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

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{{DISPLAYTITLE:ALK-positive anaplastic large cell lymphoma}}
 
{{DISPLAYTITLE:ALK-positive anaplastic large cell lymphoma}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
  
 
{{Under Construction}}
 
{{Under Construction}}
  
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Anaplastic Large Cell Lymphoma, ALK-Positive]].
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<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>
 
}}</blockquote>
  
<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
+
<span style="color:#0070C0">(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)</span>
  
 
==Primary Author(s)*==
 
==Primary Author(s)*==
  
Put your text here<span style="color:#0070C0"> (''Name and affiliation; example:'' Jane Smith, PhD, Institute of Genomics) </span>
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Miguel Gonzalez Mancera, MD, Cedars-Sinai, Los Angeles, CA
  
__TOC__
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Sumire Kitahara, MD, Cedars-Sinai, Los Angeles, CA
 +
==WHO Classification of Disease==
  
==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'''
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!Structure
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
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!Disease
 
+
|-
EXAMPLE B-symptoms (weight loss, fever, night sweats)
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|Book
 
+
|Haematolymphoid Tumours (5th ed.)
EXAMPLE Fatigue
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|-
 
+
|Category
EXAMPLE Lymphadenopathy (uncommon)
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|T-cell and NK-cell lymphoid proliferations and lymphomas
 +
|-
 +
|Family
 +
|Mature T-cell and NK-cell neoplasms
 +
|-
 +
|Type
 +
|Anaplastic large cell lymphoma
 +
|-
 +
|Subtype(s)
 +
|ALK-positive anaplastic large cell lymphoma
 +
|}
 +
==WHO Essential and Desirable Genetic Diagnostic Criteria==
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<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
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{| class="wikitable"
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|+
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|WHO Essential Criteria (Genetics)*
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|
 +
|-
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|WHO Desirable Criteria (Genetics)*
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|
 +
|-
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|Other Classification
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|
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|}
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<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
 +
==Related Terminology==
 +
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
 +
{| class="wikitable"
 +
|+
 +
|Acceptable
 +
|
 
|-
 
|-
|'''Laboratory Findings'''
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|Not Recommended
|EXAMPLE Cytopenias
+
|
 
 
EXAMPLE Lymphocytosis (low level)
 
 
|}
 
|}
  
 +
==Gene Rearrangements==
 +
==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>
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{| class="wikitable sortable"
 +
|-
 +
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
 +
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
 +
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
 +
!Established Clinical Significance Per Guidelines - Yes or No (Source)
 +
!Clinical Relevance Details/Other Notes
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
 +
|<span class="blue-text">EXAMPLE:</span> Common (CML)
 +
|<span class="blue-text">EXAMPLE:</span> D, P, T
 +
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
 +
|<span class="blue-text">EXAMPLE:</span>
 +
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span> ''CIC''
 +
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
 +
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
 +
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
 +
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
 +
|<span class="blue-text">EXAMPLE:</span> D
 +
|
 +
|<span class="blue-text">EXAMPLE:</span>
  
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
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''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).
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span> ''ALK''
 +
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
  
*Most patients (70%) present with advanced (stage III-IV) disease and B-symptoms.<ref>{{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>
+
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
==Sites of Involvement==
+
|<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).
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
 +
|<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
 +
|
 +
|
 +
|-
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|}
  
*Lymph nodes and extranodal sites (most commonly skin, bone, soft tissue, lungs and liver)
 
*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>
 
  
 +
FISH is not required for diagnosis in routine practice <ref name=":27" /><ref name=":28" />.
  
<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>
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{| class="wikitable sortable"
==Morphologic Features==
+
|-
 +
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
 +
!Diagnostic Significance (Yes, No or Unknown)
 +
!Prognostic Significance (Yes, No or Unknown)
 +
!Therapeutic Significance (Yes, No or Unknown)
 +
!Notes
 +
|-
 +
|t(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
 +
|Yes
 +
|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.
  
"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
+
'''<u>Of note, identifying the ''ALK'' fusion partner is not considered necessary in routine clinical practice.</u>'''
*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
+
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" />
#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==
+
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" />
  
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
+
*Drug resistance may develop due to:
 
+
*#Mutations of the ALK gene impairing binding of the inhibitor<ref name=":3" />; other ALK inhibitors are not currently FDA-approved for use in ALK+ ALCL
{| class="wikitable sortable"
+
*#See also gene mutations section above
 +
*#Engagement of other cell signaling pathways
 +
|-
 +
|t(1;2)(q25;p23)<ref name=":10" />
 +
|3' ''ALK'' / 5' ''TPM3''
 +
|''TPM3::ALK'' Fusion protein
 +
|13%<ref name=":10" />
 +
|No
 +
|No
 +
|No
 +
|
 
|-
 
|-
!Finding!!Marker
+
|inv(2)(p23q35)<ref name=":11" />
 +
|3' ''ALK'' / 5' ''ATIC''
 +
|''ATIC::ALK'' fusion protein
 +
|1% <ref name=":11" />
 +
|No
 +
|No
 +
|No
 +
|
 
|-
 
|-
|Positive (universal)||EXAMPLE CD1
+
|t(2;3)(p23;q12.2)<ref name=":12" />
 +
|3' ''ALK'' / 5' ''TFG''
 +
|''TFG::ALK'' fusion protein
 +
|<1%
 +
|No
 +
|No
 +
|No
 +
|
 +
|-
 +
|t(2;17)(p23;q23)<ref name=":13" />
 +
|3' ''ALK'' / 5' ''CLTC''
 +
|''CLTC::ALK'' fusion protein
 +
|<1%
 +
|No
 +
|No
 +
|No
 +
|
 
