View source for Anaplastic Large Cell Lymphoma (ALK+/ALK−)

==Primary Author(s)*==
Jennie Thurston, PhD., FACMGG
==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>==
{| class="wikitable"
|+
!Structure
!Disease
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|Book
|WHO Classification of Tumours Central Nervous System Tumours (5th ed.)
|-
|Category
|Lymphomas
|-
|Family
|Miscellaneous rare lymphomas in CNS
|-
|Type
|Anaplastic Large Cell Lymphoma (ALK+/ALK-)
|-
|Subtype
|None
|}
==Definition / Description of Disease==
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==
None
==Epidemiology / Prevalence==
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==
{| class="wikitable"
|'''Signs and Symptoms'''
|weight loss, headache, seizures, nausea, fever, or a combination
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|'''Laboratory Findings'''
|None
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==Sites of Involvement==
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==
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==
{| class="wikitable sortable"
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!Finding!!Marker
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|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>
|}
==Chromosomal Rearrangements (Gene Fusions)  ALK+ ALCL==
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{| class="wikitable sortable"
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!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)||''NPM1''::''ALK'' fusion
|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
|Yes
|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" />
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|t(X;2)(q11;p23)
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|5'MSN:: 3'ALK
|very rare, one case reported
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|For the t(X;2) translocation, localization is restricted to the membrane.<ref name=":0" />
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|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" />
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|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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|
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|the localization is restricted to granules (vesicles) in the cytoplasm<ref name=":0" />
|}
==Individual Region Genomic Gain/Loss/LOH==
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{| class="wikitable sortable"
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!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
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==Characteristic Chromosomal Patterns==
Put your text here
{| class="wikitable sortable"
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!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
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|Complex Karyotype<ref name=":0" />
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|See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with anapestic large cell lymphoma<ref name=":0" />.
|}
==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table
{| class="wikitable sortable"
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!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
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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.
==Epigenomic Alterations==
<br />
==Genes and Main Pathways Involved==
Put your text here and fill in the table
{| class="wikitable sortable"
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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
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|ALK; Gene fusions resulting in overexpression
|Activation of JAK/STAT3 signaling pathway
|Increased cell growth and proliferation
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==Genetic Diagnostic Testing Methods==
IHC, FISH, and RT-PCR
==Familial Forms==
None
==Additional Information==
<br />
==Links==
<br />
==References==
<references /><ref name=":0" />

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==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.
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