What are the differential diagnoses of Acute Myeloid Leukemia (AML)?

Differential Diagnosis of Acute Myeloid Leukemia (AML)

When evaluating a patient with suspected AML, the primary differential diagnoses include acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS), mixed phenotype acute leukemia (MPAL), and other myeloid neoplasms—each distinguished by specific blast percentages, immunophenotyping, and cytogenetic features. 1

Key Diagnostic Threshold

• AML requires ≥20% blasts in bone marrow or peripheral blood, except for specific recurrent genetic abnormalities [t(15;17), t(8;21), inv(16), or t(16;16)] where any blast percentage suffices for diagnosis 1
• This 20% threshold is the critical dividing line separating AML from MDS 2

Primary Differential Diagnoses

Acute Lymphoblastic Leukemia (ALL)

• Distinguished by lymphoid lineage markers rather than myeloid markers 1
• ALL blasts express CD19 (strong) with CD79a, cCD22, or CD10 for B-lineage, or cytoplasmic/surface CD3 for T-lineage 1
• Peripheral blood typically shows ≥20% lymphoblasts with elevated white blood cell counts (often >30,000/μL) 3
• Critical distinction: AML blasts express myeloperoxidase (MPO) or monocytic markers (NSE, CD11c, CD14, CD64, lysozyme), while ALL blasts do not 1

Myelodysplastic Syndromes (MDS)

• MDS has <20% blasts in bone marrow or peripheral blood, which is the defining distinction from AML 2
• Lower-risk MDS subtypes (RCUD, RARS, RCMD) have <5% blasts 2
• Higher-risk MDS (RAEB-1 and RAEB-2) have 5-9% and 10-19% blasts respectively 2
• Progression to AML occurs when blast count reaches ≥20% 2
• MDS often shows multilineage dysplasia and specific cytogenetic abnormalities 1

Mixed Phenotype Acute Leukemia (MPAL)

• MPAL expresses markers of both myeloid and lymphoid lineages on the same blast population or separate blast populations 1
• For myeloid lineage assignment in MPAL: requires MPO or at least 2 monocytic markers (NSE, CD11c, CD14, CD64, lysozyme) 1
• For B-lineage: CD19 (strong) plus CD79a, cCD22, or CD10 1
• For T-lineage: cytoplasmic or surface CD3 1
• MPAL with BCR-ABL1 should be treated as BCR-ABL1-positive ALL, not as AML 1

AML with Myelodysplasia-Related Changes

• Diagnosed when AML (≥20% blasts) occurs with: 1
  • Prior history of MDS or MDS/MPN, OR
  • Myelodysplasia-related cytogenetic abnormalities (complex karyotype, del(5q), -7/del(7q), etc.), OR
  • Multilineage dysplasia in ≥50% of cells in 2+ lineages
• Must exclude recurrent genetic abnormalities and prior cytotoxic therapy 1

Therapy-Related Myeloid Neoplasms

• History of prior chemotherapy (alkylating agents, topoisomerase II inhibitors) or radiation therapy is the defining feature 1
• No longer subcategorized by agent type due to frequent combination exposures 1
• Can present as AML or MDS depending on blast percentage 1

Myeloid Proliferations Related to Down Syndrome

• Distinct WHO entity specific to patients with Down syndrome 4
• Includes transient abnormal myelopoiesis (in newborns) and myeloid leukemia associated with Down syndrome 4
• Requires complete blood count screening in newborns with Down syndrome 4

Blastic Plasmacytoid Dendritic Cell Neoplasm

• Rare entity listed separately in WHO classification 1
• Distinguished by specific immunophenotype distinct from typical AML markers 1

Essential Diagnostic Workup

Morphology and Cell Counts

• Count 200 leukocytes on peripheral blood smears and 500 nucleated cells on bone marrow smears 1
• Include myeloblasts, monoblasts, and megakaryoblasts in blast count 1
• In monocytic/myelomonocytic AML, count monoblasts and promonocytes (not mature monocytes) as blast equivalents 1
• Do not count erythroblasts as blasts except in pure erythroid leukemia 1

Immunophenotyping Markers

For AML diagnosis: 1

• Precursor markers: CD34, CD38, CD117, CD133, HLA-DR
• Granulocytic markers: CD13, CD15, CD16, CD33, CD65, cytoplasmic MPO
• Monocytic markers: NSE, CD11c, CD14, CD64, lysozyme, CD4, CD11b, CD36
• Megakaryocytic markers: CD41, CD61, CD42
• Erythroid marker: CD235a (glycophorin A)

Cytogenetic and Molecular Analysis

• Mandatory for risk stratification and classification 5, 6
• Most commonly altered genes: FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, TP53 5
• Recurrent genetic abnormalities define specific AML subtypes regardless of blast percentage 1

Common Pitfalls to Avoid

• Do not diagnose AML based solely on blast percentage without immunophenotyping—MPAL and ALL can present with similar blast counts but require different treatment 1
• Do not count mature monocytes as blasts in monocytic AML—only monoblasts and promonocytes count 1
• Do not overlook prior MDS or chemotherapy history—these change the AML classification to specific subtypes with different prognoses 1
• Do not assume all blasts are myeloid—always perform flow cytometry to exclude lymphoid lineage 1
• In patients with Down syndrome, recognize this as a distinct entity requiring specialized management 4