 2 was the hottest exon in China. Two patients died at the time of diagnosis for severe infection or hepatic coma. Three were alive and waiting for haematopoietic stem cell transplantation (HSCT). CONCLUSION: For patients with severe EBV-associated HLH, hypogammaglobulinaemia, lymphoma and aplastic anaemia, possibility of XLP should be considered and if confirmed, HSCT should be performed as soon as possible.

Post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLDs) are a group of conditions that involve uncontrolled proliferation of lymphoid cells as a consequence of extrinsic immunosuppression after organ or haematopoietic stem cell transplant. PTLDs show some similarities to classic lymphomas in the non-immunosuppressed general population. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in many early-onset cases, through multiple mechanisms. The incidence of PTLD varies with the type of transplant; a clear distinction should therefore be made between the conditions after solid organ transplant and after haematopoietic stem cell transplant. Recipient EBV seronegativity and the intensity of immunosuppression are among key risk factors. Symptoms and signs depend on the localization of the lymphoid masses. Diagnosis requires histopathology, although imaging techniques can provide additional supportive evidence. Pre-emptive intervention based on monitoring EBV levels in blood has emerged as the preferred strategy for PTLD prevention. Treatment of established disease includes reduction of immunosuppression and/or administration of rituximab (a B cell-specific antibody against CD20), chemotherapy and EBV-specific cytotoxic T cells. Despite these strategies, the mortality and morbidity remains considerable. Patient outcome is influenced by the severity of presentation, treatment-related complications and risk of allograft loss. New innovative treatment options hold promise for changing the outlook in the future.

Clinical characteristics and prognostic factors of patients with mature T-cell lymphoid malignancies: a single-institution study of 225 cases.

Mature T-cell lymphoid malignancies comprise a group of heterogeneous diseases that vary in clinicopathological features, biological behavior, treatment response, and prognosis. Bone marrow (BM) infiltration is more commonly present in mature T-cell lymphoid malignancies compared with their B-cell counterparts and hence important for differential diagnosis. In this study, clinical characteristics and prognostic factors were analyzed in 225 patients with mature T-cell lymphoid malignancies treated in a single institution. These included 29 cases of T-cell lymphoproliferative disorders (T-LPD, all with BM infiltration) and 196 cases of T-/natural-killer-cell lymphoma (T/NKCL, 56 with BM infiltration and 140 without BM infiltration). The estimated 5-year overall survival (OS) rates of T-LPD and T/NKCL were 96.6% and 37.3%, respectively. T-LPD patients were less likely to exhibit poor performance status, advanced disease stage, presence of B symptoms, or abnormal level of serum ß-2 microglobulin. With similar pathological characteristics, T/NKCL patients with BM infiltration showed significantly lower response rates and shorter OS than those without BM infiltration (P = 0.0264 and P < 0.0001, respectively). Multivariate analysis indicated that poor performance status, advanced disease stage, elevated serum lactate dehydrogenase level, and BM involvement were independent unfavorable prognostic factors. The Glasgow Prognostic Score may be more efficient than the International Prognostic Index in predicting disease outcome in T/NKCL. In conclusion, clinical characteristics may be useful in more effectively stratifying patients with mature T-cell lymphoid malignancies.

BIRC4 Mutation: An Important Rare Cause of Uveitis.

We report a 6-year-old man with chronic severe recalcitrant bilateral anterior uveitis and a remote history of hemophagocytic lymphocytic histiocytosis secondary to Epstein-Barr virus infection. The patient was treated for idiopathic uveitis after an initial extensive evaluation failed to reveal a specific diagnosis. The patient failed to achieve sustained inactive disease with multiple monotherapies including topical glucocorticoid, methotrexate, infliximab, mycophenolate mofeti, and cyclosporine. Disease control was finally attained with a combination of cyclosporine and adalimumab. After more recent testing, he was found to have a novel deletion on the BIRC4 (baclovirus inhibitor of apoptosis repeat containing protein 4) gene, the causative gene for X-linked lymphoproliferative syndrome type 2. We conclude that male patients with chronic idiopathic uveitis should be questioned about a history of hemophagocytic lymphocytic histiocytosis during their workup and screened for BIRC4 mutation if appropriate.

Recent Concise Viewpoints of Chronic Active Epstein-Barr Virus Infection.

