scholarly journals Large B-Cell Lymphomas in Pediatric and Young Adults Display Clinically Relevant Molecular Features Distinguishable from Adult Counterparts

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1567-1567
Author(s):  
Joan Enric Ramis-Zaldivar ◽  
Blanca Gonzalez-Farre ◽  
Balagué Olga ◽  
Verónica Celis ◽  
Ferran Nadeu ◽  
...  
Keyword(s):  
Young Adult ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cervical Region ◽  
Age Group ◽  
B Cell Lymphomas ◽  
Molecular Features ◽  
Homozygous Deletions ◽  
Large B Cell

Abstract BACKGROUND Pediatric aggressive large B-cell lymphomas (LBCL) share morphological and phenotypic features with adult types but seem to have better prognosis. Additionally, a specific subtype carrying IRF4 translocations (LBCL-IRF4) has been recently identified in this age group. In adults, the cell-of-origin (COO) distinction of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures (germinal center B-cell like, GCB and activated B-cell like, ABC) and more recently clusters of genetic alterations have identified molecularly distinct DLBCL subsets that may benefit from novel therapeutic targets. The integration of pediatric population in these clinically relevant molecular subgroups and its clinical importance is not well known. The aim of this study was to characterize the molecular heterogeneity of LBCL in pediatric and young adult patients and evaluate their potential clinical impact. DESIGN Sixty-one LBCL diagnosed in patients ≤25 years-old (median age 14 years old, male/female 38/23) were included in the study. Molecular analyses included fluorescence in situ hybridization for MYC, BCL2, IRF4 and BCL6, copy number (CN) analysis (Oncoscan, Affymetrix), COO Lymph2Cx assay (NanoString) and targeted next generation sequencing of 96 B-cell lymphoma driver genes (SureSelect XT, Agilent Technologies). CNA and mutational profiles were compared to those previously published in adult DLBCL. Correlation of molecular features and event free survival (EFS) was performed using Kaplan-Meier curves. RESULTS Histologically, 33 were DLBCL, 20 LBCL-IRF4 and 8 high grade B-cell lymphomas, not otherwise specified (HGBCL). Nodal disease was present in 57%, mainly in the cervical region. COO distribution was: 68% GCB, 18% ABC and 13% unclassified. Most of LBCL-IRF4 cases were GCB-COO (73%). The IRF4 translocation was demonstrated in 16 out of 19 cases diagnosed as LBCL-IRF4 and an IGH rearrangement was seen in the other 3. Five cases carried MYC-breaks (3 DLBCL and 2 HGBCL) and two cases carried BCL6-breaks (1DLBCL and 1HGBCL). BCL2 rearrangements were absent. CN analysis detected alterations in 46/51 cases with recurrent gains (>15%) of 1q, 2p16, 11q, trisomies 7 and 12, and recurrent losses (>10%) of 1p36, 6q21-q22, 15q24, 17p13 and 19p13. Recurrent homozygous deletions were observed at 19p13/CD70 (6 cases), 9p13/CDKN2A (3 cases) and 13q14/RB1 (2 cases). Alteration patterns suggestive of chromothripsis were found in 10% (5/51) of the cases. No ABC-DLBCL related alterations such as 3p21-p14, 6q21-q25, 9p21.3 and 17p13 losses were seen. Targeted sequencing detected a total of 434 variants in 44 of 47 cases (mean 9.2 mutations/case). A pipeline for selection of driver mutations revealed a total of 270 mutations (62%) with potential functional effect. Recurrent mutations found in >15% of the cases affected IRF4, SOCS1, PIM1, CARD11, ACTB and CCND3 genes. In comparison to adult DLBCL, pediatric and young adult cases had significantly lower incidence of MYD88 (5 cases), CREBBP,TP53 (3 cases each) and TNFRSF14 (2 cases) mutations which are strongly associated with the definition of established mutational clusters in adult DLBCL. In our cohort, the morphological subtypes displayed different molecular profiles. IRF4 variants (some cases with >7 variants) and mutations in NF-kB pathway (CARD11, CD79B and MYD88-non L265P) were found specifically in the LBCL-IRF4 subgroup, whereas mutations in GCB related genes such as SOCS1 and EZH2 were particularly seen in cases with DLBCL diagnosis. All 49 patients with available follow-up received chemotherapy as first line treatment (41% containing Rituximab). Variables significantly associated with poor EFS in univariate analysis were age >18 years, ABC-COO, Stage IV, high genetic complexity (chromothripsis and/or >10 CN alterations), 2p16/REL gain/amplification, 9p21.3/CDKN2A homozygous deletions, MYC rearrangements and mutations in MYC, TP53 and DDX3X genes. CONCLUSION Despite pediatric/young-adult LBCL having overlapping features with adult disease our findings suggest that LBCL in young age have specific molecular mechanisms and highlight potential key drivers of these lymphomas in this age group. Disclosures No relevant conflicts of interest to declare.