|-
 
|-
|Positive (subset)||EXAMPLE CD2
+
|t(X;2)(q11-22;p23)<ref name=":14" />
 +
|3' ''ALK'' / 5' ''MSN''
 +
|''MSN::ALK'' fusion protein
 +
|<1%
 +
|No
 +
|No
 +
|No
 +
|
 
|-
 
|-
|Negative (universal)||EXAMPLE CD3
+
|t(2;19)(p23;p13.1)<ref name=":6" />
 +
|3' ''ALK'' / 5' ''TPM4''
 +
|''TPM4::ALK'' fusion protein
 +
|<1%
 +
|No
 +
|No
 +
|No
 +
|
 
|-
 
|-
|Negative (subset)||EXAMPLE CD4
+
|t(2;22)(p23;q11.2)<ref name=":15" />
|}
+
|3' ''ALK'' / 5' ''MYH9''
 
+
|''MYH9::ALK'' fusion protein
 
+
|<1%
<blockquote class='blockedit'>{{Box-round|title=v4:Immunophenotype|The content below was from the old template. Please incorporate above.}}
+
|No
[[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>:
+
|No
 
+
|No
*'''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"
 
 
|-
 
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
+
|t(2;17)(p23;q25)<ref name=":6" />
!Diagnostic Significance (Yes, No or Unknown)
+
|3' ''ALK'' / 5' ''RNF213''
!Prognostic Significance (Yes, No or Unknown)
+
|''RNF213::ALK'' fusion protein
!Therapeutic Significance (Yes, No or Unknown)
+
|<1%
!Notes
+
|No
 +
|No
 +
|No
 +
|
 
|-
 
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
+
|t(2;9)(p23;q33)<ref name=":16" />
EXAMPLE 30% (add reference)
+
|3' ''ALK'' / 5' ''TRAF-1''
|Yes
+
|''TRAF-1::ALK'' fusion protein
 +
|<1%
 +
|No
 +
|No
 
|No
 
|No
|Yes
+
|
|EXAMPLE
 
 
 
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
 
 
|}
 
|}
 
 
  
<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>{{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>
  
  
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
+
<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
 
* Chromosomal Rearrangements (Gene Fusions)
 
* Chromosomal Rearrangements (Gene Fusions)
 
* Individual Region Genomic Gain/Loss/LOH
 
* Individual Region Genomic Gain/Loss/LOH
 
* Characteristic Chromosomal Patterns
 
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
+
* Gene Mutations (SNV/INDEL)}}</blockquote>
 
Diagnosis
 
Diagnosis
  
 
*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 231: Line 321:
 
*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>
 
**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)
 
**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)
*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>{{Cite journal|last=Werner|first=Michael T.|last2=Zhao|first2=Chen|last3=Zhang|first3=Qian|last4=Wasik|first4=Mariusz A.|date=02 16, 2017|title=Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target|url=https://pubmed.ncbi.nlm.nih.gov/27879258|journal=Blood|volume=129|issue=7|pages=823–831|doi=10.1182/blood-2016-05-717793|issn=1528-0020|pmid=27879258}}</ref><ref name=":2" /><ref>{{Cite journal|displayauthors=1|last=Food and Drug Administration|first=|date=January 2021|title=FDA approves crizotinib for children and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma|url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-crizotinib-children-and-young-adults-relapsed-or-refractory-systemic-anaplastic-large?utm_medium=email&utm_source=govdelivery|journal=|volume=|pages=|via=}}</ref>
+
*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">{{Cite journal|last=Werner|first=Michael T.|last2=Zhao|first2=Chen|last3=Zhang|first3=Qian|last4=Wasik|first4=Mariusz A.|date=02 16, 2017|title=Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target|url=https://pubmed.ncbi.nlm.nih.gov/27879258|journal=Blood|volume=129|issue=7|pages=823–831|doi=10.1182/blood-2016-05-717793|issn=1528-0020|pmid=27879258}}</ref><ref name=":2" /><ref name=":22">{{Cite journal|displayauthors=1|last=Food and Drug Administration|first=|date=January 2021|title=FDA approves crizotinib for children and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma|url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-crizotinib-children-and-young-adults-relapsed-or-refractory-systemic-anaplastic-large?utm_medium=email&utm_source=govdelivery|journal=|volume=|pages=|via=}}</ref>
 
**Drug resistance may develop due to:  
 
**Drug resistance may develop due to:  
 
**#Mutations of the ALK gene impairing binding of the inhibitor<ref name=":3">{{Cite journal|last=Zdzalik|first=Daria|last2=Dymek|first2=Barbara|last3=Grygielewicz|first3=Paulina|last4=Gunerka|first4=Pawel|last5=Bujak|first5=Anna|last6=Lamparska-Przybysz|first6=Monika|last7=Wieczorek|first7=Maciej|last8=Dzwonek|first8=Karolina|date=2014-04|title=Activating mutations in ALK kinase domain confer resistance to structurally unrelated ALK inhibitors in NPM-ALK-positive anaplastic large-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/24509625|journal=Journal of Cancer Research and Clinical Oncology|volume=140|issue=4|pages=589–598|doi=10.1007/s00432-014-1589-3|issn=1432-1335|pmc=3949014|pmid=24509625}}</ref>; other ALK inhibitors are not currently FDA-approved for use in ALK+ ALCL
 
