Compendium of Cancer Genome Aberrations

HAEM5:ALK-positive anaplastic large cell lymphoma: Difference between revisions

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{{DISPLAYTITLE:ALK-positive anaplastic large cell lymphoma}}
{{DISPLAYTITLE:ALK-positive anaplastic large cell lymphoma}}
 
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (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-Positive]].
<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-Positive]].
}}</blockquote>
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<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)*==
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Sumire Kitahara, MD, Cedars-Sinai, Los Angeles, CA
Sumire Kitahara, MD, Cedars-Sinai, Los Angeles, CA
==WHO Classification of Disease==


__TOC__
==Cancer Category / Type==
*[[HAEM4:Mature T- and NK-cell Neoplasms]]
==Cancer Sub-Classification / Subtype==
*Systemic T-cell lymphoma
==Definition / Description of Disease==
Anaplastic Large Cell Lymphoma, ALK-Positive (ALK+ ALCL) is a T-cell lymphoma characterized by usually large lymphoma cells with abundant cytoplasm and pleomorphic nuclei, often horse-shoe shaped (see Morphologic Features below), with a chromosomal rearrangement involving the ALK gene resulting in expression of ALK protein and CD30
==Synonyms / Terminology==
*Ki-1 (CD30) lymphoma - obsolete
==Epidemiology / Prevalence==
*ALCL ([[ALK]]+, ALK-, and primary cutaneous) account for <5% of all cases of non-Hodgkin lymphoma (NHL)<ref name=":0" />
*ALK+ ALCL<ref name=":0">Arber DA, et al., (2017). Anaplastic large cell lymphoma, ALK-positive, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p413-418.</ref>
**~3% of adult NHL
**10-20% of childhood lymphomas
**Most frequent in the first three decades of life
**Male:female = 1.5:1
==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
|Most patients (70%) present with advanced (stage III-IV) disease and B-symptoms.<ref name=":19" />
!Disease
|-
|-
|'''Laboratory Findings'''
|Book
|Noncontributory
|Haematolymphoid Tumours (5th ed.)
|}
 
 
<blockquote class="blockedit">{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
 
*Most patients (70%) present with advanced (stage III-IV) disease and B-symptoms.<ref name=":19">{{Cite journal|last=Savage|first=Kerry J.|last2=Harris|first2=Nancy Lee|last3=Vose|first3=Julie M.|last4=Ullrich|first4=Fred|last5=Jaffe|first5=Elaine S.|last6=Connors|first6=Joseph M.|last7=Rimsza|first7=Lisa|last8=Pileri|first8=Stefano A.|last9=Chhanabhai|first9=Mukesh|date=2008-06-15|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/|journal=Blood|volume=111|issue=12|pages=5496–5504|doi=10.1182/blood-2008-01-134270|issn=1528-0020|pmid=18385450}}</ref>
 
</blockquote>
==Sites of Involvement==
 
 
*Lymph nodes and extranodal sites (most commonly skin, bone, soft tissue, lungs and liver)<ref name=":0" />
*Bone marrow involvement detected in 30% when using immunohistochemistry (CD30 and EMA). Can miss marrow involvement by H&E evaluation alone, which detects involvement with ~10% incidence.<ref>{{Cite journal|last=M|first=Fraga|last2=P|first2=Brousset|last3=D|first3=Schlaifer|last4=C|first4=Payen|last5=A|first5=Robert|last6=H|first6=Rubie|last7=F|first7=Huguet-Rigal|last8=G|first8=Delsol|date=1995|title=Bone marrow involvement in anaplastic large cell lymphoma. Immunohistochemical detection of minimal disease and its prognostic significance|url=https://pubmed.ncbi.nlm.nih.gov/7817951/|language=en|pmid=7817951}}</ref>
 
 
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":0" /></blockquote>
==Morphologic Features==
 
"Hallmark cells"<ref>{{Cite journal|last=Stein|first=H.|last2=Foss|first2=H. D.|last3=Dürkop|first3=H.|last4=Marafioti|first4=T.|last5=Delsol|first5=G.|last6=Pulford|first6=K.|last7=Pileri|first7=S.|last8=Falini|first8=B.|date=2000-12-01|title=CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features|url=https://pubmed.ncbi.nlm.nih.gov/11090048/|journal=Blood|volume=96|issue=12|pages=3681–3695|issn=0006-4971|pmid=11090048}}</ref><ref>{{Cite journal|last=Benharroch|first=D.|last2=Meguerian-Bedoyan|first2=Z.|last3=Lamant|first3=L.|last4=Amin|first4=C.|last5=Brugières|first5=L.|last6=Terrier-Lacombe|first6=M. J.|last7=Haralambieva|first7=E.|last8=Pulford|first8=K.|last9=Pileri|first9=S.|date=1998-03-15|title=ALK-positive lymphoma: a single disease with a broad spectrum of morphology|url=https://pubmed.ncbi.nlm.nih.gov/9490693/|journal=Blood|volume=91|issue=6|pages=2076–2084|issn=0006-4971|pmid=9490693}}</ref>
 
*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
*Present in varying proportions
*Seen in all morphological variants/patterns of ALK+ ALCL
 
Morphological variants/patterns
 
#Common (60%): predominant population of large hallmark cells
#Lymphohistiocytic (10%): lymphoma cells are admixed with numerous reactive histiocytes that may obscure the lymphoma cells; lymphoma cells often cluster around vessels and are often smaller than in the common pattern
#Small cell (5-10%): predominant population of smaller lymphoma cells; hallmark cells are often concentrated around vessels; may also see "fried egg cells" (pale cytoplasm with central nucleus) or signet ring-like cells; can misdiagnose of peripheral T-cell lymphoma, NOS
#Hodgkin-like (3%): mimics nodular sclerosis classic Hodgkin lymphoma
#Composite (15%): more than one pattern in a single lymph node
 
When lymph node is only partially involved, lymphoma characteristically grows in the sinuses, which may mimic a metastatic tumor.
 
==Immunophenotype==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
 
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
|Category
|T-cell and NK-cell lymphoid proliferations and lymphomas
|-
|-
|Positive (universal) - Cell membrane and Golgi; large lymphoma cells show strongest staining; smaller cells may show weak, partial to negative staining||CD30
|Family
|Mature T-cell and NK-cell neoplasms
|-
|-
|Positive (universal) - Cellular location of ALK staining varies depending on ALK translocation partner. In the most common t(2;5), most cases show both cytoplasmic and nuclear||ALK
|Type
|Anaplastic large cell lymphoma
|-
|-
|Positive (subset)||EMA
|Subtype(s)
|ALK-positive anaplastic large cell lymphoma
|}
==Related Terminology==
 
{| class="wikitable"
|+
|Acceptable
|Anaplastic large cell lymphoma, ALK-positive
|-
|-
|Negative - >75% of cases are CD3-negative||CD3
|Not Recommended
|N/A
|}
 
==Gene Rearrangements==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: 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"
|-
|-
|Positive (70%)
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
|CD4
!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
|-
|-
|Negative in majority of cases
|<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)
|CD8
|<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 in majority of cases
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|CD2
|<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).
|-
|-
|Positive in majority of cases
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|CD5
|<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
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|TIA1
|<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
|
|
|-
|-
|Positive
|
|Granzyme B
|
|-
|
|Positive
|
|Perforin
|
|-
|
|Variably positive
|
|CD45
|
|-
|Positive (universal)
|CD25
|-
|Negative (universal)
|BCL2
|}
|}




<blockquote class="blockedit">{{Box-round|title=v4:Immunophenotype|The content below was from the old template. Please incorporate above.}}
FISH is not required for diagnosis in routine practice <ref name=":27" /><ref name=":28" />.
[[ALK]]+ ALCL show the following staining pattern<ref>{{Cite journal|last=Montes-Mojarro|first=Ivonne A.|last2=Steinhilber|first2=Julia|last3=Bonzheim|first3=Irina|last4=Quintanilla-Martinez|first4=Leticia|last5=Fend|first5=Falko|date=2018-04-04|title=The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)|url=https://pubmed.ncbi.nlm.nih.gov/29617304/|journal=Cancers|volume=10|issue=4|pages=E107|doi=10.3390/cancers10040107|issn=2072-6694|pmc=5923362|pmid=29617304}}</ref><ref>{{Cite journal|last=Stein|first=H.|last2=Foss|first2=H. D.|last3=Dürkop|first3=H.|last4=Marafioti|first4=T.|last5=Delsol|first5=G.|last6=Pulford|first6=K.|last7=Pileri|first7=S.|last8=Falini|first8=B.|date=2000-12-01|title=CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features|url=https://pubmed.ncbi.nlm.nih.gov/11090048/|journal=Blood|volume=96|issue=12|pages=3681–3695|issn=0006-4971|pmid=11090048}}</ref>:
 
