Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma association is not only restricted to elderly patients

Diffuse large B‐cell lymphoma (DLBCL), the most common group of malignant lymphomas, account for 30% of adult non‐Hodgkin lymphomas. The 2008 World Health Organization (WHO) classification included a new entity, Epstein‐Barr virus (EBV)+ DLBCL of the elderly, affecting patients aged 50 years or older. However, some reports of younger EBV+ DLBCL cases, without evidence of underlying immunosuppression, can be found. The role of EBV in tumor microenvironment composition in DLBCL is still not well understood. Our aim was to assess EBV presence and latency pattern as well as tumor T‐cell population in an adult DLBCL series of Argentina. The study was conducted on biopsies from 75 DLBCL patients. EBERs expression was performed by in situ hybridization, while EBV gene expression was analyzed using real‐time polymerase chain reaction. LMP1, LMP2A, EBNA2, EBNA3A, CD4, CD8 and Foxp3 expression was assessed by immunohistochemistry. Nine percent of cases showed EBV expression, with similar frequency among patients younger than 50 years and 50 years or older (13% and 8%, respectively). T‐cell subsets were not altered by EBV presence. Latency type II was the most frequently observed, together with lytic gene expression in EBV+ DLBCL, with ≥20% of EBERs+ cells. These findings suggest that EBV+ DLBCL in our series was similar to the previously described in Asia and Latin‐America, displaying latency II or III expression profile and no age‐specific characteristics. Finally, EBV+ DLBCL may be an entity that is not only restricted to patients who are older than 50 years of age, in consequence the age cutoff revision may be a current goal.     

Response and survival benefit with chemoimmunotherapy in Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma

Epstein‐Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) is a haematologic malignancy with poor prognosis when treated with chemotherapy. We evaluated response and survival benefits of chemoimmunotherapy in EBV‐positive DLBCL patients. A total of 117 DLBCL patients were included in our retrospective analysis; 33 were EBV‐positive (17 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R‐CHOP] and 16 with CHOP), and 84 were EBV‐negative (all treated with R‐CHOP). The outcomes of interest were complete response (CR) and overall survival (OS) in EBV‐positive DLBCL patients (R‐CHOP versus CHOP) and in DLBCL patients treated with R‐CHOP (EBV‐positive vs EBV‐negative). There were no differences in the clinical characteristics between EBV‐positive and EBV‐negative DLBCL patients. Among EBV‐positive DLBCL patients, R‐CHOP was associated with higher odds of CR (OR 3.14, 95% CI 0.75‐13.2; P = .10) and better OS (hazard ratio 0.30, 95% confidence interval [CI] 0.09‐0.94; P = .04). There were no differences in CR rate (OR 0.52, 95% CI 0.18‐1.56; P = .25) or OS (hazard ratio 0.93, 95% CI 0.32‐2.67; P = .89) between EBV‐positive and EBV‐negative DLBCL patients treated with R‐CHOP. Based on our study, the addition of rituximab to CHOP is associated with improved response and survival in EBV‐positive DLBCL patients. Epstein‐Barr virus status does not seem to affect response or survival in DLBCL patients treated with R‐CHOP.     

A natural HIV p17 protein variant up‐regulates the LMP‐1 EBV oncoprotein and promotes the growth of EBV‐infected B‐lymphocytes: Implications for EBV‐driven lymphomagenesis in the HIV setting

Human immunodeficiency virus p17 matrix protein is released by infected cells and may accumulate within lymphoid tissues where it may deregulate the biological activities of different cell populations by binding to CXCR1 and CXCR2 cellular receptors. S75X, a natural p17 variant, was recently shown to enhance the malignant properties of lymphoma cells. We investigated a reference p17 protein and the S75X variant for their ability to bind to Epstein–Barr virus (EBV)‐infected primary and fully transformed B‐lymphocytes and trigger downstream effects of potential pathogenic relevance. We demonstrate that EBV infection of primary B‐lymphocytes or the ectopic expression of the latent membrane protein‐1 viral oncoprotein in EBV‐negative B‐cells up‐regulates CXCR2, but not CXCR1. Multispectral imaging flow cytometry showed that EBV‐infected primary B‐cells more efficiently bind and internalize p17 proteins as compared with activated B‐lymphocytes. The S75X variant bound more efficiently to EBV‐infected primary and fully transformed B‐lymphocytes compared with reference p17, because of a higher affinity to CXCR2, and enhanced the proliferation of these cells, an effect associated with cyclin D2 and D3 up‐regulation and increased interleukin‐6 production. Notably, the S75X variant markedly up‐regulated latent membrane protein‐1 expression at both mRNA and protein levels and enhanced the activation of Akt, ERK1/2 and STAT3 signaling, thereby contributing to EBV⁺ B‐cell growth promotion. These results indicate that EBV infection sensitizes B‐lymphocytes to CXCR2‐mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV‐driven lymphomagenesis in the human immunodeficiency virus setting.     

