Helicobacter pylori CagA EPIYA Motif Variations Affect Metabolic Activity in B Cells.

BACKGROUND: Helicobacter pylori (Hp) colonizes the human stomach and can induce gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. Clinical observations suggest a role for the Hp virulence factor cytotoxin-associated gene A (CagA) in pathogenesis. The pathogenic activity of CagA is partly regulated by tyrosine phosphorylation of C-terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in host cells. However, CagA differs considerably in EPIYA motifs, whose functions have been well characterized in epithelial cells. Since CagA is fragmented in immune cells, different CagA variants may exhibit undetected functions in B cells. METHODS: B cells were infected with Hp isolates and isogenic mutants expressing different CagA EPIYA variants. CagA translocation and tyrosine phosphorylation were investigated by Western blotting. Apoptosis was analyzed by flow cytometry and metabolic activity was detected by an MTT assay. RESULTS: Isogenic CagA EPIYA variants are equally well translocated into B cells, followed by tyrosine phosphorylation and cleavage. B cell apoptosis was induced in a CagA-independent manner. However, variants containing at least one EPIYA-C motif affected metabolic activity independently of phosphorylation or multiplication of EPIYA-C motifs. CONCLUSIONS: The diverse structure of CagA regulates B cell physiology, whereas B cell survival is independent of CagA.

Retrospective Analysis of 9 Cases of Primary Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma and Literature Review.

BACKGROUND Primary pulmonary mucosa-associated lymphoma tissue lymphoma is rare and is often misdiagnosed because of its diverse and nonspecific clinical features. The aim of this study was to raise awareness among clinicians and to share our experience of treating and managing such patients. MATERIAL AND METHODS This retrospective study was conducted between 1 January 2009 and 31 October 2017 at the First Affiliated Hospital of Guangxi Medical University. All cases were confirmed via pathology and immunohistochemistry. In addition, we reviewed all relevant literature. RESULTS Altogether, 21 patients (7 female, 14 male) with a median age of 54 (range, 19-84) years were diagnosed with primary pulmonary mucosa-associated lymphoma. Expiratory dyspnea, repeated cough and expectoration, and weight loss were the most common symptoms. Pulmonary lesions were found via physical examination in 10 patients who had no obvious symptoms. Chest computed tomography showed nodules, pulmonary consolidation, bronchial bronchogram, ground-glass opacity, and mediastinal lymph node enlargement. Some patients were misdiagnosed with tuberculosis and pneumonia, while others were initially diagnosed with cancer. Tumor pathology and immunocytochemistry indicated primary pulmonary mucosa-associated lymphoma tissue lymphoma. Six patients underwent chemotherapy, 5 underwent surgery, 4 underwent surgery and chemotherapy, 3 were only observed, and 3 refused treatment. CONCLUSIONS The development of primary pulmonary mucosa-associated lymphoid tissue lymphoma is slow and insidious. Having no specific clinical symptoms and imaging findings, it is easily misdiagnosed. Final diagnosis is made via pathologic evaluation and immunohistochemistry. Surgery and chemotherapy are the primary treatment modalities and yield a good prognosis.

Mucosa-associated lymphoid tissue lymphoma of the trachea associated with idiopathic pulmonary fibrosis: A case report and literature review.

RATIONALE: Mucosa-associated lymphoid tissue (MALT) lymphoma of the trachea is a rare disease that has been shown to be associated with chronic antigenic stimulation. There have been few reports of MALT lymphoma of the trachea in association with idiopathic pulmonary fibrosis (IPF). PATIENT CONCERNS: A 73-year-old patient visited with a 2-year history of dyspnea on exertion and productive cough, which had worsened 1 month ago. DIAGNOSES: MALT lymphoma of the trachea associated with IPF. INTERVENTIONS: After taking into consideration the age, poor performance status, and comorbidities of the patient and the extent of disease, we utilized an observational approach as a treatment strategy. OUTCOMES: The patient is well without any evidence of progression for 12 months since the initial diagnosis. LESSONS: We present a case of MALT lymphoma of the trachea associated with IPF. A common predisposing factor may exist for tracheal MALT lymphoma and IPF. As there are no randomized clinical trials focusing on tracheal MALT lymphoma, individualized treatment decision is important, and in some cases, simply monitoring the patient might be the most appropriate approach.

Children and adolescents with marginal zone lymphoma have an excellent prognosis with limited chemotherapy or a watch-and-wait strategy after complete resection.

