Virus-positive Diffuse Large B-cell Lymphoma Research Articles

Kaempferol inhibits the proliferation and migration of Epstein-Barr virus-positive diffuse large B-cell lymphoma cells

Purpose: To assess the effect of kaempferol on the growth, apoptosis, and motility of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) cells, and to elucidate its mechanism of action. 
 Methods: Human DLBCL cells were used to generate EBV-positive (EBV +) cell line Pfeiffer. CCK-8, colony formation, flow cytometry (FCM), and immunoblot assays were employed to determine the effects of kaempferol on the growth and apoptosis of EBV + DLBCL cells. Cell motility was evaluated by Transwell and immunoblot assays. Immunoblot assay was further conducted to unravel the mechanism of action. 
 Results: Kaempferol inhibited the growth of EBV + DLBCL cells. It also enhanced the apoptosis of EBV + DLBCL cells, but inhibited the motility of the cells. Furthermore, kaempferol inhibited PI3K/AKT axis, thereby suppressing DLBCL. 
 Conclusion: Kaempferol inhibits the growth and motility of EBV + DLBCL cells via PI3K/AKT axis. It is therefore a potential drug for the treatment of DLBCL.

Polatuzumab Vedotin (Polivy)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses polatuzumab vedotin (Polivy), 30 mg or 140 mg single-use vial, lyophilized powder for solution for IV infusion.
 Indication: Polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, indicated for the treatment of adult patients with previously untreated large B-cell lymphoma, including diffuse large B-cell lymphoma not otherwise specified, high-grade B-cell lymphoma, Epstein-Barr virus-positive diffuse large B-cell lymphoma not otherwise specified, and T-cell/histiocyte-rich large B-cell lymphoma.

A Case of Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma Occurring in Thyroid Gland

Epstein-Barr virus positive diffuse large B-cell lymphoma is very rare malignant tumor in thyroid gland. Compared to Epstein-Barr virus negative diffuse large B-cell lymphoma, it tends to have more extranodal involvement, does not respond to chemoimmunotherapy well, and has worse prognosis. We have encountered a patient with Epstein-Barr virus positive diffuse large B-cell lymphoma of thyroid gland in 75-year-old female presenting with aggravating dyspnea and neck pain.

Characteristics and Prognosis of Epstein Barr Virus-Positive Diffuse Large B-Cell Lymphoma: A Retrospective, Single-Center Study

Objective: The aim of this study was to analyze the clinical characteristics and prognosis of Epstein Barr virus-positive diffuse large B-cell lymphoma (EBV+DLBCL) in a Chinese cohort. Methods: A total of 57 patients diagnosed with EBV+DLBCL from January 1, 2013 to December 31, 2020 were included, and 228 concurrent patients with EBV-DLCBL served as control. The differences between the two groups were compared and the prognosis factors were identified by univariate and multivariate analysis. Results: There were 38 man in the EBV+DLBCL group, with a median age of 56 years (rang, 18 to 88). Tumor cells originated from GCB in 15 patients (26.3%), and from non-GCB in 40 patients (70.2%). There were 34 patients (59.6%) with Epstein Barr virus infection. Compared with EBV-DLCBL patients, patients with EBV+DLBCL had B symptoms, hypoalbuminemia, anemia and extranodal involvement>1 more frequently, as well as higher LDH and β2-Microglobulin levels (P < 0.05 foe all). The most common extranodal sites involved were digestive tract, especially, the stomach, nasopharynx, bone marrow and bone. Immunohistochemical staining showed 24 patients (42.1%) in the EBV+DLBCL group were CD30 positive, compared with xxx in patients with EBV﹣DLCBL (P < 0.001). After treatment with rituximab combined with chemotherapy, the EBV+DLBCL patients had a complete response rate and a overall response rate of 55.5% (30/54) and 83.3% (45/54), respectively. With a median follow-up time of 28 months, 22.2% (10/45) patients relapsed. The overall response rate and recurrent rate were similar between the two groups. In multivariate analysis, increased β2-Microglobulin level and bone marrow invasion were independent risk factors for PFS, while increased β2-Microglobulin level and decreased HB were independent risk factors for OS in patients with EBV+DLBCL. Conclusion: The majority of EBV+DLBCL patients were non-GCB.β2-Microglobulin level and bone marrow invasion were independent risk factors for PFS in patients with EBV+DLBCL, while β2-Microglobulin and HB were independent risk factors for OS in patients with EBV+DLBCL. The therapeutical potentials of targeted medicines, such as CD30 inhibitors and PD-1 inhibitors, deserve to be explored in the future. Keywords：Epstein Barr virus, diffuse large B-cell lymphoma, prognostic factors

