Splenic small B-cell lymphoma with predominant red pulp involvement: a diffuse variant of splenic marginal zone lymphoma?

2002 ◽  
Vol 40 (1) ◽  
pp. 22-30 ◽  
Author(s):  
M Mollejo ◽  
P Algara ◽  
M S Mateo ◽  
M Sanchez-Beato ◽  
E Lloret ◽  
...  
Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2422-2422
Author(s):  
Jose A. Martinez-Climent ◽  
Cristina Robledo ◽  
Manuela Mollejo ◽  
Anton Parker ◽  
Juan L. Garcia ◽  
...  

Abstract Splenic marginal zone lymphoma (SMZL) is an indolent B cell malignancy whose diagnosis is based on lymphocyte morphology, immunophenotype and marrow and/or splenic histology. Unlike other lymphomas, there is not a common chromosomal translocation specific for SMZL, and genetic prognostic factors are poorly defined. To investigate the pattern of genomic aberrations in SMZL, we applied comparative genomic hybridization to BAC microarrays (array CGH) to a well characterized series of 75 SMZL specimens. We applied two different 1 Mb-resolution BAC arrays: UCSF HumArray 3.2 and a novel array CGH platform developed at Univ. of Salamanca. These arrays allowed us to detect DNA copy number changes across the genome with high accuracy in 67 of 75 patient samples. Data were compared with our previous array CGH studies of 170 samples from different B-cell lymphoma subgroups. FISH studies for IGH, IGK and IGL translocations and 7q deletion were performed on tissue microarrays in 24 cases. Of the 67 samples, 19 (28%) showed a normal genomic profile. The median number of genomic aberrations per tumor was 2.2 (1.3 gains and 0.9 losses), which was lower than the rates detected in other lymphoma subgroups (diffuse large cell lymphoma, 6.4; mantle cell lymphoma, 6; follicular lymphoma, 4.5) and comparable to MALT lymphomas (2 abnormalities per tumor). SMZL cells showed a genomic pattern characterized by gain of chromosomes 3q24-q29 (18%), 6p (9%), 12q (9%), and 18q (4%) and loss of 7q32 (34%), 8p21-p23 (13%), 17p13 (10%) at P53 locus and 6q21-q27 (9%). Notably, no alterations of the P16/ARF (9p21) or MYC loci (8q24) were detected. Correlation of array CGH data with conventional cytogenetics, FISH and LOH studies revealed a high concordance. Detailed mapping of 7q deletions delineated a consensus region of loss of 3 Mb in 7q32. This 7q deletion was almost exclusive to SMZL, being observed in only 5 of 170 non-SMZL B-cell lymphomas (p=0.0000001). Four cases presented IG-translocation. Mutation of IGH was observed in 62% and correlated with a complex karyotype (61 vs. 13%; p=0,0008) whereas unmutated IGH correlated with the deletion of 7q (56 vs. 23%; p=0,01). Among the various genomic abnormalities, only the deletion of 8p or the presence of a complex karyotype correlated with inferior overall survival (OS) (median OS, 58 vs. 110 months, p=0,004; and 60 vs. 105 months, p=0,01; respectively). In summary, array CGH has defined a pattern of genomic aberrations in SMZL that differs from other B-cell lymphoma subgroups and that may predict overall survival. Because the deletion of 7q32 is the most distinctive genetic marker in SMZL, the identification of a putative tumor suppressor gene inactivated within the region of deletion seems mandatory.


Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 627-632 ◽  
Author(s):  
Dan Jones ◽  
Richard J. Benjamin ◽  
Aliakbar Shahsafaei ◽  
David M. Dorfman

Chemotaxis in leukocytes is mediated through binding of soluble chemokines to transmembrane G-protein coupled receptors. The chemokine receptor CXCR3 has been previously shown to be widely expressed on activated T cells and to mediate T-cell chemotaxis on binding to various ligands, including Mig, IP-10, and ITAC. By using immunohistochemical and flow cytometric analysis, we report that CXCR3 is also expressed on a subset of peripheral blood B cells and in distinct subtypes of B-cell lymphoma. CXCR3 immunohistochemical or flow cytometric expression was seen in 37 of 39 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (diffusely positive in 33 cases), whereas mantle cell lymphoma (30 cases), follicular lymphoma (27 cases), and small noncleaved cell lymphoma (8 cases) were negative in all but 2 cases. Strong CXCR3 expression was also seen in splenic marginal zone lymphoma (14 of 14 cases) and in the monocytoid and plasmacytic cells in extranodal marginal zone lymphoma (15 of 16 cases). This differential expression of CXCR3 in B-cell tumors contrasts with that of another B-cell–associated chemokine receptor, BLR1/CXCR5, which we show here is expressed on all types of B-cell lymphoma tested. We also report that the CXCR3 ligand, Mig, is coexpressed on tumor cells in many cases of CLL/SLL (10 of 13 cases examined) with Mig expression less frequently seen in other B-cell lymphoma subtypes. Coexpression of CXCR3 and its ligand, Mig, may be an important functional interaction in B-CLL, as well as a useful diagnostic marker for the differential diagnosis of small cell lymphomas.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 617-617
Author(s):  
Wee-Joo Chng ◽  
Gaofeng Huang ◽  
Paul J. Kurtin ◽  
Ahmet Dogan ◽  
Ellen Remstein

