Anaplastic Large Cell Lymphoma, ALK-Negative

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Primary Author(s)*

Derick Okwan-Duodu, MD, PhD; Sumire Kitahara, MD

Cedars-Sinai Medical Center

Cancer Category/Type

Cancer Sub-Classification / Subtype[1][2]

  • Anaplastic Large Cell Lymphoma, ALK-Negative

Definition / Description of Disease[3][4]

  • Anaplastic large cell lymphomas (ALCL), ALK-negative, is a CD30+ T-cell lymphoma that is morphologically and immunophenotypically indistinguishable (but lacks ALK protein expression) from ALK+ ALCL
  • Three major molecular subtypes
    • DUSP22-positive subtype (30%) THIS IS 30% OF ALK(-) CASES?
    • TP63-positive subtype (8%) THIS IS 8% OF ALK(-) CASES?
    • Triple-negative subtype (DUSP22 negative, TP63 negative, ALK negative) 62% OF ALK(-) CASES?
    • Emerging subtypes:
      • ERBB4 expression (~25%): mutually exclusive with other rearrangements (TP63, DUSP22, ROS or TYK translocations)[5]

Synonyms / Terminology

  • N/A

Epidemiology / Prevalence[6]

  • More common in adults than children (peak incidence 6th decade of life)
  • Less than 3% of all Non-Hodgkin's lymphoma
  • M:F 1.5:1

Clinical Features[6]

  • B symptoms of weight loss, fevers, chills
  • Peripheral and/or abdominal lymphadenopathy
  • Most patients present with advanced stage disease

Sites of Involvement

  • Nodal (predominantly abdominal lymphadenopathy) in a sinusoidal pattern
  • Extranodal (skin, soft tissue, gastrointestinal, bone) in about 20% of cases
    • If involving the skin or GI tract, cases must be distinguished from primary cutaneous ALCL or CD30+ enteropathy-associated/other intestinal T-cell lymphomas, respectively

Morphologic Features

  • Tissue effacement by cohesive sheets of large, pleomorphic neoplastic cells, with or without prominent nucleoli, with varying proportions of hallmark cells YOU HAVE GOOD DESCRIPTION OF HALMARK CELLS IN THE ALK+ PAGE. SUGGEST COPYING HERE.
    • DUSP22-rearranged subtype tends to lack large pleomorphic cells and show more "doughnut" cells ADD VERY BRIEF DESCRIPTION OF DOUGHNUT CELLS.
  • Intrasinusoidal growth pattern seen in cases with preserved nodal architecture

Immunophenotype[6][7][1]

DUSP22-rearranged subtype (? 30% OF ALK(-) CASES)

Finding Marker
Positive (universal) CD30*, CD43 (almost universally)
Negative (universal) ALK, TP63, EBER, LMP-1
Positive (frequent) CD2, CD3, CD4+ cases more common than CD8, CD5, Clusterin
Negative (frequent) TIAI, granzyme B, perforin, EMA, PAX5

*Strong and diffuse CD30 staining; should be equal intensity in all cells

TP63 subtype (? 8% OF ALK(-) CASES)

WOULD IT BE BETTER TO SAY "TP63 REARRANGED SUBTYPE"?

Finding Marker
Positive (universal) CD30*, CD43 (almost universally), P63, CD4+ cases more common than CD8
Negative (universal) ALK, EBER, LMP-1
Positive (frequent) CD2, CD3, CD4, CD5, TIA1, granzyme B, perforin, clusterin
Negative (very frequent) EMA

Triple-negative subtype (? 62% OF ALK(-) CASES)

Finding Marker
Positive (universal) CD30*, CD43 (almost universally), CD2, CD3, CD4+ cases more common than CD8, CD5, TIA1, granzyme B, perforin, EMA
Negative (universal) ALK, P63, EBER, LMP-1
Positive (common) EMA, clusterin
Negative (frequent) PAX5, CD20, CD79a, CD15

Chromosomal Rearrangements (Gene Fusions)[8][9]