**#Mutations of the ALK gene impairing binding of the inhibitor<ref name=":3">{{Cite journal|last=Zdzalik|first=Daria|last2=Dymek|first2=Barbara|last3=Grygielewicz|first3=Paulina|last4=Gunerka|first4=Pawel|last5=Bujak|first5=Anna|last6=Lamparska-Przybysz|first6=Monika|last7=Wieczorek|first7=Maciej|last8=Dzwonek|first8=Karolina|date=2014-04|title=Activating mutations in ALK kinase domain confer resistance to structurally unrelated ALK inhibitors in NPM-ALK-positive anaplastic large-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/24509625|journal=Journal of Cancer Research and Clinical Oncology|volume=140|issue=4|pages=589–598|doi=10.1007/s00432-014-1589-3|issn=1432-1335|pmc=3949014|pmid=24509625}}</ref>; other ALK inhibitors are not currently FDA-approved for use in ALK+ ALCL
 
**#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 262: Line 406:
 
!Notes
 
!Notes
 
|-
 
|-
|EXAMPLE
+
|17p
 
+
|Gain
7
+
|17p11-pter
|EXAMPLE Loss
+
|
|EXAMPLE
+
|No
 
+
|Unclear
chr7:1- 159,335,973 [hg38]
+
|No
|EXAMPLE
+
|
 
+
|-
chr7
+
|17p
|Yes
+
|Gain
|Yes
+
|17q24 -qter
 +
|
 +
|No
 +
|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 346: Line 492:
 
|}
 
|}
 
 
 +
<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"
Line 387: Line 597:
 
!Notes
 
!Notes
 
|-
 
|-
|EXAMPLE: TP53; Variable LOF mutations
+
|LRP1B<ref name=":4" />
 
+
|TSG
EXAMPLE:
+
|19%
 
+
|No
EGFR; Exon 20 mutations
+
|No
 
+
|No
EXAMPLE: BRAF; Activating mutations
+
|No
|EXAMPLE: TSG
+
|No
|EXAMPLE: 20% (COSMIC)
+
|<br />
 
+
|-
EXAMPLE: 30% (add Reference)
+
|NOTCH1<ref name=":5" />
|EXAMPLE: IDH1 R123H
+
|Activating mutation
|EXAMPLE: EGFR amplification
+
|9.3% (p.Thr349Pro)
 +
10.2% (p.Thr311Pro)
 +
|No
 +
|No
 +
|No
 +
|No
 +
|Yes
 +
|May be a biomarker for risk of relapse<ref name=":5" />
 +
|-
 +
|TP53<ref name=":4" />
 +
|TSG
 +
|11%
 +
|No
 +
|No
 +
|No
 +
|Yes
 +
|No
 
|
 
|
 +
|-
 +
|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
 
|
 
|
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
+
|Yes
<br />
+
|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
 +
 
 +
*
 
|}
 
|}
 
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
 
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
  
  
<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
+
<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
  
 
*Limited literature on somatic mutations in ALK+ ALCL
 
*Limited literature on somatic mutations in ALK+ ALCL
Line 452: Line 686:
 
A variety of mechanisms for the acquired resistance to ALK inhibitors, such as crizotinib, have been described:
 
A variety of mechanisms for the acquired resistance to ALK inhibitors, such as crizotinib, have been described:
  
