View source for High-Grade B-cell Lymphoma, Not Otherwise Specified (NOS)

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==Primary Author(s)*==

Aiko Otsubo, PhD, Indiana University

__TOC__

==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<ref name=":0">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.</ref>, 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<ref name=":0" />. 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%)<ref name=":1">{{Cite journal|last=Li|first=Jiayin|last2=Liu|first2=Xiaoyin|last3=Yao|first3=Zhihua|last4=Zhang|first4=Mingzhi|date=2020|title=High-Grade B-Cell Lymphomas, Not Otherwise Specified: A Study of 41 Cases|url=https://pubmed.ncbi.nlm.nih.gov/32214848|journal=Cancer Management and Research|volume=12|pages=1903–1912|doi=10.2147/CMAR.S243753|issn=1179-1322|pmc=7082796|pmid=32214848}}</ref>. 

==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<ref name=":1" /><ref name=":2">{{Cite journal|last=Li|first=Shaoying|last2=Seegmiller|first2=Adam C.|last3=Lin|first3=Pei|last4=Wang|first4=Xuan J.|last5=Miranda|first5=Roberto N.|last6=Bhagavathi|first6=Sharathkumar|last7=Medeiros|first7=L. Jeffrey|date=2015-02|title=B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/25103070|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=28|issue=2|pages=208–217|doi=10.1038/modpathol.2014.95|issn=1530-0285|pmid=25103070}}</ref><ref name=":3">{{Cite journal|last=Perry|first=Anamarija M.|last2=Crockett|first2=David|last3=Dave|first3=Bhavana J.|last4=Althof|first4=Pamela|last5=Winkler|first5=Lisa|last6=Smith|first6=Lynette M.|last7=Aoun|first7=Patricia|last8=Chan|first8=Wing C.|last9=Fu|first9=Kai|date=2013-07|title=B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and burkitt lymphoma: study of 39 cases|url=https://pubmed.ncbi.nlm.nih.gov/23600716|journal=British Journal of Haematology|volume=162|issue=1|pages=40–49|doi=10.1111/bjh.12343|issn=1365-2141|pmid=23600716}}</ref>. Clinical signs can include unexplained fever, lymphadenopathy, night sweats, decreased body mass, abdominal pain, and abdominal distension<ref name=":1" />.

==Sites of Involvement==

Lymph nodes. Involvement of extranodal sites such as the gastrointestinal tract, bone marrow and the central nervous system is also frequent<ref name=":1" /><ref name=":2" />.

==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<ref name=":0" />.

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<ref name=":0" /><ref name=":4">{{Cite journal|last=Li|first=Shaoying|last2=Lin|first2=Pei|last3=Medeiros|first3=L. Jeffrey|date=2018-08|title=Advances in pathological understanding of high-grade B cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/29989509|journal=Expert Review of Hematology|volume=11|issue=8|pages=637–648|doi=10.1080/17474086.2018.1494567|issn=1747-4094|pmid=29989509}}</ref><ref>{{Cite journal|last=Ok|first=Chi Young|last2=Medeiros|first2=L. Jeffrey|date=2020-01|title=High-grade B-cell lymphoma: a term re-purposed in the revised WHO classification|url=https://pubmed.ncbi.nlm.nih.gov/31735344|journal=Pathology|volume=52|issue=1|pages=68–77|doi=10.1016/j.pathol.2019.09.008|issn=1465-3931|pmid=31735344}}</ref>. 

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<ref>{{Cite journal|last=Kanagal-Shamanna|first=Rashmi|last2=Medeiros|first2=L. Jeffrey|last3=Lu|first3=Gary|last4=Wang|first4=Sa A.|last5=Manning|first5=John T.|last6=Lin|first6=Pei|last7=Penn|first7=Gerald M.|last8=Young|first8=Ken H.|last9=You|first9=M. James|date=2012-11|title=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|url=https://pubmed.ncbi.nlm.nih.gov/22804688|journal=Histopathology|volume=61|issue=5|pages=945–954|doi=10.1111/j.1365-2559.2012.04301.x|issn=1365-2559|pmid=22804688}}</ref>.

==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<ref name=":0" /><ref name=":1" /> 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<ref name=":1" /><ref>{{Cite journal|last=Hüttl|first=Katrin S.|last2=Staiger|first2=Annette M.|last3=Richter|first3=Julia|last4=Ott|first4=M. Michaela|last5=Kalmbach|first5=Sabrina|last6=Klapper|first6=Wolfram|last7=Biesdorf|first7=Anne-Sophie|last8=Trümper|first8=Lorenz|last9=Rosenwald|first9=Andreas|date=2021-03-02|title=The "Burkitt-like" immunophenotype and genotype is rarely encountered in diffuse large B cell lymphoma and high-grade B cell lymphoma, NOS|url=https://pubmed.ncbi.nlm.nih.gov/33655392|journal=Virchows Archiv: An International Journal of Pathology|doi=10.1007/s00428-021-03050-4|issn=1432-2307|pmid=33655392}}</ref>.

{| class="wikitable sortable"
|-
!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.

