2016 Revision to the WHO classification of acute lymphoblastic leukemia

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B Cell Acute Lymphoblastic Leukemia/Lymphoma

Two important new provisional entities have been recognized in B cell acute lymphoblastic leukemia/lymphoma (B-ALL) with recurrent genetic abnormalities, which are titled as Intrachromosomal amplification of chromosome 21 (iAMP21) and BCR-ABL-like B lymphoblastic leukemia/lymphoma.

iAMP21 was defined as three or more extra copies of RUNX1 on a single abnormal chromosome 21 (a total of five or more RUNX1 signals per cell)[1,2] with a complex structure comprising multiple regions of gain, amplification, inversion and deletion, identified from cytogenetics, fluorescence in situ hybridisation (FISH) and genomic analysis[3] iAMP21 cases was originally identified in childhood acute lymphoblastic leukemia (ALL)[4,5]. Prospective screening in recent childhood trials (Medical Research Council ALL97, United Kingdom (UK) ALL2003 and Children’s Oncology Group (COG) ALL trials) has determined the incidence to be 2%. iAMP21 patients generally had low white cell counts (WCCs) with a median age of 9–11 years[2,6] and had an inferior outcome when treated on standard therapy as compared with other patients treated on the same protocols[1]. However, when iAMP21 patients treated as high risk showed improved outcome regardless of the backbone chemotherapy regimen given, indicating iAMP21 patients will to be treated as cytogenetic high risk, receive intensive chemotherapy.

The BCR-ABL-like ALL is another high-risk subtype. Genetic studies revealed it had a high frequency of deletions in genes involved in B-cell development, including IKZF1, E2A, EBF1, PAX5 and et al, which was similar to the signature of BCR-ABL1-positive ALL[7,8]. Common features of BCR-ABL1-like ALL include translocations involving other tyrosine kinases, or alternatively translocations involving either the cytokine receptor-like factor 2 (CRLF2), or, less commonly, rearrangements leading to truncation and activation of the erythropoietin receptor (EPOR)[9]. Rearrangement of CRLF2 is associated with mutation of JAK kinases, particularly common in children with Down syndrome, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. The translocation results in upregulation of CRLF2 gene product, which can be detected by flow cytometry. The cases with translocations of tyrosine kinase genes invloving ABL1 (with partners other than BCR), ABL2, PDGFRB, NTRK3, TYK2, CSF1R and JAK2, have shown remarkable responses to TKI therapy[10], especially those with EBF1-PDGFRB translocations[11]. Patients with BCR-ABL1-like ALL show a high frequency of alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS, but these deletions also occur in high frequency in other types of ALL as well[8].

Another highlights is the unique association between low hypodiploid ALL and TP53 mutations that are often constitutional. The hypodiploid subgroup is heterogeneous and comprises ALL with a chromosome number of <46. By multiple whole genomic profiling of 124 hypodiploid ALL cases, inherited origin of the TP53 mutation was identified.[12,13].

T Cell Acute Lymphoblasticleukemia/ Lymphomal

A new pathologic entity in T cell acute lymphoblastic leukemia/lymphoma (T-ALL) is recognized asindolent T-lymphoblastic proliferation (iT-LBP). It typically involves lymphoid tissue of the upper aerodigestive tract but may occur in other locations and usually form a tumor mass. Microscopic features of involved lymph nodes shows these lymphoblasts localize predominantly to interfollicular/ paracortical regions[1419], with less cytologically atypical features than the usual T-lymphoblastic lymphoma.

Its phenotype reflects a developmentally normal, non-aberrant phenotype and the proliferations are not clonal, indicating it is a non-neoplastic entity that may mimic T-lymphoblastic lymphoma and do not require treatment[20].

The proposed Criteria for the diagnosis of an iT-LBP is as below (Table 1)[20]:

Table 1

Proposed Criteria for the diagnosis of an iT-LBP

Major criteria
1. TdT +/CD3 + T cells In sheets or dense clusters primarily In interfollicularregions;
2. Preservation of general follicular lymphoid architecture;
3. Small-sized to medium-sized T cells without significant morphologic atypia;
4. Noaberrantantigenexpression;
5. NonclonalTdT + T cells;
6. No associated thymic epithelium
7. Clinical evidence of indolence, > 6 mo follow-up without significant progression in the absence of treatment

Ancillary findings

Can be associated with Castleman disease and/or follicular dendritic cell tumors/sarcomas

Can be associated with patients with concurrent AITL or history of AITL (AITL indicates angioimmunoblastic T-cell lymphoma)

iT-LBP have been associated with Castleman disease and/ or follicular dendritic cell tumors and also been seen in cases of AITL and may persist in multiple lymph node sites even after clearance of AITL[20,21].

