High-grade B-cell lymphoma, NOS
Haematolymphoid Tumours (5th ed.)
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editHAEM5 Conversion NotesThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:High-Grade B-cell Lymphoma, Not Otherwise Specified (NOS).
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Primary Author(s)*
Aiko Otsubo, PhD, Indiana University
Cancer Category / Type
High-Grade B-cell Lymphoma
Cancer Sub-Classification / Subtype
High-Grade B-cell Lymphoma, Not Otherwise Specified (NOS)
Definition / Description of Disease
High-Grade B-cell Lymphoma, Not Otherwise Specified (HGBL, NOS) was a new entity in the 2016 WHO classification of Tumours of Haematopoietic and Lymphoid Tissues[1], partially replacing ‘B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma (BCLU)’, which was defined in the 2008 WHO edition. This entity consists of a heterogeneous group of aggressive mature B-cell lymphomas. HGBL, NOS lacks the combination of rearrangements required for categorization as ‘High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements’, and does not meet the criteria for a diagnosis of diffuse large B-cell lymphoma (DLBCL), or Burkitt lymphoma (BL). Given this is a relatively newly defined entity, further refinement may occur over time as more data emerges.
Synonyms / Terminology
HGBL, NOS
Epidemiology / Prevalence
HGBL, NOS is rare in the context of other aggressive lymphomas. The true incidence is unknown, since in the literature this entity has commonly been grouped together with HGBL with MYC and BCL2 and/or BCL6 rearrangements. In general, affected patients are older adults (≥60 years), with incidence increasing with age. Both males and females are affected[1]. A study of 41 cases showed the median age of onset was 41 (range of 12 to 79). This study also showed slightly higher incidence in males (63%) than females (37%)[2].
Clinical Features
Put your text here and fill in the table (Instruction: Can include references in the table)
| Signs and Symptoms | EXAMPLE Asymptomatic (incidental finding on complete blood counts)
EXAMPLE B-symptoms (weight loss, fever, night sweats) EXAMPLE Fatigue EXAMPLE Lymphadenopathy (uncommon) |
| Laboratory Findings | EXAMPLE Cytopenias
EXAMPLE Lymphocytosis (low level) |
editv4:Clinical FeaturesThe content below was from the old template. Please incorporate above.Patients with HGBL, NOS typically present with clinically aggressive, advanced-stage disease, characterized by a high International Prognostic Index (IPI), and short survival. Both extranodal involvement and increased serum lactate dehydrogenase are common[2][3][4]. Clinical signs can include unexplained fever, lymphadenopathy, night sweats, decreased body mass, abdominal pain, and abdominal distension[2].
Sites of Involvement
Lymph nodes. Involvement of extranodal sites such as the gastrointestinal tract, bone marrow and the central nervous system is also frequent[2][3].
Morphologic Features
Two major morphological variants are present:
- most commonly, Burkitt-like morphology associated with a clinical phenotype more akin to Burkitt lymphoma than DLBCL
- more rarely, blastoid morphology[1].
Cases with the former morphology were designated as BCLU in the 2008 WHO classification. These cases are characterized by a diffuse proliferation of predominantly medium-sized cells with variable nuclear shape and size. A starry-sky appearance with many mitotic figures and prominent apoptosis can be seen in many cases. A subset of these cases very closely mimic BL; however, they are included in HGBL, NOS when atypical immunophenotype (e.g. diffuse and strong BCL2 expression) or genetic abnormalities (e.g. a complex karyotype) are present[1][5][6].
In the latter, cells have blastoid appearance which can look like lymphoblastic lymphoma, but lack TdT and CCND1 expression. A starry-sky pattern is common in this variant[7].
Immunophenotype
The immunophenotype is variable due to the heterogeneous nature of this entity, the WHO describes a limited set of common markers, as detailed in the table below.
MYC expression is variable[1][2] and at least partially dependent on the concurrent presence or absence of MYC rearrangements or copy number changes.
A germinal center-like immunophenotype is common accounting for 65-76% of cases with CD10 and 83-90% of cases with BCL6 expression[2][8].
| Finding | Marker |
|---|---|
| Positive (universal) | Pan B-cell markers such as CD19, CD20, and CD22 |
| Positive (subset) | CD10, Ki-67, MYC, BCL2, BCL6, IRF4/MUM1 |
| Negative (universal) | TdT, CD34, CCND1 |
| Negative (subset) | CD10, Ki-67, MYC, BCL2, BCL6, IRF4/MUM1 |
Chromosomal Rearrangements (Gene Fusions)
Put your text here and fill in the table
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE t(9;22)(q34;q11.2) | EXAMPLE 3'ABL1 / 5'BCR | EXAMPLE der(22) | EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference) |
Yes | No | Yes | EXAMPLE
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the old template. Please incorporate above.There are no recurrent chromosomal rearrangements associated with HGBL, NOS.
