Clinicopathological analysis of primary intestinal diffuse large B‐cell lymphoma: Prognostic evaluation of CD5, PD‐L1, and Epstein‐Barr virus on tumor cells

Abstract

BackgroundPrimary intestinal diffuse large B‐cell lymphoma (iDLBCL) is rare. In this study, we investigated the clinicopathological features of this disease to further understand the prognostic value of CD5, programmed cell death ligand 1 (PD‐L1), and Epstein‐Barr virus (EBV) on tumor cells.MethodsTumor specimens from 62 patients consecutively diagnosed with primary iDLBCL at a single institution were analyzed.ResultsOur series consisted of EBV‐positive (EBV+) iDLBCL (n = 10), de novo CD5+ iDLBCL (n = 4), and DLBCL, not otherwise specified (DLBCL‐NOS; n = 48). Notably, seven of 10 EBV+ cases had treated lymphoma‐associated (n = 4) or iatrogenic immunodeficiency (n = 3). Two of 10 EBV+ cases expressed PD‐L1 on tumor cells, whereas the remaining eight were positive for PD‐L1 on microenvironment immune cells. Only one DLBCL‐NOS case had neoplastic PD‐L1 expression with a giant cell‐rich appearance. Both EBV‐harboring and PD‐L1 expression on tumor cells, but not CD5, were associated with worse overall survival (OS) in iDLBCL patients receiving rituximab‐containing chemotherapy (P = 0.0354, P = 0.0092, and P = 0.1097, respectively). Multivariate analysis identified PD‐L1 positivity on tumor cells (P = 0.0106), PD‐L1 negativity on microenvironment immune cells (P = 0.0193), and EBV positivity (P = 0.0324) as poor independent prognostic factors for OS. Among iDLBCL cases without any EBV association, CD5 positivity, or neoplastic PD‐L1 expression, high PD‐L1 expression (≥40%) on microenvironment immune cells predicted an extremely favorable outcome.ConclusionEBV+ iDLBCL mainly comprised immunodeficiency‐associated patients, which may highlight the specificity of the intestine. PD‐L1 expression on tumor cells or microenvironment immune cells was found to have an opposite prognostic impact in iDLBCL.

EBV Positivity and Programmed Death-ligand 1 Expression in Diffuse Large B-cell Lymphoma: A Systematic Review

“…All eleven articles (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) were cross-sectional studies published between 2015 and 2019. Four articles originated from Japan (24,(28)(29)(30), Figure 1. PRISMA Flow Diagram (20) showing the stages of the review process, alongside lists of reasons for exclusion before the final number of included studies was reached.…”

“…Patient characteristics were described to varied degree, and most were not equally distributed within and between studies. Three articles (25,(28)(29) addressed all relevant characteristics relating to age, gender, cell of origin, IPI and chemotherapy treatment, none were provided within one study (24), and in one (30) the characteristics were mixed with other lymphomas, hence, were not included in this review. When cell of origin proportions were combined from nine studies addressing this parameter (22-23, 25-29, 31, 32) where 850 samples were addressed, the overall proportion for EBV+ cases was 0.19 GCB and 0.81 N-GCB, while EBVcases was 0.50 GCB and 0.50 N-GCB.…”

“…When cell of origin proportions were combined from nine studies addressing this parameter (22-23, 25-29, 31, 32) where 850 samples were addressed, the overall proportion for EBV+ cases was 0.19 GCB and 0.81 N-GCB, while EBVcases was 0.50 GCB and 0.50 N-GCB. Seven studies addressed age (23, 25, 27-29, 31, 32), and the median age for EBV+ groups ranged from 56 to 74 while for EBV-cases it ranged from 54 to 67; patients with an age of <60 years were included in four studies (25,(28)(29)31). Gender was addressed by six studies (23, 25, 28-29, 31, 32) where 805 samples were distinguished (466 males and 339 females), with overall male to female ratio (M:F) of 1.37.…”

“…Gender was addressed by six studies (23, 25, 28-29, 31, 32) where 805 samples were distinguished (466 males and 339 females), with overall male to female ratio (M:F) of 1.37. Of the six studies addressing IPI (23, 25, 28-29, 31, 32), EBV+ cases were of higher proportion in four out of six studies (25,29,31,32) looking at IPI 3-5, with one study noting marginal difference in proportion between EBV+ and EBV-cases (28). Four studies specified chemotherapy approach (27,(29)(30)(31) relating to the patient characteristics and therapies were predominantly of Rituximab-containing nature.…”

“…EBV-encoded small RNAs (EBER) in situ hybridization (ISH) was applied in eleven studies, while two also applied genetic analysis (24)(25). Overall, seven studies examined PD-L1+ expression via immunohistochemistry (IHC) staining (22)(23)(26)(27)(28)(29)(30), four papers applied genetic analysis (24-25, 27, 32) and one utilised flow cytometry (31). A combination of IHC and genetic analysis was used in one study (27).…”