Primary diffuse large B-cell lymphomas of central nervous system exhibit remarkably high prevalence of oncogenic MYD88 and CD79B mutations

Yamada, So; Ishida, Yasuo; Matsuno, Akira; Yamazaki, Kazuto

doi:10.3109/10428194.2014.979413

Cited by 82 publications

(64 citation statements)

References 18 publications

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“…The frequent utilization of V H 4-34 in ABC DLBCL cases is consistent with previous work demonstrating an enrichment for V H 4-34 among DLBCL cases classified as "non-GCB" by immunostaining (20). Primary central nervous system lymphoma (PCNSL) is a type of DLBCL that has an ABC phenotype (38) and acquires several of the pathognomonic mutations of ABC DLBCL (39)(40)(41)(42). V H 4-34 is used in 55% of PCNSL cases, an enrichment that suggests that this V H segment confers a selective advantage in PCNSL, as in nodal ABC DLBCL.…”

Section: Discussionmentioning

confidence: 99%

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Young

Schmitz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

159

156

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The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) relies on chronic active B-cell receptor (BCR) signaling. BCR pathway inhibitors induce remissions in a subset of ABC DLBCL patients. BCR microclusters on the surface of ABC cells resemble those generated following antigen engagement of normal B cells. We speculated that binding of lymphoma BCRs to self-antigens initiates and maintains chronic active BCR signaling in ABC DLBCL. To assess whether antigenic engagement of the BCR is required for the ongoing survival of ABC cells, we developed isogenic ABC cells that differed solely with respect to the IgH V region of their BCRs. In competitive assays with wild-type cells, substitution of a heterologous V region impaired the survival of three ABC lines. The viability of one V H 4-34 + ABC line and the ability of its BCR to bind to its own cell surface depended on V region residues that mediate the intrinsic autoreactivity of V H 4-34 to self-glycoproteins. The BCR of another ABC line reacted with self-antigens in apoptotic debris, and the survival of a third ABC line was sustained by reactivity of its BCR to an idiotypic epitope in its own V region. Hence, a diverse set of self-antigens is responsible for maintaining the malignant survival of ABC DLBCL cells. IgH V regions used by the BCRs of ABC DLBCL biopsy samples varied in their ability to sustain survival of these ABC lines, suggesting a screening procedure to identify patients who might benefit from BCR pathway inhibition.lymphoma | cancer biology | B-cell receptor

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Section: Discussionmentioning

confidence: 99%

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Young

Schmitz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

159

156

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“…Recent studies indicated that a high frequency (>75%) of MYD88 L265P mutations (an adaptor protein mediating toll-like receptor and interleukin-1 signaling) in the DLBCL subtype of PCNSL may be an initiator of disease. Additionally, most MYD88 L265P-positive patients have CD79B or CARD11 mutations (B cell receptor signaling pathway)282930. In addition, the constitutive activation of the nuclear factor (NF)- κB pathway is a hallmark of B cell PCNSL31.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid IL-10 and IL-10/IL-6 as Accurate Diagnostic Biomarkers for Primary Central Nervous System Large B-cell Lymphoma

Song

Zhang

et al. 2016

Sci Rep

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Early diagnosis of primary central nervous system lymphoma (PCNSL) represents a challenge, and cerebrospinal fluid (CSF) cytokines may be diagnostic biomarkers for PCNSL. We used an electrochemiluminescence immunoassay to measure interleukin (IL)-10, IL-6, IL-8 and tumor necrosis factor α (TNF-α) in the CSF of 22 B cell PCNSL patients and 80 patients with other CNS diseases. CSF IL-10 was significantly higher in PCNSL patients than in the control group (median 74.7 pg/ml vs < 5.0 pg/ml, P < 0.000). Using a CSF IL-10 cutoff value of 8.2 pg/ml, the diagnostic sensitivity and specificity were 95.5% and 96.1%, respectively (AUC, 0.957; 95% CI, 0.901–1.000). For a CSF IL-10/IL-6 cutoff value of 0.72, the sensitivity was 95.5%, and the specificity was 100.0% (AUC, 0.976; 95% CI, 0.929–1.000). An increased CSF IL-10 level at diagnosis and post-treatment was associated with poor Progression free survival (PFS) for patients with PCNSL (P = 0.0181 and P = 0.0002, respectively). A low diagnostic value for PCNSL was found with CSF IL-8 or TNF-α. In conclusion, increased CSF IL-10 was a reliable diagnostic biomarker for large B cell PCNSL, and an IL-10/IL-6 ratio facilitates differentiation from other conditions, especially a CNS infection.

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“…2). MYD88 L265P mutations are also reported in a small proportion of other SBLs and a subset of large B cell lymphomas of non-germinal center/activated B cell type, particularly those of leg type and those at immune privileged sites (CNS and testis) [25, 36, 62]. The variable results for the reported frequency of MYD88 mutation in LPL and other lymphoid neoplasms relate in part to use of detection methods with different sensitivities, differences in the proportion of neoplastic cells in the samples studied, possible inclusion of misdiagnosed cases with a lack of tissue confirmation in some studies, and some results based on investigation of very few cases.…”

Section: Lymphoplasmacytic Lymphoma and The Impact Of Myd88 L265p Mutmentioning

confidence: 99%

The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing

et al. 2015

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Plasmacytic differentiation may occur in almost all small B cell lymphomas (SBLs), although it varies from being uniformly present (as in lymphoplasmacytic lymphoma (LPL)) to very uncommon (as in mantle cell lymphomas (MCLs)). The discovery of MYD88 L265P mutations in the vast majority of LPLs has had a major impact on the study of these lymphomas. Review of the cases contributed to the 2014 European Association for Haematopathology/Society for Hematopathology slide workshop illustrated how mutational testing has helped refine the diagnostic criteria for LPL, emphasizing the importance of identifying a clonal monotonous lymphoplasmacytic population and highlighting how LPL can still be diagnosed with extensive nodal architectural effacement, very subtle plasmacytic differentiation, follicular colonization, or uncommon phenotypes such as CD5 or CD10 expression. MYD88 L265P mutations were found in 11/11 LPL cases versus only 2 of 28 other SBLs included in its differential diagnosis. Mutational testing also helped to exclude other cases that would have been considered LPL in the past. The workshop also highlighted how plasmacytic differentiation can occur in chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, SOX11 negative MCL, and particularly in marginal zone lymphomas, all of which can cause diagnostic confusion with LPL. The cases also highlighted the difficulty in distinguishing lymphomas with marked plasmacytic differentiation from plasma cell neoplasms. Some SBLs with plasmacytic differentiation can be associated with amyloid, other immunoglobulin deposition, or crystal-storing histiocytosis, which may obscure the underlying neoplasm. Finally, although generally indolent, LPL may transform, with the workshop cases suggesting a role for TP53 abnormalities.

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Primary diffuse large B-cell lymphomas of central nervous system exhibit remarkably high prevalence of oncogenic MYD88 and CD79B mutations

Cited by 82 publications

References 18 publications

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Cerebrospinal Fluid IL-10 and IL-10/IL-6 as Accurate Diagnostic Biomarkers for Primary Central Nervous System Large B-cell Lymphoma

The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing

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