Difference between revisions of "HAEM5:ALK-negative anaplastic large cell lymphoma"

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{{DISPLAYTITLE:ALK-negative anaplastic large cell lymphoma}}
 
{{DISPLAYTITLE:ALK-negative anaplastic large cell lymphoma}}
  
−
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
+
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
  
 
{{Under Construction}}
 
{{Under Construction}}
  
−
<blockquote class="blockedit">{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Anaplastic Large Cell Lymphoma, ALK-Negative]].
+
<blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Anaplastic Large Cell Lymphoma, ALK-Negative]].
 
}}</blockquote>
 
}}</blockquote>
  
−
<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>
+
<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 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>
  
 
==Primary Author(s)*==
 
==Primary Author(s)*==
Line 20: Line 20:
 
__TOC__
 
__TOC__
  
−
==Cancer Category / Type==
+
==WHO Classification of Disease==
  
−
*[[HAEM4:Mature T- and NK-cell Neoplasms]]
+
{| class="wikitable"
−
 
+
!Structure
−
==Cancer Sub-Classification / Subtype==
+
!Disease
−
 
+
|-
−
*Anaplastic Large Cell Lymphoma, ALK-Negative<ref name=":0" /><ref>{{Cite journal|last=Al|first=Feldman|last2=A|first2=Dogan|last3=Di|first3=Smith|last4=Me|first4=Law|last5=Sm|first5=Ansell|last6=Sh|first6=Johnson|last7=Jc|first7=Porcher|last8=N|first8=Ozsan|last9=Ed|first9=Wieben|date=2011|title=Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing|url=https://pubmed.ncbi.nlm.nih.gov/21030553/|language=en|doi=10.1182/blood-2010-08-303305|pmc=PMC3035081|pmid=21030553}}</ref>
+
|Book
 +
|Haematolymphoid Tumours (5th ed.)
 +
|-
 +
|Category
 +
|T-cell and NK-cell lymphoid proliferations and lymphomas
 +
|-
 +
|Family
 +
|Mature T-cell and NK-cell neoplasms
 +
|-
 +
|Type
 +
|Anaplastic large cell lymphoma
 +
|-
 +
|Subtype(s)
 +
|ALK-negative anaplastic large cell lymphoma
 +
|}
  
 
==Definition / Description of Disease==
 
==Definition / Description of Disease==
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==Clinical Features==
 
==Clinical Features==
  
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
+
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>
 
{| class="wikitable"
 
{| class="wikitable"
 
|'''Signs and Symptoms'''
 
|'''Signs and Symptoms'''
Line 60: Line 74:
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
−
|Not specific  
+
|Not specific
 
|}
 
|}
  
Line 158: Line 172:
 
|No
 
|No
 
|
 
|
−
* <nowiki>*</nowiki> These rearrangements are considered mutually exclusive; however, a single case with both ''DUSP22'' and ''TP63'' rearrangement has been described<ref name=":11" />. Can also be seen in a fraction of other PTCL.
+
*<nowiki>*</nowiki> These rearrangements are considered mutually exclusive; however, a single case with both ''DUSP22'' and ''TP63'' rearrangement has been described<ref name=":11" />. Can also be seen in a fraction of other PTCL.
−
* 5-year overall survival > 90%
+
*5-year overall survival > 90%
−
* '''Therapeutic Implications'''
+
*'''Therapeutic Implications'''
 
**Multi-agent chemotherapy (CHOEP or CHOP-based) as first-line, with or without radiotherapy of involved site
 
**Multi-agent chemotherapy (CHOEP or CHOP-based) as first-line, with or without radiotherapy of involved site
 
**High dose chemotherapy and autologous stem cell transplantation for remission
 
**High dose chemotherapy and autologous stem cell transplantation for remission
Line 176: Line 190:
 
|No
 
|No
 
|
 
|
−
* *See t(6;7) notes
+
*<nowiki>*See t(6;7) notes</nowiki>
−
* 5-year overall survival > 17%
+
*5-year overall survival 17%
 
|-
 
|-
 
|t(10;19)(q24;p13)
 