EBV-Positive Diffuse Large B-Cell Lymphoma in Association with Polyurethane Textured Breast Implants: Case Report and Literature Overview.

Lymphomas associated with breast implants are mostly of the T-cell type which typically present as a late-onset seroma or palpable mass adjacent to the implant. Primary lymphomas of the breast, in the absence of breast implants, are mostly of the B-cell type. However, we present a case of an Epstein-Barr virus-positive diffuse large B-cell lymphoma in a patient with polyurethane textured implants. A 75-year-old woman presented with a sudden onset of swelling in her right breast. Her medical history revealed a unilateral mastectomy at the age of 48 for an invasive ductal adenocarcinoma in her left breast. Reconstruction was performed using bilateral McGhan style 150 implants. Nine years later, she was diagnosed with Baker IV capsular contracture and bilateral rupture, as seen on magnetic resonance imaging. A complete capsulectomy with implant change (Polytech, Replicon® SL HP) and mastopexy on the right was performed. Given her history and the sudden onset of swelling, the situation was concerning. Ultrasound showed a large mass in contact with the implant and an effusion around it. After mastectomy withexplantation and capsulectomy, she was diagnosed with an Epstein-Barr virus-associated diffuse large B-cell lymphoma (DLBCL) of the capsule in association with textured breast implants. We report the first case of polyurethane textured implant association with the rare entity of EBV+ DLBCL. Our aim is to renew awareness of the clinical significance of late periprosthetic seroma and highlight the need for documenting all cases to advance our understanding of breast implant-associated lymphoma. This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Necrotic lymphadenopathy in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Necrotic lymphadenopathy in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Primary hepatic Epstein–Barr virus-positive diffuse large B-cell lymphoma associated with azathioprine immunosuppression: a case report

BackgroundHepatic masses are relatively common findings, and the diagnostic approach often begins by identifying patient and mass characteristics that are risk factors for malignancy. Chronic immunosuppression is a known risk factor for various malignancies, and azathioprine in particular has been reported in association with solid and hematologic malignancies, including diffuse large B-cell lymphoma.Case presentationA 46-year-old white woman presented to clinic with several weeks of gastrointestinal symptoms and was found to have a hepatic mass on imaging. Her history was notable for neuromyelitis optica spectrum disorder on chronic immunosuppression with azathioprine. It was initially thought to be an inflammatory adenoma. On 6-month follow-up imaging, the mass had grown rapidly in size and was surgically resected. Further workup determined the mass to be an iatrogenic immunodeficiency-associated Epstein–Barr virus-positive diffuse large B-cell lymphoma confined to the liver. Azathioprine was discontinued and the patient underwent treatment with rituximab with no evidence of recurrence 2 years after the initiation of treatment.ConclusionsThis case report describes the first time hepatic Epstein–Barr virus-positive diffuse large B-cell lymphoma has been reported with azathioprine, which highlights the unique sequelae of chronic immunosuppression, including atypical hematologic malignancies, and the importance of considering chronic immunosuppression in the diagnostic evaluation of a hepatic mass.

TET2 and LILRB1 mutations are frequent in Epstein-Barr virus-positive diffuse large B-cell lymphoma especially in elderly patients.

