Acute Myeloid Leukemia (AML) with Minimal Differentiation
Celeste Eno, PhD, Cedars Sinai Medical Center, Los Angeles, Fabiola Quintero-Rivera, MD, FACMG, University of California Irvine
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. 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
• 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
• 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.
• Patients present with evidence of bone marrow failure
• Some patients present with leukocytosis and numerous circulating blasts
Sites of Involvement
Bone Marrow: hematopoietic stem cell
• 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
• 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
• 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)
• 50% case Nuclear TdT is positive (may be of favorable prognostic significance)
• CD7 positive in 40% cases
• CD4 may have expression
• Pediatric cases: CD33 bright
• 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.
- This translocation has also been reported in ALL
• t(10;11)(p12;q14) has an intermediate to poor prognosis .
- Most cases show immature morphology.
- This translocation has also been reported in many other hematological malignancies.
|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
• Unbalanced abnormalities
• Most common: del(5q) or t(5q) and loss of chromosome 7 or del(7q) 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
• Pediatric: Chromosome 5 aberrations, trisomy 21 and hypodiploidy more common in AML M0 than non-M0 counterparts
• +4 sole; intermediate/poor prognosis
• +10 sole; intermediate/poor prognosis
• 11q gain MLL amplification; poor prognosis
• Loss and haploinsufficiency of ETV6 through deletion may be a leukemogenic step in AML-M0
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
• Loss and haploinsufficiency of ETV6 result of heterozygous/homozygous mutations may be a leukemogenic step in AML-M0
• Mutations of RUNX1 occur in ~30% of cases, 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.
• High frequency of gene mutations in epigenetic modifiers implies that epigenetic deregulation and may lead to the pathogenesis of AML-M0.
• Histone acetylation and methylation patterns for patients with primary AML (all types) is ongoing.
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).
• Patients treated with only chemotherapy in conventional doses.
• Stem cell transplantation may contribute to a longer remission and prolongation of the survival.
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Differential Diagnosis: Acute Lymphoblastic Leukemia (more common), mixed phenotype acute leukemia, leukemic phase of large cell lymphoma (less common)
Put your links here
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