View source for HAEM4Backup:Anaplastic Large Cell Lymphoma, ALK-Negative

==Primary Author(s)*==

Miguel Gonzalez Mancera, MD

Sumire Kitahara, MD

Cedars-Sinai, Los Angeles, CA

__TOC__

==Cancer Category/Type==

*[[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 [[Anaplastic Large Cell Lymphoma, ALK-Positive|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==

*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" />

==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)==

{| 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>{{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(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>{{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.

==Characteristic Chromosomal Aberrations / Patterns==

*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.

==Genomic Gain/Loss/LOH==
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%'''
|}

==Gene Mutations (SNV/INDEL)==
{| 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>{{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" />

==Epigenomics (Methylation)==

*See above mutations in epigenetic modifier genes

==Genes and Main Pathways Involved==

*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

==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

*
*

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

*'''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>{{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>{{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>

==Familial Forms==

*Not described

==Other Information==

*None

==Links==

*See references.

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

==Notes==
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