Data on management of pediatric marginal zone lymphoma (MZL) are scarce. This retrospective study assessed characteristics and outcome in 66 patients who were <18 years old. Forty-four (67%) had an extranodal MZL (EMZL), 21 (32%) a nodal MZL (NMZL), and one patient a splenic MZL. Thirty-three patients (50%) received a variable combination of adjuvant chemotherapy/immunotherapy/radiotherapy, while the remainder, including 20 of 21 with NMZL, entered an active observation period. Overall survival was excellent (98 ± 2%), although 11 patients relapsed (17%; NMZL, n = 1; EMZL, n = 10), seven after any therapy and four after complete resection only. In conclusion, outcome of NZML, in particular, seems to be excellent after (in)complete resection and observation only.

[Non-Hodgkin's lymphoma mimicking Mikulicz disease: a case report].

IgG4-related disease is a systemic disorder involving a spectrum of multiple indications, and various histopathological features are shared among different IgG4-related disease subtypes, which challenge diagnosis, although certain syndromes have organ-specific involvement. Among them, Mikulicz's disease affecting the salivary and lacrimal glands, distinguished by often elevated levels of serum IgG4, infiltration of IgG4+ plasma cells into target tissues, and diffuse swelling, mass formation, or fibrosis of affected organs. However, there are several diseases, which could manifest as salivary gland swelling, mimicking Mikulicz's disease, such as Sjogren's syndrome, mumps virus infection, obstruction of parotid duct, non-Hodgkin's lymphoma (NHL), and so on. So differential diagnosis is important and essential as to the salivary gland swelling. In this paper, we analyzed a case of a 59-year-old male with symmetric salivary gland swelling. Mikulicz's disease was misdiagnosed at the beginning without biopsy. Prednisone treatment ever seemed to be effective and antibiotics had no effect. Besides salivary involvement, the patient also manifested as testicle swelling and severe pancytopenia with the development of the disease, which rarely appeared in Mikulicz's disease. Physical examination showed skin, sclera yellow dye, swollen submandibular, sublingual and lacrimal gland and splenomegaly. As a result, biopsy of right submandibular gland was made, and mucosa-associated lymphoid tissue lymphoma was confirmed by morphology and immunohistochemistry. Bone marrow biopsy also confirmed that lymphoma cells were found in the bone marrow. Finally, the diagnosis of mucosa-associated lymphoid tissue lymphoma (Phase IVE, Group A) was made on the patient, who was transferred to the hematology department for the treatment. NHL, especially, primary extranodal lymphoma usually involves the salivary gland, and painless swelling of the salivary gland is a common manifestation, similar with Mikulicz's disease. So although salivary gland swelling is often associated with autoimmune diseases such as Sjogren's syndrome and IgG4-related disease, the awareness and suspicion of a possibility of NHL are essential for rheumatologists. Biopsy is a necessary examination to decrease or avoid misdiagnosis.

Primary pulmonary MALT lymphoma - case report and literature overview.

OBJECTIVE: Primary pulmonary lymphomas (PPL) are rarely taken into consideration in the differential diagnosis of lung lesions. The aim of this report is to characterize the symptoms, diagnosis and treatment of primary MALT lymphoma of the lung. CASE REPORT: We present the case of a 48-year-old man who was admitted to hospital with a history of coughing, fever, fatigue and non-specific lesions on his chest X-ray. RESULTS: The patient was treated for pneumonia, but showed no improvement. A computer tomography revealed atypical lesions. After an initial examination and tests, no diagnosis could be established. A thoracotomy with an open lung biopsy was performed and MALT lymphoma was finally diagnosed. The patient underwent chemotherapy and showed a significant improvement. CONCLUSIONS: Primary MALT lymphoma is a rare disease and its diagnosis is difficult. There is no non-invasive test that is specific enough, so a proper diagnosis can only be established by a histopathological examination. The disease has a slow and mild course and the response to treatment is satisfactory.

Intracranial Marginal Zone B-Cell Lymphoma Mimicking Meningioma.

