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Epstein-Barr virus–positive (EBV-positive) B-cell lymphomas are common in immunocompromised patients and remain an unmet medical need. Here we report that MDM2 inhibitors (MDM2is) navtemadlin and idasanutlin have potent in vivo activity in EBV-positive B-cell lymphoma established in immunocompromised mice. Tumor regression was observed in all 5 EBV-positive xenograft–associated B-cell lymphomas treated with navtemadlin or idasanutlin. Molecular characterization showed that treatment with MDM2is resulted in activation of p53 pathways and downregulation of cell cycle effectors in human lymphoma cell lines that were either EBV-positive or had undetectable expression of BCL6, a transcriptional inhibitor of the TP53 gene. Moreover, treatment with navtemadlin resulted in tumor regression and prevented systemic dissemination of EBV-positive lymphoma derived from 2 juvenile patients with posttransplant lymphoproliferative diseases, including 1 whose tumor was resistant to virus-specific T-cell therapy. These results provide proof-of-concept for targeted therapy of EBV-positive lymphoma with MDM2is and the feasibility of using EBV infection or loss of BCL6 expression to identify responders to MDM2is.

Immunodeficiency-associated lymphoproliferative disorders are associated with latent infection by Epstein-Barr virus (EBV). Most cases of EBV-positive immunodeficiency-associated lymphoproliferative disorders arise from B cells, although some are of T-cell or natural killer origin. Cutaneous involvement is unusual and sporadically reported in the literature. We describe a rare case of an EBV-positive T-cell lymphoma presenting in the skin of a 32-year-old woman using adalimumab for neurosarcoidosis.

How Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) occasionally occurs following chronic inflammation remains to be elucidated. The case of a 57‐year‐old man who developed pulmonary EBV‐positive DLBCL from underlying silicosis lesions is presented. Immunohistochemical examination of the resected silicosis lesions showed predominant helper T cells and M1/M2 macrophages, with a lack of B cells, regulatory T cells, and resident memory T cells. Two years later, EBV‐positive DLBCL emerged unexpectedly from the silicosis. The imbalance of the immune cells in the microenvironment, at least in part, may help explain how chronic inflammation contributes to EBV‐positive DLBCL., The underlying silicosis lesions showed predominant Th cells and M1/M2 macrophages, with a lack of B cells, Treg cells, and TRM cells. The imbalance of the immune cells in the microenvironment, at least in part, may help to explain how chronic inflammation contributes to EBV‐positive diffuse large B‐cell lymphoma.

Background Epstein–Barr virus (EBV) positive gastric cancer (GC) has been described as a distinct molecular subtype of the disease, especially associated with gastric carcinoma with lymphoid stroma (GCLS). The possibility that EBV associated GC (EBVaGC) had better prognosis and may be susceptible to immunotherapy has increased the interest in this subtype. However, immune checkpoint and survival of EBVaGC are still controversial, especially with regard to GCLS and conventional gastric adenocarcinoma (CGA). This study aimed to evaluate the clinicopathological characteristics, immunohistochemical profiles and prognosis of EBVaGC according to the histological type GCLS and CGA. Methods we retrospectively evaluated a series of EBVaGC who underwent gastrectomy with D2-lymphadenectomy. Biomarkers and tumor-infiltrating cells were evaluated by immunohistochemistry. PD-L1 was evaluated using a combined positive score (CPS). Results From a total of 30 EBVaGC, 14 (46.7%) were identified as GCLS and 16 (53.3%) as CGA (9 Intestinal, 6 diffuse, 1 undetermined). There were no significant differences in age, sex, and pTNM between GCLS and CGA. CPS-positivity and high-CD8+ was significantly higher in GCLS compared with CGA (P = 0.007 and P = 0.005, respectively). Diffuse EBVaGC had worse survival than intestinal type (P = 0.020). There was no difference in survival between GCLS and intestinal CGA (P = 0.260). In multivariate analysis, CPS and pN status were related with survival in EBVaGC. Conclusions CGLS was associated with a predominance of CD8+ cell infiltration and PD-L1 expression. CPS and lymph node metastasis were independent factors associated with prognosis in EBVaGC. These results suggest that specifically EBV-positive GCLS may be prime candidates for PD-1 directed therapy.