|t(10;19)(q24;p13)
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|No
 
|No
 
|
 
|
−
* 5-year overall survival 42% for cases lacking all DUSP22, TP63 and ALK rearrangements<ref name=":0" /><ref name=":15" />
+
*5-year overall survival 42% for cases lacking all DUSP22, TP63 and ALK rearrangements<ref name=":0" /><ref name=":15" />
 
|-
 
|-
 
|t(1;19)(p34;p13)
 
|t(1;19)(p34;p13)
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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.'') </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. Do not delete table.'') </span>
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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|No
 
|No
 
|No
 
|No
−
|Prevalence 30%
+
|
 +
*Prevalence 30%
 +
*Numerous genes affected
 
|-
 
|-
 +
|6p
 +
|Gain
 +
|25.3
 +
|
 +
|No
 +
|No
 +
|No
 +
|
 +
*Prevalence 30%
 +
*Gene affected: ''DUSP22''
 +
|-
 +
|8q
 +
|Gain
 +
|24.22
 +
|
 +
|No
 +
|No
 +
|No
 +
|
 +
*Prevalence 16-23%
 +
*Genes affected: NDRG1, ''PHF20L1, SLA, ST3GAL1, TG, WISP1''
 +
|-
 +
|1p
 +
|Loss
 +
|13.3-p12
 +
36.33-36.32
 +
|
 +
|No
 +
|No
 +
|No
 +
|
 +
*Prevalence 19-26%
 +
|-
 +
|'''6q'''
 +
|'''Loss > CN-LOH'''
 +
|21
 +
|
 +
|No
 +
|No
 +
|No
 +
|
 +
*Prevalence 35%
 +
*Genes affected: '''''PRDM1''', ATG5''
 +
|-
 +
|10p
 +
|Loss
 +
|11.23-p11.22
 +
|
 +
|No
 +
|No
 +
|No
 +
|
 +
*Prevalence 23%
 +
|-
 +
|13q
 +
|Loss
 +
|32.3-q33.3
 +
|
 +
|No
 +
|No
 +
|No
 +
|
 +
*Prevalence 23%
 +
*Genes affected: ''CDC16, CUL4A,FOXO1A, BRCA2, LHFP, LCP1''
 +
|-
 +
|16q
 +
|Loss
 +
|23.2
 
|
 
|
−
|EXAMPLE Gain
 
−
|EXAMPLE
 
−
 
−
chr8:1-145,138,636 [hg38]
 
−
|EXAMPLE
 
−
 
−
chr8
 
 
|No
 
|No
 
|No
 
|No
 
|No
 
|No
−
|EXAMPLE
+
|
−
 
+
*Prevalence 29%
−
Common recurrent secondary finding for t(8;21) (add reference).
+
*Genes affected: ''MAF, WWOX''
 +
|-
 +
|17p
 +
|Loss
 +
|'''13.3-p12'''
 +
|
 +
|No
 +
|Yes?**
 +
|No
 +
|
 +
*Prevalence: 42%
 +
*Gene affected: ''TP53''
 
|}
 
|}
  
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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'')</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. Do not delete table.'')</span>
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 382: Line 470:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
+
|N/A
−
 
+
|N/A
−
Co-deletion of 1p and 18q
+
|N/A
−
|Yes
+
|N/A
−
|No
+
|N/A
−
|No
 
−
|EXAMPLE:
 
−
 
 
−
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
 
|}
 
|}
  
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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 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>
+
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>
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 412: Line 496:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE: TP53; Variable LOF mutations
+
|''TP53''
 +
|TSG
 +
|23%<ref name=":6" />
 +
|No
 +
|N/A
 +
|No
 +
|Yes
 +
|No
 +
|<br />
 +
|-
 +
|''STAT3''
 +
|Oncogene
 +
|26%<ref name=":6" />
 +
|No
 +
|N/A
 +
|No
 +
|Yes
 +
|No
 +
|
 +
* Not seen in PTCL-NOS<ref name=":2" /> or ALK+ ALCL<ref name=":2" /><ref name=":6" />
  