*'''CD30+:''' Cell membrane and Golgi; large lymphoma cells show strongest staining; smaller cells may show weak, partial to negative staining
*'''ALK+:''' cellular location of ALK staining varies depending on ALK translocation partner. In the most common t(2;5), most cases show both cytoplasmic and nuclear ALK staining. In the small cell variant, staining is usually restricted to the nucleus
*EMA+: some cases show positivity in only a proportion of lymphoma cells
*'''CD3(-):''' >75% of cases are CD3-negative
*CD4>>>CD8
*CD2 and CD5: Majority positive
*Cytotoxic marker(s)+: TIA1, granzyme B and/or perforin
*'''CD45: variably positive'''
*CD25+
*'''BCL2-negative'''
 
</blockquote>
==Chromosomal Rearrangements (Gene Fusions)==
 
Put your text here and fill in the table


{| class="wikitable sortable"
{| class="wikitable sortable"
Line 163: Line 118:
!Notes
!Notes
|-
|-
|t(2;5)(p23;q35)||3' ''ALK'' / 5' ''NPM1''<ref name=":20" />||''NPM1::ALK'' fusion protein||84%<ref name=":0" />
|t(2;5)(p23;q35)||3' ''ALK'' / 5' ''NPM1''<ref name=":20" />||''NPM1::ALK'' fusion protein||84%<ref name=":0">Arber DA, et al., (2017). Anaplastic large cell lymphoma, ALK-positive, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p413-418.</ref>
|No
|No
|No
|No
|Yes
|Yes
|ALK inhibition ([https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-crizotinib-children-and-young-adults-relapsed-or-refractory-systemic-anaplastic-large#:~:text=Approvals%20and%20Databases-,FDA%20approves%20crizotinib%20for%20children%20and%20young%20adults%20with%20relapsed,systemic%20anaplastic%20large%20cell%20lymphoma&text=On%20January%2014%2C%202021%2C%20the,(Xalkori%2C%20Pfizer%20Inc.) crizotinib]) can be an effective 2nd-line therapeutic strategy as ALK is essential for the proliferation and survival of ALK+ ALCL cells<ref name=":21" /><ref name=":2" /><ref name=":22" />
|Approximately 80% of cases show a cytogenetic translocation t(2;5) (NPM1-ALK, t(2;5)(p23;q35)) which fuses the ''ALK'' gene to the nucleophosmine (NPM) gene at 5q35, resulting in the overexpression and constitutive activation of a chimeric ALK fusion protein, which plays an important role in ALK-mediated oncogenesis.
 
 
<u>Of note, identifying the ''ALK'' fusion partner is not considered necessary in routine clinical practice.</u>
 
 
Detecting minimal residual disease by PCR for ''[[NPM1-ALK]]'' (not readily commercially available) in bone marrow and peripheral blood during treatment could identify patients at risk of relapse<ref name=":29" />
 
 
ALK inhibition ([https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-crizotinib-children-and-young-adults-relapsed-or-refractory-systemic-anaplastic-large#:~:text=Approvals%20and%20Databases-,FDA%20approves%20crizotinib%20for%20children%20and%20young%20adults%20with%20relapsed,systemic%20anaplastic%20large%20cell%20lymphoma&text=On%20January%2014%2C%202021%2C%20the,(Xalkori%2C%20Pfizer%20Inc.) crizotinib]) can be an effective 2nd-line therapeutic strategy as ALK is essential for the proliferation and survival of ALK+ ALCL cells<ref name=":21" /><ref name=":2" /><ref name=":22" />


*Drug resistance may develop due to:  
*Drug resistance may develop due to:  
Line 257: Line 221:


