Testicular Diffuse Large B-Cell Lymphoma-Clinical, Molecular, and Immunological Features

Abstract

Primary testicular lymphoma is a rare lymphoma entity, yet it is the most common testicular malignancy among elderly men. The majority of the cases represent non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) with aggressive clinical behavior and a relatively high relapse rate. Due to the rareness of the disease, no randomized clinical trials have been conducted and the currently recognized standard of care is based on retrospective analyses and few phase II trials. During recent years, the tumor microenvironment (TME) and tumor-related immunity have been the focus of many tumor biology studies, and the emergence of targeted therapies and checkpoint inhibitors has significantly modulated the field of cancer therapies. Testicular DLBCL (T-DLBCL) is presented in an immune-privileged site of the testis, and the roles of NF-κB pathway signaling, 9p24.1 aberrations, and tumor-infiltrating immune cells, especially immune checkpoint expressing lymphocytes and macrophages, seem to be unique compared to other lymphoma entities. Preliminary data on the use of immune checkpoint inhibitors in the treatment of T-DLBCL are promising and more studies are ongoing.

Keywords: lymphoma immunology; testicular diffuse large B-cell lymphoma; tumor micro-environment.

Figure 1

Dysregulated NF-κB signaling in T-DLBCL. Genomic alterations in the BCR and TLR signaling result in constitutive activation of NF-κB signaling. Aberrations typical for T-DLBCL are marked with red stars. BTK, Bruton’s tyrosine kinase; IRAK, interleukin-1 receptor-associated kinases; JAK, Janus kinase; MALT1, mucosa-associated lymphoid tissue; MTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PKCβ, protein kinase C beta; STAT, signal transducer and activator of transcription; SYK: spleen-associated tyrosine kinase; TLR, toll-like receptor. Adapted from King et al., 2021 [88].

Figure 2

Examples of distinct cell types in the T-DLBCL and their impact on survival. (A) Multiplex-IHC (mIHC) image (upper panel) showing high proportion of T cells in T-DLBCL TME. CD3 = blue, CD4 = white, CD8 = red, and CD56 = green (scale bar 20 μm). In the lower panel, Kaplan Meier plot demonstrating the impact of high T cell proportions on improved survival in T-DLBCL patients. (B) In the upper panel mIHC image showing FoxP3⁺Tbet⁺CD4⁺ T cells in the T-DLBCL TME. CD3 = green, CD4 = cyan, FoxP3 = red, T-bet = blue. In the lower panel Kaplan Meier plot demonstrating the inferior effect of FoXP3-Tbet-positivity on T-DLBCL survival. (C) In the upper panel, mIHC image showing high levels of PD-L1-positive macrophages in the T-DLBCL TME. PD-L1 = blue, PD-L2 = red, CD68 = white, c-Maf = green (scale bar 40 μm). In the lower panel, Kaplan–Meier plot demonstrating the impact of low PD-L1-positive macrophages on poorer survival in T-DLBCL. The figure was reproduced and adapted from Pollari et al., 2018, Leivonen et al., 2019, and Pollari et al., 2020 with the permission of the Ferrata Storti Foundation (A,C) and John Wiley and Sons, Inc. (Hoboken, NJ, USA) (B) [23,24,120].