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

From Compendium of Cancer Genome Aberrations
Jump to navigation Jump to search
[checked revision][pending revision]
 
(26 intermediate revisions by 3 users not shown)
Line 1: Line 1:
 
{{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 focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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 in a table, click nearby within the table and select the > symbol that appears. 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 16: Line 16:
  
 
Cedars-Sinai, Los Angeles, CA
 
Cedars-Sinai, Los Angeles, CA
 +
==WHO Classification of Disease==
  
__TOC__
 
 
==Cancer Category / Type==
 
 
*[[HAEM4:Mature T- and NK-cell Neoplasms]]
 
 
==Cancer Sub-Classification / Subtype==
 
 
*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>
 
 
==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 [[HAEM5:ALK-positive anaplastic large cell lymphoma|ALK(+) ALCL]]<ref name=":9">{{Cite journal|last=Ad|first=Attygalle|last2=J|first2=Cabeçadas|last3=P|first3=Gaulard|last4=Es|first4=Jaffe|last5=D|first5=de Jong|last6=Yh|first6=Ko|last7=J|first7=Said|last8=W|first8=Klapper|date=2014|title=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|url=https://pubmed.ncbi.nlm.nih.gov/24128129/|language=en|doi=10.1111/his.12251|pmc=PMC6364972|pmid=24128129}}</ref><ref name=":7">{{Cite journal|last=Sh|first=Swerdlow|last2=E|first2=Campo|last3=Sa|first3=Pileri|last4=Nl|first4=Harris|last5=H|first5=Stein|last6=R|first6=Siebert|last7=R|first7=Advani|last8=M|first8=Ghielmini|last9=Ga|first9=Salles|date=2016|title=The 2016 revision of the World Health Organization classification of lymphoid neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/26980727/|language=en|doi=10.1182/blood-2016-01-643569|pmc=PMC4874220|pmid=26980727}}</ref>
 
*Three major molecular subtypes of ALK (-) ALCL<ref name=":9" /><ref name=":7" />:
 
**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)<ref name=":4" />
 
 
==Synonyms / Terminology==
 
 
*N/A
 
 
==Epidemiology / Prevalence==
 
 
*More common in adults than children (peak incidence 6th decade of life)<ref name=":1">{{Cite journal|last=G|first=Hapgood|last2=Kj|first2=Savage|date=2015|title=The biology and management of systemic anaplastic large cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/25869285/|language=en|pmid=25869285}}</ref>
 
*Less than 3% of all Non-Hodgkin's lymphoma<ref name=":1" />
 
*M:F 1.5:1<ref name=":1" />
 
 
==Clinical Features==
 
 
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'''
+
!Structure
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
+
!Disease
 
 
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
 
 
EXAMPLE Fatigue
 
 
 
EXAMPLE Lymphadenopathy (uncommon)
 
|-
 
|'''Laboratory Findings'''
 
|EXAMPLE Cytopenias
 
 
 
EXAMPLE Lymphocytosis (low level)
 
|}
 
 
 
 
 
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
 
 
 
*B symptoms of weight loss, fevers, chills<ref name=":1" />
 
*Peripheral and/or abdominal lymphadenopathy<ref name=":1" />
 
*Most patients present with advanced stage disease<ref name=":1" />
 
 
 
</blockquote>
 
==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<ref name=":1" /><ref>{{Cite journal|last=M|first=Herling|last2=Gz|first2=Rassidakis|last3=D|first3=Jones|last4=A|first4=Schmitt-Graeff|last5=Ah|first5=Sarris|last6=Lj|first6=Medeiros|date=2004|title=Absence of Epstein-Barr virus in anaplastic large cell lymphoma: a study of 64 cases classified according to World Health Organization criteria|url=https://pubmed.ncbi.nlm.nih.gov/15116326/|language=en|pmid=15116326}}</ref><ref name=":0" />
 
 
 
 
 
'''DUSP22-rearranged subtype'''
 
 
 
{| class="wikitable sortable"
 
 
|-
 
|-
!Finding!!Marker
+
|Book
 +
|Haematolymphoid Tumours (5th ed.)
 
|-
 
|-
|Positive (universal)||CD30*, CD43 (almost universally)
+
|Category
 +
|T-cell and NK-cell lymphoid proliferations and lymphomas
 
|-
 
|-
|Negative (universal)||'''ALK''', '''TP63''', EBER, LMP-1
+
|Family
 +
|Mature T-cell and NK-cell neoplasms
 
|-
 
|-
|Positive (frequent)
+
|Type
|CD2, CD3, CD4+ cases more common than CD8, CD5, Clusterin
+
|Anaplastic large cell lymphoma
 
|-
 
|-
|Negative (frequent)
+
|Subtype(s)
|TIAI, granzyme B, perforin, EMA, PAX5
+
|ALK-negative anaplastic large cell lymphoma
 
|}
 
|}
<nowiki>*</nowiki>Strong and diffuse CD30 staining; should be equal intensity in all cells
 
  
'''TP63-rearranged subtype'''  
+
==WHO Essential and Desirable Genetic Diagnostic Criteria==
 
+
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable sortable"
+
{| class="wikitable"
 +
|+
 +
|WHO Essential Criteria (Genetics)*
 +
|
 
|-
 
|-
!Finding!!Marker
+
|WHO Desirable Criteria (Genetics)*
 +
|
 
|-
 
|-
|Positive (universal)||CD30*, CD43 (almost universally), '''P63''', CD4+ cases more common than CD8
+
|Other Classification
 +
|
 +
|}
 +
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
 +
==Related Terminology==
 +
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
 +
{| class="wikitable"
 +
|+
 +
|Acceptable
 +
|
 
|-
 
|-
|Negative (universal)||'''ALK''', EBER, LMP-1
+
|Not Recommended
|-
+
|
|Positive (frequent)
 
|CD2, CD3, CD4, CD5, TIA1, granzyme B, perforin, clusterin
 
|-
 
|Negative (very frequent)
 
|EMA
 
 
|}
 
|}
 
'''Triple-negative subtype''' 
 
  
 +
==Gene Rearrangements==
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
!Finding!!Marker
+
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
 +
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
 +
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
 +
!Established Clinical Significance Per Guidelines - Yes or No (Source)
 +
!Clinical Relevance Details/Other Notes
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
 +
|<span class="blue-text">EXAMPLE:</span> Common (CML)
 +
|<span class="blue-text">EXAMPLE:</span> D, P, T
 +
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
 +
|<span class="blue-text">EXAMPLE:</span>
 +
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). BCR::ABL1 is generally favorable in CML (add reference).
 