*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>{{Cite journal|last=Guérin|first=Annie|last2=Sasane|first2=Medha|last3=Zhang|first3=Jie|last4=Macalalad|first4=Alexander R.|last5=Galebach|first5=Philip|last6=Jarvis|first6=John|last7=Kageleiry|first7=Andrew|last8=Culver|first8=Kenneth|last9=Wu|first9=Eric Q.|date=2015-06|title=ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/25914136/|journal=Cancer Epidemiology|volume=39|issue=3|pages=307–312|doi=10.1016/j.canep.2015.04.005|issn=1877-783X|pmid=25914136}}</ref><ref>{{Cite journal|last=Gainor|first=Justin F.|last2=Varghese|first2=Anna M.|last3=Ou|first3=Sai-Hong Ignatius|last4=Kabraji|first4=Sheheryar|last5=Awad|first5=Mark M.|last6=Katayama|first6=Ryohei|last7=Pawlak|first7=Amanda|last8=Mino-Kenudson|first8=Mari|last9=Yeap|first9=Beow Y.|date=2013-08-01|title=ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/23729361/|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=19|issue=15|pages=4273–4281|doi=10.1158/1078-0432.CCR-13-0318|issn=1557-3265|pmc=3874127|pmid=23729361}}</ref><ref name=":7">{{Cite journal|last=Doebele|first=Robert C.|last2=Pilling|first2=Amanda B.|last3=Aisner|first3=Dara L.|last4=Kutateladze|first4=Tatiana G.|last5=Le|first5=Anh T.|last6=Weickhardt|first6=Andrew J.|last7=Kondo|first7=Kimi L.|last8=Linderman|first8=Derek J.|last9=Heasley|first9=Lynn E.|date=2012-03-01|title=Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/22235099/|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=18|issue=5|pages=1472–1482|doi=10.1158/1078-0432.CCR-11-2906|issn=1557-3265|pmc=3311875|pmid=22235099}}</ref><ref name=":8">{{Cite journal|last=Isozaki|first=Hideko|last2=Takigawa|first2=Nagio|last3=Kiura|first3=Katsuyuki|date=2015-04-30|title=Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer|url=https://pubmed.ncbi.nlm.nih.gov/25941796/|journal=Cancers|volume=7|issue=2|pages=763–783|doi=10.3390/cancers7020763|issn=2072-6694|pmc=4491683|pmid=25941796}}</ref><ref name=":9">{{Cite journal|last=Sasaki|first=Takaaki|last2=Koivunen|first2=Jussi|last3=Ogino|first3=Atsuko|last4=Yanagita|first4=Masahiko|last5=Nikiforow|first5=Sarah|last6=Zheng|first6=Wei|last7=Lathan|first7=Christopher|last8=Marcoux|first8=J. Paul|last9=Du|first9=Jinyan|date=2011-09-15|title=A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors|url=https://pubmed.ncbi.nlm.nih.gov/21791641/|journal=Cancer Research|volume=71|issue=18|pages=6051–6060|doi=10.1158/0008-5472.CAN-11-1340|issn=1538-7445|pmc=3278914|pmid=21791641}}</ref><ref>{{Cite journal|last=Toyokawa|first=Gouji|last2=Hirai|first2=Fumihiko|last3=Inamasu|first3=Eiko|last4=Yoshida|first4=Tsukihisa|last5=Nosaki|first5=Kaname|last6=Takenaka|first6=Tomoyoshi|last7=Yamaguchi|first7=Masafumi|last8=Seto|first8=Takashi|last9=Takenoyama|first9=Mitsuhiro|date=2014-12|title=Secondary mutations at I1171 in the ALK gene confer resistance to both Crizotinib and Alectinib|url=https://pubmed.ncbi.nlm.nih.gov/25393798/|journal=Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer|volume=9|issue=12|pages=e86–87|doi=10.1097/JTO.0000000000000358|issn=1556-1380|pmid=25393798}}</ref><ref>{{Cite journal|last=Li|first=Yanrong|last2=Wang|first2=Kai|last3=Song|first3=Na|last4=Hou|first4=Kezuo|last5=Che|first5=Xiaofang|last6=Zhou|first6=Yang|last7=Liu|first7=Yunpeng|last8=Zhang|first8=Jingdong|date=2020-06|title=Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/31177400/|journal=Investigational New Drugs|volume=38|issue=3|pages=599–609|doi=10.1007/s10637-019-00802-7|issn=1573-0646|pmid=31177400}}</ref>
+
*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">{{Cite journal|last=Guérin|first=Annie|last2=Sasane|first2=Medha|last3=Zhang|first3=Jie|last4=Macalalad|first4=Alexander R.|last5=Galebach|first5=Philip|last6=Jarvis|first6=John|last7=Kageleiry|first7=Andrew|last8=Culver|first8=Kenneth|last9=Wu|first9=Eric Q.|date=2015-06|title=ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/25914136/|journal=Cancer Epidemiology|volume=39|issue=3|pages=307–312|doi=10.1016/j.canep.2015.04.005|issn=1877-783X|pmid=25914136}}</ref><ref name=":24">{{Cite journal|last=Gainor|first=Justin F.|last2=Varghese|first2=Anna M.|last3=Ou|first3=Sai-Hong Ignatius|last4=Kabraji|first4=Sheheryar|last5=Awad|first5=Mark M.|last6=Katayama|first6=Ryohei|last7=Pawlak|first7=Amanda|last8=Mino-Kenudson|first8=Mari|last9=Yeap|first9=Beow Y.|date=2013-08-01|title=ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/23729361/|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=19|issue=15|pages=4273–4281|doi=10.1158/1078-0432.CCR-13-0318|issn=1557-3265|pmc=3874127|pmid=23729361}}</ref><ref name=":7">{{Cite journal|last=Doebele|first=Robert C.|last2=Pilling|first2=Amanda B.|last3=Aisner|first3=Dara L.|last4=Kutateladze|first4=Tatiana G.|last5=Le|first5=Anh T.|last6=Weickhardt|first6=Andrew J.|last7=Kondo|first7=Kimi L.|last8=Linderman|first8=Derek J.|last9=Heasley|first9=Lynn E.|date=2012-03-01|title=Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/22235099/|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=18|issue=5|pages=1472–1482|doi=10.1158/1078-0432.CCR-11-2906|issn=1557-3265|pmc=3311875|pmid=22235099}}</ref><ref name=":8">{{Cite journal|last=Isozaki|first=Hideko|last2=Takigawa|first2=Nagio|last3=Kiura|first3=Katsuyuki|date=2015-04-30|title=Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer|url=https://pubmed.ncbi.nlm.nih.gov/25941796/|journal=Cancers|volume=7|issue=2|pages=763–783|doi=10.3390/cancers7020763|issn=2072-6694|pmc=4491683|pmid=25941796}}</ref><ref name=":9">{{Cite journal|last=Sasaki|first=Takaaki|last2=Koivunen|first2=Jussi|last3=Ogino|first3=Atsuko|last4=Yanagita|first4=Masahiko|last5=Nikiforow|first5=Sarah|last6=Zheng|first6=Wei|last7=Lathan|first7=Christopher|last8=Marcoux|first8=J. Paul|last9=Du|first9=Jinyan|date=2011-09-15|title=A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors|url=https://pubmed.ncbi.nlm.nih.gov/21791641/|journal=Cancer Research|volume=71|issue=18|pages=6051–6060|doi=10.1158/0008-5472.CAN-11-1340|issn=1538-7445|pmc=3278914|pmid=21791641}}</ref><ref name=":25">{{Cite journal|last=Toyokawa|first=Gouji|last2=Hirai|first2=Fumihiko|last3=Inamasu|first3=Eiko|last4=Yoshida|first4=Tsukihisa|last5=Nosaki|first5=Kaname|last6=Takenaka|first6=Tomoyoshi|last7=Yamaguchi|first7=Masafumi|last8=Seto|first8=Takashi|last9=Takenoyama|first9=Mitsuhiro|date=2014-12|title=Secondary mutations at I1171 in the ALK gene confer resistance to both Crizotinib and Alectinib|url=https://pubmed.ncbi.nlm.nih.gov/25393798/|journal=Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer|volume=9|issue=12|pages=e86–87|doi=10.1097/JTO.0000000000000358|issn=1556-1380|pmid=25393798}}</ref><ref name=":26">{{Cite journal|last=Li|first=Yanrong|last2=Wang|first2=Kai|last3=Song|first3=Na|last4=Hou|first4=Kezuo|last5=Che|first5=Xiaofang|last6=Zhou|first6=Yang|last7=Liu|first7=Yunpeng|last8=Zhang|first8=Jingdong|date=2020-06|title=Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/31177400/|journal=Investigational New Drugs|volume=38|issue=3|pages=599–609|doi=10.1007/s10637-019-00802-7|issn=1573-0646|pmid=31177400}}</ref>
 