<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>


*ALK(+) ALCL is characterized by chromosomal translocations involving ''ALK'' gene, a receptor tyrosine kinase domain at 2p23.
*ALK(+) ALCL is characterized by chromosomal translocations involving ''ALK'' gene, a receptor tyrosine kinase domain at 2p23.
*Approximately 80% of cases show a cytogenetic translocation t(2;5) (NPM1-ALK, t(2;5)(p23;q35)) which fuses the ''ALK'' gene to the nucleophosmine (NPM) gene at 5q35, resulting in the overexpression and constitutive activation of a chimeric ALK fusion protein, which plays an important role in ALK-mediated oncogenesis.<ref name=":20">{{Cite journal|last=Morris|first=S. W.|last2=Kirstein|first2=M. N.|last3=Valentine|first3=M. B.|last4=Dittmer|first4=K. G.|last5=Shapiro|first5=D. N.|last6=Saltman|first6=D. L.|last7=Look|first7=A. T.|date=1994-03-04|title=Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/8122112/|journal=Science (New York, N.Y.)|volume=263|issue=5151|pages=1281–1284|doi=10.1126/science.8122112|issn=0036-8075|pmid=8122112}}</ref>
*Approximately 80% of cases show a cytogenetic translocation t(2;5) (NPM1-ALK, t(2;5)(p23;q35)) which fuses the ''ALK'' gene to the nucleophosmine (NPM) gene at 5q35, resulting in the overexpression and constitutive activation of a chimeric ALK fusion protein, which plays an important role in ALK-mediated oncogenesis.<ref name=":20">{{Cite journal|last=Morris|first=S. W.|last2=Kirstein|first2=M. N.|last3=Valentine|first3=M. B.|last4=Dittmer|first4=K. G.|last5=Shapiro|first5=D. N.|last6=Saltman|first6=D. L.|last7=Look|first7=A. T.|date=1994-03-04|title=Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/8122112/|journal=Science (New York, N.Y.)|volume=263|issue=5151|pages=1281–1284|doi=10.1126/science.8122112|issn=0036-8075|pmid=8122112}}</ref>
**
**
*''ALK'' translocations may be seen in multiple malignancies including epithelial malignancies<ref>{{Cite journal|last=Holla|first=Vijaykumar R.|last2=Elamin|first2=Yasir Y.|last3=Bailey|first3=Ann Marie|last4=Johnson|first4=Amber M.|last5=Litzenburger|first5=Beate C.|last6=Khotskaya|first6=Yekaterina B.|last7=Sanchez|first7=Nora S.|last8=Zeng|first8=Jia|last9=Shufean|first9=Md Abu|date=2017-1|title=ALK: a tyrosine kinase target for cancer therapy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171696/|journal=Cold Spring Harbor Molecular Case Studies|volume=3|issue=1|pages=a001115|doi=10.1101/mcs.a001115|issn=2373-2873|pmc=5171696|pmid=28050598}}</ref><ref>{{Cite journal|last=Amatu|first=Alessio|last2=Somaschini|first2=Alessio|last3=Cerea|first3=Giulio|last4=Bosotti|first4=Roberta|last5=Valtorta|first5=Emanuele|last6=Buonandi|first6=Pasquale|last7=Marrapese|first7=Giovanna|last8=Veronese|first8=Silvio|last9=Luo|first9=David|date=2015-12-22|title=Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701996/|journal=British Journal of Cancer|volume=113|issue=12|pages=1730–1734|doi=10.1038/bjc.2015.401|issn=0007-0920|pmc=4701996|pmid=26633560}}</ref><ref>{{Cite journal|last=Camidge|first=D. Ross|last2=Kono|first2=Scott A.|last3=Lu|first3=Xian|last4=Okuyama|first4=Sonia|last5=Barón|first5=Anna E.|last6=Oton|first6=Ana B.|last7=Davies|first7=Angela M.|last8=Varella-Garcia|first8=Marileila|last9=Franklin|first9=Wilbur|date=2011-04|title=Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed|url=https://pubmed.ncbi.nlm.nih.gov/21336183/|journal=Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer|volume=6|issue=4|pages=774–780|doi=10.1097/JTO.0b013e31820cf053|issn=1556-1380|pmc=3626562|pmid=21336183}}</ref><ref>{{Cite journal|last=Choi|first=Young Lim|last2=Takeuchi|first2=Kengo|last3=Soda|first3=Manabu|last4=Inamura|first4=Kentaro|last5=Togashi|first5=Yuki|last6=Hatano|first6=Satoko|last7=Enomoto|first7=Munehiro|last8=Hamada|first8=Toru|last9=Haruta|first9=Hidenori|date=2008-07-01|title=Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/18593892/|journal=Cancer Research|volume=68|issue=13|pages=4971–4976|doi=10.1158/0008-5472.CAN-07-6158|issn=1538-7445|pmid=18593892}}</ref><ref>{{Cite journal|last=Kelly|first=Lindsey M.|last2=Barila|first2=Guillermo|last3=Liu|first3=Pengyuan|last4=Evdokimova|first4=Viktoria N.|last5=Trivedi|first5=Sumita|last6=Panebianco|first6=Federica|last7=Gandhi|first7=Manoj|last8=Carty|first8=Sally E.|last9=Hodak|first9=Steven P.|date=2014-03-18|title=Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964116/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=111|issue=11|pages=4233–4238|doi=10.1073/pnas.1321937111|issn=0027-8424|pmc=3964116|pmid=24613930}}</ref><ref>{{Cite journal|last=Ambrosini|first=Margherita|last2=Del Re|first2=Marzia|last3=Manca|first3=Paolo|last4=Hendifar|first4=Andrew|last5=Drilon|first5=Alexander|last6=Harada|first6=Guilherme|last7=Ree|first7=Anne Hansen|last8=Klempner|first8=Samuel|last9=Mælandsmo|first9=Gunhild Mari|date=2022-04|title=ALK Inhibitors in Patients With ALK Fusion-Positive GI Cancers: An International Data Set and a Molecular Case Series|url=https://pubmed.ncbi.nlm.nih.gov/35476549/|journal=JCO precision oncology|volume=6|pages=e2200015|doi=10.1200/PO.22.00015|issn=2473-4284|pmid=35476549}}</ref>, inflammatory myofibroblastic tumor<ref>{{Cite journal|last=Bridge|first=Julia A.|last2=Kanamori|first2=Masahiko|last3=Ma|first3=Zhigui|last4=Pickering|first4=Diane|last5=Hill|first5=D. Ashley|last6=Lydiatt|first6=William|last7=Lui|first7=Man Yee|last8=Colleoni|first8=Gisele W. B.|last9=Antonescu|first9=Cristina R.|date=2001-8|title=Fusion of the ALK Gene to the Clathrin Heavy Chain Gene, CLTC, in Inflammatory Myofibroblastic Tumor|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850566/|journal=The American Journal of Pathology|volume=159|issue=2|pages=411–415|issn=0002-9440|pmc=1850566|pmid=11485898}}</ref><ref>{{Cite journal|last=Lawrence|first=B.|last2=Perez-Atayde|first2=A.|last3=Hibbard|first3=M. K.|last4=Rubin|first4=B. P.|last5=Dal Cin|first5=P.|last6=Pinkus|first6=J. L.|last7=Pinkus|first7=G. S.|last8=Xiao|first8=S.|last9=Yi|first9=E. S.|date=2000-08|title=TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors|url=https://pubmed.ncbi.nlm.nih.gov/10934142/|journal=The American Journal of Pathology|volume=157|issue=2|pages=377–384|doi=10.1016/S0002-9440(10)64550-6|issn=0002-9440|pmc=1850130|pmid=10934142}}</ref><ref>{{Cite journal|last=Ma|first=Zhigui|last2=Hill|first2=D. Ashley|last3=Collins|first3=Margaret H.|last4=Morris|first4=Stephan W.|last5=Sumegi|first5=Janos|last6=Zhou|first6=Ming|last7=Zuppan|first7=Craig|last8=Bridge|first8=Julia A.|date=2003-05|title=Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor|url=https://pubmed.ncbi.nlm.nih.gov/12661011/|journal=Genes, Chromosomes & Cancer|volume=37|issue=1|pages=98–105|doi=10.1002/gcc.10177|issn=1045-2257|pmid=12661011}}</ref>, non-Hodgkin's lymphoma<ref>{{Cite journal|last=Pan|first=Zenggang|last2=Hu|first2=Shimin|last3=Li|first3=Min|last4=Zhou|first4=Yi|last5=Kim|first5=Young S.|last6=Reddy|first6=Vishnu|last7=Sanmann|first7=Jennifer N.|last8=Smith|first8=Lynette M.|last9=Chen|first9=Mingyi|date=2017-01|title=ALK-positive Large B-cell Lymphoma: A Clinicopathologic Study of 26 Cases With Review of Additional 108 Cases in the Literature|url=https://pubmed.ncbi.nlm.nih.gov/27740969/|journal=The American Journal of Surgical Pathology|volume=41|issue=1|pages=25–38|doi=10.1097/PAS.0000000000000753|issn=1532-0979|pmid=27740969}}</ref><ref>{{Cite journal|last=Laurent|first=Camille|last2=Do|first2=Catherine|last3=Gascoyne|first3=Randy D.|last4=Lamant|first4=Laurence|last5=Ysebaert|first5=Loïc|last6=Laurent|first6=Guy|last7=Delsol|first7=Georges|last8=Brousset|first8=Pierre|date=2009-09-01|title=Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/19636007/|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=27|issue=25|pages=4211–4216|doi=10.1200/JCO.2008.21.5020|issn=1527-7755|pmid=19636007}}</ref><ref>{{Cite journal|last=Sakamoto|first=Kana|last2=Nakasone|first2=Hideki|last3=Togashi|first3=Yuki|last4=Sakata|first4=Seiji|last5=Tsuyama|first5=Naoko|last6=Baba|first6=Satoko|last7=Dobashi|first7=Akito|last8=Asaka|first8=Reimi|last9=Tsai|first9=Chien-Chen|date=2016-04|title=ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern|url=https://pubmed.ncbi.nlm.nih.gov/26781614/|journal=International Journal of Hematology|volume=103|issue=4|pages=399–408|doi=10.1007/s12185-016-1934-1|issn=1865-3774|pmid=26781614}}</ref>, and ALK+ histiocytosis <ref>{{Cite journal|last=Takeyasu|first=Yuki|last2=Okuma|first2=Hitomi S.|last3=Kojima|first3=Yuki|last4=Nishikawa|first4=Tadaaki|last5=Tanioka|first5=Maki|last6=Sudo|first6=Kazuki|last7=Shimoi|first7=Tatsunori|last8=Noguchi|first8=Emi|last9=Arakawa|first9=Ayumu|date=2021|title=Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors|url=https://pubmed.ncbi.nlm.nih.gov/34036223/|journal=JCO precision oncology|volume=5|pages=PO.20.00383|doi=10.1200/PO.20.00383|issn=2473-4284|pmc=8140781|pmid=34036223}}</ref><ref>{{Cite journal|last=Chang|first=Kenneth Tou En|last2=Tay|first2=Amos Zhi En|last3=Kuick|first3=Chik Hong|last4=Chen|first4=Huiyi|last5=Algar|first5=Elizabeth|last6=Taubenheim|first6=Nadine|last7=Campbell|first7=Janine|last8=Mechinaud|first8=Francoise|last9=Campbell|first9=Martin|date=2019-05|title=ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion|url=https://pubmed.ncbi.nlm.nih.gov/30573850/|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=32|issue=5|pages=598–608|doi=10.1038/s41379-018-0168-6|issn=1530-0285|pmid=30573850}}</ref><ref>{{Cite journal|last=Chan|first=John K. C.|last2=Lamant|first2=Laurence|last3=Algar|first3=Elizabeth|last4=Delsol|first4=Georges|last5=Tsang|first5=William Y. W.|last6=Lee|first6=King C.|last7=Tiedemann|first7=Karin|last8=Chow|first8=Chung W.|date=2008-10-01|title=ALK+ histiocytosis: a novel type of systemic histiocytic proliferative disorder of early infancy|url=https://pubmed.ncbi.nlm.nih.gov/18660380/|journal=Blood|volume=112|issue=7|pages=2965–2968|doi=10.1182/blood-2008-03-147017|issn=1528-0020|pmid=18660380}}</ref>.