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Prevalence
*t(6;7)(p25.3;q32.3) DUSP22/FRA7H[10] 30%[1]
*t(3;3)(q22;q26.2), inv(3)(q26q28) TP63/TBL1XR1[11] 8%[1]
t(10;19)(q24;p13) NFKB2/TYK2 rare[12]
t(1;19)(p34;p13) PABPC4/TYK2 rare[12]
t(6;10)(q22;q24) NFKB2/ROS1 rare[12]

* These rearrangements are considered mutually exclusive; however, a single case with both DUSP22 and TP63 rearrangement has been described[13]. Can also be seen in a fraction of other PTCL.

Characteristic Chromosomal Aberrations / Patterns

  • Gene expression profiling and comparative genomic hybridization studies have shown that ALK+ and ALK(-) ALCL share restricted genomic signatures and/or preferential genomic aberrations[14][15][16]
  • Several genes are similarly expressed in ALK+ and ALK(-) samples, suggesting a common ALCL signature, that permit differential diagnosis of ALCL from PTCL-NOS[17]
  • See other sections.

Genomic Gain/Loss/LOH[18][19][20]

  • In general, recurrent lesions are more common in ALK(-) than ALK+ disease
  • 6q21 losses associated with 17p deletions seen in ~25% of cases of ALK(-) ALCL[18]
  • None are diagnostically helpful for the distinction between ALK(-) ALCL from other entities
Chromosome Number Gain/Loss/Amp/LOH Region Genes Prevalence
1q Gain numerous 30%
6p Gain 25.3 DUSP22 30%
8q Gain 24.22 NDRG1, PHF20L1, SLA, ST3GAL1, TG, WISP1 16-23%
1p Loss 13.3-p12

36.33-36.32

26%

19%

6q Loss > CN-LOH;

See also below for somatic mutations

21 PRDM1, ATG5 35%
10p Loss 11.23-p11.22 23%
13q Loss 32.3-q33.3 CDC16, CUL4A,FOXO1A, BRCA2, LHFP, LCP1 23%
16q Loss 23.2 MAF, WWOX 29%
17p Loss 13.3-p12 TP53 42%

Gene Mutations (SNV/INDEL)

Gene Presumed mechanism Frequency Notes
STAT3*[12][21] Activating 10-26% Not seen in PTCL-NOS[12] or ALK+ ALCL[12][21]
JAK1*[12][21] Activating 15-26% Not seen in PTCL-NOS[12] or ALK+ ALCL[12][21]
PRDM1/BLIMP1[18] Tumor suppressor 6% (2/31)
NOTCH1[22] Activating 15%
TP53[21] Tumor suppressor 23%
KMT2D[21] Tumor suppressor 20%

*Double mutated for JAK1+STAT3 in 7-11%[12][21]

Other mutations

  • Epigenetic modifier genes: TET2[12][21]
  • Uncommon: FAS, STIM2[12]; LRP1B (9%), EPHA5[21]

Epigenomics (Methylation)

  • See above mutations in epigenetic modifier genes

Genes and Main Pathways Involved

  • JAK-STAT
    • When JAK/STAT3 mutations absent, NFkB2-ROS1 and NFkB2-TYK2 fusions may constitutively activate STAT pathway[12]

Diagnostic Testing Methods

  • Morphologic and immunophenotypic characterization
    • Strong CD30 staining of equal intensity help distinguish from PTCL, NOS, classic Hodgkin lymphoma, diffuse large B-cell lymphoma, and enteropathy associated T-cell lymphoma (type 2)
    • Exclusion of ALK+ ALCL cases by immunostain for ALK
    • P63 immunostain to identify TP63 rearranged. Immunophenotyping is not sensitive and is thus used as screening before FISH analysis. A ≥ 30% threshold yields 100% sensitivity[23]
  • FISH studies:
    • DUSP22 (IRF4/DUSP22) break-apart probe
    • TP63 rearrangement

