Epstein-Barr Virus Positive B-Cell Lymphoproliferative Disorder of the Gastrointestinal Tract

Simple Summary Epstein-Barr virus (EBV) contributes to the reactive and neoplastic lymphoid proliferation of B-, T-, and NK-cell lineages, which represent a vast clinicopathological spectrum ranging from indolent, self-limited disease to aggressive lymphomas. EBV-positive B-cell lymphoproliferative disorder (EBV+ B-LPD) is the most common of these diseases, accounting for 3% to 15% of diffuse large B-cell lymphomas. The spectrum of EBV+ B-LPD is expanding with advances in understanding immunosenescence and iatrogenic immunodeficiency in the era of immune-oncology. We review EBV+ B-LPD affecting the gastrointestinal tract with a focus on the PD-L1 expression in tumor and non-malignant immune cells to better understand this peculiar disease. Abstract Epstein-Barr virus positive B-cell lymphoproliferative disorder (EBV+ B-LPD) encompasses a broad clinicopathological spectrum and distinct clinical behavior that relatively favors the gastrointestinal (GI) tract. In this review, we provide an update on the clinicopathological features and biological behavior of EBV-positive mucocutaneous ulcer (EBVMCU) and primary EBV+ diffuse large B-cell lymphoma (DLBCL) of the GI tract. EBVMCU is a newly recognized entity but well known as an indolent and self-limited EBV+ B-LPD occurring in various immunodeficiencies. In contrast, EBV+ DLBCL constitutes the largest group of EBV+ B-LPDs and is regarded as an aggressive neoplasm. These two distinct diseases have historically been distinguished in the reappraisal of age-related EBV-associated B-LPDs but are challenging in routine practice regarding their differential diagnostic and therapeutic approaches. An increasing number of reports indicate that they are epidemiologically prevalent beyond western and eastern countries, but their comprehensive analysis is still limited. We also describe the PD-L1 positivity of tumorous large cells and non-malignant immune cells, which is relevant for the prognostic delineation among patients with primary DLBCL of the GI tract with and without EBV on tumor cells.


Introduction
Epstein-Barr virus (EBV) is a gamma herpes virus that infects the majority of the world population. EBV induces B-cell transformation, and disruption of a finely balanced relationship between the virus and host immune system can lead to EBV + B-cell lymphoproliferative disorders (B-LPDs), which represent a wide and expanding clinicopathological spectrum ranging from indolent and self-limited disease to aggressive lymphoma. Dojcinov et al. recently divided EBV + B-LPDs into five categories: infectious mononucleosis (IM); EBV + DLBCL, not otherwise specified (NOS); EBVMCU; DLBCL-associated lymphoma, and nasopharyngeal carcinoma [40]. Latency III is linked to immunodeficiencyassociated LPDs arising in the setting of immunosuppression due to HIV infection, posttransplantation, and other iatrogenic causes, such as MTX and anti-TNF-α therapy.
Some studies have reported that the presence of EBV is restricted to lymphoid cells, not benign epithelial cells, in gastritis lesions and normal colonic mucosa [41,42]. In the stomach, a positive correlation between EBVDNA load and Helicobacter pylori positivity has been reported, which suggests that the H. pylori infection could trigger EBV to switch from the latent to lytic phase of its life cycle [43,44]. In addition, EBV infection of tumor cells is detected in approximately 9% of gastric cancer (GC) cases; it is categorized as one of the major GC types and characterized by a high frequency of amplification and elevated expression of PD-L1 [45][46][47]. Notably, EBV + GC is an attractive target for anti-PD-1/PD-L1 therapy in the current era [48,49].
In the intestine, EBV replication has been reported to be associated with severe inflammatory bowel disease and mucosal inflammation [50]. The presence of EBV-infected B lymphocytes in colonic lesions of IBD may indicate a potential role of EBV in colonic immune disturbances, which may be caused by the inflammatory process itself, immunosuppressive medication, or a combination of both. In contrast, Lopes et al. showed that mucosal EBV load does not correlate with the presence of inflammation or endoscopic severity despite a higher prevalence of EBV infection in IBD [51]. Whether EBV is involved in the pathogenesis or is an innocent bystander remains unclear, but active inflammation with intramucosal expansion of EBV-infected B-lymphocytes in IBD patients may cause local impairment. In IBD patients exposed to thiopurines or anti-TNF agents, particularly in combination, the risk of LPDs, mostly associated with EBV, is higher [52][53][54]. Thiopurines are cytotoxic for NK and cytotoxic T cells, which restrict proliferation of EBV-infected and immortalized B cells, which could be associated with lymphomagenesis [55].

