Features Of Burkitt Lymphoma Research Articles

Network and Computational Drug Repurposing Analysis for c-Myc Inhibition in Burkitt Lymphoma.

The treatment rate of Burkitt lymphoma (BL) is still low in low-income countries and among elderly patients. The c-Myc dysregulation induced by mutations is one of the characteristics of BL. However, studies on the downstream signaling pathways of c-Myc are still lacking. This study aimed to identify the signaling pathways regulated by c-Myc. Network and gene set analyses using c-Myc inhibition (i.e., c-Myc knock-down and c-Myc inhibitor treatment) transcriptome datasets for BL cell lines were performed to determine the pathways regulated by c-Myc. In addition, computational drug repurposing was used to identify drugs that can regulate c-Myc downstream signaling pathway. Computational drug repurposing revealed that the ERK/MAPK signaling pathway is regulated by c-Myc in BL and that this pathway can be modulated by vorinostat. Furthermore, in the pharmacogenomics database, vorinostat showed a cell viability half-maximal inhibitory concentration of less than 2 μM in the BL cell lines. The downstream signaling pathway regulated by c-Myc and the drug that can modulate this pathway is presented for the first time.

Impact of timing and precision of histopathological diagnosis on outcomes of patients with Burkitt lymphoma and high-grade B-cell lymphoma.

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive B-cell non-Hodgkin lymphomas (B-NHL) with a generally favorable prognosis after immunochemotherapy. The outcome of BL is superior to DLBCL. In 2016, a distinct group of lymphomas displaying characteristics of both BL and DLBCL (high grade B-cell lymphoma, HGBL) was introduced into the WHO classification. Histopathological discrimination of BL, DLBCL, and HGBL may be challenging. Data on the frequency of histopathological difficulties resulting in revision of the final diagnosis of BL/DLBCL/HGBL and its impact on the prognosis are limited. We assessed histopathological features and clinical outcomes of 66 patients with suspected diagnosis of BL at the reporting institution between 2010 and 2020. The median age was 51 years (range 19-82) and final histopathological diagnosis revealed BL (n=40), DLBCL (n=12), or HGBL (n=14). Patients with DLBCL and HGBL were either treated with DLBCL-directed (83.3% and 35.7%) or BL-directed (16.7% and 64.3%) protocols. Patients in whom diagnosis was revised from DLBCL to BL after initiation of DLBCL-directed treatment had a significantly inferior progression-free survival (PFS) than patients initially diagnosed with BL (p=0.045), thus resembling rather the prognosis of DLBCL/HGBL. There was no difference between patients with DLBCL and HGBL, respectively, regarding PFS and OS (p=0.38 and p=0.27). These results suggest that timely and precise histopathological diagnosis as well as reference histopathological review of the underlying lymphoma is critical to determine up-front treatment strategies. Consequently, selection of more aggressive treatment protocols in case of difficulties with discrimination between DLBCL/HGBL/BL may be a reasonable approach.

Clinicopathologic characteristics of Burkitt lymphoma of the head and neck in a non-endemic region—a Danish nationwide study

Background Burkitt lymphoma rarely presents in head and neck (H&N) in Western countries. Aims/objectives We aimed to characterise clinicopathological features of H&N Burkitt lymphoma in Denmark representing a non-endemic region. Material and methods Clinical records were reviewed for a nationwide cohort of patients diagnosed with H&N Burkitt lymphoma in Denmark between 1980 and 2018. The diagnosis was histologically validated. Results Thirty-four patients with H&N Burkitt lymphoma (highest incidence in age group 0–9 years, male-to-female ratio 4.7:1) were included. Thirty-three lymphomas (97%) were extranodal. The tumour was visible at the clinical examination in 81% (n = 22) of the cases. The palatine tonsils were the most frequent location (n = 13, 38%) and 52% (n = 17) of the patients were diagnosed in advanced stage. Lymphoma was the tentative clinical diagnosis in 23% of the cases. The 5-year overall- and disease-specific survival was 78% and 81%, respectively. Conclusions Due to the rarity of Burkitt lymphoma of the H&N, there is a high risk of clinical misdiagnosis. Our findings suggest which symptoms and clinical presentations to be aware of in the diagnostics work up that could lead to the diagnosis of Burkitt lymphoma.

