Current and potential use of pathological targets in the treatment of Hodgkin lymphoma
Authors: Antonino Carbone, Annunziata Gloghini
Journal: American Journal of Hematology (2018)

Diagnosis and classification of classical Hodgkin lymphoma (CHL) evolved from traditional histologic classifications to the current World Health Organization (WHO) multiparameter system.1 Although HL classification has not formally changed over the last two decades, updates concerning HL subtypes have incorporated information with significant clinical and biological implications.1 These updates in addition to the expanding knowledge and understanding of CHL biology can really impact diagnosis and management of affected patients. Based on the morphologic characteristics of the Hodgkin and Reed–Sternberg (HRS) cells and the composition of the cell microenvironment, four subtypes have been recognized: lymphocyte-rich CHL (LRCHL), nodular sclerosis (NS) CHL, mixed cellularity (MC) CHL, and lymphocyte depletion (LD) CHL. In MC CHL, lymphocytes, eosinophils, granulocytes, histiocytes/macrophages, plasma cells, mast cells are observed. A great number of fibroblast-like cells and fibrosis are frequently found in NS CHL.2 Currently, a reliable diagnosis of CHL is based on the expression of aberrant phenotype by HRS cells. HRS cells consistently express CD30, CD15, CD40, and IRF4/MUM1.1, 2 Clearly, the co-expression of CD30 and CD15 by typical HRS cells within an appropriate background which is rich in inflammatory cells, sclerosing collagen, and CD4+/PD-1+ T-cells, provides a sharp separation between CHL and large B-cell lymphomas or other pathologic conditions. Although expression of other molecular markers in CHL,1, 2 including B-cell associated antigens (CD20, CD79, and PAX5), germinal center B-cell markers (BCL6), and molecules involved in antigen presentation (MHC class II, CD80, CD86) is not considered today of diagnostic utility, it now represents a therapeutic target. Moreover, the cross-talk between HRS cells and their microenvironment may have a pathogenetic role thus suggesting that both HRS cells and microenvironmental cells may represent a promising target to reduce the long-term toxicities of chemo-radiotherapy in chemosensitive patients and also to effectively treat primary refractory and patients with early-relapsed CHL. While the immunophenotype of HRS cells is identical in the histologic subtypes of CHL, their association with Epstein–Barr virus (EBV) infection is different: EBV infection is detectable in HRS cells of MC and LD CHL subtypes, but less frequently in the other CHL subtypes.3 Importantly, the EBV infection of HRS cells of CHL is variable and depends on the immunocompetence status of the host. In particular, EBV infection is detected in virtually all cases of CHL occurring in patients with HIV infection.1, 3 EBV-positive HRS cells express a relatively restricted set of viral genes, the so-called type II latency pattern, including LMP-1, and LMP-2 latent proteins, EBNA-1, and EBERs RNAs. Genetic studies have demonstrated that multiple signaling pathways are deregulated in HRS cells, suggesting the potential significance of their therapeutically targeting.4, 5 Recently, new therapeutic agents have emerged that target the aberrant phenotype of CHL tumor cells, deregulated oncogenic pathways, and immune escape6-9 (Figure 1). Active yet non-curative drugs, have obtained substantial responses in refractory/relapsed patients (reviewed in Refs. 6, 8-10). Table 1 highlights novel approaches that target the phenotype of HRS cells and deregulated oncogenic pathways or which interfere with the tumor microenvironment and tumor–host interface. Schematic presentation of HRS cell and surrounding microenvironmental cells, phenotypic features, and oncogenic pathways targetable by novel agents. Abbreviations: CART, chimeric antigen receptor T cell; CTL, cytotoxic T cells; TAM, tumor-associated macrophages; TREG, regulatory T cells. Restored B-cell phenotype with re-expression of CD20. [Color figure can be viewed at wileyonlinelibrary.com] In conclusion, what do we expect to do today in clinical research? Prospective trials with therapeutic approaches guided by novel pathologic and biologic insights are expected. In fact, new technologies have improved our understanding of the genetics of CHL and recent discoveries are now being translated into clinical research as new diagnostics and treatments. It is conceivable that the most promising strategy in future clinical trials will be the testing of novel agents targeting HRS cells along with the cell microenvironment. Predictive biomarkers that are based on underlying tumor pathobiology probably will enable the early identification of chemorefractory patients (eg, PD-1/PD-L1 expression on HRS cells or microenvironmental cells). What do we expect to do today in clinical practice? Needless to say, a careful pathologic analysis, comprising the definition of CHL subtype, remains the first step for leading the detection of therapeutic targets for CHL. The translation of recent discoveries into the clinical setting requires additional information including (1) the characteristics of the tumor microenvironment together with (2) the phenotype of HRS cells and (3) the list of markers expressed by microenvironmental T lymphocytes, (4) the presence of other predictive biomarkers detected by immunohistochemistry, and (5) the status of EBV infection of HRS cells by EBER in situ hybridization. Furthermore, to support the success of the therapeutic targeting of CHL, information on the expression of other targetable HRS cell markers or on active deregulated pathways should be determined upon physician's request and added in the pathologic report. AC is Chairman of the Italian TNM Staging Committee—UICC; Member of WHO IARC Monograph Working Group on Biological Agents, Lyon, 2009. The Authors thanks Elettra Gislon, an English speaker, for editing the manuscript. None AC and AG designed and wrote the manuscript