BACKGROUND: Marginal zone B-cell lymphoma of the meninges is a rare pathologic subtype of central nervous system lymphoma that can mimic the radiologic appearance of meningioma. CASE DESCRIPTION: We present a unique case of a 57-year-old man who presented with neurologic symptoms of severe headache, memory loss, mental status changes, and depression. Subsequent magnetic resonance imaging of the brain demonstrated an enhancing mass tracking along the anterior falx and anterior skull base with extension into the ethmoid sinus, which was radiographically consistent with meningioma. However, pathologic examination revealed numerous sheets of plasma cells and plasmacytoid lymphocytes that were immunopositive for CD20. These combined features were indicative of marginal zone B-cell lymphoma. No evidence of systemic disease was found. CONCLUSIONS: Although rare, marginal zone B-cell lymphoma must be considered in the differential diagnosis of an extra-axial enhancing mass. We review the contemporary literature and discuss preoperative radiologic differentiation of these 2 very different histopathologies.

[Visceral leishmaniasis concurrent with splenic marginal zone B-cell lymphoma].

Splenic marginal zone B-cell lymphoma (SMZBCL) is a rare non-Hodgkin B-cell lymphoma that presents with morphologically mature lymphoid cells corresponding in their immunological characteristics to secondary follicular marginal zone lymphocytes. It is clinically characterized by splenomegaly, moderate lymphocytosis, usually focal bone marrow lesion, sometimes moderate of monoclonal immunoglobulin in the serum (generally IgM or IgG) and/or urea, and a relatively benign course. Leishmaniasis is a transmissible natural focal infectious endemic disease that has a great diversity of clinical manifestations. The authors describe Russia's first case of SMZBCL concurrent with visceral leishmaniasis in a 52-year-old female patient admitted to a hematology hospital with weakness, splenomegaly, and lymphadenopathy. The simultaneous detection of lymphoma and leishmaniasis in the same biopsy specimen is extremely rare. Visceral leishmaniasis should be borne in mind as an opportunistic infection in patients with malignancies, particularly in immunocompromised persons who live or have stayed in the endemic areas.

Asymptomatic tracheal MALT lymphoma discovered on spirometric findings presenting with elevated respiratory resistance.

BACKGROUND: Central airway obstruction (CAO) may be caused by various etiologies. However, conventional chest X-rays are rarely diagnostic for patients with CAO. CASE PRESENTATION: We here described a 64-year-old asymptomatic female with tracheal mucosa-associated lymphoid tissue lymphoma discovered on spirometric findings during a complete physical examination. The plateau of forced expiratory flow was consistent with CAO. A decreased peak expiratory flow rate was noted at least 3 years before the diagnosis, and was attributed to an insufficient effort by the patient. Impulse oscillometric measurements, which were taken during quiet breathing and were effort-independent, suggested elevated respiratory resistance. These abnormalities completely disappeared after radiation therapy. CONCLUSION: The addition of impulse oscillometry to spirometry may be useful for screening CAO in routine health examinations.

Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2-MALT1 in MALT lymphoma.

MALT1 is the only known paracaspase and is a critical mediator of B- and T-cell receptor signalling. The function of the MALT1 gene is subverted by oncogenic chimeric fusions arising from the recurrent t(11;18)(q21;q21) aberration, which is the most frequent translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. API2-MALT1-positive MALT lymphomas manifest antibiotic resistance and aggressive clinical behaviour with poor clinical outcome. However, the mechanisms underlying API2-MALT1-induced MALT lymphomagenesis are not fully understood. Here we show that API2-MALT1 induces paracaspase-mediated cleavage of the tumour suppressor protein LIMA1. LIMA1 binding by API2-MALT1 is API2 dependent and proteolytic cleavage is dependent on MALT1 paracaspase activity. Intriguingly, API2-MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo. Importantly, primary MALT lymphomas harbouring the API2-MALT1 fusion uniquely demonstrate LIMA1 cleavage fragments. Our studies reveal a novel paracaspase-mediated oncogenic gain-of-function mechanism in the pathogenesis of MALT lymphoma.

Anti-CXCL13 antibody can inhibit the formation of gastric lymphoid follicles induced by Helicobacter infection.

Helicobacter suis infects the stomachs of both animals and humans, and can induce gastric mucosa-associated lymphoid tissue (MALT) lymphomas. It is known that CXC chemokine ligand 13 (CXCL13) is highly expressed in the Helicobacter-infected mice and gastric MALT lymphoma patients, but the pathway that links the activation of CXCL13 and the formation of gastric MALT lymphomas remains unclear. In this study, we examined whether CXCL13 neutralization would interfere with the formation of gastric lymphoid follicles including B cells, CD4+T cells, dendritic cells (DCs), and follicular DCs (FDCs) in germinal centers to determine the role of CXCL13 in the formation of B-cell aggregates after H. suis infection. Moreover, the expression of genes associated with the lymphoid follicle formation was also effectively suppressed by anti-CXCL13 antibody treatment. These results suggest that the upregulation of CXCL13 has an important role in the development of gastric MALT lymphomas and highlight the potential of anti-CXCL13 antibody for protection against Helicobacter-induced gastric diseases.