*The G1269A mutation, in which the glycine at 1269 is substituted with an alanine, causes steric hindrance, resulting in decreased affinity for crizotinib.<ref>{{Cite journal|last=Friboulet|first=Luc|last2=Li|first2=Nanxin|last3=Katayama|first3=Ryohei|last4=Lee|first4=Christian C.|last5=Gainor|first5=Justin F.|last6=Crystal|first6=Adam S.|last7=Michellys|first7=Pierre-Yves|last8=Awad|first8=Mark M.|last9=Yanagitani|first9=Noriko|date=2014-06|title=The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/24675041/|journal=Cancer Discovery|volume=4|issue=6|pages=662–673|doi=10.1158/2159-8290.CD-13-0846|issn=2159-8290|pmc=4068971|pmid=24675041}}</ref><ref>{{Cite journal|last=Alshareef|first=Abdulraheem|last2=Zhang|first2=Hai-Feng|last3=Huang|first3=Yung-Hsing|last4=Wu|first4=Chengsheng|last5=Zhang|first5=Jing Dong|last6=Wang|first6=Peng|last7=El-Sehemy|first7=Ahmed|last8=Fares|first8=Mohamed|last9=Lai|first9=Raymond|date=2016-09-19|title=The use of cellular thermal shift assay (CETSA) to study Crizotinib resistance in ALK-expressing human cancers|url=https://pubmed.ncbi.nlm.nih.gov/27641368/|journal=Scientific Reports|volume=6|pages=33710|doi=10.1038/srep33710|issn=2045-2322|pmc=5027386|pmid=27641368}}</ref>
 
*The G1269A mutation, in which the glycine at 1269 is substituted with an alanine, causes steric hindrance, resulting in decreased affinity for crizotinib.<ref>{{Cite journal|last=Friboulet|first=Luc|last2=Li|first2=Nanxin|last3=Katayama|first3=Ryohei|last4=Lee|first4=Christian C.|last5=Gainor|first5=Justin F.|last6=Crystal|first6=Adam S.|last7=Michellys|first7=Pierre-Yves|last8=Awad|first8=Mark M.|last9=Yanagitani|first9=Noriko|date=2014-06|title=The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/24675041/|journal=Cancer Discovery|volume=4|issue=6|pages=662–673|doi=10.1158/2159-8290.CD-13-0846|issn=2159-8290|pmc=4068971|pmid=24675041}}</ref><ref>{{Cite journal|last=Alshareef|first=Abdulraheem|last2=Zhang|first2=Hai-Feng|last3=Huang|first3=Yung-Hsing|last4=Wu|first4=Chengsheng|last5=Zhang|first5=Jing Dong|last6=Wang|first6=Peng|last7=El-Sehemy|first7=Ahmed|last8=Fares|first8=Mohamed|last9=Lai|first9=Raymond|date=2016-09-19|title=The use of cellular thermal shift assay (CETSA) to study Crizotinib resistance in ALK-expressing human cancers|url=https://pubmed.ncbi.nlm.nih.gov/27641368/|journal=Scientific Reports|volume=6|pages=33710|doi=10.1038/srep33710|issn=2045-2322|pmc=5027386|pmid=27641368}}</ref>
 
*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 472: Line 710:
 
==Genes and Main Pathways Involved==
 
==Genes and Main Pathways Involved==
  
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
+
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
 
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
+
|ALK; fusion protein derivatives
|EXAMPLE: MAPK signaling
+
|Ras-ERK<ref name=":30" />
|EXAMPLE: Increased cell growth and proliferation
+
|Increased cell growth and proliferation
 
|-
 
|-
|EXAMPLE: CDKN2A; Inactivating mutations
+
|ALK; fusion protein derivatives
|EXAMPLE: Cell cycle regulation
+
|JAK/STAT3<ref name=":30" />
|EXAMPLE: Unregulated cell division
+
|Cell survival and phenotypic changes
 
|-
 
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
+
|ALK; fusion protein derivatives
|EXAMPLE:  Histone modification, chromatin remodeling
+
|PI3K/AKT/mTOR<ref name=":30" />
|EXAMPLE:  Abnormal gene expression program
+
|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 502: Line 751:
 
*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==
Line 519: Line 771:
  
 
==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
 +
 +
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
  
*None
+
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 527: Line 852:
  
 
==References==
 
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
+
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
  
'''
+
<br />
  
 
==Notes==
 
==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage)Additional global feedback or concerns are also welcome.
+
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representativeWhen pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
 +
 
 +
Prior Author(s): 
 +
 
 +
       
  
 
<nowiki>*</nowiki>''Citation of this Page'': “ALK-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>.
 
