Nodal Marginal Zone Research Articles

Chemolysis of a Uric Acid Stone in a Horseshoe Kidney

Chemolysis of kidney stone is not unheard of. However, to our knowledge, there is no previous report of chemolysis of a kidney stone in a horseshoe kidney. We report the first ever case of chemolysis of a stone in a horseshoe kidney. As part of his visible haematuria workup 4 years ago, a 66-year-old gentleman with a history of gout was found to have a horseshoe kidney. In early 2017, he was seen in the urology clinic with some non-specific abdominal pain without a recent history of visible haematuria, lower urinary tract symptoms, and urinary tract infections. His CT KUB (computed tomography of kidneys, ureters and bladder), revealed a 1.3cm stone in his horseshoe kidney [Figure 1 and 2]. At the same time, his CT KUB has also picked up some retroperitoneal lymphadenopathy in the abdomen and pelvis which were suspicious of lymphoma. His serum uric acid level was noted to be normal. Subsequently, he underwent a laparoscopic right iliac lymph node biopsy which confirmed nodal marginal zone non-Hodgkin's B-cell lymphoma. He was reviewed by the haematology team and they decided to adopt a watch and wait approach to his disease with quarterly CT CAP (computed tomography of chest, abdomen and pelvis) scans. During this period of time, he had several gout attacks and he was started on allopurinol i.e. 100mg once a day. He also considerably increased his daily fluid intake. 6 months after his initial CT KUB, he was found to be completely stone free on his CT scan [Figure 3 and 4].

High-throughput sequencing of nodal marginal zone lymphomas identifies recurrent BRAF mutations

Nodal marginal zone lymphoma (NMZL) is a rare small B-cell lymphoma lacking disease-defining phenotype and precise diagnostic markers. To better understand the mutational landscape of NMZL, particularly in comparison to other nodal small B-cell lymphomas, we performed whole-exome sequencing, targeted high-throughput sequencing, and array-comparative genomic hybridization on a retrospective series. Our study identified for the first time recurrent, diagnostically useful, and potentially therapeutically relevant BRAF mutations in NMZL. Sets of somatic mutations that could help to discriminate NMZL from other closely related small B-cell lymphomas were uncovered and tested on unclassifiable small B-cell lymphoma cases, in which clinical, morphological, and phenotypical features were equivocal. Application of targeted gene panel sequencing gave at many occasions valuable clues for more specific classification.

Clinical and laboratory characteristics of 11 cases of chronic B lymphocyte proliferation disease without lymphoid proliferation

Objective To explore the clinical and laboratory characteristics of chronic B lymphocyte proliferation disease (B-CLPD) without typical lymphoid proliferation. Methods The clinical records of patients with B-CLPD only characterized by pancytopenia form January 2007 to March 2016 in hematology department of Xinjiang Uygur Autonomous Region People's Hospital were collected, and the cell morphology, bone marrow pathology, cytogenetics and molecular characteristics were retrospectively analyzed. Results The median age of 11 patients was 68 years old. The lymphocyte ratio of peripheral blood smears in all patients increased in different level (0.36-0.68), but absolute lymphocyte count was normal or decreased (0.59×109-1.99×109). Lymphocyte-like plasma cell or small numbers of plasma cell can be seen in the bone marrow smears of 4 cases and lymphocytes with irregular burr-like protrusions were observed in 2 cases while there were no characteristic morphological changes in remained 5 cases. Immunophenotypical analysis showed that all patients expressed CD19, CD20, CD22, SmIg, not expressed CD5, CD10 which with scores of 0-2 according to chronic lymphocytic leukemia (CLL) points system; CD103, CD11C, CD25 and FMC7 were highly expressed in 2 cases while there were no characteristic expression in remaining cases. There were no abnormal karyotypes observed from the conventional cytogenetic and fluorescence in situ hybridization (FISH) analysis (both of IgH/CCND1, bcl-2/IgH were negative) in all patients. 8 patients were found IgH gene rearrangement, MYD88L256P and BRAF V600E was positive in 5 cases and 2 cases respectively. 5 cases were diagnosed as Waldenstrom macroglobulinemia, 3 cases were B-CLPD, 2 cases were hairy cell leukemia, 1 case was nodal marginal zone B-cell lymphoma after comprehensive analysis of their clinical and laboratory data. Conclusion Even if there are no increased peripheral blood lymphocytes in pancytopenia patients, it is necessary to perform bone marrow smears, immunophenotyping, IgH gene rearrangement, cytogenetics and other molecular laboratory tests to exclude B-CLPD, and reduce misdiagnosis. Key words: Chronic B lymphocyte proliferation disease; Diagnosis; Cell morphology; Immunologic techniques; Cytogenetics; Molecular biology