Clinicopathological analysis of oral Burkitt's lymphoma in pediatric patients: A systematic review

The aim of this study was to integrate the available data regarding pediatric Burkitt's lymphoma (BL) of the oral cavity. A systematic review was conducted following PRISMA guidelines, through a specific search strategy. Twenty-nine publications were included in this study, resulting in a total of 144 cases. Oral BL was predominantly found in males (75.7%). The mandible was the most involved site (37.5%), and all cases clinically exhibited a swelling. Presence of EBV was observed in 33.3% of the cases, and 4 cases reported HIV-positive patients (33.3%). Chemotherapy was the leading treatment choice for oral BL (94.9%), and the overall 5-year survival was 54.3%. Regarding the quality assessment of the studies, most (19 studies; 65.5%) were classified as an overall moderate risk of bias. In conclusion, the clinicopathological characteristics of oral BL in the pediatric population comprise the sporadic and intermediate subtypes. Despite its aggressiveness, this malignancy presents a moderate overall survival.

Glycolytic enzyme hexokinase II is a putative therapeutic target in B-cell malignant lymphoma

Hexokinase II (HXKII) is a key regulator of glucose metabolism that converts glucose to glucose 6-phosphate. Furthermore, HXKII blocks mitochondria-dependent apoptosis by inhibiting the release of cytochrome c. HXKII overexpression is frequently observed in several types of cancer and confers chemoresistance to cancer cells. In the present study, we found that compared with cell lines generated from diffuse large-B-cell lymphoma (DLBCL) patients, cell lines with features of Burkitt lymphoma have higher levels of HXKII because of the activation of both c-MYC and HIF-1. Under normoxia, HXKII levels were correlated with the growth ability of each B-cell lymphoma cell line. HXKII levels were further enhanced when the B-cell lymphoma cells were cultured under hypoxia. The high levels of HXKII induced by hypoxia conferred cisplatin resistance in all tested B-cell lymphoma cell lines. The HDAC inhibitor panobinostat significantly suppressed HXKII expression under both normoxic and hypoxic conditions. Importantly, panobinostat reversed the anti-lymphoma action of cisplatin, and this effect was diminished by hypoxia. These data suggest that HXKII plays different roles, including in the regulation of glycolysis and inhibition of apoptosis, depending on its expression levels. Furthermore, inhibition of HXKII expression by panobinostat may represent a new and attractive strategy to overcome cisplatin resistance.

The accuracy of diagnosing Burkitt lymphoma in serous effusion specimen: A cytological‐histological correlation with ancillary studies

The objective of this study is to evaluate the effectiveness of diagnosing Burkitt lymphoma (BL) in serous effusion (SE) specimen and summarise the characteristics of BL in SE. We also assess the utility of a germinal centre-associated marker, LMO2, in the differential diagnosis of BL in SE specimens. Eleven cases of malignant SE caused by BL were reviewed. SE cytology and histological biopsy diagnoses were compared to determine the concordance rates. A uniform population of non-cohesive medium-sized lymphoid cells with frequent apoptosis was found on SE smears or cell block sections. Cytoplasmic and nuclear vacuoles presented in seven cases. Immunophenotyping demonstrated positivity for CD79a (three of three cases), CD10 (seven of 11 cases), BCL6 (nine of 11 cases), MUM-1 (one of nine cases), CD20 and MYC (11 cases). LOM2 was negative in nine of nine cases. Both IGH/MYC rearrangement and MYC rearrangement were identified in four of six cases, and two of six cases carried isolated MYC rearrangement or isolated IGH/MYC rearrangement, respectively. The diagnoses of eight BLs and three B-cell non-Hodgkin lymphomas were established according to cytomorphology and ancillary studies. SE cytology provided initial pathological diagnoses for eight cases (six BLs and two non-Hodgkin lymphomas). Histodiagnoses were available for eight cases. The concordance rate of cytological-histological diagnosis was 62.5% (five of eight cases). Combining cytomorphology and ancillary studies enables the accurate diagnosis of BL in SE specimens. Furthermore, LMO2 may be a useful marker in the differential diagnosis of BL.