The Outcome of Diffuse Large B Cell Lymphoma Patients in Adolescent and Young Adult Age Group

2020 ◽  
Author(s):  
Semih Başcı ◽  
Mehmet Bakırtaş ◽  
Tuğçe Nur Yiğenoğlu ◽  
Bahar Uncu Ulu ◽  
Hikmetullah Batgi ◽  
...  
Keyword(s):  
Young Adult ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Adolescent And Young Adult ◽  
Age Group ◽  
Adult Age ◽  
Large B Cell Lymphoma ◽  
Large B Cell

T-cell-rich B-cell lymphomas: diagnosis and response to therapy of 44 patients.

1995 ◽  
Vol 13 (7) ◽  
pp. 1742-1750 ◽  
Author(s):  
J P Greer ◽  
W R Macon ◽  
R E Lamar ◽  
S N Wolff ◽  
R S Stein ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Combination Chemotherapy ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Response To Therapy ◽  
B Cell Lymphomas ◽  
Intermediate Grade ◽  
Large B Cell

PURPOSE Clinicopathologic features of 44 patients with well-documented T-cell-rich B-cell lymphomas (TCRBCLs) were reviewed to determine if there were distinguishing clinical characteristics and to evaluate the responsiveness to therapy. PATIENTS AND METHODS Forty-one patients had de novo TCRBCL, while three patients had a prior diagnosis of diffuse large B-cell lymphoma. Seventeen TCRBCLs were identified from a retrospective analysis of 176 lymphomas diagnosed before 1988 as peripheral T-cell lymphoma (PTCLs). The initial pathologic diagnosis was incorrect in 36 of 44 cases (82%), usually due to the absence of adequate immunophenotypic and/or genotypic studies at the initial study. RESULTS The median age of patients was 53 years (range, 17 to 92), and the male-to-female ratio was 1.4:1. B symptoms were present in 22 of 41 patients (54%); splenomegaly was detected in 11 patients (25%). Clinical stage at diagnosis was as follows: I (n = 8), II (n = 6), III (n = 15), IV (n = 14), and unstaged (n = 1). Although therapy was heterogeneous, the disease-free survival (DFS) and overall survival (OS) rates at 3 years for patients with de novo TCRBCL were 29% and 46%, respectively. A complete response (CR) to combination chemotherapy for intermediate-grade lymphomas was observed in 16 of 26 patients (62%); 11 of these patients (42%) had a continuous CR, compared with one of 14 patients (7%) who received radiation therapy or therapy for low-grade lymphoma or Hodgkin's disease (HD) (P < .05). However, there was no difference in OS between patients who received chemotherapy for intermediate-grade lymphoma versus other therapies (49% v 48%) due to a high response rate to salvage therapies, including seven patients without disease after marrow transplantation. CONCLUSION TCRBCLs are difficult to recognize without immunoperoxidase studies. Patients with TCRBCL have clinical features similar to patients with other large B-cell lymphomas, except they may have more splenomegaly and advanced-stage disease; they should receive combination chemotherapy directed at large-cell lymphomas.

bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related.

1998 ◽  
Vol 16 (6) ◽  
pp. 2080-2085 ◽  
Author(s):  
F A Geelen ◽  
M H Vermeer ◽  
C J Meijer ◽  
S C Van der Putte ◽  
E Kerkhof ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
European Organization ◽  
Clinical Behavior ◽  
Large B Cell Lymphoma ◽  
Cutaneous Lymphomas ◽  
Distinct Disease ◽  
Large B Cell