*'''''ALK translocations may be seen in multiple malignancies including epithelial malignancies<ref>{{Cite journal|last=Holla|first=Vijaykumar R.|last2=Elamin|first2=Yasir Y.|last3=Bailey|first3=Ann Marie|last4=Johnson|first4=Amber M.|last5=Litzenburger|first5=Beate C.|last6=Khotskaya|first6=Yekaterina B.|last7=Sanchez|first7=Nora S.|last8=Zeng|first8=Jia|last9=Shufean|first9=Md Abu|date=2017-1|title=ALK: a tyrosine kinase target for cancer therapy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171696/|journal=Cold Spring Harbor Molecular Case Studies|volume=3|issue=1|pages=a001115|doi=10.1101/mcs.a001115|issn=2373-2873|pmc=5171696|pmid=28050598}}</ref><ref>{{Cite journal|last=Amatu|first=Alessio|last2=Somaschini|first2=Alessio|last3=Cerea|first3=Giulio|last4=Bosotti|first4=Roberta|last5=Valtorta|first5=Emanuele|last6=Buonandi|first6=Pasquale|last7=Marrapese|first7=Giovanna|last8=Veronese|first8=Silvio|last9=Luo|first9=David|date=2015-12-22|title=Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701996/|journal=British Journal of Cancer|volume=113|issue=12|pages=1730–1734|doi=10.1038/bjc.2015.401|issn=0007-0920|pmc=4701996|pmid=26633560}}</ref><ref>{{Cite journal|last=Camidge|first=D. Ross|last2=Kono|first2=Scott A.|last3=Lu|first3=Xian|last4=Okuyama|first4=Sonia|last5=Barón|first5=Anna E.|last6=Oton|first6=Ana B.|last7=Davies|first7=Angela M.|last8=Varella-Garcia|first8=Marileila|last9=Franklin|first9=Wilbur|date=2011-04|title=Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed|url=https://pubmed.ncbi.nlm.nih.gov/21336183/|journal=Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer|volume=6|issue=4|pages=774–780|doi=10.1097/JTO.0b013e31820cf053|issn=1556-1380|pmc=3626562|pmid=21336183}}</ref><ref>{{Cite journal|last=Choi|first=Young Lim|last2=Takeuchi|first2=Kengo|last3=Soda|first3=Manabu|last4=Inamura|first4=Kentaro|last5=Togashi|first5=Yuki|last6=Hatano|first6=Satoko|last7=Enomoto|first7=Munehiro|last8=Hamada|first8=Toru|last9=Haruta|first9=Hidenori|date=2008-07-01|title=Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/18593892/|journal=Cancer Research|volume=68|issue=13|pages=4971–4976|doi=10.1158/0008-5472.CAN-07-6158|issn=1538-7445|pmid=18593892}}</ref><ref>{{Cite journal|last=Kelly|first=Lindsey M.|last2=Barila|first2=Guillermo|last3=Liu|first3=Pengyuan|last4=Evdokimova|first4=Viktoria N.|last5=Trivedi|first5=Sumita|last6=Panebianco|first6=Federica|last7=Gandhi|first7=Manoj|last8=Carty|first8=Sally E.|last9=Hodak|first9=Steven P.|date=2014-03-18|title=Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964116/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=111|issue=11|pages=4233–4238|doi=10.1073/pnas.1321937111|issn=0027-8424|pmc=3964116|pmid=24613930}}</ref><ref>{{Cite journal|last=Ambrosini|first=Margherita|last2=Del Re|first2=Marzia|last3=Manca|first3=Paolo|last4=Hendifar|first4=Andrew|last5=Drilon|first5=Alexander|last6=Harada|first6=Guilherme|last7=Ree|first7=Anne Hansen|last8=Klempner|first8=Samuel|last9=Mælandsmo|first9=Gunhild Mari|date=2022-04|title=ALK Inhibitors in Patients With ALK Fusion-Positive GI Cancers: An International Data Set and a Molecular Case Series|url=https://pubmed.ncbi.nlm.nih.gov/35476549/|journal=JCO precision oncology|volume=6|pages=e2200015|doi=10.1200/PO.22.00015|issn=2473-4284|pmid=35476549}}</ref>, inflammatory myofibroblastic tumor<ref>{{Cite journal|last=Bridge|first=Julia A.|last2=Kanamori|first2=Masahiko|last3=Ma|first3=Zhigui|last4=Pickering|first4=Diane|last5=Hill|first5=D. Ashley|last6=Lydiatt|first6=William|last7=Lui|first7=Man Yee|last8=Colleoni|first8=Gisele W. B.|last9=Antonescu|first9=Cristina R.|date=2001-8|title=Fusion of the ALK Gene to the Clathrin Heavy Chain Gene, CLTC, in Inflammatory Myofibroblastic Tumor|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850566/|journal=The American Journal of Pathology|volume=159|issue=2|pages=411–415|issn=0002-9440|pmc=1850566|pmid=11485898}}</ref><ref>{{Cite journal|last=Lawrence|first=B.|last2=Perez-Atayde|first2=A.|last3=Hibbard|first3=M. K.|last4=Rubin|first4=B. P.|last5=Dal Cin|first5=P.|last6=Pinkus|first6=J. L.|last7=Pinkus|first7=G. S.|last8=Xiao|first8=S.|last9=Yi|first9=E. S.|date=2000-08|title=TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors|url=https://pubmed.ncbi.nlm.nih.gov/10934142/|journal=The American Journal of Pathology|volume=157|issue=2|pages=377–384|doi=10.1016/S0002-9440(10)64550-6|issn=0002-9440|pmc=1850130|pmid=10934142}}</ref><ref>{{Cite journal|last=Ma|first=Zhigui|last2=Hill|first2=D. Ashley|last3=Collins|first3=Margaret H.|last4=Morris|first4=Stephan W.|last5=Sumegi|first5=Janos|last6=Zhou|first6=Ming|last7=Zuppan|first7=Craig|last8=Bridge|first8=Julia A.|date=2003-05|title=Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor|url=https://pubmed.ncbi.nlm.nih.gov/12661011/|journal=Genes, Chromosomes & Cancer|volume=37|issue=1|pages=98–105|doi=10.1002/gcc.10177|issn=1045-2257|pmid=12661011}}</ref>, non-Hodgkin's lymphoma<ref>{{Cite journal|last=Pan|first=Zenggang|last2=Hu|first2=Shimin|last3=Li|first3=Min|last4=Zhou|first4=Yi|last5=Kim|first5=Young S.|last6=Reddy|first6=Vishnu|last7=Sanmann|first7=Jennifer N.|last8=Smith|first8=Lynette M.|last9=Chen|first9=Mingyi|date=2017-01|title=ALK-positive Large B-cell Lymphoma: A Clinicopathologic Study of 26 Cases With Review of Additional 108 Cases in the Literature|url=https://pubmed.ncbi.nlm.nih.gov/27740969/|journal=The American Journal of Surgical Pathology|volume=41|issue=1|pages=25–38|doi=10.1097/PAS.0000000000000753|issn=1532-0979|pmid=27740969}}</ref><ref>{{Cite journal|last=Laurent|first=Camille|last2=Do|first2=Catherine|last3=Gascoyne|first3=Randy D.|last4=Lamant|first4=Laurence|last5=Ysebaert|first5=Loïc|last6=Laurent|first6=Guy|last7=Delsol|first7=Georges|last8=Brousset|first8=Pierre|date=2009-09-01|title=Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/19636007/|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=27|issue=25|pages=4211–4216|doi=10.1200/JCO.2008.21.5020|issn=1527-7755|pmid=19636007}}</ref><ref>{{Cite journal|last=Sakamoto|first=Kana|last2=Nakasone|first2=Hideki|last3=Togashi|first3=Yuki|last4=Sakata|first4=Seiji|last5=Tsuyama|first5=Naoko|last6=Baba|first6=Satoko|last7=Dobashi|first7=Akito|last8=Asaka|first8=Reimi|last9=Tsai|first9=Chien-Chen|date=2016-04|title=ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern|url=https://pubmed.ncbi.nlm.nih.gov/26781614/|journal=International Journal of Hematology|volume=103|issue=4|pages=399–408|doi=10.1007/s12185-016-1934-1|issn=1865-3774|pmid=26781614}}</ref>, and ALK+ histiocytosis''''' ''<ref>{{Cite journal|last=Takeyasu|first=Yuki|last2=Okuma|first2=Hitomi S.|last3=Kojima|first3=Yuki|last4=Nishikawa|first4=Tadaaki|last5=Tanioka|first5=Maki|last6=Sudo|first6=Kazuki|last7=Shimoi|first7=Tatsunori|last8=Noguchi|first8=Emi|last9=Arakawa|first9=Ayumu|date=2021|title=Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors|url=https://pubmed.ncbi.nlm.nih.gov/34036223/|journal=JCO precision oncology|volume=5|pages=PO.20.00383|doi=10.1200/PO.20.00383|issn=2473-4284|pmc=8140781|pmid=34036223}}</ref><ref>{{Cite journal|last=Chang|first=Kenneth Tou En|last2=Tay|first2=Amos Zhi En|last3=Kuick|first3=Chik Hong|last4=Chen|first4=Huiyi|last5=Algar|first5=Elizabeth|last6=Taubenheim|first6=Nadine|last7=Campbell|first7=Janine|last8=Mechinaud|first8=Francoise|last9=Campbell|first9=Martin|date=2019-05|title=ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion|url=https://pubmed.ncbi.nlm.nih.gov/30573850/|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=32|issue=5|pages=598–608|doi=10.1038/s41379-018-0168-6|issn=1530-0285|pmid=30573850}}</ref><ref>{{Cite journal|last=Chan|first=John K. C.|last2=Lamant|first2=Laurence|last3=Algar|first3=Elizabeth|last4=Delsol|first4=Georges|last5=Tsang|first5=William Y. W.|last6=Lee|first6=King C.|last7=Tiedemann|first7=Karin|last8=Chow|first8=Chung W.|date=2008-10-01|title=ALK+ histiocytosis: a novel type of systemic histiocytic proliferative disorder of early infancy|url=https://pubmed.ncbi.nlm.nih.gov/18660380/|journal=Blood|volume=112|issue=7|pages=2965–2968|doi=10.1182/blood-2008-03-147017|issn=1528-0020|pmid=18660380}}</ref>.''