Identification of ADGRE5 as discriminating MYC target between Burkitt lymphoma and diffuse large B-cell lymphoma

BackgroundMYC is a heterogeneously expressed transcription factor that plays a multifunctional role in many biological processes such as cell proliferation and differentiation. It is also associated with many types of cancer including the malignant lymphomas. There are two types of aggressive B-cell lymphoma, namely Burkitt lymphoma (BL) and a subgroup of diffuse large cell lymphoma (DLBCL), which both carry MYC translocations and overexpress MYC but both differ significantly in their clinical outcome. In DLBCL, MYC translocations are associated with an aggressive behavior and poor outcome, whereas MYC-positive BL show a superior outcome.MethodsTo shed light on this phenomenon, we investigated the different modes of actions of MYC in aggressive B-cell lymphoma cell lines subdivided into three groups: (i) MYC-positive BL, (ii) DLBCL with MYC translocation (DLBCLpos) and (iii) DLBCL without MYC translocation (DLBCLneg) for control. In order to identify genome-wide MYC-DNA binding sites a chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) was performed. In addition, ChIP-Seq for H3K4me3 was used for determination of genomic regions accessible for transcriptional activity. These data were supplemented with gene expression data derived from RNA-Seq.ResultsBioinformatics integration of all data sets revealed different MYC-binding patterns and transcriptional profiles in MYC-positive BL and DLBCL cell lines indicating different functional roles of MYC for gene regulation in aggressive B-cell lymphomas. Based on this multi-omics analysis we identified ADGRE5 (alias CD97) - a member of the EGF-TM7 subfamily of adhesion G protein-coupled receptors - as a MYC target gene, which is specifically expressed in BL but not in DLBCL regardless of MYC translocation.ConclusionOur study describes a diverse genome-wide MYC-DNA binding pattern in BL and DLBCL cell lines with and without MYC translocations. Furthermore, we identified ADREG5 as a MYC target gene able to discriminate between BL and DLBCL irrespectively of the presence of MYC breaks in DLBCL. Since ADGRE5 plays an important role in tumor cell formation, metastasis and invasion, it might also be instrumental to better understand the different pathobiology of BL and DLBCL and help to explain discrepant clinical characteristics of BL and DLBCL.

The changing clinical pattern of endemic Burkitt lymphoma in Western Africa: Experience from a tertiary center in Ghana.

Burkitt lymphoma (BL) is the most common childhood cancer in Ghana, where the endemic variant is the predominant subtype and historically presents as a highly chemo-sensitive jaw tumor. This study aimed to update the current epidemiological characteristics of childhood BL in our institution. Patient data for all children diagnosed with BL and seen at Korle Bu Teaching Hospital between January 2007 and December 2012 were retrospectively analyzed. BL was diagnosed in 173 children (<13 years) during the study period, with the abdomen as the most common tumor site (46%) followed by the jaw (31%). Abdominal tumors were associated with advanced/disseminated disease (P=0.002), and were more likely to occur in females irrespective of tumor stage (relative risk=1.56 [95% CI; 1.1-12.3]). Twenty-five percent (43/173) of the study cohort died and mortality was influenced by increasing age (P=0.02) and advanced disease (P=0.03). Treatment delay was experienced by nine in ten patients primarily due to familial financial constraint (75%). Treatment abandonment was observed as a first event in 94% of patients and two thirds of children in the study were eventually lost to follow-up. The predominance of primary abdominal tumors in our study cohort may indicate a changing epidemiological pattern of BL in Ghana. High rates of treatment delay and abandonment were evident and are likely to be contributing factors to the poor childhood cancer survival outcomes seen in resource-limited countries in Africa.

