Anaplastic Large Cell Lymphoma (ALK+/ALK−)
Primary Author(s)*
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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]
|
| 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
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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 |
|---|---|---|---|---|
| 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
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| 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
- ↑ 1.00 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.
- ↑ 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.
- ↑ 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.
- ↑ 4.0 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.
- ↑ 5.0 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.
- ↑ 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
- ↑ 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]
- ↑ Jaffe ES. Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology. Modern Pathol. 2001;14:219-228.
- ↑ Kadin ME. Primary Ki-1-positive anaplastic large-cell lymphoma: a distinct clinicopathologic entity. Ann Oncol. 1994;5:S25-S30.
- ↑ 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.
- ↑ 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.
- ↑ 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,
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Notes
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