ETP-ALL is a distinct pathobiologic entity confers a dire prognosis. The cell for clonal expansion is a very early immigrant from the bone marrow to the thymus, a cell expressing abundant T-lineage, stem-cell and myeloid-associated transcripts, and possessing both lymphoid and myeloid developmental potential[22-26]. The specific immunophenotype of ETP-ALL is CD1-, CD5weak, CD8-, or coexpression of stem cell and/or myeloid markers CD34, CD117, HLADR, CD13, CD33, CD11b or CD65 and its distinct molecular features are FLT3 mutations and absence of NOTCH1 mutations[27,28]. ETP-ALL was associated with an inferior clearance of leukemia cells after the first phase of remission induction therapy and extremely poor event-free and overall survival in patients treated on intensified chemo-therapeutic protocols both at the St Jude Children’s Research Hospital and the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)[29].

Conflict of Interest None declared.

REFERENCES

  • 1

    Harrison CJ Moorman AV Schwab C Carroll AJ Raetz EA Devidas M et al. An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome. Leukemia 2014;28:1015-21.

    • Crossref
    • Export Citation
  • 2

    Heerema NA Carroll AJ Devidas M Loh ML Borowitz MJ Gastier-Foster JM et al. Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children’s oncology group studies: a report from the children’s oncology group. J Clin Oncol 2013;31:3397-402.

    • Crossref
    • Export Citation
  • 3

    Rand V Parker H Russell LJ Schwab C Ensor H Irving J et al. Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acutelymphoblastic leukemia. Blood 2011; 117:6848–55.

    • Crossref
    • Export Citation
  • 4

    Harewood L Robinson H Harris R Al Obaidi MJ Jalali GR Martineau M et al. Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases. Leukemia 2003; 17:547–53.

    • Crossref
    • Export Citation
  • 5

    Soulier J Trakhtenbrot L Najfeld V Lipton JM Mathew S Avet-Loiseau H et al. Amplification of band q22 of chromosome 21 including AML1 in older children with acute lymphoblastic leukemia: anemergingmolecularcytogeneticsubgroup. Leukemia 2003; 17:1679–82.

    • Crossref
    • Export Citation
  • 6

    Moorman AV Robinson H Schwab C Richards SM Hancock J Mitchell CD et al. Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials. J Clin Oncol 2013;31:3389–96.

    • Crossref
    • Export Citation
  • 7

    Den Boer ML van Slegtenhorst M De Menezes RX Cheok MH Buijs-Gladdines JG Peters ST et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 2009;10:125-34.

    • Crossref
    • Export Citation
  • 8

    Mullighan CG Su X Zhang J Radtke I Phillips LA Miller CB et al.Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009;360:470-80.

    • Crossref
    • Export Citation
  • 9

    Roberts KG Morin RD Zhang J Hirst M Zhao Y Su X et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 2012;22:153-66.

    • Crossref
    • Export Citation
  • 10

    Roberts KG Li Y Payne-Turner D Harvey RC Yang YL Pei D et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 2014;371:1005-15.

    • Crossref
    • Export Citation
  • 11

    Weston BW Hayden MA Roberts KG Bowyer S Hsu J Fedoriw G et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol 2013;31:e413-6.

    • Crossref
    • Export Citation
  • 12

    Holmfeldt L Wei L Diaz-Flores E Walsh M Zhang J Ding L et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 2013;45:242-52.

    • Crossref
    • Export Citation
  • 13

    Mühlbacher V Zenger M Schnittger S Weissmann S Kunze F Kohlmann A et al. Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%. Genes Chromosomes Cancer 2014;53:524-36.

    • Crossref
    • Export Citation
  • 14

    Velankar MM Nathwani BN Schlutz MJ Bain LA Arber DA Slovak ML et al. Indolent T-lymphoblastic proliferation: report of a case with a 16-year course without cytotoxic therapy. Am J Surg Pathol 1999; 23:977–81.

    • Crossref
    • Export Citation
  • 15

    Ohgami RS Zhao S Ohgami JK Leavitt MO Zehnder JL West RB et al. TdT+ T-lympho-blastic populations are increased in Castleman disease in Castleman disease in association with follicular dendritic cell tumors and in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2012;36:1619–28.

    • Crossref
    • Export Citation
  • 16

    Kim WY Kim H Jeon YK Kim CW. Follicular dendritic cell sarcoma with immature T-cell proliferation. Hum Pathol 2010;41:129–33.

    • Crossref
    • Export Citation
  • 17

    Qian YW Weissmann D Goodell L August D Strair R. Indolent T-lymphoblastic proliferation in Castleman lymphadenopathy. Leuk Lymphoma 2009;50:306–8.