A Unique Cutaneous Presentation of Burkitt Lymphoma

Few reports of cutaneous Burkitt lymphoma exist in the literature. Here, the authors describe the case of a human immunodeficiency virus-positive individual with the rare diagnosis of cutaneous Burkitt lymphoma. Three weeks before the development of his cutaneous lesions, the patient experienced bilateral lower extremity paralysis, and an epidural mass was found. Bone marrow biopsy findings and serum protein electrophoresis seemed consistent with multiple myeloma. The visible appearance of the skin lesions raised concern for cutaneous involvement by myeloma; however, the skin biopsy showed morphological and immunohistochemical features of Burkitt lymphoma. In this case report, the authors discuss the histopathologic findings of the cutaneous lesions in consideration with the bone marrow biopsy findings.

Acute Lymphoblastic Leukemia with Mature B-Cell Phenotype and t(9;11;11)(p22;q23;p11.2): A Case Study and Literature Review

Acute Lymphoblastic Leukemia with Mature B-Cell Phenotype and t(9;11;11)(p22;q23;p11.2): A Case Study and Literature Review

Clinicopathological features of aggressive B-cell lymphomas including B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell and Burkitt lymphomas: a study of 44 patients from Argentina

Aggressive B-cell lymphomas incorporate a wide spectrum of lymphomas that pose challenges in diagnosis as well as treatment. We evaluated the clinicopathological features of 44 patients with aggressive B-cell lymphomas which were classified into 3 groups based on the World Health Organization 2008 classification as follows: including 30 cases of diffuse large B-cell lymphoma (DLBCL), 8 cases of Burkitt lymphoma (BL) and 6 cases of B-cell lymphoma, unclassifiable, with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (BCLU). Male predominance was observed in BL and BCLU groups and the mean age varied from 29 years in BL, 61 years in DLBCL and 70 years in BCLU. Patients with BCLU presented at more advanced stages and had a higher international prognostic index. By immunohistochemistry, they shared characteristics of both BL (including more frequent expression of SOX11) and DLBCL. FISH analyses showed three cases with more than one rearrangement: one MYC/BCL2 and two BCL2/BCL6, in addition to which one case with BCL2/IGH translocation and another with MYC rearrangement were also detected. The mean follow-up survival time of BCLU was 6.6 months, which was significantly shorter in comparison to DLBCL (31 months) and BL (30 months), respectively. The importance of recognizing this BCLU group relies on its different clinical course, poor prognosis and shorter survival than DLBCL and BL. An accurate diagnosis is critical for risk stratification and to improve therapeutic approaches and outcomes.

Does the proliferation fraction help identify mature B cell lymphomas with double‐ and triple‐hit translocations?

The entity 'B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL)' refers to B cell neoplasms that share overlapping characteristics of BL and DLBCL. A subset of these 'grey-zone lymphomas' possesses C-MYC and IGH translocations but, in addition, contains additional rearrangements of BCL2 and/or BCL6 genes. The aim of this study was to investigate if the proliferation fraction by Ki67 immunostaining can be used to identify such double-/triple-hit lymphomas. We studied 492 cases of mature aggressive B cell neoplasms by histology, immunohistochemistry and interphase fluorescence in-situ hybridization (FISH) using break-apart probes against C-MYC, BCL2, BCL6, IGH, MALT1, PAX5 and CCND1. Forty Burkitt lymphomas and 28 cases of MYC(+) double-/triple-hit lymphomas were identified. Of the latter, 77% and 54% displayed proliferation fractions exceeding 75% and 90%, respectively. With a cut-off of >75% by Ki67 immunostaining, the sensitivity and specificity for detection of MYC(+) double/triple translocations was 0.77 and 0.36. Raising the proliferation fraction criterion to >90% improved the specificity to 0.62 at the expense of a low sensitivity of 0.54. Immunostaining for Ki67 is not a useful approach to prescreen B cell lymphomas for MYC(+) double/triple translocations.

Burkitt Lymphoma: Much More than MYC

Chromosomal translocations causing deregulated c-MYC expression are detectable in most Burkitt lymphoma cases. However, little is known about the additional lesions necessary for lymphomagenesis. Now, two independent studies, one of which was performed by Sander etal. in this issue of Cancer Cell, identify constitutive PI3K signaling and CyclinD3 mutations as cooperating lesions in both mice and humans. The results have directly actionable therapeutic implications.

