Contributed by Suzanne Bakdash, MD, MPH and Sandra S. Kaplan, MD
Published on line in September 2005
This previously-healthy patient presented to a pediatrician for a routine 12-month check-up and was found to be anemic, Hgb 8.2 g/dL (normal range for age 6 months - 2 years: 10.5 - 13.5), and thrombocytopenic, platelets 21,000x10E+06/L (normal range for age 6 months - 2 years: 150 - 450). There was no report of weight loss, epistaxis, easy bleeding or bruising, but the patient's mother had noticed occasional "dots" on the toddler's skin over the last few days. The child's physical exam was unremarkable.
The initial work-up included an evaluation of the peripheral blood, which demonstrated a leukoerythroblastic reaction with a rare circulating blast, occasional nucleated red blood, occasional smudge cells and 9% atypical lymphs, in addition to the normochromic normocytic anemia and thrombocytopenia. A bone marrow biopsy and aspirate demonstrated normocellular bone marrow with trilineage hematopoiesis, 3% blasts, reticulin fibrosis and absent iron stores. The patient received a red blood cell transfusion and was discharged in good condition.
Within two weeks, the patient's clinical status deteriorated and a repeat evaluation of the peripheral blood demonstrated marked anemia (Hgb 7.0 g/dl (normal: 10.5 - 13.5), Hct 19.6% (normal: 33.0 - 39.0), RBC 2.47x10E+12/L (normal: 3.70 - 5.30)) with leukoerythroblastosis (blasts 10%) and dysplastic changes. The bone marrow aspirate was dilute with near absence of hematopoiesis and increased blasts (10%), some with megakaryoblastic features. The bone marrow biopsy was markedly fibrotic with an atypical mononuclear cell infiltrate. Comprehensive immunohistochemical evaluation was not helpful in establishing the lineage of these cells. The flow cytometric immunophenotypic studies were also inconclusive, with a subset of approximately 14% of total cells expressing CD61 and no apparent co-expression or increased expression of CD34 or CD117. Classical cytogenetic evaluation of the bone marrow aspirate demonstrated a predominantly hyperdiploid karyotype with 50 chromosomes and a t(1;10) translocation; no constitutional trisomy 21 was present. Although not definitive, these findings, together with the clinical presentation, were most suggestive of an acute myeloid leukemia of megakaryoblastic lineage (FAB M7) and the patient was treated accordingly.
Evaluation of the patient's peripheral blood and bone marrow following the first cycle of chemotherapy demonstrated persistent disease. Evaluation after the second round of chemotherapy (approximately two months after initial presentation) also demonstrated persistent disease with the following characteristics:
Peripheral blood: leukopenia with neutrophilia and left shift (likely due to recent Neupogen therapy), circulating blasts (16%) and anemia (table 1). A variety of circulating cells were seen, including blasts with convoluted nuclei and some with cytoplasmic blebbing (figures 1a, 1b, 1c and 1d). Occasional giant platelets were also seen (figure 2). Hypogranular neutrophils and neutrophils with cytotoxic granulation were also seen.
Bone Marrow: The aspirate was dilute with markedly decreased trilineage hematopoiesis and 83% blasts (figures 3a and 3b). The blasts were occasionally clustered and mostly large with dark blue cytoplasm and prominent cytoplasmic blebbing and pseudopod formation at the edges (figure 4a, 4b, 4c and 4d). Megakaryocytes were also present, many of which were large and hyperlobate with occasional dysplastic forms (figure 5).
Numerous histiocytes containing cellular debris were also seen (figures 3a and 6). An immunocytochemical stain for CD61 strongly highlighted platelets, megakaryocytes and the blast population; histiocytes and other cells of non-megakaryocytic lineage were negative (figures 7a, 7b, 7c and 7d). The bone marrow biopsy was 50 - 60% cellular with numerous blasts, many with convoluted nuclei (figure 8).
Flow Cytometry and Cytogenetics: Flow cytometric immunophenotypic studies performed on the bone marrow aspirate demonstrated a population of cells that co-expressed CD61 and CD13/33 (approximately 8% of total cells); however, as with the earlier flow cytometry studies, CD34 and CD117 were not expressed.
Classical cytogenetic analysis again demonstrated a hyperdiploid karyotype with 48-51 chromosomes and a t(1;10) translocation similar to the karyotype seen in the previous assessment.