Disparity analysis and prognostic value of pretreatment whole blood Epstein-Barr virus DNA load and Epstein-Barr encoding region status in lymphomas: A retrospective multicenter study in Huaihai Lymphoma Working Group.

Elevated Epstein-Barr virus (EBV) DNA load is common in lymphomas. However, it remains unclear whether the disparity in viral load and its prognostic value in lymphomas are correlated with Epstein-Barr encoding region (EBER) status. In this retrospective multicenter study, we collected the data of pretreatment whole blood EBV DNA (pre-EBV DNA) and EBER status and evaluated their disparity and prognostic values in lymphomas. A total of 454 lymphoma patients from December 2014 to August 2020 were retrospectively retrieved. Mann-Whitney U test, Kruskal-Wallis test and Bonferroni's adjustment were used to explore the disparity of EBV DNA and EBER status in lymphomas. Time-dependent receiver operating characteristic analysis and MaxStat analysis were used to determine optimal cutoff points of pre-EBV DNA load. Univariable and multivariable Cox proportional hazards models were established for the estimation of prognostic factors. The positive rate of EBV DNA in natural killer T-cell lymphoma (NKTL) patients was higher than that in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin lymphoma (HL) patients, and the median positive pre-EBV copy number of NKTL was also higher than that of FL and DLBCL. EBV DNA could clearly distinguish the prognosis of DLBCL, NKTL, HL and peripheral T-cell lymphoma, and the integration of EBER status and EBV DNA could differentiate the prognosis of HL patients. Multivariable results revealed that pre-EBV DNA load had an effect on the prognosis of NKTL, FL and DLBCL. The status of pre-EBV DNA and EBER were disparate. Whole blood pre-EBV DNA predicted the prognosis of lymphomas, and the combination of EBV and EBER status could differentiate the prognosis of HL.

Clinicopathologic characteristics of follicular lymphoma in hepatitis C virus-infected patients.

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. It has been hypothesized that chronic hepatitis C virus (HCV) infection stimulates IGH-BCL2 clone proliferation, leading to development of FL. Furthermore, regression of FL after antiviral treatment without chemotherapy has been reported in HCV-infected patients. To clarify the relationship between HCV and FL, we compared the prevalence of IGH-BCL2 translocation and other clinicopathologic characteristics between HCV-infected and HCV-uninfected FL patients and determined the impact of HCV eradication on the oncologic outcomes of HCV-infected FL patients. The study included HCV-infected patients (cases) with FL seen at our institution during 2004-2018. Cases were matched with HCV-uninfected FL patients (controls) according to year of lymphoma diagnosis, sex, and hepatitis B serology. We studied 19 cases and 57 controls. More cases than controls had splenic involvement of FL (26% vs 5%, P = 0.02), higher histologic grade (grade 3 in 56% vs 24%, P = 0.01), absent or weak CD10 expression (42% vs 11%, P = 0.005), and absent BCL2 expression (33% vs 4%, P = 0.004). Compared to controls, cases had a lower rate of detection of IGH-BCL2 translocation (31% vs 68%, P = 0.02). Finally, cases with a sustained virologic response (virologic cure of HCV) had a better 10-year overall survival rate than did cases not treated with antivirals or controls (P = 0.001). In conclusion, HCV-infected patients with FL have unique clinicopathologic characteristics including improved overall survival with HCV eradication. The pathogenesis of FL in HCV-infected patients seems unrelated to antiapoptotic effect of IGH-BCL2 rearrangement.

[Interferon-regulating activity of the celagrip antiviral drug and its influence on formation of reactive oxygen species and expression of innate immunity genes in the follicular lymphoma patients].