EBV-Positive Mucocutaneous Ulcer (EBVMCU)
EBVMCU, first recognized by Dojcinov et al., is defined as an ulcerating EBV + B-LPD affecting the skin and mucosal surfaces, with a typically indolent course and spontaneous regression in some cases.

Clinical Features
EBVMCU occurs in iatrogenic immunosuppressed patients with autoimmune disorders and inflammatory bowel disease receiving MTX, CYA, AZA, TNF-α antibody, tacrolimus (Tac), or steroid treatment, in solid organ or bone marrow transplant recipients, in HIV-positive patients, after other lymphoma or tumor treatment, and in elderly patients. Elderly subjects are markedly restricted and deficient in their epitope-specific T-cell repertoire, leading to an increased risk of infection for the host [18,56].
The disease manifests as shallow, sharply circumscribed ulcers located mostly in the oropharyngeal mucosa, skin, and GI tract without associated systemic symptoms, lymphadenopathy, or involvement of any other site. A large superficial non-healing wound is an important diagnostic clue, and biopsy is warranted to determine the underlying pathology. Note that lesion may be underestimated as a non-specific ulcer in routine endoscopic diagnosis or over-diagnosed as monomorphic large B-cell proliferation (i.e., DLBCL) and simply polymorphic PTLD in pathological diagnosis, without recognition of iatrogenic induced EBVMCU. In a Japanese cohort of 34 patients with EBVMCU, 90% of the cases received immunosuppressants, such as MTX or hydroxycarcamide [57]. The diseases were frequently identified in the gingiva or tonsil, and a small number of cases had multiple ulcers.
In the setting of solid organ transplant-related immunosuppression, Hart et al. identified EBVMCU in 10% of transplant recipients with EBV + post-transplant lymphoproliferative disorder (PTLD) [58]. In their cohort, all seven patients with EBVMCU received solid organ transplants, but not hematopoietic stem cell transplants. EBVMCU may not develop in patients who receive a great level of immunosuppression, which prevents a localized response to EBV infection. Interestingly, they reported that none of the patients had EBV DNA detectable in the blood, and the patients remained PCR-negative in the blood during the follow-up period despite the biopsies being strongly positive by EBER-ISH. The lack of quantifiable EBV viremia may be an additional distinguishing feature of EBVMCU but should be validated in a future series.

Pathological Features
The lesions exhibit polymorphous infiltration of plasma cells, lymphocytes, histiocytes, and eosinophils, with atypical large B-cell blasts with Hodgkin/Reed-Sternberg (HRS) cell-like morphology [18]. Focal necrosis and angioinvasion are frequently seen. The large cell-predominant pattern may mimic DLBCL in a subset of cases. These large transformed cells are partially positive for CD20 and exhibit PAX5, Oct-2, MUM1, CD30, and EBER positivity, but are CD10 and BCL6 negative with a non-germinal center immunophenotype. CD15 is positive in 50% of cases. The background T cells consist of CD4-positive and CD8positive lymphocytes. Less than 50% of EBVMCU cases have clonal Ig gene rearrangements or clonal T-cell rearrangement.

