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

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==Primary Author(s)*==
==Primary Author(s)*==
Put your text here
Jennie Thurston, PhD., FACMGG
==WHO Classification of Disease<ref name=":0">Li, W. The 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors. In Leukemia; Weijie, L., Ed.; Exon Publications: Brisbane, Australia, 2022; pp. 1–21, <nowiki>ISBN 978-0-645-33207-0</nowiki>.</ref>==
==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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==Definition / Description of Disease==
==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>
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==
None
None
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|'''Signs and Symptoms'''
|'''Signs and Symptoms'''
|Headache, seizures, nausea, fever, or a combination
|weight loss, headache, seizures, nausea, fever, or a combination
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|'''Laboratory Findings'''
|'''Laboratory Findings'''
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The cerebrospinal fluid may be involved. The large atypical neoplastic cells may have cytoplasmic azurophilic granules<ref name=":0" />
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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!Notes
!Notes
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|EXAMPLE
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7
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|EXAMPLE Loss
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|EXAMPLE
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chr7:1- 159,335,973 [hg38]
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|EXAMPLE
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chr7
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|Yes
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|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).
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|EXAMPLE
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8
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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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|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
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|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==
Put your text here
<br />
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
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Put your text here and fill in the table
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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
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|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
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|EXAMPLE:  Histone modification, chromatin remodeling
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|EXAMPLE:  Abnormal gene expression program
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==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
FISH w/ ALK BA probe
IHC, FISH, and RT-PCR
==Familial Forms==
==Familial Forms==
Put your text here
None
==Additional Information==
==Additional Information==
Put your text here
<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" />
 
(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 />

Latest revision as of 11:13, 2 February 2025

Primary Author(s)*

Jennie Thurston, PhD., FACMGG

WHO Classification of Disease[1]

Structure Disease
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.[2] 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.[3] 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).[1][4][5] ALK+ ALCL occurs as single or multiple supratentorial parenchymal lesions.[1]

Synonyms / Terminology

None

Epidemiology / Prevalence

ALK+ ALCL occurs from early childhood to young adulthood with a male preponderance.[6][5]

ALK− ALCL affects adults (median age: 65 years), also with a male preponderance.[4]

Clinical Features

Signs and Symptoms weight loss, headache, seizures, nausea, fever, or a combination
Laboratory Findings None

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.[7][1]

ALK− ALCL occurs as single or multiple lesions, usually supratentorial[1]

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[8]

The cerebrospinal fluid may be involved. The large atypical neoplastic cells may have cytoplasmic azurophilic granules[1]

Immunophenotype

Finding Marker
Positive (universal) CD30+, ALK+, and EMA+, may express one or more T-cell antigens[9]

Chromosomal Rearrangements (Gene Fusions) ALK+ ALCL

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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[10][11] 30 to 50% of ALCL[1]

(COSF198) ([12])

Yes Yes Yes Localized in both cytoplasm and nucleus.[1]


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.[1]

t(X;2)(q11;p23) 5'MSN:: 3'ALK very rare, one case reported For the t(X;2) translocation, localization is restricted to the membrane.[1]
t(1;2)(q25;p23) 5'TPM3::3'ALK rare, four cases reported TPM3::ALK is constitutively activated[1]
inv(2)(p23q35) 5'ATIC::3'ALK rare ider(2)(q10)inv(2) has been found in some cases, carrying 2 additional copies of the ATIC::ALK hybrid gene; frequent complex karyotypes[1]
t(2;3)(p23;q21) 5'TFG::3-ALK very rare, two cases reported
t(2;17)(p23;q23) 5'CLTC::3'ALK very rare, one case reported
t(2;19)(p23; p13.1) 5'TPM4::3'ALK very rare, one case reported
t(2;22)(p23;q11.2) 5'CLTCL1::3'ALK very rare, one or two cases the localization is restricted to granules (vesicles) in the cytoplasm[1]

Individual Region Genomic Gain/Loss/LOH

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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

Characteristic Chromosomal Patterns

Put your text here

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
Complex Karyotype[1] See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with anapestic large cell lymphoma[1].

Gene Mutations (SNV/INDEL)

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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

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


Genes and Main Pathways Involved

Put your text here and fill in the table

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
ALK; Gene fusions resulting in overexpression Activation of JAK/STAT3 signaling pathway Increased cell growth and proliferation

Genetic Diagnostic Testing Methods

IHC, FISH, and RT-PCR

Familial Forms

None

Additional Information


Links


References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 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: https://tumourclassification.iarc.who.int/chapters/45.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 4.0 4.1 ALK-negative anaplastic large cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:ALK-negative_anaplastic_large_cell_lymphoma.
  5. ↑ 5.0 5.1 ALK-positive anaplastic large cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:ALK-positive_anaplastic_large_cell_lymphoma.
  6. ↑ 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
  7. ↑ 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]
  8. ↑ Jaffe ES. Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology. Modern Pathol. 2001;14:219-228.
  9. ↑ Kadin ME. Primary Ki-1-positive anaplastic large-cell lymphoma: a distinct clinicopathologic entity. Ann Oncol. 1994;5:S25-S30.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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,

[1]

(use "Cite" icon at top of page)

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 CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

  1. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named :0
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