INTRODUCTION: Medicines from the group of interferon inducers (IFNs) "swith on" the synthesis of type 1 interferons (IFN-I) and induce the expression of IFN-stimulated genes (ISGs) that regulate innate immunity reactions and protect the host from infectious agents and the tumour pathology.The purpose of the study was to determine the role of the drug celagrip (CA) in the activation of innate immunity genes and the effect on the production of reactive oxygen species (ROS) in patients with follicular lymphoma (FL). OBJECTIVES:  to study the intensity of ROS production and the level of expression of the IFN-α2, IFN-λ1, ISG15, BCL2, P53(TP53) and USP18 genes in response to the treatment of blood cells of patients with FL with the preparation of CA. MATERIAL AND METHODS: The study involved primary cancer patients diagnosed with follicular lymphoma (FL) and healthy volunteers. A kinetic analysis of the dynamics of production of reactive oxygen species (ROS) was performed in whose blood cells, and the expression of the group of genes was determined by real-time PCR in response to CA processing. RESULTS AND DISCUSSION: ROS production by blood cells of patients with FL and volunteers in the presence of CA significantly decreased (P < 0.05). The level of gene expression of ISG15, P53(TR53) and USP 18 in the group of patients with FL was significantly higher than that in the group of volunteers. When treating blood cells with CA, it becomes possible to divide patients with FL into groups with a positive and negative response in accordance with the level of expression of the USP18 gene. We divided FL patients into groups with a positive and negative response in accordance with the level of USP18 gene expression after treatment of blood cells with CA. CONCLUSIONS: The CA drug reduces the production of ROS and simultaneously stimulates the activity of the innate immunity genes ISG15, P53(TP53) and USP18 in the blood cells of patients with FL.

Clinicopathological features of primary splenic follicular lymphoma.

Follicular lymphoma (FL) is a low-grade lymphoma that is usually characterized by generalized lymphadenopathy. Extranodal invasion by FL generally involves the bone marrow, skin, and duodenum; splenic infiltration often occurs in the advanced stages. However, primary splenic FL is very rare. Hence, few studies have been performed on splenic FL, and its clinicopathological features have not been established. This study aimed to investigate the clinicopathological features of primary splenic FL, as compared to nodal FL. We analyzed 17 patients diagnosed with primary splenic FL and 153 control patients with systemic FL. Hepatitis C virus (HCV)-positive status was significantly more common in patients with splenic FL than in the control patients (p = 0.02). Ann Arbor stage III or IV (p = 0.0003) and high-risk FLIPI (Follicular Lymphoma International Prognostic Index) (p = 0.03) were significantly less common in patients with splenic FL than in the control patients; however, the overall and progression-free survival curves were not significantly different between the groups. Among the 17 patients with splenic FL, the progression-free survival was significantly worse in patients who underwent splenectomy without receiving postoperative chemotherapy than in those who did (p = 0.03). These results suggest that primary splenic FL should be considered different from systemic FL; accordingly, its management should also be conducted differently.

Follicular lymphoma in situ in the spleen of a patient with autoimmune hemolytic anemia and carrying HCV was associated with more clonal B-cells than t(14;18) positive B-cells.

Certain autoimmune conditions are associated with an increased risk of lymphoid malignancy. We report a 65-year old patient with autoimmune hemolytic anemia (AIHA) complicated by a follicular lymphoma (FL) in situ and other B-cell clones in the spleen. This diagnosis was made by immunohistochemistry, flow cytometry, and Southern blot analysis of the B-cell receptor. Chromosomal analysis revealed 46,XX,t(14;18)(q32;q21) 2/20, 46,XX,del(7)(q?),del(11)(q?) 2/20, and 46,XX 16/20. It has been speculated that these preneoplastic conditions do not progress to overt FL and other lymphomas without a second lymphomagenic insult. However, AIHA confers a 27.4-fold higher risk of such an insult leading to lymphoma compared with the normal healthy population. Without any therapy after splenectomy, our current study patient remained healthy with no lymphoma development for 28 months. Based on this case, we discuss the pathophysiology of lymphomagenesis in a spleen with AIHA and the roles of a splenectomy for preventing further lymphomagenesis in AIHA patients.

