Progress in pathologyB-cell lymphomas with features intermediate between distinct pathologic entities. From pathogenesis to pathology☆
Introduction
Progress in understanding molecular pathogenesis of lymphoid malignancies has in most instances allowed a pathogenetic-based approach to lymphoma classification [1]. This approach identifies lymphomas associated with infectious agents, lymphomas with deregulation of apoptosis and survival pathways, lymphomas with deregulation of the cell cycle, lymphomas with deregulation of the cell signaling or transcriptional regulation, and lymphomas associated with host's immunosuppression [1]. Lymphomas occurring specifically in immunosuppresed patients are closely linked to viral diseases and fall in a spectrum of B-cell differentiation where those associated with Epstein-Barr virus (EBV) or Kaposi-associated herpesvirus commonly exhibit plasmablastic differentiation [2].
Irrespective of the underlying causes, most of these lymphomas are considered to be distinct clinical and pathologic entities. They have characteristic immunophenotype and known genetic abnormalities and can be recognized by pathologists with available techniques.
Published in September 2008, the updated World Health Organization (WHO) [3] classification builds upon the advances of the past [3], [4], better defines heterogeneous categories of disease, and introduces provisional borderline categories for cases that do not clearly fit into one entity [3]. These borderline categories, which include lymphoid malignancies already known as gray zone lymphomas, demonstrate overlapping clinical, morphological, and/or immunophenotypic features between well-established entities and pose real diagnostic challenge.
The present review will deal with the molecular pathogenesis and pathologic features of B-cell lymphomas with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). Specifically, the focus will be on the categories intermediate between primary mediastinal large B-cell lymphoma (PMLBCL) and classical HL (cHL) and those intermediate between T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and nodular lymphocyte predominant HL (NLPHL). Furthermore, the review will include a special section on the new category that has been created for cases showing features intermediate between DLBCL and Burkitt lymphoma (BL) [3] (Fig. 1).
Section snippets
T-cell/histiocyte-rich large B-cell lymphoma and NLPHL
Although THRLBCL is an aggressive DLBCL, its morphology can resemble NLPHL, a rare indolent B-cell lymphoma. Actually, recent studies suggest that these 2 entities are closely related [5], [6], [7]. At the same time, there is increasing understanding of the overlap that occurs in the “gray zone” between DLBCL and HL [5], [6], [7], [8].
Primary mediastinal large B-cell lymphoma and cHL
Formerly, the term gray zone lymphoma has been assigned to neoplasms exhibiting intermediate features between cHL and DLBCL, such that definitive classification as cHL or DLBCL is impossible even after extensive immunophenotypic and molecular studies. The interface between nodular sclerosis HL and PMLBCL is currently felt to comprise a spectrum of lymphomas showing biological transition: these lymphomas are termed mediastinal gray zone lymphomas[17], [18], [19], [20].
Diffuse large B-cell lymphoma NOS and BL
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL NOS and BL is the terminology adopted by WHO classification [3] for aggressive B-cell lymphomas with morphologic, phenotypic, and genetic features, which overlap between BL and DLBCL. Formerly, these would usually been in the unclassified category or classified as Burkitt-like lymphomas. This is not a distinct entity in the WHO but is useful for classifying cases, which do not meet the diagnostic criteria for BL or DLBCL
Unresolved issues: treatment options and pathologic predictors of outcome
Despite recent progress in immunologic markers, it is still a challenge to differentiate NLPHL from THRLBCL in some cases. Unfortunately, there are still no reliable immunologic markers currently available for the clinical differentiation of NLPHL from THRLBCL [7]. Nevertheless, lymphoma cases showing overlapping features between THRLBCL and NLPHL were not recognized as “B-cell lymphoma, unclassifiable” within the provisional borderline categories because in the 2008 Classification [3] the
Acknowledgments
The authors would like to thank Gianni Roncato for photographic contributions, Maria Morelli and Alda Tosi for the preparation of the manuscript, and Dr Elisa Bonomi who contributed to the critical revision of the diagnostic algorithm reported in Fig 5.
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This work was supported in part by a Grant from the Ministero della Salute, Rome, within the framework of the “Progetto Integrato Oncologia-Advanced Molecular Diagnostics” project (RFPS-2006-2-339723.2) (to A.Car.).