M4 myelomonocytic leukemia is an acute myeloid leukemia with both granulocytic and monocytic differentiation. According to FAB classification criteria, the sum of bone marrow myeloblasts and monoblasts must be greater than 30% but less than 80%, and greater than 20% of marrow cells must be of monocyte lineage. Monocyte lineage can be verified by bone marrow reactivity with non-specific esterase (NSE) or a serum or urine lysozyme level greater than 3 times normal. In addition, the number of monocytic cells in the blood should be 5x109/L or greater. In variants where either the bone marrow monocyte percentage or the peripheral blood monocyte count do not meet M4 criteria, the diagnosis may still be made if the serum or urine lysozyme is greater than 3 times normal.
AML M4 makes up 15-25% of all AML cases. The median age at diagnosis of M4 AML is 50 years, although it is seen in both children and adults. Clinically, organomegally and lymphadenopathy are commonly seen, as is leukocytosis.
The M4 with eosinophilia (M4Eo) subtype, in addition to meeting the M4 criteria, is characterized by increased bone marrow eosinophils. These eosinophils typically have large, basophilic granules that stain with chloroacetate ester (CAE) and periodic acid-Schiff (PAS). In addition, almost all M4Eo AMLs have abnormalities of chromosome 16. M4Eo accounts for about 30% of M4 AMLs, and appears to be equally distributed between children and adults. Compared to other types of AML, M4Eo has a higher incidence of extramedullary disease and CNS relapse.
The abnormalities in chromosome 16 associated with M4Eo include inv(16)(p13q22), t(16;16)(p13q22) and del(16)(q22). In inv(16) a chimeric gene results from the juxtaposition of the core binding factor beta (CBFß) gene from 16q22 and the MYH11 gene from 16p13. MYH11 codes for the smooth muscle form of myosin heavy chain and CBFß codes for the human homolog of a subunit of the mouse transcription factor complex CBF (also called PEBP2), which binds to the core site of the murine leukemia virus. The role of the fusion protein in leukemogenesis is yet to be fully understood. Reverse transcriptase PCR methods have recently been used to detect the fusion transcripts of the chimeric gene in peripheral blood and bone marrow, and have also demonstrated several different CBFß/MYH11 chimeric transcripts. Translocations of 16 appear to have the same breakpoints as those seen in inv(16) with a similar chimeric gene. No similar chimeric gene or gene product has been identified in patients with del(16q).
Prognostically, inv(16) AML M4Eo is the most favorable subtype of the disease, with 5 year survival rates approaching 50%. No similar survival advantage is associated with del(16q). Other karyotypic abnormalities frequently found in association with inv(16) include trisomy 22, 8, and 21. While these trisomies alone typically confer a poor prognosis, recent studies suggest there is no significant difference in survival or remission duration when these karyotypic abnormalities are found in association with inv(16).
Immunophenotyping by flow cytometry in cases of AML is an important tool for identifying and quantifying leukemic cell populations, distinguishing AML from ALL, and providing correlation with the morphologic FAB subtype. The case presented here shows immunophenotypic findings typical of a myelomonocytic leukemia. Two malignant cell populations are identified; the first shows immunophenotypic features of immature myeloid blasts and early granulocytic precursors, while the second shows monocytic differentiation. These populations can be identified as abnormal, both by their quantity and their aberrant expression of CD markers. The immunophenotypic findings confirm an AML with early granulocytic and monocytic maturation, consistent with FAB M4.
AML M4Eo is an acute myelomonocytic leukemia with several features that aid in its diagnosis. Bone marrow biopsy shows a myeloid cell population with monocytic differentiation, distinguished by NSE staining of the bone marrow or elevated serum or urine lysozyme. Abnormal eosinophils are also seen, and can be identified using CAE or PAS staining. Almost all M4Eos show karyotypic abnormalities of chromosome 16, with inv(16) offering the best prognosis. Finally, immunophenotyping using flow cytometry allows identification of a myeloid leukemia as well as identification and quantification of the myeloid and monocytic subpopulations. Together, morphology, cytogenetics and immunophenotyping contribute to the diagnosis of AML M4Eo.