Bailey.Glen at 21:41, 4 December 2023

2023-12-04T21:41:38Z

← Older revision		Revision as of 16:41, 4 December 2023
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	==Cancer Category/Type==		==Cancer Category/Type==

	*[[Mature T- and NK-cell Neoplasms]]		*[[HAEM4:Mature T- and NK-cell Neoplasms]]

	==Cancer Sub-Classification / Subtype==		==Cancer Sub-Classification / Subtype==
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	==Definition / Description of Disease==		==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>		*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" />:		*Three major molecular subtypes of ALK (-) ALCL<ref name=":9" /><ref name=":7" />:
	**DUSP22-rearranged subtype (30%)		**DUSP22-rearranged subtype (30%)

Bailey.Glen at 18:57, 3 November 2023

2023-11-03T18:57:14Z

@@ Line 1: / Line 1: @@
 ==Primary Author(s)*==
@@ Line 323: / Line 328: @@
 ==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.

Bailey.Glen: Created page with "==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]..."

2023-11-03T18:23:39Z

Created page with "==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]..."

New page

==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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HAEM4:Anaplastic Large Cell Lymphoma, ALK-Negative - Revision history

Bailey.Glen at 21:41, 4 December 2023

Bailey.Glen at 18:57, 3 November 2023

Bailey.Glen: Created page with "==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]..."

Bailey.Glen: Created page with "==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]..."