−
EXAMPLE:
+
*Ruxolitinib may be used to target JAK-STAT pathway (not FDA-approved)<ref name=":13" />
−
 
+
|-
−
EGFR; Exon 20 mutations
+
|''JAK1''
−
 
+
|Oncogene
−
EXAMPLE: BRAF; Activating mutations
+
|26%<ref name=":6" />
−
|EXAMPLE: TSG
+
|No
−
|EXAMPLE: 20% (COSMIC)
+
|N/A
−
 
+
|No
−
EXAMPLE: 30% (add Reference)
+
|Yes
−
|EXAMPLE: IDH1 R123H
+
|No
−
|EXAMPLE: EGFR amplification
+
|
 +
* Not seen in PTCL-NOS<ref name=":2" /> or ALK+ ALCL<ref name=":2" /><ref name=":6" />
 +
|-
 +
|PRDM1/BLIMP1<ref name=":5" />
 +
|TSG
 +
|6%
 +
|No
 +
|N/A
 +
|No
 +
|No
 +
|No
 
|
 
|
 +
|-
 +
|[[NOTCH1]]<ref name=":16" />
 +
|Oncogene
 +
|15%
 +
|No
 +
|No
 +
|No
 +
|No
 +
|No
 
|
 
|
 +
|-
 +
|KMT2D<ref name=":6" />
 +
|TSG
 +
|20%
 +
|No
 +
|No
 +
|No
 +
|No
 +
|No
 
|
 
|
−
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
 
−
<br />
 
 
|}
 
|}
 
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.
 
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.
Line 456: Line 585:
 
|
 
|
 
|-
 
|-
−
|[[NOTCH1]]<ref>{{Cite journal|last=Larose|first=Hugo|last2=Prokoph|first2=Nina|last3=Matthews|first3=Jamie D.|last4=Schlederer|first4=Michaela|last5=Högler|first5=Sandra|last6=Alsulami|first6=Ali F.|last7=Ducray|first7=Stephen P.|last8=Nuglozeh|first8=Edem|last9=Fazaludeen|first9=Feroze M. S.|date=2020-04-23|title=Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target|url=https://haematologica.org/article/view/9725|journal=Haematologica|language=en|doi=10.3324/haematol.2019.238766|issn=1592-8721}}</ref>
+
|[[NOTCH1]]<ref name=":16">{{Cite journal|last=Larose|first=Hugo|last2=Prokoph|first2=Nina|last3=Matthews|first3=Jamie D.|last4=Schlederer|first4=Michaela|last5=Högler|first5=Sandra|last6=Alsulami|first6=Ali F.|last7=Ducray|first7=Stephen P.|last8=Nuglozeh|first8=Edem|last9=Fazaludeen|first9=Feroze M. S.|date=2020-04-23|title=Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target|url=https://haematologica.org/article/view/9725|journal=Haematologica|language=en|doi=10.3324/haematol.2019.238766|issn=1592-8721}}</ref>
 
|Activating
 
|Activating
 
|15%
 
|15%
Line 485: Line 614:
 
==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.'')</span>
+
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>
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
 
|-
−
|EXAMPLE: BRAF and MAP2K1; Activating mutations
+
|''STAT3''<ref name=":2" />
−
|EXAMPLE: MAPK signaling
+
|JAK-STAT pathway
−
|EXAMPLE: Increased cell growth and proliferation
+
|Increased cell growth and proliferation
 
|-
 
|-
−
|EXAMPLE: CDKN2A; Inactivating mutations
+
|''NFkB2-ROS1'' fusion<ref name=":2" />
−
|EXAMPLE: Cell cycle regulation
+
|JAK-STAT pathway
−
|EXAMPLE: Unregulated cell division
+
|Increased cell growth and proliferation
 
|-
 
|-
−
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
+
|''NFkB2-TYK2'' fusion<ref name=":2" />
−
|EXAMPLE:  Histone modification, chromatin remodeling
+
|JAK-STAT pathway
−
|EXAMPLE:  Abnormal gene expression program
+
|Increased cell growth and proliferation
 
|}
 
|}
  

Latest revision as of 17:38, 6 September 2024


Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Anaplastic Large Cell Lymphoma, ALK-Negative.

