HAEM4Backup:ALK-Positive Large B-cell Lymphoma

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Primary Author(s)*

Manando Nakasaki, MD, PhD (University of California, Irvine)

Fabiola Quintero-Rivera, MD, FACMG (University of California, Irvine)

Cancer Category/Type

Mature B cell neoplasm

Cancer Sub-Classification / Subtype

Large B-cell lymphomas

Definition / Description of Disease

Diffuse, monomorphic neoplasm of large B-cells with a plasmablastic immunophenotype and ALK expression due to ALK rearrangement

Synonyms / Terminology

Not recommended: ALK-positive plasmablastic B-cell lymphoma; ALK-positive diffuse large B-cell lymphoma

Epidemiology / Prevalence

  • <1% of large B-cell lymphomas
    • ~ 200 cases reported in literature to date[1]
  • Range: 9-85 years; median: ~ 40 years[2][3]
  • Male to Female ratio: 3-4:1[4][5]

Clinical Features

Signs and Symptoms Asymptomatic lymphadenopathy

B-symptoms

Laboratory Findings Serum LDH elevation

Sites of Involvement

  • Lymph nodes are most commonly involved (~ 75%)
  • Extranodal sites: bone marrow, GI tract, liver, epidural space, ovaries, skeletal system, nasopharyngeal/nasal area, tongue, and brain[6][7][8]

Morphologic Features

  • Partial or diffuse effacement of lymph node architecture
  • Lymphoma cells infiltrate sinusoids[9][10]
  • Monomorphic infiltrate of large cells with abundant amphophilic or eosinophilic cytoplasm

Immunophenotype

Finding Marker
Positive (universal) ALK, CD138, VS38, IRF4/MUM1, BLIMP1, XBP1
Positive (subset) EMA (90%), Cytoplasmic Ig (90%), IgA (80%), CD45 (90%), CD30 (15%), CD4 (50%), CD57 (10%), CD43, Cytokeratin (10%)
Negative (universal) Pan-T cell antigens, CD8, B-cell antigens, CD10, BCL-6, Cyclin-D1, HHV8

Chromosomal Rearrangements (Gene Fusions)

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) ALK Immunostain Pattern Prevalence Notes
t(2;17)(p23;q23) CLTC::ALK Cytoplasmic; granular Most common [11]
t(2;5)(p23;q35) NPM::ALK Nuclear and cytoplasmic [12]
t(2;5)(p23;q35.3) SQSTM1::ALK Cytoplasmic; diffuse [13]
inv(2)(p23q13) or t(2;2)(p23;q13) RANBP2::ALK Nuclear membrane and perinuclear punctate [14]
inv(2)(p21p23) EML4::ALK Cytoplasmic; diffuse [15]
inv(2)(p21q31.1) or t(2;2)(p23;q31.1) GORASP2::ALK Cytoplasmic; diffuse [16]
Cryptic SEC31A::ALK Cytoplasmic; granular [17]

Individual Region Genomic Gain/Loss/LOH

Gains or amplifications of MYC (~50% of cases)[18]

Characteristic Chromosomal Patterns

N/A

Gene Mutations (SNV/INDEL)

N/A

Epigenomic Alterations

N/A

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
ALK rearrangement; Activating fusions JAK/STAT, PI3K/AKT, MAPK/ERK and phospholipase C gamma 2 (PLCG2) pathways Transformation, increased growth and inhibition of apoptosis

Genetic Diagnostic Testing Methods

  • Detection of ALK rearrangement by NGS or FISH
  • Monoclonal IGH rearrangements by PCR