Diffuse large B-cell lymphoma (DLBCL) harboring Epstein-Barr virus (EBV) primarily occurs in patients who have underlying immunodeficiency or in elderly patients but is also reported in young, immunocompetent patients. The authors investigated the pathologic differences in EBV-positive DLBCL in these three groups of patients. In total, 57 patients with EBV-positive DLBCL were included in the study; of these, 16 patients had associated immunodeficiency, 10 were young (younger than 50years), and 31 were elderly (aged 50years or older). Immunostaining for CD8, CD68, PD-L1, and EBV nuclear antigen 2, and panel-based next-generation sequencing was performed on formalin-fixed, paraffin-embedded blocks. Immunohistochemistry revealed EBV nuclear antigen 2 positivity in 21 of the 49 patients. The degree of CD8-positive and CD68-positive immune cell infiltration and PD-L1 expression did not differ significantly in each group. Extranodal site involvement was more common in young patients (p=.021). In mutational analysis, the genes with the highest mutation frequency were PCLO (n=14), TET2 (n=10), and LILRB1 (n=10). For the TET2 gene, all 10 mutations were found in elderly patients (p=.007). Compared with a validation cohort, both TET2 and LILRB1 showed a higher mutation frequency in EBV-positive patients than in EBV-negative patients. EBV-positive DLBCL occurring in three different age and immune status groups showed similar pathologic characteristics. Notably, a high frequency of TET2 and LILRB1 mutations was characteristic of this disease in elderly patients. Further studies are needed to determine the role of TET2 and LILRB1 mutations in the development of EBV-positive DLBCL along with immune senescence. Epstein-Barr virus-positive diffuse large B-cell lymphoma occurring in three different groups (immunodeficiency-associated, young, and elderly) showed similar pathologic characteristics. The frequency of TET2 and LILRB1 mutations was high in elderly patients with Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Genomic Profiling and Clinicopathological Features in Peruvian Patients with EBV-Positive Diffuse Large B-Cell Lymphomas, NOS

Introduction: Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is a newly recognized entity by the World Health Organization. EBV+ DLBCL, NOS is commonly encountered in Latin American countries and carries a dismal prognosis. It has been published studies that have evaluated the genetic profiling in EBV +DLBCL from Asian and Western countries. However, there are lacking of studies from Latin America. This study aimed to characterize and compare the genetic profiling and clinicopathological features in Peruvian EBV+ with EBV- DLBCL patients. Methods: This retrospective cohort study included patients ≥18 years from one institution in Peru from 2010 to 2020. Hematopathologists reviewed pathological samples to confirm the diagnosis of EBV+ DLBCL cases. An EBV+ case was confirmed when the EBER test had a positivity more or equal to 40%. We collected clinicopathological data by reviewing the medical records of the patients. Twenty paraffin-embedded biopsy samples were analyzed and tumor DNA was purified using silica columns (QIAGEN, Valencia, CA, USA). The quantity and quality of the purified DNA were evaluated by spectrophotometry. We compared the genetic profiling with ten EBV+ versus ten EBV- DLBCL samples. Results: Twenty-two candidate genes were selected from previous reports of exome analysis with the diagnosis of DLBC. The median age at diagnosis was similar in both groups (58 years old, range 19-89). There was a male predominance in EBV+ (57%) compared to EBV- DLBCL cases (43%). Sixty-eight percent of patients with EBV+ had advanced disease (Ann arbor stage III-IV), compared to 48% of EBV- DLBCL patients. The non-germinal center was more common in EBV+ (60%) than EBV- cases (40%). All patients received either R-CHOP-like regimens as a first-line treatment. The overall response rate was 91% for EBV- compared to 74% for EBV+ DLBCL. We found mutations in MYC (10%), NOTCH2 (5%), STAT6 (5%) , ANKRD11(5%), TP53 (5%), KMT2A (5%), YY1 (5%), CARD11 (5%), ARID1A (5%) and RHOA (5%) in EBV+ cases, meanwhile, ARID1A (10%) , CCR6 (10%), KMT2A (5%), CARD11(5%), NOTCH2 (5%), TP53 (5%), and ANKRD11(5%) in EBV - DLBCL cases. Conclusions: This is the first Latin American study that have performed the genomic pattern in Peruvian EBV+ in comparison to EBV- DLBCL patients. Overall, our data suggest that Peruvian EBV+ DLBCL have different genetic profiling compared to East and Western countries. Also, we found that EBV+ and EBV- patients share similar drive mutations. Our findings should be validated in a larger prospective cohort of Latin American patients.

