HAEM4Backup:Acute Myeloid Leukemia (AML) with Minimal Differentiation

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Primary Author(s)*

Celeste Eno, PhD, Cedars Sinai Medical Center, Los Angeles, Fabiola Quintero-Rivera, MD, FACMG, University of California Irvine


Cancer Category/Type

Acute Myeloid Leukemia

Cancer Sub-Classification / Subtype

Acute Myeloid Leukemia (AML) with minimal differentiation

Definition / Description of Disease

This is a distinct entity in the World Health Organization (WHO) classification system within the section of Acute Myeloid Leukemia (AML), Not Otherwise Specified[1]. This entity does not meet the criteria for inclusion in any of the other AML groups (i.e. AML with Recurrent Genetic Abnormalities, AML with Myelodysplasia-Related Changes, or Therapy-Related Myeloid Neoplasms).

• Recognized as a distinct entity in 1987[2]

• Rare subtype of acute leukemia without evidence of morphological or cytochemical myeloid differentiation

• Characterize as myeloid through use of immunohistochemistry, flow cytometry or EM cytochemistry

• More than 20% myeloid blasts in bone marrow or peripheral blood

• Less than 3% MPO or Sudan black B positivity by light-microscopic enzyme cytochemical analysis[3]

• No definitive evidence of lymphoid differentiation

Synonyms / Terminology

AML M0 (FAB classification)

Epidemiology / Prevalence

Approximately <5% AML cases. Affects all age groups though most patients are infants or older adults.

Clinical Features

• Patients present with evidence of bone marrow failure

• Anemia

• Thrombocytopenia

• Neutropenia

• Some patients present with leukocytosis and numerous circulating blasts

Sites of Involvement

Bone Marrow: hematopoietic stem cell

Morphologic Features

• Blasts are usually medium–sized with dispersed nuclear chromatin

• Markedly hypercellular bone marrow with poorly differentiated blasts

• Round or slightly indented nuclei with one or two nucleoli

• Agranular cytoplasm with variable degree of basinophila

• No Auer rods

• Residual normal population of maturing neutrophils may be present

• Less frequently, blasts are small, with more dispersed chromatin, inconspicuous nucleoli and scant cytoplasm resembling that of lymphoblasts.

• MPO and CAE and Sudan Black B staining is negative

Immunophenotype

POSITIVE

• For any one of the myelomonocytic lineage antigens not expressed on normal B- or T-lymphoid cells: CD13, CD14, CD15, CD33, or CD64

• Or MPO positive detected by ultrastructural cytochemical analysis, immunohistochemical analysis or flow cytometric analysis[3]

• Most cases express early hematopoetic associated antigens: CD34, HLA-DR

• Approximately 60% of cases express CD33

• Blast cells express at mostly two myeloid-associated markers, CD13 and KIT (CD117)[4]

• 50% case Nuclear TdT is positive (may be of favorable prognostic significance)

• CD7 positive in 40% cases

• CD4 may have expression[5]

• Pediatric cases: CD33 bright


NEGATIVE:

• Lack antigens associated with myeloid and monocytic maturation: CD11b, CD14,3 CD153, CD36, CD41, CD61, CD64 and CD65

• CD38 and/or HLA-DR may be decreased

• No monocytic differentiation: no coexpression of CD64 and CD36

• Blasts are negative for the B-cell and T-cell cytoplasmic lymphoid markers CD5, cCD3, cCD79a and cCD22

• MPO negative by cytochemistry, but maybe positive in some blasts by flow cytometry or immunohistochemistry.

• Glycophorin A

• Pediatric cases: Negative for TdT, CD34 and CD13 (weak)

Chromosomal Rearrangements (Gene Fusions)

There is no recurrent rearrangements in this entity.

• t(7;12)(q36;p13), cytogenetically cryptic, leads to MNX1 deregulation and a poor prognosis.

- The morphology of cases is variable, but a significant portion is AML with minimal differentiation or without maturation most common in children[6][7].

- This translocation has also been reported in ALL

• t(10;11)(p12;q14) has an intermediate to poor prognosis[8] .

- Most cases show immature morphology.

- This translocation has also been reported in many other hematological malignancies[9].

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
t(7;12)(q36;p13) 5’ HLXB9 – 3’ ETV6 der(12) Rare
t(10;11)(p12;q14) 5’ CALM – 3’ AF10 Rare

Characteristic Chromosomal Aberrations / Patterns

• No specific chromosomal abnormality is identified

• Complex karyotype[10]

• Unbalanced abnormalities

• Most common: del(5q) or t(5q) and loss of chromosome 7 or del(7q)[10][11] the presence of these abnormalities would place the case in the category of AML with myelodysplasia-related changes per new WHO classification (2017).