BACKGROUND Primary non-Hodgkin’s lymphoma of the frontal sinus is extremely rare. In addition, Epstein-Barr virus (EBV) has been reported to play a role in the development of human immunodeficiency virus (HIV)-related malignant lymphomas. To the best of our knowledge, there is no report for the HIV-associated, EBV-positive primary diffuse large B-cell lymphoma (DLBCL) in the frontal sinus. CASE SUMMARY We present a unique case of HIV-associated, EBV-positive DLBCL in the frontal sinus in a 46-year-old man. Computed tomography of paranasal sinuses revealed dense opacification of the right frontal sinus with combined soft tissue swelling. Based on the clinical and radiological findings, the initial diagnosis was complicated frontal sinusitis, presenting Pott’s puffy tumor. Unexpectedly, HIV testing was positive on preoperative laboratory test, and the frontal sinus lesion was confirmed as EBV-positive DLBCL on biopsy. CONCLUSION Through this article, we suggest that EBV-positive DLBCL should be considered as possible diagnosis for patients with nonspecific space-occupying lesion of the paranasal sinuses. We also highlight an importance of clinical suspicion in diagnosing HIV infection because HIV serology is not routinely tested in patients with paranasal sinus problem.

Epstein–Barr virus-positive ulcer (EBV + U) is a recently reported B cell lymphoproliferative disorder in the oral cavity, oropharynx, gastrointestinal tract and skin, principally in immunosuppressed patients. A 53-year-old female patient with rheumatoid arthritis treated with methotrexate, presenting ulcers of unknown duration on the dorsum and the lateral left border of the tongue. Excisional biopsy, histopathological analysis and histochemical stains for syphilis (Warthin–Starry), mycotic diseases (Grocott silver methenamine), tuberculosis (Ziehl–Neelsen), immunohistochemistry tests for herpesvirus type 8 (CMV), EBV (LMP-1) and DNA extraction for polymerase chain reaction (PCR) assay to CMV, EBV and herpes simplex virus-1 were performed. Posterior to PCR assay, the final diagnosis was EBV + U in the oral cavity. Acyclovir® was prescribed, showing clinical improvement. A case of EBV + U with clinical characteristics similar to other lesions or conditions has been reported. Special assays are necessary for an accurate diagnosis and treatment.

Plasmablastic lymphoma (PBL) is a rare and aggressive type of non-Hodgkin lymphoma (NHL) which is typically seen in the setting of an immunocompromised state, classically associated with human immunodeficiency virus infection. It is often also associated with Epstein–Barr virus infection. It has an immunophenotype of a terminally differentiated B lymphocyte. The diagnosis of PBL is challenging due to complex overlap with myeloma and other B-cell NHL having a plasmablastic morphology. In the past few years, there are an increasing number of cases being identified in patients with no known immunocompromised state. We hereby report a case series of four such cases in immunocompetent patients with different sites of involvement and varied presentation to add to the literature.

We encountered a patient with multiple myeloma treated with autologous hematopoietic stem cell transplantation (HSCT) who developed repeated episodes of enteritis but regressed spontaneously. An endoscopic examination revealed no abnormalities, but biopsy specimens showed massive infiltration of CD4+ and Epstein-Barr encoding region (EBER+) abnormal lymphocytes in which a high copy number of Epstein Barr virus (EBV) genomes was detected by quantitative polymerase chain reaction (qPCR). EBV infection was exclusively detected in CD4+ T-cells, leading to a diagnosis of EBV-positive CD4+ T-cell lymphoproliferative disorder (LPD). This case suggests that an immediate biopsy and examinations, including qPCR for EBV DNA, should be considered for patients with recurrent enteritis after autologous HSCT, regardless of endoscopic findings.

Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the 2016 World Health Organization classification of lymphoid neoplasms. EBV+DLBCL, NOS, is an aggressive B-cell lymphoma associated with chronic EBV infection and poor prognosis with standard chemotherapeutic approaches. We present the case of a 71-year-old male hospitalized for generalized lymphadenopathy, unexplained weight loss, and intermittent fever with pancytopenia and a very high EBV viral load. An inguinal lymph node was biopsied and reported at two different centers as Classic Hodgkin lymphoma and EBV associated lymphoproliferative, respectively. The patient was subsequently rebiopsied and a cervical lymph node was subjected to detail histopathologic and immunohistochemical evaluation by clonality studies resulting in a final diagnosis of EBV positive DLBCL, NOS. This case highlights the potential diagnostic pitfalls due to the morphologic heterogeneity of this entity and immunohistochemical overlap with Hodgkin lymphoma, T-cell rich large B-cell Lymphoma, and diffuse large B-cell lymphoma (DLBCL, NOS).

Primary cutaneous EBV‐positive diffuse large B‐cell lymphoma is an exceptional and aggressive neoplasia with a poorer prognosis than other cutaneous lymphoma. Our observation points out the rarity of the presentation and the dismal clinical course.

Epstein Barr virus-positive lymphoma results from the loss of homeostatic balance between Epstein Barr virus and immune cells. In this study, we investigated the mechanism underlying reduction in Epstein Barr virus-positive lymphoma cell proliferation and apoptosis by silymarin, an anti-inflammatory/antioxidant molecule extracted from Silybum�marianum (milk thistle). We examined the effect of silymarin on Raji cell proliferation, apoptosis, the expression of latent membrane protein�1, the proteins related to apoptosis, and the activation of nuclear factor kappa-B. Results showed that silymarin inhibited the proliferation and promoted apoptosis of Raji cells in a concentration-dependent manner. Also, silymarin reduced phosphorylated inhibitor of nuclear factor kappa-B and p65 levels. Silymarin treatment elevated latent membrane protein 1 expression and knockdown of this protein led to increased proliferation inhibition and apoptosis by silymarin. In conclusion, nuclear factor kappa-B and latent membrane protein 1 knockdown could work in concert with silymarin in suppressing Epstein Barr virus-positive lymphoma cell proliferation and inducing apoptosis.

Post-transplant lymphoproliferative disease (PTLD) can arise as a complication after solid organ transplantation. Epstein-Barr virus (EBV) infection is a known risk factor and is known to drive disease manifestation. PTLD can occur in EBV-negative recipients and with EBV-negative donor organs, however, EBV-negative PTLD pathogenesis is unknown. Here, we present PTLD presenting as intussusception in a patient with a historic simultaneous pancreas-kidney transplant (SPK). This case study presents the first documented case of EBV-negative post-transplant lymphoproliferative disease in an EBV-seropositive SPK recipient from an EBV-positive donor. Here we describe the diagnosis and management of this patient, discuss the differences between EBV positive and negative driven post-transplant lymphoproliferative disease, and highlight areas of research opportunity in the latter.

We report a case of an elderly male who presented with enlarged abdominal lymph nodes and was diagnosed as having Epstein-Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS). He was started on chemotherapy which had to be discontinued after three cycles due to the development of life-threatening pneumocystis carinii pneumonia and poor performance status. Within two years, the patient presented with features of relapse. A repeat histopathological examination of the lymph node showed features of peripheral T-cell lymphoma, NOS and the clonality was confirmed by T-cell receptor gamma chain rearrangement assay. More studies are needed to understand the association of EBV+ DLBCL, NOS with other lymphomas.

A 60-year-old Japanese woman was diagnosed with celiac disease (CeD) and treated with a gluten-free diet. For five years, she had a good clinical course. However, she complained of inappetence and nausea. Colonoscopy revealed ulcerative tumors in the terminal ileum. A histological examination of biopsy specimens from the ulcerative tumor showed diffuse infiltration of large atypical lymphocytes. Immunohistologically, the atypical lymphoid cells were positive for cluster of differentiation (CD) 10 and CD20. Many Epstein-Barr virus-encoded small RNA (EBER)-positive atypical lymphocytes were detected by in situ hybridization. This represents the first reported case of Epstein-Barr virus-positive intestinal diffuse large B-cell lymphoma complicated with CeD.

