EBV-positive B-cell lymphomas and lymphoproliferative disorders: Review from the perspective of immune escape and immunodeficiency

Abstract

Background: Epstein-Barr virus (EBV) is detected in a variety of B-cell lymphomas (BCLs) and B-cell lymphoproliferative disorders (B-LPDs). Immunodeficiency has been considered to play a key role in the pathogenesis of these diseases. In addition, immune escape of tumor cells may also contribute to the development of EBV⁺ BCLs and B-LPDs. The PD-1/PD-L1 pathway is particularly important for immune escape of tumor cells that contribute to development of lymphoma through suppression of cytotoxic T-cell function. We now consider PD-L1 immunohistochemistry (IHC) a very useful method for predicting whether tumor cells of lymphoid malignancies are characterized by the immune escape mechanism.

Methods: We reviewed articles of EBV⁺ BCLs and B-LPDs from the perspective of immune escape and immunodeficiency, particularly focusing on PD-L1 IHC.

Results: Based on PD-L1 IHC, we consider that EBV⁺ BCL and B-LPD can be classified into three types: "immunodeficiency", "immune escape", and "immunodeficiency + immune escape" type. The immunodeficiency type includes EBV⁺ diffuse large BCL (DLBCL) of the elderly, EBV⁺ sporadic Burkitt lymphoma, EBV⁺ mucocutaneous ulcer, and methotrexate (MTX)-associated B-LPD. The immune escape type includes EBV⁺ classic Hodgkin lymphoma (CHL) and EBV⁺ DLBCL of the young. The immunodeficiency + immune escape type includes CHL type MTX-associated LPD and a minor subset of EBV⁺ DLBCL of the elderly.

Conclusions: Recently, good results have been reported for immune check-point inhibitors in treating lymphoma. Lymphomas and LPDs characterized by immune escape are regarded as good candidates for PD1/PD-L1 blockade therapy. Therefore, from both the clinical and pathological perspective, we suggest that lymphoma diagnosis should be made considering immune escape and immunodeficiency.

Keywords: EBV-positive lymphoma; PD-L1; immune escape; immunodeficiency; lymphoproliferative disorder.

FIGURE 1

Histological and immunohistochemical features of EBV‐positive diffuse large B‐cell lymphoma (DLBCL) of the elderly. (A) Histologically, a polymorphic pattern is observed in this case (HE ×400). (B) The tumor cells show positive staining for EBER (×400). (C) PD‐L1 expression was detected in 11% of EBV⁺ DLBCL of the elderly (×400)

FIGURE 2

Histological and immunohistochemical features of EBV‐positive mixed cellularity classic Hodgkin lymphoma (CHL). (A) Hodgkin and Reed–Sternberg (HRS) cells proliferate on a background containing extensive non‐neoplastic immune cells (HE ×400). (B) The HRS cells are CD30‐positive (×400) and (C) EBER‐positive (×400). (D) All of the EBV⁺ CHLs show positive staining for PD‐L1 (×400)

FIGURE 3

Macroscopic, histological, and immunohistochemical features of EBV‐positive mucocutaneous ulcer (EBVMCU). (A) EBVMCU macroscopically shows a sharply circumscribed mucosal ulcer. (B) Histologically, EBVMCU shows infiltration of intermediate to large atypical lymphoid cells with polymorphous background (HE ×400). (C) EBER is detected in the large atypical lymphoid cells (×400). (D) Most of the cases are negative for PD‐L1 on tumor cells (×400)

FIGURE 4

Histological and immunohistochemical features of classic Hodgkin lymphoma (CHL)‐type methotrexate (MTX)‐associated lymphoproliferative disorder (LPD). (A) Hodgkin and Reed–Sternberg (HRS) cells proliferate on a background containing extensive non‐neoplastic immune cells (HE ×400). (B) The HRS cells are CD30‐positive (×400) and (C) EBER‐positive (×400). (D) Most of the CHL‐type MTX‐associated LPDs stain positive for PD‐L1 (×400)