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Nil recurrent rearrangements
editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).Please incorporate this section into the relevant tables found in:
- Chromosomal Rearrangements (Gene Fusions)
- Individual Region Genomic Gain/Loss/LOH
- Characteristic Chromosomal Patterns
- Gene Mutations (SNV/INDEL)
HGBL, NOS is associated with an aggressive clinical course with poor prognosis. Some studies suggest that despite the poor prognosis, clinical outcomes may be slightly better than those of HGBL with MYC and BCL2 and/or BCL6 rearrangements[4][9][10]. Patients with double-expressor lymphoma (DHL) or a MYC rearrangement (SHL) have shown inferior overall survival than those without them in this entity[2]. A prognostic significance of various factors such as morphology of the tumor cells, types of genetic abnormalities and MYC translocation partner remains not fully understood since subgroup analysis is very limited and studies on this aspect have been conducted mainly in DLBCL cases[1][11].
There is no established standard therapy. In some studies patients treated with a high-intensity chemotherapy (DA-EPOCH-R, R-CODOX-M/IVAC, or R-Hyper-CVAD) have shown better clinical outcomes than those treated with R-CHOP, but further studies are needed to establish optimal treatment[2].
Individual Region Genomic Gain / Loss / LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)
| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE
7 |
EXAMPLE Loss | EXAMPLE
chr7:1- 159,335,973 [hg38] |
EXAMPLE
chr7 |
Yes | Yes | No | EXAMPLE
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE
8 |
EXAMPLE Gain | EXAMPLE
chr8:1-145,138,636 [hg38] |
EXAMPLE
chr8 |
No | No | No | EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference). |
editv4:Genomic Gain/Loss/LOHThe content below was from the old template. Please incorporate above.The 11q-gain/loss aberration has been reported in two cases of HGBL, NOS with MYC rearrangement[12]. The 11q gains in these cases were larger than 50 Mbp, with accompanying 10-18 Mbp terminal telomeric losses. Overlapping duplicated and deleted regions of these cases were shown in the table.
Chromosome Number Gain/Loss/Amp/LOH Region 11 Gain 11q13.1q23.3 11 Loss 11q24.2q25
Characteristic Chromosomal Patterns
Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)
| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
editv4:Characteristic Chromosomal Aberrations / PatternsThe content below was from the old template. Please incorporate above.This entity is genetically heterogeneous and the karyotype is often complex. By definition, concurrent MYC and BCL2 or BCL6 rearrangements are not seen. Isolated MYC rearrangement is common, being present in 20-35% of cases[1][2][4][5]. Similarly, isolated rearrangements of BCL2 or/and BCL6 have been reported, occurring 14%-25% of reported cases. Copy number changes or amplification of MYC, BCL2, or/and BCL6 have been reported approximately in 20% of cases[2][4][5]. 27-29% of cases do not display any copy number or structural abnormalities involving MYC, BCL2, or BCL6[2][4].
Gene Mutations (SNV / INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.)
| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.There are few focused studies of sequence variation in HGBL, NOS. One study investigated nine cases, interrogating 13 genes that are frequently mutated in either BL or DLBCL. Variants in ID3, CCND3, MYC, BCL2, CREBBP, and SGK1 were found in these cases, indicating their variant profiles overlap with those of BL and DLBCL. Although the sample size was small, it is noteworthy that ID3 mutations were found in all eight cases with isolated MYC rearrangements[13].
Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other) ID3 L64F (hetero), Y48* (homo), L64fs (hetero), C47fs, V82_Q100del (biallelic), S49F, P56S, Q63fs (biallelic), P56S, p.R72_V73insRGV (biallelic), L64F, P56S (biallelic) Tumor Suppressor LOF 8/9 cases[13] CCND3 T283I, I290T Oncogene GOF 2/9 cases MYC V117M, P78S, S244A, P72T, G99R, L164V, L55P, Q247*, V317I Oncogene GOF 4/9 cases BCL2 N172H, P123S, P46S, P59S, G193V, P40S, A67V, F112L, N163K Oncogene GOF 5/9 cases CREBBP R1319*, C1723S, P1488L, Y1503C, Y1450C Tumor Suppressor LOF 4/9 cases SGK1 G8R Oncogene[14] GOF 1/9 cases Other Mutations
Type Gene/Region/Other Concomitant Mutations Presence of complex karyotype is common Secondary Mutations Unknown Mutually Exclusive Concurrent MYC and BCL2 or BCL6 rearrangement
Epigenomic Alterations
An epigenomic characterization of HGBL, NOS is not currently published.
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Can include references in the table.)
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.MYC
BCL2
BCL6
ID3
CCND3
CREBBP
SGK1
Genetic Diagnostic Testing Methods
- Histopathology
- Immunohistochemistry
- Karyotype analysis and FISH for MYC, BCL2 or BCL6 gene rearrangement to rule out DH or TH lymphoma.