    • Crossref
    • Export Citation
  • 18

    Strauchen JA. Indolent T-lymphoblastic proliferation: report of a case with an 11-year history and association with myasthenia gravis. Am J Surg Pathol 2001;25:411–5.

    • Crossref
    • Export Citation
  • 19

    Hartert M Strobel P Dahm M Nix W Marx A Vahl CF. A follicular dendritic cell sarcoma of the mediastinum with immature T cells and association with myasthenia gravis. Am J Surg Pathol 2010; 34:742–5.

  • 20

    Ohgami RS Arber DA Zehnder JL Natkunam Y Warnke RA. Indolent Tlymphoblastic proliferation (iT-LBP): a review of clinical and pathologic features and distinction from malignant T-lymphoblastic lymphoma. Adv Anat Pathol 2013;20:137-40.

    • Crossref
    • Export Citation
  • 21

    Walters MP Macon WR Kurtin PJ et al. Follicular dendritic cell sarcoma frequently contains intratumoral TdT-positive T cells that are associated with paraneoplastic autoimmune multiorgan syndrome (PAMS) 100th USCAP Annual Meeting 2011.

  • 22

    Rothenberg EV Moore JE Yui MA. Launching the T-cell-lineage developmental programme. Nat Rev Immunol 2008;8:9–21.

    • Crossref
    • Export Citation
  • 23

    Bell JJ Bhandoola A. The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 2008;452:764–7.

    • Crossref
    • Export Citation
  • 24

    Wada H Masuda K Satoh R Kakugawa K Ikawa T Katsura Y et al. Adult T-cell progenitors retain myeloid potential. Nature 2008;452:768–72.

    • Crossref
    • Export Citation
  • 25

    Balciunaite G Ceredig R Rolink AG. The earliest subpopulation of mouse thymocytes contains potent T significant macrophage and natural killer cell but no B-lymphocyte potential. Blood 2005;105:1930–6.

    • Crossref
    • Export Citation
  • 26

    Weerkamp F Baert MR Brugman MH Dik WA de Haas EF Visser TP et al. Human thymus contains multipotent progenitors with T/B lymphoid myeloid and erythroid lineage potential. Blood 2006;107:3131–7.

    • Crossref
    • Export Citation
  • 27

    Goldberg JM Silverman LB Levy DE Dalton VK Gelber RD Lehmann L et al. Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 2003;21:3616–22.

    • Crossref
    • Export Citation
  • 28

    Pui CH Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006;354:166–78.

    • Crossref
    • Export Citation
  • 29

    Inukai T Kiyokawa N Campana D Coustan-Smith E Kikuchi A Kobayashi M et al. Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children’s Cancer Study Group Study L99-15. Br J Haematol 2012;156:358-65.

    • Crossref
    • Export Citation

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  • 1

    Harrison CJ Moorman AV Schwab C Carroll AJ Raetz EA Devidas M et al. An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome. Leukemia 2014;28:1015-21.

    • Crossref
    • Export Citation
  • 2

    Heerema NA Carroll AJ Devidas M Loh ML Borowitz MJ Gastier-Foster JM et al. Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children’s oncology group studies: a report from the children’s oncology group. J Clin Oncol 2013;31:3397-402.

    • Crossref
    • Export Citation
  • 3

    Rand V Parker H Russell LJ Schwab C Ensor H Irving J et al. Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acutelymphoblastic leukemia. Blood 2011; 117:6848–55.

    • Crossref
    • Export Citation
  • 4

    Harewood L Robinson H Harris R Al Obaidi MJ Jalali GR Martineau M et al. Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases. Leukemia 2003; 17:547–53.

    • Crossref
    • Export Citation
  • 5

    Soulier J Trakhtenbrot L Najfeld V Lipton JM Mathew S Avet-Loiseau H et al. Amplification of band q22 of chromosome 21 including AML1 in older children with acute lymphoblastic leukemia: anemergingmolecularcytogeneticsubgroup. Leukemia 2003; 17:1679–82.

    • Crossref
    • Export Citation
  • 6

    Moorman AV Robinson H Schwab C Richards SM Hancock J Mitchell CD et al. Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials. J Clin Oncol 2013;31:3389–96.

    • Crossref
    • Export Citation
  • 7

    Den Boer ML van Slegtenhorst M De Menezes RX Cheok MH Buijs-Gladdines JG Peters ST et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 2009;10:125-34.

    • Crossref
    • Export Citation
  • 8

    Mullighan CG Su X Zhang J Radtke I Phillips LA Miller CB et al.Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009;360:470-80.

