Molecular Lesions Of Signalling Pathway Genes In Indolent B-Cell Lymphoproliferations Mimicking Splenic Marginal Zone Lymphoma

Almost 60% cases of splenic marginal zone lymphoma (SMZL) cases harbor molecular lesions affecting signalling pathways involved in normal marginal zone (MZ) differentiation, including the NOTCH pathway, the NF-kB pathway, the toll-like receptor (TLR) pathway and the B-cell receptor (BCR) pathway. However, little is known with regard to these lesions in other indolent B-cell lymphoproliferative disorders mimicking SMZL.

Candidate gene mutations (NOTCH2, NOTCH1, BIRC3, TNFAIP3, TRAF3, IKBKB, MYD88, CD79A, CD79B, CARD11) were investigated in 60 indolent B-cell lymphoproliferative disorders, including nodal marginal zone lymphoma (NMZL=33), monoclonal B-cell lymphocytosis showing a MZL-like phenotype (MZL-like MBL=16), and variant hairy cell leukemia (vHCL=11). In all cases, tumor representation was >50% in order to allow the detection of clonal lesions. All cases lacked the BRAF V600E mutation as assessed by AS-PCR.

Overall, the genetics of NMZL and MZL-like MBL was consistent with that of SMZL, suggesting the involvement of a common oncogenic pathway in these disorders. Among NMZL, 51% (17/33) of cases were characterized by mutually exclusive genetic lesions affecting MZ differentiation genes, including NOTCH2 stabilizing mutations in 24% (8/33) of cases, TNFAIP3 disrupting mutations in 12% (4/33), MYD88 activating mutations in 12% (4/33), and NOTCH1, TRAF3 and BIRC3 mutations in 3% (1/33) of cases each. Among MZL-like MBL, 37% (6/16) of cases harbored mutually exclusive lesions of MZ genes, including MYD88 mutations in 25% (4/16) of cases, NOTCH2 mutations in 12% (2/16), and TNFAIP3 and CD79B mutations in 6% (1/16) of cases each. On the contrary, all cases (n=11) of vHCL lacked mutations of NOTCH, NF-kB, TLR or BCR genes, suggesting that none of these signaling pathways plays a relevant role in this disease. Among NMZL, MYD88 mutations were enriched among cases harboring an IgM type monoclonal component (3/4, 75% vs 1/18, 5%, p=.010) and showing cytological clues of plasma cell differentiation of lymph node tumor cells (3/6, 50% vs 0/9; p=.040). NOTCH2 mutations did not correlate with any pathologic feature (i.e. lymph node pattern of infiltration, presence of monocytoid B cells, immunoglobulin gene usage or mutation status). Among MZL-like MBL, neither MYD88 mutations nor NOTCH2 mutations correlated with specific clinico-pathologic features (i.e. presence of an IgM type monoclonal component, intrasinusoidal bone marrow infiltration, plasma cell differentiation).

These data suggest that: i) SMZL, NMZL and MZL-like MBL share a similar genotype and are all promoted by the same molecular deregulation of MZ differentiation genes; and ii) vHCL stands as a genetically different entity among indolent B-cell lymphoproliferations. These data might help to refine the differential diagnosis of indolent B-cell lymphoproliferations mimicking SMZL.

No relevant conflicts of interest to declare.