Pathology review identifies frequent misdiagnoses in recurrent classic Hodgkin lymphoma in a nationwide cohort: implications for clinical and epidemiological studies.

Patients treated for classic Hodgkin lymphoma (CHL) have a reported 13-fold increased risk of developing subsequent non-Hodgkin lymphoma (NHL). In light of the growing awareness of CHL mimickers, this study re-assesses this risk based on an in-depth pathology review of a nationwide cohort of patients diagnosed with CHL in the Netherlands (2006-2013) and explores the spectrum of CHL mimickers. Among 2,669 patients with biopsy-proven CHL, 54 were registered with secondary NHL. On review, CHL was confirmed in 25/54 patients. In six of these, the subsequent lymphoma was a primary mediastinal B-cell lymphoma/mediastinal gray zone lymphoma, biologically related to CHL and 19/25 were apparently unrelated B-cell NHL. In 29/54 patients, CHL was reclassified as NHL, including T-cell lymphomas with secondary Hodgkin-like B-blasts (n=15), Epstein Barr virus-positive diffuse large B-cell lymphoma (n=8), CD30+ T-cell lymphoma (n=3) and indolent B-cell proliferations (n=3). Higher age, disseminated disease at presentation, extensive B-cell marker expression and association with Epstein-Barr virus were identified as markers to alert for CHL mimickers. Based on these data, the risk of developing NHL after CHL treatment was re-calculated to 3.6-fold (standardized incidence ratio 3.61; confidence interval: 2.29-5.42). In addition, this study highlights the clinicopathological pitfalls leading to misinterpretation of CHL and consequences for the care of individual patients, interpretation of trials and epidemiological assessments.

EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk-stratification, and management.

Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the WHO classification of lymphoid neoplasms since 2016. EBV+ DLBCL, NOS, is an aggressive B-cell lymphoma associated with EBV infection, and a poor prognosis with standard chemotherapeutic approaches. The diagnosis is made through a careful pathological evaluation. Detection of EBV-encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for percentage of positive cells has not been defined. The differential diagnosis includes plasmablastic lymphoma (PBL), DLBCL associated with chronic inflammation, primary effusion lymphoma (PEL), among others. The International Prognostic Index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD-1/PD-L1 are emerging as potential adverse but targetable biomarkers. Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV-negative DLBCL in the era of chemoimmunotherapy. Therefore, the inclusion of patients in clinical trials when available is recommended. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.

A Novel Prognostic Index for Patients with EBV-DLBCL NOS: A Study from the Grupo De Estudio Latinoamericano De Linfoproliferativos (GELL)