    • Crossref
    • Export Citation
  • 9

    Roberts KG Morin RD Zhang J Hirst M Zhao Y Su X et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 2012;22:153-66.

    • Crossref
    • Export Citation
  • 10

    Roberts KG Li Y Payne-Turner D Harvey RC Yang YL Pei D et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 2014;371:1005-15.

    • Crossref
    • Export Citation
  • 11

    Weston BW Hayden MA Roberts KG Bowyer S Hsu J Fedoriw G et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol 2013;31:e413-6.

    • Crossref
    • Export Citation
  • 12

    Holmfeldt L Wei L Diaz-Flores E Walsh M Zhang J Ding L et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 2013;45:242-52.

    • Crossref
    • Export Citation
  • 13

    Mühlbacher V Zenger M Schnittger S Weissmann S Kunze F Kohlmann A et al. Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%. Genes Chromosomes Cancer 2014;53:524-36.

    • Crossref
    • Export Citation
  • 14

    Velankar MM Nathwani BN Schlutz MJ Bain LA Arber DA Slovak ML et al. Indolent T-lymphoblastic proliferation: report of a case with a 16-year course without cytotoxic therapy. Am J Surg Pathol 1999; 23:977–81.

    • Crossref
    • Export Citation
  • 15

    Ohgami RS Zhao S Ohgami JK Leavitt MO Zehnder JL West RB et al. TdT+ T-lympho-blastic populations are increased in Castleman disease in Castleman disease in association with follicular dendritic cell tumors and in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2012;36:1619–28.

    • Crossref
    • Export Citation
  • 16

    Kim WY Kim H Jeon YK Kim CW. Follicular dendritic cell sarcoma with immature T-cell proliferation. Hum Pathol 2010;41:129–33.

    • Crossref
    • Export Citation
  • 17

    Qian YW Weissmann D Goodell L August D Strair R. Indolent T-lymphoblastic proliferation in Castleman lymphadenopathy. Leuk Lymphoma 2009;50:306–8.

    • Crossref
    • Export Citation
  • 18

    Strauchen JA. Indolent T-lymphoblastic proliferation: report of a case with an 11-year history and association with myasthenia gravis. Am J Surg Pathol 2001;25:411–5.

    • Crossref
    • Export Citation
  • 19

    Hartert M Strobel P Dahm M Nix W Marx A Vahl CF. A follicular dendritic cell sarcoma of the mediastinum with immature T cells and association with myasthenia gravis. Am J Surg Pathol 2010; 34:742–5.

  • 20

    Ohgami RS Arber DA Zehnder JL Natkunam Y Warnke RA. Indolent Tlymphoblastic proliferation (iT-LBP): a review of clinical and pathologic features and distinction from malignant T-lymphoblastic lymphoma. Adv Anat Pathol 2013;20:137-40.

    • Crossref
    • Export Citation
  • 21

    Walters MP Macon WR Kurtin PJ et al. Follicular dendritic cell sarcoma frequently contains intratumoral TdT-positive T cells that are associated with paraneoplastic autoimmune multiorgan syndrome (PAMS) 100th USCAP Annual Meeting 2011.

  • 22

    Rothenberg EV Moore JE Yui MA. Launching the T-cell-lineage developmental programme. Nat Rev Immunol 2008;8:9–21.

    • Crossref
    • Export Citation
  • 23

    Bell JJ Bhandoola A. The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 2008;452:764–7.

    • Crossref
    • Export Citation
  • 24

    Wada H Masuda K Satoh R Kakugawa K Ikawa T Katsura Y et al. Adult T-cell progenitors retain myeloid potential. Nature 2008;452:768–72.

    • Crossref
    • Export Citation
  • 25

    Balciunaite G Ceredig R Rolink AG. The earliest subpopulation of mouse thymocytes contains potent T significant macrophage and natural killer cell but no B-lymphocyte potential. Blood 2005;105:1930–6.

    • Crossref
    • Export Citation
  • 26

    Weerkamp F Baert MR Brugman MH Dik WA de Haas EF Visser TP et al. Human thymus contains multipotent progenitors with T/B lymphoid myeloid and erythroid lineage potential. Blood 2006;107:3131–7.

    • Crossref
    • Export Citation
  • 27

    Goldberg JM Silverman LB Levy DE Dalton VK Gelber RD Lehmann L et al. Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 2003;21:3616–22.

    • Crossref
    • Export Citation
  • 28

    Pui CH Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006;354:166–78.

    • Crossref
    • Export Citation
  • 29

    Inukai T Kiyokawa N Campana D Coustan-Smith E Kikuchi A Kobayashi M et al. Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children’s Cancer Study Group Study L99-15. Br J Haematol 2012;156:358-65.

    • Crossref
    • Export Citation
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