[[File:FISH break apart probe for ALK gene .jpg|alt=|none|thumb|640x640px|FISH break apart probe for ''ALK'' gene showing a split signal indicating ''ALK'' rearrangement in a case of ALK(+) ALCL.]]
[[File:FISH break apart probe for ALK gene .jpg|alt=|none|thumb|640x640px|FISH break apart probe for ''ALK'' gene showing a split signal indicating ''ALK'' rearrangement in a case of ALK(+) ALCL.]]
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|}
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>


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* 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


*As stated above, the diagnosis is based on histology and immunohistochemistry
*As stated above, the diagnosis is based on histology and immunohistochemistry
*FISH is not required for diagnosis in routine practice <ref>{{Cite journal|last=Falini|first=B.|last2=Bigerna|first2=B.|last3=Fizzotti|first3=M.|last4=Pulford|first4=K.|last5=Pileri|first5=S. A.|last6=Delsol|first6=G.|last7=Carbone|first7=A.|last8=Paulli|first8=M.|last9=Magrini|first9=U.|date=1998-09|title=ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum|url=https://pubmed.ncbi.nlm.nih.gov/9736036/|journal=The American Journal of Pathology|volume=153|issue=3|pages=875–886|doi=10.1016/S0002-9440(10)65629-5|issn=0002-9440|pmc=1853018|pmid=9736036}}</ref><ref>{{Cite journal|last=Pittaluga|first=S.|last2=Wlodarska|first2=I.|last3=Pulford|first3=K.|last4=Campo|first4=E.|last5=Morris|first5=S. W.|last6=Van den Berghe|first6=H.|last7=De Wolf-Peeters|first7=C.|date=1997-08|title=The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements|url=https://pubmed.ncbi.nlm.nih.gov/9250148/|journal=The American Journal of Pathology|volume=151|issue=2|pages=343–351|issn=0002-9440|pmc=1858018|pmid=9250148}}</ref>
*FISH is not required for diagnosis in routine practice <ref name=":27">{{Cite journal|last=Falini|first=B.|last2=Bigerna|first2=B.|last3=Fizzotti|first3=M.|last4=Pulford|first4=K.|last5=Pileri|first5=S. A.|last6=Delsol|first6=G.|last7=Carbone|first7=A.|last8=Paulli|first8=M.|last9=Magrini|first9=U.|date=1998-09|title=ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum|url=https://pubmed.ncbi.nlm.nih.gov/9736036/|journal=The American Journal of Pathology|volume=153|issue=3|pages=875–886|doi=10.1016/S0002-9440(10)65629-5|issn=0002-9440|pmc=1853018|pmid=9736036}}</ref><ref name=":28">{{Cite journal|last=Pittaluga|first=S.|last2=Wlodarska|first2=I.|last3=Pulford|first3=K.|last4=Campo|first4=E.|last5=Morris|first5=S. W.|last6=Van den Berghe|first6=H.|last7=De Wolf-Peeters|first7=C.|date=1997-08|title=The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements|url=https://pubmed.ncbi.nlm.nih.gov/9250148/|journal=The American Journal of Pathology|volume=151|issue=2|pages=343–351|issn=0002-9440|pmc=1858018|pmid=9250148}}</ref>


Prognosis
Prognosis
Line 339: Line 306:
*Different ''ALK'' translocation partners do not have prognostic significance
*Different ''ALK'' translocation partners do not have prognostic significance
*Survival is predicted by International Prognostic Index (IPI) with overall long term survival rate approaching 80%
*Survival is predicted by International Prognostic Index (IPI) with overall long term survival rate approaching 80%
*Detecting minimal residual disease by PCR for ''[[NPM1-ALK]]'' (not readily commercially available) in bone marrow and peripheral blood during treatment could identify patients at risk of relapse<ref>{{Cite journal|last=C|first=Damm-Welk|last2=L|first2=Mussolin|last3=M|first3=Zimmermann|last4=M|first4=Pillon|last5=W|first5=Klapper|last6=I|first6=Oschlies|last7=Es|first7=d'Amore|last8=A|first8=Reiter|last9=W|first9=Woessmann|date=2014|title=Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/24297868/|language=en|pmid=24297868}}</ref>
*Detecting minimal residual disease by PCR for ''[[NPM1-ALK]]'' (not readily commercially available) in bone marrow and peripheral blood during treatment could identify patients at risk of relapse<ref name=":29">{{Cite journal|last=C|first=Damm-Welk|last2=L|first2=Mussolin|last3=M|first3=Zimmermann|last4=M|first4=Pillon|last5=W|first5=Klapper|last6=I|first6=Oschlies|last7=Es|first7=d'Amore|last8=A|first8=Reiter|last9=W|first9=Woessmann|date=2014|title=Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/24297868/|language=en|pmid=24297868}}</ref>
*Small-cell or lymphohistiocytic patterns tend to present with disseminated disease and have a less favorable prognosis than the common pattern<ref>{{Cite journal|last=L|first=Lamant|last2=K|first2=McCarthy|last3=E|first3=d'Amore|last4=W|first4=Klapper|last5=A|first5=Nakagawa|last6=M|first6=Fraga|last7=J|first7=Maldyk|last8=I|first8=Simonitsch-Klupp|last9=I|first9=Oschlies|date=2011|title=Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study|url=https://pubmed.ncbi.nlm.nih.gov/22084369/|language=en|pmid=22084369}}</ref>
*'''''Small-cell or lymphohistiocytic patterns tend to present with disseminated disease and have a less favorable prognosis than the common pattern<ref>{{Cite journal|last=L|first=Lamant|last2=K|first2=McCarthy|last3=E|first3=d'Amore|last4=W|first4=Klapper|last5=A|first5=Nakagawa|last6=M|first6=Fraga|last7=J|first7=Maldyk|last8=I|first8=Simonitsch-Klupp|last9=I|first9=Oschlies|date=2011|title=Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study|url=https://pubmed.ncbi.nlm.nih.gov/22084369/|language=en|pmid=22084369}}</ref>'''''
*NOTCH1 may be a biomarker for risk of relapse<ref name=":5" />
*NOTCH1 may be a biomarker for risk of relapse<ref name=":5" />


Therapy
'''''Therapy'''''


*CD30 expression on ALCL (ALK+ or ALK-) allows for targeted therapy<ref name=":2">{{Cite journal|displayauthors=1|last=National Comprehensive Cancer Network|first=|date=January 2021|title=NCCN Clinical Practice Guidelines in Oncology: T-cell lymphomas|url=https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf|journal=|volume=|pages=|via=}}</ref>
*CD30 expression on ALCL (ALK+ or ALK-) allows for targeted therapy<ref name=":2">{{Cite journal|displayauthors=1|last=National Comprehensive Cancer Network|first=|date=January 2021|title=NCCN Clinical Practice Guidelines in Oncology: T-cell lymphomas|url=https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf|journal=|volume=|pages=|via=}}</ref>
Line 352: Line 319:
**#See also gene mutations section above
**#See also gene mutations section above
**#Engagement of other cell signaling pathways
**#Engagement of other cell signaling pathways
*Preclinical models suggest role of:
*'''''Preclinical models suggest role of:'''''
**Combination therapy with hypomethylating agents (such as azacitidine) and epigenetic modifying drugs (such as romidepsin, a histone deacetylase inhibitor)<ref>{{Cite journal|last=Rozati|first=Sima|last2=Cheng|first2=Phil F.|last3=Widmer|first3=Daniel S.|last4=Fujii|first4=Kazuyasu|last5=Levesque|first5=Mitchell P.|last6=Dummer|first6=Reinhard|date=2016-04-15|title=Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL|url=https://pubmed.ncbi.nlm.nih.gov/26660520|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=22|issue=8|pages=2020–2031|doi=10.1158/1078-0432.CCR-15-1435|issn=1557-3265|pmid=26660520}}</ref>
**'''''Combination therapy with hypomethylating agents (such as azacitidine) and epigenetic modifying drugs (such as romidepsin, a histone deacetylase inhibitor)<ref>{{Cite journal|last=Rozati|first=Sima|last2=Cheng|first2=Phil F.|last3=Widmer|first3=Daniel S.|last4=Fujii|first4=Kazuyasu|last5=Levesque|first5=Mitchell P.|last6=Dummer|first6=Reinhard|date=2016-04-15|title=Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL|url=https://pubmed.ncbi.nlm.nih.gov/26660520|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=22|issue=8|pages=2020–2031|doi=10.1158/1078-0432.CCR-15-1435|issn=1557-3265|pmid=26660520}}</ref>'''''
**Inhibitors of HSP90 and mTOR inhibition<ref name=":3" />
**'''''Inhibitors of HSP90 and mTOR inhibition<ref name=":3" />'''''
**NOTCH1 inhibition by γ-secretase inhibitors (GSI) in combination with crizotinib may provide synergistic anti-tumor activity, or as a single agent in ALK-inhibitor resistant cell lines<ref name=":5" />
**'''''NOTCH1 inhibition by γ-secretase inhibitors (GSI) in combination with crizotinib may provide synergistic anti-tumor activity, or as a single agent in ALK-inhibitor resistant cell lines<ref name=":5" />'''''