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.

BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a rare severe complication after renal transplantation, with an incidence of approximately 0.3%-2.0% in patients undergoing renal transplantation. The clinical manifestations of PTLD are often nonspecific, leading to tremendous challenges in the clinical diagnosis and treatment of PTLD. CASE SUMMARY We report two Epstein-Barr virus (EBV)-positive PTLD cases whose main clinical manifestations were digestive tract symptoms. Both of them admitted to our hospital because of extranodal infiltration symptoms and we did not suspect of PTLD until the pathology confirmation. Luckily, they responded well to the treatment of rituximab. We also discuss the virological monitoring, clinical characteristics, diagnosis, and treatment of PTLD. CONCLUSION PTLD is a deceptive disease and difficult to diagnose. Once patients are confirmed with PTLD, immune suppressant dosage should be immediately reduced and rituximab should be used as first-line therapy.

Background Ossified chronic subdural hematoma (CSH) associated with neoplasm has rarely been reported in the literature. We describe a patient with ossified CSH and underlying large B-cell lymphoma and discuss the relationship between lymphoma and CSH, emphasizing clinical characteristics, tumorigenic mechanism, and histopathologic analysis. Case Description A 46-year-old man with a history of alcohol abuse and a right frontotemporoparietal and left frontal ossified CSH that was diagnosed 2 years previously presented with headache and memory loss over 6 days. The patient was being followed with serial imaging, which showed the static state of the mass and no other lesions 7 months before admission. He underwent right frontotemporoparietal craniectomy to remove the ossified CSH and tumor. When the bone was lifted and the thin dura was opened, a hard, thick, ossified capsule was observed. No apparent tumor invasion was noted in the skull or epidural space. Despite refusing further chemotherapy and radiation therapy, the patient has been disease-free and working for 5 years. Conclusions Based on reported cases and relevant literature, large B-cell lymphoma may be associated with ossified CSH.

To present a case of necrotizing retinitis with Epstein-Barr virus (EBV)-positive ocular fluid in a patient with sudden unilateral vision loss, which was successfully treated with intravitreal methotrexate (MTX) injections.Retrospective case report.An 83-year-old female who had been on methylprednisolone for 20 years due to interstitial pneumonia developed vitreous opacity and extensive necrotizing retinitis with retinal hemorrhage sparing the posterior pole in the left eye. Multiplex polymerase chain reaction (PCR) for viral DNA using vitreous sample was positive for EBV but negative for herpes simplex virus, varicella-zoster virus, and cytomegalovirus. Real-time PCR detected EBV-DNA in aqueous humor but not in peripheral blood sample. Serologic testing was negative forIntravitreal MTX may be an effective treatment option for patients with necrotizing retinitis and EBV-positive ocular fluid not responding to conventional antiviral therapy.

We report a fulminant case of classical Hodgkin lymphoma (CHL). The patient died only approximately 2 months after the onset of subjective symptoms. Autopsy specimens revealed atypical cells resembling Hodgkin and Reed-Sternberg (HRS) cells in a rich inflammatory background in various organs. There were marked, characteristic angiodestructive lesions from infiltrating HRS-like cells and numerous macrophages. The HRS-like cells were infected with Epstein-Barr virus (EBV), immunohistochemically positive for PAX5 and CD30, and negative for CD3, CD20, and ALK. Most B-cell markers other than PAX5 were negative, and the HRS-like cells also expressed cytotoxic molecules. Monoclonal rearrangement of immunoglobulin heavy chain was detected by PCR analysis. According to the 2016 WHO classification, we diagnosed mixed cellularity CHL. However, EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified and EBV-positive B-cell lymphoma, unclassifiable with features intermediate between DLBCL and CHL were considered as differential diagnoses because both tumors are aggressive EBV-positive large B-cell neoplasms with reactive inflammatory cells and sometimes contains HRS-like cells. The clinical condition of the current case was closer to these two entities than to CHL. A diagnosis of EBV-positive large B-cell neoplasms was difficult because of overlapping morphological and immunohistochemical characteristics, but should be considered for prognosis.