[Pulmonary malt lymphoma]. / Lymphome du MALT pulmonaire.

This review will describe the current knowledge in the pathophysiology, diagnosis, prognosis and treatment of pulmonary MALT (Mucosa Associated Lymphoid Tissue) lymphoma. Pulmonary MALT lymphomas are low-grade B cell lymphoma and are the most frequent lymphomas arising from the lung. Tumour cells arise from mucosa associated lymphoid tissue. Unlike other sites, no pathogen has been associated with pulmonary location of MALT lymphoma. However addictive translocations involving the MALT1 gene are frequently evidenced Patients are frequently asymptomatic and present with a chronic alveolar opacity. Diagnosis requires histology that may be retrieved by minimally invasive procedures during bronchial endoscopy or by CT scan guided percutaneous biopsies. Prognosis is good and treatment may vary with abstention, surgery, radiotherapy, immunotherapy or chemotherapy.

MALT lymphoma of the small bowel with protein-losing enteropathy.

Mucosa-associated lymphoid tissue (MALT) lymphoma usually arises from chronic inflammation. We herein report a case of small intestinal MALT lymphoma with protein-losing enteropathy (PLE). A 73-year-old woman presented with lower leg edema and severe hypoalbuminemia. She had a medical history of pylorus-preserving pancreaticoduodenectomy with Billroth II reconstruction. Oral and anal route double-balloon enteroscopies revealed irregular nodular mucosal lesions with erosion extending from the jejunum to terminal ileum. Histopathological evaluation of the biopsied mucosa showed proliferation of small-to-medium-sized lambda light chain-restricted B cells. Plasmacytic differentiation and lymphoepithelial lesions were present, leading to the diagnosis of MALT lymphoma. Tc-99m albumin scintigraphy indicated tracer exudation in the small bowel, suggesting the presence of PLE. Combination immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen improved both MALT lymphoma and PLE, whereas rituximab monotherapy was not successful. This case is considered to be common type of MALT lymphoma at an uncommon site and is distinct from immunoproliferative small intestinal disease (IPSID). To our knowledge, this is the first case of non-IPSID-type small intestinal MALT lymphoma complicated by PLE. Gastrointestinal reconstruction may be responsible for underlying chronic inflammation via small intestinal bacterial overgrowth.

Lymphomas of the gastro-intestinal tract - pathophysiology, pathology, and differential diagnosis.

The gastrointestinal tract (GIT) is the most commonly involved site of extranodal lymphomas. The close association between chronic inflammation and specific GIT lymphomas not only provide interesting insights into the pathobiology of lymphomas but also poses unique diagnostic challenges. A clear understanding of marginal zone and mucosa associated lymphoid tissue (MALT) in health and disease is helpful to place GIT lymphomas in proper context. A wide variety of lymphomas besides MALT lymphomas occur in various parts of the GIT. The characteristic pathological, immunophenotypic, and genetic features of different GIT lymphomas categorized according to World Health Organization (WHO) classification are presented. The epidemiological, clinical, and pathological features of lymphomas occurring in each part of the GIT are summarized and the key points regarding lymphomas at each site are emphasized. A tabular summary of the important differential diagnostic considerations at each site is given and suggestions for a minimal diagnostic work up are provided.

Rare case of a primary non-dural central nervous system low grade B-cell lymphoma and literature review.

We present a case of a 70-year-old HIV negative man with a five-year history of progressive dysnomia and new onset right extremity numbness, dysarthria, and blurry vision. On magnetic resonance imaging (MRI), an infiltrative enhancing tumor was noted. Follow up brain biopsy results revealed a small lymphocytic infiltrate with scattered plasma cells in a predominantly perivascular growth pattern. Flow-cytometric findings revealed a lambda monotypic B-cell population. The morphology and the flow cytometric findings were consistent with involvement by a low grade B-cell lymphoma. Subsequent positron emission tomography (PET) studies along with bone marrow biopsy and serum protein electrophoresis showed no evidence of systemic disease. The above findings are consistent with involvement by a non-dural extranodal marginal zone B-cell lymphoma (MZBCL) primary to the central nervous system (CNS). This is the first reported case of a primary CNS MZBCL with flow cytometric analysis. A review of literature on this rare entity is also included.