|-
 
|-
|Positive (universal)||CD30*, CD43 (almost universally), CD2, CD3, CD4+ cases more common than CD8, CD5, TIA1, granzyme B, perforin, EMA
+
|<span class="blue-text">EXAMPLE:</span> ''CIC''
 +
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
 +
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
 +
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
 +
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
 +
|<span class="blue-text">EXAMPLE:</span> D
 +
|
 +
|<span class="blue-text">EXAMPLE:</span>
 +
 
 +
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
 
|-
 
|-
|Negative (universal)||'''ALK''', '''P63''', EBER, LMP-1
+
|<span class="blue-text">EXAMPLE:</span> ''ALK''
 +
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
 +
 
 +
 
 +
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
 +
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
 +
|<span class="blue-text">EXAMPLE:</span> N/A
 +
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
 +
|<span class="blue-text">EXAMPLE:</span> T
 +
|
 +
|<span class="blue-text">EXAMPLE:</span>
 +
 
 +
Both balanced and unbalanced forms are observed by FISH (add references).
 
|-
 
|-
|Positive (common)
+
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|EMA, clusterin
+
|<span class="blue-text">EXAMPLE:</span> N/A
 +
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
 +
|<span class="blue-text">EXAMPLE:</span> N/A
 +
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
 +
|<span class="blue-text">EXAMPLE:</span> D, P, T
 +
|
 +
|
 
|-
 
|-
|Negative (frequent)||PAX5, CD20, CD79a, CD15
+
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 
|}
 
|}
==Chromosomal Rearrangements (Gene Fusions)==
 
 
Put your text here and fill in the table
 
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 156: Line 131:
 
!Notes
 
!Notes
 
|-
 
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
+
|*t(6;7)(p25.3;q32.3)||DUSP22/FRA7H<ref name=":10" />||DUSP22/FRA7H fusion protein||30%<ref name=":0" />
EXAMPLE 30% (add reference)
+
|No
 
|Yes
 
|Yes
 +
|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.
 +
*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<ref name=":13" /><ref name=":3" /> (not FDA-approved)
 +
***Bromodomain and extra-terminal proteins (BET) inhibitors may target ERBB4 pathway<ref name=":3" /><ref name=":14" />
 +
|-
 +
|*t(3;3)(q22;q26.2), inv(3)(q26q28)
 +
|TP63/TBL1XR1<ref name=":12" />
 +
|TP63/TBL1XR1 fusion protein
 +
|8%<ref name=":0" />
 
|No
 
|No
 
|Yes
 
|Yes
|EXAMPLE
+
|No
 
+
|
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).
+
*<nowiki>*See t(6;7) notes</nowiki>
 +
*5-year overall survival 17%
 +
|-
 +
|t(10;19)(q24;p13)
 +
|NFKB2/TYK2
 +
|NFKB2/TYK2 fusion protein
 +
|rare<ref name=":2" />
 +
|No
 +
|No
 +
|No
 +
|
 +
*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)
 +
|PABPC4/TYK2
 +
|PABPC4/TYK2 fusion protein
 +
|rare<ref name=":2" />
 +
|No
 +
|No
 +
|No
 +
|
 +
|-
 +
|t(6;10)(q22;q24)
 +
|NFKB2/ROS1
 +
|NFKB2/ROS1 fusion protein
 +
|rare<ref name=":2" />
 +
|No
 +
|No
 +
|No
 +
|
 
|}
 
|}
 
 
  
<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}
+
<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 173: Line 193:
 
!Chromosomal Rearrangement<ref>{{Cite journal|last=Pileri|first=Stefano|date=2011-05-01|title=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.|url=http://dx.doi.org/10.3410/f.10182958.10970056}}</ref><ref>{{Cite journal|last=Da|first=Wada|last2=Me|first2=Law|last3=Ed|first3=Hsi|last4=Dj|first4=Dicaudo|last5=L|first5=Ma|last6=Ms|first6=Lim|last7=Ad|first7=Souza|last8=Ni|first8=Comfere|last9=Rh|first9=Weenig|date=2011|title=Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies|url=https://pubmed.ncbi.nlm.nih.gov/21169992/|language=en|doi=10.1038/modpathol.2010.225|pmc=PMC3122134|pmid=21169992}}</ref>!!Genes in Fusion (5’ or 3’ Segments)!!Prevalence
 
!Chromosomal Rearrangement<ref>{{Cite journal|last=Pileri|first=Stefano|date=2011-05-01|title=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.|url=http://dx.doi.org/10.3410/f.10182958.10970056}}</ref><ref>{{Cite journal|last=Da|first=Wada|last2=Me|first2=Law|last3=Ed|first3=Hsi|last4=Dj|first4=Dicaudo|last5=L|first5=Ma|last6=Ms|first6=Lim|last7=Ad|first7=Souza|last8=Ni|first8=Comfere|last9=Rh|first9=Weenig|date=2011|title=Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies|url=https://pubmed.ncbi.nlm.nih.gov/21169992/|language=en|doi=10.1038/modpathol.2010.225|pmc=PMC3122134|pmid=21169992}}</ref>!!Genes in Fusion (5’ or 3’ Segments)!!Prevalence
 