Improved biological insight and influence on management in indolent lymphoma. Talk 3: update on nodal and splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are rare indolent chronic B-cell lymphomas. Prognosis is typically good with median survival around 10-15 years. Management is generally based on the presence of symptoms or high tumor burden. There are no standard treatments for these 2 entities, and therapeutic strategies are rapidly evolving. Clinical developments for these 2 entities are oriented by genomic studies, with largely overlapping mutational profiles involving the NOTCH, B-cell receptor (BcR) and nuclear factor κB (NF-κB) signaling, chromatin remodeling, and the cytoskeleton. Although new therapeutic options based on targeting signaling pathways and overcoming resistance are increasingly available, few specific prospective studies are performed for these rare subtypes, limiting the conclusions that can be drawn. Novel drugs targeting B-cell signaling have shown promise, including ibrutinib and copanlisib. The second-generation oral immunomodalator (IMiD) lenalidomide showed impressive results when combined with rituximab. Other potential solutions include targeting the NF-κB, JAK/STAT, BCL2, NOTCH, and Toll-like receptor signaling pathways; however, studies in these 2 MZL entities are yet to prove a definitive benefit. Molecular profiling is now a cornerstone of diagnostic, prognostic, and therapeutic strategies to offer patient- and disease-specific solutions. The development of a wider range of effective targeted therapies and prognostic biomarkers is keenly awaited and is expected to strongly affect the natural history of SMZL and NMZL.

Canine nodal marginal zone lymphoma: Descriptive insight into the biological behaviour.

Canine nodal marginal zone lymphoma (nMZL) is classified as an indolent lymphoma. Such lymphomas are typified by low mitotic rate and slow clinical progression. While the clinical behaviour of canine splenic MZL has been described, characterized by an indolent course and a good prognosis following splenectomy, there are no studies specifically describing nMZL. The aim of this study was to describe the clinical features of and outcome for canine nMZL. Dogs with histologically confirmed nMZL undergoing a complete staging work-up (including blood analysis, flow cytometry [FC] on lymph node [LN], peripheral blood and bone marrow, imaging, histology and immunohistochemistry on a surgically removed peripheral LN) were retrospectively enrolled. Treatment consisted of chemotherapy or chemo-immunotherapy. Endpoints were response rate (RR), time to progression (TTP) and lymphoma-specific survival (LSS). A total of 35 cases were enrolled. At diagnosis, all dogs showed generalized lymphadenopathy. One-third was systemically unwell. All dogs had stage V disease; one-third also had extranodal involvement. The LN population was mainly composed of medium-sized CD21+ cells with scant resident normal lymphocytes. Histology revealed diffuse LN involvement, referring to "late-stage" MZL. Median TTP and LSS were 149 and 259 days, respectively. Increased LDH activity and substage b were significantly associated with a shorter LSS. Dogs with nMZL may show generalized lymphadenopathy and an advanced disease stage. Overall, the outcome is poor, despite the "indolent" designation. The best treatment option still needs to be defined.