PURPOSE Primary cutaneous large B-cell lymphoma (PCLBCL) that presents on the leg has recently been recognized as a distinct disease entity. These lymphomas have a reduced disease-free survival and a worse prognosis as compared with the more common, morphologically similar PCLBCL that present on the head or trunk. Studies in noncutaneous diffuse large B-cell lymphomas suggest a relationship between the expression of bcl-2 protein and clinical behavior. In the present study, we investigated whether these two groups of PCLBCL differ in the expression of bcl-2 protein and the presence of t(4;18), known as one of the causes of bcl-2 overexpression. PATIENTS AND METHODS Paraffin sections from pretreatment biopsies of 14 PCLBCLs of the head or trunk and nine PCLBCLs of the legs were investigated for expression of bcl-2 protein using immunohistochemistry, and for the presence of the 14;18 translocation using polymerase chain reaction (PCR) amplification with primers against both the major breakpoint region (mbr) and the minor cluster region (mcr) of bcl-2. For reasons of comparison, nine secondary cutaneous large B-cell lymphomas (SCLBCLs) were also studied. RESULTS Expression of bcl-2 protein was found in all nine PCLBCLs of the leg and in all nine SCLBCLs, but not in any of the 14 PCLBCLs on the head and trunk. The t(14;18) was only detected in two of seven SCLBCLs, but not in the five PCLBCLs of the leg or the eight PCLBCLs on the head or trunk studied. CONCLUSION The striking differences in bcl-2 expression between PCLBCL of the head or trunk and PCLBCL on the leg suggest that bcl-2 expression is site-related and may contribute to the different clinical behavior between these two groups of lymphomas. In addition, they underscore that PCLBCL on the head and trunk and PCLBCL on the leg are distinct disease entities, as recently recognized in the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas.

The clinicopathological and molecular features of sinusoidal large B-cell lymphoma

2020 ◽  
Author(s):  
Junpeng Xu ◽  
Peifeng Li ◽  
Jia Chai ◽  
Kangjie Yu ◽  
Tianqi Xu ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Molecular Features ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Grey Zone Lymphomas: Lymphomas with Intermediate Features

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Sylvia Hoeller ◽  
Christiane Copie-Bergman
Keyword(s):  
B Cell ◽  
Who Classification ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
World Health ◽  
Grey Zone ◽  
B Cell Lymphomas ◽  
Large B Cell Lymphoma ◽  
Large B Cell

The current classification of lymphoid neoplasms is based on clinical information, morphology, immunophenotype, and molecular genetic characteristics. Despite technical and scientific progress, some aggressive B-cell lymphomas with features overlapping between two different types of lymphomas remain difficult to classify. The updated 2008 World Health Organization (WHO) classification of Tumours of the Hematopoietic and Lymphoid Tissues has addressed this problem by creation of two new provisional categories of B-cell lymphomas, unclassifiable; one with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma and the second with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. We review here the diagnostic criteria of these two provisional entities and discuss new scientific findings in light of the 2008 WHO classification.

Immunohistochemical Expression Pattern of Germinal Center and Non-Germinal Center Markers Correlates with Prognosis in Diffuse Large B-Cell Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4636-4636
Author(s):  
Carlos Chiattone ◽  
Marineide P. Carvalho ◽  
Roberto P. Paes ◽  
Karina C.B. Ribeiro ◽  
Fernando Soares
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Immunohistochemical Expression ◽  
Molecular Features ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Recent studies have shown correlations between diffuse large B-cell lymphoma (DLCBL) prognosis and molecular features using genome profiles by cDNA microarrays. Since this analysis is not routinely used, immunohistochemical tests for prediction of DLBCL survival are gaining major importance, using markers as, CD10, BCL-6 and MUM-1 to identify germinal center B-cell (GCB) and non-GCB, respectively. The goal of this study was to evaluate the significant effect on survival within GCB and non-GCB subgroup. Patients and Methods: Seventy-four untreated pts (median age: 58 yrs: 38M/36F) with DLBCL de novo diagnosed in a single institution, treated with CHOP-like regimens. Tissue microarrays (TMA) blocks were created from paraffin-embedded, formalin-fixed block and stained with antibodies to CD20 (clone L26, Dako), CD10 (clone 56C6; Novocastra; NCL-CD10-270), BCL-6 (clone GI 191E/A8; Cell Mark; CMC 798) and MUM1 (clone MUM1p; Dako, CA; M7259). Results. Cases were subclassified using CD10, BCL-6, and MUM1 expression, and 25 cases (33.8%) were considered GCB and 49 cases (66.2%) non-GCB. The 2-year overall survival (OS) for the GCB group was 80% compared with only 38.9% for the non-GCB (p&lt;0.001). In the multivariate analysis, only the International Prognostic Index score (IPI 3-4 HR=2.6, p=0.013) and the GCB phenotype (Non-GCB HR=2.7, p=0.054) were independent prognostic factors. In summary, immunohistochemical expression of CD10, BCL-6 and MUM1 are able to determine the GCB and non-GCB subtypes of DLBCL and predict survival.