|-
 
|-
|*t(6;7)(p25.3;q32.3)||DUSP22/FRA7H<ref>{{Cite journal|last=Feldman|first=Andrew L.|last2=Dogan|first2=Ahmet|last3=Smith|first3=David I.|last4=Law|first4=Mark E.|last5=Ansell|first5=Stephen M.|last6=Johnson|first6=Sarah H.|last7=Porcher|first7=Julie C.|last8=Ozsan|first8=Nazan|last9=Wieben|first9=Eric D.|date=2011-01-20|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|journal=Blood|volume=117|issue=3|pages=915–919|doi=10.1182/blood-2010-08-303305|issn=1528-0020|pmc=3035081|pmid=21030553}}</ref>||30%<ref name=":0">{{Cite journal|last=Er|first=Parrilla Castellar|last2=Es|first2=Jaffe|last3=Jw|first3=Said|last4=Sh|first4=Swerdlow|last5=Rp|first5=Ketterling|last6=Ra|first6=Knudson|last7=Js|first7=Sidhu|last8=Ed|first8=Hsi|last9=S|first9=Karikehalli|date=2014|title=ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes|url=https://pubmed.ncbi.nlm.nih.gov/24894770/|language=en|doi=10.1182/blood-2014-04-571091|pmc=PMC4148769|pmid=24894770}}</ref>
+
|*t(6;7)(p25.3;q32.3)||DUSP22/FRA7H<ref name=":10">{{Cite journal|last=Feldman|first=Andrew L.|last2=Dogan|first2=Ahmet|last3=Smith|first3=David I.|last4=Law|first4=Mark E.|last5=Ansell|first5=Stephen M.|last6=Johnson|first6=Sarah H.|last7=Porcher|first7=Julie C.|last8=Ozsan|first8=Nazan|last9=Wieben|first9=Eric D.|date=2011-01-20|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|journal=Blood|volume=117|issue=3|pages=915–919|doi=10.1182/blood-2010-08-303305|issn=1528-0020|pmc=3035081|pmid=21030553}}</ref>||30%<ref name=":0">{{Cite journal|last=Er|first=Parrilla Castellar|last2=Es|first2=Jaffe|last3=Jw|first3=Said|last4=Sh|first4=Swerdlow|last5=Rp|first5=Ketterling|last6=Ra|first6=Knudson|last7=Js|first7=Sidhu|last8=Ed|first8=Hsi|last9=S|first9=Karikehalli|date=2014|title=ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes|url=https://pubmed.ncbi.nlm.nih.gov/24894770/|language=en|doi=10.1182/blood-2014-04-571091|pmc=PMC4148769|pmid=24894770}}</ref>
 
|-
 
|-
|*t(3;3)(q22;q26.2), inv(3)(q26q28)||TP63/TBL1XR1<ref>{{Cite journal|last=Vasmatzis|first=George|last2=Johnson|first2=Sarah H.|last3=Knudson|first3=Ryan A.|last4=Ketterling|first4=Rhett P.|last5=Braggio|first5=Esteban|last6=Fonseca|first6=Rafael|last7=Viswanatha|first7=David S.|last8=Law|first8=Mark E.|last9=Kip|first9=N. Sertac|date=2012-09-13|title=Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/22855598|journal=Blood|volume=120|issue=11|pages=2280–2289|doi=10.1182/blood-2012-03-419937|issn=1528-0020|pmc=5070713|pmid=22855598}}</ref>||8%<ref name=":0" />
+
|*t(3;3)(q22;q26.2), inv(3)(q26q28)||TP63/TBL1XR1<ref name=":12">{{Cite journal|last=Vasmatzis|first=George|last2=Johnson|first2=Sarah H.|last3=Knudson|first3=Ryan A.|last4=Ketterling|first4=Rhett P.|last5=Braggio|first5=Esteban|last6=Fonseca|first6=Rafael|last7=Viswanatha|first7=David S.|last8=Law|first8=Mark E.|last9=Kip|first9=N. Sertac|date=2012-09-13|title=Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/22855598|journal=Blood|volume=120|issue=11|pages=2280–2289|doi=10.1182/blood-2012-03-419937|issn=1528-0020|pmc=5070713|pmid=22855598}}</ref>||8%<ref name=":0" />
 
|-
 
|-
 
|t(10;19)(q24;p13)
 
|t(10;19)(q24;p13)
Line 189: Line 209:
 
|rare<ref name=":2" />
 
|rare<ref name=":2" />
 
|}
 
|}
<nowiki>*</nowiki> These rearrangements are considered mutually exclusive; however, a single case with both ''DUSP22'' and ''TP63'' rearrangement has been described<ref>{{Cite journal|last=K|first=Karube|last2=Al|first2=Feldman|date=2020|title="Double-hit" of DUSP22 and TP63 rearrangements in anaplastic large cell lymphoma, ALK-negative|url=https://pubmed.ncbi.nlm.nih.gov/32106310/|language=en|pmid=32106310}}</ref>. 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">{{Cite journal|last=K|first=Karube|last2=Al|first2=Feldman|date=2020|title="Double-hit" of DUSP22 and TP63 rearrangements in anaplastic large cell lymphoma, ALK-negative|url=https://pubmed.ncbi.nlm.nih.gov/32106310/|language=en|pmid=32106310}}</ref>. Can also be seen in a fraction of other PTCL.
  
 +
<blockquote class="blockedit">
 +
<center><span style="color:Maroon">'''End of V4 Section'''</span>
 +
----
 
</blockquote>
 
</blockquote>
  
  
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
+
<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
 
* Characteristic Chromosomal Patterns
 
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
+
* Gene Mutations (SNV/INDEL)}}</blockquote>
  
 
*'''Diagnosis'''  
 
*'''Diagnosis'''  
**In general, ALK(-) ALCL has a worse prognosis when compared to ALK (+) ALCL<ref name=":7" />
+
**In general, ALK(-) ALCL has a worse prognosis when compared to ALK (+) ALCL<ref name=":7">{{Cite journal|last=Sh|first=Swerdlow|last2=E|first2=Campo|last3=Sa|first3=Pileri|last4=Nl|first4=Harris|last5=H|first5=Stein|last6=R|first6=Siebert|last7=R|first7=Advani|last8=M|first8=Ghielmini|last9=Ga|first9=Salles|date=2016|title=The 2016 revision of the World Health Organization classification of lymphoid neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/26980727/|language=en|doi=10.1182/blood-2016-01-643569|pmc=PMC4874220|pmid=26980727}}</ref>
 
**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%<ref name=":8" />
 
**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%<ref name=":8" />
  
Line 207: Line 230:
 
**When compared to ALK(+) ALCL, ALK(-) ALCL has a generally poorer prognosis, however:
 
**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 <ref name=":8">{{Cite journal|last=Kj|first=Savage|last2=Nl|first2=Harris|last3=Jm|first3=Vose|last4=F|first4=Ullrich|last5=Es|first5=Jaffe|last6=Jm|first6=Connors|last7=L|first7=Rimsza|last8=Sa|first8=Pileri|last9=M|first9=Chhanabhai|date=2008|title=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|url=https://pubmed.ncbi.nlm.nih.gov/18385450/|language=en|pmid=18385450}}</ref><ref>{{Cite journal|last=D|first=Sibon|last2=M|first2=Fournier|last3=J|first3=Brière|last4=L|first4=Lamant|last5=C|first5=Haioun|last6=B|first6=Coiffier|last7=S|first7=Bologna|last8=P|first8=Morel|last9=J|first9=Gabarre|date=2012|title=Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte trials|url=https://pubmed.ncbi.nlm.nih.gov/23045585/|language=en|pmid=23045585}}</ref>
 
