of B-Cell Lymphomas: Diagnosis and Biomarker Discovery

Expected immunophenotype

Follicular lymphoma

CD19+, CD20+, IgM ± IgD, monotypic sIg+, CD10+, bcl-6+, bcl-2 ±, HGAL, LMO2; associated with CD21+/CD23+ follicular dendritic cell meshworks

Lymphoplasmacytic lymphoma

CD19+, CD20+, monotypic sIg+, IgM, CD22+, CD79a+, CD5 ∓; plasma cells have monotypic cytoplasmic Ig

Mantle cell lymphoma

CD19+, CD20+, monotypic sIg+, IgM ± IgD, CD5+, CD23− or weakly+, cyclinD1+, SOX11± , LEF1 −

Diffuse large B cell lymphoma, nos

CD19+, CD20+, monotypic sIg+ or absent sIg, BCL2± . MYC+ in some cases of typical DLBCL, nos, and in BCL-U

∙ Germinal center B like

Hans: (CD10+) or (CD10−/bcl-6+/MUM1−)

Choi: (GCET+/MUM1−) or (GCET−/CD10+) or (GCET−/CD10−/BCL6+/FOXP1−)

Tally: Scoring system favors CD10, GCET, and LMO2 >30 %

∙ Non-germinal center B like

Hans: (CD10−/BCL6−) or (CD10−/BCL6+/MUM1+)

Choi: (GCET+/MUM1+) or (GCET−/CD10−/BCL6+/FOXP1+) or (GCET−/CD10−/BCL6−)

Tally: Scoring system favors MUM1, FOXP1, and LMO2 <30 %

Primary mediastinal (thymic) large B-cell lymphoma

CD19+, CD20+, CD22+, CD79a+, MAL+, cREL+, CD200, MUM1, CD23, BCL2±, BCL6±, CD30± (weak, heterogeneous), surface Ig weak to absent

Burkitt lymphoma

CD19+, CD20+, CD10+, BCL6+, BCL2-, monotypic sIg+, MUM1−, MYC+, Ki67 > 95 %. Cases associated with EBV: EBV-encoded RNA+/EBNA-1+ and LMP1−/EBNA-2−

Table 2

Recently investigated molecular biomarkers in selected B-cell non-Hodgkin lymphomas

	Molecular biomarker	Useful method for detection	Significance
Lymphoplasmacytic lymphoma	MYD88 L265P mutation	Allele-specific PCR	Fairly sensitive and specific for LPL/WM and IgM MGUS diagnosis. May be predictive of disease burden and indicate risk of progression in IgM MGUS
Mantle cell lymphoma	SOX11 transcription factor overexpression	Immunohistochemistry (especially monoclonal anti-SOX11^MRQ−58, Cell Marque, Rocklin, CA)	Good biomarker for MCL diagnosis, including cyclin D1-negative variant. May be a useful prognostic parameter, but studies are conflicting. May be a promising prospect for MRD analysis. Suppresses terminal B-cell differentiation and drives angiogenesis in MCL [97].
Diffuse aggressive B-cell lymphoma	“double-hit” genotype (dual BCL2 and MYC translocations are most common)	Fluorescence in situ hybridization (FISH) detects genetic translocation	Prognostic biomarker (worse progression-free and overall survival). Double-protein-positive (MYC and BCL2 protein by immunohistochemistry) independently predicts a worse survival in rituximab–CHOP-treated patients with DLBCL
Diffuse large B-cell lymphoma	Germinal center B cell-like (GCB) versus activated B cell-like (ABC) gene expression profile	Several immunohistochemistry—based algorithms, or new multiplex gene expression assay (ICEPlex^® system, PrimeraDx, Mansfield, MA)	Prognostic and biologically significant. The ABC subtype has a worse outcome and indicates activation of the B-cell receptor and NF-κB pathways. This may also predict response to targeted therapies and support clinical trials

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