What are the major subtypes of Acute Myeloid Leukemia (AML) based on the World Health Organization (WHO) classification?

Major Subtypes of AML Based on WHO Classification

The WHO 2008 classification organizes AML into four major categories: (1) AML with recurrent genetic abnormalities, (2) AML with myelodysplasia-related changes, (3) Therapy-related myeloid neoplasms, and (4) AML not otherwise specified (NOS), plus additional distinct entities. 1

1. AML with Recurrent Genetic Abnormalities

This category has expanded significantly and now includes the following specific entities 1:

Established Entities:

• AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 - These three entities (t(8;21), inv(16)/t(16;16), and t(15;17)) are unique in that the genetic abnormality alone is sufficient for AML diagnosis regardless of blast percentage 1
• AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 1
• Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA - Variant RARA translocations (involving ZBTB16, NUMA1, NPM1, or STAT5B) should be diagnosed separately as they may have different features and ATRA resistance 1
• AML with t(9;11)(p22;q23); MLLT3-MLL - This entity was redefined to focus specifically on t(9;11); other MLL translocations should be specified separately 1
• AML with t(6;9)(p23;q34); DEK-NUP214 - Newly added entity 1
• AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 - Newly added entity 1
• AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 - Newly added entity 1

Provisional Entities:

• AML with mutated NPM1 - Found in 50-60% of cytogenetically normal AML; associated with approximately 50% survival at 4 years when considered alone, and ~60% when NPM1-mutated and FLT3-ITD negative 1
• AML with mutated CEBPA - Found in approximately 15% of cytogenetically normal AML; associated with nearly 60% 4-year survival 1

Critical distinction: For all entities except t(8;21), inv(16)/t(16;16), and t(15;17), a blast count of ≥20% in peripheral blood or bone marrow is required for AML diagnosis 1

Important note: FLT3 mutations are not considered a distinct entity but should be tested in all cases due to prognostic significance (found in 30-40% of cytogenetically normal AML, associated with only 20-25% 4-year survival) 1

2. AML with Myelodysplasia-Related Changes

This category was renamed from "AML with multilineage dysplasia" and now encompasses cases meeting any of the following three criteria 1:

• Prior history of MDS or MDS/MPN that evolved to AML with ≥20% blasts 1
• Myelodysplasia-related cytogenetic abnormalities (specific list includes abnormalities like -7/del(7q), -5/del(5q), i(17q), complex karyotype with ≥3 unrelated abnormalities, and various balanced translocations) 1
• Multilineage dysplasia affecting ≥50% of cells in two or more myeloid lineages 1

Clinical significance: This category encompasses up to 48% of all AML patients and is associated with worse prognosis compared to AML-NOS 2

3. Therapy-Related Myeloid Neoplasms

• This remains a distinct entity but is no longer subcategorized by type of prior therapy (alkylating agent vs. topoisomerase II inhibitor) since most patients receive both types of treatment 1
• Encompasses the full spectrum of therapy-related disorders (t-AML, t-MDS, t-MDS/MPN) occurring after cytotoxic chemotherapy and/or radiation 3

4. AML Not Otherwise Specified (NOS)

This category includes cases that don't fulfill criteria for other categories and accounts for only 25-30% of all AML cases 1. It includes the following subtypes based on morphologic and immunophenotypic features 1:

• AML with minimal differentiation 1
• AML without maturation 1
• AML with maturation 1
• Acute myelomonocytic leukemia 1
• Acute monoblastic/monocytic leukemia 1
• Acute erythroid leukemia (subdivided into pure erythroid leukemia and erythroleukemia, erythroid/myeloid) 1
• Acute megakaryoblastic leukemia (excluding Down syndrome-related and those with specific translocations) 1
• Acute basophilic leukemia 1
• Acute panmyelosis with myelofibrosis 1

5. Additional Distinct Entities

Myeloid Sarcoma

• Extramedullary proliferation of myeloid blasts that disrupts normal tissue architecture (previously called granulocytic sarcoma or chloroma) 1

Myeloid Proliferations Related to Down Syndrome

• Transient abnormal myelopoiesis (transient myeloproliferative disorder) - unique to newborns with Down syndrome 1, 4
• Myeloid leukemia associated with Down syndrome - recognized as a distinct entity with unique clinical, biological, and genetic features 4, 5

Blastic Plasmacytoid Dendritic Cell Neoplasm

• Now recognized as a distinct myeloid-related neoplasm 1

Key Clinical Pitfalls

Common diagnostic errors to avoid:

• Do not diagnose AML-MRC based solely on morphologic dysplasia without checking for the other two criteria (prior MDS/MPN history or MDS-related cytogenetics) 1
• Always exclude therapy-related disease before using certain cytogenetic abnormalities as evidence for AML-MRC 1
• Remember that cases with t(8;21), inv(16)/t(16;16), or t(15;17) are diagnosed as AML regardless of blast count, but all other genetic subtypes require ≥20% blasts 1
• Test for NPM1, CEBPA, and FLT3 mutations in all cytogenetically normal AML cases for proper risk stratification 1