<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>.
Line 544: Line 873:
  
 
Cedars-Sinai, Los Angeles, CA
 
Cedars-Sinai, Los Angeles, CA
 
+
[[Category:HAEM5]]
__TOC__
+
[[Category:DISEASE]]
 
+
[[Category:Diseases A]]
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]]
 

Latest revision as of 12:32, 24 March 2025

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Anaplastic Large Cell Lymphoma, ALK-Positive.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Miguel Gonzalez Mancera, MD, Cedars-Sinai, Los Angeles, CA

Sumire Kitahara, MD, Cedars-Sinai, Los Angeles, CA

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category T-cell and NK-cell lymphoid proliferations and lymphomas
Family Mature T-cell and NK-cell neoplasms
Type Anaplastic large cell lymphoma
Subtype(s) ALK-positive anaplastic large cell lymphoma

WHO Essential and Desirable Genetic Diagnostic Criteria

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

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

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

Related Terminology

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

Acceptable
Not Recommended

Gene Rearrangements

Gene Rearrangements

Put your text here and fill in the table (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.)

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

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).

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

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

EXAMPLE: ALK EXAMPLE: ELM4::ALK


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

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

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

EXAMPLE: ABL1 EXAMPLE: N/A EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. EXAMPLE: N/A EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) EXAMPLE: D, P, T


FISH is not required for diagnosis in routine practice [1][2].

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
t(2;5)(p23;q35) 3' ALK / 5' NPM1[3] NPM1::ALK fusion protein 84%[4] No No Yes 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.


Of note, identifying the ALK fusion partner is not considered necessary in routine clinical practice.


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[5]


ALK inhibition (crizotinib) can be an effective 2nd-line therapeutic strategy as ALK is essential for the proliferation and survival of ALK+ ALCL cells[6][7][8]

  • Drug resistance may develop due to:
    1. Mutations of the ALK gene impairing binding of the inhibitor[9]; other ALK inhibitors are not currently FDA-approved for use in ALK+ ALCL
    2. See also gene mutations section above
    3. Engagement of other cell signaling pathways
t(1;2)(q25;p23)[10] 3' ALK / 5' TPM3 TPM3::ALK Fusion protein 13%[10] No No No
inv(2)(p23q35)[11] 3' ALK / 5' ATIC ATIC::ALK fusion protein 1% [11] No No No
t(2;3)(p23;q12.2)[12] 3' ALK / 5' TFG TFG::ALK fusion protein <1% No No No
t(2;17)(p23;q23)[13] 3' ALK / 5' CLTC CLTC::ALK fusion protein <1% No No No
t(X;2)(q11-22;p23)[14] 3' ALK / 5' MSN MSN::ALK fusion protein <1% No No No
t(2;19)(p23;p13.1)[15] 3' ALK / 5' TPM4 TPM4::ALK fusion protein <1% No No No
t(2;22)(p23;q11.2)[16] 3' ALK / 5' MYH9 MYH9::ALK fusion protein <1% No No No
t(2;17)(p23;q25)[15] 3' ALK / 5' RNF213 RNF213::ALK fusion protein <1% No No No
t(2;9)(p23;q33)[17] 3' ALK / 5' TRAF-1 TRAF-1::ALK fusion protein <1% No No No


editv4:Chromosomal Rearrangements (Gene Fusions)
The content below was from the old template. Please incorporate above.
  • 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.[3]
  • ALK translocations may be seen in multiple malignancies including epithelial malignancies[18][19][20][21][22][23], inflammatory myofibroblastic tumor[24][25][26], non-Hodgkin's lymphoma[27][28][29], and ALK+ histiocytosis [30][31][32].
FISH break apart probe for ALK gene showing a split signal indicating ALK rearrangement in a case of ALK(+) ALCL.


Table below shows described ALK translocations with ALK staining pattern, and frequency of cases. Of note, identifying the ALK fusion partner is not considered necessary in routine clinical practice.