Introduction: Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is a newly recognized entity by the World Health Organization. EBV+ DLBCL, NOS is commonly encountered in Latin American countries and carries a dismal prognosis. Current prognostic models such as the Oyama and the International Prognostic Index (IPI) score have limited prognostic value in this patient population. Therefore, we aim to evaluate the ability of these models to risk stratify patients and propose a novel prognostic model in the largest cohort of Latin American patients with EBV+ DLBCL, NOS.Methods: This retrospective cohort study included patients ≥18 years from six Latin American countries diagnosed and treated at tertiary centers from 2010 to 2020. Hematopathologists at each institution reviewed pathological samples to confirm the diagnosis of EBV+ DLBCL, NOS. We collected clinicopathological data by reviewing the medical records of the patients. The primary endpoint was overall survival (OS), defined as the time from the date of diagnosis until death from any cause or last visit. The secondary endpoint, progression-free survival (PFS), was defined as the time from diagnosis until death, progression, or last visit. Our novel model (Grupo de Estudio Latinomericano de Linfoproliferativos [GELL] Score) includes the Eastern Cooperative Oncology Group (ECOG) performance status ≥2, extranodal involvement >1, serum albumin <3.5 g/dL, serum lactate dehydrogenase (LDH) above the upper limit of normal, and platelet-to-lymphocyte ratio >455. We assigned a value of 1 to each of the abovementioned elements in the score and classified the patients as low (0 points), intermediate (1-2 points), and high (3-5) risk. OS and PFS probabilities were computed with the Kaplan-Meier method and compared with the log-rank test. We used Cox regression to evaluate the proportional hazard ratios (HR) of each score for our study outcomes. The C-index was employed to measure discrimination of each model. We used cross-validation to evaluate the model performance.Results: A total of 154 patients with EBV+ DLBCL, NOS were included in this analysis. The median age at diagnosis was 58 years (range 19-86 years) with a slight male predominance (53%). EBER was positive in all cases (range 1-100%). Clinically, 39% presented ECOG ≥2, 57% had B symptoms, 50% had an extranodal disease as a primary tumor, and 71% had Ann Arbor stage III/IV. Fifty-one percent of the patients had an elevated LDH level, and 43% had albumin <3.5 g/dL. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen was administered in 79% of individuals as first-line treatment. The overall response rate was 80% (62% complete response and 18% partial response). With a median follow-up of 61 months, the 5-year OS and PFS rates were 61% and 47%, respectively. The 5-year OS rates of patients with low, intermediate, and high-risk disease according to the GELL score was 90%, 59%, and 33%, respectively (Fig 1A). The 5-year PFS rates were 82%, 39%, and 23%, respectively (Fig 2A). Table 1 shows the Cox regression and the discrimination analysis for each of the scores. The GELL score has the highest discriminatory index for OS and PFS compared to the IPI, Revised-IPI, National Comprehensive Cancer Network-IPI, and the Oyama score (Figure 1 and 2).Conclusions: This study proposes a novel score for risk stratification of patients with EBV+ DLBCL, NOS. The GELL score appears to better discriminate OS and PFS than previous scores. Our results should be validated in an independent prospective cohort. [Display omitted] DisclosuresRamirez-Ibarguen: Asofarma: Consultancy; MSD: Consultancy; Abbvie: Speakers Bureau; Astra Zeneca: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Perini: Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau. Oliver: Roche: Other: conference support and fees ; Abbvie: Other: conference support and fees . Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

The Incidence of Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis.

Simple SummaryThe worldwide prevalence of Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) is undetermined. There is no clearly defined cut-off for EBV-encoded RNA (EBER) positivity in tumor cells by in situ hybridization. A lack of common criteria for positive expression of EBER has been raised as a limitation for interpreting and understanding the geographic and ethnic disparity of prevalence of EBV+ DLBCL. We conducted a systematic literature review and meta-analysis to establish the proportions of EBV+ DLBCL patients. Results showed that the pooled proportion of EBER positivity was 7.9% in patients with de novo DLBCL. The prevalence of EBV+ DLBCL was significantly higher in Asia and South America compared with Western countries. A tendency for lower pooled proportions was observed in studies using a higher cut-off for EBER positivity. The patients’ age did not significantly affect the prevalence. These findings may improve our current knowledge of the EBV+ DLBCL.The worldwide prevalence of Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) is undetermined. There is no clearly defined cut-off for EBV-encoded RNA (EBER) positivity in tumor cells by in-situ hybridization. The purpose of this study was to establish the proportions of EBV+ DLBCL patients and influence of the different cut-offs for EBER positivity, geographical location, and age on the prevalence of EBV+ DLBCL. PubMed and EMBASE were searched for studies published up to May 28, 2020 that reported proportions of EBER positivity in immunocompetent and de novo DLBCL patients. The pooled proportions were computed by an inverse variance method for calculating the weights and the DerSimonian–Laird method. Multiple subgroup analyses were conducted to explore any heterogeneity. Thirty-one studies (8249 patients) were included. The pooled proportion of EBV+ DLBCL was 7.9% (95% CI, 6.2–10.0%) with significant heterogeneity among studies (p < 0.001). The prevalence of EBV+ DLBCL was significantly higher in Asia and South America compared with Western countries (p < 0.01). The cut-offs for EBER positivity (10%, 20%, 50%) and patients’ age (≥50 years vs. <50 years) did not significantly affect the prevalence (p ≥ 0.10). EBV+ DLBCL is rare with a pooled proportion of 7.9% in patients with DLBCL and the geographic heterogeneity was confirmed.

