View source for HAEM5:ALK-negative anaplastic large cell lymphoma

{{DISPLAYTITLE:ALK-negative anaplastic large cell lymphoma}}

[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

{{Under Construction}}

<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>

<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>

==Primary Author(s)*==

Miguel Gonzalez Mancera, MD

Sumire Kitahara, MD

Cedars-Sinai, Los Angeles, CA

__TOC__

==WHO Classification of Disease==

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

==Definition / Description of Disease==

*Anaplastic large cell lymphomas (ALCL), [[ALK]]-negative, is a CD30+ T-cell lymphoma that is morphologically and immunophenotypically indistinguishable (but lacks ALK protein expression) from [[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. Do not delete table.'') </span>
{| class="wikitable"
|'''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
|}


<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
|-
|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
|}
==Chromosomal Rearrangements (Gene Fusions)==

Put your text here and fill in the table

{| class="wikitable sortable"
|-
!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<ref name=":10" />||DUSP22/FRA7H fusion protein||30%<ref name=":0" />
|No
|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
|Yes
|No
|
*<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.}}

{| class="wikitable sortable"
|-
!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 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 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)
|NFKB2/TYK2
|rare<ref name=":2">{{Cite journal|last=R|first=Crescenzo|last2=F|first2=Abate|last3=E|first3=Lasorsa|last4=F|first4=Tabbo'|last5=M|first5=Gaudiano|last6=N|first6=Chiesa|last7=F|first7=Di Giacomo|last8=E|first8=Spaccarotella|last9=L|first9=Barbarossa|date=2015|title=Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/25873174/|language=en|doi=10.1016/j.ccell.2015.03.006|pmc=PMC5898430|pmid=25873174}}</ref>
|-
|t(1;19)(p34;p13)
|PABPC4/TYK2
|rare<ref name=":2" />
|-
|t(6;10)(q22;q24)
|NFKB2/ROS1
|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 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>


<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)
* 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<ref name=":7" />
**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" />

*'''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 <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 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" />
***Often concomitant loss and seen in almost a quarter of cases
**Mutations with significantly shorter OS compared to wild-type<ref name=":6" />
***STAT3, [[TP53]]
**Prognostic significance of ERB4 and COL29A1 co-expressing subtypes unclear <ref name=":4">{{Cite journal|last=I|first=Scarfò|last2=E|first2=Pellegrino|last3=E|first3=Mereu|last4=I|first4=Kwee|last5=L|first5=Agnelli|last6=E|first6=Bergaggio|last7=G|first7=Garaffo|last8=N|first8=Vitale|last9=M|first9=Caputo|date=2016|title=Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts|url=https://pubmed.ncbi.nlm.nih.gov/26463425/|language=en|pmid=26463425}}</ref>

*'''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">{{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 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>
==Individual Region Genomic Gain / Loss / LOH==

Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!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''
|}

<blockquote class="blockedit">{{Box-round|title=v4: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<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>:

*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<ref name=":5" />
*None are diagnostically helpful for the distinction between  ALK(-) ALCL from other entities

{| class="wikitable sortable"
|-
!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%'''
|}

</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. Do not delete table.'')</span>

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|N/A
|N/A
|N/A
|N/A
|N/A
|}

<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>
*Several genes are similarly expressed in ALK(+) and ALK(-) samples, suggesting a common ALCL signature, that permit differential diagnosis of ALCL from PTCL-NOS<ref>{{Cite journal|last=Piva|first=Roberto|last2=Agnelli|first2=Luca|last3=Pellegrino|first3=Elisa|last4=Todoerti|first4=Katia|last5=Grosso|first5=Valentina|last6=Tamagno|first6=Ilaria|last7=Fornari|first7=Alessandro|last8=Martinoglio|first8=Barbara|last9=Medico|first9=Enzo|date=2010-03-20|title=Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/20159827|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=28|issue=9|pages=1583–1590|doi=10.1200/JCO.2008.20.9759|issn=1527-7755|pmid=20159827}}</ref>
*See other sections.

