Pediatric Mature B-cell neoplasms
2023-06-25 Sheng Xiao, MD , Chunxiao Yang Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2. Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)
Classification
Definition
Pediatric Mature B-cell lymphoma results from the malignant transformation of B lymphocytes that have undergone differentiation and maturation at different stages depending on the subtype of lymphoma. While chronic lymphocytic leukemia (CLL) is a common mature B-cell tumor in adults, it is rare in pediatric patients. In contrast, Burkitt lymphoma is predominantly present in children and young adults and is the largest group of pediatric non-Hodgkin lymphomas. The genomic profile of mature B-cell lymphomas is important for both diagnostic and prognostic purposes. For example, the demonstration of IG::MYC is diagnostically important for Burkitt lymphoma. Diffuse large B cell lymphoma (DLBCL) can be subgrouped by molecular markers to provide prognostic stratification and indicate a combination therapy of traditional R-CHOP therapy with targeted drugs.1,2
| Pediatric Mature B-cell neoplasms | Genetic marker(s) | ||
|---|---|---|---|
| Primary mediastinal large B-cell lymphoma | CD274(PD-L1) and PDCD1LG2(PD-L2) gain/amplification/rearrangement, REL and BCL11A gain, or CIITA mutation/rearrangment are common findings in pediatric PMLBL.3-5. Rearrangements of BCL2, BCL6, and MYC genes are rare to absent.6 Patients are senstitive to PD-1/PD-L1 inhibitors. | ||
| Diffuse large B-cell lymphoma NOS | Mutations of the SOCS1, KMT2D, or BCL6 are common in pediatric Diffuse large B-cell lymphoma NOS. Most pediatric DLBCL NOS are GCB subtype, with similar mutations as seen in adult counterparts.7 BCL6 rearrangement, but not MYC and BCL2 rearrangement, was seen in pediatric DLBCL NOS.7-9 | ||
| EBV-positive diffuse large B-cell lymphoma NOS | Mutations of the CCR6, CCR7, DAPK1, TNFRSF21, CSNK2B, YY1 are common in pediatric EBV-positive diffuse large B-cell lymphoma NOS. Additional chromosome aberrations include 9p24 alteration. EBV-positive DLBCL NOS has lower mutational burden as compared to EBV-negative DLBCL-NOS, consistent with the hypothesis that EBV-driven pathogenesis requires fewer driver mutations.10 The presence of EBV has been reported to be mutually exclusive with either MYD88 and/or CD79A mutations.11 | ||
| Large B-cell lymphoma with IRF4 rearrangement | In most cases, the IRF4 fusion partner is IGH resulting from t(6;14)(p25;q32), although IGK, IGL, or unknown partners are reported. BCL2 and MYC are not rearranged, however, BCL6 can be rearranged.7,12 Because this rearrangement is cytogenetically cryptic, FISH or DNA NGS are needed for the diagnosis.The overall outcome of LBCL-IRF4 is favourable in paediatric patients.13 | ||
| Pediatric-type follicular lymphoma | Common genomic alterations in PTFL include 1p36 deletion or CN-LOH targeting TNFRSF14(44-54%), MAP2K1 (43-49%),14-17 or IRF8 (15-50%).17,18 | ||
| Pediatric nodal marginal zone lymphoma | The dominant driver genes are mutated KLF2, NOTCH2, or AMOTL1. Additional frequently mutated genes include MAP2K1, TNFRSF14, KMT2D, IRF8, and NOTCH2. Additional chromosome aberrations includetrisomy 3, trisomy 18.18 Pediatric NMZL is similar to adult NMZL with low genome complexity and is negative for MYC, BCL2, BCL6, and IRF4 rearrangements.19 | ||
| ALK-positive large B-cell lymphoma | Rearranged ALK is the dominant driver, with t(2;17)(p23;q23)CLTC::ALK being the most commonly observed, although t(2;5)(p23;q35)NPM1::ALK has also been reported.20 The prognosis of ALK+ LBL is poor, with a 5-year overall survival of 25 %.21 However, these patients are sensitive to new-generation ALK inhibitors Alectinib and Lorlatinib.22 | ||
