Compendium of Cancer Genome Aberrations

Anaplastic Large Cell Lymphoma (ALK+/ALK−): Difference between revisions

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==Primary Author(s)*==
==Primary Author(s)*==
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Jennie Thurston, PhD., FACMGG
==WHO Classification of Disease==
==WHO Classification of Disease<ref name=":0">Deckert, M, Ferry, JA, Paulus, W, et al. Anaplastic large cell lymphoma (ALK+/ALK−). In: WHO Classification of Tumours Editorial Board. Central nervous system tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2021 [cited 2025 02 2]. (WHO classification of tumours series, 5th ed.; vol. 6). Available from: <nowiki>https://tumourclassification.iarc.who.int/chapters/45</nowiki>.</ref>==
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==Cancer Sub-Classification / Subtype==
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==Definition / Description of Disease==
==Definition / Description of Disease==
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Primary central nervous system lymphoma (PCNSL) represents approximately 4% of all primary brain tumors and 1% to 2% of non-Hodgkin lymphoma.<ref>Villano JL, Koshy M, Shaikh H, et al. Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer. 2011;105:1414-1418.</ref> PCNSL is defined as a lymphoma confined to the brain, spinal cord, and/or eye. Diffuse large B-cell lymphomas make up more than 95% of PCNSL cases.<ref>Camilleri-Broët S, Martin A, Moreau A, et al. Primary central nervous system lymphomas in 72 immunocompetent patients: pathologic findings and clinical correlations. Am J Clin Pathol. 1998;110:607-612.</ref> Anaplastic large cell lymphoma (ALCL) is a distinctive CD30-positive peripheral T-cell lymphoma that is rare in the CNS and is separated into two distinct types: ALK-positive (ALK+ ALCL) and ALK-negative (ALK− ALCL).<ref name=":0" /><ref name=":2">ALK-negative anaplastic large cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, <nowiki>https://ccga.io/index.php/HAEM5:ALK-negative_anaplastic_large_cell_lymphoma</nowiki>.</ref><ref name=":3">ALK-positive anaplastic large cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, <nowiki>https://ccga.io/index.php/HAEM5:ALK-positive_anaplastic_large_cell_lymphoma</nowiki>.</ref>  ALK+ ALCL occurs as single or multiple supratentorial parenchymal lesions.<ref name=":0" />
==Synonyms / Terminology==
==Synonyms / Terminology==
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None
==Epidemiology / Prevalence==
==Epidemiology / Prevalence==
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ALK+ ALCL occurs from early childhood to young adulthood with a male preponderance.<ref name=":1">George, D.H.; Scheithauer, B.W.; Aker, F.V.; Kurtin, P.J.; Burger, P.C.; Cameselle-Teijeiro, J.; McLendon, R.E.; Parisi, J.E.; Paulus, W.; Roggendorf, W.; et al. Primary Anaplastic Large Cell Lymphoma of the Central Nervous System: Prognostic Effect of ALK-1 Expression. Am. J. Surg. Pathol. 2003, 27, 487–493</ref><ref name=":3" />
 
ALK− ALCL affects adults (median age: 65 years), also with a male preponderance.<ref name=":2" />
==Clinical Features==
==Clinical Features==
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{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|'''Signs and Symptoms'''
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|weight loss, headache, seizures, nausea, fever, or a combination
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|'''Laboratory Findings'''
|EXAMPLE Cytopenias
|None
EXAMPLE Lymphocytosis (low level)
|}
|}
==Sites of Involvement==
==Sites of Involvement==
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ALK+ ALCL occurs as single or multiple supratentorial parenchymal lesions with or without infratentorial involvement, and rarely with spinal cord involvement. Extension to involve the meninges and (rarely) the skull can occur.<ref>Karikari, I.O.; Thomas, K.K.; Lagoo, A.; Cummings, T.J.; George, T.M. Primary Cerebral ALK-1-Positive Anaplastic Large Cell Lymphoma in a Child. Pediatr. Neurosurg. 2007, 43, 516–521. [CrossRef] [PubMed]</ref><ref name=":0" />
 
ALK− ALCL occurs as single or multiple lesions, usually supratentorial<ref name=":0" />
==Morphologic Features==
==Morphologic Features==
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ALK+ ALCL shows a diffuse proliferation of large atypical cells with abundant cytoplasm, including hallmark cells with bean-shaped nuclei and an eosinophilic paranuclear area<ref>Jaffe ES. Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology. Modern Pathol. 2001;14:219-228.</ref>
 