We characterize the clinicopathological features of two patients (one 38 year old woman and one 42 year old man, both of Chinese ethnicity) with Epstein Barr Virus positive non-keratinizing nasopharyngeal carcinoma from an endemic region with prominent presence of amyloid and one case with both amyloid and abundant intracytoplasmic hyaline globules. The amyloid material was positive for Congo red and showed apple green birefringence when examined under polarized light. The amyloid was immunoreactive for cytokeratins and was located both intra- and extracellularly. Frequently the amyloid had a light microscopical spherical appearance and displayed peripheral radiating fibrils from a central homogenous core. One of the patients had a unique presentation of nasopharyngeal carcinoma with perceived hemoptysis and coughing up two pieces of tumor tissue. In reality, the nasopharyngeal tumor was polypoid and the two fragments were pinched of from the main tumor mass.

Lymphomas of the oral cavity are rare and the most frequent type is diffuse large B-cell lymphoma (DLBCL). Epstein-Barr virus (EBV) is known to be associated with the development of different lymphomas. In 2008, the World Health Organization provisionally included the EBV-positive DLBCL of the elderly in the classification of hematopoietic and lymphoid tumors as a lymphoma occurring in older individuals without any known immunodeficiency. However, it has since been recognized that this entity may occur in younger individuals and present similar clinical parameters in both age groups. As a result, the 2017 revision has declined the term elderly and modified it to EBV-positive DLBCL, not otherwise specified (NOS). In this report, we describe a rare case of EBV-positive DLBCL, NOS, presenting as a painless swelling in the oral cavity. This entity shows a more aggressive clinical course than EBV-negative DLBCL, and other lymphoproliferative disorders should be considered in the differential diagnosis.

In 2014, The Cancer Genome Atlas provided a molecular classification defining Epstein-Barr virus (EBV)-positive gastric cancer as a separate subtype. While its prognostic role is still debatable, emerging potential biomarker role for personalized treatment strategies is already recognized by international guidelines. We report a case with successful combined therapy of a 64-year-old EBV-positive gastric cancer male patient. Patient initially presented with locally advanced gastric cancer, which was treated surgically; three years later patient developed recurrence within the remnant stomach and was treated surgically. Two years after operation patient developed distant metastases and was enrolled in a clinical trials’ (NCT01630083) arm 2: receiving chemotherapy and monoclonal antibody claudiximab. This treatment induced durable disease stabilisation for 34 months. After progression, second line chemotherapy with docetaxel and cisplatin provided additional disease stabilisation and symptom control for 8 months. Patient’s overall survival reached 9.1 years. Presented report shows EBV- ositive gastric cancer case with better overall survival compared to reported average, which contributes to the meaningfulness of its distinction as a separate subtype, evidence that targeted therapy is more effective in selected patient groups, and EBV as an emerging biomarker.

Primary central nervous system lymphoma (PCNSL) and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) can share clinical features and may be indistinguishable, even after brain biopsy. We encountered a case of Epstein-Barr virus-positive (EBV+) PCNSL recurrence in a patient with clinical features of CLIPPERS, and repeat brain biopsy was required to reach the correct diagnosis. Four years after the initial diagnosis and treatment of PCNSL, "peppering" punctate enhanced lesions with transient steroid responsiveness were detected during brain magnetic resonance imaging (MRI). A second brain biopsy supported a diagnosis of CLIPPERS, while a third biopsy confirmed the diagnosis of recurrent PCNSL.

Angioimmunoblastic T‐cell lymphoma (AITL) is the subtype of mature T‐cell non‐Hodgkin lymphoma. Compared with diffuse large B‐cell lymphoma (DLBCL), AITL patients are frequently accompanied with Epstein–Barr virus (EBV) infection. To date, there is no report on the subsequent development of AITL in patients with EBV‐positive DLBCL. We performed a rare case of EBV‐positive AITL developing one year after initial diagnosis of EBV‐positive DLBCL. The patient showed poor response to the chemotherapy regimen, and poor survival., The left inguinal lymph node biopsy of initial diagnosis shows morphological (A, X200) and IHC staining with positive for CD20 (B, X200), PAX‐5 (C, X200), and Ki‐67 (D, X200).