A Case of Mucosa-Associated Lymphoid Tissue Lymphoma in Nasopharynx and Thyroid Gland

Mucosa associated lymphoid tissue (MALT) lymphoma refers to a type of marginal zone lymphomas, which represent a group of non-Hodgkin lymphomas originated from B lymphocytes of marginal zone. They are classified as extranodal MALT type (MALT lymphoma), splenic marginal zone B-cell lymphoma and nodal marginal zone B-cell lymphoma according to clinical and therapeutic implications of the tumor. MALT lymphoma is the most common type of marginal zone lymphoma, and about 5-8% of all B-cell lymphomas are diagnosed as MALT lymphoma. MALT lymphomas are usually found in the gastrointestinal tract, mostly in the stomach associated with H pylori infection; the non-gastric MALT lymphoma can also be found in the salivary gland, lung, head and neck, ocular adnexa, skin, thyroid, or breast. However, the involvement of nasal cavity and nasopharynx is rare. Based on our recent experience and a review of related literature, we report a case of MALT lymphoma that occurred in the nasopharynx and thyroid gland, which were treated with localized radiotherapy. Key words: Mucosa-associated lymphoid tissue lymphoma ㆍ Nasopharynx ㆍ Thyroid gland

Results of Upfront Therapy for Marginal Zone Lymphoma.

Marginal zone lymphomas (MZLs) are indolent disorders composed of 3 subtypes: extranodal marginal zone lymphoma (MALT), splenic marginal zone lymphoma (SMZL), and nodal marginal zone lymphoma (NMZL). Early-stage MALT is treated with radiotherapy or antibiotics, and advanced MALT and NMZL are managed with either watch and wait or chemotherapy. SMZLs are treated with splenectomy or rituximab. However, because these approaches have failed to cure patients with SMZL and NMZL, we have systematically used upfront chemotherapy for them, as well as for advanced MALT. We report the outcomes of this approach. A total of 44 patients with MZL were identified from our database and divided into 2 groups. Group 1 (22 with early-stage MALT) patients received either radiotherapy (n = 17) or antibiotics with or without surgery (n = 5). Group 2 included 9 patients with advanced MALT, 9 with SMZL, and 4 with NMZL. Group 2 was treated with FND-R (fludarabine 25 mg/m2 on days 1 to 3, mitoxantrone 10 mg/m2 on day 1, dexamethasone 20 mg on days 1 to 5, and rituximab 375 mg/m2 on day 1; n = 14) or CHOP-R (cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 2 mg intravenous push on day 1, prednisone 100 mg/m2 orally on days 1 to 5, rituximab 375 mg/m2 on day 1; n = 8), followed by maintenance rituximab for 70%. All patients achieved complete remission, and only 2 patients in group 1 had developed a relapse at 70 and 75 months. Both relapses were stage I MALT that had initially been treated with radiotherapy. Both were salvaged with FND-R and remained free of disease at 27 and 39 months after the relapse. At 10 years, the failure-free survival for the 44 patients was 80% and the overall survival was 100%. None of the patients in group 2 developed a relapse. The long-term toxicities have been acceptable. The excellent responses using upfront chemotherapy for MZL suggests that this disorder is curable. Our results should be confirmed in a prospective trial.

A pediatric-type follicular lymphoma with marginal zone and monotypic intracytoplasmic plasmacytic differentiation

Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are rare indolent lymphomas that are distinctive entities with excellent prognoses. We present the histopathology and the immunophenotypic, cytogenetic, and gene rearrangement findings of a unique, heretofore, unreported case of a 15-year old boy with a right-groin mass (5.5×4.5×3.5cm) with three discrete malignant components: 1) follicular lymphoma positive for CD20, CD10, and BCL6, but negative for BCL2; by flow cytometry, 9% of the cells were kappa monotypic B-cells that expressed CD10, CD19, CD20, and CD38; 2) typical marginal zone B-cell differentiation; marginal zone B-cells were positive for CD20, CD43, BCL2, and MUM-1, but CD10 and BCL6 negative. A small subset was weakly positive for intracytoplasmic IgM and kappa consistent with early plasmacytic differentiation; 3) Plasmacytoid forms, intracytoplasmic globules and crystals strongly expressed intracytoplasmic monotypic IgM and kappa.

The value of detecting immunoglobulin gene rearrangements in the diagnosis of B-cell lymphoma.