<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 370: Line 391:
!Notes
!Notes
|-
|-
|2q
|17p
|Gain
|17p11-pter
|
|No
|Unclear
|No
|
|-
|17p
|Gain
|Gain
|Chr 2:29,192,774-29,921,586
|17q24 -qter
|EXAMPLE
|
 
chr7
|No
|No
|Yes
|Unclear
|No
|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 reference).
|-
|-
|EXAMPLE
|4q
 
|Loss
8
|4q13-q28
|EXAMPLE Gain
|
|EXAMPLE
|No
 
|Unclear
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
|No
|No
|
|-
|11q
|Loss
|11q14-q23
|
|No
|No
|Unclear
|No
|No
|EXAMPLE
|
 
Common recurrent secondary finding for t(8;21) (add reference).
|}
|}


<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>


Frequent secondary chromosomal imbalances are seen in ALK+ ALCL (58% of cases), as based on comparative genomic hybridization analysis<ref>{{Cite journal|last=I|first=Salaverria|last2=S|first2=Beà|last3=A|first3=Lopez-Guillermo|last4=V|first4=Lespinet|last5=M|first5=Pinyol|last6=B|first6=Burkhardt|last7=L|first7=Lamant|last8=A|first8=Zettl|last9=D|first9=Horsman|date=2008|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/|language=en|pmid=18275429}}</ref>.
Frequent secondary chromosomal imbalances are seen in ALK+ ALCL (58% of cases), as based on comparative genomic hybridization analysis<ref>{{Cite journal|last=I|first=Salaverria|last2=S|first2=Beà|last3=A|first3=Lopez-Guillermo|last4=V|first4=Lespinet|last5=M|first5=Pinyol|last6=B|first6=Burkhardt|last7=L|first7=Lamant|last8=A|first8=Zettl|last9=D|first9=Horsman|date=2008|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/|language=en|pmid=18275429}}</ref>.
Line 450: Line 477:
|}
|}
<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 class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>


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)==
==Gene Mutations (SNV/INDEL)==
{| 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.


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>


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!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)'''
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
Line 510: Line 601:
|No
|No
|Yes
|Yes
|
|May be a biomarker for risk of relapse<ref name=":5" />
|-
|-
|TP53<ref name=":4" />
|TP53<ref name=":4" />
Line 522: Line 613:
|
|
|-
|-
|ALK
|ALK<ref name=":24" /><ref name=":7" /><ref name=":8" /><ref name=":9" /><ref name=":25" /><ref name=":26" /><ref name=":23" />
|Therapeutic Resistance mutations
|
|
|No
|No
|No
|
|
|
|Yes
|
|ALK kinase domain secondary mutations, including L1196 M, G1269A, L1152R, C1156Y, I1171T, F1174 L, G1202R, and S1206Y, have been identified as the key mechanism of resistance
|
 
|
|
|
*ALK kinase domain secondary mutations, including L1196 M, G1269A, L1152R, C1156Y, I1171T, F1174 L, G1202R, and S1206Y, have been identified as the key mechanism of resistance<ref name=":23" /><ref name=":24" /><ref name=":7" /><ref name=":8" /><ref name=":9" /><ref name=":25" /><ref name=":26" />
*
*
|}
|}
Line 537: Line 628:




<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>


*Limited literature on somatic mutations in ALK+ ALCL
*Limited literature on somatic mutations in ALK+ ALCL
Line 584: Line 675:
*Gain in ALK copy number and loss of ALK gene rearrangement have also been implicated in the development of acquired resistance to crizotinib.<ref name=":7" /><ref name=":8" /><ref name=":9" /><br />
*Gain in ALK copy number and loss of ALK gene rearrangement have also been implicated in the development of acquired resistance to crizotinib.<ref name=":7" /><ref name=":8" /><ref name=":9" /><br />


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==


Line 600: Line 695:
==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"
|-
|-
Line 606: Line 701:
|-
|-
|ALK; fusion protein derivatives
|ALK; fusion protein derivatives
|Ras-ERK
|Ras-ERK<ref name=":30" />
|Increased cell growth and proliferation
|Increased cell growth and proliferation
|-
|-
|ALK; fusion protein derivatives
|ALK; fusion protein derivatives
|JAK/STAT3
|JAK/STAT3<ref name=":30" />
|Cell survival and phenotypic changes
|Cell survival and phenotypic changes
|-
|-
|ALK; fusion protein derivatives
|ALK; fusion protein derivatives
|PI3K/AKT/mTOR
|PI3K/AKT/mTOR<ref name=":30" />
|Cell survival and phenotypic changes
|Cell survival and phenotypic changes
|}
|}


<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">
*ALK-NPM-STAT3 induces:
**See Epigenomics section above
**TGF beta, IL-10, PD-L1/CD274 to create immunosuppressive microenvironment and evasion of immune system<ref name=":31" /><ref name=":32" /><ref name=":33" />
**ICOS expression (CD28 costimulatory receptor superfamily)
**HIF1α expression induces expression of VEGF (tumor angiogenesis); allows lymphoma cells to adapt to hypoxic conditions<ref name=":34" />
*Expression of embryonic genes (SOX2, SALL4) promoting stem cell-like program
*Deregulation of microRNAs (miR-155, miR-101, miR-17-92 cluster, miR-26a, miR-16)<ref name=":35" /><ref name=":36" /><ref name=":37" /><ref name=":38" /><ref name=":39" />
 