Cutaneous Epstein-Barr virus–positive diffuse large B-cell lymphoma, not otherwise specified: A systematic review and comparative analysis with Epstein-Barr virus–negative, leg type

To the Editor: Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an EBV-associated B-cell lymphoma often presenting in elderly patients without any known immunodeficiencies.1,2 For a systematic review to characterize cutaneous EBV-positive DLBCL-NOS, we searched 5 databases (Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/dby7kdtzk8.1).3 We also searched the Asan Medical Center database for cases of cutaneous EBV-positive DLBCL-NOS and primary cutaneous EBV-negative DLBCL–leg type for comparative analysis.

T-cell lymphoma with a granulomatous lesion of the lungs after autologous hematopoietic stem cell transplantation for Epstein\u2013Barr virus-positive diffuse large B-cell lymphoma: a unique rare case of metachronous B-cell and T-cell lymphoma

BackgroundEpstein–Barr virus (EBV) is associated with the pathogenesis of a variety of malignancies, most notably lymphomas. Especially in the background of immunodeficiency, such as primary immunodeficiency disorder (PID) and post-transplant lymphoproliferative disorder (PTLD), the role of EBV might be crucial. PIDs are rare heterogeneous diseases affecting the development and/or the function of the innate and adaptive immune system. Malignancy is the second-highest cause of death after infection, and lymphoma accounts for about half of malignancies. The most frequently reported lymphoma type is diffuse large B-cell lymphoma (DLBCL) and the incidence of T-cell lymphoma is rare. PTLDs are also rare serious lymphoid and/or plasmacytic proliferative disorders that occur after undergoing solid organ or hematopoietic stem cell transplantation (HSCT). In the context of HSCT, most reported PTLDs have occurred in patients who received allogenic HSCT, but only a few cases have been reported in autologous HSCT (AutoHSCT) recipients.Case presentationA 53-year-old female patient initially presented with enlargement of the left cervical lymph nodes and was diagnosed with EBV-positive DLBCL. She was treated with R-CHOP, R-ACES, and AutoHSCT and went into remission. Four years later, computed tomography results revealed multiple lung nodules and abnormal infiltration, and sustained and progressing hypogammaglobulinemia was observed. The pathological specimen of video-assisted thoracoscopic surgical lung biopsy demonstrated extensive invasion of lymphocytes with notable granuloma findings. Flow cytometric immunophenotyping analysis showed that lymphocytes were positive for CD3 and CD5; especially, CD3 was expressed in the cytoplasm. Southern blot analysis revealed rearrangements of the T-cell receptor Cβ1 gene. She was diagnosed with peripheral T-cell lymphoma, not otherwise specified, accompanied by notable granulomatous lesions.ConclusionHere, as a unique case of metachronous B-cell and T-cell lymphoma, we report a rare case of T-cell lymphoma that mainly affected the lungs with the presentation of notable granulomatous findings following AutoHSCT for EBV-positive DLBCL at the age of 53 years. These lung lesions of granulomatous T-cell lymphoma could be related to the underlying primary immunodeficiency background associated with sustained hypogammaglobulinemia.

Epstein-Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified: A diagnostic challenge

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).

EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2020 update on diagnosis, risk-stratification and management.

Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the 2016 WHO classification of lymphoid neoplasms. EBV+ DLBCL, NOS, is an aggressive B-cell lymphoma associated with chronic EBV infection, and a poor prognosis with standard chemotherapeutic approaches. The diagnosis is made through a careful pathological evaluation. Detection of EBV-encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for positivity has not been defined. The differential diagnosis includes plasmablastic lymphoma (PBL), DLBCL associated with chronic inflammation and primary effusion lymphoma (PEL), among others. The International Prognostic Index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD-1/PD-L1 are emerging as potential adverse but targetable biomarkers. Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV-negative DLBCL in the era of chemoimmunotherapy. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.