(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); to add (or move) a row or column to a table, click 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 Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

Primary Author(s)*

Miguel Gonzalez Mancera, MD

Sumire Kitahara, MD

Cedars-Sinai, Los Angeles, CA

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category T-cell and NK-cell lymphoid proliferations and lymphomas
Family Mature T-cell and NK-cell neoplasms
Type Anaplastic large cell lymphoma
Subtype(s) ALK-negative anaplastic large cell lymphoma

Definition / Description of Disease

  • Anaplastic large cell lymphomas (ALCL), ALK-negative, is a CD30+ T-cell lymphoma that is morphologically and immunophenotypically indistinguishable (but lacks ALK protein expression) from ALK(+) ALCL[1][2]
  • Three major molecular subtypes of ALK (-) ALCL[1][2]:
    • DUSP22-rearranged subtype (30%)
    • TP63-rearranged subtype (8%)
    • Triple-negative subtype (DUSP22 negative, TP63 negative, ALK negative)
    • Emerging subtypes:
      • ERBB4 expression (~25%): mutually exclusive with other rearrangements (TP63, DUSP22, ROS or TYK translocations)[3]

Synonyms / Terminology

  • N/A

Epidemiology / Prevalence

  • More common in adults than children (peak incidence 6th decade of life)[4]
  • Less than 3% of all Non-Hodgkin's lymphoma[4]
  • M:F 1.5:1[4]

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete table.)

Signs and Symptoms B-symptoms (weight loss, fever, night sweats)[4]

Peripheral and/or Lymphadenopathy[4]

Most patients present with advanced stage disease[4]

Laboratory Findings Not specific


editv4:Clinical Features
The content below was from the old template. Please incorporate above.
  • B symptoms of weight loss, fevers, chills[4]
  • Peripheral and/or abdominal lymphadenopathy[4]
  • Most patients present with advanced stage disease[4]

Sites of Involvement

  • Nodal (predominantly abdominal lymphadenopathy) in a sinusoidal pattern
  • Extranodal (skin, soft tissue, gastrointestinal, bone) in about 20% of cases
    • If involving the skin or GI tract, cases must be distinguished from primary cutaneous ALCL or CD30+ enteropathy-associated/other intestinal T-cell lymphomas, respectively

Morphologic Features

  • Tissue effacement by cohesive sheets of large, pleomorphic neoplastic cells, with or without prominent nucleoli, with varying proportions of hallmark cells
  • "Hallmark cells"
    • Lymphoma cells characterized by eccentric, horseshoe-shaped or kidney-shaped nuclei, often with eosinophilic cytoplasm accentuated near the nucleus
    • Usually large in size, but may also be smaller
    • Less common that in classic variant of ALK (+) ALCL
  • DUSP22-rearranged subtype tends to lack large pleomorphic cells and show smaller, monomorphic cells with central nuclear pseudoinclusions (doughnut cells)
  • Intrasinusoidal growth pattern seen in cases with preserved nodal architecture

Immunophenotype

Immunohistochemical patterns vary by subtype[4][5][6]


DUSP22-rearranged subtype

Finding Marker
Positive (universal) CD30*, CD43 (almost universally)
Negative (universal) ALK, TP63, EBER, LMP-1
Positive (frequent) CD2, CD3, CD4+ cases more common than CD8, CD5, Clusterin
Negative (frequent) TIAI, granzyme B, perforin, EMA, PAX5

*Strong and diffuse CD30 staining; should be equal intensity in all cells

TP63-rearranged subtype

Finding Marker
Positive (universal) CD30*, CD43 (almost universally), P63, CD4+ cases more common than CD8
Negative (universal) ALK, EBER, LMP-1
Positive (frequent) CD2, CD3, CD4, CD5, TIA1, granzyme B, perforin, clusterin
Negative (very frequent) EMA