Chromosomal

Anomaly

ALK partner ALK staining pattern Percentage

of cases

t(2;5)(p23;q35) NPM1 Nuclear, nucleolar, diffuse cytoplasmic 84%
t(1;2)(q25;p23)[10] TPM3 Diffuse cytoplasmic with peripheral intensification 13%
inv(2)(p23q35)[11] ATIC Diffuse cytoplasmic 1%
t(2;3)(p23;q12.2)[12] TFG Diffuse cytoplasmic <1%
t(2;17)(p23;q23)[13] CLTC Granular cytoplasmic <1%
t(X;2)(q11-22;p23)[14] MSN Membrane <1%
t(2;19)(p23;p13.1)[15] TPM4 Diffuse cytoplasmic <1%
t(2;22)(p23;q11.2)[16] MYH9 Diffuse cytoplasmic <1%
t(2;17)(p23;q25)[15] RNF213 Diffuse cytoplasmic <1%
t(2;9)(p23;q33)[17] TRAF-1 Diffuse cytoplasmic <1%
End of V4 Section


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)

Diagnosis

  • As stated above, the diagnosis is based on histology and immunohistochemistry
  • FISH is not required for diagnosis in routine practice [1][2]

Prognosis

  • ALK+ ALCL has a better survival rate compared to ALK-negative ALCL
    • However, differences in patient age (younger in ALK+) may account for this better survival[33]
  • 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%
  • 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[5]
  • Small-cell or lymphohistiocytic patterns tend to present with disseminated disease and have a less favorable prognosis than the common pattern[34]
  • NOTCH1 may be a biomarker for risk of relapse[35]

Therapy

  • CD30 expression on ALCL (ALK+ or ALK-) allows for targeted therapy[7]
    • First-line therapy: Brentuximab (anti-CD30) vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone)
  • ALK inhibition (crizotinib) can be an effective 2nd-line therapeutic strategy as ALK is essential for the proliferation and survival of ALK+ ALCL cells[6][7][8]
    • Drug resistance may develop due to:
      1. Mutations of the ALK gene impairing binding of the inhibitor[9]; other ALK inhibitors are not currently FDA-approved for use in ALK+ ALCL
      2. See also gene mutations section above
      3. Engagement of other cell signaling pathways
  • Preclinical models suggest role of:
    • Combination therapy with hypomethylating agents (such as azacitidine) and epigenetic modifying drugs (such as romidepsin, a histone deacetylase inhibitor)[36]
    • Inhibitors of HSP90 and mTOR inhibition[9]
    • 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[35]
End of V4 Section

Individual Region Genomic Gain/Loss/LOH

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

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

7

EXAMPLE: Loss EXAMPLE:

chr7

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE: No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE:

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

EXAMPLE:

17

EXAMPLE: Amp EXAMPLE:

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

EXAMPLE:

ERBB2

EXAMPLE: D, P, T EXAMPLE:

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

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
17p Gain 17p11-pter No Unclear No
17p Gain 17q24 -qter No Unclear No
4q Loss 4q13-q28 No Unclear No
11q Loss 11q14-q23 No Unclear No
editv4:Genomic Gain/Loss/LOH
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Frequent secondary chromosomal imbalances are seen in ALK+ ALCL (58% of cases), as based on comparative genomic hybridization analysis[37].

Chromosome Number Gain/Loss/Amp/LOH Frequency Comment
2q Gain 12%
4q Loss 28%
11q22 (ATM) Loss, LOH 28%
13q Loss 28% Also see in ALK- cases
7p Gain 12% Also seen in ALK- cases
17p13 (TP53) Gain 28%
17p13 (TP53) Loss[38] 9% More common in ALK- cases (42%)
17q24-qter Gain 28%
End of V4 Section

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern Molecular Pathogenesis Prevalence -

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

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

Co-deletion of 1p and 18q

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

Microsatellite instability - hypermutated

EXAMPLE: Common (Endometrial carcinoma) EXAMPLE: P, T
editv4:Characteristic Chromosomal Aberrations / Patterns
The content below was from the old template. Please incorporate above.

See other sections.

End of V4 Section

Gene Mutations (SNV/INDEL)

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

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

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


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


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

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


Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
LRP1B[39] TSG 19% No No No No No
NOTCH1[35] Activating mutation 9.3% (p.Thr349Pro)

10.2% (p.Thr311Pro)

No No No No Yes May be a biomarker for risk of relapse[35]
TP53[39] TSG 11% No No No Yes No
ALK[40][41][42][43][44][45][46] 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

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


editv4:Gene Mutations (SNV/INDEL)
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  • Limited literature on somatic mutations in ALK+ ALCL
Gene Function or Presumed Mechanism Frequency
LRP1B[39] Tumor suppressor 19%
NOTCH1[35] Activating 9.3% (p.Thr349Pro)

10.2% (p.Thr311Pro)

TP53[39] Tumor suppressor 11%
  • Epigenetic modifier genes: KMT2D, TET2, EP300, KMT2C[39]
  • Other mutations: EPHA5


Negative genes mutations:

  • JAK1, STAT3: Mutations described in ALK(-) ALCL[47], and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)[48]
  • RHOA, DNMT3A, CD28: Mutations described in peripheral T cell-lymphoma (PTCL), NOS, and in angioimmunoblastic T-cell lymphoma (AITL)[49]
  • IDH2 mutations are relatively specific for AITL[50][51]

A variety of mechanisms for the acquired resistance to ALK inhibitors, such as crizotinib, have been described:

  • 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[46][40][41][42][43][44][45]
  • The G1269A mutation, in which the glycine at 1269 is substituted with an alanine, causes steric hindrance, resulting in decreased affinity for crizotinib.[52][53]
  • Gain in ALK copy number and loss of ALK gene rearrangement have also been implicated in the development of acquired resistance to crizotinib.[41][42][43]
End of V4 Section