To date, there is no report on the subsequent development of AITL in patients with EBV-positive DLBCL. We performed a rare case of EBV-positive AITL developing one year after initial diagnosis of EBV-positive DLBCL. The patient showed poor response to the chemotherapy regimen, and poor surviva

Background: Angioimmunoblastic T-cell lymphoma (AITL) is the sub-type of mature T-cell non-Hodgkin lymphoma. Compared with diffuse large B-cell lymphoma (DLBCL), AITL patients are frequently accompany with Epstein–Barr virus(EBV) infection. To date, there is no report on the subsequent development of AITL in patients with EBV-positive DLBCL. We performed a rare case of EBV-positive AITL developing one year after initial diagnosis of EBV-positive DLBCL. The patient showed poor response to the chemotherapy regimen, and poor survival.Case presentation: A 83-year-old Chinese male presented with enlarged lymph nodes in the neck and bilateral inguinal. Immunohistochemically (IHC), the atypical cells were strongly positive for CD20, CD19, PAX-5 and MUM-1, but negative for CD3, CD5, CD10, Bcl-6, CyclinD1, CD138 and TdT. Besides, in situ hybridization for EBV-encoded small RNA (EBER) staining was also strongly positive. The patient was diagnosed with EBV-positive DLBCL, and transformed to Angioimmunoblastic T-cell lymphoma one year after initial diagnosis of EBV-positive DLBCL. Unfortunately, the patient ultimately died three months after diagnosed AITL. The overall survival time of this patient is fifteen months. Conclusions: Transformed EBV-positive AITL is a rare type of lymphoma with high malignancy and a generally poor prognosis. The accurate diagnosis should be depended on immunophenotype and morphology.

Some patients diagnosed with methotrexate-associated lymphoproliferative disorder (MTX-LPD) develop spontaneous regression upon the discontinuation of MTX, whereas others require chemotherapy. The mechanisms underlying this differential response and the capacity to spontaneously regress are not clearly understood. We evaluated numerous clinicopathological features in 63 patients diagnosed with MTX-LPD, with a special focus on those with Epstein-Barr virus (EBV)-positive mucocutaneous lesions (EBVMCL). The diagnosis of EBVMCL included cases of both EBV-positive mucocutaneous ulcers (EBVMCU) and diffuse gingival swelling associated with proliferation of EBV-positive large B-cells. Of the four subgroups of MTX-LPD, one-year treatment-free survival (TFS) after the discontinuation of MTX was achieved among those with EBVMCL (100%), diffuse large B-cell lymphoma (57%), Hodgkin-like lesions (60%), or classical Hodgkin lymphoma (29%); a significant difference in TFS was observed when comparing the responses of patients with EBVMCL to the those diagnosed with other subtypes. Multivariate analysis revealed predictive factors for prolonged TFS that included EBV-positive lesions and comparatively low levels of serum LDH. Taken together, our study suggests that a diagnosis of EBVMCL is related to the overall clinical outcome after the discontinuation of MTX.

Composite lymphoma (CL) is a very rare clinical entity defined by the presence of two or more different subtypes of lymphoma in the same lymph node. We report a case of CL in a 78-year-old male presenting with leukocytosis and swelling of multiple lymph nodes. A left axillary node biopsy showed atypical lymphocytes in both the interfollicular and follicular areas. Immunohistochemistry revealed that mantle cell lymphoma (MCL) was mainly present in the interfollicular area and follicular lymphoma (FL) was present in the follicular area. Polymerase chain reaction analysis of immunoglobulin heavy chain gene rearrangements confirmed that they were clonally related neoplasms. However, Epstein-Barr virus (EBV) DNA was detected in only FL cells, suggesting that MCL and FL had split into two clones in the early steps of pathogenesis. This is the first reported case of CL with EBV-negative B-cell non-Hodgkin lymphoma (NHL) and EBV-positive B-cell NHL with a clonal relationship. We discuss the developmental processes of these two lymphomas.