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Diagnosis
    • INDICATE IF MORPHOLOGY AND IMMUNOPHENOTYPING ARE SUFFICIENT IN MOST CASES.
    • FISH studies as above WHEN ARE THESE NEEDED? CERTAIN DDX'S?
    • In triple-negative ALCL (negative for ALK, DUSP22, P63 rearrangements), a 3-gene model (TNFRSF8 (aka CD30), BATF3, and TMOD1) distinguishes ALK(-) ALCL from PTCL, NOS with > 97% accuracy[24]
      • Not routinely performed, but this study adapted RT-qPCR protocols to FFPE tissues where RNA qualities are typically poor to be able to translate GEP study findings to routine clinical settings
    • Presence of STAT3 and/or JAK1 mutations seem to favor ALK(-) ALCL over PTCL-NOS[12]
    • ERBB4+ cases may be identified using digital droplet PCR or immunostaining for MMP9 (a protein highly correlated with ERBB4 expression)
      • Not routinely performed
  • Prognosis
    • When compared to ALK+ ALCL, ALK(-) ALCL has a generally poorer prognosis, however:
      • When stratified for age, prognosis between ALK(-) and ALK+ ALCL appears similar [25][26]
    • 5-year overall survival > 90% for DUSP22-rearranged ALK(-) ALCL, 17% for TP63-rearranged ALK(-) ALCL, and 42% for cases lacking all DUSP22, TP63 and ALK rearrangements[1][27]
    • Patients with 6q21/PRDM1 and/or 17p loss showed an inferior outcome than patients with normal 6q21 and 17p; not clear if mainly due to TP53 deletion due to study size[18]
      • often concomitant loss and seen in almost a quarter of cases
    • Mutations with significantly shorter OS compared to wild-type[21]
    • Prognostic significance of ERB4 and COL29A1 co-expressing subtypes unclear [5]
  • Therapeutic Implications
    • Multi-agent chemotherapy (CHOEP or CHOP-based) as first-line, with or without radiotherapy of involved site
    • High dose chemotherapy and autologous stem cell transplantation for remission
    • DUSP22 subtype may not gain additional benefit from autologous stem cell transplantation in first remission
    • Theoretical:
      • Ruxolitinib may be used to target JAK-STAT pathway[28][29] (not FDA-approved)
      • Bromodomain and extra-terminal proteins (BET) inhibitors may target ERBB4 pathway[29][30]

Familial Forms

  • Not described

Other Information

  • None

Links

  • See references.

References

(use "Cite" icon at top of page)

