Definition/General
Introduction:
Acute Myeloid Leukemia (AML) is a clonal hematopoietic malignancy characterized by proliferation and accumulation of immature myeloid cells (blasts) in bone marrow, blood, and other tissues
It represents 80% of acute leukemias in adults.
Origin:
Arises from hematopoietic stem cells or committed myeloid progenitors
Results from acquired genetic alterations affecting normal differentiation and proliferation control mechanisms.
Classification:
WHO 2016 Classification based on genetics, morphology, and clinical features
Major categories include AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related AML, and AML NOS.
Epidemiology:
Median age 65 years
Incidence increases with age
Male predominance
10,000+ cases annually in India
Environmental exposures (benzene, alkylating agents) increase risk.
Clinical Features
Presentation:
Fatigue and weakness (anemia)
Bleeding/bruising (thrombocytopenia)
Infections (neutropenia)
Fever
Bone pain
Hepatosplenomegaly
Lymphadenopathy (uncommon).
Symptoms:
Fatigue, weakness, dyspnea
Easy bruising, petechiae, bleeding
Recurrent infections
Fever
Bone/joint pain
Gum hypertrophy (M4/M5)
Visual disturbances (leukostasis).
Risk Factors:
Previous chemotherapy/radiation
Myelodysplastic syndromes
Congenital disorders (Down syndrome, Fanconi anemia)
Benzene exposure
Smoking
Advanced age.
Screening:
No routine screening
Diagnosed by peripheral blood smear and bone marrow examination
Complete blood count shows cytopenias with circulating blasts.
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Gross Description
Appearance:
Bone marrow hypercellular (>80% cellularity typical)
Red to gray appearance
Soft consistency
May show areas of necrosis or fibrosis.
Characteristics:
Hypercellular bone marrow
Extramedullary involvement possible (chloromas)
Spleen and liver may be enlarged
Lymph nodes usually normal size.
Size Location:
Primarily involves bone marrow
Peripheral blood involvement
Extramedullary sites: skin, gums, CNS, testes
Chloromas in various organs.
Multifocality:
Systemic disease by definition
Multifocal bone marrow involvement
Extramedullary disease in subset of patients
CNS involvement in some subtypes.
Microscopic Description
Histological Features:
Bone marrow shows >20% blasts (WHO criteria)
Blasts are large cells with high nuclear-cytoplasmic ratio
Open chromatin with prominent nucleoli
Auer rods may be present.
Cellular Characteristics:
Myeloblasts: Large cells (12-20 μm)
High N:C ratio
Fine chromatin
1-3 nucleoli
Variable cytoplasm
Auer rods pathognomonic when present.
Architectural Patterns:
Diffuse replacement of normal marrow elements
Decreased normal hematopoiesis
Fibrosis may be present
Necrosis in aggressive cases.
Grading Criteria:
Diagnosis requires ≥20% blasts in bone marrow or blood
Exception: AML with specific genetic abnormalities (e.g., t(8;21), inv(16)) regardless of blast count.
Immunohistochemistry
Positive Markers:
Myeloid markers: CD13, CD33, CD117, MPO (myeloperoxidase)
CD34 (immature blasts)
CD68 (monocytic)
Lysozyme (monocytic)
TdT variable.
Negative Markers:
B-cell markers (CD19, CD20) negative
T-cell markers (CD3, CD5) negative
Lymphoid markers generally negative.
Diagnostic Utility:
MPO positivity confirms myeloid lineage
CD34 indicates immaturity
Combination of markers helps classify AML subtypes
Flow cytometry essential for diagnosis.
Molecular Subtypes:
Immunophenotype correlates with genetic subtypes
Aberrant antigen expression common
Minimal residual disease monitoring by flow cytometry.
Molecular/Genetic
Genetic Mutations:
FLT3 mutations (30%)
NPM1 mutations (50%)
CEBPA mutations (10%)
IDH1/IDH2 mutations (20%)
DNMT3A mutations (25%)
TP53 mutations (complex karyotype).
Molecular Markers:
Cytogenetic abnormalities in 50-60%
Molecular mutations detected by NGS
Chromosomal translocations create fusion genes
Complex karyotype indicates poor prognosis.
Prognostic Significance:
Cytogenetics most important prognostic factor
Favorable: t(8;21), inv(16), t(15;17)
Intermediate: normal karyotype with NPM1 mutation
Adverse: complex karyotype, TP53 mutations.
Therapeutic Targets:
FLT3 inhibitors (midostaurin, gilteritinib)
IDH inhibitors (ivosidenib, enasidenib)
Targeted therapy based on molecular profile
All-trans retinoic acid for APL.
Differential Diagnosis
Similar Entities:
Acute lymphoblastic leukemia
Myelodysplastic syndromes
Aplastic anemia
Viral infections (EBV, CMV)
Malignant lymphoma
Metastatic carcinoma.
Distinguishing Features:
AML: MPO+, CD13+, CD33+, Auer rods
ALL: TdT+, CD19+ or CD3+
MDS: <20% blasts, dysplasia
Reactive: <5% blasts, no cytogenetic abnormalities.
Diagnostic Challenges:
Distinction from ALL (mixed lineage leukemia)
Therapy-related vs de novo AML
Blast count borderline cases
Acute megakaryoblastic leukemia.
Rare Variants:
Acute megakaryoblastic leukemia
Acute erythroid leukemia
Acute basophilic leukemia
Mixed phenotype acute leukemia
Myeloid sarcoma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy
Diagnosis
Acute Myeloid Leukemia
WHO Classification
WHO 2016: [specific AML category]
Blast Count
Bone marrow blasts: [X]%, Peripheral blood blasts: [X]%
Morphological Features
Myeloblasts with [specific features], Auer rods: [present/absent]
Immunophenotype
Flow cytometry: CD13+, CD33+, MPO+, [other markers]
Cytogenetics
Karyotype: [result], FISH: [if performed]
Molecular Studies
NGS: [mutations detected], [therapeutic implications]
Risk Stratification
Risk group: [Favorable/Intermediate/Adverse] based on cytogenetics/molecular
Prognostic Factors
Prognostic factors: [age, cytogenetics, molecular mutations]
Final Diagnosis
Final diagnosis: AML, [specific subtype], [risk group]