Epstein‐Barr virus and risk of non‐Hodgkin lymphoma in the cancer prevention study‐II and a meta‐analysis of serologic studies

Epstein‐Barr virus (EBV) causes rare, malignant lymphomas. The role of EBV in other non‐Hodgkin lymphomas (NHLs) remains unclear, but mildly reduced immune function could lead to reactivation of EBV and subsequent NHL. We examined the association between prospectively‐collected plasma EBV antibodies and NHL risk in the Cancer Prevention Study‐II (CPS‐II) Nutrition Cohort and conducted a meta‐analysis of our and published results. The CPS‐II study included 225 NHL cases and 2:1 matched controls. No associations were observed between EBV serostatus or antibody levels and risk of NHL overall. However, when including only the three most common types of NHL (diffuse large B‐cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma), high compared to low early antigen (EA‐D) diffuse and BZLF1‐encoded replication activator antibodies were associated with approximately 60% higher risk of NHL. Odds ratios (ORs) for EBV nuclear antigen‐1 and viral capsid antigen (VCA)‐p18 were elevated but not statistically significant. In the meta‐analysis, both EA (summary OR = 1.52, 95% confidence interval (CI): 1.16–2.00) and VCA (summary OR = 1.20, 95% CI: 1.00–1.44) were positively associated with NHL risk. These results suggest EBV may be associated with a wider spectrum of NHL subtypes, but further study is needed to confirm and fully understand these associations.     

Serologic markers of viral infection and risk of non‐Hodgkin lymphoma: A pooled study of three prospective cohorts in China and Singapore

Incidence rates of non‐Hodgkin lymphoma (NHL) and distributions of certain viruses differ between East Asian and Western populations. There are limited data on associations between serologic markers of multiple viral infections in pre‐diagnostic blood and NHL risk in East Asians. We conducted a nested case‐control study of 214 NHL cases and 214 matched controls from three population‐based prospective cohorts in Shanghai and Singapore. Antibodies against antigens from herpesviruses, Hepatitis B (HBV) and C (HCV) virus and polyomaviruses were measured in plasma or serum using fluorescent bead‐based multiplex assays. Conditional logistic regression was used to evaluate associations between antibody levels and NHL risk. An increased risk of NHL was observed for higher compared to lower EA‐D (Odds Ratio (OR) = 2.04, 95% Confidence Interval (CI) = 1.10‐3.81; p_trend = 0.005) and ZEBRA (OR = 2.17, 95% CI = 0.96‐4.89; p_trend = 0.008) Epstein‐Barr Virus (EBV) antibodies, as well as for antibody seropositivity against the IE1A human herpesvirus‐6 (HHV‐6) antigen (OR = 1.85, 95% CI = 1.04‐3.29). An increased NHL risk was also observed for higher compared to lower antibodies against the HBV‐HBc and HBe antigens. An increased risk of NHL in relation to EBV and HBV infection in East Asians is consistent with findings in several studies of Western populations, suggesting similar viral risk factors for NHL in these diverse populations with distinct patterns of NHL. The association between HHV‐6 antibodies and NHL has not previously been reported in a prospective study in this population and will require replication.     

The prognostic significance of EBV DNA load and EBER status in diagnostic specimens from diffuse large B‐cell lymphoma patients