• Near tetraploid karyotypes[12]

• Pediatric: Chromosome 5 aberrations, trisomy 21 and hypodiploidy more common in AML M0 than non-M0 counterparts[13]

Genomic Gain/Loss/LOH

• +4 sole; intermediate/poor prognosis

• +8[10]

• +10 sole; intermediate/poor prognosis[14]

• 11q gain MLL amplification; poor prognosis[10]

• +13 sole; poor prognosis[10][11][15] and associated with TdT expression[16]

• +14[10]

• del(11q)

• Loss and haploinsufficiency of ETV6 through deletion may be a leukemogenic step in AML-M0[7]

Gene Mutations (SNV/INDEL)

• Co-existence of gene mutations is common

• FLT3 Mutations: ITD and TKD, 16-22% of cases

• RAS: K-RAS and N-RAS

• IDH1 and IDH2 mutations[17]

• Loss and haploinsufficiency of ETV6 result of heterozygous/homozygous mutations may be a leukemogenic step in AML-M0[7]

• Mutations of RUNX1 occur in ~30% of cases[15], and correlates with the presence of trisomy 13 and increased FLT3 expression. De novo cases with RUNX1 mutations are now classified as the provisional entity of AML with mutated RUNX1 in the 2017 WHO[1].

Epigenomics (Methylation)

• High frequency of gene mutations in epigenetic modifiers implies that epigenetic deregulation and may lead to the pathogenesis of AML-M0[17].

• Histone acetylation and methylation patterns for patients with primary AML (all types) is ongoing[18].

Genes and Main Pathways Involved

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Diagnostic Testing Methods

• Bone Marrow and peripheral blood examination for >20% blasts

• Cytochemical analysis, MPO and/or Sudan black B staining (undetectable - 3% positivity) for MPO

• Flow analysis: o Lack of expression of lymphoid-specific antigens cyCD3 for T cells and cyCD79 and cyCD22 for B cells o Positivity for any one of the myelomonocytic lineage antigens known not to be expressed on normal T-lymphoid cells (such as CD13, CD14, CD15, CD33, or CD64)

• Conventional G-banding cytogenetics

• FISH in cases of MLL (KMT2A) amplification and cryptic translocations involving ETV6

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

• Adverse outcome in children. May relate to a lack of more favorable AML cytogenetic abnormalities, such as t(8;21) and inv 16 and presence of high-risk abnormalities (i.e. chromosome 5)[13].

• Patients treated with only chemotherapy in conventional doses.

• Stem cell transplantation may contribute to a longer remission and prolongation of the survival[12].

• MDR1/p-170 protein is positive in blasts and mediates multidrug resistance in adults. This protein functions as a barrier, reducing intracellular concentrations of chemotherapeutics[19][20].

Familial Forms

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Other Information

Differential Diagnosis: Acute Lymphoblastic Leukemia (more common), mixed phenotype acute leukemia, leukemic phase of large cell lymphoma (less common)