PD-L1 Expression
A handful of studies have reported PD-L1 expression in EBVMCU. Satou et al. described the lack of PD-L1 expression on tumor cells in seven cases with MTX-associated EBVMCU using two different clones (SP142 and E1J2J) [59], which is consistent with findings reported by Daroontum et al. in 13 cases of EBVMCU associated with treated lymphoma or MTX [60]. Interestingly, in their subsequent series, one possibly exceptional EBVMCU case in which multiple EBV-driven B-LPDs developed after spontaneous regression of the disease was found to have PD-L1 expression on tumor cells at the time of the initial onset of EBVMCU [61]. This PD-L1 expression detected by immunohistochemistry (clone SP142) may be related to unusual clinical behavior after the spontaneous regression of EBVMCU. In contrast, Prieto et al. reported that all three cases with EBVMCU were positive for PD-L1 on large cells and HRS-like cells when using clone 28-8 [23]. This discordance in PD-L1 expression between studies is thought to be due to the use of different anti-PD-L1 antibody clones (SP142 vs. . However, a definitive conclusion cannot be drawn because of a limited number of cases examined, and this issue is expected to be clarified in a larger study.

Treatment and Clinical Course
Repeatedly, EBVMCU is characterized by a self-limited indolent course; generally, spontaneous remission after reduction or discontinuation of immunosuppression as the initial treatment within approximately 8 weeks. This is distinct from the behavior in EBV + DLBCL, though some patients with EBVMCU occasionally require therapeutic intervention, including standard chemotherapy and radiotherapy [18,23,57,59,62]. Therefore, it is essential for clinicians to consider EBVMCU in the differential diagnosis of mucocutaneous ulcers to avoid excessive treatment. Although the reduction of immune suppression is not possible in age-related cases without any additional iatrogenic immunosuppression, approximately 60% are expected to have spontaneous complete remission during the clinical course [18]. Interestingly, patients with treated lymphoma-associated EBVMCU have been reported to have worse survival than patients with MTX-associated EBVMCU because of lymphoma relapse or unrelated causes [60]. EBVMCU in the setting of treated lymphoma may be predictive of an aggressive clinical course.

giEBVMCU in Patients with IBD
Six patients with EBVMCU in IBD consisted of three with Crohn's disease, two with ulcerative colitis, and one without any available information. Except for the one with Crohn's disease presenting with an anal lesion, all cases had rectal involvement, two of which were accompanied by synchronous involvement of the colon. Macroscopically, most cases had ulcerated lesions during treatment with immunosuppressive regimens, including AZA, IFX, MTX, 6-mercaptopurine, and CYA, whereas only one used mesalazine alone and had a non-specific erythematous lesion. Interestingly, two cases had multiple lesions, which is not typical for ordinal EBVMCU [20,22]. In most EBVMCU cases with IBD, the clinical course was benign with complete recovery by reduction of immune suppression or aggressive therapy. Two patients achieved complete remission upon reduction of immune suppression. One patient with ulcerative colitis received rituximab because colonic biopsies showed persistent necrotic ulceration with EBV-positive immunoblasts after 4 weeks, though the ulcer slightly decreased in size by reduction of immune suppression and achieved complete remission [22]. The other patient with Crohn's disease finally underwent proctectomy with terminal colostomy due to an inability to control the rectal symptoms despite cessation of AZA and IFX [21]. The third patient using only mesalazine did not receive any therapy and presented with stable persistent disease without symptomatology for 6 months [23]. The remaining patient with Crohn's disease treated with AZA and adalimumab in the past presented an aggressive clinical course, developing widespread classic Hodgkin lymphoma 18 months after cessation of IFX and MTX [20].
Although the treatment strategy for IBD after regression of LPD is not well established, reintroduction of immune suppression is usually avoided to prevent relapse of the LPD. However, long-term follow-up data on disease activity in IBD are still not available among patients with giEBVMCU, and Satou et al. recently indicated that most RA patients suffer from exacerbation of the disease with polyarticular inflammation after 2 months after withdrawal of immune suppression [59]. Guidelines or recommendations for treatment after the regression of a LPD should be developed in IBD patients with EBVMCU.