Epstein–Barr virus (EBV)‐encoded small RNA in situ hybridization (EBER‐ISH) is a widely accepted method to evaluate EBV involvement in diffuse large B‐cell lymphoma (DLBCL), although little is known regarding associations between EBV DNA load and the EBER status and whether EBV DNA load data provide additional clinical information. In this study, we quantified EBV DNA load in diagnostic specimens from DLBCL patients diagnosed at our hospital to evaluate clinical implications of EBV DNA load in diagnostic specimens as contrasted with EBER‐ISH. Among 140 DLBCL patients without underlying immunodeficiency, 51 were evaluable for both EBER and EBV DNA load, 83 for EBER only and one for EBV DNA load only. The median EBV DNA load was 708 copies/µg. Although EBV DNA load was significantly higher for EBER‐positive patients than for EBER‐negative patients (p < 0.001), EBV DNA was detected in up to 72% of EBER‐negative patients. Progression‐free survival and overall survival were significantly worse for patients with EBV DNA load above 700 copies/µg than for those with EBV DNA load below 700 copies/µg (p = 0.009 and p = 0.003); they were also significantly worse for EBER‐positive patients than for EBER‐negative patients (p < 0.001 and p = 0.001). Even among EBER‐negative patients, higher EBV DNA load conferred worse progression‐free survival and overall survival (p = 0.041 and p = 0.013). These findings indicate that EBV DNA load in diagnostic specimens is not a simple surrogate for the EBER status and may be a potential biomarker associated with EBV involvement and prognosis in DLBCL. Copyright © 2015 John Wiley & Sons, Ltd.     

Plasma Epstein‐Barr virus DNA for pediatric Burkitt lymphoma diagnosis,prognosis and response assessment in Malawi

Point‐of‐care tools are needed in sub‐Saharan Africa (SSA) to improve pediatric Burkitt lymphoma (BL) diagnosis and treatment. We evaluated plasma Epstein–Barr virus (pEBV) DNA as a pediatric BL biomarker in Malawi. Prospectively enrolled children with BL were compared to classical Hodgkin lymphoma (cHL) and nonlymphoma diagnoses. Pediatric BL patients received standardized chemotherapy and supportive care. pEBV DNA was measured at baseline, mid‐treatment, and treatment completion. Of 121 assessed children, pEBV DNA was detected in 76/88 (86%) with BL, 16/17 (94%) with cHL, and 2/16 (12%) with nonlymphoma, with proportions higher in BL versus nonlymphoma (p < 0.001) and similar in BL versus cHL (p = 0.69). If detected, median pEBV DNA was 6.1 log₁₀copies/mL for BL, 4.8 log₁₀copies/mL for cHL, and 3.4 log₁₀copies/mL for nonlymphoma, with higher levels in BL versus cHL (p = 0.029), and a trend toward higher levels in BL versus nonlymphoma (p = 0.062). pEBV DNA declined during treatment in the cohort overall and increased in several children before clinical relapse. Twelve‐month overall survival was 40% in the cohort overall, and for children with baseline pEBV detected, survival was worse if baseline pEBV DNA was ≥6 log₁₀copies/mL versus <6 log₁₀copies/mL (p = 0.0002), and also if pEBV DNA was persistently detectable at mid‐treatment versus undetectable (p = 0.041). Among children with baseline pEBV DNA detected, viremia was the only significant risk factor for death by 12 months in multivariate analyses (adjusted hazard ratio 1.35 per log₁₀copies/mL, 95% CI 1.04–1.75, p = 0.023). Quantitative pEBV DNA has potential utility for diagnosis, prognosis, and response assessment for pediatric BL in SSA.     

Disease patterns in pediatric classical Hodgkin lymphoma: a report from a developing area in Brazil

Epidemiological patterns established about 20 years ago, divided classical Hodgkin lymphoma (cHL) in three entities with regard to Epstein–Barr virus (EBV) status and histological subtypes and suggested different epidemiological patterns associated with degree of economic development. Here, we investigated histopathological features and EBV association in 100 consecutive pediatric cHL cases occurring in Rio de Janeiro (Brazil). Age at diagnosis ranged from 3 to 18 years (median 14 years) with 27% of cases ≤10 years. Unexpectedly, we did not observe an early childhood peak with most cases occurring in the >10 years age group. Nodular sclerosis (NS) was the most frequent subtype (69%) and was more frequently observed in the >10 years age group, followed by mixed cellularity (MC, 23%) which was distributed equally between age groups. EBV was identified in 44.8% of cases, without preferential association with age groups (≤10 years vs. >10 years). MC cases were independently associated with EBV infection of tumour cells (p = 0.045) and with a CD4/CD20 ratio <1 in the microenvironment (p = 0.014). Our results suggest that a gradual shift from childhood peak to early adulthood peak may be observed in developing regions. The development of MC subtype may result from early exposure to EBV in the context of an impaired immune system reflected by a CD4/CD20 ratio <1. Conversely, it is possible that NS originates predominantly in the context of a better immune response against EBV and/or tumour antigens expressed in the neoplastic cells. Copyright © 2011 John Wiley & Sons, Ltd.     

