University of Virginia Health System

Acute Myelomonocytic Leukemia
(M4 AML, Naegeli's acute leukemia, AMML)

(a) M4 acute leukemia- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

(b) AML M4 with Auer rods- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

(c) M4Eo AML- Bone marrow aspirate smear, Wright-Giemsa stain, 1000x

Description:

This subtype represents up to 20% of all adult AMLs, and carries the eponysm, Naegeli's acute monocytic leukemia, and was one of the first biphenotypic (monocyte-myelocyte) leukemia described. The bilineage nature of this subtype was later established by cytochemistry (clonal cells stained for myeloperoxidase and non-specific esterase), and later by immunophenotyping. This subtype is thought to arise from an early hematopoietic progenitor with the capacity to differentiate down the myeloid and monocytic lines.

The morphologic appearance of clonal cells range from typical myeloblasts and monoblasts to promonocytes, and cells that are difficult to categorize as belonging to either lineage (a). The cells range in size and shape from typical myeloblasts and monoblasts to cells that show features of maturation down the monocytic lineage. The cytoplasm is scant in those that resemble myeloblasts, but more abundant in those that demonstrate differentiation down the monocytic lineage. In the more differentiated cells, cytoplasmic granules that resemble promonocytes (fine granulation with a "salt and pepper" appearance) are seen. Auer rods may be seen (b). The nuclear:cytoplasmic ratio is quite variable depending on the degree of maturation down the monocytic lineage. As with normal monocytic differentiation, nuclear indentation is seen at a more immature stage than in cells of the myeloid lineage. The nucleus is quite variable in size and shape, and nucleoli are especially prominent in those with monoblastic and promonocytic features.

A variant of M4, referred to as M4Eo, is now well characterized both morphologically and cytogenetically, and may represent up to 10% of all adult AMLs, and usually occurs at a younger age. In addition to the morphologic findings seen in M4 AML, a variable number of differentiating eosinophils are present, sometimes up to 50% or more of the nucleated cells on a bone marrow aspirate. The eosinophils are atypical (dysplastic), especially those at the late promyelocyte-early myelocyte stage (c). Coarse basophilic granules are seen with a variable number of eosinophilic granules. The more mature eosinophils are less atypical. The morphologic picture is diagnostic and is associated with the INV(16) cytogenetic abnormality.

Cytochemistry:

The clonal cells stain positive for the myeloid markers, myeloperoxidase (MPO) and chloroacetate esterase, and the monocytic marker, non-specific esterase (NSE) which is not inhibited by flouride. The cells with features of myeloblasts show more MPO positivity while those with features of monocytes show more NSE positivity- some cells stain with both.

In the M4Eo subtype, the eosinophils stain like normal neutrophils (e.g. MPO+, Sudan black B+, NSE+) and not normal eosinophils.

Immunophenotype:

• Stem cell and hematopoietic progenitor cell markers- CD34 positivity variable in the M4 subtype, but usually strongly positive in M4Eo subtype
• Myeloid lineage markers- CD13+, CD33±
• Monocyte lineage markers- CD14+, CD116±, CD11c±, CD4±

Clinical and Laboratory Manifestations:

In addition to those discussed for acute leukemia in general, involvement of other organs e.g. gums, skin (leukemia cutis), meninges, liver and spleen are more frequently observed. Patients with the M4Eo subtype tend to have higher levels of leukocytosis.

Prognosis:

A cure rate of 60-70% is seen in those with the M4Eo subtype. Otherwise the prognosis depends on many other factors, (e.g. age, those with a preceeding myelodysplastic or myeloproliferative disorder, or exposure to leukemogenic agents).

Note: The presence of the M4Eo variant with the associated INV(16) abnormality trumps all other bad prognostic factors including the presence of bad cytogenetics in association with the INV(16) abnormality. This dominant role of the good cytogenetic abnormalities also is seen with the t(8;21) and t(15;17) abnormalities. In chronic lymphocytic leukemia, the opposite occurs, the bad cytogenetic abnormalities trump the good.

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
• Adriaansen HJ, Boekhorst AW, Hagemeijer AM, et al: Acute myeloid leukemia M4 with bone marrow eosinophilia (M4Eo) and INV(16) (p13q22) exhibits a specific immunophenotype with CD2 expression. Blood 81:3043, 1993 

For all publication requests, please complete the image permission form and we will respond to your request shortly.