***When stratified for age, prognosis between ALK(-) and ALK(+) ALCL appears similar <ref name=":8">{{Cite journal|last=Kj|first=Savage|last2=Nl|first2=Harris|last3=Jm|first3=Vose|last4=F|first4=Ullrich|last5=Es|first5=Jaffe|last6=Jm|first6=Connors|last7=L|first7=Rimsza|last8=Sa|first8=Pileri|last9=M|first9=Chhanabhai|date=2008|title=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|url=https://pubmed.ncbi.nlm.nih.gov/18385450/|language=en|pmid=18385450}}</ref><ref>{{Cite journal|last=D|first=Sibon|last2=M|first2=Fournier|last3=J|first3=Brière|last4=L|first4=Lamant|last5=C|first5=Haioun|last6=B|first6=Coiffier|last7=S|first7=Bologna|last8=P|first8=Morel|last9=J|first9=Gabarre|date=2012|title=Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte trials|url=https://pubmed.ncbi.nlm.nih.gov/23045585/|language=en|pmid=23045585}}</ref>
**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<ref name=":0" /><ref>{{Cite journal|last=Mb|first=Pedersen|last2=Sj|first2=Hamilton-Dutoit|last3=K|first3=Bendix|last4=Rp|first4=Ketterling|last5=Pp|first5=Bedroske|last6=Im|first6=Luoma|last7=Ca|first7=Sattler|last8=Rl|first8=Boddicker|last9=Nn|first9=Bennani|date=2017|title=DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study|url=https://pubmed.ncbi.nlm.nih.gov/28522440/|language=en|doi=10.1182/blood-2016-12-755496|pmc=PMC5533203|pmid=28522440}}</ref>
+
**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<ref name=":0" /><ref name=":15">{{Cite journal|last=Mb|first=Pedersen|last2=Sj|first2=Hamilton-Dutoit|last3=K|first3=Bendix|last4=Rp|first4=Ketterling|last5=Pp|first5=Bedroske|last6=Im|first6=Luoma|last7=Ca|first7=Sattler|last8=Rl|first8=Boddicker|last9=Nn|first9=Bennani|date=2017|title=DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study|url=https://pubmed.ncbi.nlm.nih.gov/28522440/|language=en|doi=10.1182/blood-2016-12-755496|pmc=PMC5533203|pmid=28522440}}</ref>
 
**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<ref name=":5" />
 
**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<ref name=":5" />
 
***Often concomitant loss and seen in almost a quarter of cases
 
***Often concomitant loss and seen in almost a quarter of cases
Line 219: Line 242:
 
**DUSP22 subtype may not gain additional benefit from autologous stem cell transplantation in first remission
 
**DUSP22 subtype may not gain additional benefit from autologous stem cell transplantation in first remission
 
**Theoretical:
 
**Theoretical:
***Ruxolitinib may be used to target JAK-STAT pathway<ref>{{Cite journal|last=R|first=Roskoski|date=2016|title=Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases|url=https://pubmed.ncbi.nlm.nih.gov/27473820/|language=en|pmid=27473820}}</ref><ref name=":3">{{Cite journal|last=E|first=Mereu|last2=E|first2=Pellegrino|last3=I|first3=Scarfò|last4=G|first4=Inghirami|last5=R|first5=Piva|date=2017|title=The heterogeneous landscape of ALK negative ALCL|url=https://pubmed.ncbi.nlm.nih.gov/28061468/|language=en|doi=10.18632/oncotarget.14503|pmc=PMC5392347|pmid=28061468}}</ref> (not FDA-approved)
+
***Ruxolitinib may be used to target JAK-STAT pathway<ref name=":13">{{Cite journal|last=R|first=Roskoski|date=2016|title=Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases|url=https://pubmed.ncbi.nlm.nih.gov/27473820/|language=en|pmid=27473820}}</ref><ref name=":3">{{Cite journal|last=E|first=Mereu|last2=E|first2=Pellegrino|last3=I|first3=Scarfò|last4=G|first4=Inghirami|last5=R|first5=Piva|date=2017|title=The heterogeneous landscape of ALK negative ALCL|url=https://pubmed.ncbi.nlm.nih.gov/28061468/|language=en|doi=10.18632/oncotarget.14503|pmc=PMC5392347|pmid=28061468}}</ref> (not FDA-approved)
***Bromodomain and extra-terminal proteins (BET) inhibitors may target ERBB4 pathway<ref name=":3" /><ref>{{Cite journal|last=A|first=Chaidos|last2=V|first2=Caputo|last3=A|first3=Karadimitris|date=2015|title=Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence|url=https://pubmed.ncbi.nlm.nih.gov/26137204/|language=en|doi=10.1177/2040620715576662|pmc=PMC4480520|pmid=26137204}}</ref>
+
***Bromodomain and extra-terminal proteins (BET) inhibitors may target ERBB4 pathway<ref name=":3" /><ref name=":14">{{Cite journal|last=A|first=Chaidos|last2=V|first2=Caputo|last3=A|first3=Karadimitris|date=2015|title=Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence|url=https://pubmed.ncbi.nlm.nih.gov/26137204/|language=en|doi=10.1177/2040620715576662|pmc=PMC4480520|pmid=26137204}}</ref>
  
 +
<blockquote class="blockedit">
 +
<center><span style="color:Maroon">'''End of V4 Section'''</span>
 +
----
 
</blockquote>
 
</blockquote>
==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>
+
==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 rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
 +
{| class="wikitable sortable"
 +
|-
 +
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
 +
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
 +
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
 +
!'''Clinical Relevance Details/Other Notes'''
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>
 +
7
 +
|<span class="blue-text">EXAMPLE:</span> Loss
 +
|<span class="blue-text">EXAMPLE:</span>
 +
chr7
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Unknown
 +
|<span class="blue-text">EXAMPLE:</span> D, P
 +
|<span class="blue-text">EXAMPLE:</span> No
 +
|<span class="blue-text">EXAMPLE:</span>
 +
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 references).
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>
 +
8
 +
|<span class="blue-text">EXAMPLE:</span> Gain
 +
|<span class="blue-text">EXAMPLE:</span>
 +
chr8
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Unknown
 +
|<span class="blue-text">EXAMPLE:</span> D, P
 +
|
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Common recurrent secondary finding for t(8;21) (add references).
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>
 +
17
 +
|<span class="blue-text">EXAMPLE:</span> Amp
 +
|<span class="blue-text">EXAMPLE:</span>
 +
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
 +
|<span class="blue-text">EXAMPLE:</span>
 +
''ERBB2''
 +
|<span class="blue-text">EXAMPLE:</span> D, P, T
 +
|
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
 +
|-
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|}
 +
 