ObjectiveTo discuss the clinical value of immunoglobulin gene rearrangements in the diagnosis of B-cell lymphoma.MethodsA total of 209 cases of B-cell lymphomas and 35 cases of reactive lymphoid hyperplasia were selected for DNA extraction and PCR amplification using the BIOMED-2 primer system. Gel electrophoresis of heteroduplexes was used to analyze immunoglobulin gene rearrangements.ResultsA total of 209 cases of B-cell lymphoma, including 69 extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue, 63 diffuse large B-cell lymphomas, 39 follicular lymphomas, 15 small lymphocytic lymphomas, 6 plasmacytomas, 6 mantle cell lymphomas, 7 nodal marginal zone B-cell lymphomas, and 4 lymphoplasmacytoid lymphomas, were examined. Immunoglobulin gene rearrangements were found in all 209 cases, with 93 IGHA, 122 IGHB, 98 IGHC, 167 IGK, 100 IGL, 167 IGHA/B/C, 204 IGH/IGK, 209 IGH/IGK/IGL, 129 IGH+IGK, 81 IGH+IGL, 83 IGK+IGL and 68 IGH+IGK+IGL gene rearrangements. Immunoglobulin gene rearrangements were not found in the 35 cases of reactive lymphoid hyperplasia. IGH and IGK gene rearrangements were mainly found in mantle cell lymphomas, small lymphocytic lymphomas, extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue and diffuse large B-cell lymphomas. The IGH gene rearrangement was mainly found in lymphoplasmacytoid lymphomas and follicular lymphomas. IGK and IGL gene rearrangements were mainly found in plasmocytoma, and the IGK gene rearrangement was mainly found in nodal marginal zone B-cell lymphomas.ConclusionsThe BIOMED-2 standardized immunoglobulin gene rearrangement detection system is an important tool in B-cell lymphoma diagnosis. Analysis of IGH, IGK and IGL gene rearrangements is valuable in confirming the classification of B-cell NHL.

Pediatric-type Follicular Lymphoma and Pediatric Nodal Marginal Zone Lymphoma: Recent Clinical, Morphologic, Immunophenotypic, and Genetic Insights.

Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are 2 of the rarest B-cell lymphomas. Although they are both predominantly seen in children, they can manifest in the adult population as well. Our understanding of these lymphomas has advanced rapidly in recent years such that we not only have a firm grasp of the morphologic and immunophenotypic findings, but also have a deeper insight into critical genetic and molecular pathways of these diseases. This review will cover the clinical and pathologic characteristics, treatment, prognosis, and important differential diagnoses of these entities.

Unusual course of generalized lymph node primary plasmacytoma in a patient with Sj\xf6gren\u2019s syndrome: a case report

BackgroundPrimary lymph node plasmacytoma is a rare disease that typically involves lymph nodes of the neck. In only 15% of cases is the disease generalized. Here, we present a case of generalized lymph node plasmacytoma in a patient with Sjögren’s syndrome with an unusual course.Case presentationA 48-year-old white woman presented to our hospital with enlargement of groups of lymph nodes, liver, and spleen. Her medical history was consistent with a 12-year course of Sjögren’s syndrome. Blood and urine immunochemistry showed a massive (72 g/l) M-gradient formed from immunoglobulin Aκ in the serum and monoclonal free κ-type light chains in her urine. A skeletal X-ray revealed no bone destruction. Cytological and histological bone marrow assays showed no signs of plasma cell infiltration. The microarchitecture of her neck and inguinal lymph nodes was destroyed. Only small remnants of B cell follicles were found, while the interfollicular areas were expanded and infiltrated by CD138, MuM1, CD43, and IgAκ-positive plasma cells. After nine cycles of doxorubicin, cyclophosphamide, vincristine, and prednisolone chemotherapy, complete remission was achieved. However, the lymphoma relapsed 3 months later, with histological verification in her femoral lymph node. Despite the absence of subsequent adequate therapy, she gradually achieved complete remission of plasmacytoma with the disappearance of paraproteins.ConclusionsCurrently, primary lymph node plasmacytoma is generally considered a nodal marginal zone lymphoma with an extensive plasmacytic differentiation. In our case, despite the critical histological and immunohistochemical evaluation of three lymph node biopsies from different anatomical areas at different times, no signs of nodal marginal zone lymphoma were found. An 18-year follow-up of our patient with primary lymph node plasmacytoma demonstrated an extremely unusual clinical course. Initially, primary lymph node plasmacytoma was refractory to chemotherapy. However, subsequently, she underwent a complete spontaneous remission of plasmacytoma.