Abstract Although classified as marginal zone lymphomas under the WHO classification, the molecular relationship between splenic marginal zone lymphoma (SMZL), extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), and nodal marginal zone lymphoma (NMZL) has not been clarified. Furthermore, lymphoplasmacytic lymphoma (LPL) can show clinical morphologic and immunophenotypic overlap with these entities and may present a diagnostic challenge. In this analysis of gene expression data generated using the Affymetrix U133plus 2.0 chip from 32 SMZL, 25 MALTs (GI, salivary gland and lung), 23 NMZL and 25 LPL, we aim to identify the molecular relationship between these pathological entities using unsupervised methods, identify disease specific signatures and markers using supervised methods and also the functional implications of these signatures using a modified gene-set enrichment analysis. Using hierarchical clustering, MALT lymphoma forms a tight cluster regardless of tumor site. In addition, SMZL and NMZL form another large cluster. LPLs are divided into 2 main clusters with occasional samples interspersed amongst the SMZL and NMZL. There is no correlation between the percentage of CD20-positive B-cells, CD3-positive T-cells or CD138- positive plasma cells or tissue origin of the tumor and the way the samples are clustered. However, the separation of the LPLs into 2 major cluster correspond to the presence and absence of underlying Waldenstrom Macroglobulinaemia (WM), suggesting that the genes distinguishing the 2 clusters are potential markers for differentiating WM LPL from non-WM LPL. Next, using supervised analysis we identified a cluster of genes including MMP7, LTF and SFRP2 with high signals specific to MALTs, while other genes including PRDM1 (BLIMP1), XBP1 and TNFRSF17 (BCMA) were specifically over-expressed in LPL. These may therefore represent novel diagnostic marker differentiating these entities. Several of these are further validated at the protein level using immunohistochemistry on a tissue microarray. Consistent with the unsupervised analysis, SMZL and NMZL have little difference and share the over-expression of CD22 and WNT3 among other genes. Clustering of these samples based on the pathways and genesets that are enriched in the individual tumors as compared to their normal tissue counterpart showed a mutually exclusive pattern with significant enrichment of NFKB-related genesets and genes in LPL and MALT, and significant enrichment of B-cell receptor signaling genesets and genes in SMZL and NMZL. Our analysis, for the first time, describes the molecular relationship between these closely related lymphomas. In the process, we identified novel diagnostic markers that may differentiate these conditions and also new insights into molecular pathways that are differentially activated in the different conditions. These may represent potential therapeutic targets


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4806-4806
Author(s):  
William Fricke

Abstract CD11b is well known as an integrin, Mac-1, is often complexed with CD18, and is found on monocytes, granulocytes, and natural killer cells. It also serves as a receptor for iC3b. However, its occurrence in B cell chronic lymphoproliferative disorders is not generally recognized and has not been fully evaluated. To address this issue, a series of B cell leukemias and lymphomas referred for primary diagnosis was evaluated for the presence of CD11b. The purpose was to determine the frequency of its expression on these tumors and to evaluate its diagnostic value. Consecutive cases referred for flow cytometry as possible lymphoproliferative disease were analyzed. Included were bone marrow, peripheral blood, and lymph nodes. All cases were diagnosed according to the WHO classification based on immunophenotypic, morphologic, and clinical findings. The morphologic criteria of Melo (1986) and Bennett (1989) were used for classification of chronic lymphocytic leukemia (CLL), CLL/prolymphocytic leukemia (CLL/PLL), mixed CLL, and PLL. Cases identified as not related to chronic lymphocytic leukemia or prolymphocytic leukemia were recorded but not further analyzed. Similarly, lymph node and spleen-based tumors were excluded from the final analysis. CD11b was present on cells from 32 of 123 cases, including occasional follicular lymphoma, (5/35); mantle cell lymphoma, (1/8); diffuse large B cell lymphoma, (3/9); hairy cell leukemia, (3/5); multiple myeloma, (1/2); lymphoplasmacytic lymphoma, (2/2); nodal marginal zone lymphoma, 0/1); and splenic marginal zone lymphoma, (1/1). However, it was most consistently expressed on CLL that contained increased numbers of prolymphocytes or large cells and on PLL. A total of 16 such cases were found. Morphologic assessment showed them to include 8 CLL/PLL, 3 mixed CLL, 4 PLL, and 1 typical CLL. The typical CLL case included both large cells and prolymphocytes but did not have more than 10% PLs. Five of the 16 cases (31%) were negative for CD5, CD23, and CD38 but were positive for FMC-7. In contrast, the other 11 cases were all CD5(+) and CD23(+); 3/11 were positive for CD38; and 5/11 were positive for FMC-7. Forty-five CLLs also were identified during the study, of which 27 had sufficient data for comparison. Twenty-six of the 27 CLLs were morphologically typical. The remaining case was mixed CLL. All of the CLLs were CD11b(−), CD5(+) and CD23(+); 15/43 were CD38(+), and 6/43 were FMC-7(+). The findings show that CD11b is expressed on chronic B cell lymphoproliferative disorders. In particular, it is expressed on almost all CLL cases that contain large cells or prolymphocytes and on PLL. Inclusion of CD11b in routine screening panels of possible chronic B cell leukemiaa will improve diagnosis of these disorders.