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 235: Line 313:
 
!Notes
 
!Notes
 
|-
 
|-
|EXAMPLE
+
|1q
 
+
|Gain
7
+
|
|EXAMPLE Loss
+
|
|EXAMPLE
+
|No
 
+
|No
chr7:1- 159,335,973 [hg38]
+
|No
|EXAMPLE
+
|
 
+
*Prevalence 30%
chr7
+
*Numerous genes affected
|Yes
+
|-
|Yes
+
|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
 
|No
|EXAMPLE
+
|
 
+
*Prevalence 23%
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).
+
*Genes affected: ''CDC16, CUL4A,FOXO1A, BRCA2, LHFP, LCP1''
 
|-
 
|-
|EXAMPLE
+
|16q
 
+
|Loss
8
+
|23.2
|EXAMPLE Gain
+
|
|EXAMPLE
+
|No
 
+
|No
chr8:1-145,138,636 [hg38]
 
|EXAMPLE
 
 
 
chr8
 
 
|No
 
|No
 +
|
 +
*Prevalence 29%
 +
*Genes affected: ''MAF, WWOX''
 +
|-
 +
|17p
 +
|Loss
 +
|'''13.3-p12'''
 +
|
 
|No
 
|No
 +
|Yes?**
 
|No
 
|No
|EXAMPLE
+
|
 
+
*Prevalence: 42%
Common recurrent secondary finding for t(8;21) (add reference).
+
*Gene affected: ''TP53''
 
|}
 
|}
  
<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
+
<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
 
The pattern of genomic copy number changes and loss of heterozygosity have been described<ref name=":5">{{Cite journal|last=M|first=Boi|last2=A|first2=Rinaldi|last3=I|first3=Kwee|last4=P|first4=Bonetti|last5=M|first5=Todaro|last6=F|first6=Tabbò|last7=R|first7=Piva|last8=Pm|first8=Rancoita|last9=A|first9=Matolcsy|date=2013|title=PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/24004669/|language=en|pmid=24004669}}</ref><ref>{{Cite journal|last=G|first=Vasmatzis|last2=Sh|first2=Johnson|last3=Ra|first3=Knudson|last4=Rp|first4=Ketterling|last5=E|first5=Braggio|last6=R|first6=Fonseca|last7=Ds|first7=Viswanatha|last8=Me|first8=Law|last9=Ns|first9=Kip|date=2012|title=Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/22855598/|language=en|doi=10.1182/blood-2012-03-419937|pmc=PMC5070713|pmid=22855598}}</ref><ref>{{Cite journal|last=Y|first=Zeng|last2=Al|first2=Feldman|date=2016|title=Genetics of anaplastic large cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/26104084/|language=en|doi=10.3109/10428194.2015.1064530|pmc=PMC4732699|pmid=26104084}}</ref>:
 
The pattern of genomic copy number changes and loss of heterozygosity have been described<ref name=":5">{{Cite journal|last=M|first=Boi|last2=A|first2=Rinaldi|last3=I|first3=Kwee|last4=P|first4=Bonetti|last5=M|first5=Todaro|last6=F|first6=Tabbò|last7=R|first7=Piva|last8=Pm|first8=Rancoita|last9=A|first9=Matolcsy|date=2013|title=PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/24004669/|language=en|pmid=24004669}}</ref><ref>{{Cite journal|last=G|first=Vasmatzis|last2=Sh|first2=Johnson|last3=Ra|first3=Knudson|last4=Rp|first4=Ketterling|last5=E|first5=Braggio|last6=R|first6=Fonseca|last7=Ds|first7=Viswanatha|last8=Me|first8=Law|last9=Ns|first9=Kip|date=2012|title=Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/22855598/|language=en|doi=10.1182/blood-2012-03-419937|pmc=PMC5070713|pmid=22855598}}</ref><ref>{{Cite journal|last=Y|first=Zeng|last2=Al|first2=Feldman|date=2016|title=Genetics of anaplastic large cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/26104084/|language=en|doi=10.3109/10428194.2015.1064530|pmc=PMC4732699|pmid=26104084}}</ref>:
  
Line 337: Line 479:
 
|}
 
|}
  
 +
<blockquote class="blockedit">
 +
<center><span style="color:Maroon">'''End of V4 Section'''</span>
 +
----
 
</blockquote>
 
</blockquote>
==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>
 
  
 +
==Characteristic Chromosomal or Other Global Mutational Patterns==
 +
Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Chromosomal Pattern
 
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
+
!Molecular Pathogenesis
!Prognostic Significance (Yes, No or Unknown)
+
!'''Prevalence -'''
!Therapeutic Significance (Yes, No or Unknown)
+
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
!Notes
+
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
 +
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
 +
!'''Clinical Relevance Details/Other Notes'''
 
|-
 
|-
|EXAMPLE
+
|<span class="blue-text">EXAMPLE:</span>
 
 
 
Co-deletion of 1p and 18q
 
Co-deletion of 1p and 18q
|Yes
+
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|No
+
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|No
+
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE:
+
|
 
+
|
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
+
|-
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Microsatellite instability - hypermutated
 +
|
 +
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
 +
|<span class="blue-text">EXAMPLE:</span> P, T
 +
|
 +
|
 +
|-
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 
|}
 
|}
 
+
<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}
 
  
 
*Gene expression profiling and comparative genomic hybridization studies have shown that ALK(+) and ALK(-) ALCL share restricted genomic signatures and/or preferential genomic aberrations<ref>{{Cite journal|last=Thompson|first=Mary Ann|last2=Stumph|first2=Jennifer|last3=Henrickson|first3=Sarah E.|last4=Rosenwald|first4=Andreas|last5=Wang|first5=Qifu|last6=Olson|first6=Sandy|last7=Brandt|first7=Stephen J.|last8=Roberts|first8=Jeremy|last9=Zhang|first9=Xueqiong|date=2005-05|title=Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/15948116|journal=Human Pathology|volume=36|issue=5|pages=494–504|doi=10.1016/j.humpath.2005.03.004|issn=0046-8177|pmid=15948116}}</ref><ref>{{Cite journal|last=Piccaluga|first=Pier Paolo|last2=Agostinelli|first2=Claudio|last3=Califano|first3=Andrea|last4=Rossi|first4=Maura|last5=Basso|first5=Katia|last6=Zupo|first6=Simonetta|last7=Went|first7=Philip|last8=Klein|first8=Ulf|last9=Zinzani|first9=Pier Luigi|date=2007-03|title=Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets|url=https://pubmed.ncbi.nlm.nih.gov/17304354|journal=The Journal of Clinical Investigation|volume=117|issue=3|pages=823–834|doi=10.1172/JCI26833|issn=0021-9738|pmc=1794115|pmid=17304354}}</ref><ref>{{Cite journal|last=Salaverria|first=Itziar|last2=Beà|first2=Silvia|last3=Lopez-Guillermo|first3=Armando|last4=Lespinet|first4=Virginia|last5=Pinyol|first5=Magda|last6=Burkhardt|first6=Birgit|last7=Lamant|first7=Laurence|last8=Zettl|first8=Andreas|last9=Horsman|first9=Doug|date=2008-03|title=Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/18275429|journal=British Journal of Haematology|volume=140|issue=5|pages=516–526|doi=10.1111/j.1365-2141.2007.06924.x|issn=1365-2141|pmid=18275429}}</ref>
 