Familial Forms

N/A

Additional Information

N/A

Links

N/A

References

  1. ↑ Castillo, Jorge J.; et al. (2021-12). "Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK + LBCL): a systematic review of clinicopathological features and management". Leukemia & Lymphoma. 62 (12): 2845–2853. doi:10.1080/10428194.2021.1941929. ISSN 1029-2403. PMID 34151703 Check |pmid= value (help). Check date values in: |date= (help)
  2. ↑ Pan, Zenggang; et al. (2017-01). "ALK-positive Large B-cell Lymphoma: A Clinicopathologic Study of 26 Cases With Review of Additional 108 Cases in the Literature". The American Journal of Surgical Pathology. 41 (1): 25–38. doi:10.1097/PAS.0000000000000753. ISSN 1532-0979. PMID 27740969. Check date values in: |date= (help)
  3. ↑ Castillo, Jorge J.; et al. (2021-12). "Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK + LBCL): a systematic review of clinicopathological features and management". Leukemia & Lymphoma. 62 (12): 2845–2853. doi:10.1080/10428194.2021.1941929. ISSN 1029-2403. PMID 34151703 Check |pmid= value (help). Check date values in: |date= (help)
  4. ↑ Sukswai, Narittee; et al. (2020-01). "Diffuse large B-cell lymphoma variants: an update". Pathology. 52 (1): 53–67. doi:10.1016/j.pathol.2019.08.013. ISSN 1465-3931. PMID 31735345. Check date values in: |date= (help)
  5. ↑ Castillo, Jorge J.; et al. (2021-12). "Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK + LBCL): a systematic review of clinicopathological features and management". Leukemia & Lymphoma. 62 (12): 2845–2853. doi:10.1080/10428194.2021.1941929. ISSN 1029-2403. PMID 34151703 Check |pmid= value (help). Check date values in: |date= (help)
  6. ↑ Morgan, Elizabeth A.; et al. (2012). "Anaplastic lymphoma kinase-positive large B-cell lymphoma: an underrecognized aggressive lymphoma". Advances in Hematology. 2012: 529572. doi:10.1155/2012/529572. ISSN 1687-9112. PMC 3299366. PMID 22474449.
  7. ↑ Pan, Zenggang; et al. (2017-01). "ALK-positive Large B-cell Lymphoma: A Clinicopathologic Study of 26 Cases With Review of Additional 108 Cases in the Literature". The American Journal of Surgical Pathology. 41 (1): 25–38. doi:10.1097/PAS.0000000000000753. ISSN 1532-0979. PMID 27740969. Check date values in: |date= (help)
  8. ↑ Laurent, Camille; et al. (2009-09-01). "Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 27 (25): 4211–4216. doi:10.1200/JCO.2008.21.5020. ISSN 1527-7755. PMID 19636007.
  9. ↑ Pan, Zenggang; et al. (2017-01). "ALK-positive Large B-cell Lymphoma: A Clinicopathologic Study of 26 Cases With Review of Additional 108 Cases in the Literature". The American Journal of Surgical Pathology. 41 (1): 25–38. doi:10.1097/PAS.0000000000000753. ISSN 1532-0979. PMID 27740969. Check date values in: |date= (help)
  10. ↑ Sukswai, Narittee; et al. (2020-01). "Diffuse large B-cell lymphoma variants: an update". Pathology. 52 (1): 53–67. doi:10.1016/j.pathol.2019.08.013. ISSN 1465-3931. PMID 31735345. Check date values in: |date= (help)
  11. ↑ Gascoyne, Randy D.; et al. (2003-10-01). "ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases". Blood. 102 (7): 2568–2573. doi:10.1182/blood-2003-03-0786. ISSN 0006-4971. PMID 12763927.
  12. ↑ Onciu, Mihaela; et al. (2003-10-01). "ALK-positive plasmablastic B-cell lymphoma with expression of the NPM-ALK fusion transcript: report of 2 cases". Blood. 102 (7): 2642–2644. doi:10.1182/blood-2003-04-1095. ISSN 0006-4971. PMID 12816858.
  13. ↑ Takeuchi, Kengo; et al. (2011-03). "Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma". Haematologica. 96 (3): 464–467. doi:10.3324/haematol.2010.033514. ISSN 1592-8721. PMC 3046280. PMID 21134980. Check date values in: |date= (help)
  14. ↑ Lee, Seung Eun; et al. (2014-12). "Identification of RANBP2-ALK fusion in ALK positive diffuse large B-cell lymphoma". Hematological Oncology. 32 (4): 221–224. doi:10.1002/hon.2125. ISSN 1099-1069. PMID 24470379. Check date values in: |date= (help)
  15. ↑ Sakamoto, Kana; et al. (2016-04). "ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern". International Journal of Hematology. 103 (4): 399–408. doi:10.1007/s12185-016-1934-1. ISSN 1865-3774. PMID 26781614. Check date values in: |date= (help)
  16. ↑ Ise, Mikiko; et al. (2019-02). "Identification of a novel GORASP2-ALK fusion in an ALK-positive large B-cell lymphoma". Leukemia & Lymphoma. 60 (2): 493–497. doi:10.1080/10428194.2018.1493731. ISSN 1029-2403. PMID 30187817. Check date values in: |date= (help)
  17. ↑ Bedwell, Clare; et al. (2011-02). "Cytogenetically complex SEC31A-ALK fusions are recurrent in ALK-positive large B-cell lymphomas". Haematologica. 96 (2): 343–346. doi:10.3324/haematol.2010.031484. ISSN 1592-8721. PMC 3031708. PMID 21109691. Check date values in: |date= (help)
  18. ↑ Valera, Alexandra; et al. (2013-10). "ALK-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 26 (10): 1329–1337. doi:10.1038/modpathol.2013.73. ISSN 1530-0285. PMC 6368829. PMID 23599149. Check date values in: |date= (help)

Notes

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