| Lymphomatoid granulomatosis | Lymphomatoid granulomatosis is an EBV-associated B-cell lymphoproliferative disorder with rich T-cell infiltration. IG clonality can be seen in most grade 2 and 3 lesions, although different rearrangements can be identified from different lesions. TCR clonality can also be detected.23 A single case of pulmonary lymphomatoid granulomatosis showed a mutation of MPEG1 (macrophage-expressed gene 1).24 | ||
| Plasmablastic lymphoma | Activated MYC is the dominant driver, with MYC rearrangement (IGH::MYC from t(8;14)(q24;q32), IGK::MYC fromt(2;8)(p12;q24), IGL::MYC from t(8;22)(q24;q11)) being more commonly observed in HIV-positive (80%) than in HIV-negative patients (40-60%).25-27 PRDM1, an MYC signaling inhibitor, is mutated in 45% of cases.28 Other recurrent mutations include STAT3, BRAF, EP300, CD79A, and CD79B.26 PML is an aggressive tumor, although the prognosis is better in pediatric patients as compared to adults.29 | ||
| Mediastinal grey zone lymphoma | The genomic profile of mediastinal grey-zone lymphoma overlaps with those in nodular sclerosis classic Hodgkin lymphoma (NSCHL) and primary mediastinal large B-cell lymphoma (PMBL). Chromosome gains at 2p16.1 (REL locus) and/or 9p24.1 (CD274(PD-L1) and PDCD1LG2(PD-L2) locus) are common findings.30 Other changes including 9p24.1 rearrangement and 3'UTR deletions/mutations of CD274(PD-L1) and PDCD1LG2(PD-L2) are reported.31 | ||
| Burkitt lymphoma | MYC rearrangement is the dominant driver in BL, including (IGH::MYC from t(8;14)(q24;q32), IGK::MYC from t(2;8)(p12;q24), and IGL::MYC from t(8;22)(q24;q11). The MYC breakpoint is within MYC or nearby in most sporadic and immunodeficiency-associated BL, but could be hundreds of kilobases upstream from MYC promoter in endemic BL (similar to those in DLBCL or MM).32,33 Additional frequently mutated genes include TCF3, ID3, CCND3. Patients without MYC rearrangement but with 11q aberrations belong to another entity, large B-cell lymphoma with aberrations of 11q.13 | ||
| Large B-cell lymphoma with 11q aberration | LBCL-11q has a morphology and immunophenotype that resemble Burkitt lymphoma but lacks MYC rearrangement. Instead, a proximal gain and a telomeric loss of 11q are observed. Additional frequently mutated genes include BTG2, DDX3X, ETS1, EP300, GNA13. Additional chromosome aberrations include 12q12-q21.1 gain, 6q12.1-q21 loss.34 A subset of cases may show no gain but only the telomeric loss.35 Different from BL, ID3-TCF3 pathway is not involved. |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 29641966 | 2018 | Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. | Schmitz R et al |
| 2 | 32289277 | 2020 | A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications. | Wright GW et al |
| 3 | 8608249 | 1996 | Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. | Joos S et al |
| 4 | 11241792 | 2001 | Gain of chromosome arm 9p is characteristic of primary mediastinal B-cell lymphoma (MBL): comprehensive molecular cytogenetic analysis and presentation of a novel MBL cell line. | Bentz M et al |
| 5 | 17728785 | 2007 | Further delineation of chromosomal consensus regions in primary mediastinal B-cell lymphomas: an analysis of 37 tumor samples using high-resolution genomic profiling (array-CGH). | Wessendorf S et al |
| 6 | 8669486 | 1996 | Molecular characterization of primary mediastinal B cell lymphoma. | Tsang P et al |
| 7 | 31738823 | 2020 | Distinct molecular profile of IRF4-rearranged large B-cell lymphoma. | Ramis-Zaldivar JE et al |
| 8 | 16424389 | 2006 | Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. | Oschlies I et al |