Molecular genetic features of sporadic Burkitt's lymphoma in children

To investigate the molecular genetic features and diagnostic aspects of sporadic Burkitt's lymphoma (BL) in children. Tissue microarray was constructed to include 64 cases of pediatric BL and 6 cases of pediatric diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry and fluorescence in-situ hybridization for c-myc, bcl-2, bcl-6, IgH, myc/IgH and bcl-2/IgH gene were performed. Cases of pediatric Burkitt's lymphomas were subclassified into three groups based on their cellular orgins: the germinal center (GC) group, the late-germinal center (late-GC) group and the post-germinal center (post-GC) group. Among 64 Burkitt's lymphomas studied, expression of CD20, CD10, bcl-6, bcl-2 and MUM1 by immunohistochemistry were 100% (64 cases), 98.4% (63 cases), 96.9% (62 cases), 0 (0 cases) and 23.4% (15 cases), respectively. Various gene rearrangements were found involving the c-myc 93.1% (54/58 cases) and IgH 82.8% (48/58 cases). Detailed rearrangements are as follows: 46 cases (85.2%) myc/IgH gene translocation along with c-myc and IgH gene rearrangement; 4 cases (7.4%) c-myc gene rearrangement without IgH and myc/IgH abnormality; 4 cases (7.4%) without c-myc, IgH or myc/IgH gene rearrangement. No case showed bcl-2 gene abnormality (100%). Fifty nine cases showed normal bcl-6 gene status. One case had bcl-6 gene rearrangement and amplification with the pathologic and immunophenotypic characteristics of BL, leading to a revised pathological diagnosis of B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma (DLBCL/BL). Two cases showed c-myc gene rearrangement. Two cases showed bcl-6 gene amplification and 6 DLBCL cases had a normal status of bcl-2/IgH. A majority of pediatric sporadic BL arise from the germinal center B cells, most of which have c-myc gene rearrangement. It is useful to distinguish BL and DLBCL by multiple genes detection.

The incidence, clustering and characteristics of Burkitt lymphoma in the Northwest province of Cameroon

The epidemiology of Burkitt lymphoma (BL) has never been documented in Cameroon. Data were collected from 16 hospitals, the Delegation of Public Health and the regional pathologist in the Northwest province of Cameroon on all BL cases. The incidence of BL in this region is 5.9/100,000 children aged <15 years/year - the second highest incidence documented to date. Significant clustering was also identified in Ndop, a low-lying region with a high malaria endemicity, at 21.5 cases/100,000 children aged <15 year/year (P < 0.001).

Clinical, Immunophenotypic, and Genetic Analysis of Adult Lymphomas With Morphologic Features of Burkitt Lymphoma

Clinical, Immunophenotypic, and Genetic Analysis of Adult Lymphomas With Morphologic Features of Burkitt Lymphoma

Burkitt Transformation of Mantle Cell Lymphoma

The associated poor prognosis and potentially aggressive behavior of mantle cell lymphoma and its blastoid variants make differentiation from other non-Hodgkin B-cell lymphomas especially important. We present a case of mantle cell lymphoma with a marked leukemic component, which demonstrated both a typical nodular mantle cell pattern and Burkitt lymphoma within a single lymph node removed at the time of splenectomy. The presence of CD5, CD10, and Bcl-1 co-expression by immunohistochemistry and detectable t(11;14) and cMYC gene rearrangement by FISH analyses in the Burkitt region support a transformation of mantle cell lymphoma over a concomitant malignancy. A limited number of mantle cell lymphomas demonstrating dual t(11;14) and chromosome 8q24 cMYC gene rearrangements have been previously reported in the literature. They demonstrate an extremely aggressive course with a very poor prognosis. Although the accelerated terminal phase of this patient's clinical course mirrors these previous published cases; none have described the combined morphologic and immunophenotypic features of Burkitt lymphoma reported here. This case provides further support for the aggressive nature of these lymphomas and demonstrates the utility of flow cytometry, immunohistochemistry, and cytogenetic techniques in avoiding potential errors in their diagnosis, prognosis, and treatment.