Triple-negative subtype

Finding Marker
Positive (universal) CD30*, CD43 (almost universally), CD2, CD3, CD4+ cases more common than CD8, CD5, TIA1, granzyme B, perforin, EMA
Negative (universal) ALK, P63, EBER, LMP-1
Positive (common) EMA, clusterin
Negative (frequent) PAX5, CD20, CD79a, CD15

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
*t(6;7)(p25.3;q32.3) DUSP22/FRA7H[7] DUSP22/FRA7H fusion protein 30%[6] No Yes No
  • * These rearrangements are considered mutually exclusive; however, a single case with both DUSP22 and TP63 rearrangement has been described[8]. Can also be seen in a fraction of other PTCL.
  • 5-year overall survival > 90%
  • Therapeutic Implications
    • Multi-agent chemotherapy (CHOEP or CHOP-based) as first-line, with or without radiotherapy of involved site
    • High dose chemotherapy and autologous stem cell transplantation for remission
    • DUSP22 subtype may not gain additional benefit from autologous stem cell transplantation in first remission
    • Theoretical:
      • Ruxolitinib may be used to target JAK-STAT pathway[9][10] (not FDA-approved)
      • Bromodomain and extra-terminal proteins (BET) inhibitors may target ERBB4 pathway[10][11]
*t(3;3)(q22;q26.2), inv(3)(q26q28) TP63/TBL1XR1[12] TP63/TBL1XR1 fusion protein 8%[6] No Yes No
  • *See t(6;7) notes
  • 5-year overall survival 17%
t(10;19)(q24;p13) NFKB2/TYK2 NFKB2/TYK2 fusion protein rare[13] No No No
  • 5-year overall survival 42% for cases lacking all DUSP22, TP63 and ALK rearrangements[6][14]
t(1;19)(p34;p13) PABPC4/TYK2 PABPC4/TYK2 fusion protein rare[13] No No No
t(6;10)(q22;q24) NFKB2/ROS1 NFKB2/ROS1 fusion protein rare[13] No No No


editv4:Chromosomal Rearrangements (Gene Fusions)
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Chromosomal Rearrangement[15][16] Genes in Fusion (5’ or 3’ Segments) Prevalence
*t(6;7)(p25.3;q32.3) DUSP22/FRA7H[7] 30%[6]
*t(3;3)(q22;q26.2), inv(3)(q26q28) TP63/TBL1XR1[12] 8%[6]
t(10;19)(q24;p13) NFKB2/TYK2 rare[13]
t(1;19)(p34;p13) PABPC4/TYK2 rare[13]
t(6;10)(q22;q24) NFKB2/ROS1 rare[13]

* These rearrangements are considered mutually exclusive; however, a single case with both DUSP22 and TP63 rearrangement has been described[8]. Can also be seen in a fraction of other PTCL.


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)
  • Diagnosis
    • In general, ALK(-) ALCL has a worse prognosis when compared to ALK (+) ALCL[2]
    • ALK(-) ALCL has shown superior prognosis when compared to PTCL, NOS. The 5-year failure-free survival rate was 36% vs 20%, and overall survival rate was 49% vs 32%[17]
  • Prognosis
    • When compared to ALK(+) ALCL, ALK(-) ALCL has a generally poorer prognosis, however:
      • When stratified for age, prognosis between ALK(-) and ALK(+) ALCL appears similar [17][18]
    • 5-year overall survival > 90% for DUSP22-rearranged ALK(-) ALCL, 17% for TP63-rearranged ALK(-) ALCL, and 42% for cases lacking all DUSP22, TP63 and ALK rearrangements[6][14]
    • Patients with 6q21/PRDM1 and/or 17p loss showed an inferior outcome than patients with normal 6q21 and 17p; not clear if mainly due to TP53 deletion due to study size[19]
      • Often concomitant loss and seen in almost a quarter of cases
    • Mutations with significantly shorter OS compared to wild-type[20]
    • Prognostic significance of ERB4 and COL29A1 co-expressing subtypes unclear [3]
  • Therapeutic Implications
    • Multi-agent chemotherapy (CHOEP or CHOP-based) as first-line, with or without radiotherapy of involved site
    • High dose chemotherapy and autologous stem cell transplantation for remission
    • DUSP22 subtype may not gain additional benefit from autologous stem cell transplantation in first remission
    • Theoretical:
      • Ruxolitinib may be used to target JAK-STAT pathway[9][10] (not FDA-approved)
      • Bromodomain and extra-terminal proteins (BET) inhibitors may target ERBB4 pathway[10][11]

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. Do not delete table.)

