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

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:

  1. most commonly, Burkitt-like morphology associated with a clinical phenotype more akin to Burkitt lymphoma than DLBCL
  2. 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)

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

Characteristic Chromosomal Aberrations / Patterns

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].

Genomic Gain/Loss/LOH

The 11q-gain/loss aberration has been reported in two cases of HGBL, NOS with MYC rearrangement[9]. 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

Gene Mutations (SNV/INDEL)

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[10].

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[10]
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[11] 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

Epigenomics (Methylation)

An epigenomic characterization of HGBL, NOS is not currently published.

Genes and Main Pathways Involved

MYC

BCL2

BCL6

ID3

CCND3

CREBBP

SGK1

Diagnostic Testing Methods

  • Histopathology
  • Immunohistochemistry
  • Karyotype analysis and FISH for MYC, BCL2 or BCL6 gene rearrangement to rule out DH or TH lymphoma.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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][12][13]. 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][14].

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].

Familial Forms

Not applicable.

Other Information

No additional information.

Links

High-Grade B-cell Lymphoma

MYC

BCL2

BCL6

References

(use "Cite" icon at top of page)

  1. 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. 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. 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. 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. 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)
  6. 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)
  7. 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)
  8. 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).
  9. 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.
  10. 10.0 10.1 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)
  11. 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).
  12. 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.
  13. 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)
  14. 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.

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, 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, p129-171.

Notes

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