  1. 1.0 1.1 1.2 1.3 1.4 Er, Parrilla Castellar; et al. (2014). "ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes". doi:10.1182/blood-2014-04-571091. PMC 4148769. PMID 24894770.CS1 maint: PMC format (link)
  2. Al, Feldman; et al. (2011). "Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing". doi:10.1182/blood-2010-08-303305. PMC 3035081. PMID 21030553.CS1 maint: PMC format (link)
  3. Ad, Attygalle; et al. (2014). "Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward - report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology". doi:10.1111/his.12251. PMC 6364972. PMID 24128129.CS1 maint: PMC format (link)
  4. Sh, Swerdlow; et al. (2016). "The 2016 revision of the World Health Organization classification of lymphoid neoplasms". doi:10.1182/blood-2016-01-643569. PMC 4874220. PMID 26980727.CS1 maint: PMC format (link)
  5. 5.0 5.1 I, Scarfò; et al. (2016). "Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts". PMID 26463425.
  6. 6.0 6.1 6.2 G, Hapgood; et al. (2015). "The biology and management of systemic anaplastic large cell lymphoma". PMID 25869285.
  7. M, Herling; et al. (2004). "Absence of Epstein-Barr virus in anaplastic large cell lymphoma: a study of 64 cases classified according to World Health Organization criteria". PMID 15116326.
  8. Pileri, Stefano (2011-05-01). "Faculty Opinions recommendation of Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing".
  9. Da, Wada; et al. (2011). "Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies". doi:10.1038/modpathol.2010.225. PMC 3122134. PMID 21169992.CS1 maint: PMC format (link)
  10. Feldman, Andrew L.; et al. (2011-01-20). "Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing". Blood. 117 (3): 915–919. doi:10.1182/blood-2010-08-303305. ISSN 1528-0020. PMC 3035081. PMID 21030553.
  11. Vasmatzis, George; et al. (2012-09-13). "Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas". Blood. 120 (11): 2280–2289. doi:10.1182/blood-2012-03-419937. ISSN 1528-0020. PMC 5070713. PMID 22855598.
  12. 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 12.10 12.11 12.12 12.13 R, Crescenzo; et al. (2015). "Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma". doi:10.1016/j.ccell.2015.03.006. PMC 5898430. PMID 25873174.CS1 maint: PMC format (link)
  13. K, Karube; et al. (2020). ""Double-hit" of DUSP22 and TP63 rearrangements in anaplastic large cell lymphoma, ALK-negative". PMID 32106310 Check |pmid= value (help).
  14. Thompson, Mary Ann; et al. (2005-05). "Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas". Human Pathology. 36 (5): 494–504. doi:10.1016/j.humpath.2005.03.004. ISSN 0046-8177. PMID 15948116. Check date values in: |date= (help)
  15. Piccaluga, Pier Paolo; et al. (2007-03). "Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets". The Journal of Clinical Investigation. 117 (3): 823–834. doi:10.1172/JCI26833. ISSN 0021-9738. PMC 1794115. PMID 17304354. Check date values in: |date= (help)
  16. Salaverria, Itziar; et al. (2008-03). "Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas". British Journal of Haematology. 140 (5): 516–526. doi:10.1111/j.1365-2141.2007.06924.x. ISSN 1365-2141. PMID 18275429. Check date values in: |date= (help)
  17. Piva, Roberto; et al. (2010-03-20). "Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 28 (9): 1583–1590. doi:10.1200/JCO.2008.20.9759. ISSN 1527-7755. PMID 20159827.
  18. 18.0 18.1 18.2 18.3 M, Boi; et al. (2013). "PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma". PMID 24004669.
  19. G, Vasmatzis; et al. (2012). "Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas". doi:10.1182/blood-2012-03-419937. PMC 5070713. PMID 22855598.CS1 maint: PMC format (link)
  20. Y, Zeng; et al. (2016). "Genetics of anaplastic large cell lymphoma". doi:10.3109/10428194.2015.1064530. PMC 4732699. PMID 26104084.CS1 maint: PMC format (link)
  21. 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 21.9 Lobello, Cosimo; et al. (2020-11-27). "STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma". Leukemia: 1–6. doi:10.1038/s41375-020-01093-1. ISSN 1476-5551.
  22. Larose, Hugo; et al. (2020-04-23). "Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target". Haematologica. doi:10.3324/haematol.2019.238766. ISSN 1592-8721.
  23. X, Wang; et al. (2017). "Expression of p63 protein in anaplastic large cell lymphoma: implications for genetic subtyping". doi:10.1016/j.humpath.2017.01.003. PMC 5518937. PMID 28153507.CS1 maint: PMC format (link)
  24. L, Agnelli; et al. (2012). "Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma". PMID 22740451.
  25. Kj, Savage; et al. (2008). "ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project". PMID 18385450.
  26. D, Sibon; et al. (2012). "Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte trials". PMID 23045585.
  27. Mb, Pedersen; et al. (2017). "DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study". doi:10.1182/blood-2016-12-755496. PMC 5533203. PMID 28522440.CS1 maint: PMC format (link)
  28. R, Roskoski (2016). "Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases". PMID 27473820.
  29. 29.0 29.1 E, Mereu; et al. (2017). "The heterogeneous landscape of ALK negative ALCL". doi:10.18632/oncotarget.14503. PMC 5392347. PMID 28061468.CS1 maint: PMC format (link)
  30. A, Chaidos; et al. (2015). "Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence". doi:10.1177/2040620715576662. PMC 4480520. PMID 26137204.CS1 maint: PMC format (link)

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