The cerebrospinal fluid may be involved. The large atypical neoplastic cells may have cytoplasmic azurophilic granules<ref name=":0" />
==Immunophenotype==
==Immunophenotype==
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!Finding!!Marker
!Finding!!Marker
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|-
|Positive (universal)||EXAMPLE CD1
|Positive (universal)||CD30+, ALK+, and EMA+, may express one or more T-cell antigens<ref>Kadin ME. Primary Ki-1-positive anaplastic large-cell lymphoma: a distinct clinicopathologic entity. Ann Oncol. 1994;5:S25-S30.</ref>
|-
|Positive (subset)||EXAMPLE CD2
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|Negative (universal)||EXAMPLE CD3
|-
|Negative (subset)||EXAMPLE CD4
|}
|}
==Chromosomal Rearrangements (Gene Fusions)==
==Chromosomal Rearrangements (Gene Fusions) ALK+ ALCL==
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!Notes
!Notes
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
|t(2;5)(p23;q35)||''NPM1''::''ALK'' fusion
EXAMPLE 30% (add reference)
|5' NPM1::3' ALK on der(5). constitutive activation of the catalytic domain of ALK.  Kinase function activated by oligomerization of NPM1::ALK mediated by the NPM1 portion<ref>Geetha, N.; Sreelesh, K.P.; Nair, R.; Mathews, A. Anaplastic large cell lymphoma presenting as a cerebellar mass. Hematol. Oncol. Stem Cell Ther. 2014, 7, 157–161. </ref><ref>Benharroch D, Meguerian-Bedoyan Z, Lamant L, et al. ALK-positive lymphoma: a single disease with a broad spectrum of morphology. Blood. 1998;91:2076-2084.</ref>||30 to 50% of ALCL<ref name=":0" />
(COSF198)
(<ref>John G Tate, Sally Bamford, Harry C Jubb, Zbyslaw Sondka, David M Beare, Nidhi Bindal, Harry Boutselakis, Charlotte G Cole, Celestino Creatore, Elisabeth Dawson, Peter Fish, Bhavana Harsha, Charlie Hathaway, Steve C Jupe, Chai Yin Kok, Kate Noble, Laura Ponting, Christopher C Ramshaw, Claire E Rye, Helen E Speedy, Ray Stefancsik, Sam L Thompson, Shicai Wang, Sari Ward, Peter J Campbell, Simon A Forbes, COSMIC: the Catalogue Of Somatic Mutations In Cancer, ''Nucleic Acids Research'', Volume 47, Issue D1, 08 January 2019, Pages D941–D947,</ref>)
|Yes
|Yes
|No
|Yes
|Yes
|EXAMPLE
|Yes
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).
|Localized in both cytoplasm and nucleus.<ref name=":0" />
 
 
In translocations other than the t(2;5), i.e. in t(2;Var) involving various partners and ALK, the fusion protein has a cytoplasmic localization; they are therefore called "cytoplasm only" ALK+ ALCL.<ref name=":0" />
|-
|t(X;2)(q11;p23)
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|5'MSN:: 3'ALK
|very rare, one case reported
|
|
|
|For the t(X;2) translocation, localization is restricted to the membrane.<ref name=":0" />
|-
|t(1;2)(q25;p23)
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|5'TPM3::3'ALK
|rare, four cases reported
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|TPM3::ALK is constitutively activated<ref name=":0" />
|-
|inv(2)(p23q35)
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|5'ATIC::3'ALK
|rare
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|ider(2)(q10)inv(2) has been found in some cases, carrying 2 additional copies of the ATIC::ALK hybrid gene; frequent complex karyotypes<ref name=":0" />
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|t(2;3)(p23;q21)
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|5'TFG::3-ALK
|very rare, two cases reported
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|t(2;17)(p23;q23)
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|5'CLTC::3'ALK
|very rare, one case reported
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|t(2;19)(p23; p13.1)
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|5'TPM4::3'ALK
|very rare, one case reported
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|-
|t(2;22)(p23;q11.2)
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|5'CLTCL1::3'ALK
|very rare, one or two cases
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|the localization is restricted to granules (vesicles) in the cytoplasm<ref name=":0" />
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==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==
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!Notes
!Notes
|-
|-
|EXAMPLE
|
7
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|EXAMPLE Loss
|
|EXAMPLE
|
chr7:1- 159,335,973 [hg38]
|
|EXAMPLE
|
chr7
|
|Yes
|
|Yes
|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
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8
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|EXAMPLE Gain
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|EXAMPLE
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chr8:1-145,138,636 [hg38]
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|EXAMPLE
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chr8
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|No
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|No
|No
|EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference).
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==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal Patterns==
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!Notes
!Notes
|-
|-
|EXAMPLE
|Complex Karyotype<ref name=":0" />
Co-deletion of 1p and 18q
|
|Yes
|
|No
|
|No
|See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with anapestic large cell lymphoma<ref name=":0" />.
|EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
|}
==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
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!Notes
!Notes
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
EXAMPLE:
EGFR; Exon 20 mutations
EXAMPLE: BRAF; Activating mutations
|EXAMPLE: TSG
|EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference)
|EXAMPLE: IDH1 R123H
|EXAMPLE: EGFR amplification
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|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
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|}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.
==Epigenomic Alterations==
==Epigenomic Alterations==
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<br />
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|ALK; Gene fusions resulting in overexpression
|EXAMPLE: MAPK signaling
|Activation of JAK/STAT3 signaling pathway
|EXAMPLE: Increased cell growth and proliferation
|Increased cell growth and proliferation
|-
|-
|EXAMPLE: CDKN2A; Inactivating mutations
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|EXAMPLE: Cell cycle regulation
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|EXAMPLE: Unregulated cell division
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|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|
|EXAMPLE:  Histone modification, chromatin remodeling
|
|EXAMPLE:  Abnormal gene expression program
|
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
Put your text here
IHC, FISH, and RT-PCR
==Familial Forms==
==Familial Forms==
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None
==Additional Information==
==Additional Information==
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<br />
==Links==
==Links==
Put your text placeholder here (use "Link" icon at top of page)
<br />
==References==
==References==
<references />(use "Cite" icon at top of page)
<references /><ref name=":0" />
===EXAMPLE Book===
 
#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, 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, p129-171.


(use "Cite" icon at top of page)
==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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
<references />
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