*Gene expression profiling and comparative genomic hybridization studies have shown that ALK(+) and ALK(-) ALCL share restricted genomic signatures and/or preferential genomic aberrations<ref>{{Cite journal|last=Thompson|first=Mary Ann|last2=Stumph|first2=Jennifer|last3=Henrickson|first3=Sarah E.|last4=Rosenwald|first4=Andreas|last5=Wang|first5=Qifu|last6=Olson|first6=Sandy|last7=Brandt|first7=Stephen J.|last8=Roberts|first8=Jeremy|last9=Zhang|first9=Xueqiong|date=2005-05|title=Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/15948116|journal=Human Pathology|volume=36|issue=5|pages=494–504|doi=10.1016/j.humpath.2005.03.004|issn=0046-8177|pmid=15948116}}</ref><ref>{{Cite journal|last=Piccaluga|first=Pier Paolo|last2=Agostinelli|first2=Claudio|last3=Califano|first3=Andrea|last4=Rossi|first4=Maura|last5=Basso|first5=Katia|last6=Zupo|first6=Simonetta|last7=Went|first7=Philip|last8=Klein|first8=Ulf|last9=Zinzani|first9=Pier Luigi|date=2007-03|title=Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets|url=https://pubmed.ncbi.nlm.nih.gov/17304354|journal=The Journal of Clinical Investigation|volume=117|issue=3|pages=823–834|doi=10.1172/JCI26833|issn=0021-9738|pmc=1794115|pmid=17304354}}</ref><ref>{{Cite journal|last=Salaverria|first=Itziar|last2=Beà|first2=Silvia|last3=Lopez-Guillermo|first3=Armando|last4=Lespinet|first4=Virginia|last5=Pinyol|first5=Magda|last6=Burkhardt|first6=Birgit|last7=Lamant|first7=Laurence|last8=Zettl|first8=Andreas|last9=Horsman|first9=Doug|date=2008-03|title=Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/18275429|journal=British Journal of Haematology|volume=140|issue=5|pages=516–526|doi=10.1111/j.1365-2141.2007.06924.x|issn=1365-2141|pmid=18275429}}</ref>
Line 367: Line 525:
 
*See other sections.
 
*See other sections.
  
 +
<blockquote class="blockedit">
 +
<center><span style="color:Maroon">'''End of V4 Section'''</span>
 +
----
 
</blockquote>
 
</blockquote>
==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>
+
==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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
 +
{| class="wikitable sortable"
 +
|-
 +
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
 +
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
 +
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
 +
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
 +
!'''Clinical Relevance Details/Other Notes'''
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>''EGFR''
 +
 
 +
<br />
 +
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
 +
|<span class="blue-text">EXAMPLE:</span> Oncogene
 +
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
 +
|<span class="blue-text">EXAMPLE:</span> T
 +
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
 +
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
 +
<br />
 +
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
 +
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
 +
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
 +
|<span class="blue-text">EXAMPLE:</span> P
 +
|
 +
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
 +
|<span class="blue-text">EXAMPLE:</span> Activating mutations
 +
|<span class="blue-text">EXAMPLE:</span> Oncogene
 +
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
 +
|<span class="blue-text">EXAMPLE:</span> T
 +
|
 +
|
 +
|-
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
 +
 
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 380: Line 585:
 
!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.
  
  
<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
+
<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
 
{| class="wikitable"
 
{| class="wikitable"
 
!Gene
 
!Gene
Line 424: Line 674:
 
|
 
|
 
|-
 
|-
|[[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 446: Line 696:
 
*Uncommon: FAS, STIM2<ref name=":2" />; LRP1B (9%), EPHA5<ref name=":6" />
 
*Uncommon: FAS, STIM2<ref name=":2" />; LRP1B (9%), EPHA5<ref name=":6" />
  
 +
<blockquote class="blockedit">
 +
<center><span style="color:Maroon">'''End of V4 Section'''</span>
 +
----
 
</blockquote>
 
</blockquote>
 +
 
==Epigenomic Alterations==
 
==Epigenomic Alterations==
  
Line 453: Line 707:
 
==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
 
|}
 
|}
  
<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
+
<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
  
 
*JAK-STAT<ref name=":2" />
 
*JAK-STAT<ref name=":2" />
Line 478: Line 732:
 
**When ''JAK/STAT3'' mutations absent, ''NFkB2-ROS1'' and ''NFkB2-TYK2'' fusions may constitutively activate STAT pathway
 
**When ''JAK/STAT3'' mutations absent, ''NFkB2-ROS1'' and ''NFkB2-TYK2'' fusions may constitutively activate STAT pathway
  
 +
<blockquote class="blockedit">
 +
<center><span style="color:Maroon">'''End of V4 Section'''</span>
 +
----
 
</blockquote>
 
</blockquote>
 
==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
Line 500: Line 757:
  