giEBVMCU in Patients with Organ Transplant
Hart et al. and Isnard et al. reported on five solid organ transplant recipients with giEBVMCU [58,69]. Four patients were immunosuppressed after kidney transplants and the remaining one after a lung transplant. Three of these patients had EBVMCU in the colorectum and one each in the esophagus and terminal ileum. The duration of immunosuppressive therapy before symptoms onset ranged from 8 to 72 months (median 24 months). All of the patients achieved complete remission with reduction of immune suppression and additional rituximab therapy.

giEBVMCU in Patients with irColitis
Pugh et al. reported that four (25%) of 16 patients with irColitis had EBVMCU of the colorectum. All of the cases presented with multiple well-defined, punched-out, crateriform ulcerating lesions with normal intervening mucosa and perforation. As perforation rarely occurs in patients with EBVMCU in other settings, this punched-out ulcerating lesion leading to perforation may be a clinical hallmark of EBVMCU in irColitis patients [24]. All four cases received anti-CTLA-4 treatment for melanoma, and one of them was treated with a combination of anti-CTLA-4 and anti-PD1 regimens. One patient had steroid-refractory colitis with additional IFX therapy. All had a favorable clinical course after surgical resection of the perforated giEBVMCU, except for one who experienced a deteriorated clinical course after the operation. In this cohort, EBV-positive lymphoid cells were identified at the ulcer base in surgically resected specimens. Therefore, we should pay attention to the possibility of sampling error in endoscopic biopsy specimens of EBVMCU. Interestingly, one case had a Crohn's-like cobblestone appearance with multiple fissuring ulcerations in the small intestine. The authors indicated that the diversification of the T-cell repertoire, brought by CTLA-4 blockade, is associated with immune-related adverse events. They also described that the diversification inhibits EBV-induced lymphoma growth in both mice and humans [73][74][75], which appears to be contradictive with the development of EBVMCU in the setting of irColitis. The giEBVMCU arising in patients with irColitis may not be caused by immunodeficiency, and mechanism of their development should be clarified in the future. Patients with this irColitis-related giEBVMCU are expected to increase in number, and further studies of this peculiar disease are needed.

giEBVMCU in the Other Patients
Dojcinov et al. and Nomura et al. reported on three patients with RA and giEB-VMCU [18,68]. The immune suppression regimens included MTX, AZA and PSL. One of the cases evaluated had esophageal ulcer with complete remission after reduction of immune suppression. Another case had a jejunal ulcer and good clinical course but underwent surgical resection because of perforation.
Daroontum et al. reported two cases with treated lymphoma-associated giEBVMCU in the stomach (Figure 1) and intestine within 1 year of the cessation of chemotherapy for adult T-cell leukemia/lymphoma. They prompted us to be aware of EBVMCU in the setting of intensively treated hematolymphoid malignancy [60]. Both of our cases achieved complete remission on the reduction of immune suppression or without any therapy, but one of them died due to complications 4 months after allogeneic transplantation. Karube et al. also reported a patient with treated lymphoma-associated giEBVMCU with a history of classic Hodgkin lymphoma, who was unique in having multiple ulcerative and unusually elevated lesions in the large intestine, followed by EBV + DLBCL in the liver [67]. PCR analysis of the immunoglobulin heavy chain gene rearrangement revealed that all lesions were clonally distinct, suggesting that histologically and clonally distinct B cells can simultaneously proliferate in the EBV-associated setting. were clonally distinct, suggesting that histologically and clonally distinct B cells can simultaneously proliferate in the EBV-associated setting. Zanelli et al. reported on two immunocompetent patients with giEBVMCU in advanced age diagnosed based on the surgically resected specimen for colonic diverticulitis. One of these patients was treated with immunosuppressive agents, including MTX and PSL [65,72]. In addition to advanced age, chronic and localized mucosal irritation from diverticulitis may favor the localized proliferation of EBV-infected cells.

