Anaplastic Large Cell Lymphoma, ALK-Negative

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editPREVIOUS EDITION
This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

Miguel Gonzalez Mancera, MD

Sumire Kitahara, MD

Cedars-Sinai, Los Angeles, CA

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Anaplastic Large Cell Lymphoma, ALK-Negative[1][2]

Definition / Description of Disease

  • 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[3][4]
  • Three major molecular subtypes of ALK (-) ALCL[3][4]:
    • DUSP22-rearranged subtype (30%)
    • TP63-rearranged subtype (8%)
    • Triple-negative subtype (DUSP22 negative, TP63 negative, ALK negative)
    • Emerging subtypes:
      • ERBB4 expression (~25%): mutually exclusive with other rearrangements (TP63, DUSP22, ROS or TYK translocations)[5]

Synonyms / Terminology

  • N/A

Epidemiology / Prevalence

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

Clinical Features

  • B symptoms of weight loss, fevers, chills[6]
  • Peripheral and/or abdominal lymphadenopathy[6]
  • Most patients present with advanced stage disease[6]

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
  • "Hallmark cells"
    • Lymphoma cells characterized by eccentric, horseshoe-shaped or kidney-shaped nuclei, often with eosinophilic cytoplasm accentuated near the nucleus
    • Usually large in size, but may also be smaller
    • Less common that in classic variant of ALK (+) ALCL
  • DUSP22-rearranged subtype tends to lack large pleomorphic cells and show smaller, monomorphic cells with central nuclear pseudoinclusions (doughnut cells)
  • Intrasinusoidal growth pattern seen in cases with preserved nodal architecture

Immunophenotype

Immunohistochemical patterns vary by subtype[6][7][1]


DUSP22-rearranged subtype

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-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

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)

Chromosomal Rearrangement[8][9] 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

The pattern of genomic copy number changes and loss of heterozygosity have been described[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[12]
    • STAT3 mutants are constitutively phosphorylated
    • JAK1 mutants lead to the constitutive phosphorylation of STAT and synergize with STAT3 mutants
    • When JAK/STAT3 mutations absent, NFkB2-ROS1 and NFkB2-TYK2 fusions may constitutively activate STAT pathway

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 monomorphic epitheliotropic intestinal T-cell lymphoma
    • 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]
  • Presence of STAT3 and/or JAK1 mutations seem to favor ALK(-) ALCL over PTCL-NOS[12]
  • FISH studies necessary to subtype:
    • DUSP22 (IRF4/DUSP22) break-apart probe
    • TP63 rearrangement
  • ERBB4(+) cases may be identified using digital droplet PCR or immunostaining for MMP9 (a protein highly correlated with ERBB4 expression)
    • Not routinely performed

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Diagnosis
    • In general, ALK(-) ALCL has a worse prognosis when compared to ALK (+) ALCL[4]
    • ALK(-) ALCL has shown superior prognosis when compared to PTCL, NOS. The 5-year failure-free survival rate was 36% vs 20%, and overall survival rate was 49% vs 32%[24]
  • 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 [24][25]
    • 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][26]
    • 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[27][28] (not FDA-approved)
      • Bromodomain and extra-terminal proteins (BET) inhibitors may target ERBB4 pathway[28][29]

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. ↑ 3.0 3.1 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. ↑ 4.0 4.1 4.2 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 6.3 6.4 6.5 6.6 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. ↑ 24.0 24.1 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.
  25. ↑ 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.
  26. ↑ 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)
  27. ↑ R, Roskoski (2016). "Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases". PMID 27473820.
  28. ↑ 28.0 28.1 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)
  29. ↑ 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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