{| class="wikitable sortable"
|-
!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<ref name=":0" /><ref name=":1" /><ref name=":3" /><ref name=":4" />. 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<ref name=":1" /><ref name=":3" /><ref name=":4" />. 27-29% of cases do not display any copy number or structural abnormalities involving ''MYC'', ''BCL2'', or ''BCL6''<ref name=":1" /><ref name=":3" />.

==Genomic Gain/Loss/LOH==

The 11q-gain/loss aberration has been reported in two cases of HGBL, NOS with ''MYC'' rearrangement<ref name=":5">{{Cite journal|last=Grygalewicz|first=Beata|last2=Woroniecka|first2=Renata|last3=Rymkiewicz|first3=Grzegorz|last4=Rygier|first4=Jolanta|last5=Borkowska|first5=Klaudia|last6=Kotyl|first6=Aleksandra|last7=Blachnio|first7=Katarzyna|last8=Bystydzienski|first8=Zbigniew|last9=Nowakowska|first9=Beata|date=2017-12-20|title=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|url=https://pubmed.ncbi.nlm.nih.gov/29272887|journal=American Journal of Clinical Pathology|volume=149|issue=1|pages=17–28|doi=10.1093/ajcp/aqx139|issn=1943-7722|pmc=5848380|pmid=29272887}}</ref>. 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. 

{| class="wikitable sortable"
|-
!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<ref name=":6">{{Cite journal|last=Momose|first=S.|last2=Weißbach|first2=S.|last3=Pischimarov|first3=J.|last4=Nedeva|first4=T.|last5=Bach|first5=E.|last6=Rudelius|first6=M.|last7=Geissinger|first7=E.|last8=Staiger|first8=A. M.|last9=Ott|first9=G.|date=2015-08|title=The diagnostic gray zone between Burkitt lymphoma and diffuse large B-cell lymphoma is also a gray zone of the mutational spectrum|url=https://pubmed.ncbi.nlm.nih.gov/25673238|journal=Leukemia|volume=29|issue=8|pages=1789–1791|doi=10.1038/leu.2015.34|issn=1476-5551|pmid=25673238}}</ref>.

{| class="wikitable sortable"
|-
!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<ref name=":6" />
|-
|''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<ref>{{Cite journal|last=Gao|first=Jie|last2=Sidiropoulou|first2=Eirini|last3=Walker|first3=Ieuan|last4=Krupka|first4=Joanna A.|last5=Mizielinski|first5=Karol|last6=Usheva|first6=Zelvera|last7=Samarajiwa|first7=Shamith A.|last8=Hodson|first8=Daniel J.|date=2021-09-16|title=SGK1 mutations in DLBCL generate hyperstable protein neoisoforms that promote AKT independence|url=https://pubmed.ncbi.nlm.nih.gov/33988691|journal=Blood|volume=138|issue=11|pages=959–964|doi=10.1182/blood.2020010432|issn=1528-0020|pmid=33988691}}</ref>
|GOF
|1/9 cases
|}	
		
===Other Mutations===
{| class="wikitable sortable"
|-
!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<ref name=":3" /><ref>{{Cite journal|last=Lin|first=Pei|last2=Dickason|first2=Timothy J.|last3=Fayad|first3=Luis E.|last4=Lennon|first4=Patrick A.|last5=Hu|first5=Peter|last6=Garcia|first6=Mar|last7=Routbort|first7=Mark J.|last8=Miranda|first8=Roberto|last9=Wang|first9=Xumei|date=2012-03-15|title=Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/21882178|journal=Cancer|volume=118|issue=6|pages=1566–1573|doi=10.1002/cncr.26433|issn=1097-0142|pmid=21882178}}</ref><ref>{{Cite journal|last=Cook|first=James R.|last2=Goldman|first2=Bryan|last3=Tubbs|first3=Raymond R.|last4=Rimsza|first4=Lisa|last5=Leblanc|first5=Michael|last6=Stiff|first6=Patrick|last7=Fisher|first7=Richard|date=2014-04|title=Clinical significance of MYC expression and/or "high-grade" morphology in non-Burkitt, diffuse aggressive B-cell lymphomas: a SWOG S9704 correlative study|url=https://pubmed.ncbi.nlm.nih.gov/24625415|journal=The American Journal of Surgical Pathology|volume=38|issue=4|pages=494–501|doi=10.1097/PAS.0000000000000147|issn=1532-0979|pmc=3955880|pmid=24625415}}</ref>. Patients with double-expressor lymphoma (DHL) or a ''MYC'' rearrangement (SHL) have shown inferior overall survival than those without them in this entity<ref name=":1" />. 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<ref name=":0" /><ref>{{Cite journal|last=Rosenwald|first=Andreas|last2=Bens|first2=Susanne|last3=Advani|first3=Ranjana|last4=Barrans|first4=Sharon|last5=Copie-Bergman|first5=Christiane|last6=Elsensohn|first6=Mad-Helenie|last7=Natkunam|first7=Yaso|last8=Calaminici|first8=Maria|last9=Sander|first9=Birgitta|date=2019-12-10|title=Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium|url=https://pubmed.ncbi.nlm.nih.gov/31498031|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=37|issue=35|pages=3359–3368|doi=10.1200/JCO.19.00743|issn=1527-7755|pmid=31498031}}</ref>.

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<ref name=":1" />.

==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)
<references />
===EXAMPLE Book===

#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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