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
1q Gain No No No
  • Prevalence 30%
  • Numerous genes affected
6p Gain 25.3 No No No
  • Prevalence 30%
  • Gene affected: DUSP22
8q Gain 24.22 No No No
  • Prevalence 16-23%
  • Genes affected: NDRG1, PHF20L1, SLA, ST3GAL1, TG, WISP1
1p Loss 13.3-p12

36.33-36.32

No No No
  • Prevalence 19-26%
6q Loss > CN-LOH 21 No No No
  • Prevalence 35%
  • Genes affected: PRDM1, ATG5
10p Loss 11.23-p11.22 No No No
  • Prevalence 23%
13q Loss 32.3-q33.3 No No No
  • Prevalence 23%
  • Genes affected: CDC16, CUL4A,FOXO1A, BRCA2, LHFP, LCP1
16q Loss 23.2 No No No
  • Prevalence 29%
  • Genes affected: MAF, WWOX
17p Loss 13.3-p12 No Yes?** No
  • Prevalence: 42%
  • Gene affected: TP53
editv4:Genomic Gain/Loss/LOH
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The pattern of genomic copy number changes and loss of heterozygosity have been described[19][21][22]:

  • In general, recurrent lesions are more common in ALK(-) than ALK(+) disease
  • 6q21 losses associated with 17p deletions seen in ~25% of cases of ALK(-) ALCL[19]
  • None are diagnostically helpful for the distinction between ALK(-) ALCL from other entities
Chromosome Number Gain/Loss/Amp/LOH Region Genes Prevalence
1q Gain numerous 30%
6p Gain 25.3 DUSP22 30%
8q Gain 24.22 NDRG1, PHF20L1, SLA, ST3GAL1, TG, WISP1 16-23%
1p Loss 13.3-p12

36.33-36.32

26%

19%

6q Loss > CN-LOH;

See also below for somatic mutations

21 PRDM1, ATG5 35%
10p Loss 11.23-p11.22 23%
13q Loss 32.3-q33.3 CDC16, CUL4A,FOXO1A, BRCA2, LHFP, LCP1 23%
16q Loss 23.2 MAF, WWOX 29%
17p Loss 13.3-p12 TP53 42%

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. Do not delete table.)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
N/A N/A N/A N/A N/A
editv4:Characteristic Chromosomal Aberrations / Patterns
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  • Gene expression profiling and comparative genomic hybridization studies have shown that ALK(+) and ALK(-) ALCL share restricted genomic signatures and/or preferential genomic aberrations[23][24][25]
  • Several genes are similarly expressed in ALK(+) and ALK(-) samples, suggesting a common ALCL signature, that permit differential diagnosis of ALCL from PTCL-NOS[26]
  • See other sections.

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 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.)

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
TP53 TSG 23%[20] No N/A No Yes No
STAT3 Oncogene 26%[20] No N/A No Yes No
  • Ruxolitinib may be used to target JAK-STAT pathway (not FDA-approved)[9]
JAK1 Oncogene 26%[20] No N/A No Yes No
PRDM1/BLIMP1[19] TSG 6% No N/A No No No
NOTCH1[27] Oncogene 15% No No No No No
KMT2D[20] TSG 20% No No No No No

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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Gene Presumed mechanism Frequency Notes
STAT3*[13][20] Activating 10-26% Not seen in PTCL-NOS[13] or ALK+ ALCL[13][20]
JAK1*[13][20] Activating 15-26% Not seen in PTCL-NOS[13] or ALK+ ALCL[13][20]
PRDM1/BLIMP1[19] Tumor suppressor 6% (2/31)
NOTCH1[27] Activating 15%
TP53[20] Tumor suppressor 23%
KMT2D[20] Tumor suppressor 20%