EBV-Positive Diffuse Large B-Cell Lymphoma (EBV + DLBCL)
EBV + DLBCL, NOS was first described in Japan, and is defined as an EBV-positive clonal B-cell lymphoid proliferation in the 2017 WHO classification. Other well-defined lymphoma entities, such as lymphomatoid granulomatosis, acute or recent EBV infection, Zanelli et al. reported on two immunocompetent patients with giEBVMCU in advanced age diagnosed based on the surgically resected specimen for colonic diverticulitis. One of these patients was treated with immunosuppressive agents, including MTX and PSL [65,72]. In addition to advanced age, chronic and localized mucosal irritation from diverticulitis may favor the localized proliferation of EBV-infected cells.

EBV-Positive Diffuse Large B-Cell Lymphoma (EBV + DLBCL)
EBV + DLBCL, NOS was first described in Japan, and is defined as an EBV-positive clonal B-cell lymphoid proliferation in the 2017 WHO classification. Other well-defined lymphoma entities, such as lymphomatoid granulomatosis, acute or recent EBV infection, plasmablastic lymphoma and DLBCL associated with chronic inflammation, and EBVMCU, are excluded from this category.

Clinical Features
EBV + DLBCL was originally documented among elderly patients >60 years of age [6,7]. Most patients present with extranodal, clinically aggressive disease and have no history of immunosuppression. EBV has been reported in 3-15% of patients with DLBCL [7][8][9]76]. It is more prevalent in East Asia and relatively rare in Western countries. Although a lack of uniform criteria, including the percentage of EBV + tumor cells required for diagnosis, accounts for reported differences in disease prevalence and prognostic features [14][15][16], a threshold of 80% for the diagnosis of EBV + DLBCL is recommended in the 2017 WHO classification to avoid the inclusion of cases in which EBV may be a bystander in nonneoplastic cells.
Elderly patients with EBV + DLBCL, NOS exhibit a high prevalence of B symptoms (35-50%) and extranodal disease (40-70%), including skin, lung, and GI tract [7,77,78]. The pathogenetic mechanism in elderly patients is thought to be immunosenescence, a complex spectrum of regressive changes that affect immune competence and immune surveillance over EBV infection as a result of age. T-cell responses appear to be the most profoundly affected. The naive CD8 + EBV-specific T-cell pool is diminished and replaced by senescent and functionally inferior effector memory cells, resulting in a reduction of the T-cell antigenic repertoire. Such changes generate an environment similar to iatrogenic immunosuppression [79][80][81]. In contrast, patients ≤45 years of age with EBV + DLBCL, NOS have nodal disease, with only 11% exhibiting extranodal involvement [10].
The addition of rituximab to anthracycline-based chemotherapy has improved the survival outcome in patients with common DLBCL [82,83]. The treatment strategy for EBV + DLBCL is usually in concordance with the current approach for common DLBCL. Elderly patients with EBV + DLBCL, NOS have poor survival, which is clearly contrasted by a favorable outcome among young patients with a nodal disease [6,7,10,15]. Some studies have documented contradictory conclusions regarding with the prognostic impact of EBV among DLBCL patients in the rituximab era because of differences in age, the different percentages of EBV harbored on tumor cells for diagnosis, and the small number of enrolled cases [14][15][16][17]84].

PD-L1 Expression
Among patients with common DLBCL, the frequency of PD-L1 expression has been reported to be 6% to 26% with different cut-off values and anti-PD-L1 monoclonal antibodies [34,[85][86][87]. In general, an alteration in chromosome 9p24.1 is rarely found, and the structural variations disrupting the 3 untranslated region of the PD-L1 gene, which correlates with PD-L1 expression, is detected in 8% of common DLBCL cases [85,88]. However, whether this PD-L1 expression on malignant tumor cells has an adverse prognostic impact is still controversial [34,86,89]. PD-L1 is also expressed on nonmalignant immune cells, such as macrophages and dendritic cells in DLBCL; thus, the prognostic significance is unproven because of the paucity of reports.

