University of Virginia Health System

Acute Promyelocytic Leukemia
(M3 AML, APML)

(a) M3 AML- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

(b) M3 AML with "angel wings"- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

(c) M3 AML with Auer rods- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

Description:

This subtype represents up to 10% of adults with AML, and is seen more at a younger age.

The appearance of M3 AML cells on a Wright-Giemsa stain of the peripheral blood or bone marrow aspirate is essentially diagnostic (a, b, c). Unlike other AMLs and ALLs, the maturation arrest does not occur at the agranular blast level, but at the promyelocyte-late myelocyte stage. Although the size and shape of the clonal cells vary, most are approximately the size of a normal segmented neutrophil. They differ from normal promyelocytes and those seen in acute agranulocytosis by not having a well developed Golgi apparatus. The nuclear:cytoplasmic ratio is quite variable. The cytoplasmic color ranges from light blue to pink and contains a variable number of granules that may have a pink, red, or dark purple color. The granules may be very abundant and so densely packed as to partially obscure the nucleus. Auer rods are frequently seen (c), and may occur in bundles (fagot cells). The nuclear size varies and the shape is quite variable, ranging from round, oval, indented, reniform, to some that have the appearance of "angel wings" (b). The nuclear chromatin is coarse, variably clumped, and nucleoli may or may not be visible.

Two subtypes of M3 AML are recognized based on morphologic appearance as seen on a Wright-Giemsa stain:

• Hypergranular M3: Is the most common subtype, representing up to 80% of cases. As the name implies, cytoplasmic granulation is prominent, and large (giant) granules may be seen. Auer rods are common.
• Variant microgranular (hypogranular) (M3v): Again, as the name implies, granulation is sparce, and in some cells granules are not seen on a Wright-Giemsa stain even though the myeloperoxidase, Sudan black B, and chloroacetate esterase stains are strongly positive. Auer rods are not usually seen.

Cytochemistry:

The cells are strongly myeloperoxidase, Sudan black B and chloroacetate esterase positive.

Immunophenotype:

• Stem cell and hematopoietic progenitor cell markers: CD34-, HLA-DR-
• Myeloid lineage markers: CD13+ and CD33+; CD117- and CD15-.

Cytogenetics:

The signature and diagnostic cytogenetic abnormality is the t(15;17), and has the same diagnostic significance as the t(9;22) in chronic myelocytic leukemia. It is a balanced translocation from the long arm of chromosome 17, the locus of the retinoic acid receptor-α gene, to a site on the long arm of chromosome 15 which is the locus for the promyelocytic leukemia (PML) gene.

Clinical and Laboratory Manifestations:

In addition to those discussed for other acute leukemias in general (see under acute leukemia), patients with the M3 AML subtype frequently present with a coagulopathy that results from a combination of disseminated intravascular coagulation (DIC) and primary fibrinolysis.

The peripheral blood blast count is considerably lower in the hypergranular subtype compared to the microgranular (hypogranular, M3v) subtype in which the count is frequently above 100,000/cumm.

Differential Diagnosis:

The morphologic features of M3 AML cells are diagnostic in most cases. Some cases of M2 AML with many type II blasts, and some M4 AMLs may present a diagnostic problem, and require cytogenetics to differentiate.

Prognosis:

With the use of all-trans-retinoic acid, usually in combination with an anthracycline, the prognosis is excellent with 70% or more cured. Arsenic trioxide is also a very effective agent.

General References:

• Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Am Intern Med 103:620, 1985
• Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumors of hematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumors, Lyon, France: IARC Press, 2001
• Wang ZY, Chen Z: Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 111:2505, 2008 

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