Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoproliferation encompasses a broad range of clinicopathologic findings, including specific subtypes, for example, EBV+ mucocutaneous ulcer. Here we reassessed 36 cases of primary EBV+ diffuse large B-cell lymphomas (16 men and 20 women; median age, 69.5 y; range, 35 to 84 y), including 8 immunosuppressed patients (Lugano stage II-IV; median age, 74 y), 7 nonimmunosuppressed patients with stage I disease (median age, 69 y), and 21 nonimmunosuppressed patients with stage II-IV disease (median age, 69 y). All immunosuppressed patients exhibited iatrogenic immunodeficiency and an ulcerative appearance, with ulcer sites including the stomach (1 patient), small intestine (6 patients), and rectum (1 patient). Four patients were in the setting of treated lymphoma-associated immunosuppression. Immunosuppressed patients had higher incidences of intestinal involvement (P=0.001) and perforation (n=2) compared with advanced stage nonimmunosuppressed patients. Among nonimmunosuppressed stage I patients, lesions were restricted to the stomach, none showed multiple lesions or elevated serum lactate dehydrogenase, and the overall survival curve plateaued, although it was not statistically significant (P=0.0581). One nonimmunosuppressed stage I patient with a polypoid lesion exhibited spontaneous regression within 2 months after diagnosis, while another with bulky disease pursued an aggressive clinical course. Nonimmunosuppressed stage I cases without bulky masses may be considered EBV mucocutaneous ulcer with local progression. Our results demonstrated that primary EBV+ gastrointestinal diffuse large B-cell lymphoma could be delineated into 3 groups based on immune status and clinical stage, revealing distinguishing features useful as a pragmatic guide for diagnostic and therapeutic approaches.
BackgroundIntravascular large B‐cell lymphoma (IVLBCL) is a rare form of diffuse large B‐cell lymphoma (DLBCL) arising in extranodal sites. PD‐L1 expression of tumor cells has been reported in IVLBCL cells, but its clinicopathological relevance remains to be elucidated.AimsThis study was aimed to reveal the characteristics of PD‐L1+ IVLBCL.Methods and resultsNeoplastic PD‐L1 expression was examined in 34 cases of IVLBCL and clinicopathological characteristics between patients with PD‐L1+ and PD‐L1− IVLBCL were compared. We assessed PD‐L1 expression with SP142 antibody. Twelve (35%) of 34 cases showed positivity for PD‐L1. The PD‐L1+ group had significantly lower survival rates compared to the PD‐L1− group. The PD‐L1+ IVLBCL group also had a significantly lower age distribution and a lower frequency of patients older than 60 years compared to the PD‐L1− group. Very recently, we speculate that there is possible link between PD‐L1+ IVLBCL and PD‐L1+ extranodal DLBCL‐NOS (eDLBCL) because features of the two groups showed overlapping. Therefore, we compared the clinicopathological characteristics of the PD‐L1+ IVLBCL and PD‐L1+ eDLBCL. There were no significant differences in clinicopathological parameters and prognosis.ConclusionThe worse prognosis of the PD‐L1+ group might be caused by immune evasion mechanisms, which are linked to PD‐L1 expression. Therefore, PD‐L1+ IVLBCL cases might be regarded as good candidates for targeted immunotherapy. We also highlighted the overlapping features of PD‐L1+ IVLBCL and PD‐L1+ eDLBCL. This result suggests that they should be regarded as one entity, immune evasion‐related extranodal large B‐cell lymphoma.
Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNS-DLBCL) is rare. Thirtynine patients consecutively diagnosed as having PCNS-DLBCL were analyzed to highlight the prognostic value of the expression of programmed cell death ligand-1 (PD-L1) by neoplastic cells and immune cells in the microenvironment. They were positive for CD20 in all (100%), CD5 in two (5%), CD10 in nine (23%), BCL-2 in 27 (69%), BCL-6 in 34 (87%), and MUM-1 in 37 (95%). Only one case was positive for neoplastic PD-L1, with an unexpectedly long clinical course of 92 months. The remaining 38 cases were further divided into three groups based on the percentage of PD-L1 + cells among microenvironmental immune cells. Cutoffs of < 5%, 5-40%, and ≥ 40% successfully stratified mean prognoses with three-year overall survival (OS) of 21%, 63%, and 100% (P = 0.009), respectively. Progression-free survival (PFS) and OS were different between the groups with and without methotrexate (MTX)-containing chemotherapy (P = 0.007 and P < 0.001, respectively). Multivariate analysis identified three independent adverse factors of OS: PD-L1 negativity (< 5%) on microenvironmental immune cells (P = 0.027), deep structure involvement (P = 0.034), and performance status (PS) 2-4 (P = 0.009). The study showed that PD-L1 expression on immune cells in the microenvironment was associated with prognosis among patients with PCNS-DLBCL.
The Epstein–Barr virus (EBV) is the cause of several malignancies, including diffuse large B cell lymphoma (DLBCL). We recently found that EBV genomes in EBV-positive cancer specimens have various deletions (Okuno et al. Nat Microbiol. 2019). Here, we focus on the deletion of C promoter (Cp), which transcribes EBV nuclear antigen (EBNA) genes in type III latency. The Cp deletion found in a DLBCL patient (332 bp) was introduced into EBV-BAC of the B95-8 strain. Interestingly, the dCp virus transformed B cells more efficiently than WT and revertant strains. Deletion of Cp also promoted tumor formation and severe pathogenicity in a mouse xenograft model. RNA sequencing and qRT–PCR analyses revealed that Cp transcription was undetectable in the dCp cells. Instead, transcription from the W promoter (Wp), an alternative promoter for EBNA, was activated in the dCp mutant. We also found that the expression of latent membrane protein 2A (LMP2A) was somehow induced in the dCp mutant. Double knockout of Cp and LMP2A indicated that LMP2A is crucial for B cell transformation, but the increased transformation induced by Cp deletion cannot be explained by LMP2A alone. We also tested the effect of an anti-apoptotic viral BCL2 homolog, BHRF1, because its expression was reportedly induced more efficiently by that of Wp. However, increased growth transformation via Cp deletion was not due to the BHRF1 gene. Taken together, the results indicated that deletion of a specific region in Cp increased in vitro transformation and the rate of progression of EBV-positive lymphoproliferative disorders in vivo. Our data suggest that genomic alteration not only of the host but also the virus promotes EBV-positive tumor generation and expansion, although the molecular mechanism underlying this phenomenon is still unclear. However, LMP2A and BHRF1 are not involved.
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