*Double mutated for JAK1+STAT3 in 7-11%[13][20]

Other mutations

  • Epigenetic modifier genes: TET2[13][20]
  • Uncommon: FAS, STIM2[13]; LRP1B (9%), EPHA5[20]

Epigenomic Alterations

  • See above mutations in epigenetic modifier genes

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
STAT3[13] JAK-STAT pathway Increased cell growth and proliferation
NFkB2-ROS1 fusion[13] JAK-STAT pathway Increased cell growth and proliferation
NFkB2-TYK2 fusion[13] JAK-STAT pathway Increased cell growth and proliferation
editv4:Genes and Main Pathways Involved
The content below was from the old template. Please incorporate above.
  • JAK-STAT[13]
    • STAT3 mutants are constitutively phosphorylated
    • JAK1 mutants lead to the constitutive phosphorylation of STAT and synergize with STAT3 mutants
    • When JAK/STAT3 mutations absent, NFkB2-ROS1 and NFkB2-TYK2 fusions may constitutively activate STAT pathway

Genetic Diagnostic Testing Methods

  • Morphologic and immunophenotypic characterization
    • Strong CD30 staining of equal intensity help distinguish from PTCL, NOS, classic Hodgkin lymphoma, diffuse large B-cell lymphoma, and monomorphic epitheliotropic intestinal T-cell lymphoma
    • Exclusion of ALK(+) ALCL cases by immunostain for ALK
    • P63 immunostain to identify TP63 rearranged. Immunophenotyping is not sensitive and is thus used as screening before FISH analysis. A ≥ 30% threshold yields 100% sensitivity[28]
  • Presence of STAT3 and/or JAK1 mutations seem to favor ALK(-) ALCL over PTCL-NOS[13]
  • FISH studies necessary to subtype:
    • DUSP22 (IRF4/DUSP22) break-apart probe
    • TP63 rearrangement
  • ERBB4(+) cases may be identified using digital droplet PCR or immunostaining for MMP9 (a protein highly correlated with ERBB4 expression)
    • Not routinely performed

Familial Forms

  • Not described

Additional Information

  • None

Links

  • See references.