Analysis of Clinical Characteristics for 24 Cases of Nodal Marginal Zone Lymphoma.

Objective To summarize and investigate the characteristics of nodal marginal zone lymphoma (NMZL). <strong>Method</strong> The clinical data and laboratory characteristics of of NMZL patients admitted in our hospital between January 2002 and September 2013 were analyzed retrospectively. <strong>Results</strong> Twenty-four patients were enrolled in the study. The median age was 54.4 (28-70) years,and the male/female ratio was 1:1. Most of the patients (95%) had bone marrow involvement,40.9% (9/22) had elevated lactate dehydrogenase level,8.3% (2/24) had the positive expression of hepatitis C virus antibody,33.3% (6/18) had positive autoimmune antibodies,and 33.3% (8/24) had monoclonal immunoglobulins in the serum. All of the patients expressed CD19 and CD20 cell markers,whereas none of them expressed CD10 cell marker. The positive rate of CD5 marker was 10% (1/10),the positive rate of CD23 marker was 50% (5/10),whereas no patient had the expressions of both CD5 and CD23 at the same time. The total overall remission rate was 81.25%,and the total complete remission rate was 56.2%. The separate overall remission and complete remission rate had increasing trends in rituximab subgroup than subgroups without using rituximab(P=0.136,P=0.262).<strong>Conclusion</strong> NMZL has a low incidence and can be seen in both males and females. It often invades bone marrow. Rituximab may increase the response rate and even improve the progression free survival.

Detection of MYD88 L265P and WHIM-like CXCR4 mutation in patients with IgM monoclonal gammopathy related disease.

A broad spectrum of diseases are associated with IgM monoclonal gammopathy, including Waldenstrom macroglobulinemia (WM), various types of B cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), primary amyloidosis (AL), and monoclonal gammopathy of undetermined significance (MGUS); these are called IgM monoclonal gammopathy related diseases (IgM-RD). We investigated MYD88 L265P and WHIM-like CXCR4 mutations in various IgM-RD. Patients with serum immunofixation electrophoresis confirmed IgM monoclonal gammopathy who had enough material for DNA extraction and presented between January 2008 and October 2016 at Peking Union Medical College Hospital were enrolled in this cohort. We performed real-time allele-specific-polymerase chain reaction and Sanger sequencing to explore the presence of MYD88 L265P and WHIM-like CXCR4 mutations. One hundred and twelve patients (64 male and 48 female patients) were included in this retrospective study. The median age at diagnosis was 62years (range, 30-84years). In total, 64 patients (57.1%) carried the MYD88 L265P mutation and 14 patients (12.5%) carried the CXCR4 WHIM-like mutation. We identified the MYD88 L265P somatic variant in cases with WM (39/42), MGUS (8/18), NHL (14/41, including 4/13 diffuse large B cell lymphoma (DLBCL), 1/8 mucosa-associated lymphoid tissue, 3/6 splenic marginal zone lymphoma (SMZL), 1/4 chronic lymphocytic leukemia, 2/3 nodal marginal zone lymphoma (NMZL), 1/2 mantle cell lymphoma, 1 Burkitt lymphoma, and 1 B cell NHL that could not be classified), primary AL (2/2), and IgM-PN (1/1). The mutation was absent in five patients with Cryoglobulinemia, two with primary cold agglutinin disease and one with MM. The CXCR4 WHIM-like mutation was present in 10/42 patients with WM, 3/41 with NHL (1 DLBCL, 1 SMZL, and 1 NMZL), and 1/18 patients with IgM MGUS. Among the patients with NHL, those with the mutated MYD88 L265P genotype were younger and had lower level of IgG and IgA than the patients with the wild-type genotype. Patients with the mutated MYD88 L265P genotype with WM and MZL were compared. More male patients, higher levels of IgM and lower levels of LDH were found in the WM group. There was no significant difference in overall survival between the two groups. We present a study of the prevalence of the MYD88 L265P mutation and CXCR4 WHIM-like mutation in IgM RD. The MYD88 L265P mutation may play a key role in the pathogenesis of IgM monoclonal gammopathies. It would be interesting in the future to use MYD88 mutation status to differentiate among diseases.