Genomic Rearrangements Involving Programmed Death Ligands Are Recurrent In Primary Mediastinal Large B-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 635-635 ◽  
Author(s):  
David D. W. Twa ◽  
Fong Chun Chan ◽  
Susana Ben-Neriah ◽  
Bruce W. Woolcock ◽  
King L. Tan ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Transcript Levels ◽  
Barr Virus ◽  
Large B Cell Lymphoma ◽  
Programmed Death ◽  
Large B Cell

Abstract Introduction Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive malignancy commonly diagnosed in young adult females. In recent years, mutational and gene expression profiling has established genotypic and phenotypic similarity of PMBCL with both classical Hodgkin and diffuse large B-cell lymphoma (DLBCL). In-depth analyses of genomes and transcriptomes have highlighted several inactivating mutations (SOCS1, TP53), chromosomal amplifications (2p, 9p, Xp, Xq) and translocations (CIITA) thought to be integral in establishing and/or maintaining the PMBCL phenotype. Programmed death ligands (PDL) 1 (CD274) and 2 (PDCD1LG2), which are located on chromosome 9p24.1, are two emerging genes of interest that have been shown to be altered in PMBCL and can induce T-cell anergy by binding to the receptor, programmed death 1. Here, we describe the recurrence of chromosomal rearrangements of the PDL locus in various B-cell lymphomas and explore the association of these rearrangements with transcript levels. Methods To establish the frequency of CD274 and PDCD1LG2 aberration, we conducted fluorescence in situ hybridization (FISH) on 551 clinical samples and 20 established cell lines using in-house break-apart probes. Epstein-Barr virus encoded RNA in situ hybridization was also carried out on the clinical cohort. The clinical cases, sourced from the British Columbia Cancer Agency’s Centre for Lymphoid Cancer tissue repository, consisted of 125 PMBCLs, 216 DLBCLs, 130 primary DLBCL of the central nervous system (PCNSL), 12 nodular lymphocyte predominant Hodgkin lymphomas (NLPHL) and 68 follicular lymphomas (FL) with diagnoses based on the WHO classification. The DLBCL cohort could be further subdivided into 134 nodal DLBCLs and 82 testicular DLBCLs (T-DLBCL). Quantitative real-time PCR (qRT-PCR) was subsequently conducted on 17 cell lines and a clinical sub-cohort of 76 samples, for which fresh-frozen material was available, to determine the effect of mutations on transcript expression. We then characterized the PDL aberrations of two clinical PMBCL cases and three cell lines (DEV, L-428, L-1236), at base pair resolution, by applying the bioinformatic tools, nFuse, deFuse and destruct to both newly produced and previously published whole genome (WGS) and whole transcriptome (RNA-seq) libraries. Results FISH revealed a PDL locus (9p24.1) break-apart frequency of 20% (25/125) in PMBCL. There were no differences in any known clinical parameters or frequency of Epstein-Barr virus positivity between positive and negative PDL break-apart cases. Break-apart frequencies in other malignancies were calculated to be 3% in DLBCL, 7% in T-DLBCL and 1% in PCNSL; no positive cases were identified in either NLPHL or FL. The proportion of break-apart positive cases was significantly higher in PMBCL as compared to the other lymphomas surveyed (P < 0.05). Further, in agreement with the published literature, we observed an amplification frequency of the PDL locus in 36% (45/125) of PMBCLs. qRT-PCR established that PDCD1LG2 transcript levels were significantly higher in cases with 9p24.1 locus rearrangements compared to copy number neutral (P = 0.0003), gain (P = 0.001) and amplified cases (P = 0.005). Likewise, CD274 transcript levels were significantly higher in rearranged cases compared to copy number neutral cases (P = 0.03). Following the analysis of WGS and RNA-seq libraries, we were able to characterize four novel fusion transcripts involving the 9p24.1 locus: PDCD1LG2-NRG1 (PMBCL clinical case), PDCD1LG2-IGHV7-81 (L-1236), CIITA-PDCD1LG2 (DEV) and KIAA1432-CLDN14 (L-428). Aberrations involving both NRG1 and CIITA have previously been implicated in breast cancer and B-cell lymphomas, respectively. We also identified a translocation in another PMBCL clinical case with breakpoints in the intergenic spaces near LRMP and CD274, though this rearrangement did not produce a fusion transcript. Conclusion Taken together, our findings show that rearrangement of the PDL locus is recurrent in PMBCL, characteristic of PMBCL and leads to overexpression of PDL transcripts. Given the well-referenced function of PDLs in repressing the anti-tumor response, these data suggest that targeting the PDL axis in a subgroup of B-cell lymphomas holds clinical promise. Disclosures: No relevant conflicts of interest to declare.

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