August 2009
Written by Andrew Laramore, M.D., third year Resident in Pathology, UNC-Chapel Hill.

Submitting Pathologist
Edward Lipford, M.D., Chairman of Pathology, Carolinas Medical Center, Charlotte, North Carolina

Diagnosis
Acute myeloid leukemia with inv(16)(p13q22) and bone marrow eosinophilia (AML M4Eo)

Clinical History
This 52 year old male presented with pancytopenia, splenomegaly, and multiple cutaneous nodules at recent acupuncture needle insertion sites.

Microscopy
Bone marrow sections demonstrate hypercellularity (see Figure 1).

At high magnification in tissue sections and this can be seen to be due to infiltration by immature monocytic cells with abnormal eosinophils (see Figure 2).
Marrow smears reveal a range of immature monocytic cells, including promonocytes, and abnormal eosinophils with large basophilic granules are conspicuous (see arrows in Figure 3).
Peripheral blood smears show scattered monoblasts, promonocytes, myeloblasts, and atypical eosinophils (see arrow in Figure 4).

Ancillary Studies
Cytogenetics identified a chromosome 16 inversion, a balanced translocation involving chromosomes 2 and 3, and trisomy 22 in cells cultured from the patient's bone marrow.

Discussion
Acute myelomonocytic leukemia with abnormal eosinophils (AML M4Eo) was a distinct entity within the original French-American-British (FAB) classification system of acute myeloid leukemias, that is now defined by the presence of abnormalities of chromosome 16q22, usually inv(16)(p13q22) as in our case, or in other cases t(16;16)(p13.1q22) (1). While the specific mechanism is not completely understood, this genetic abnormality is closely associated with the specific morphologic, clinical, and prognostic features that characterize AML M4Eo (2).

Microscopy will typically reveal a predominance of eosinophils, blasts, and monocytic cells within the bone marrow. The cytomorphology of the myeloblasts and monoblasts is consistent with the cytologic features observed in acute myelomonocytic leukemia (AML M4). The eosinophils in AML M4Eo, which are present in all stages of maturation, usually show dysplastic characteristics such as the presence of large eosinophilic and basophilic cytoplasmic granules and aberrant staining with naphthol-AS-D-choloacetate-esterase. (1,3) Recognition of this histologic picture supports a diagnosis of AML M4Eo, but it is important to remember that the histology may vary from case to case. For example, the abnormalities of chromosome 16 which define AML M4Eo are not always associated with eosinophilia, and AML M4Eo may fail to demonstrate either myeloid or monocytic differentiation. For this reason cases with inv(16)(p13.1q22) or t(16;16)(p13.1q22) may still be classified as acute leukemia even if the blast percentage is less than 20% (1-3).

While AML M4Eo may present at any age, it is usually diagnosed in younger patients. Typical clinical features of disease include organomegaly and leukocytosis. With regard to prognosis, clinical trials have documented a favorable prognostic association among acute myeloid leukemias with inv(16)(p13.1q22) or t(16;16)(p13.1q22), and similarly, improved outcome is associated with the presence of +22 (4-5).

References

1. Steven H. Swerdlow, Elias Campo, Nancy Lee Harris, Elaine S. Jaffe, Stefano A. Pileri.
   WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. World Health Organization. 4th ed. Geneva:WHO Press;111-112.
2. Haferlach T, Winkemann M, Löffler H, Schoch R, Gassmann W, Fonatsch C, Schoch C, Poetsch M, Weber-Matthiesen K, Schlegelberger B.
   The abnormal eosinophils are part of the leukemic cell population in acute myelomonocytic leukemia with abnormal eosinophils (AML M4Eo) and carry the pericentric inversion 16: a combination of May-Grünwald-Giemsa staining and fluorescence in situ hybridization. Blood. 1996;87:2459-2463. More online »
3. Adriaansen HJ, Boekhorst PA, Hagemeijer AM, van der Schoot CE, Delwel HR, van Dongen JJ.
   Acute myeloid leukemia M4 with bone marrow eosinophilia (M4Eo) and inv(16)(p13q22) exhibits a specific immunophenotype with CD2 expression. Blood. 1993;81:3043-51. More online »
4. Schiffer CA, Lee EJ, Tomiyasu T, Wiernik PH, Testa JR.
   Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia. Blood. 1989;73:263-270. More online »
5. Marlton P, Keating M, Kantarjian H, Pierce S, O'Brien S, Freireich EJ, Estey E.
   Cytogenetic and clinical correlates in AML patients with abnormalities of chromosome 16. Leukemia 1995:9;965-971. More online »

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