Epstein-Barr virus-positive follicular lymphoma.

Epstein-Barr virus (EBV) -associated follicular lymphoma is only rarely reported. Herein, we report the largest series analyzing prevalence and clinicopathologic characteristics of EBV-associated follicular lymphoma occurring in unselected cases. Out of 382 analyzed cases, 10 EBV-positive follicular lymphomas were identified (prevalence=2.6%, 95% confidence interval 1.3-4.0%). All EBV-positive follicular lymphomas showed EBV-encoded small RNA-positive lymphoma cells present in a follicular distribution. Of these, eight also had tissue available for testing of expression of latent membrane protein 1 (LMP1), out of which six (75%) were positive. There was a significant association with grades 3A-3B follicular lymphoma (P<0.0001) and CD30 expression (P=0.0002). EBV-positive follicular lymphomas were otherwise morphologically and immunophenotypically indistinguishable from EBV-negative cases of similar grade. Nine of the EBV-positive follicular lymphomas occurred in patients with no known history of immunosuppression, while one patient had a history of hydroxychloroquine administration for Sjögren's syndrome. The mean age in the EBV-positive and -negative follicular lymphomas was 56 (range 31-83 years) and 49 years (range 25-92 years), respectively, with no statistically significant difference. Seven of the patients with EBV-positive follicular lymphoma had additional biopsies from different time points available for review, all of which showed progression of disease in the form of progression of tumor grade. Five of these progressed to diffuse large B-cell lymphoma, one of which had tissue available for testing and was EBV-positive. Our findings suggest that EBV infection may have a role in lymphomagenesis and/or disease progression in a subset of follicular lymphomas, thereby expanding the spectrum of recognized EBV-associated B-cell lymphomas.

Resolution of Small Bowel Follicular Lymphoma With Treatment of Concomitant Hepatitis B.

We report a case of small bowel follicular lymphoma regression with hepatitis B virus treatment. Our patient underwent surveillance colonoscopy that showed profound nodularity in the terminal ileum that was consistent with non-Hodgkin's lymphoma (NHL) on biopsy. Upon further testing the patient was found to be infected with hepatitis B virus. We decided to treat hepatitis B first to prevent its reactivation if the patient underwent therapy for NHL and with the thought that NHL can be stimulated by immunological response to antigens. Our patient was started on Entecavir, and fortunately the NHL regressed with no recurrence on follow-up endoscopies and biopsies.

Primary cutaneous diffuse large B-cell lymphoma, leg type: diagnostic considerations.

CONTEXT: Primary cutaneous diffuse large B-cell lymphoma, leg type, may show features that overlap with other lymphomas. However, timely recognition of this entity can have important clinical and therapeutic implications. OBJECTIVE: To review the clinical, morphologic, and immunophenotypic characteristics of primary cutaneous diffuse large B-cell lymphoma, leg type, and juxtapose these features with other diagnostic considerations. In particular, other variants of primary cutaneous diffuse large B-cell lymphoma, as well as primary cutaneous follicle center lymphoma, will be reviewed. Additionally, systemic/extracutaneous lymphomas will be discussed, including diffuse large B-cell lymphoma, not otherwise specified, Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly, and lymphomatoid granulomatosis. DATA SOURCES: Relevant literature will be reviewed and key differentiating findings will be highlighted. CONCLUSIONS: Although primary cutaneous diffuse large B-cell lymphoma, leg type, may show aspects that overlap with other lymphomas, it can be distinguished from other entities in the differential diagnosis.

Human herpesvirus 6 positive Reed-Sternberg cells in nodular sclerosis Hodgkin lymphoma.

