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

Piccaluga, Pier Paolo; Califano, Andrea; Klein, Ulf; Agostinelli, Claudio; Bellosillo, Beatríz; Gimeno, Eva; Serrano, Sergi; Solé, Francisco; Zang, Yonghui; Falini, Brunangelo; Zinzani, Pier Luigi; Pileri, Stefano

doi:10.3324/haematol.12754

Cited by 70 publications

(64 citation statements)

References 22 publications

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“…Of these subtypes, FL grade 3 (FL3) have gained considerable interest because of their unresolved status as indolent or aggressive neoplasms, and their varying immunophenotypic, cytogenetic and possibly clinical features. [5][6][7][8][9][10][11][12][13] Currently, the WHO classification defines two types of FL3, one being composed of centroblasts and centrocytes (FL3A), the other harboring exclusively centroblasts (FL3B).…”

Section: Discussionmentioning

confidence: 99%

Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles

Horn¹,

Schmelter²,

Leich³

et al. 2011

Haematologica

146

100

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The online version of this article has a Supplementary Appendix. BackgroundAccording to the current World Health Organization Classification of Lymphoid Tumours, follicular lymphoma is subclassified into three grades according to the number of centroblasts. Follicular lymphoma grade 3 can be further divided into types A and B. Almost all available genetic data on grade 3B follicular lymphomas have been generated from tumors with an additional diffuse large B-cell lymphoma component. The purely follicular type of follicular lymphoma grade 3B is a rare neoplasm. Design and MethodsWe performed a detailed immunohistochemical (CD10, IRF4/MUM1, BCL2, Ig light chains) and genetic (translocations of BCL2, BCL6, MYC, IRF4) characterization of the largest series of purely follicular cases of grade 3B follicular lymphoma available to date, comprising 23 tumor samples. We also included 25 typical grade 1 or 2 follicular lymphomas, 9 follicular lymphomas with large centrocytes and/or high proliferation indices (FL/LCC), 12 cases of follicular lymphoma grade 3A, 16 cases of diffuse large B-cell lymphoma/follicular lymphoma grade 3B and 15 follicular lymphomas in which a straightforward distinction between grades 3A and 3B was not possible. ResultsTranslocations affecting BCL2 and BCL6 genes are rare in grade 3B follicular lymphomas (2/23, 9% and 4/23, 17%) when compared with grade 1 or 2 follicular lymphomas (22/25, 88%, P<0.001 and 0/25, P<0.05), FL/LCC (7/9, 78%, P<0.001 and 2/9, 22%), grade 3A follicular lymphomas (7/12, 58%, P<0.01 and 2/12, 17%), unclassified grade 3 follicular lymphomas (6/15, 40% and 2/15, 13%) and diffuse large B-cell lymphoma/follicular lymphoma grade 3B (2/16, 13% and 8/16, 50%, P<0.05). MYC translocations were detected occasionally in FL/LCC, follicular lymphoma grade 3B, and diffuse large B-cell lymphoma/follicular lymphoma grade 3B (13%-22%), but not in grade 1, 2 or 3A follicular lymphomas (P<0.05 when compared with follicular lymphoma grade 3B). Both follicular lymphoma grade 3B and diffuse large B-cell lymphoma/follicular lymphoma grade 3B were enriched in samples with a CD10 -IRF4/MUM1 + immunophenotype (8/19, 42% and 7/16, 44%), with the vast majority of them lacking BCL2 translocations. In contrast, 42/46 grade 1 or 2 follicular lymphomas, FL/LCC and grade 3A follicular lymphomas were CD10 + (91%) while 0/46 expressed IRF4/MUM1. None of the tumor samples tested with increased IRF4/MUM1-expression harbored a translocation of the IRF4 gene locus. ConclusionsOur results show that grade 3B follicular lymphomas form a distinct category of follicular lymphomas with infrequent BCL2 and BCL6 translocations, while grades 1, 2 and 3A follicular lymphomas and FL/LCC display homogeneous features with frequent BCL2 translocations and a CD10 + IRF4/MUM1 -immunophenotype.

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Section: Discussionmentioning

confidence: 99%

Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles

Horn¹,

Schmelter²,

Leich³

et al. 2011

Haematologica

146

100

View full text Add to dashboard Cite

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“…Based on the immunophenotype (CD10 -, MUM1 + ) and frequent BCL-6 gene rearrangement, it has been suggested that these BCL-2-negative FL may have a late-stage GC or post-GC cell origin, and are probably more closely related to diffuse large B-cell lymphomas (DLBCL). 10,18 However, in a recently published study based on gene expression analysis, Piccaluga et al 19 suggested that grade 3B FL does after all belong to the group of FL rather than DLBCL. The authors also propose a possible revision of the histological grading of FL, with their simple distinction into FL (grade 1-3A) and FL/large cell (grade 3B).…”

Section: Introductionmentioning

confidence: 99%

Somatic hypermutation of IGVH genes and aberrant somatic hypermutation in follicular lymphoma without BCL-2 gene rearrangement and expression

Gagyi¹,

Balogh²,

Bödör³

et al. 2008

Haematologica

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BackgroundFollicular lymphoma is characterized by the t(14;18) translocation resulting in constitutive expression of BCL-2 protein; however approximately 10-15% of follicular lymphomas do not express BCL-2 protein, and a small fraction of these cases does not exhibit translocation of the BCL-2 gene either. It is highly debated whether cases of follicular lymphoma without BCL-2 gene rearrangement and expression represent a separate lymphoma entity with distinct biological characteristics, different from the BCL-2-positive cases.

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“…Moreover, Hans et al 21 found no difference in outcome between FL3A and FL3B, and another study, also based on cases with a purely follicular growth pattern, found a gene signature in FL3B that was closer to FL than to DLBCL of the germinal center B-cell (GCB) type. 22 Thus, the final decision was to combine FL grades 1 and 2 into one category (FL1-2 of 3) and make the distinction between FL3A and FL3B mandatory rather than optional. This issue will need to be revisited when more data are available.…”

Section: Follicular Lymphoma: Grading and Variantsmentioning

confidence: 99%

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications

Campo

Swerdlow

Harris

et al. 2011

Blood

1,782

1,414

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The World Health Organization classification of lymphoid neoplasms updated in 2008 represents a worldwide consensus on the diagnosis of these tumors and is based on the recognition of distinct diseases, using a multidisciplinary approach. The updated classification refined the definitions of well-recognized diseases, identified new entities and variants, and incorporated emerging concepts in the understanding of lymphoid neoplasms. However, some questions were unresolved, such as the extent to which specific genetic or molecular alterations define certain tumors, and the status of provisional entities, categories for which the World Health Organization working groups felt there was insufficient evidence to recognize as distinct diseases at this time. In addition, since its publication, new findings and ideas have been generated. This review summarizes the scientific rationale for the classification, emphasizing changes that have had an effect on practice guidelines. The authors address the criteria and significance of early or precursor lesions and the identification of certain lymphoid neoplasms largely associated with particular age groups, such as children and the elderly. The issue of borderline categories having overlapping features with large B-cell lymphomas, as well as several provisional entities, is reviewed. These new observations chart a course for future research in the field. (Blood. 2011

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

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

Cited by 70 publications

References 22 publications

Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles

Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles

Somatic hypermutation of IGVH genes and aberrant somatic hypermutation in follicular lymphoma without BCL-2 gene rearrangement and expression

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications

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