Chronic active Epstein-Barr virus infection (CAEBV) is characterized mainly by prolonged or intermittent fever, lymphadenopathy and hepatosplenomegaly without definite underlying diseases at the diagnosis. Patients with CAEBV also may have various life-threatening conditions including hematological, neurological, pulmonary, cardiac, digestive tract, ocular and/or dermal disorders. Additionally, during the course of illness, they often develop hematological malignancies such as T cell, NK cell or B cell lymphoproliferative disorder (LPD) and/or lymphoma. No causative pathogenetic mechanisms have been sufficiently clarified, and additionally no promising efficacious treatment was demonstrated except for the hematopoietic stem cell transplantation (HSCT) in cases who develop T cell or NK cell LPD or lymphoma. This minireview outlines the recent development for the comprehensive viewpoints of CAEBV mainly regarding to virological, immunological, pathological and therapeutical progresses.

Post-transplant lymphoproliferative disorder after kidney transplantation: time to adopt monitoring of Epstein-Barr virus?

Although post-transplant lymphoproliferative disorder is a classical complication encountered after kidney transplantation, its diagnosis can still be challenging and its outcome life-threatening. Most cases are related to Epstein-Barr virus (EBV) infection and occur mainly in the first year post-transplant, favoured by the seronegative EBV status of the recipient transplanted with a kidney from a seropositive donor, and strong immunosuppression. We report the case of a young kidney-pancreas transplant recipient who developed post-transplant lymphoproliferative disorder (PTLD) early after transplantation, with a rapid fatal issue. We review the pathogenesis, clinical presentation, and management of PTLD with a focus on prevention.

Posttransplantation lymphoproliferative disease: proposed imaging classification.

Posttransplantation lymphoproliferative disease (PTLD) is the second most common tumor in adult transplant recipients. Most cases of PTLD are attributed to Epstein-Barr virus. Decreased levels of immunosurveillance against this tumor virus as a result of immunosuppressive regimens are thought to account for most cases of PTLD. Histologically, PTLD ranges from relatively benign lymphoid hyperplasia to poorly differentiated lymphoma, and tissue sampling is required to establish the subtype. The frequency of PTLD varies depending on the type of allograft and immunosuppressive regimen. PTLD has a bimodal manifestation, with most cases occurring within the first year after transplantation and a second peak occurring 4-5 years after transplantation. Patients are often asymptomatic or present with nonspecific symptoms, and a mass visible at imaging may be the first clue to the diagnosis. Imaging plays an important role in identifying the presence of disease, guiding tissue sampling, and evaluating response to treatment. The appearance of PTLD at imaging can vary. It may be nodal or extranodal. Extranodal disease may involve the gastrointestinal tract, solid organs, or central nervous system. Solid organ lesions may be solitary or multiple, infiltrate beyond the organ margins, and obstruct organ outflow. Suggestive imaging findings should prompt tissue sampling, because knowledge of the PTLD subtype is imperative for appropriate treatment. Treatment options include reducing immunosuppression, chemotherapy, radiation therapy, and surgical resection of isolated lesions.

Targeted activation of human Vγ9Vδ2-T cells controls epstein-barr virus-induced B cell lymphoproliferative disease.

Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) after transplantation remains a serious and life-threatening complication. Herein we showed that the aminobisphosphonate pamidronate-expanded human Vγ9Vδ2-T cells efficiently killed EBV-transformed autologous lymphoblastoid B cell lines (EBV-LCL) through γ/δ-TCR and NKG2D receptor triggering and Fas and TRAIL engagement. By inoculation of EBV-LCL in Rag2(-/-)γc(-/-) mice and humanized mice, we established lethal EBV-LPD with characteristics close to those of the human disease. Adoptive transfer of pamidronate-expanded Vγ9Vδ2-T cells alone effectively prevented EBV-LPD in Rag2(-/-)γc(-/-) mice and induced EBV-LPD regression in EBV(+) tumor-bearing Rag2(-/-)γc(-/-) mice. Pamidronate treatment inhibited EBV-LPD development in humanized mice through selective activation and expansion of Vγ9Vδ2-T cells. This study provides proof-of-principle for a therapeutic approach using pamidronate to control EBV-LPD through Vγ9Vδ2-T cell targeting.

PUMA protein in p53 regulatory molecule pattern determines the prognosis for patients with lymphoproliferative diseases.

The pool of apoptosis regulator proteins (p53, PUMA, p21, and MDM2) in the bone marrow, lymph node, and other tumor substrate cells were studied by immunocytochemical analysis in patients with chronic lymphoproliferative diseases. Two groups of patients were distinguished, with the disease course differing by activities of the studied molecules. Activity of p53 was the minimum in the group with benign course of the disease, and protein p21 was not detected; MDM2 protein was present in moderate amounts in the presence of high PUMA activity. High activities of p53, p21, and MDM2 and low PUMA activity were found in tumor cells of patients with malignant disease. These data can serve as a prognostic sign determining the aggressiveness of chronic lymphoproliferative disease course and for determining the strategy of chemotherapy and its correction.