Nodular sclerosis classical Hodgkin lymphoma (NSCHL) is a subtype of CHL affecting young adults and manifesting either with a systemic nodal disease or alternatively with a mediastinal mass. Although histologically similar, mediastinal and non-mediastinal NSCHL differ for clinical behaviour and response to polychemotherapy treatment. Mediastinal NSCHL tends to do not spread to other lymph nodes, to have frequent recurrences, and to benefit from a more intensified therapy. Moreover, mediastinal NSCHL exhibits many clinicopathologic and molecular similarities with primary mediastinal diffuse large B cell lymphoma (PMBL), suggesting their origin from a thymic B cell. The lack of comparative analysis between mediastinal and non-mediastinal NSCHL limits our knowledge and the possibility to support the hypothesis that they could represent two different entities.
We propose to apply the integrative approach of RNA-sequencing to a cohort of mediastinal and non-mediastinal NSCHL to identify possible differences non only in terms of the molecular alterations that characterized tumour cells, but also on the non-neoplastic inflammatory background that influences the growth and dissemination of tumour cells. We will indeed integrate genes mutations and translocations with the gene expression profiles to define possible different tumour microenvironmental interactions that could support the definition of mediastinal NSCHL as a clinically and pathogenetically distinct type of CHL. The possible results of our study might provide important bases for the development of more ad hoc therapeutical strategies.
The integrative approach of RNAseq will provide important information not only on tumoral genetic alterations but also about the complex tumour-microenvironment interactions that influence tumour biology. Indeed, the inability of CHL of the mediastinum to spread to other lymph nodes, as it usually occurs in non-mediastinal CHL, as well as the different rate of response to ABVD, could be related not only to intrinsic molecular characteristics of neoplastic cells but also to different microenvironmental scenery.
Moreover, a different cell of origin could be postulated for mediastinal and non-mediastinal CHL. A close relationship of NSCHL to PMBCL and a possible origin from a thymic B cell has been described in recent studies (1). Both entities share several features. The low-affinity immunoglobulin (Ig)E receptor CD23, known to be expressed on thymic B cells and PMLBCL, is also expressed in some cases of CHL. Both CHL and PMBL lack the expression of immunoglobulin (Ig) and HLA class I antigens. Lastly, MAL a protein associated with lipid rafts in T cells and epithelial cells, is expressed in PMBL and in some cases of mediastinal NSCHL (1).
Expression of genes associated with infiltrating T-cells (IL6ST, CTLA4, CD28, and ICOS), and with immune regulation (IL1R2, IL32, IL7R, and TNIP3) have been reported to be upregulated in CHL where are thought to be related to its inflammatory background (2). In mediastinal B cell lymphomas, a thymic CD4 T cell signature and a macrophage cell signature have been found to be upregulated in CHL compared to PMBL (3). The identification of differently expressed genes by both tumour cells and by non-neoplastic microenvironment cells in mediastinal and non-mediastinal NSCHL may further support the hypothesis of a different cell of origin of the two diseases.
The extensive and comprehensive comparison of the transcriptome and of the molecular alterations in mediastinal and non-mediastinal CHL that we propose may substantially contribute to current knowledge shedding light on the comprehension of the biological mechanism responsible for their different clinical behaviour. Our results could also put the bases for the development of new, and more ad-hoc, targeted therapies for mediastinal NSCHL.
References
1-The Cancer Journal.2009;15:129-137
2-WHO classification of Haematopoietic and Lymphoid Tissues rev. 4th edition, IARC: Lyon 2017
3-Blood Cancer Discov.2020;1:155-161