Bone Marrow Biopsy, Aspirate, and Particle Preparation:
The marrow cellularity approached 100% both in the biopsy and in the particle preparation (Figs. 22 and 23). The cells were predominantly blasts and these blasts are large with moderately abundant cytoplasm and nuclei with dispersed chromatin. Numerous eosinophils were seen in the particle preparation, aspirate smears, and biopsy. Cytochemical stains demonstrated that approximately 10% of the immature cells were peroxidase positive and approximately 10% were positive for nonspecific esterase (Figs. 11 and 10). Flow cytometry demonstrated that approximately 14 and 22 percent of cells were positive for CD34 and CD117 respectively (Figs. 14 and 15). These cells were myeloid and coexpressed CD13/33. Many were also HLA-DR and TdT positve (Figs. 16 and 17). Approximately 23 percent of the cells were CD14 positive suggesting monocytoid differentiation (Fig. 18). Taken together these features were most compatible with Acute myelomonocytic leukemia with a noted increase in eosinophils. Despite the impressive, widespread infiltrate the eosinophils DID NOT exhibit morphologic atypia or have the characteristic inv(16) cytogenetic abnormality that is associated with M4Eo, a distinct subtype of AML and part of the differential diagnosis in this case.
Acute myelomonocytic leukemia (AMML) is remarkable for its involvement of both myeloid and monocytoid precursors. Criteria for diagnosis are that the bone marrow should have >20% blasts as it should in other myeloid leukemias. Blasts and/or promonocytes should also compromise >20% but less than 80% of total marrow cells. This requirement of 20-79% monocytoid cells serves to distinguish this distinct clinicopathologic entity from AML with or without maturation which may have a prominent monocytoid component and from acute monocytic leukemia (M5) with a requirement for >80% monocytoid cells. As was the case in our patient, a high number of circulating monocytoid cells is commonly seen. If the number of circulating monocytoid cells exceeds 5x10^9 cells/L, the diagnosis of AMML may be considered even when the monocytoid involvement of marrow does not meet criteria for diagnosis.
Clinical features typically include fever and fatigue. The laboratory features of anemia and thrombocytopenia are also likely to be present. High WBC counts are noted at the time of initial workup. A remarkable clinical feature of neoplastic monocytoid proliferations includes extramedullary and particularly gingival infiltration of the neoplastic cells. Our patient did have some swelling of the gums when she presented, giving a clinical hint that perhaps there was monocyte involvement. However, extrameduallry masses, cutaneous, and gingival involvement are more likely to be found in pure acute monocytic leukemia (FAB M5).
Acute myelomonocytic leukemia makes up 15-25% of all AMLs. It is manifest in all age groups but is more common in older individuals. The median age is thought to be around 50 and there is a slight male predisposition. Our patient, being young and female, is therefore not a classic candidate for this disease.
Monoblasts are typically large with abundant cytoplasm and may show pseudopod formation. As we saw in our patient, scattered vacuoles are frequently present. Nuclear features include a round smooth contour with dispersed or somewhat lacy chromatin, especially in promonocytes. Additionally, promonocytes tend to have more irregular convoluted nuclear contours (Fig. 5) Monocytoid cells may be difficult to distinguish on routine section and so histochemistry is often utilized. A minimum of 3% blasts should be positive for myeloperoxidase and we saw this in our patient (Fig. 10) who showed ~10% positivity. NSE staining that is inhibitable by NaF is used to help highlight the monocytoid elements that are present. In our patient ~10% of immature cells showed positivity (Fig. 11). It is noted that the quality of NSE staining can be variable and should not be substituted for morphology or staining methods with greater specificity and reproducibility. This is evident in our case where only 10% of monocytoid cells are identified by NSE staining but follow up flow cytometry studies using antibody for CD14 show 23% of analyzed cells to be positive.
AMML variably expresses the myleoid antigen CD13/33 (Fig. 15) along with some monocytoid markers like CD14 and lysozyme as we saw in our patient (Figs. 13 and 18).
Perhaps the most interesting part of this case was the unique and complex three-way cytogenetic aberration present in the neoplastic clone: ish t(5;12;22)(q33;p13;q13) (Fig. 19) The t(5;22)(q31;q11.2) has not previously been reported in AML however the involvement of chromosome 5 at band 5q31~33 in deletions and translocations has previously been reported in AML. A number of genes for growth factors, including interleukin genes, have been mapped to this region. Also it should be noted that involvement of the 5q31~33 region has been associated with chronic eosinophilic leukemia and in one case of Acute Lymphoblastic Leukemia(ALL) with eosinophilia. Thus a specific molecular lesion can be identified which may explain the hypereosinophilia in this case. Additionally, a t(5;12)(q33;p13) translocation has consistently been seen chronic myelomonocytic leukemia and involves the TEL/Platelet-derived growth factor receptor beta gene rearrangement which results in a fusion protein tyrosine kinase that is constitutively activated and resides in the cytosol of affected cells. The activity of this fusion protein has been inhibited by STI571 and so proper identification of this aberrant molecule may have significant implications regarding therapy.
In summary, this case was presented to draw attention to the disease entity of AMML and to illustrate a case that involved unique clinical, morphologic, and cytogenetics features. The patient was a young woman with gingival infiltration by the neoplastic clone, which had ish t(5;12;22)(q33;p13;q13) and not previously reported in AML. The translocations have been reported in other disease states and can perhaps explain the patient's eosinophilia, and may be useful in customizing her therapy. Morpholog-ically, the amount of eosinophilic infiltrate in both the peripheral blood and bone marrow was striking but did not exhibit any significant atypia and serves to illustrate the subtle differences between this case, best diagnosed as AMML, and AMML-Eo, which is a distinct clinicopathologic entity with its own cytogenetic aberration
Contributed by Sourav Ray, MD and Sandra Kaplan, MD