Classical Hodgkin lymphoma (HL) exhibits a bi-modal age distribution that suggests an infectious aetiology. However, most cases of nodular sclerosis HL (NSHL) are Epstein-Barr virus (EBV) negative (60-90%). Previous studies regarding human herpesvirus 6 (HHV-6) positivity of HL have led to conflicting results. In order to clarify this situation, we examined NSHL biopsies for the presence and distribution of HHV-6 by immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH). PCR identified HHV-6 DNA in 86% of NSHL cases. As HHV-6 DNA was also identified in most cases of reactive lymphoid hyperplasia, we sought to localize the virus to specific cells by IHC, which detected HHV-6 in Reed-Sternberg (RS) cells of nearly half (48%) of NSHL cases. Dual CD30/HHV-6 immunostaining confirmed HHV-6 immunoreactivity in CD30+ RS cells, and HHV-6 PCR positivity was confirmed in laser capture microdissection-isolated CD30+ RS cells. FISH demonstrated multiple copies of HHV-6 genome in scattered cells. In contrast, EBV+ RS cells were identified in only 24% of the cases. HHV-6+ cases trended toward a younger age than EBV+ cases. These results conclusively demonstrate that RS cells in many cases of NSHL are HHV-6 positive, and suggest that HHV-6 may play a role in NSHL pathogenesis, particularly in younger patients with EBV-negative disease.

High frequency of t(14;18) in Hodgkin's lymphoma associated with follicular lymphoma.

t(14;18) is a common cytogenetic abnormality in B-cell lymphoma, especially in follicular lymphoma (FL), but is rarely seen in Hodgkin's lymphoma (HL). However, due to the small number of cases, the incidence of t(14;18) in HL associated with FL remains unclear. In this study, we applied chromogenic in situ hybridization and fluorescence in situ hybridization for t(14;18) on paraffin-embedded tissue from four HL associated with FL cases and 11 HL cases without a history of FL for comparison. t(14;18) was present in all of the three successfully-tested HL associated with FL cases and one case without a history of FL. The frequency of t(14;18) was significantly high in HL associated with FL (p = 0.013). All Hodgkin's and Reed-Sternberg (HRS) cells having t(14;18) showed immunoreactivity for BCL2 and were negatively stained for nuclear factor-κB (NF-κB), even in Epstein-Barr virus (EBV)-infected cases. However, HRS cells without t(14;18) showed BCL2 and NF-κB immunoreactivity in 33% and 57% of cases, respectively. There was an inverse correlation between t(14;18) and NF-κB. In conclusion, we assume the incidence of t(14;18) in HL associated with FL is higher than previously believed and BCL2 expression derived from t(14;18) may play a role in the pathogenesis of HL associated with FL.

Peripheral T cell lymphomas with follicular T helper phenotype: a new basket or a distinct entity? Revising Karl Lennert's personal archive.

AIMS: To revise 25 cases selected from Karl Lennert's personal archive (21) and Bologna and Frankfurt Registries (four) because of cytological similarities. METHODS AND RESULTS: All cases were provided with paraffin blocks and studied by immunohistochemistry and molecular techniques. While phenotyping was very informative, among molecular studies only EBER in situ-hybridization (ISH) was successful. Twenty-two cases were concluded as peripheral T cell lymphomas (PTCL). Of these, six were reclassified as angioimmunoblastic T cell lymphoma (AITL), 13 as PTCL, not otherwise specified (NOS), including four follicular variants and one tumour with T-zone pattern, and three as borderline tumours between AITL and PTCL/NOS. All these cases consisted homogeneously of small/medium-sized elements with mild nuclear atypia and an evident rim of clear/pale cytoplasm. On immunohistochemistry, they regularly expressed three to six follicular helper T cell (FTH)-associated markers. EBER-ISH revealed scattered EBV-infected B cells in all tumours except those with 'follicular' growth pattern. The content of follicular dendritic cells and high-endothelial venules varied significantly depending on the histotype. CONCLUSIONS: This study shows that: (i) historical material can be still employed usefully, and (ii) the FTH-phenotype corresponds to a broad spectrum of PTCLs that might form a new category to be validated in future molecular and clinicopathological analyses.