Familial Forms
Not applicable.
Additional Information
No additional information.
Links
HAEM4:High-Grade B-cell Lymphoma
References
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Kluin PM, et al., (2017). High-grade B-cell lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p340-341.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Li, Jiayin; et al. (2020). "High-Grade B-Cell Lymphomas, Not Otherwise Specified: A Study of 41 Cases". Cancer Management and Research. 12: 1903–1912. doi:10.2147/CMAR.S243753. ISSN 1179-1322. PMC 7082796 Check
|pmc=value (help). PMID 32214848 Check|pmid=value (help). - ↑ 3.0 3.1 Li, Shaoying; et al. (2015-02). "B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 28 (2): 208–217. doi:10.1038/modpathol.2014.95. ISSN 1530-0285. PMID 25103070. Check date values in:
|date=(help) - ↑ 4.0 4.1 4.2 4.3 4.4 Perry, Anamarija M.; et al. (2013-07). "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and burkitt lymphoma: study of 39 cases". British Journal of Haematology. 162 (1): 40–49. doi:10.1111/bjh.12343. ISSN 1365-2141. PMID 23600716. Check date values in:
|date=(help) - ↑ 5.0 5.1 5.2 Li, Shaoying; et al. (2018-08). "Advances in pathological understanding of high-grade B cell lymphomas". Expert Review of Hematology. 11 (8): 637–648. doi:10.1080/17474086.2018.1494567. ISSN 1747-4094. PMID 29989509. Check date values in:
|date=(help) - ↑ Ok, Chi Young; et al. (2020-01). "High-grade B-cell lymphoma: a term re-purposed in the revised WHO classification". Pathology. 52 (1): 68–77. doi:10.1016/j.pathol.2019.09.008. ISSN 1465-3931. PMID 31735344. Check date values in:
|date=(help) - ↑ Kanagal-Shamanna, Rashmi; et al. (2012-11). "High-grade B cell lymphoma, unclassifiable, with blastoid features: an unusual morphological subgroup associated frequently with BCL2 and/or MYC gene rearrangements and a poor prognosis". Histopathology. 61 (5): 945–954. doi:10.1111/j.1365-2559.2012.04301.x. ISSN 1365-2559. PMID 22804688. Check date values in:
|date=(help) - ↑ Hüttl, Katrin S.; et al. (2021-03-02). "The "Burkitt-like" immunophenotype and genotype is rarely encountered in diffuse large B cell lymphoma and high-grade B cell lymphoma, NOS". Virchows Archiv: An International Journal of Pathology. doi:10.1007/s00428-021-03050-4. ISSN 1432-2307. PMID 33655392 Check
|pmid=value (help). - ↑ Lin, Pei; et al. (2012-03-15). "Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma". Cancer. 118 (6): 1566–1573. doi:10.1002/cncr.26433. ISSN 1097-0142. PMID 21882178.
- ↑ Cook, James R.; et al. (2014-04). "Clinical significance of MYC expression and/or "high-grade" morphology in non-Burkitt, diffuse aggressive B-cell lymphomas: a SWOG S9704 correlative study". The American Journal of Surgical Pathology. 38 (4): 494–501. doi:10.1097/PAS.0000000000000147. ISSN 1532-0979. PMC 3955880. PMID 24625415. Check date values in:
|date=(help) - ↑ Rosenwald, Andreas; et al. (2019-12-10). "Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 37 (35): 3359–3368. doi:10.1200/JCO.19.00743. ISSN 1527-7755. PMID 31498031.
- ↑ Grygalewicz, Beata; et al. (2017-12-20). "The 11q-Gain/Loss Aberration Occurs Recurrently in MYC-Negative Burkitt-like Lymphoma With 11q Aberration, as Well as MYC-Positive Burkitt Lymphoma and MYC-Positive High-Grade B-Cell Lymphoma, NOS". American Journal of Clinical Pathology. 149 (1): 17–28. doi:10.1093/ajcp/aqx139. ISSN 1943-7722. PMC 5848380. PMID 29272887.
- ↑ 13.0 13.1 Momose, S.; et al. (2015-08). "The diagnostic gray zone between Burkitt lymphoma and diffuse large B-cell lymphoma is also a gray zone of the mutational spectrum". Leukemia. 29 (8): 1789–1791. doi:10.1038/leu.2015.34. ISSN 1476-5551. PMID 25673238. Check date values in:
|date=(help) - ↑ Gao, Jie; et al. (2021-09-16). "SGK1 mutations in DLBCL generate hyperstable protein neoisoforms that promote AKT independence". Blood. 138 (11): 959–964. doi:10.1182/blood.2020010432. ISSN 1528-0020. PMID 33988691 Check
|pmid=value (help).
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. *Citation of this Page: “High-grade B-cell lymphoma, NOS”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:High-grade_B-cell_lymphoma,_NOS.