 
==Additional Information==
 
==Additional Information==
 +
This disease is <u>defined/characterized</u> as detailed below:
 +
 +
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 [[HAEM5:ALK-positive anaplastic large cell lymphoma|ALK(+) ALCL]]<ref name=":9">{{Cite journal|last=Ad|first=Attygalle|last2=J|first2=Cabeçadas|last3=P|first3=Gaulard|last4=Es|first4=Jaffe|last5=D|first5=de Jong|last6=Yh|first6=Ko|last7=J|first7=Said|last8=W|first8=Klapper|date=2014|title=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|url=https://pubmed.ncbi.nlm.nih.gov/24128129/|language=en|doi=10.1111/his.12251|pmc=PMC6364972|pmid=24128129}}</ref><ref name=":7" />
 +
 +
*Three major molecular subtypes of ALK (-) ALCL<ref name=":9" /><ref name=":7" />:
 +
**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)<ref name=":4" />
 +
 +
The <u>epidemiology/prevalence</u> of this disease is detailed below:
 +
 +
*More common in adults than children (peak incidence 6th decade of life)<ref name=":1">{{Cite journal|last=G|first=Hapgood|last2=Kj|first2=Savage|date=2015|title=The biology and management of systemic anaplastic large cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/25869285/|language=en|pmid=25869285}}</ref>
 +
*Less than 3% of all Non-Hodgkin's lymphoma<ref name=":1" />
 +
*M:F 1.5:1<ref name=":1" />
 +
 +
The <u>clinical features</u> of this disease are detailed below:
 +
 +
Signs and symptoms - B-symptoms (weight loss, fever, night sweats)<ref name=":1" />; Peripheral and/or Lymphadenopathy<ref name=":1" />; Most patients present with advanced stage disease<ref name=":1" />
 +
 +
Laboratory findings - Not specific
 +
 +
The <u>sites of involvement</u> of this disease are detailed below:
 +
 +
*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
  
*None
+
The <u>morphologic features</u> of this disease are detailed below:
  
 +
*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
 +
 +
The <u>immunophenotype</u> of this disease is detailed below:
 +
 +
Immunohistochemical patterns vary by subtype<ref name=":1" /><ref>{{Cite journal|last=M|first=Herling|last2=Gz|first2=Rassidakis|last3=D|first3=Jones|last4=A|first4=Schmitt-Graeff|last5=Ah|first5=Sarris|last6=Lj|first6=Medeiros|date=2004|title=Absence of Epstein-Barr virus in anaplastic large cell lymphoma: a study of 64 cases classified according to World Health Organization criteria|url=https://pubmed.ncbi.nlm.nih.gov/15116326/|language=en|pmid=15116326}}</ref><ref name=":0" />
 +
 +
'''DUSP22-rearranged subtype'''
 +
{| class="wikitable sortable"
 +
|-
 +
!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
 +
|}
 +
<nowiki>*</nowiki>Strong and diffuse CD30 staining; should be equal intensity in all cells
 +
 +
'''TP63-rearranged subtype'''
 +
 +
{| class="wikitable sortable"
 +
|-
 +
!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''' 
 +
 +
{| class="wikitable sortable"
 +
|-
 +
!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
 +
|}
 
==Links==
 
==Links==
  
Line 508: Line 854:
  
 
==References==
 
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''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.''</span> <span style="color:#0070C0">''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''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
+
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. 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. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
  
'''
+
<br />
  
 
==Notes==
 
==Notes==
<nowiki>*</nowiki>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.
+
<nowiki>*</nowiki>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 [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representativeWhen pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
 +
 
 +
Prior Author(s): 
 +
 
 +
       
 
<nowiki>*</nowiki>''Citation of this Page'': “ALK-negative anaplastic large cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:ALK-negative_anaplastic_large_cell_lymphoma</nowiki>.
 
<nowiki>*</nowiki>''Citation of this Page'': “ALK-negative anaplastic large cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:ALK-negative_anaplastic_large_cell_lymphoma</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]]
+
[[Category:HAEM5]]
 +
[[Category:DISEASE]]
 +
[[Category:Diseases A]]

Latest revision as of 12:31, 24 March 2025

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 focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). 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 in a table, click nearby within the table and select the > symbol that appears. 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

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE: ABL1 EXAMPLE: BCR::ABL1 EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: Common (CML) EXAMPLE: D, P, T EXAMPLE: Yes (WHO, NCCN) 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). BCR::ABL1 is generally favorable in CML (add reference).

EXAMPLE: CIC EXAMPLE: CIC::DUX4 EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. EXAMPLE: t(4;19)(q25;q13) EXAMPLE: Common (CIC-rearranged sarcoma) EXAMPLE: D EXAMPLE:

DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).

EXAMPLE: ALK EXAMPLE: ELM4::ALK


Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1

EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. EXAMPLE: N/A EXAMPLE: Rare (Lung adenocarcinoma) EXAMPLE: T EXAMPLE:

Both balanced and unbalanced forms are observed by FISH (add references).

EXAMPLE: ABL1 EXAMPLE: N/A EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. EXAMPLE: N/A EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) EXAMPLE: D, P, T
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[1] DUSP22/FRA7H fusion protein 30%[2] No Yes No
  • * These rearrangements are considered mutually exclusive; however, a single case with both DUSP22 and TP63 rearrangement has been described[3]. 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[4][5] (not FDA-approved)
      • Bromodomain and extra-terminal proteins (BET) inhibitors may target ERBB4 pathway[5][6]
*t(3;3)(q22;q26.2), inv(3)(q26q28) TP63/TBL1XR1[7] TP63/TBL1XR1 fusion protein 8%[2] 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[8] No No No
  • 5-year overall survival 42% for cases lacking all DUSP22, TP63 and ALK rearrangements[2][9]
t(1;19)(p34;p13) PABPC4/TYK2 PABPC4/TYK2 fusion protein rare[8] No No No
t(6;10)(q22;q24) NFKB2/ROS1 NFKB2/ROS1 fusion protein rare[8] No No No


editv4:Chromosomal Rearrangements (Gene Fusions)
The content below was from the old template. Please incorporate above.
Chromosomal Rearrangement[10][11] Genes in Fusion (5’ or 3’ Segments) Prevalence
*t(6;7)(p25.3;q32.3) DUSP22/FRA7H[1] 30%[2]
*t(3;3)(q22;q26.2), inv(3)(q26q28) TP63/TBL1XR1[7] 8%[2]
t(10;19)(q24;p13) NFKB2/TYK2 rare[8]
t(1;19)(p34;p13) PABPC4/TYK2 rare[8]
t(6;10)(q22;q24) NFKB2/ROS1 rare[8]

* These rearrangements are considered mutually exclusive; however, a single case with both DUSP22 and TP63 rearrangement has been described[3]. Can also be seen in a fraction of other PTCL.

End of V4 Section


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[12]
    • 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%[13]
  • 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 [13][14]
    • 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[2][9]
    • 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[15]
      • Often concomitant loss and seen in almost a quarter of cases
    • Mutations with significantly shorter OS compared to wild-type[16]
    • Prognostic significance of ERB4 and COL29A1 co-expressing subtypes unclear [17]
  • 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[4][5] (not FDA-approved)
      • Bromodomain and extra-terminal proteins (BET) inhibitors may target ERBB4 pathway[5][6]
End of V4 Section

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE: 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 references).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE:

Common recurrent secondary finding for t(8;21) (add references).