Composite Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma and Epstein-Barr virus-negative diffuse large B-cell lymphoma in the parotid salivary gland of a patient with Sj\xf6gren\u2019s syndrome and rheumatoid arthritis: a case report

BackgroundEpstein-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 presentationWe 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.ConclusionsOur 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.

Epstein–Barr virus-positive diffuse large B-cell lymphoma features disrupted antigen capture/presentation and hijacked T-cell suppression

ABSTRACT Background: B cells can function as antigen-presenting cells by presenting antigens captured by the B-cell receptor (BCR) on Class II Major Histocompatibility Complex (MHC II) to T cells. In addition, B-cells can also maintain immune homeostasis by expressing PD-L1 and suppressing T-cell activity. Epstein-Barr virus (EBV) infection can disrupt B-cell function and lead to B cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Here we show that EBV-positive DLBCL (EBV+ DLBCL) has decreased expression of BCR and MHC II, but over-expressed PD-L1, which may lead to immune evasion. Methods: An EBV+ DLBCL cohort (n = 30) and an EBV- DLBCL control cohort (n = 83) were established. Immunostaining of PD-L1, MHC II, MHC II Transactivator (CIITA) and pBTK was performed on automated stainer. H-score was used to denote the results of staining of PD-L1 and pBTK. Break apart and deletion of CIITA locus was studied by fluorescent in situ hybridization. Surface immunoglobulin mean fluorescent insensitivity (MFI) was detected by flow cytometry to demonstrate the level BCR. Results: EBV+ DLBCL showed significantly lower expression of CIITA and MHC II compared to EBV- DLBCL. Genetic aberrations involving CIITA were also more common in EBV+ DLBCL, with 23% break apart events and 6% deletion events, comparted to 2% break apart and 0% deletion in EBV- DLBCL. In addition to the loss of antigen presentation molecule, the antigen capture receptor, BCR, was also down-regulated in EBV+ DLBCL. Accordingly, BCR signaling was also significantly decreased in EBV+ DLBCL as denoted by the respective pBTK levels. Conclusions: EBV+ DLBCL shows over expression of the T-cell inhibitory ligand, PD-L1. Antigen capture and presentation system were disrupted, and T-cell inhibitory molecule was hijacked in EBV+ DLBCL, which may contribute to immune escape in this high risk disease. Therapies targeting these aberrations may improve the outcome of patients with EBV+ DLBCL.

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

ObjectiveEpstein‐Barr virus‐positive diffuse large B‐cell lymphoma (EBV‐pos DLBCL) is a recently identified entity. Data regarding outcome to frontline immuno‐chemotherapy are conflicting. Although the prognostic impact of the tumour microenvironment (TME) in EBV‐neg DLBCL is well‐established, it remains untested whether the TME influences survival in EBV‐pos DLBCL. There are no data with new digital gene expression technologies that simultaneously interrogate the virus, B cells and the tumour microenvironment (TME).MethodsWe used the NanoString™ platform in a population‐based cohort of 433 patients to establish if the technology could detect EBV in the tumour biopsies and to investigate the influence that EBV has on the complex tumour microenvironment of DLBCL.ResultsIncidence of EBV‐pos DLBCL was 6.9% with 5‐year survival of 65% vs 82% in EBV‐neg DLBCL (P = 0.018). EBV‐pos tissues had similar expression of T‐cell genes compared to EBV‐neg DLBCL but higher levels of the antigen‐presenting molecule B2M. This was countered by elevated PD‐L1, PD‐L2, LAG3 and TIM3 immune checkpoints and a higher CD163/CD68 “M2” macrophage score.ConclusionIn EBV‐pos DLBCL, the TME is immuno‐tolerogenic and may explain the poor outcomes seen in this subtype of DLBCL.