Epigenomic Alterations

  • NPM-ALK via STAT3-activated DNA methyltransferases[54] uses epigenetic silencing mechanisms to:
    • Downregulate tumor suppressor genes to maintain its own expression (i.e. to inhibit downregulation of NPM-ALK). Silenced tumor suppressors include:
      • STAT5A[55]
      • SHP-1 phosphotyrosine phosphatase[56]
      • IL-2Rγ[57]
      • miR-150[58]
      • DNMT1 mRNA inhibitor miR-21[57]
    • Silence T-cell receptor complex and signaling pathway (CD3e, ZAP70, LAT, SLP76)[59]
  • Histone H3 lysine 27 (H3K27) trimethylation silences promoters of important T-cell transcription factor genes (GATA3, TCF1 and LEF1)[60]
  • Reader is directed to this review for more comprehensive review of epigenetics in peripheral T-cell lymphomas[61]

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
ALK; fusion protein derivatives Ras-ERK[62] Increased cell growth and proliferation
ALK; fusion protein derivatives JAK/STAT3[62] Cell survival and phenotypic changes
ALK; fusion protein derivatives PI3K/AKT/mTOR[62] Cell survival and phenotypic changes
  • ALK-NPM-STAT3 induces:
    • See Epigenomics section above
    • TGF beta, IL-10, PD-L1/CD274 to create immunosuppressive microenvironment and evasion of immune system[63][64][65]
    • ICOS expression (CD28 costimulatory receptor superfamily)
    • HIF1α expression induces expression of VEGF (tumor angiogenesis); allows lymphoma cells to adapt to hypoxic conditions[66]
  • 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)[67][68][69][70][71]
editv4:Genes and Main Pathways Involved
The content below was from the old template. Please incorporate above.
  • Activation of the ALK catalytic domain leads to the oncogenic properties of the ALK protein, leading to activation of multiple signaling cascades including[62]:
    • RAS-ERK
    • JAK/STAT
      • STAT3 is a pivotal transcription factor in most ALCL subtypes:
        • NPM1/ALK and variants lead to expression of ALK fusion proteins with constitutive ALK tyrosine kinase activity, which converges in the activation of the downstream oncogenic transcription factor STAT3[47][49].
        • In the absence of ALK fusions there are activation JAK1 and/or STAT3 mutations in ALK(-) ALCL [47], and some BIA-ALCL. [72].
    • PI3K/AKT/mTOR
  • ALK-NPM-STAT3 induces:
    • See Epigenomics section above
    • TGF beta, IL-10, PD-L1/CD274 to create immunosuppressive microenvironment and evasion of immune system[63][64][65]
    • ICOS expression (CD28 costimulatory receptor superfamily)
    • HIF1α expression induces expression of VEGF (tumor angiogenesis); allows lymphoma cells to adapt to hypoxic conditions[66]
  • 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)[67][68][69][70][71]
End of V4 Section

Genetic Diagnostic Testing Methods

  • Diagnosis is based on histologic evaluation and immunohistochemical positivity for CD30 and ALK on the T-lymphoma cells.
  • FISH using an ALK breakapart probe or karyotype analysis can detect ALK translocations, but is not required for diagnosis as it can be established by morphology and immunohistochemistry.

Familial Forms

  • None

Additional Information

This disease is defined/characterized 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 epidemiology/prevalence of this disease is detailed below:

  • ALCL (ALK+, ALK-, and primary cutaneous) account for <5% of all cases of non-Hodgkin lymphoma (NHL)[4]
  • ALK+ ALCL[4]
    • ~3% of adult NHL
    • 10-20% of childhood lymphomas
    • Most frequent in the first three decades of life
    • Male:female = 1.5:1

The clinical features of this disease are detailed below:

Signs and symptoms - Most patients (70%) present with advanced (stage III-IV) disease and B-symptoms.[73]

Laboratory findings - Noncontributory

The sites of involvement of this disease are detailed below:

  • Lymph nodes and extranodal sites (most commonly skin, bone, soft tissue, lungs and liver)[4]
  • 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.[74]

The morphologic features of this disease are detailed below:

"Hallmark cells"[75][76]

  • 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

  1. Common (60%): predominant population of large hallmark cells
  2. 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
  3. 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
  4. Hodgkin-like (3%): mimics nodular sclerosis classic Hodgkin lymphoma
  5. 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 immunophenotype of this disease is detailed below:

  • CD30 expression on ALCL (ALK+ or ALK-) allows for targeted therapy[7]. First-line therapy: 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

  • See References.

References

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  1. Jump up to: 1.0 1.1 Falini, B.; et al. (1998-09). "ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum". The American Journal of Pathology. 153 (3): 875–886. doi:10.1016/S0002-9440(10)65629-5. ISSN 0002-9440. PMC 1853018. PMID 9736036. Check date values in: |date= (help)
  2. Jump up to: 2.0 2.1 Pittaluga, S.; et al. (1997-08). "The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements". The American Journal of Pathology. 151 (2): 343–351. ISSN 0002-9440. PMC 1858018. PMID 9250148. Check date values in: |date= (help)
  3. Jump up to: 3.0 3.1 Morris, S. W.; et al. (1994-03-04). "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Science (New York, N.Y.). 263 (5151): 1281–1284. doi:10.1126/science.8122112. ISSN 0036-8075. PMID 8122112.
  4. Jump up to: 4.0 4.1 4.2 4.3 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.
  5. Jump up to: 5.0 5.1 C, Damm-Welk; et al. (2014). "Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma". PMID 24297868.
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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):


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

Other Sections

Primary Authors*


Miguel Gonzalez Mancera, MD

Sumire Kitahara, MD

Cedars-Sinai, Los Angeles, CA