Difference between revisions of "HAEM5:High-grade B-cell lymphoma, NOS"

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{{DISPLAYTITLE:High-grade B-cell lymphoma, NOS}}
 
{{DISPLAYTITLE:High-grade B-cell lymphoma, NOS}}
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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
  
 
{{Under Construction}}
 
{{Under Construction}}
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}}</blockquote>
 
}}</blockquote>
  
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<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click nearby within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
+
<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
  
 
==Primary Author(s)*==
 
==Primary Author(s)*==
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==Clinical Features==
 
==Clinical Features==
  
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Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
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Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
 
{| class="wikitable"
 
{| class="wikitable"
 
|'''Signs and Symptoms'''
 
|'''Signs and Symptoms'''
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|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
+
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
  
−
<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
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EXAMPLE B-symptoms (weight loss, fever, night sweats)
  
−
<span class="blue-text">EXAMPLE:</span> Fatigue
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EXAMPLE Fatigue
  
−
<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
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EXAMPLE Lymphadenopathy (uncommon)
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
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|<span class="blue-text">EXAMPLE:</span> Cytopenias
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|EXAMPLE Cytopenias
  
−
<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
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EXAMPLE Lymphocytosis (low level)
 
|}
 
|}
  
  
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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}
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<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The 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<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" />.
 
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" />.
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!Notes
 
!Notes
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
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|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
−
<span class="blue-text">EXAMPLE:</span> 30% (add reference)
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EXAMPLE 30% (add reference)
 
|Yes
 
|Yes
 
|No
 
|No
 
|Yes
 
|Yes
−
|<span class="blue-text">EXAMPLE:</span>
+
|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).
 
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).
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−
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}
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<blockquote class='blockedit'>{{Box-round|title=v4: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.
 
There are no recurrent chromosomal rearrangements associated with HGBL, NOS.
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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Please incorporate this section into the relevant tables found in:
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<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
 
* Chromosomal Rearrangements (Gene Fusions)
 
* Chromosomal Rearrangements (Gene Fusions)
 
* Individual Region Genomic Gain/Loss/LOH
 
* Individual Region Genomic Gain/Loss/LOH
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==Individual Region Genomic Gain / Loss / LOH==
 
==Individual Region Genomic Gain / Loss / LOH==
  
−
Put your text here and fill in the table <span style="color:#0070C0">(''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. Do not delete table.'') </span>
+
Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span>
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|EXAMPLE
  
 
7
 
7
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|<span class="blue-text">EXAMPLE:</span> Loss
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|EXAMPLE Loss
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|<span class="blue-text">EXAMPLE:</span>
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|EXAMPLE
  
 
chr7:1- 159,335,973 [hg38]
 
chr7:1- 159,335,973 [hg38]
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|<span class="blue-text">EXAMPLE:</span>
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|EXAMPLE
  
 
chr7
 
chr7
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|Yes
 
|Yes
 
|No
 
|No
−
|<span class="blue-text">EXAMPLE:</span>
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|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).
 
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).
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span>
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|EXAMPLE
  
 
8
 
8
−
|<span class="blue-text">EXAMPLE:</span> Gain
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|EXAMPLE Gain
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|<span class="blue-text">EXAMPLE:</span>
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|EXAMPLE
  
 
chr8:1-145,138,636 [hg38]
 
chr8:1-145,138,636 [hg38]
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|<span class="blue-text">EXAMPLE:</span>
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|EXAMPLE
  
 
chr8
 
chr8
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|No
 
|No
 
|No
 
|No
−
|<span class="blue-text">EXAMPLE:</span>
+
|EXAMPLE
  
 
Common recurrent secondary finding for t(8;21) (add reference).
 
Common recurrent secondary finding for t(8;21) (add reference).
 
|}
 
|}
  
−
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}
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<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The 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<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.  
 
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.  
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==Characteristic Chromosomal Patterns==
 
==Characteristic Chromosomal Patterns==
  
−
Put your text here <span style="color:#0070C0">(''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. Do not delete table.'')</span>
+
Put your text here <span style="color:#0070C0">(''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'')</span>
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span>
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|EXAMPLE
  
 
Co-deletion of 1p and 18q
 
Co-deletion of 1p and 18q
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|No
 
|No
 
|No
 
|No
−
|<span class="blue-text">EXAMPLE:</span>
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|EXAMPLE:
  
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
|}
 
|}
  
−
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}
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<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The 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<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" />.
 
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" />.
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==Gene Mutations (SNV / INDEL)==
 
==Gene Mutations (SNV / INDEL)==
  
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as 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. Do not delete table.'') </span>
+
Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations
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|EXAMPLE: TP53; Variable LOF mutations
  
−
<span class="blue-text">EXAMPLE:</span>
+
EXAMPLE:
  
 
EGFR; Exon 20 mutations
 
EGFR; Exon 20 mutations
  
−
<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
+
EXAMPLE: BRAF; Activating mutations
−
|<span class="blue-text">EXAMPLE:</span> TSG
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|EXAMPLE: TSG
−
|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
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|EXAMPLE: 20% (COSMIC)
  
−
<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
+
EXAMPLE: 30% (add Reference)
−
|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
+
|EXAMPLE: IDH1 R123H
−
|<span class="blue-text">EXAMPLE:</span> EGFR amplification
+
|EXAMPLE: EGFR amplification
 
|
 
|
 
|
 
|
 
|
 
|
−
|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
+
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
 
<br />
 
<br />
 
|}
 
|}
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−
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}
+
<blockquote class='blockedit'>{{Box-round|title=v4: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<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>.
 
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>.
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==Genes and Main Pathways Involved==
 
==Genes and Main Pathways Involved==
  
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
+
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
+
|EXAMPLE: BRAF and MAP2K1; Activating mutations
−
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
+
|EXAMPLE: MAPK signaling
−
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
+
|EXAMPLE: Increased cell growth and proliferation
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
+
|EXAMPLE: CDKN2A; Inactivating mutations
−
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
+
|EXAMPLE: Cell cycle regulation
−
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
+
|EXAMPLE: Unregulated cell division
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
+
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
−
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
+
|EXAMPLE:  Histone modification, chromatin remodeling
−
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
+
|EXAMPLE:  Abnormal gene expression program
 
|}
 
|}
  
−
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}
+
<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
  
 
''MYC''
 
''MYC''

Revision as of 19:19, 3 September 2024

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes
This 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).

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

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 Features
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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)

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)
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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/LOH
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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 / Patterns
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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)
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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 Involved
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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

MYC

BCL2

BCL6

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. ↑ 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. ↑ 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.
  10. ↑ 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)
  11. ↑ 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.
  12. ↑ 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. ↑ 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)
  14. ↑ 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 09/3/2024, https://ccga.io/index.php/HAEM5:High-grade_B-cell_lymphoma,_NOS.

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