Epstein–Barr virus presence in pediatric diffuse large B‐cell lymphoma reveals a particular association and latency patterns: Analysis of viral role in tumor microenvironment

Non‐Hodgkin's lymphoma represents 6–10% of pediatric malignancies, and diffuse large B‐cell lymphoma (DLBCL) is one of the three major subtypes. The 2008 WHO classification included a new entity, Epstein–Barr virus (EBV)‐positive DLBCL of the elderly, affecting patients >50 years. It has been demonstrated that EBV may play a role in tumor microenvironment composition, disturbing antitumor immune response and disease progression. As most studies were performed in adults, our aim was to assess EBV presence and latency pattern, as well as T‐cell microenvironment in a pediatric DLBCL series of Argentina. The study was conducted on formalin‐fixed paraffin‐embedded biopsies from 25 DLBCL patients. EBV‐encoded small nuclear early regions (EBERs) expression was performed by in situ hybridization, whereas EBV gene expression was analyzed using real‐time PCR. Epstein–Barr virus latent membrane proteins (LMP)1, LMP2A, CD3, CD4, CD8 and Foxp3 expression were assessed by immunohistochemistry (IHC). Forty percent of cases showed EBV expression, with a significantly higher incidence among patients <10 years (p = 0.018), and with immunosuppressed (p = 0.023). T‐cell subsets were not altered by EBV presence. Full EBV latency antigen expression (latency type III) was the most frequently pattern observed, together with BZLF1 lytic gene expression. One patient showed II‐like pattern (LMP1 without LMP2A expression). Based exclusively on IHC, some patients showed latency II/III (EBERs and LMP1 expression) or I (EBERs only). These findings suggest that EBV association in our series was higher than the previously demonstrated for elderly DLBCL and that EBV latency pattern could be more complex from those previously observed. Therefore, EBV could be an important cofactor in pediatric DLBCL lymphomagenesis.     

Primary diffuse large B‐cell lymphoma of the tonsil

BACKGROUND: The purpose was to evaluate the prognostic factors and treatment outcome of Indian patients with primary diffuse large B-cell lymphoma (DLBCL) of the tonsil treated at a single institution. METHODS: In all, 121 patients with DLBCL of the tonsil, treated at the Tata Memorial Hospital, Mumbai, India, from January 1990 to December 2002, were included. The median age was 45 years and the majority of patients (68%) were males. Systemic symptoms were present in 12% of patients; 28% presented with stage I and 67% had stage II disease. Treatment consisted of a combination of chemotherapy (CTh) and radiotherapy (RT) for the majority of patients (69.4%). Among those receiving RT, 64% received an RT dose of > or =45 Gy. RESULTS: After a median follow-up of 62 months, disease-free survival (DFS) and overall survival (OS) were 66.4% and 81.6%, respectively. Significant prognostic factors included: WHO performance score > or =2 (OS: 72.1% vs 95.6%, P = .016), bulky tumors (OS: 68.5% vs 86.9%, P = .001), presence of B-symptoms (OS: 36.7% vs 79.6%, P < .001), and Ann Arbor stage. On multivariate analysis; WHO performance score > or =2 (hazard ratio [HR], 4.27; 95% confidence interval [CI], 1.20-15.12), and B symptoms (HR, 6.27; 95% CI, 2.38-16.48), retained statistical significance. CTh + RT resulted in a significantly better outcome than those treated with CTh alone (OS: 85.7% vs 70.7%, P = .008). The complete response (P = .053), DFS (P = .039), and OS (P = .014) rates were significantly better for patients receiving an RT dose > or =45 Gy. CONCLUSIONS: Tumor bulk, WHO performance score, the presence of B symptoms, and Ann Arbor stage significantly influence outcome. A combined modality treatment, consisting of CTh and RT (with an RT dose of > or =45 Gy), results in a satisfactory outcome in patients with this uncommon neoplasm.     