Mucosa-Associated Lymphoid-Tissue Lymphoma of the Cecum and Rectum: A Case Report.

A colonic mucosa-associated lymphoid-tissue (MALT) lymphoma is relatively rare compared to lymphomas of the stomach or small intestine. We present a case of a MALT lymphoma in the cecum and rectum found during screening colonoscopy. A 54-year-old female, who had undergone right-breast-conserving surgery with axillary dissection due to an invasive ductal carcinoma and a left-breast excisional biopsy due to microcalcification following adjuvant chemoradiation therapy 3 years earlier, was found to have 3-mm-sized smooth elevated lesions in both the cecum and rectum. No pathologic lesion or lymphadenopathy was found at any other site, but chronic gastritis negative for Helicobacter pylori infection was found. The polyps were removed by using an endoscopic biopsy and revealed an extra nodal marginal zone B-cell MALT lymphoma, showing positive for CD3 and CD20 by immunohistochemical staining. The patient underwent close observation without any additional treatment and has shown no evidence of recurrence as of her last visit.

B-Cell and Classical Hodgkin Lymphomas Associated With Immunodeficiency: 2015 SH/EAHP Workshop Report-Part 2.

The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology submitted small and large B-cell lymphomas (BCLs), including classical Hodgkin lymphoma (CHL), in the context of immunodeficiency. Clinicopathologic and molecular features were studied to explore unifying concepts in malignant B-cell proliferations across immunodeficiency settings. Cases submitted to the workshop spanned small BCLs presenting as nodal or extranodal marginal zone lymphoma and lymphoplasmacytic lymphoma, Epstein-Barr virus (EBV) positive in 75% of cases. Submitted large BCLs formed a spectrum from diffuse large B-cell lymphoma (DLBCL) to CHL across immunodeficiency settings. Additional studies demonstrated overexpression of PD-L1 and molecular 9p24 alterations in the large BCL spectrum and across different immunodeficiency settings. Small BCLs occur in all immunodeficiency settings, and EBV positivity is essential for their recognition as immunodeficiency related. Large BCLs include a spectrum from DLBCL to CHL across all immunodeficiency settings; immunohistochemical and molecular features are suggestive of shared pathogenetic mechanisms involving PD-L1 immune checkpoints.

Progress of marginal zone lymphoma

Marginal zone lymphoma (MZL) accounts for approximately 10% of non-Hodgkin lymphoma (NHL). It can be divided into three specific entities: extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma(NMZL) and splenic marginal zone lymphoma (SMZL). MALT lymphoma is the most frequent overall, representing 7.5% of all NHLs. Reports on research progress of MZL in the 58th American Society of Hematology Annual Meeting covered multiple respects which ranged from basic research to clinical prognosis and treatment. Based on the technology such as flow cytometry, cytogenetics and FISH, further study on pathogenesis of MZL is developing, and new prognostic index system can help to stratify patients more exactly and give a guidance to treatment. What's more, the change of therapy and new drugs will benefit to the clinical efficacy and safety of MZL patients. Key words: Lymphoma, marginal zone; American Society of Hematology Annual Meeting

A case report of nodal marginal zone lymphoma: Diagnosis and management

AbstractNodal marginal zone B-cell lymphoma (NMZL) is a rare subtype of non-Hodgkin lymphoma, usually presented at advanced stage. The treatment for NMZL is currently consistent with follicular lymphoma which includes observation for asymptomatic patients to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or CHOP plus rituximab regimen, fludarabine or bendamustine and rituximab (B-R) for advanced, symptomatic patients. The B-R regimen is effective and could be evaluated further as the first-line therapy.

Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma of the Colon: A Case Report and a Literature Review

Patient: Female, 56Final Diagnosis: Colonic MALT lymphomaSymptoms: Epigastric painMedication: —Clinical Procedure: Colonoscopy and biopsySpecialty: Gastroenterology and HepatologyObjective:Rare diseaseBackground:Non-Hodgkin lymphoma (NHL) is a well-known hematologic malignancy. The gastrointestinal (GI) tract is the most commonly involved extra nodal site. MALT lymphomas are uncommon, accounting for 5% of all NHL. Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the prototype seen in association with Helicobacter pylori. Colonic MALT lymphoma is rare and comprises only 2.5% of the MALT lymphomas. Its etiology and treatment is not well established.Case Report:A 56-year-old Hispanic woman presented to the clinic with symptoms of chronic epigastric pain for the past three years and a 13-pound weight loss over the past two months. The patient did not have any prior medical conditions. Her systemic examination was unremarkable, while her routine labs revealed mild anemia. An upper endoscopy and colonoscopy for colorectal cancer screening were performed revealing erosive gastropathy with duodenal ulcers and a 5 cm broad based polypoid mass in the hepatic flexure respectively. Computed tomography (CT) of the abdomen revealed a round, well demarcated mass at the hepatic flexure of the colon. The histopathology and immunophenotyping were consistent with extra nodal marginal zone of MALT lymphoma. Stool testing for H. pylori was positive. The patient received two weeks of H. pylori eradication therapy and four cycles of rituximab. Repeat colonoscopy after completion of chemotherapy showed complete resolution of the MALT lymphoma.Conclusions:Unlike gastric MALT lymphoma, treatment of colonic MALT lymphoma is not standardized. Chemotherapy and surgical resection have been utilized to successfully treat it. Only a handful of cases have reported successful treatment of colonic MALT lymphoma with rituximab monotherapy.

High Frequency of Somatic Mutations of KMT2D and CARD11 Genes in Cold Agglutinin Disease