</blockquote>
 
<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>


*
*
*Activation of the ALK catalytic domain leads to the oncogenic properties of the ALK protein, leading to activation of multiple signaling cascades including<ref>{{Cite journal|last=M|first=Boi|last2=E|first2=Zucca|last3=G|first3=Inghirami|last4=F|first4=Bertoni|date=2015|title=Advances in understanding the pathogenesis of systemic anaplastic large cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/25559471/|language=en|pmid=25559471}}</ref>:
*Activation of the ALK catalytic domain leads to the oncogenic properties of the ALK protein, leading to activation of multiple signaling cascades including<ref name=":30">{{Cite journal|last=M|first=Boi|last2=E|first2=Zucca|last3=G|first3=Inghirami|last4=F|first4=Bertoni|date=2015|title=Advances in understanding the pathogenesis of systemic anaplastic large cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/25559471/|language=en|pmid=25559471}}</ref>:
**RAS-ERK
**RAS-ERK
**JAK/STAT
**JAK/STAT
Line 630: Line 736:
*ALK-NPM-STAT3 induces:
*ALK-NPM-STAT3 induces:
**See Epigenomics section above
**See Epigenomics section above
**TGF beta, IL-10, PD-L1/CD274 to create immunosuppressive microenvironment and evasion of immune system<ref>{{Cite journal|last=Marzec|first=Michal|last2=Zhang|first2=Qian|last3=Goradia|first3=Ami|last4=Raghunath|first4=Puthiyaveettil N.|last5=Liu|first5=Xiaobin|last6=Paessler|first6=Michele|last7=Wang|first7=Hong Yi|last8=Wysocka|first8=Maria|last9=Cheng|first9=Mangeng|date=2008-12-30|title=Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)|url=https://pubmed.ncbi.nlm.nih.gov/19088198|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=105|issue=52|pages=20852–20857|doi=10.1073/pnas.0810958105|issn=1091-6490|pmc=2634900|pmid=19088198}}</ref><ref>{{Cite journal|last=Kasprzycka|first=Monika|last2=Zhang|first2=Qian|last3=Witkiewicz|first3=Agnieszka|last4=Marzec|first4=Michal|last5=Potoczek|first5=Magdalena|last6=Liu|first6=Xiaobin|last7=Wang|first7=Hong Yi|last8=Milone|first8=Michael|last9=Basu|first9=Samik|date=2008-08-15|title=Gamma c-signaling cytokines induce a regulatory T cell phenotype in malignant CD4+ T lymphocytes|url=https://pubmed.ncbi.nlm.nih.gov/18684941|journal=Journal of Immunology (Baltimore, Md.: 1950)|volume=181|issue=4|pages=2506–2512|doi=10.4049/jimmunol.181.4.2506|issn=1550-6606|pmc=2586884|pmid=18684941}}</ref><ref>{{Cite journal|last=Yamamoto|first=Ryo|last2=Nishikori|first2=Momoko|last3=Tashima|first3=Masaharu|last4=Sakai|first4=Tomomi|last5=Ichinohe|first5=Tatsuo|last6=Takaori-Kondo|first6=Akifumi|last7=Ohmori|first7=Katsuyuki|last8=Uchiyama|first8=Takashi|date=2009-11|title=B7-H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19703193|journal=Cancer Science|volume=100|issue=11|pages=2093–2100|doi=10.1111/j.1349-7006.2009.01302.x|issn=1349-7006|pmid=19703193}}</ref>
**TGF beta, IL-10, PD-L1/CD274 to create immunosuppressive microenvironment and evasion of immune system<ref name=":31">{{Cite journal|last=Marzec|first=Michal|last2=Zhang|first2=Qian|last3=Goradia|first3=Ami|last4=Raghunath|first4=Puthiyaveettil N.|last5=Liu|first5=Xiaobin|last6=Paessler|first6=Michele|last7=Wang|first7=Hong Yi|last8=Wysocka|first8=Maria|last9=Cheng|first9=Mangeng|date=2008-12-30|title=Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)|url=https://pubmed.ncbi.nlm.nih.gov/19088198|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=105|issue=52|pages=20852–20857|doi=10.1073/pnas.0810958105|issn=1091-6490|pmc=2634900|pmid=19088198}}</ref><ref name=":32">{{Cite journal|last=Kasprzycka|first=Monika|last2=Zhang|first2=Qian|last3=Witkiewicz|first3=Agnieszka|last4=Marzec|first4=Michal|last5=Potoczek|first5=Magdalena|last6=Liu|first6=Xiaobin|last7=Wang|first7=Hong Yi|last8=Milone|first8=Michael|last9=Basu|first9=Samik|date=2008-08-15|title=Gamma c-signaling cytokines induce a regulatory T cell phenotype in malignant CD4+ T lymphocytes|url=https://pubmed.ncbi.nlm.nih.gov/18684941|journal=Journal of Immunology (Baltimore, Md.: 1950)|volume=181|issue=4|pages=2506–2512|doi=10.4049/jimmunol.181.4.2506|issn=1550-6606|pmc=2586884|pmid=18684941}}</ref><ref name=":33">{{Cite journal|last=Yamamoto|first=Ryo|last2=Nishikori|first2=Momoko|last3=Tashima|first3=Masaharu|last4=Sakai|first4=Tomomi|last5=Ichinohe|first5=Tatsuo|last6=Takaori-Kondo|first6=Akifumi|last7=Ohmori|first7=Katsuyuki|last8=Uchiyama|first8=Takashi|date=2009-11|title=B7-H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19703193|journal=Cancer Science|volume=100|issue=11|pages=2093–2100|doi=10.1111/j.1349-7006.2009.01302.x|issn=1349-7006|pmid=19703193}}</ref>
**ICOS expression (CD28 costimulatory receptor superfamily)
**ICOS expression (CD28 costimulatory receptor superfamily)
**HIF1α expression induces expression of VEGF (tumor angiogenesis); allows lymphoma cells to adapt to hypoxic conditions<ref>{{Cite journal|last=Martinengo|first=Cinzia|last2=Poggio|first2=Teresa|last3=Menotti|first3=Matteo|last4=Scalzo|first4=Maria Stella|last5=Mastini|first5=Cristina|last6=Ambrogio|first6=Chiara|last7=Pellegrino|first7=Elisa|last8=Riera|first8=Ludovica|last9=Piva|first9=Roberto|date=2014-11-01|title=ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis|url=https://pubmed.ncbi.nlm.nih.gov/25193384|journal=Cancer Research|volume=74|issue=21|pages=6094–6106|doi=10.1158/0008-5472.CAN-14-0268|issn=1538-7445|pmid=25193384}}</ref>
**HIF1α expression induces expression of VEGF (tumor angiogenesis); allows lymphoma cells to adapt to hypoxic conditions<ref name=":34">{{Cite journal|last=Martinengo|first=Cinzia|last2=Poggio|first2=Teresa|last3=Menotti|first3=Matteo|last4=Scalzo|first4=Maria Stella|last5=Mastini|first5=Cristina|last6=Ambrogio|first6=Chiara|last7=Pellegrino|first7=Elisa|last8=Riera|first8=Ludovica|last9=Piva|first9=Roberto|date=2014-11-01|title=ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis|url=https://pubmed.ncbi.nlm.nih.gov/25193384|journal=Cancer Research|volume=74|issue=21|pages=6094–6106|doi=10.1158/0008-5472.CAN-14-0268|issn=1538-7445|pmid=25193384}}</ref>
*Expression of embryonic genes (SOX2, SALL4) promoting stem cell-like program
*Expression of embryonic genes (SOX2, SALL4) promoting stem cell-like program
*Deregulation of microRNAs (miR-155, miR-101, miR-17-92 cluster, miR-26a, miR-16)<ref>{{Cite journal|last=Rodriguez|first=Antony|last2=Vigorito|first2=Elena|last3=Clare|first3=Simon|last4=Warren|first4=Madhuri V.|last5=Couttet|first5=Philippe|last6=Soond|first6=Dalya R.|last7=van Dongen|first7=Stijn|last8=Grocock|first8=Russell J.|last9=Das|first9=Partha P.|date=2007-04-27|title=Requirement of bic/microRNA-155 for normal immune function|url=https://pubmed.ncbi.nlm.nih.gov/17463290|journal=Science (New York, N.Y.)|volume=316|issue=5824|pages=608–611|doi=10.1126/science.1139253|issn=1095-9203|pmc=2610435|pmid=17463290}}</ref><ref>{{Cite journal|last=Merkel|first=Olaf|last2=Hamacher|first2=Frank|last3=Laimer|first3=Daniela|last4=Sifft|first4=Eveline|last5=Trajanoski|first5=Zlatko|last6=Scheideler|first6=Marcel|last7=Egger|first7=Gerda|last8=Hassler|first8=Melanie R.|last9=Thallinger|first9=Christiane|date=2010-09-14|title=Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK- anaplastic large-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/20805506|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=107|issue=37|pages=16228–16233|doi=10.1073/pnas.1009719107|issn=1091-6490|pmc=2941277|pmid=20805506}}</ref><ref>{{Cite journal|last=Spaccarotella|first=Elisa|last2=Pellegrino|first2=Elisa|last3=Ferracin|first3=Manuela|last4=Ferreri|first4=Cristina|last5=Cuccuru|first5=Giuditta|last6=Liu|first6=Cuiling|last7=Iqbal|first7=Javeed|last8=Cantarella|first8=Daniela|last9=Taulli|first9=Riccardo|date=2014-01|title=STAT3-mediated activation of microRNA cluster 17~92 promotes proliferation and survival of ALK-positive anaplastic large cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/23975180|journal=Haematologica|volume=99|issue=1|pages=116–124|doi=10.3324/haematol.2013.088286|issn=1592-8721|pmc=4007939|pmid=23975180}}</ref><ref>{{Cite journal|last=Zhu|first=Haifeng|last2=Vishwamitra|first2=Deeksha|last3=Curry|first3=Choladda V.|last4=Manshouri|first4=Roxsan|last5=Diao|first5=Lixia|last6=Khan|first6=Aarish|last7=Amin|first7=Hesham M.|date=2013-05|title=NPM-ALK up-regulates iNOS expression through a STAT3/microRNA-26a-dependent mechanism|url=https://pubmed.ncbi.nlm.nih.gov/23338972|journal=The Journal of Pathology|volume=230|issue=1|pages=82–94|doi=10.1002/path.4171|issn=1096-9896|pmc=3940725|pmid=23338972}}</ref><ref>{{Cite journal|last=Dejean|first=E.|last2=Renalier|first2=M. H.|last3=Foisseau|first3=M.|last4=Agirre|first4=X.|last5=Joseph|first5=N.|last6=de Paiva|first6=G. R.|last7=Al Saati|first7=T.|last8=Soulier|first8=J.|last9=Desjobert|first9=C.|date=2011-12|title=Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/21778999|journal=Leukemia|volume=25|issue=12|pages=1882–1890|doi=10.1038/leu.2011.168|issn=1476-5551|pmid=21778999}}</ref>
*Deregulation of microRNAs (miR-155, miR-101, miR-17-92 cluster, miR-26a, miR-16)<ref name=":35">{{Cite journal|last=Rodriguez|first=Antony|last2=Vigorito|first2=Elena|last3=Clare|first3=Simon|last4=Warren|first4=Madhuri V.|last5=Couttet|first5=Philippe|last6=Soond|first6=Dalya R.|last7=van Dongen|first7=Stijn|last8=Grocock|first8=Russell J.|last9=Das|first9=Partha P.|date=2007-04-27|title=Requirement of bic/microRNA-155 for normal immune function|url=https://pubmed.ncbi.nlm.nih.gov/17463290|journal=Science (New York, N.Y.)|volume=316|issue=5824|pages=608–611|doi=10.1126/science.1139253|issn=1095-9203|pmc=2610435|pmid=17463290}}</ref><ref name=":36">{{Cite journal|last=Merkel|first=Olaf|last2=Hamacher|first2=Frank|last3=Laimer|first3=Daniela|last4=Sifft|first4=Eveline|last5=Trajanoski|first5=Zlatko|last6=Scheideler|first6=Marcel|last7=Egger|first7=Gerda|last8=Hassler|first8=Melanie R.|last9=Thallinger|first9=Christiane|date=2010-09-14|title=Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK- anaplastic large-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/20805506|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=107|issue=37|pages=16228–16233|doi=10.1073/pnas.1009719107|issn=1091-6490|pmc=2941277|pmid=20805506}}</ref><ref name=":37">{{Cite journal|last=Spaccarotella|first=Elisa|last2=Pellegrino|first2=Elisa|last3=Ferracin|first3=Manuela|last4=Ferreri|first4=Cristina|last5=Cuccuru|first5=Giuditta|last6=Liu|first6=Cuiling|last7=Iqbal|first7=Javeed|last8=Cantarella|first8=Daniela|last9=Taulli|first9=Riccardo|date=2014-01|title=STAT3-mediated activation of microRNA cluster 17~92 promotes proliferation and survival of ALK-positive anaplastic large cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/23975180|journal=Haematologica|volume=99|issue=1|pages=116–124|doi=10.3324/haematol.2013.088286|issn=1592-8721|pmc=4007939|pmid=23975180}}</ref><ref name=":38">{{Cite journal|last=Zhu|first=Haifeng|last2=Vishwamitra|first2=Deeksha|last3=Curry|first3=Choladda V.|last4=Manshouri|first4=Roxsan|last5=Diao|first5=Lixia|last6=Khan|first6=Aarish|last7=Amin|first7=Hesham M.|date=2013-05|title=NPM-ALK up-regulates iNOS expression through a STAT3/microRNA-26a-dependent mechanism|url=https://pubmed.ncbi.nlm.nih.gov/23338972|journal=The Journal of Pathology|volume=230|issue=1|pages=82–94|doi=10.1002/path.4171|issn=1096-9896|pmc=3940725|pmid=23338972}}</ref><ref name=":39">{{Cite journal|last=Dejean|first=E.|last2=Renalier|first2=M. H.|last3=Foisseau|first3=M.|last4=Agirre|first4=X.|last5=Joseph|first5=N.|last6=de Paiva|first6=G. R.|last7=Al Saati|first7=T.|last8=Soulier|first8=J.|last9=Desjobert|first9=C.|date=2011-12|title=Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/21778999|journal=Leukemia|volume=25|issue=12|pages=1882–1890|doi=10.1038/leu.2011.168|issn=1476-5551|pmid=21778999}}</ref>


