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Simple Summary: Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoid neoplasm and includes morphologically and molecularly heterogeneous disease subtypes. Genetic aberrations of tumor cells are strongly related to the signature of the tumor microenvironment. In this review, we summarize common genetic aberrations associated with immune escape, immune cell subs involved in DLBCL pathogenesis, and distinct microenvironmental signatures identified using next-generation sequencing and single-cell technologies. We also discuss the pathogenic role of immunosenescence in Epstein-Barr virus-positive DLBCL. Moreover, as DLBCL exhibits unique pathogenesis in immune-privileged sites, we also present a hypothetical model of DLBCL development in immune-privileged sites. Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and is the most common type of malignant lymphoid neoplasm. While some DLBCLs exhibit strong cell-autonomous survival and proliferation activity, others depend on interactions with non-malignant cells for their survival and proliferation. Recent next-generation sequencing studies have linked these interactions with the molecular classification of DLBCL. For example, germinal center B-cell-like DLBCL tends to show strong associations with follicular T cells and epigenetic regulation of immune recognition molecules, whereas activated B-cell-like DLBCL shows frequent genetic aberrations affecting the class I major histocompatibility complex. Single-cell technologies have also provided detailed information about cell–cell interactions and the cell composition of the microenvironment of DLBCL. Aging-related immunological deterioration, i.e., immunosenescence, also plays an important role in DLBCL pathogenesis, especially in Epstein-Barr virus-positive DLBCL. Moreover, DLBCL in "immune-privileged sites"—where multiple immune-modulating mechanisms exist—shows unique biological features, including frequent down-regulation of immune recognition molecules and an immune-tolerogenic tumor microenvironment. These advances in understanding the immunology of DLBCL may contribute to the development of novel therapies targeting immune systems. [ABSTRACT FROM AUTHOR]

The programmed death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in the pathogenesis of Epstein-Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS). Here, we describe PD-L1 expression by EBV+ DLBCL, NOS in order to evaluate its possible contribution to the pathogenesis of this tumor. The study included 57 cases of EBV+ DLBCL, NOS. The median patient age was 69 years and 95% (n = 54) were aged > 45. Extranodal lesions were present in 39 (69%) at initial diagnosis. PD-L1 expression (mAb SP142-positive staining) was present in more than 5% of tumor cells in only six cases (11%), in clear contrast to the 77% reported in cases aged under 45 years. Among the PD-L1+ cases, three were nodal lesions. All six PD-L1+ cases progressed in the 3 years after diagnosis and four of the six patients died of the disease within 2 years. PD-L1+ cases had significantly shorter PFS (P = 0.002) and relatively short OS (P = 0.26), compared with PD-L1- cases. EBV+ DLBCL, NOS in the elderly infrequently expressed PD-L1 and had poor prognosis. PD-L1 expression in EBV+ DLBCL, NOS of the elderly sheds light on the pathogenetic role of immune senescence. [ABSTRACT FROM AUTHOR]

Inhibitors of programmed cell‐death 1 (PD‐1) and programmed cell‐death ligand 1 (PD‐L1) have revolutionized cancer therapy. Nodal cytotoxic T‐cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non‐CTLs. Here we investigated PD‐L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD‐L1 (nPD‐L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRαβ type, three were TCRγδ type and three were TCR‐silent type. Six of the seven cases exhibited a lethal clinical course despite multi‐agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD‐L1+ cases, two of three examined had structural variations of PD‐L1 disrupting 3′‐UTR region. Notably, all of the TCRγδ‐type nodal CTL cases showed nPD‐L1 or miPD‐L1 positivity (3 and 10 cases, respectively). TCRγδ‐type cases comprised 42% of nPD‐L1+ cases (P = 0.043 vs. PD‐L1−), and 35% of miPD‐L1+ cases (P = 0.037 vs. PD‐L1−). The results indicate that PD‐L1+ nodal CTL cases, especially of the TCRγδ type, are potential candidates for anti‐PD‐1/PD‐L1 therapies. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age‐related EBV‐associated B‐cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency‐associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV‐positive (EBV+) diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B‐cells often have a Hodgkin/Reed‐Sternberg (HRS)‐like appearance and are shared beyond the diagnostic categories of mature B‐cell neoplasms, mature T‐cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency‐associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD‐L1). Assessing PD‐L1 positivity by staining with the anti‐PD‐L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B‐cells harboring EBV. [ABSTRACT FROM AUTHOR]

Objectives: We describe results of programmed death ligand 1 (PD-L1) immunohistochemical assessment in methotrexate (MTX)-associated lymphoproliferative disorders (LPDs) and highlight the characteristics of classic Hodgkin lymphoma (CHL) type MTX-LPD.Methods: Fifty cases of MTX-LPD, including CHL type (n = 9), diffuse large B-cell lymphoma type (n = 15), and polymorphic B-cell LPD (n = 21), were investigated.Results: Staining with anti-PD-L1 clone SP142 was exclusively found in CHL type (89%) but not in the others. Cases of CHL type MTX-LPD involved nodal disease and were associated with Epstein-Barr virus. They were histopathologically characterized by a vaguely nodular pattern, predominance of mononuclear cells, and strong expression of at least one pan-B-cell marker. Their clinical course was variable, with spontaneous regression in 5 patients, relapse in 2, and a fatal course in 1.Conclusions: The PD-L1 (clone SP142) workup aids the diagnostic approach to patients with MTX-LPD. CHL type MTX-LPD appears to represent a unique morphologic variant of CHL. [ABSTRACT FROM AUTHOR]