Clinical and genetic characteristics of Japanese Burkitt lymphomas with or without leukemic presentation.

To clarify the clinical and genetic features of Burkitt lymphoma with or without leukemic presentation, we have conducted clinical, cytogenetic, and genetic studies. Of 40 Japanese patients with Burkitt lymphoma examined by cytogenetic and/or fluorescence in situ hybridization analysis or Southern blot analysis using MYC probes, 35 patients had t(8;14) translocations, and 5 had t(8;22). Breakpoints were located far upstream of MYC in 4 (12%) of 33 tumors with t(8;14), and Epstein-Barr virus infection was found in 3 (8%) of 40 tumors. These findings are similar to those reported for non-Japanese patients with the sporadic form of Burkitt lymphoma. Clinical and genetic characteristic were compared for 30 patients presenting with lymphoma and 10 presenting with leukemia. The overall survival was shorter in aggressively treated leukemia patients than in aggressively treated lymphoma patients (P = .003); however, the incidence rates of TP53 mutation, p16INK4a deletion, and p15INK4b deletion that were found in 6 (15%) of 40,3 (9%) of 35, and 2 (6%) of 35 tumors, respectively, were similar between the 2 subtypes. Thus, the present study has shown the different prognoses for the 2 subtypes of Burkitt lymphoma but has failed to clarify the genetic backgrounds that may explain the different outcomes.

Predominance and characteristics of Burkitt lymphoma among children with non-Hodgkin lymphoma in northeastern Brazil.

The purpose of this paper was to define the histologic distribution, clinical features, and treatment response of childhood non-Hodgkin lymphoma (NHL) in northeastern Brazil. We reviewed medical records and histopathologic studies of 98 children treated for NHL from 1980 to 1987 at a major pediatric cancer center in Recife, Brazil. Treatment outcome was evaluated in relation to tumor burden (stage and serum LDH) and type of therapy (LSA2L2 vs other multiagent chemotherapy). There was a striking predominance of the small noncleaved cell (Burkitt) subtype, which occurred in 92 of the 98 children and adolescents diagnosed with NHL. Subsequent analyses focused on these patients. The majority (n = 84) had advanced (stage III/IV) disease at diagnosis. The abdomen was the most common site of disease (84 cases); jaw involvement was rare (three cases). Five-year event-free survival (excluding treatment refusals) was significantly better for patients with limited vs advanced stage disease (75 +/- 14% vs 42 +/- 6%; P < 0.04). Elevated serum LDH (>500 U/l) was associated with a poorer outcome (P = 0.008). The type of chemotherapy did not affect EFS (P = 0.95). Only 39% of patients are long-term survivors, reflecting the high rate of septic deaths (25% of patients) and parental refusal/abandonment of therapy (10%). Epstein-Barr virus (EBV) was detected in tumor cells from eight of the 11 cases studied. In clinical presentation, these cases resemble sporadic Burkitt lymphoma, yet in their apparent responsiveness to LSA2L2 therapy and association with EBV, they do not. Childhood NHL in northeastern Brazil is predominantly of the Burkitt subtype, and is associated with clinical features that appear to distinguish it from the endemic and sporadic forms of this tumor. These cases may represent a third or intermediate subtype of Burkitt lymphoma.

Promotion of IL8, IL10, TNFα and TNFβ production by EBV infection

Burkitt's lymphoma (BL) represents a high malignant B cell tumour. It has been proposed that cytokines are responsible for some of the characteristics of BL. We have analysed a panel of different BL and lymphoblastoid cell lines (LCLs) for the expression of cytokines, including: IL1α, IL1β, IL2, IL3, IL4, IL6, IL8, IL10, TNFα and TNFβ and for the soluble cytokine receptor for IL2 (sIL2R). Our results show that expression of IL8, IL10, TNFα or TNFβ was detected frequently in several of the Burkitt or lymphoblastoid cell lines. There was a correlation between Epstein-Barr virus (EBV) infection and cytokine protein production. Our results suggest that EBV promote the expression of IL8, IL10, TNFα and TNFβ.