MYD88 mutation-positive indolent B-cell lymphoma with CNS involvement: Bing-Neel syndrome mimickers

Abstract

MYD88 p.L265P mutation occurs in over 90% of Waldenström's macroglobulinemia (WM), which is characterized by lymphoplasmacytic lymphoma (LPL) with monoclonal IgM. WM requires careful diagnosis due to overlapping features with other B-cell malignancies. Bing-Neel syndrome (BNS), a rare complication of WM, involves central nervous system (CNS) invasion. This report describes two cases of morphologically low-grade B-cell lymphoma in the bone marrow accompanied by the presence of a large B-cell lymphoma in the brain and a common MYD88 p.L265P mutation, which were eventually established as BNS mimickers. Although the two components in these cases showed the same identical light-chain restriction, different immunoglobulin heavy-chain rearrangement peaks indicated distinct lymphoma stem cells for CNS and bone marrow lesions. These clinical cases emphasize the challenges in diagnosing BNS. Based on the findings, biopsy is recommended for accurate identification of the clonal relationship and MYD88 mutation status.

Keywords: Bing–Neel syndrome; Waldenström’s macroglobulinemia; bone marrow; central nervous system lymphoma; mutation.

Fig. 1

Case details of Case 1. (A) Magnetic resonance imaging was performed, revealing a single mass in the left cerebellar peduncle. It was hypointense on T1- and T2-weighted imaging. The mass was surrounded by a diffuse hyperintense lesion on fluid-attenuated inversion recovery imaging, suggesting edema. After contrast administration, the mass was homogeneously enhanced. (B) Immunofixation analysis was positive for IgM-λ M protein. (C, D) The bone marrow aspiration smear showed small lymphoid cells with relatively coarse chromatin. Their nuclei were located off-center in the cytoplasm, implying plasma cell differentiation. On immunohistochemistry, the cells were positive for CD20, but CD138 positive cells were rare. Flow cytometric analysis (FCM) showed immunopositivity for CD20, CD19, CD22, FMC7, and immunoglobulin kappa buy negativity for CD5 and CD23. MYD88 p.L265P mutation was positive on polymerase chain reaction (PCR) analysis of bone marrow samples. (E) Open brain biopsy of the tumor was performed. Tumor histology showed diffuse proliferation of large atypical lymphoid cells. Nuclear fission or apoptosis was observed. Immunophenotypic analysis by FCM showed positivity for CD20, CD79, CD10, and free light-chain restriction to κ. (F) Immunohistochemistry was positive for CD20, CD79a, and CD10 and negative for CD5 and Bcl2. Ki67 was positive in 80%. MYD88 p.L265P mutation was positive on PCR analysis of bone marrow specimens. (G) IgH rearrangement analysis revealed different immunoglobulin heavy-chain peaks between the bone marrow and brain samples.

Fig. 2

Case details of Case 2. (A) Magnetic resonance imaging (MRI) showed a single mass in the right basal ganglia, which was hypointense on T1- and T2-weighted imaging. The mass was homogeneously enhanced on contrast MRI and surrounded by a diffuse hyperintense lesion on fluid-attenuated inversion recovery imaging, which is suspected to be subcortical edema. (B) Computed tomography showed splenomegaly but no significant lymphadenopathy. (C) IgG-λ M protein was identified. (D, E) Bone marrow aspiration smear showed small lymphoid cells with relatively coarse chromatin. On immunohistochemistry, they were positive for CD20, CD79a, IgD, and MNDA. Although some CD138-positive plasma cells were scattered, no significant light-chain restriction was observed. Flow cytometric analysis revealed immunopositivity for CD20, CD19, CD22, CD79a, FMC7, CD25, HLA-DR and immunoglobulin kappa. However, CD5, CD10, and CD23 were negative. MYD88 p.L265P mutation was positive by polymerase chain reaction (PCR) analysis in bone marrow samples. (F, G) Open brain biopsy was performed for the tumor. Tumor histology showed diffuse proliferation of medium to large blastoid lymphoid cells. Immunohistochemistry was positive for CD20, BCL2, and BCL6 but negative for CD5, CD23, CD30, Cyclin D1, LEF1, and Bcl2 were negative. Ki67 was positive in 80%. (T cell receptor rearrangement was negative and B-cell receptor rearrangement was positive by Western blotting, data not shown) MYD88 L265P mutation was positive on PCR analysis on bone marrow samples. (H) By IgH rearrangement analysis, the CNS lesion harbors two IgH peak patterns. One is identical to the bone marrow lesion, whereas the other is not.

Fig. 3

Schematic of the hypothesis of the pathological findings in our cases. (A) In Case 1, common lymphoma stem cell with MYD88 p.L265P mutation infiltrates mainly into the bone marrow and central nervous system (CNS). (B) In Case 2, lymphoma stem cell mainly infiltrates into the spleen, then the bone marrow and CNS.