| 9 | 28643426 | 2017 | Cell-of-origin classification by gene expression and MYC-rearrangements in diffuse large B-cell lymphoma of children and adolescents. | Szczepanowski M et al |
| 10 | 34039950 | 2021 | Genomic insights into the pathogenesis of Epstein-Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing. | Gebauer N et al |
| 11 | 34072731 | 2021 | Advances in the Pathogenesis of EBV-Associated Diffuse Large B Cell Lymphoma. | Chabay P et al |
| 12 | 21487109 | 2011 | Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. | Salaverria I et al |
| 13 | 32239695 | 2020 | Experience with provisional WHO-entities large B-cell lymphoma with IRF4-rearrangement and Burkitt-like lymphoma with 11q aberration in paediatric patients of the NHL-BFM group. | Au-Yeung RKH et al |
| 14 | 23445872 | 2013 | Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas. | Martin-Guerrero I et al |
| 15 | 27257180 | 2016 | Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene. | Schmidt J et al |
| 16 | 27325104 | 2016 | Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations. | Louissaint A Jr et al |
| 17 | 28533310 | 2017 | Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation. | Schmidt J et al |
| 18 | 27338637 | 2016 | A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma. | Ozawa MG et al |
| 19 | 36394631 | 2023 | Follicular lymphoma and marginal zone lymphoma: how many diseases? | Laurent C et al |
| 20 | 12750159 | 2003 | ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma. | De Paepe P et al |
| 21 | 19636007 | 2009 | Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis. | Laurent C et al |
| 22 | 35802834 | 2022 | Next-generation ALK inhibitors are highly active in ALK-positive large B-cell lymphoma. | Soumerai JD et al |
| 23 | 25321327 | 2015 | Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations. | Song JY et al |
| 24 | 35812680 | 2022 | Pulmonary lymphomatoid granulomatosis in a 4-year-old girl: A case report. | Yao JW et al |
| 25 | 20962620 | 2010 | IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas. | Valera A et al |
| 26 | 32273478 | 2021 | Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma. | Garcia-Reyero J et al |
| 27 | 24832164 | 2014 | Clinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients: single-center series of 25 cases and meta-analysis of 277 reported cases. | Morscio J et al |
| 28 | 27687004 | 2017 | Plasmablastic lymphoma phenotype is determined by genetic alterations in MYC and PRDM1. | Montes-Moreno S et al |
| 29 | 23036261 | 2013 | Plasmablastic lymphoma in pediatric patients: clinicopathologic study of three cases. | Pather S et al |
| 30 | 21822207 | 2011 | Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations. | Eberle FC et al |
| 31 | 31697821 | 2019 | Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade. | Chapuy B et al |
| 32 | 3458257 | 1986 | Chromosomal breakpoints and structural alterations of the c-myc locus differ in endemic and sporadic forms of Burkitt lymphoma. | Pelicci PG et al |
| 33 | 22711821 | 2012 | Mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation. | Kovalchuk AL et al |
| 34 | 30733272 | 2019 | Burkitt-like lymphoma with 11q aberration: a germinal center-derived lymphoma genetically unrelated to Burkitt lymphoma. | Gonzalez-Farre B et al |
| 35 | 24398325 | 2014 | A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma. | Salaverria I et al |
Citation
Sheng Xiao, MD ; Chunxiao Yang
Pediatric Mature B-cell neoplasms
Atlas Genet Cytogenet Oncol Haematol. 2023-06-25
Online version: http://atlasgeneticsoncology.org/solid-tumor/209181/pediatric-mature-b-cell-neoplasms