EXAMPLE:

17

EXAMPLE: Amp EXAMPLE:

17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]

EXAMPLE:

ERBB2

EXAMPLE: D, P, T EXAMPLE:

Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.


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
The content below was from the old template. Please incorporate above.

The pattern of genomic copy number changes and loss of heterozygosity have been described[15][18][19]:

  • 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[15]
  • 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%
End of V4 Section

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern Molecular Pathogenesis Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

Co-deletion of 1p and 18q

EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). EXAMPLE: Common (Oligodendroglioma) EXAMPLE: D, P
EXAMPLE:

Microsatellite instability - hypermutated

EXAMPLE: Common (Endometrial carcinoma) EXAMPLE: P, T
editv4:Characteristic Chromosomal Aberrations / Patterns
The content below was from the old template. Please incorporate above.
  • Gene expression profiling and comparative genomic hybridization studies have shown that ALK(+) and ALK(-) ALCL share restricted genomic signatures and/or preferential genomic aberrations[20][21][22]
  • Several genes are similarly expressed in ALK(+) and ALK(-) samples, suggesting a common ALCL signature, that permit differential diagnosis of ALCL from PTCL-NOS[23]
  • See other sections.
End of V4 Section

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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T   Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:EGFR


EXAMPLE: Exon 18-21 activating mutations EXAMPLE: Oncogene EXAMPLE: Common (lung cancer) EXAMPLE: T EXAMPLE: Yes (NCCN) EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations


EXAMPLE: Variable LOF mutations EXAMPLE: Tumor Supressor Gene EXAMPLE: Common (breast cancer) EXAMPLE: P EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations EXAMPLE: Activating mutations EXAMPLE: Oncogene EXAMPLE: Common (melanoma) EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


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%[16] No N/A No Yes No
STAT3 Oncogene 26%[16] No N/A No Yes No
  • Ruxolitinib may be used to target JAK-STAT pathway (not FDA-approved)[4]
JAK1 Oncogene 26%[16] No N/A No Yes No
PRDM1/BLIMP1[15] TSG 6% No N/A No No No
NOTCH1[24] Oncogene 15% No No No No No
KMT2D[16] 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)
The content below was from the old template. Please incorporate above.
Gene Presumed mechanism Frequency Notes
STAT3*[8][16] Activating 10-26% Not seen in PTCL-NOS[8] or ALK+ ALCL[8][16]
JAK1*[8][16] Activating 15-26% Not seen in PTCL-NOS[8] or ALK+ ALCL[8][16]
PRDM1/BLIMP1[15] Tumor suppressor 6% (2/31)
NOTCH1[24] Activating 15%
TP53[16] Tumor suppressor 23%
KMT2D[16] Tumor suppressor 20%

*Double mutated for JAK1+STAT3 in 7-11%[8][16]

Other mutations

  • Epigenetic modifier genes: TET2[8][16]
  • Uncommon: FAS, STIM2[8]; LRP1B (9%), EPHA5[16]
End of V4 Section

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[8] JAK-STAT pathway Increased cell growth and proliferation
NFkB2-ROS1 fusion[8] JAK-STAT pathway Increased cell growth and proliferation
NFkB2-TYK2 fusion[8] 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[8]
    • 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
End of V4 Section

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[25]
  • Presence of STAT3 and/or JAK1 mutations seem to favor ALK(-) ALCL over PTCL-NOS[8]
  • 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

This disease is defined/characterized as detailed below:

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[26][12]

  • Three major molecular subtypes of ALK (-) ALCL[26][12]:
    • 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)[17]

The epidemiology/prevalence of this disease is detailed below:

  • More common in adults than children (peak incidence 6th decade of life)[27]
  • Less than 3% of all Non-Hodgkin's lymphoma[27]
  • M:F 1.5:1[27]

The clinical features of this disease are detailed below:

Signs and symptoms - B-symptoms (weight loss, fever, night sweats)[27]; Peripheral and/or Lymphadenopathy[27]; Most patients present with advanced stage disease[27]

Laboratory findings - Not specific

The sites of involvement of this disease are detailed below:

  • 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

The morphologic features of this disease are detailed below:

  • 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

The immunophenotype of this disease is detailed below:

Immunohistochemical patterns vary by subtype[27][28][2]

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

Links

  • See references.

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. 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. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

  1. Jump up to: 1.0 1.1 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.
  2. Jump up to: 2.0 2.1 2.2 2.3 2.4 2.5 2.6 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)
  3. Jump up to: 3.0 3.1 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).
  4. Jump up to: 4.0 4.1 4.2 R, Roskoski (2016). "Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases". PMID 27473820.
  5. Jump up to: 5.0 5.1 5.2 5.3 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)
  6. Jump up to: 6.0 6.1 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)
  7. Jump up to: 7.0 7.1 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.
  8. Jump up to: 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 8.14 8.15 8.16 8.17 8.18 8.19 8.20 8.21 8.22 8.23 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)
  9. Jump up to: 9.0 9.1 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)
  10. 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".
  11. 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)
  12. Jump up to: 12.0 12.1 12.2 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)
  13. Jump up to: 13.0 13.1 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.
  14. 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.
  15. Jump up to: 15.0 15.1 15.2 15.3 15.4 M, Boi; et al. (2013). "PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma". PMID 24004669.
  16. Jump up to: 16.00 16.01 16.02 16.03 16.04 16.05 16.06 16.07 16.08 16.09 16.10 16.11 16.12 16.13 16.14 16.15 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.
  17. Jump up to: 17.0 17.1 I, Scarfò; et al. (2016). "Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts". PMID 26463425.
  18. 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)
  19. 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)
  20. 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)
  21. 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)
  22. 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)
  23. 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.
  24. Jump up to: 24.0 24.1 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.
  25. 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)
  26. Jump up to: 26.0 26.1 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)
  27. Jump up to: 27.0 27.1 27.2 27.3 27.4 27.5 27.6 G, Hapgood; et al. (2015). "The biology and management of systemic anaplastic large cell lymphoma". PMID 25869285.
  28. 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.


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 Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):


*Citation of this Page: “ALK-negative anaplastic large cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/24/2025, https://ccga.io/index.php/HAEM5:ALK-negative_anaplastic_large_cell_lymphoma.