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Gene expression analysis provides a potential rationale for revising the histological grading of follicular lymphomas

¹ Department of Hematology and Oncology "L. and A. Seràgnoli", Hematopathology and Hematology Units, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
² Institute for Cancer Genetics
³ Center for Computational Biology and Biochemistry
⁷ The Herbert Irving Comprehensive Cancer Center, Columbia University, NY, USA
⁴ Unitat de Recerca en Neoplàsies Hematològiques-Parc Recerca Biomèdica Barcelona (URNHE-PRBB), Barcelona, Spain
⁵ Laboratori de Citogenètica i Biologia Molecular, Departament de Patologia
⁶ Clinical Hematology Department, Hospital del Mar, IMAS, Barcelona, Spain and ⁶Hematopathology, Insitute of Hematology, Monteluce Hospital, Perugia University, Perugia, Italy

Correspondence: Pier Paolo Piccaluga, MD, PhD, Head, Molecular Pathology Laboratory, Unit of Hematopathology, Department of Hematology and Oncology "L. and A. Seràgnoli", S. Orsola Malpighi Hospital, University of Bologna Via Massarenti, 9, 40138 Bologna, Italy. E-mail:pierpaolo.piccaluga{at}unibo.it

Background: Follicular lymphomas are currently subdivided into grades I, II, IIIa and IIIb. This distinction is, however, questioned.

Design and Methods: We studied the gene expression profile of 43 follicular lymphomas, 50 B-cell non-Hodgkin’s lymphomas of different histotype, and 20 samples of normal B-lymphocytes in order to assess: (i) the relationship of follicular lymphoma with normal B cells and other B-cell non-Hodgkin’s lymphomas; (ii) whether follicular lymphoma is a unique disease; and (iii) whether follicular lymphoma grade IIIb is closer to follicular lymphoma or diffuse large B-cell lymphoma of the germinal center B-cell type.

Results: First, we found that the molecular profile of follicular lymphoma is intimately related to that of normal germinal center B cells, irrespectively of the histological grade. Secondly, we observed that follicular lymphoma has a relatively homogeneous gene expresion profile that is distinct from that of other B-cell non-Hodgkin’s lymphoma and does not include discrete molecular subgroups. However, by further clustering samples according to signatures differentially expressed among follicular lymphomas or in follicular lymphomas versus diffuse large B-cell lymphoma, we showed that grade I–IIIa tumors tend to cluster together, while grade IIIb follicular lymphoma constitutes a distinct subgroup, whose molecular signature is closer to that of the remaining follicular lymphomas than to that of diffuse large B-cell lymphoma of the germinal center B-cell type.

Conclusions: These data support the hypothesis that grade IIIb follicular lymphoma does indeed belong to the group of follicular lymphomas rather than diffuse large B-cell lymphomas, and also suggests a possible revision of the histological grading of follicular lymphomas, with their simple distinction into follicular lymphoma (grade I–IIIa) and follicular lymphoma/large cell (grade IIIb).

Key words: follicular lymphoma, non Hodgkin’s lymphoma, histological grading, DNA micro-array.

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