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
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==Additional Information==
==Additional Information==
This disease is <u>defined/characterized</u> as detailed below:
Anaplastic Large Cell Lymphoma, ALK-Positive (ALK+ ALCL) is a T-cell lymphoma characterized by usually large lymphoma cells with abundant cytoplasm and pleomorphic nuclei, often horse-shoe shaped (see Morphologic Features below), with a chromosomal rearrangement involving the ALK gene resulting in expression of ALK protein and CD30
The <u>epidemiology/prevalence</u> of this disease is detailed below:
*ALCL ([[ALK]]+, ALK-, and primary cutaneous) account for <5% of all cases of non-Hodgkin lymphoma (NHL)<ref name=":0" />
*ALK+ ALCL<ref name=":0" />
**~3% of adult NHL
**10-20% of childhood lymphomas
**Most frequent in the first three decades of life
**Male:female = 1.5:1
The <u>clinical features</u> of this disease are detailed below:
Signs and symptoms - Most patients (70%) present with advanced (stage III-IV) disease and B-symptoms.<ref name=":19">{{Cite journal|last=Savage|first=Kerry J.|last2=Harris|first2=Nancy Lee|last3=Vose|first3=Julie M.|last4=Ullrich|first4=Fred|last5=Jaffe|first5=Elaine S.|last6=Connors|first6=Joseph M.|last7=Rimsza|first7=Lisa|last8=Pileri|first8=Stefano A.|last9=Chhanabhai|first9=Mukesh|date=2008-06-15|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/|journal=Blood|volume=111|issue=12|pages=5496–5504|doi=10.1182/blood-2008-01-134270|issn=1528-0020|pmid=18385450}}</ref>
Laboratory findings - Noncontributory
The <u>sites of involvement</u> of this disease are detailed below:
*Lymph nodes and extranodal sites (most commonly skin, bone, soft tissue, lungs and liver)<ref name=":0" />
*Bone marrow involvement detected in 30% when using immunohistochemistry (CD30 and EMA). Can miss marrow involvement by H&E evaluation alone, which detects involvement with ~10% incidence.<ref>{{Cite journal|last=M|first=Fraga|last2=P|first2=Brousset|last3=D|first3=Schlaifer|last4=C|first4=Payen|last5=A|first5=Robert|last6=H|first6=Rubie|last7=F|first7=Huguet-Rigal|last8=G|first8=Delsol|date=1995|title=Bone marrow involvement in anaplastic large cell lymphoma. Immunohistochemical detection of minimal disease and its prognostic significance|url=https://pubmed.ncbi.nlm.nih.gov/7817951/|language=en|pmid=7817951}}</ref>
The <u>morphologic features</u> of this disease are detailed below:
"Hallmark cells"<ref>{{Cite journal|last=Stein|first=H.|last2=Foss|first2=H. D.|last3=Dürkop|first3=H.|last4=Marafioti|first4=T.|last5=Delsol|first5=G.|last6=Pulford|first6=K.|last7=Pileri|first7=S.|last8=Falini|first8=B.|date=2000-12-01|title=CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features|url=https://pubmed.ncbi.nlm.nih.gov/11090048/|journal=Blood|volume=96|issue=12|pages=3681–3695|issn=0006-4971|pmid=11090048}}</ref><ref>{{Cite journal|last=Benharroch|first=D.|last2=Meguerian-Bedoyan|first2=Z.|last3=Lamant|first3=L.|last4=Amin|first4=C.|last5=Brugières|first5=L.|last6=Terrier-Lacombe|first6=M. J.|last7=Haralambieva|first7=E.|last8=Pulford|first8=K.|last9=Pileri|first9=S.|date=1998-03-15|title=ALK-positive lymphoma: a single disease with a broad spectrum of morphology|url=https://pubmed.ncbi.nlm.nih.gov/9490693/|journal=Blood|volume=91|issue=6|pages=2076–2084|issn=0006-4971|pmid=9490693}}</ref>
*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
*Present in varying proportions
*Seen in all morphological variants/patterns of ALK+ ALCL


*None
Morphological variants/patterns
 
#Common (60%): predominant population of large hallmark cells
#Lymphohistiocytic (10%): lymphoma cells are admixed with numerous reactive histiocytes that may obscure the lymphoma cells; lymphoma cells often cluster around vessels and are often smaller than in the common pattern
#Small cell (5-10%): predominant population of smaller lymphoma cells; hallmark cells are often concentrated around vessels; may also see "fried egg cells" (pale cytoplasm with central nucleus) or signet ring-like cells; can misdiagnose of peripheral T-cell lymphoma, NOS
#Hodgkin-like (3%): mimics nodular sclerosis classic Hodgkin lymphoma
#Composite (15%): more than one pattern in a single lymph node
 
When lymph node is only partially involved, lymphoma characteristically grows in the sinuses, which may mimic a metastatic tumor.
 
The <u>immunophenotype</u> of this disease is detailed below:
 
* CD30 expression on ALCL (ALK+ or ALK-) allows for targeted therapy<ref name=":2" />. First-line therapy: [https://www.fda.gov/drugs/fda-approves-brentuximab-vedotin-previously-untreated-salcl-and-cd30-expressing-ptcl Brentuximab] (anti-CD30) vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone)
 
CD30+''':''' Positive (universal) - cell membrane and Golgi; large lymphoma cells show strongest staining; smaller cells may show weak, partial to negative staining
 
ALK: Positive (universal) - cellular location of ALK staining varies depending on ALK translocation partner. In the most common t(2;5), most cases show both cytoplasmic and nuclear
 
EMA: positive (subset)
 
CD3: Positive (subset)
 
CD4: Positive (70%)
 
CD5: Negative in majority of cases
 
CD8: Positive in majority of cases
 
CD2: Positive in majority of cases
 
TIA1: Positive
 
Granzyme B: Positive
 
Perforin: Positive
 
CD45: Variably positive
 
CD25: Positive (universal)
 
BCL2: Negative (universal)


==Links==
==Links==
Line 655: Line 837:


==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 />
<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 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.
 
<nowiki>*</nowiki>''Citation of this Page'': “ALK-positive 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-positive_anaplastic_large_cell_lymphoma</nowiki>.
==Other Sections==
Primary Authors*


Prior Author(s): 


Miguel Gonzalez Mancera, MD
       


Sumire Kitahara, MD
<nowiki>*</nowiki>''Citation of this Page'': “ALK-positive 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-positive_anaplastic_large_cell_lymphoma</nowiki>.
 
Cedars-Sinai, Los Angeles, CA
 
__TOC__
 
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases A]]
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