The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis

Abstract

The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20-40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.

SLAMF1/CD150 in hematologic malignancies: Silent marker or active player?

“…The 95% of all HL belong to the classical type of HL [23]. Using wide arsenal of cell surface receptors and cytokines these tumor cells create a favorable microenvironment that supports tumor cell survival and mediates immunosuppression [92][93][94]. HRS cells in up to 40% of HL cases are EBV positive with type II infection pattern and express LMP-1 protein that is linked to CD150 upregulation [94].…”

“…Using wide arsenal of cell surface receptors and cytokines these tumor cells create a favorable microenvironment that supports tumor cell survival and mediates immunosuppression [92][93][94]. HRS cells in up to 40% of HL cases are EBV positive with type II infection pattern and express LMP-1 protein that is linked to CD150 upregulation [94]. On the other hand, tumor necrosis factor (TNF) receptor family receptors, such as CD30, CD40, CD95, TACI, BCMA, and RANK on the surface of HRS are acceptors of signals from tumor microenvironment that initiate different signaling pathways in tumor cells and regulate their phenotype.…”

HIV-related Refractory Hodgkin Lymphoma: A Case Report of Complete Response to Nivolumab

“…2 While the distribution of histologic subtypes may have shifted slightly in the last 20 years with the widespread use of ART, 3 the overall incidence of HIV-HL has not significantly decreased, in contrast to dramatic decreases in the rates of Kaposi’s sarcoma, primary central nervous system lymphoma, and diffuse large B cell lymphoma, suggesting that ART-mediated immune reconstitution is not adequate to prevent Hodgkin lymphomagenesis in the HIV-infected population. 4 Additionally, the observation that EBV is invariably detectable in HIV-HL regardless of histology, 5-7 and only seen in 20-40% of cHL cases in the HIV-uninfected population, has sparked research interest in the tumor microenvironment of HIV-HL in search of the unique role of EBV in this disease. In the meantime, HIV-HL is treated under the same guidelines as cHL in the general population.…”

Is ultrasound combined with computed tomography useful for distinguishing between primary thyroid lymphoma and Hashimoto’s thyroiditis?

“…It is estimated that approximately 60-90% of most PTL cases occur in the background of thyroiditis. One of the many theories that has been proposed to explain the basis is that chronic antigenic stimulation of lymphocytes in autoimmune disorders may lead to malignant transformation [8]. A minority support the theory of aberrant somatic hypermutation [9].…”