Splenic Marginal-zone Lymphoma: One or More Entities? A Histologic, Immunohistochemical, and Molecular Study of 42 Cases

Abstract

We analyzed 42 splenic marginal-zone lymphoma (SMZL) cases diagnosed on splenectomy specimens after established World Health Organization criteria. A predominantly nodular growth pattern was observed in 24 cases; the remainder showed predominantly (11/42) or exclusively (7/42) diffuse infiltration. Twenty-one cases showed the "classic" biphasic appearance; 13 cases exhibited marginal-zone morphology; finally, 8 cases were composed predominantly of small cells. CD21 and CD35 were expressed by 12/42 and 17/38 cases, respectively. DBA.44 was detected in 24/42 cases. Seventeen of 37 cases were surface IgD (SIgD)-positive. Twenty-one of 22 analyzed cases were SIgM-positive (12/21 coexpressed SIgD). Five of 37 cases were SIgG-positive. CD27 staining was observed in 21/35 cases; 7/18 CD27-positive cases coexpressed SIgD; 7/14 CD27-negative cases were SIgD-positive. Forty IGHV-D-J rearrangements were amplified in 34/42 cases: the IGHV4-34 gene predominated, followed by IGHV1-2. Using the 98% homology cut-off, 25/40 (62.5%) IGHV sequences were considered as "mutated": 10/11 cases with monomorphous, marginal-zone morphology were IGHV-mutated; in contrast, 4/6 cases with monomorphous, small-cell morphology were IGHV-unmutated. Five of 7 cases expressing IGHV1 subgroup genes had biphasic morphology, whereas 6/9 IGHV3-expressing cases had monomorphous, marginal-zone morphology. Most IGHV-mutated cases (14/20; 70%) were SIgD-negative; in contrast, 8/11 IGHV-unmutated cases expressed SIgD. CD27 was detected in 10/17 IGHV-mutated and 6/10 IGHV-unmutated cases. Seven of 11 CD27-negative cases were IGHV-mutated; 5/7 CD27-negative/IGHV-mutated cases expressed DBA.44. These results confirm the considerable histologic, immunohistochemical, and molecular heterogeneity of SMZL and indicate an origin from the diverse resident B-cell populations of the normal SMZ.

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

“…1 Some cytogenetic, molecular and clinical information has been reported previously. 10,13,16,22 The study was conducted in accordance with the Declaration of Helsinki and approved by the local Ethics Committee of each institution.…”

Clinical and biological diversity of splenic marginal zone lymphoma

“…Although earlier reports demonstrated that cells from all SMZL cases had somatic mutations of the IgVH, suggesting that these tumors arise from memory postgerminal center B cells, subsequent studies have revealed a significant molecular heterogeneity [14-16, [25][26][27][28]. In SMZL, as in other B-cell neoplasms, the IgVH mutational status does not play a diagnostic role but has provided insights in the pathogenesis of the disease.…”

Splenic marginal zone lymphomas and lymphoplasmacytic lymphomas originate from B-cell compartments with two different antigen-exposure histories

“…In the case of one subtype of AML, acute promyelocytic leukemia (APL; FAB M3), differentiation can be induced by all-trans retinoic acid (ATRA), a treatment that is curative for many acute promyelocytic leukemia patients. 1,2 However, ATRA has not proven to be effective in the treatment of other subtypes of AML, underscoring the need to identify new compounds that can either induce differentiation as monotherapies or enhance the efficacy of ATRA therapy. Here we report that the tyrosine kinase inhibitor gefitinib markedly enhances ATRA-induced differentiation in myeloid cell lines.…”

“…For example, 1/3 of SMZL cases exhibit unmutated immunoglobulin variable heavy-chain (IgVH) genes, with a heterogeneous usage of VH segments. 2 In contrast, IgVH somatic mutations are frequent with a predominance of VH3 usage in LPL patients. 3 But, it is worthnoting that these results are not fully conclusive because they have been obtained on heterogeneous biological materials and in different separated series.…”