2001 ◽  
Vol 25 (10) ◽  
pp. 1268-1276 ◽  
Author(s):  
Francisca I. Camacho ◽  
Manuela Mollejo ◽  
María-Sol Mateo ◽  
Patrocinio Algara ◽  
Concepción Navas ◽  
...  

2006 ◽  
Vol 30 (1) ◽  
pp. 128-132 ◽  
Author(s):  
Sa A Wang ◽  
Neal Olson ◽  
Lawrence Zukerberg ◽  
Nancy Lee Harris

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3009-3009
Author(s):  
Aurélie Verney ◽  
Alexandra Traverse-Glehen ◽  
Evelyne Callet-Bauchu ◽  
Francoise Berger ◽  
Laurent Jallades ◽  
...  

Abstract Introduction Among recently discovered B cell activators responsible for signaling events leading to B-cell activation and maturation, of particular interest are the Toll-like receptors (TLRs). TLR expression is heterogeneous and variable among B-cells. In addition, abnormal TLR levels/signaling may play an important role in the pathogenesis of lymphoma, particularly in splenic marginal zone lymphoma (SMZL), since TLR pathways are recurrently targeted by genetic changes in this lymphoma. Methods Frozen spleen tissue specimens from patients with SMZL (n=13) and splenic diffuse red pulp lymphoma with villous lymphocytes (SDRPL, n=5) were analyzed for the expression of TLR1 to TLR10 in comparison to control cases (traumatic spleen, n=7) using multi-parametric flow cytometry and quantitative mRNA Taqman assay. To identify the B-cell subset, the samples were also stained with anti-CD19 and anti-CD3. All cases were studied by morphological, immunological, cytogenetic and molecular analysis. Results The TLR profile obtained at protein level by flow cytometry was closely related to that obtained at mRNA level. The SMZL/SDRPL B-cells expressed all TLRs, but with variable levels of protein expression (low for TLR1, TLR2, TLR3, TLR8, TLR9, TLR10, and high for TLR4, TLR5, TLR6 and TLR7). On the other hand, distinct TLRs profiles were observed according lymphoma subtypes. The SDRPL cases showed indeed a significant TLR2 under-expression and TLR4/TLR7 over-expression in comparison to SMZL cases and control B-cells. SMZL cases exhibited a significant TLR4/TLR8 over-expression in comparison to control B-cells. These TLR profiles were not associated with specific cytogenetic features (presence of del7q or trisomy 3) and/or immunological profile (expression of the CD11c/CD27/isotype of immunoglobulin). But, in both entities, TLR4 expression was higher in cases with mutated IGHV than in cases with unmutated IGHV. The overexpression of TLR7 MyD88-dependent signaling molecules has been reported as pathogenic mechanism for autoimmune diseases; however no more autoimmune disease or circulating auto-antibodies were associated with SDRPL cases as compared to SMZL cases. As previously reported, all cases but one SMZL case presented unmutated MyD88 (L265P mutation), and MyD88 protein evaluated here by flow cytometry was similarly expressed in both entities. While TLR7 stimulation is known to induce CD38 expression, all SDRPL cases were CD38 negative; while in SMZL cases, higher TLR7 expression was observed in CD38 positive as compared to CD38-negative cases. This may suggest the existence of an abnormal TLR7 pathway in SDRPL as opposed to SMZL. Conclusion TLR profiling should allow a better understanding of the mechanisms involved in SMZL/SDRPL pathogenesis. Present data suggest an abnormal TLR pathway involving NF-kB and/or MyD88 in the SDRPL entities. Disclosures: No relevant conflicts of interest to declare.


Piel ◽  
2017 ◽  
Vol 32 (5) ◽  
pp. 314-316
Author(s):  
Carolina Areán ◽  
Alicia Córdoba ◽  
Juan García ◽  
Amaia Larumbe

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