The Epstein–Barr virus (EBV) causes infectious mononucleosis (IM). In the case of atypical presentation, lymph node and tonsillar biopsies are required to rule out lymphoma. Here, we discuss an 83-year-old male who presented with findings suggestive of diffuse large B-cell lymphoma, which was later ruled out in favor of IM. The distinction between IM and lymphomas is quite challenging due to the extensive overlap between the two diseases. Various studies have demonstrated that EBV-positive diffuse large B-cell lymphoma mimics IM due to large B-cell proliferation in acute EBV infection. We suggest testing for acute EBV infection in addition to utilizing advanced testing to confirm IM in patients with atypical infection, to avoid misdiagnosis leading to inappropriate treatment.

Background Epstein-Barr virus (EBV)-positive gastric cancers (GCs) have been recently identified as a molecular subgroup showing excellent outcomes after surgery for early-stage disease and responsiveness to immune checkpoint inhibitors (ICIs) for metastatic stage. No data are available on the prevalence, clinical characteristics, and prognosis of this subgroup of GCs in the metastatic setting. Materials and Methods In this cohort study, we assessed the impact of EBV status in patients with metastatic GC treated with chemotherapy at two Italian institutions. Results Among the 175 cases analyzed, only 7 (4%) were EBV positive and all showed long-lasting and even complete responses to first-line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV-negative patients (3-year overall survival: 80% vs. 20.1%; hazard ratio: 0.12). Conclusion If confirmed in larger data sets, our results may give a strong rationale for investigating the addition of ICIs to chemotherapy, in order to maximize the chance of achieving durable and complete responses in this uncommon subtype of GC. Implications for Practice To date, no data are available on the prevalence and clinical characteristics of patients with Epstein-Barr virus (EBV)-positive metastatic gastric cancer (GC), a specific subtype of GC showing excellent outcomes after radical surgery in early-stage disease and responsiveness to immune checkpoint inhibitors (ICIs). This cohort study showed that patients with EBV-positive GC who did not receive ICIs had exceptional, long-lasting, and even complete responses to first-line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV-negative patients. If confirmed in larger series, these results may give a strong rationale for investigating the combination of chemotherapy and ICIs to achieve durable and potentially complete response in this uncommon subtype of GC.

Background Epstein-Barr virus is associated with many human hematopoietic neoplasms; however, Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma is extremely rare. In routine clinical practice, detection of mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma in a tissue sample presumes a clonal relation between these neoplasms and that diffuse large B-cell lymphoma developed by transformation of the mucosa-associated lymphoid tissue lymphoma. However, evidence to support this presumption is sparse and controversial. Assessment of the clonal relationship of the lymphoid components of a composite lymphoma is important for understanding its pathogenesis and correct diagnosis. Case presentation We present an unusual case of composite lymphoma (Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma/Epstein-Barr virus-negative diffuse large B-cell lymphoma) in the parotid salivary gland of a 62-year-old Caucasian woman with Sjögren’s syndrome and rheumatoid arthritis. Simultaneous occurrence of mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma in the parotid salivary gland led us to initially assume a clonal relationship between diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma. Epstein-Barr virus was detected by in situ hybridization and polymerase chain reaction in the mucosa-associated lymphoid tissue lymphoma, but not in diffuse large B-cell lymphoma, suggesting that these lymphomas were not clonally related. Fragment analysis of frame region 3 polymerase chain reaction products from microdissected mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma components revealed different clonal pattern rearrangements of the immunoglobulin heavy chain gene. Conclusions Our patient’s case highlights the importance of assessing the clonal relationships of the lymphoid components of a composite lymphoma and Epstein-Barr virus screening in mucosa-associated lymphoid tissue lymphoma in patients with autoimmune disease.