Overall Perspective of Primary giDLBCL as a Control Cohort
DLBCL is the most common lymphoma type affecting the GI tract, accounting for 39-58% of cases [92][93][94]. More than 70% of giDLBCL cases occur in the stomach [35,92]. In intestinal DLBCL (iDLBCL) cases, the most frequently involved site is the ileocecum, and approximately 10% have histological transformation of intestinal follicular lymphoma [12,13,95]. In gastric DLBCL (gDLBCL) cases, H. pylori negativity, advanced Lugano stage, elevated serum lactate dehydrogenase (LDH), multiple gastric lesions, B symptoms, and EBER positivity have been reported to be adverse prognostic factors, whereas IGHinvolved translocations are favorable prognostic factors [11,[96][97][98][99]. On the other hand, in iDLBCL cases, advanced age, perforation, microenvironment PD-L1 negativity, and EBER positivity have been shown to be adverse prognostic factors. Surgical resection followed by chemotherapy has been identified as a favorable prognostic factor among those patients [12,95,100]. Although the 5-year overall survival rates of gDLBCL and iDLBCL in the rituximab era are 88% and 71%, respectively, the anatomical site was not a prognostic factor in an entire series of giDLBCL [35].
Moreover, among 62 iDLBCL patients, 10 (16%) harbored EBV on >80% of their tumor cells [12]. EBV latency II and III were each found in three patients. Interestingly, 7 (70%) cases were related to treated lymphoma (peripheral T-cell lymphoma (n = 2), classic Hodgkin lymphoma (n = 2)) or iatrogenic immunodeficiency (MTX (n = 1), IFX (n = 1), and Tac (n = 1)). Such events related to iatrogenic immunodeficiency were not found in EBV-negative giDLBCL, except for one case of EBV-negative gDLBCL with a history of extranodal NK/T-cell lymphoma, nasal type. This close association of EBV + DLBCL with immunological deterioration appeared to be restricted to the intestine, but not in stomach. These EBV + iDLBCL patients also presented aggressive clinical features (performance status 2-4, International Prognostic Index high-intermediate/high, and multiple intestinal lesions). The worse survival of an EBV + subgroup was found with iDLBCL and gDLBCL cases.
Based on this original series, we further divided EBV + giDLBCL into immunosuppressed (IS), non-immunosuppressed (non-IS) with Lugano stage I, and non-IS with Lugano stage II1/II2/IIE/IV [101]. In the non-IS with Lugano I group, the anatomical site of involvement was restricted to the stomach. Interestingly, this group showed a favorable outcome, including one unusual patient with EBV + gDLBCL and a polypoid mass who had spontaneous regression 8 weeks after diagnosis without any treatment. This patient was speculated to bear an aspect of EBVMCU despite the polypoid, but not ulcerative, tumoral appearance. Unfortunately, no data were available regarding the natural longterm outcomes because most of the patients subsequently received rituximab-containing chemotherapy depending on their diagnosis of EBV + gDLBCL. The issue of whether EBV + giDLBCL in stage I may be classifiable as a polypoid/tumorous variant of EBVMCU in light of the favorable clinical course should be clarified in the future. When EBVMCU and EBV + DLBCL are indistinguishable based on histopathology alone, special attention should be paid to their gross endoscopic appearance, especially a sharply circumscribed ulcer and/or polypoid pattern, to identify cases with a solitary gastric EBV + B-cell lymphoproliferative lesions. To avoid excessive treatment, we recommended conservative management for 8 weeks in patients with favorable international prognostic index scores as a pragmatic approach. Of course, this should be validated in the future.

Pathological Features of Primary EBV + giDLBCL
In general, EBV + DLBCL exhibits a broad range of morphological features. Many EBV + giDLBCL cases are featured by monomorphous large B-cell proliferation and may have polymorphous infiltrate of HRS-like cells in an inflammatory background composed mainly of histiocytes and lymphocytes. Geographic necrosis and angioinvasion are common features. Most cases have a post-germinal center/activated B-cell phenotype. The majority of tumor cells express B-cell markers such as CD19, CD20, and CD79a, which are preserved with coexpression of PAX5, Oct-2, Bob.1, and MUM1. CD30 is usually positive. EBV + DLBCL, NOS has been reported to exhibit prominent nuclear factor κB and JAK/STAT pathway activation in the neoplastic cells [102,103].