Although several reports have highlighted neoplastic PD‐L1 (nPD‐L1) expression in classic Hodgkin lymphoma (CHL), some have addressed associations between its expression and detailed histopathologic features. Here we describe four cases of syncytial variant of CHL (SV‐CHL), with and without Epstein–Barr virus (EBV) association, and highlight the diagnostic utility of PD‐L1 (clone SP142) immunohistochemistry. The patients were a 61‐year‐old male, 45‐year‐old male, 85‐year‐old female, and 89‐year‐old female. All presented with cervical or axillary lymphadenopathy, which on biopsy had the established histopathologic features of SV‐CHL with a biphasic pattern of cohesive sheets of large tumor cells and typically scattered distribution of Hodgkin and Reed–Stenberg (HRS) cells. These tumor cells showed identical immunophenotypic findings for CD15, CD30, Fascin, PAX5, OCT2, BOB1 and EBV harboring, regardless of location. The exception was absent or decreased expression of nPD‐L1 from tumor cells in the confluent sheets, contrasting with HRS cell positivity in typical areas of CHL. These findings offer the first suggestion of possible downregulation of nPD‐L1 expression in association with the histopathologic progression of CHL. The results may be relevant for recognizing 'confluent' sheets in the diagnostic workup for SV‐CHL. [ABSTRACT FROM AUTHOR]

Epstein‐Barr virus (EBV)‐positive B cells have been detected in 66%‐86% of patients with angioimmunoblastic T‐cell lymphoma (AITL). However, it remains controversial whether EBV status has an impact on the survival of patients with AITL. In this study, we aimed to reevaluate the impact of EBV on the clinicopathological characteristics of AITL. In particular, we focused on the impact of EBV in younger patients with AITL. In total, 270 cases of AITL were studied. Epstein‐Barr virus‐positive B cells were detected in 191 (71%) cases (EBER+ group). Among the patients who received anthracycline‐based therapy, the EBER status did not affect the overall survival (OS) or progression‐free survival (PFS). In the younger group of AITL (≤60 years), PFS was significantly worse in the EBER− group compared to the EBER+ group (P =.0013). Furthermore, the multivariate analysis identified EBER‐negative status, thrombocytopenia, and elevated serum IgA level as significant adverse prognostic factors for PFS (P <.001, P <.001, and P =.002). Based on these findings, we constructed new prognostic model for the younger group, based on three adverse factors. We classified the patients into two risk groups: low risk (no or 1 adverse factor) and high risk (2 or 3 adverse factors). This new model for younger patients with AITL showed that both OS and PFS were significantly related to the level of risk (P <.0001). In summary, this study showed that, among younger patients with AITL, an EBER+ status significantly improved prognosis compared to an EBER− status. Our new prognostic model should be applicable to younger patients with AITL. [ABSTRACT FROM AUTHOR]

Aims: The programmed death 1 (PD1)/PD1 ligand (PD‐L1) axis plays an important role in tumour cells escape from immune control. PD‐L1 immunohistochemistry is a useful predictor of immunotherapy response, but is still not used widely in the diagnostic setting. Here we describe results using PD‐L1 immunohistochemistry during routine diagnostics in lymphoma. Methods and results: Ninety‐one lymphoproliferative disease cases sharing tumour and non‐malignant Hodgkin–Reed‐Sternberg (HRS)‐like cells with and without Epstein–Barr virus (EBV) association were investigated by immunohistochemistry for PD‐L1 (clone SP142). PD‐L1 expression was present in more than 5% of tumour or non‐malignant HRS‐like cells in 100% of EBV+ classical (C) Hodgkin lymphoma (HL) (n = 10) and EBV‐negative nodular sclerosis CHL (n = 8); 40% of EBV+ diffuse large B cell lymphoma, not otherwise specified (DLBCL–NOS) (n = 20); and 4% of nodal peripheral T cell lymphoma of follicular helper T cell type (PTCL‐TFH) (n = 22). In contrast, nodular lymphocyte‐predominant HL (n = 4), lymphocyte‐rich CHL (n = 6), EBV+ hyperplasia (n = 8), plasmablastic lymphoma (n = 3) and anaplastic lymphoma kinase‐negative anaplastic large cell lymphoma (n = 5) seldom exhibited PD‐L1 in their large cells. Assessing PD‐L1 positivity in tumour and non‐malignant large cells was helpful in differentiating between CHL versus nodal PTCL–TFH (P < 0.0001) or EBV+ DLBCL–NOS (P = 0.0052) and between EBV+ DLBCL–NOS versus nodal PTCL‐TFH (P = 0.0052), with PD‐L1 expression indicating the first diagnosis in each of those sets. Conclusion: Immunohistochemical evaluation of PD‐L1 expression in tumour and non‐malignant HRS‐like large cells may be useful for assessing either immune escape or immunodeficiency in their pathogenesis. [ABSTRACT FROM AUTHOR]