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 Ad, Attygalle; et al. (2014). "Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward - report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology". doi:10.1111/his.12251. PMC 6364972. PMID 24128129.CS1 maint: PMC format (link)
  2. ↑ 2.0 2.1 2.2 Sh, Swerdlow; et al. (2016). "The 2016 revision of the World Health Organization classification of lymphoid neoplasms". doi:10.1182/blood-2016-01-643569. PMC 4874220. PMID 26980727.CS1 maint: PMC format (link)
  3. ↑ 3.0 3.1 I, Scarfò; et al. (2016). "Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts". PMID 26463425.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 G, Hapgood; et al. (2015). "The biology and management of systemic anaplastic large cell lymphoma". PMID 25869285.
  5. ↑ M, Herling; et al. (2004). "Absence of Epstein-Barr virus in anaplastic large cell lymphoma: a study of 64 cases classified according to World Health Organization criteria". PMID 15116326.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Er, Parrilla Castellar; et al. (2014). "ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes". doi:10.1182/blood-2014-04-571091. PMC 4148769. PMID 24894770.CS1 maint: PMC format (link)
  7. ↑ 7.0 7.1 Feldman, Andrew L.; et al. (2011-01-20). "Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing". Blood. 117 (3): 915–919. doi:10.1182/blood-2010-08-303305. ISSN 1528-0020. PMC 3035081. PMID 21030553.
  8. ↑ 8.0 8.1 K, Karube; et al. (2020). ""Double-hit" of DUSP22 and TP63 rearrangements in anaplastic large cell lymphoma, ALK-negative". PMID 32106310 Check |pmid= value (help).
  9. ↑ 9.0 9.1 9.2 R, Roskoski (2016). "Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases". PMID 27473820.
  10. ↑ 10.0 10.1 10.2 10.3 E, Mereu; et al. (2017). "The heterogeneous landscape of ALK negative ALCL". doi:10.18632/oncotarget.14503. PMC 5392347. PMID 28061468.CS1 maint: PMC format (link)
  11. ↑ 11.0 11.1 A, Chaidos; et al. (2015). "Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence". doi:10.1177/2040620715576662. PMC 4480520. PMID 26137204.CS1 maint: PMC format (link)
  12. ↑ 12.0 12.1 Vasmatzis, George; et al. (2012-09-13). "Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas". Blood. 120 (11): 2280–2289. doi:10.1182/blood-2012-03-419937. ISSN 1528-0020. PMC 5070713. PMID 22855598.
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 13.10 13.11 13.12 13.13 13.14 13.15 13.16 13.17 13.18 13.19 13.20 13.21 13.22 13.23 R, Crescenzo; et al. (2015). "Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma". doi:10.1016/j.ccell.2015.03.006. PMC 5898430. PMID 25873174.CS1 maint: PMC format (link)
  14. ↑ 14.0 14.1 Mb, Pedersen; et al. (2017). "DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study". doi:10.1182/blood-2016-12-755496. PMC 5533203. PMID 28522440.CS1 maint: PMC format (link)
  15. ↑ Pileri, Stefano (2011-05-01). "Faculty Opinions recommendation of Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing".
  16. ↑ Da, Wada; et al. (2011). "Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies". doi:10.1038/modpathol.2010.225. PMC 3122134. PMID 21169992.CS1 maint: PMC format (link)
  17. ↑ 17.0 17.1 Kj, Savage; et al. (2008). "ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project". PMID 18385450.
  18. ↑ D, Sibon; et al. (2012). "Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte trials". PMID 23045585.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 M, Boi; et al. (2013). "PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma". PMID 24004669.
  20. ↑ 20.00 20.01 20.02 20.03 20.04 20.05 20.06 20.07 20.08 20.09 20.10 20.11 20.12 20.13 20.14 20.15 Lobello, Cosimo; et al. (2020-11-27). "STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma". Leukemia: 1–6. doi:10.1038/s41375-020-01093-1. ISSN 1476-5551.
  21. ↑ G, Vasmatzis; et al. (2012). "Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas". doi:10.1182/blood-2012-03-419937. PMC 5070713. PMID 22855598.CS1 maint: PMC format (link)
  22. ↑ Y, Zeng; et al. (2016). "Genetics of anaplastic large cell lymphoma". doi:10.3109/10428194.2015.1064530. PMC 4732699. PMID 26104084.CS1 maint: PMC format (link)
  23. ↑ Thompson, Mary Ann; et al. (2005-05). "Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas". Human Pathology. 36 (5): 494–504. doi:10.1016/j.humpath.2005.03.004. ISSN 0046-8177. PMID 15948116. Check date values in: |date= (help)
  24. ↑ Piccaluga, Pier Paolo; et al. (2007-03). "Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets". The Journal of Clinical Investigation. 117 (3): 823–834. doi:10.1172/JCI26833. ISSN 0021-9738. PMC 1794115. PMID 17304354. Check date values in: |date= (help)
  25. ↑ Salaverria, Itziar; et al. (2008-03). "Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas". British Journal of Haematology. 140 (5): 516–526. doi:10.1111/j.1365-2141.2007.06924.x. ISSN 1365-2141. PMID 18275429. Check date values in: |date= (help)
  26. ↑ Piva, Roberto; et al. (2010-03-20). "Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 28 (9): 1583–1590. doi:10.1200/JCO.2008.20.9759. ISSN 1527-7755. PMID 20159827.
  27. ↑ 27.0 27.1 Larose, Hugo; et al. (2020-04-23). "Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target". Haematologica. doi:10.3324/haematol.2019.238766. ISSN 1592-8721.
  28. ↑ X, Wang; et al. (2017). "Expression of p63 protein in anaplastic large cell lymphoma: implications for genetic subtyping". doi:10.1016/j.humpath.2017.01.003. PMC 5518937. PMID 28153507.CS1 maint: PMC format (link)


Notes

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