Gene expression profiling of gray zone lymphoma.

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Gray zone lymphoma (GZL) is a rare B-cell lymphoma with intermediate features between diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (cHL).
• A subset of Epstein-Barr virus (EBV)-positive DLBCL exhibits GZL-like morphology (polymorphic-EBV-L).
• Understanding the pathogenesis of GZL and polymorphic-EBV-L is crucial.

Purpose of the Study:

• To elucidate the pathogenic processes underlying GZL and polymorphic-EBV-L.
• To precisely define the GZL spectrum using gene expression profiling (GEP).
• To differentiate GZL from polymorphic-EBV-L and identify GZL subtypes.

Main Methods:

• Gene expression profiling of a large international cohort including GZL, polymorphic-EBV-L, cHL, and primary mediastinal large B-cell lymphoma (PMBCL) cases.
• Unsupervised principal component analysis to assess GZL and polymorphic-EBV-L clustering.
• Differential gene expression analysis and phenotypic characterization of the tumor microenvironment.

Main Results:

• GZL cases showed intermediate gene expression profiles between cHL and PMBCL, while polymorphic-EBV-L clustered distinctly.
• Key biological pathways in GZL involved the cell cycle and extracellular matrix, reflecting tumor cell content and microenvironment.
• GZL exhibited a predominance of regulatory macrophages compared to cHL and PMBCL.
• Two GZL subtypes, PMBCL-like and DLBCL-like, were identified, with PMBCL-like GZL associated with thymic involvement.

Conclusions:

• GEP precisely defines the GZL spectrum and distinguishes it biologically from polymorphic-EBV-L.
• GZL can be classified into two distinct subgroups: PMBCL-like and DLBCL-like GZL.
• The tumor microenvironment, particularly regulatory macrophages, plays a significant role in GZL pathogenesis.