Establishment and characterization of a novel Hodgkin lymphoma cell line,AM‐HLH,carrying the Epstein‐Barr virus genome integrated into the host chromosome

We describe the establishment and characterization of a cell line, AM‐HLH, obtained from a patient with Epstein‐Barr virus–positive (EBV⁺) nodular sclerosis–type Hodgkin lymphoma (HL). The cells were positive for CD2 and CD30 and negative for CD15. The immunoglobulin heavy‐ and κ light–chain genes were rearranged. The karyotype was of the triploid range. Southern blotting using the EBV terminal repeat probe detected 3 hybridizing bands that were identical to those of the parental HL material. The cells expressed EBV‐encoded RNAs as well as latent genes (EBNA1, EBNA2, LMP1, and LMP2A) and lytic genes (BZLF1 and BALF2). Fluorescence in situ hybridization (FISH) with the cosmid pJB8 clone containing a fragment of EBV DNA as a probe revealed multiple hybridization signals at a marker chromosome. Additional FISH using whole chromosome painting and centromere probes in combination with multicolor FISH determined that multiple EBV copies were clustered within the chromosome 20 materials of the marker chromosome. Culture supernatants of AM‐HLH contained IL‐10 as measured by the bead‐based immunoassay. It is possible that an integrated EBV genome and cellular genes on chromosome 20 were coamplified, leading to the enhanced expression of genes involved in cell growth control. The AM‐HLH cell line will be useful to clarify the role of cytokines in the development of EBV⁺ HL.     

Bendamustine is effective therapy in patients with rituximab‐refractory,indolent B‐cell non‐Hodgkin lymphoma

BACKGROUND:

Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single‐agent bendamustine in patients with rituximab‐refractory, indolent B‐cell lymphoma.

METHODS:

Eligible patients (N = 100, ages 31‐84 years) received bendamustine at a dose of 120 mg/m² by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0‐6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression‐free survival (PFS).

RESULTS:

An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

CONCLUSIONS:

Single‐agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab‐refractory indolent B‐cell lymphoma. Cancer 2010. © 2010 American Cancer Society.     

Clinical development of anti‐CD19 chimeric antigen receptor T‐cell therapy for B‐cell non‐Hodgkin lymphoma

B‐cell non‐Hodgkin lymphoma (B‐NHL) is the most frequent hematological malignancy. Although refined chemotherapy regimens and several new therapeutics including rituximab, a chimeric anti‐CD20 monoclonal antibody, have improved its prognosis in recent decades, there are still a substantial number of patients with chemorefractory B‐NHL. Anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy is expected to be an effective adoptive cell treatment and has the potential to overcome the chemorefractoriness of B‐cell leukemia and lymphoma. Recently, several clinical trials have shown remarkable efficacy of anti‐CD19 CAR T‐cell therapy, not only in B‐acute lymphoblastic leukemia but also in B‐NHL. Nonetheless, there are several challenges to overcome before introduction into clinical practice, such as: (i) further refinement of the manufacturing process, (ii) further improvement of efficacy, (iii) finding the optimal infusion cell dose, (iv) optimization of lymphocyte‐depleting chemotherapy, (v) identification of the best CAR structure, and (vi) optimization of toxicity management including cytokine release syndrome, neurologic toxicity, and on‐target off‐tumor toxicity. Several ways to solve these problems are currently under study. In this review, we describe the updated clinical data regarding anti‐CD19 CAR T‐cell therapy, with a focus on B‐NHL, and discuss the clinical implications and perspectives of CAR T‐cell therapy.     

Antibody titers against EBNA1 and EBNA2 in relation to Hodgkin lymphoma and history of infectious mononucleosis

A role for Epstein Barr virus (EBV) in Hodgkin lymphoma (HL) pathogenesis is supported by the detection of EBV genome in about one-third of HL cases, but is not well defined. We previously reported that an elevated prediagnosis antibody titer against EBV nuclear antigens (EBNA) was the strongest serologic predictor of subsequent HL. For the present analysis, we measured antibody levels against EBNA components EBNA1 and EBNA2 and computed their titer ratio (anti-EBNA1:2) in serum samples from HL cases and healthy siblings. We undertook this analysis to examine whether titer patterns atypical of well-resolved EBV infection, such as an anti-EBNA1:2 ratio ≤ 1.0, simply reflect history of infectious mononucleosis (IM), an HL risk factor, or independently predict HL risk. Participants were selected from a previous population-based case-control study according to their history of IM. We identified 55 EBV-seropositive persons with a history of IM (IM+; 33 HL cases, 22 siblings) and frequency-matched a comparison series of 173 IM history-negative, EBV-seropositive subjects on HL status, gender, age and year of blood draw (IM-; 105 cases, 58 siblings). In multivariate logistic regression models, an anti-EBNA1:2 ratio ≤ 1.0 was significantly more prevalent in HL cases than siblings (odds ratio, 95% confidence interval = 2.43, 1.05-5.65); similar associations were apparent within the IM+ and IM- groups. EBNA antibodies were not significantly associated with IM history in HL cases or siblings. These associations suggest that chronic or more severe EBV infection is a risk factor for HL, independent of IM history.     

