Abstract
Simple SummaryClassic Hodgkin lymphoma (CHL) is a well-defined lymphoid neoplasm with a minority of characteristic neoplastic cells of B cell origin, namely Hodgkin and Reed–Sternberg cells immersed in a rich reactive inflammatory infiltrate in the background. Although CHL has always been set apart from non-Hodgkin lymphomas, cases with morphological and phenotypic features intermediate between CHL and other lymphomas have been described. Whereas some of these lymphomas only represent morphological mimics, others exhibit mutational and gene expression profiles which overlap with CHL, indicating that these cases, frequently termed grey zone lymphomas, reside on the biological boundary between CHL and large B-cell lymphomas. In the present review, we aim to describe the current knowledge of these rare lymphomas, address diagnostic issues and summarize today’s concepts on the classification of grey zone lymphomas and related tumors.Classic Hodgkin lymphoma (CHL) is a well-defined neoplasm characterized by the presence of a minority of pathognomonic Hodgkin and Reed–Sternberg (HRS) cells in a reactive inflammatory background. Although genotypically of B cell origin, HRS cells exhibit a downregulated B cell program and therefore are set apart from other B cell lymphomas in the current WHO classification. However, cases with morphological and phenotypic features overlapping with CHL have been recognized, and the category of B cell lymphoma—unclassifiable—with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL, also termed grey zone lymphoma, was first introduced into the WHO classification in 2008 as provisional entity. These cases, as well as others raising a differential diagnosis of CHL can present diagnostic problems, as well as therapeutic challenges. Whereas some of these lymphomas only represent biologically unrelated morphological mimics, others, especially mediastinal grey zone lymphoma, exhibit genetic and gene expression profiles which overlap with CHL, indicating a true biological relationship. In this review, we address areas of diagnostic difficulties between CHL and other lymphoma subtypes, discuss the biological basis of true grey zone lymphoma based on recent molecular studies and delineate current concepts for the classification of these rare tumors.
Highlights
Classic Hodgkin lymphoma (CHL) is a clonal lymphoproliferative disease derived from germinal center B-cells, accounting for 15–25% of all malignant lymphomas [1,2,3,4]
CHL can usually be separated reliably from other lymphomas based on morphology and immunophenotype, some cases exhibit overlapping features with nonHodgkin lymphomas (NHL) or nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) [12,13,14]
The Hodgkin and multinucleate Reed–Sternberg (HRS)-like morphology of the neoplastic cells with co-expression of B cell markers as well as CD30 and CD15 best fit with a diagnosis of non-mediastinal grey zone lymphoma, these cases genotypically are distinct from Mediastinal Grey Zone Lymphoma (mGZL)
Summary
Classic Hodgkin lymphoma (CHL) is a clonal lymphoproliferative disease derived from germinal center B-cells, accounting for 15–25% of all malignant lymphomas [1,2,3,4]. Mediastinal CHL NS, mGZL and PMBL probably share their origin from thymic B cells and represent a clinical, biological and genetic continuum They are jointly characterized by predominance in young adults with bulky mediastinal disease and frequent presence of immune escape mechanisms, and are discerned by distinct architectural features, variable numbers of reactive inflammatory cells and different levels of B cell marker expression. The HRS-like morphology of the neoplastic cells with co-expression of B cell markers as well as CD30 and CD15 best fit with a diagnosis of non-mediastinal grey zone lymphoma, these cases genotypically are distinct from mGZL (Original magnification: (A): ×100, A inset: ×400; (B–G): ×600). NLPHL shows similarities to lymphocyte rich CHL, which was separated from NLPHL mainly by the work of the German Hodgkin lymphoma study group [9] usually exhibits a nodular growth pattern with dominance of small B-cells. Genetic analysis currently is not useful for this differential diagnosis, let alone for practical reasons due to the sparsity of tumor cells
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