Links

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References

  1. ↑ 1.0 1.1 Arber DA, et al., (2017). Acute myeloid leukaemia,NOS in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p156-158.
  2. ↑ Lee, M. S.; et al. (1987). "T-cell receptor gamma chain gene rearrangement in acute myelogenous leukemia--evidence for lymphoid lineage prematurity". Hematologic Pathology. 1 (2): 93–98. ISSN 0886-0238. PMID 2848796.
  3. ↑ 3.0 3.1 Kaleem, Z.; et al. (2001). "Diagnostic criteria for minimally differentiated acute myeloid leukemia (AML-M0). Evaluation and a proposal". American Journal of Clinical Pathology. 115 (6): 876–884. doi:10.1309/D2BR-C0V5-LEYD-HA2D. ISSN 0002-9173. PMID 11392885.
  4. ↑ Thalhammer-Scherrer, Renate; et al. (2002). "The immunophenotype of 325 adult acute leukemias: relationship to morphologic and molecular classification and proposal for a minimal screening program highly predictive for lineage discrimination". American Journal of Clinical Pathology. 117 (3): 380–389. doi:10.1309/C38D-D8J3-JU3E-V6EE. ISSN 0002-9173. PMID 11888077.
  5. ↑ Bennett, J. M.; et al. (1981). "The morphological classification of acute lymphoblastic leukaemia: concordance among observers and clinical correlations". British Journal of Haematology. 47 (4): 553–561. doi:10.1111/j.1365-2141.1981.tb02684.x. ISSN 0007-1048. PMID 6938236.
  6. ↑ Tosi, S.; et al. (2000). "t(7;12)(q36;p13), a new recurrent translocation involving ETV6 in infant leukemia". Genes, Chromosomes & Cancer. 29 (4): 325–332. doi:10.1002/1098-2264(2000)9999:99993.0.co;2-9. ISSN 1045-2257. PMID 11066076.
  7. ↑ 7.0 7.1 7.2 Silva, F. P. G.; et al. (2008). "ETV6 mutations and loss in AML-M0". Leukemia. 22 (8): 1639–1643. doi:10.1038/leu.2008.34. ISSN 1476-5551. PMID 18305557.
  8. ↑ Cancer Genome Atlas Research Network; et al. (2013). "Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia". The New England Journal of Medicine. 368 (22): 2059–2074. doi:10.1056/NEJMoa1301689. ISSN 1533-4406. PMC 3767041. PMID 23634996.
  9. ↑ Caudell, D.; et al. (2008). "The role of CALM-AF10 gene fusion in acute leukemia". Leukemia. 22 (4): 678–685. doi:10.1038/sj.leu.2405074. ISSN 1476-5551. PMC 2366104. PMID 18094714.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Klaus, Mirjam; et al. (2004). "Cytogenetic profile in de novo acute myeloid leukemia with FAB subtypes M0, M1, and M2: a study based on 652 cases analyzed with morphology, cytogenetics, and fluorescence in situ hybridization". Cancer Genetics and Cytogenetics. 155 (1): 47–56. doi:10.1016/j.cancergencyto.2004.03.008. ISSN 0165-4608. PMID 15527902.
  11. ↑ 11.0 11.1 Cuneo, A.; et al. (1995). "Cytogenetic profile of minimally differentiated (FAB M0) acute myeloid leukemia: correlation with clinicobiologic findings". Blood. 85 (12): 3688–3694. ISSN 0006-4971. PMID 7780152.
  12. ↑ 12.0 12.1 Béné, M. C.; et al. (2001). "Acute myeloid leukaemia M0: haematological, immunophenotypic and cytogenetic characteristics and their prognostic significance: an analysis in 241 patients". British Journal of Haematology. 113 (3): 737–745. doi:10.1046/j.1365-2141.2001.02801.x. ISSN 0007-1048. PMID 11380465.
  13. ↑ 13.0 13.1 Barbaric, Draga; et al. (2007). "Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961". Blood. 109 (6): 2314–2321. doi:10.1182/blood-2005-11-025536. ISSN 0006-4971. PMC 1852193. PMID 17158236.
  14. ↑ Johansson B and Harrison CJ (2015). Cancer Cytogenetics: Chromosomal and molecular genetic aberrations of tumor cells, 4th edition. Heim S and Mitelman F, Editors, Wiley-Blackwell: p62-84.
  15. ↑ 15.0 15.1 Silva, Fernando P. G.; et al. (2007). "Trisomy 13 correlates with RUNX1 mutation and increased FLT3 expression in AML-M0 patients". Haematologica. 92 (8): 1123–1126. doi:10.3324/haematol.11296. ISSN 1592-8721. PMID 17650443.
  16. ↑ Patel, Keyur P.; et al. (2013). "TdT expression in acute myeloid leukemia with minimal differentiation is associated with distinctive clinicopathological features and better overall survival following stem cell transplantation". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 26 (2): 195–203. doi:10.1038/modpathol.2012.142. ISSN 1530-0285. PMC 5485410. PMID 22936064.
  17. ↑ 17.0 17.1 Kao, Hsiao-Wen; et al. (2014). "Gene mutation patterns in patients with minimally differentiated acute myeloid leukemia". Neoplasia (New York, N.Y.). 16 (6): 481–488. doi:10.1016/j.neo.2014.06.002. ISSN 1476-5586. PMC 4198802. PMID 25022553.
  18. ↑ Hellenbrecht A. ChIP- Chip microarrays to study the epigenome in leukemia. Available at: https://www.leukemia-net.org/content/leukemias/aml/aml_information/chip_microarrays/index_eng.html. Accessed June 20, 2018.
  19. ↑ Campos, L.; et al. (1992). "Correlation of MDR1/P-170 expression with daunorubicin uptake and sensitivity of leukemic progenitors in acute myeloid leukemia". European Journal of Haematology. 48 (5): 254–258. doi:10.1111/j.1600-0609.1992.tb01803.x. ISSN 0902-4441. PMID 1353726.
  20. ↑ Wuchter, C.; et al. (1999). "Clinical significance of CD95, Bcl-2 and Bax expression and CD95 function in adult de novo acute myeloid leukemia in context of P-glycoprotein function, maturation stage, and cytogenetics". Leukemia. 13 (12): 1943–1953. doi:10.1038/sj.leu.2401605. ISSN 0887-6924. PMID 10602414.

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