Purpose Pembrolizumab, a programmed cell death protein 1 (PD1) inhibitor inhibits the interplay between PD1 of T-cell and programmed cell death ligand 1 (PDL1) on tumor cells. Although pembrolizumab has been tried to various subtypes of non-Hodgkin lymphoma (NHL), real-world data about the efficacy of pembrolizumab in NHL patients are limited. Materials and methods We analyzed the outcome of 30 relapsed or refractory NHL patients treated with pembrolizumab, and compared the outcome between Epstein-Barr virus (EBV)‒positive and negative subtypes because EBV infection of tumor cells can upregulate PDL1 expression. Results Seven patients with EBV-positive NHL showed a response including NK/T-cell lymphoma (6/14, 44%) and primary mediastinal B-cell lymphoma (1/4, 25%) whereas EBV-negative subtypes did not respond such as diffuse large B-cell lymphoma and T-lymphoblastic lymphoma. We also evaluated PDL1 expression using tumor tissue of 76 patients. High PDL1 expression (positive staining of > 50% of tumor cells) was more frequent in NK/T-cell lymphoma and primary mediastinal B-cell lymphoma than other subtypes. Thus, PDL1 expression was significantly higher in EBV-positive (18/32, 56%) than EBV-negative NHL (4/38, 11%, p < 0.001). Furthermore, NK/T-cell lymphoma patients with high PDL1 expression showed a higher response (4/6, 67%) than those with low PDL1 expression (1/5, 20%). Conclusion Pembrolizumab could be useful as a salvage treatment for relapsed or refractory EBV-positive NHL, especially NK/T-cell lymphoma. However, its efficacy in EBV-negative NHL with low or absent PDL1 expression is still not clear although pembrolizumab could be a potential treatment option for relapsed or refractory NHL.

Background: Nasopharyngeal carcinoma (NPC) treatment is mainly based on clinical staging. We hypothesize that better understanding of the molecular heterogeneity of NPC can aid in better treatment decisions. Therefore, the purpose of this study was to present our exploration of cancer gene copy-number alterations (CNAs) of Epstein-Barr virus (EBV)-positive and EBV-negative NPC. Methods: Multiplex ligation-dependent probe amplification was applied to detect CNAs of 36 cancer genes (n = 103). Correlation between CNAs, clinicopathological features, and survival were examined. Results: The CNAs occurred significantly more in EBV-negative NPC, with PIK3CA and MCCC1 (P

In primary Epstein-Barr virus (EBV) infection, the virus may infect T-cells or natural killer (NK)-cells and can cause T- and NK-cell (T/NK-cell) lymphoproliferative disease, which encompasses several disease entities with a broad clinicopathological spectrum. T/NK-cell lymphoproliferative disease arising during primary EBV infection includes clonal EBV-infected T-cell proliferation in the setting of infectious mononucleosis, EBV-associated hemophagocytic lymphohistiocytosis, and systemic T-cell lymphoma of childhood. Chronic active EBV (CAEBV) infection of the T/NK-cell type is not a simple viral infection but instead is classified as a lymphoproliferative disease. The prototype of CAEBV is a systemic form that exhibits varying degrees of clinical severity depending on the host immunity and EBV factor. Hydroa vacciniforme-like lymphoproliferative disease and mosquito-bite allergy are peculiar cutaneous forms of CAEBV that involve T/NK-cells, respectively. Abnormal activation and replication of EBV together with the proliferation and clonal expansion of infected cells, depending on the patient’s immunological response, play a key role in the pathogenesis of CAEBV of the T/NK-cells type.

The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset

Primary cutaneous EBV (Epstein-Barr virus)-positive diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), is an extremely rare disease. The clinical and pathological features of DLBCL, NOS have not been clearly illustrated. We report a case of primary cutaneous EBV-positive DLBCL, NOS in a 35-year-old Chinese male with multiple ulcerated and nodular lesions on his trunk and arms for 6 months. No other organs, except the skin, were involved. The lesions were localized in the dermis with focal necrosis. The tumor cells were immunoblastic- or centroblastic-like cells and diffusely distributed. There were numerous inflammatory cells in the background. The tumor cells were positive for CD20, PAX-5, MUM1, LMP1, CD30, and Epstein-Barr virus encodedsmall RNA, but negative for EBNA2. Polymerase chain reaction showed a monoclonal IG gene rearrangement. The patient received 6 cycles of CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin®, prednisone) chemotherapy and went into complete remission. There was no evidence of relapse after 35 months of follow-up.

Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from 10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.