</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 as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!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%<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" />

*Ruxolitinib may be used to target JAK-STAT pathway (not FDA-approved)<ref name=":13" />
|-
|''JAK1''
|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" />
|-
|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
|
|}
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.}}
{| class="wikitable"
!Gene
!Presumed mechanism
!Frequency
!Notes
|-
|STAT3*<ref name=":2" /><ref name=":6">{{Cite journal|last=Lobello|first=Cosimo|last2=Tichy|first2=Boris|last3=Bystry|first3=Vojtech|last4=Radova|first4=Lenka|last5=Filip|first5=Daniel|last6=Mraz|first6=Marek|last7=Montes-Mojarro|first7=Ivonne-Aidee|last8=Prokoph|first8=Nina|last9=Larose|first9=Hugo|date=2020-11-27|title=STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma|url=https://www.nature.com/articles/s41375-020-01093-1|journal=Leukemia|language=en|pages=1–6|doi=10.1038/s41375-020-01093-1|issn=1476-5551}}</ref>
|Activating
|10-26%
|Not seen in PTCL-NOS<ref name=":2" /> or ALK+ ALCL<ref name=":2" /><ref name=":6" />
|-
|[[JAK1]]*<ref name=":2" /><ref name=":6" />
|Activating
|15-26%
|Not seen in PTCL-NOS<ref name=":2" /> or ALK+ ALCL<ref name=":2" /><ref name=":6" />
|-
|PRDM1/BLIMP1<ref name=":5" />
|Tumor suppressor
|6% (2/31)
|
|-
|[[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
|15%
|
|-
|TP53<ref name=":6" />
|Tumor suppressor
|23%
|
|-
|KMT2D<ref name=":6" />
|Tumor suppressor
|20%
|
|}
<nowiki>*</nowiki>Double mutated for JAK1+STAT3 in 7-11%<ref name=":2" /><ref name=":6" />

====Other mutations====

*Epigenetic modifier genes: TET2<ref name=":2" /><ref name=":6" />
*Uncommon: FAS, STIM2<ref name=":2" />; LRP1B (9%), EPHA5<ref name=":6" />

</blockquote>
==Epigenomic Alterations==

*See above mutations in epigenetic modifier genes

==Genes and Main Pathways Involved==

Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|''STAT3''<ref name=":2" />
|JAK-STAT pathway
|Increased cell growth and proliferation
|-
|''NFkB2-ROS1'' fusion<ref name=":2" />
|JAK-STAT pathway
|Increased cell growth and proliferation
|-
|''NFkB2-TYK2'' fusion<ref name=":2" />
|JAK-STAT pathway
|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.}}

*JAK-STAT<ref name=":2" />
**'''<u>''STAT3'' mutants are constitutively phosphorylated</u>'''
**'''<u>''JAK1'' mutants lead to the constitutive phosphorylation of STAT and synergize with ''STAT3'' mutants</u>'''
**When ''JAK/STAT3'' mutations absent, ''NFkB2-ROS1'' and ''NFkB2-TYK2'' fusions may constitutively activate STAT pathway

</blockquote>
==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<ref>{{Cite journal|last=X|first=Wang|last2=Rl|first2=Boddicker|last3=S|first3=Dasari|last4=Js|first4=Sidhu|last5=Me|first5=Kadin|last6=Wr|first6=Macon|last7=Sm|first7=Ansell|last8=Rp|first8=Ketterling|last9=Kl|first9=Rech|date=2017|title=Expression of p63 protein in anaplastic large cell lymphoma: implications for genetic subtyping|url=https://pubmed.ncbi.nlm.nih.gov/28153507/|language=en|doi=10.1016/j.humpath.2017.01.003|pmc=PMC5518937|pmid=28153507}}</ref>
*Presence of STAT3 and/or [[JAK1]] mutations seem to favor ALK(-) ALCL over PTCL-NOS<ref name=":2" />
*FISH studies necessary to subtype:  
**DUSP22 (IRF4/DUSP22) break-apart probe
**TP63 rearrangement
*ERBB4(+) cases may be identified using digital droplet PCR or immunostaining for MMP9 (a protein highly correlated with ERBB4 expression)
**Not routinely performed

*
*

==Familial Forms==

*Not described

==Additional Information==

*None

==Links==

*See references.

==References==
(use the "Cite" icon at the top of the page) <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 />

<br />

==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>''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]]