Publications of Faculty of Medicine:Expression patterns of transcription factors in progressively transformed germinal centers and Hodgkin lymphoma: Abstract

Title:
Expression patterns of transcription factors in progressively transformed germinal centers and Hodgkin lymphoma
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Abstract:

The World Health Organization (WHO) classification of Hodgkin lymphoma (HL) distinguishes two types: Classical Hodgkin lymphoma (CHL) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). Both groups have in common that they mostly derive from B cells with rare classical cases originating from T cells. They differ in their histomorphology, immunophenotype, and clinical behavior. One of the subtypes of CHL, designated as lymphocyte-rich classical Hodgkin lymphoma (LRCHL), shares some morphological features with NLPHL. The transcription factors BSAP, BOB.1, Oct2 and MUM I are sequentially expressed in normal Bcell development In order to investigate the relationship between the CHL subgroups and NLPHL, we examined the protein expression of these transcription factors using immunohistochemistry in 15 reactive processes and 4 different subtypes of 58 HL cases. Our findings underline the B-cell origin of HL, without evidence, that reactive processes like progressively transformed germinal centers (PTGCs) are precursor lesions of HL. Furthermore, they demonstrate that LRCHL is distinct from NLPHL and that it is closely related to the mixed cellularity CHL (MCHL) in respect of BSAP, BOB.1, and Oct2 expression. It therefore occupies an intermediate position between MCHL and NLPHL. Based on MUM1 staining, LRCHL exhibits a more mature phenotype than NLPHL. Keywords Hodgkin lymphoma • Transcription factors • BSAP/Pax5 Oct2 BOB.I/OBF1 MUMUIRF4 Both authors, S.A. Steimle-Grauer and M. Tinguely, contributed equally to this work. S.A. Steimle-Grauer () • M. Tinguely • L. Seada • C. Fellbaum • M.-L. Hansmarm Senckenbereisches Institute of Pathology, Johann Wolfgang Goethe-University of Frankfurt, Theodor-Stern-Kai 7. 60596 Frankfurt am Main, Germany e-mail: Steimle-Grauer@em.uni-frankfurt.de Tel.: A-49-69-63015761 Fax: +49-69-63015241 Introduction Hodgkin lymphoma (HL) is one of the most common lymphomas in the Western world. Its cellular origin has been a controversial issue for years. Single-cell analyses of Hodgkin and Reed Sternberg (HRS) cells revealed a majority of about 98% of classical Hodgkin lymphoma (CHL) as being derived from B cells and only about 2% from T cells [6, 12, 29, 43]. In recent years, intensive research has confirmed the division into two main groups, the CHL and the rare nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). They are distinguished by their different morphology as well as by their immunophenotype. The malignant lymphocytic and histiocytic (L&H) cells in NLPHL express B-cell associated molecules as CD20, CD79a, J-chain and immunoglobulins, but lack CD30 and CD15. In contrast, the FIRS cells in CHL typically express CD30 and often CD15 but, in most instances, are devoid of CD20, CD79a, I-chain and immunoglobulins [41, 52]. Genotypically, all HLs contain rearranged immunoglobulin genes; however, both types have different patterns [5, 19, 22, 23, 26, 27]. In 1995, four cases of a variant of classical Hodgkin's disease were described as follicular Hodgkin's disease [2]. Recently, this variant of CHL, which morphologically resembled NLPHL in terms of nodular growth and lymphocyte richness, and CHL in terms of the immunophenotype, was designated as the common nodular variant of lymphocyte-rich classical Hodgkin lymphoma (LRCHL). The nodules in LRCHL, predominantly consisting of B cells, differ from those in NLPHL in that they represent expanded mantle zones with atrophic germinal centers (GCs) [1, 13]. Single-cell analyses for immunoglobulin gene rearrangements of LRCHL revealed that its tumor cells are derived from antigen experienced B cells with a mutation pattern similar to that of CHL (Brauninger et al. unpublished observations). To gain new insights into the cellular origin and the maturation stage of HL, we first examined the localization of the tumor cells in HL, focusing on LRCHL and NLPHL. Thereafter, B-cell specific activator

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