Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma

Abstract

The online version of this article has a supplementary Appendix. BackgroundMediastinal gray zone lymphoma is a newly recognized entity with transitional morphological and immunophenotypic features between the nodular sclerosis subtype of Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma. Diagnostic criteria for mediastinal gray zone lymphoma are still challenging, and the optimal therapy is as yet undetermined. Epigenetic changes have been implicated in the loss of the B-cell program in classical Hodgkin's lymphoma, and might provide a basis for the immunophenotypic alterations seen in mediastinal gray zone lymphoma. Design and MethodsWe performed a large-scale DNA methylation analysis of microdissected tumor cells to investigate the biological underpinnings of mediastinal gray zone lymphoma and its association with the related entities classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma, making comparisons with the presumptively less related diffuse large B-cell lymphoma. ResultsPrincipal component analysis demonstrated that mediastinal gray zone lymphoma has a distinct epigenetic profile intermediate between classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma but remarkably different from that of diffuse large B-cell lymphoma. Analysis of common hypo-and hypermethylated CpG targets in mediastinal gray zone lymphoma, classical Hodgkin's lymphoma, primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma was performed and confirmed the findings of the principal component analysis. Based on the epigenetic profiles we were able to establish class prediction models utilizing genes such as HOXA5, MMP9, EPHA7 and DAPK1 which could distinguish between mediastinal gray zone lymphoma, classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma with a final combined prediction of 100%. ConclusionsOur data confirm a close relationship between mediastinal gray zone lymphoma and both classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma. However, important differences were observed as well, allowing a clear distinction from both parent entities. Thus, mediastinal gray zone lymphoma cannot be assigned to either classical Hodgkin's lymphoma or primary mediastinal large B-cell lymphoma, validating the decision to create an intermediate category in the World Health Organization classification. B-cell lymphoma. Haematologica 2011;96(4):558-566. doi:10.3324/haematol.2010 This is an open-access paper.

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

“…The optimal therapeutic management of these lymphomas has not been determined. Recent biologic studies have begun to yield insights into the mechanisms modulating the plasticity of the neoplastic B cells and tumor microenvironment in CHL and DLBCL, 100,101 and they may provide data relevant to improved therapies. 102 …”

“…95,99 These observations suggested that a true biologic gray zone between these 2 entities could exist, a finding supported by profiling at the epigenetic level. 100 The 2008 WHO classification incorporates these new ideas and recognizes a provisional category of B-cell neoplasms with features intermediate between DLBCL and CHL. The category does not include the composite or sequential cases of both neoplasms.…”

Whole genome profiling and other high throughput technologies in lymphoid neoplasms—current contributions and future hopes

“…61,62 Together with more recent genetic and epigenetic studies, they also support the inclusion in the WHO classification of the category large B-cell lymphoma, unclassifiable with features intermediate between DLBCL and HL. [63][64][65][66] …”

Shades of gray between large B-cell lymphomas and Hodgkin lymphomas: differential diagnosis and biological implications

“…4 Analysis of methylation patterns has shown that mediastinal gray-zone lymphoma has a distinct epigenetic profile intermediate between CHL and PMBL but different from that of diffuse LBCL, suggesting that it is a distinct neoplasm, different from either CHL or PMBL. 20 The WHO classification in 2008 added a provisional category, B-cell lymphoma, intermediate between DLBCL and CHL. 21 It is defined as a B-lineage lymphoma that demonstrates overlapping clinical, morphological and/or immunophenotypic features between CHL and DLBCL, especially PMBL.…”