Primary cold agglutinin disease (CAD) is a hemolytic anemia mediated by monoclonal anti-I autoantibodies. CAD is caused by an underlying low grade B-cell lymphoproliferative disease of the bone marrow with a typical histology that is different from lymphoplasmacytic lymphoma and, accordingly, does not display the MYD88 L265P mutation (Randen et al., Haematologica, 2014).Since CAD is a clonal lymphoproliferative disorder, we studied the mutational landscape to further characterize the disease and identify potential novel treatment approaches.We prospectively collected bone marrow samples of CAD patients, enrolled in a clinical trial (CAD5; www.clinicaltrials.gov, NCT02689986). Exome sequencing of six cases was performed and findings were confirmed in ten additional cases using targeted sequencing. For these analyses, clonal B cells and normal T cells, used as control, were purified from bone marrow samples using fluorescent activated cell sorting. All mutations were verified by Sanger sequencing. Whole-exome sequencing was performed at BGI Tech Solutions (Hongkong) using the Agilent SureSelect Human All Exon V4 Reagent Kit and Illumina HiSeq technology. The bioinformatics pipeline consistent of BWA alignment tool (aligned to hg19); Picard tools FixMateInformation and MarkDuplicates; the Genome Analysis Toolkit (GATK) IndelRealigner and BaseRecalibrator; somatic variant detection tools Strelka, MuTect and Pindel; the annotation tool SnpEff.Recurrent somatic mutations were found in KMT2D (11/16 cases, 69%) and CARD11 (5/16, 31%) (Table 1, Figure 1-2). 7/16 (44%) of KMT2D mutations were deemed high impact mutations by SnpEff and to result in inactive protein. 2/16 (12,5%) of KMT2D mutations are missense mutations and are predicted to impair SET domain function. 2/16 (12,5%) of KMT2D mutations are classified by SnpEff as low impact mutations of which functional tests are necessary to demonstrate potential consequences for protein function. Of interest, two additional patients showed rare germline KMT2D variants that have also been seen in Kabuki syndrome patients, although these patients do not have Kabuki syndrome.CARD11 was somatically mutated in 5/16 (31%) cases. Four of those patients had a concurrent KMT2D mutation. All CARD 11 mutations were classified as moderate impact mutations by SnpEff. Mutations were tightly clustered in a 20bp sequence of the coiled-coil domain sequence (Table 1, Figure 2).KMT2D is a histone lysine methyl transferase that represses B cell lymphoma development. Mono-allelic mutations of KMT2D seem to act in a dominant fashion and cause partial loss of protein expression with cell growth advantage. KMT2D is frequently mutated in follicular lymphoma, diffuse large B cell lymphoma and nodal marginal zone lymphoma. Mono-allelic constitutional mutations cause Kabuki syndrome, characterized by distinct facial characteristics and multiple organ malformations. Patients frequently develop immune-mediated thrombocytopenia as well as auto-immune hemolytic anemia.CARD11 coiled-coil domain mutations result in constitutive NF-kB activation and enhanced NF-kB activity upon antigen receptor stimulation. Mutations were previously detected in diffuse large B cell lymphomas of activated B cell origin. Mono-allelic CARD11 coiled coil mutations are not oncogenic per se in mice and humans, but result in B-cell proliferation and auto-antibody production. Since four CAD patients showed concurrent KMT2D and CARD11 mutations, it seems likely that the mutations act in concert with anti-I B-cell receptor stimulation to contribute to CAD-associated lymphoproliferative disease.In conclusion, we demonstrated a high frequency of KMT2D and CARD11 mutations in the bone marrow B cell lymphoproliferative disease of patients with CAD. These results confirm that CAD-associated B cell lymphoproliferative disease is a distinct disease different from other known B cell lymphoproliferative diseases of the bone marrow, most notably lymphoplasmacytic lymphoma. The identification of these recurrent mutations in CAD may allow the design of novel treatment modalities. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma

AbstractPediatric-type follicular lymphoma and pediatric marginal zone lymphoma are two of the rarest B-cell lymphomas. These lymphomas occur predominantly in the pediatric population and show features distinct from their more common counterparts in adults: adult-type follicular lymphoma and adult-type nodal marginal zone lymphoma. Here we report a detailed whole-exome deep sequencing analysis of a cohort of pediatric-type follicular lymphomas and pediatric marginal zone lymphomas. This analysis revealed a recurrent somatic variant encoding p.Lys66Arg in the transcription factor interferon regulatory factor 8 (IRF8) in 3 of 6 cases (50%) of pediatric-type follicular lymphoma. This specific point mutation was not detected in pediatric marginal zone lymphoma or in adult-type follicular lymphoma. Additional somatic point mutations in pediatric-type follicular lymphoma were observed in genes involved in transcription, intracellular signaling, and cell proliferation. In pediatric marginal zone lymphoma, no recurrent mutation was identified; however, somatic point mutations were observed in genes involved in cellular adhesion, cytokine regulatory elements, and cellular proliferation. A somatic variant in AMOTL1, a recurrently mutated gene in splenic marginal zone lymphoma, was also identified in a case of pediatric marginal zone lymphoma. The overall non-synonymous mutational burden was low in both pediatric-type follicular lymphoma and pediatric marginal zone lymphoma (4.6 mutations per exome). Altogether, these findings support a distinctive genetic basis for pediatric-type follicular lymphoma and pediatric marginal zone lymphoma when compared with adult subtypes and to one another. Moreover, identification of a recurrent point mutation in IRF8 provides insight into a potential driver mutation in the pathogenesis of pediatric-type follicular lymphoma with implications for novel diagnostic or therapeutic strategies.