PD-L1 Expression of Primary EBV + giDLBCL
In our series of giDLBCL patients using PD-L1 (by clone SP142) immunohistochemistry, neoplastic cell staining was considered positive for PD-L1 (nPD-L1) when ≥5% of the lymphoid cells exhibited moderate to strong membrane staining. In addition, microenvironment immune cell staining was considered positive for PD-L1 (miPD-L1) when, among the total tissue cellularity, ≥20% comprised non-malignant cells with moderate or strong membrane or cytoplasmic PD-L1-specific staining.
EBV + giDLBCL patients with nPD-L1 expression present an aggressive clinical course [35]. One EBV + gDLBCL case exhibiting progressive disease after rituximabcontaining chemotherapy despite Lugano stage I underwent autologous peripheral blood stem cell transplantation (Figure 2A-F). The other EBV + iDLBCL case in Lugano stage II2 achieved a partial response by treatment with rituximab-containing chemotherapy but had a relapse and died of disease 10 months after diagnosis.

Conclusions
Evidence indicates that giEBVMCU frequently occurs in the colorectum and usually has an indolent and self-limited clinical course. EBVMCU should be considered in the differential diagnosis when patients in the setting of immunosuppression have ulcerating mucosal lesions without tumor mass and no detectable lesions in other sites on thorough Moreover, our EBV + giDLBCL series had high frequency of miPD-L1 expression, accounting for approximately 90% [101] (Figure 2G-L). The association of EBV + DLBCL and miPD-L1 expression was also reported by Kiyasu et al. [34]. However, among patients with EBV-negative giDLBCL, miPD-L1 expression is associated with a better outcome compared to miPD-L1 negative patients. EBV-negative iDLBCL cases with high miPD-L1 expression (>40% of immune cells) especially had a favorable outcome, with a plateau in the survival curve, whereas those with PD-L1 expression on <5% of microenvironment immune cells had extremely worse survival in the current rituximab era.
Thus far in the English literature, we first documented that PD-L1 expression on non-malignant immune cells, such as macrophages and dendritic cells, contributes to better outcomes in giDLBCL patients treated with modern immunochemotherapy.

Conclusions
Evidence indicates that giEBVMCU frequently occurs in the colorectum and usually has an indolent and self-limited clinical course. EBVMCU should be considered in the differential diagnosis when patients in the setting of immunosuppression have ulcerating mucosal lesions without tumor mass and no detectable lesions in other sites on thorough imaging studies. Although EBVMCU is defined by a localized ulcer, the spectrum of EBVMCU in the GI tract may be extended to extranodal EBV + LPD confined to a single anatomical site with not only solitary, but also multiple lesions or not only ulcerative, but also mass lesions in the future. We need to pay attention to the high frequency of EBV among DLBCL patients in the setting of treated lymphoma-associated or other iatrogenic immunodeficiencies. It is essential to recognize the clinicopathological spectrum between the two distinct diseases, EBVMCU and EBV + DLBCL, in order to provide appropriate treatment in routine practice. In addition, we hope that treatment strategies are developed in the near future because some of the patients with giEBVMCU receive aggressive treatment despite the indolent clinical course.
EBV + giDLBCL presents an aggressive clinical course, but EBV + gDLBCL cases with a single lesion in Lugano stage I have extremely favorable outcomes, which may indicate that this subgroup is distinctive and possibly classifiable as EBVMCU. In contrast to giEBVMCU, EBV + giDLBCL has a strong correlation with PD-L1 expression on tumor cells or immune cells. This pathological feature could aid in diagnosis and be useful for assessing either immune escape or immunodeficiency in the pathogenesis of EBV + B-LPDs.