Case Of Nodal Marginal Zone Lymphoma Research Articles

Immunohistochemical analysis of arachidonate 5-lipoxygenase expression in B-cell lymphomas: Implication for B cell differentiation and its analogy with lymphomagenesis.

Arachidonate 5-lipoxygenase (ALOX5) is a cardinal enzyme in the synthesis of leukotrienes, which are powerful immune-regulating lipid mediators. We previously reported that ALOX5 is preferentially expressed in B lymphocytes in the mantle zone of human lymphoid tissue. In the context of physiological relevance, the loss of the Alox5 gene in mice significantly impairs the development of follicular B helper T cells and antibody production. However, ALOX5 expression in B-cell lymphomas has not been investigated in detail. In this study, we examined ALOX5 expression in representative B-cell lymphomas and non-neoplastic lymphoid tissues by immunohistochemistry with a commercially available anti-ALOX5 antibody that can be used on formalin-fixed paraffin-embedded specimens. Interestingly, 22/22 cases of mantle cell lymphoma, 7/7 cases of chronic lymphocytic leukemia/small cell lymphoma, and 20/20 cases of follicular lymphoma expressed ALOX5. A small proportion of extranodal marginal zone lymphoma/mucosa-associated lymphoid tissue lymphoma or nodal marginal zone lymphoma cases were positive for ALOX5 (2/13 or 1/3, respectively). In contrast, no cases with diffuse large B-cell lymphoma, regardless of germinal center B cell (GCB) or non-GCB type, expressed ALOX5 (0/25 cases). These findings suggest that ALOX5 may be a novel marker for identifying the cell of origin of B-cell lymphoma. Further investigation is required to clarify the biological significance of ALOX5 expression in lymphoma cells.

IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications

The precise B cell of origin and molecular pathogenesis of nodal marginal zone lymphoma (NMZL) remain poorly defined. To date, due to the rarity of NMZL, the vast majority of already-published studies have been conducted on a limited number of samples and the technical approach to analyze the immunoglobulin genes was of amplifying rearranged variable region genes with the classical direct sequencing of the PCR products followed by cloning. Here, we studied the B cell Ig heavy-chain repertoires by next-generation sequencing (NGS) in 30 NMZL cases. Most of the cases were mutated (20/28; 71.5%) with homologies to the respective germ line genes ranging from 85 to 97, 83%, whereas 8/28 (28.5%) were unmutated. In addition, our results show that NMZL cases have a biased usage of specific immunoglobulin heavy-chain variable (IGHV) region genes. Moreover, we documented intraclonal diversity in all (100%) of the mutated cases and ongoing somatic hypermutations (SHM) have been confirmed by hundreds of reads. We analyzed the mutational pattern to detect and quantify antigen selection pressure and we found a positive selection in 4 cases, whereas in the remaining cases there was an unspecific stimulation. Finally, the disease-specific survival and the progression-free survival were significantly different between cases with mutated and unmutated IGHV genes, pointing out mutational status as a possible new biomarker in NMZL.

PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma

AbstractPIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa–associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.

Marginal zone lymphomas in children and the young adult population; characterization of genetic aberrations by FISH and RT-PCR

Marginal zone lymphomas present rarely in children and young adults as either primary nodal or extranodal disease and have an excellent prognosis. To date, chromosomal aberrations have not been analyzed in the pediatric and young adult population. We undertook a study to analyze genetic alterations in nodal and extranodal marginal zone lymphomas in children and young adults using fluorescence in situ hybridization (FISH) and RT-PCR. These findings were correlated with clinical features at presentation and immunophenotype. Forty-one cases were identified meeting these criteria. The age range was 1.5–29 years old with 49% of the cases <18 years of age. 73% of the marginal zone lymphoma cases showed evidence of light chain restriction by immunohistochemistry or flow cytometry. CD43 was coexpressed in 83%. 85% of the marginal zone lymphoma cases tested showed evidence of immunoglobulin heavy chain gene rearrangement. Fifty-nine percent of the cases were nodal marginal zone lymphomas with a median age at presentation of 16 years and an M/F ratio of 7:1. Twenty-one percent of the nodal marginal zone lymphoma cases contained genetic aberrations. Seventeen percent contained trisomy 18 with one case containing an additional trisomy 3. A translocation of the immunoglobulin heavy chain gene to an unknown partner gene was present in one case. Forty-one percent of the cases were extranodal marginal zone lymphomas with a median age of 24 years and a M/F ratio of 1.4:1. Eighteen percent of the extranodal marginal zone lymphoma cases contained genetic aberrations. The t(14;18) involving the IGH and MALT1 genes was present in one case, tetraploidy was present in one case, and another case contained trisomy 3. Overall the incidence of genetic aberrations in marginal zone lymphomas in the pediatric and young adult population is low, but the aberrations seen are similar to those seen in the adult population.