Nodular Lymphocyte Predominant Hodgkin Lymphoma and T Cell/Histiocyte Rich Large B Cell Lymphoma - Endpoints of a Spectrum of One Disease?

Abstract

In contrast to the commonly indolent clinical behavior of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), T cell/histiocyte rich large B cell lymphoma (THRLBCL) is frequently diagnosed in advanced clinical stages and has a poor prognosis. Besides the different clinical presentations of these lymphoma entities, there are variants of NLPHL with considerable histopathologic overlap compared to THRLBCL. Especially THRLBCL-like NLPHL, a diffuse form of NLPHL, often presents a histopathologic pattern similar to THRLBCL, suggesting a close relationship between both lymphoma entities. To corroborate this hypothesis, we performed gene expression profiling of microdissected tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. In unsupervised analyses, the lymphomas did not cluster according to their entity. Moreover, even in supervised analyses, very few consistently differentially expressed transcripts were found, and for these genes the extent of differential expression was only moderate. Hence, there are no clear and consistent differences in the gene expression of the tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. Based on the gene expression studies, we identified BAT3/BAG6, HIGD1A, and FAT10/UBD as immunohistochemical markers expressed in the tumor cells of all three lymphomas. Characterization of the tumor microenvironment for infiltrating T cells and histiocytes revealed significant differences in the cellular composition between typical NLPHL and THRLBCL cases. However, THRLBCL-like NLPHL presented a histopathologic pattern more related to THRLBCL than NLPHL. In conclusion, NLPHL and THRLBCL may represent a spectrum of the same disease. The different clinical behavior of these lymphomas may be strongly influenced by differences in the lymphoma microenvironment, possibly related to the immune status of the patient at the timepoint of diagnosis.

Small and big Hodgkin-Reed-Sternberg cells of Hodgkin lymphoma cell lines L-428 and L-1236 lack consistent differences in gene expression profiles and are capable to reconstitute each other

“…Gene expression analysis was performed and analyzed as previously described [11, 12]. Gene expression data are available through the GEO database (GEO accession number GSE86477).…”

Lymphoma classification update: T-cell lymphomas, Hodgkin lymphomas, and histiocytic/dendritic cell neoplasms

“…The 2008 WHO classification recommended describing NLPHL cases that progressed to a diffuse T-cell-rich pattern as ‘THRLBCL-like NLPHL’ to distinguish them from primary THRLBCL and indicated that at least focal presence of a typical NLPHL nodule be required for the diagnosis of NLPHL [1,2,80]. In the 2016 revision of the WHO classification, these cases are designated ‘THRLBCL-like transformation of NLPHL’ and have a more aggressive clinical course than typical NLPHL [2,85,86]. …”

Pathobiology of Hodgkin Lymphoma

“…In line with these data, studies of gene expression profile (GEP) carried on isolated neoplastic cells indicate that LP cells possibly originate from germinal center B cells at the transition to memory B cells. Recently, using the same approach, Hartmann et al performed GEP of microdissected tumour cells of NLPHL, THRLBCL-like NLPHL and THRLBCL and interestingly in unsupervised analyses, the examples of the three types of lymphoma did not form separate clusters 17. Moreover, even in supervised analyses, very few consistently differentially expressed transcripts were found, and for these genes the extent of differential expression was only moderate.…”