Epstein‐Barr virus‐negative extranodal “true” natural killer‐cell lymphoma harbouring a KDM6A mutation

Extranodal natural killer (NK)/T‐cell lymphoma, nasal type (ENKTL) is an extranodal aggressive T or NK‐cell lymphoma that is characteristically associated with Epstein‐Barr virus (EBV) infection and cytotoxic tissue‐destructive features. Although ENKTL is described as a distinct entity according to the 2008 WHO classification, a considerable complexity is associated with the differential diagnosis of other T‐cell lymphomas with respect to tumour cell origins, locations, and the presence of EBV infection, as well as molecular and cytogenetic abnormalities. Here, we report a rare case of EBV‐negative ENKTL, where the absence of EBV in the true NK‐lineage cells was confirmed by extensive phenotypic and genotypic analyses. Furthermore, using the next‐generation sequencing approach, we identified mutations in the tumour suppressor genes KDM6A and TP53. The clinicopathological characteristics were almost similar to those of EBV‐positive ENKTL, except for the absence of EBV and histologically apparent angioinvasiveness. This is the first reported ENKTL case with mutations in the KDM6A gene. KDM6A is one of the histone‐modifying genes that are mutated in many human diseases including haematological cancers. Epigenetic regulation of gene expression has recently been demonstrated in ENKTL, and a similar pathway is thought to play an oncogenic role in EBV‐negative ENKTL. Our report shows the extent of comprehensive examination required before making a definitive diagnosis for NK‐ and T‐cell neoplasms and broadens the therapeutic options for potential targets.     

Burkitt lymphoma versus diffuse large B‐cell lymphoma: a practical approach

Burkitt Lymphoma (BL) is listed in the World Health Organization (WHO) classification of lymphoid tumours as an “aggressive B‐cell non‐Hodgkin's lymphoma”, characterized by a high degree of proliferation of the malignant cells and deregulation of the c‐MYC gene. The main diagnostic challenge in BL is to distinguish it from diffuse large B‐cell lymphoma (DLBCL). While in children BL and DLBCL types probably do not differ clinically, and the differential diagnosis between BL and DLBCL may theoretically appear clear‐cut, in adults daily practice shows the existence of cases that have morphological features, immunophenotypic and cytogenetics intermediate between DLBCL and BL, and cannot be classified with certainty in these categories. Distinguishing between BL and DLBCL is critical, as the two diseases require different management. This review summarizes the current practical approach, including the use of a large panel of antibodies, and cytogenetic and molecular diagnostic techniques, to distinguish between BL, DLBCL and the provisional category of “B‐cell lymphoma, unclassificable, with features intermediate between diffuse large B‐cell lymphoma and Burkitt lymphoma”, now listed in the updated WHO classification. Copyright © 2009 John Wiley & Sons, Ltd.     

Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B‐cell‐derived mantle cell lymphoma

Composite lymphomas (CL) represent the occurrence of two distinct lymphomas in the same patient. Often, CL share a common cellular origin, thus representing a unique model to investigate the multistep genetic path leading to lymphomagenesis in general and to the specific development of each distinct lymphoma component in particular. Here, we present the molecular analysis of a case consisting of an unusual Hodgkin lymphoma (HL) and a mantle cell lymphoma (MCL), intimately admixed within one another in lymph nodes and bone marrow yet phenotypically distinct, in a patient who first presented with splenic/leukemic MCL two years earlier. MCL and Hodgkin and Reed/Sternberg (HRS) cells harbored identical immunoglobulin (Ig) V_H gene rearrangements with shared somatic mutations, proving their common clonal origin from a (post‐)germinal center (GC) B cell. This also demonstrates the (post‐)GC origin of MCL with mutated IgV genes. Both lymphomas carried the same CCND1/IGH translocation and, unexpectedly for HL, expressed cyclin D1 and OCT2. Thus, HRS cells are able to preserve IGH locus activity (otherwise usually silenced in HL) to promote expression of an oncogene translocated into this locus. Both lymphoma populations further showed an identical TP53 function‐impairing mutation, and later acquired a TP53 heterozygous deletion independently from one another (convergent evolution). The surprisingly close genetic relationship of the lymphomas, together with their histological intermingling and the clinical history of the patient, suggests subclonal evolution of HL from MCL as a plausible pathway in alternative to that so far described in CL, i.e. separate development from a common precursor.