Cancer Health Center

French-American-British (FAB) Classification for Childhood Acute Myeloid Leukemia

The first most comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the FAB Cooperative Group.[1,2,3,4,5] This classification system categorizes AML into the following major subtypes primarily based on morphology and immunohistochemical detection of lineage markers:

• M0: acute myeloblastic leukemia without differentiation.[6,7]M0 AML, also referred to as minimally differentiated AML, does not express myeloperoxidase (MPO) at the light microscopy level, but may show characteristic granules by electron microscopy. M0 AML can be defined by expression of cluster determinant (CD) markers such as CD13, CD33, and CD117 (c-KIT) in the absence of lymphoid differentiation. To be categorized as M0, the leukemic blasts must not display specific morphologic or histochemical features of either AML or acute lymphoblastic leukemia (ALL). M0 AML appears to be associated with an inferior prognosis in non-Down syndrome patients.[8]
• M1: acute myeloblastic leukemia with minimal differentiation but with the expression of MPO that is detected by immunohistochemistry or flow cytometry.
• M2: acute myeloblastic leukemia with differentiation.
• M3: acute promyelocytic leukemia (APL) hypergranular type.Identifying this subtype is critical since the risk of fatal hemorrhagic complication prior to or during induction is high and the appropriate therapy is different than for other subtypes of AML. (Refer to the Acute Promyelocytic Leukemia section of this summary for more information on treatment options under clinical evaluation.)
• M3v: APL, microgranular variant. Cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded. Same clinical, cytogenetic, and therapeutic implications as FAB M3.
• M4: acute myelomonocytic leukemia (AMML).
• M4Eo: AMML with eosinophilia (abnormal eosinophils with dysplastic basophilic granules).
• M5: acute monocytic leukemia (AMoL).
  • M5a: AMoL without differentiation (monoblastic).
  • M5b: AMoL with differentiation.
• M6: acute erythroid leukemia (AEL).
• M7: acute megakaryocytic leukemia (AMKL). Diagnosis of M7 can be difficult without the use of flow cytometry as the blasts can be morphologically confused with lymphoblasts. Characteristically, the blasts display cytoplasmic blebs. Marrow aspiration can be difficult due to myelofibrosis, and marrow biopsy with reticulin stain can be helpful.

Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.

Fifty percent to 60% of children with AML can be classified as having M1, M2, M3, M6, or M7 subtypes; approximately 40% have M4 or M5 subtypes. About 80% of children younger than 2 years with AML have an M4 or M5 subtype. The response to cytotoxic chemotherapy among children with the different subtypes of AML is relatively similar. One exception is FAB subtype M3, for which all-trans retinoic acid plus chemotherapy achieves remission and cure in approximately 70% to 80% of children with AML.

World Health Organization (WHO) Classification System

In 2002, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17) and those with MLL translocations, which collectively constituted nearly half of the cases of childhood AML, were classified as "AML with recurrent cytogenetic abnormalities." This classification system also decreased the bone marrow percentage of leukemic blast requirement for the diagnosis of AML from 30% to 20%; an additional clarification was made that patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered AML.[9,10,11] In 2008, WHO expanded the number of cytogenetic abnormalities linked to AML classification, and for the first time included specific gene mutations (CEBPA and NPM mutations) in its classification system.[12] (Refer to the WHO classification of myeloid leukemias section of this summary for more information.) Such a genetically based classification system links AML class with outcome and provides significant biologic and prognostic information. With new emerging technologies aimed at genetic, epigenetic, proteomic and immunophenotypic classification, AML classification will likely evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.