Epistaxis and Severe Weakness in a Patient With Multiple Myeloma

An 81-year-old white man with a 4-year history of multiple myeloma was admitted to the hospital because of epistaxis and severe weakness. Four years prior to the current admission, the patient presented with low back pain, weakness, and weight loss. Magnetic resonance imaging of the spine showed multiple lytic bone lesions with compression fracture of T12 through L1 and partial collapse of T6. Serum protein electrophoresis and immunofixation studies revealed a monoclonal immunoglobulin A band, which was 4.0 g/L (reference range, 0.46-2.87 g/L). Bone marrow aspiration and biopsy revealed a plasma cell infiltrate, comprising approximately 40% of the total cellularity. Combined findings were consistent with multiple myeloma. He was treated with melphalan, dexamethasone, and radiation of the lumbar spine and showed clinical improvement.

In the current admission, a bone marrow biopsy and aspiration were performed. The marrow biopsy was hypercellular (80%-90%) with an extensive infiltrate of sheets of large cells. In the marrow aspirate smears (Figure 1), these large cells were characterized by round nuclei, fine nuclear chromatin, and single distinct nucleoli. The cytoplasm was deeply basophilic with vacuoles. Periodic acid-Schiff stain performed on the aspirate smear showed cytoplasmic blocklike staining (Figure 2). Occasional maturing myeloid precursors and rare megakaryocytes were present. Immunophenotyping by flow cytometry showed 35% of the total cells analyzed were positive for glycophorin A. These cells were negative for myeloid-, lymphoid-, and plasma cell-associated antigens. Immunohistochemical stain of the marrow core biopsy showed many of the atypical cells were positive for hemoglobin A. No gene rearrangement of the immunoglobulin heavy or light chains were detected by molecular genetic studies.

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Therapy-related acute myeloid leukemia constitutes approximately 5% to 10% of all cases of acute myeloid leukemia' and has been frequently described to occur after Hodgkin and non-Hodgkin lymphomas, acute lymphoblastic leukemia, and multiple myeloma. The risk of developing a therapy-related acute myeloid leukemia varies in relation to different previous malignancies and previous therapies.1,2 The cumulative risk of secondary acute myeloid leukemia in myeloma is reported to be 17.4% at 50 months and 10.0% at 8 years.1 The most important determinant in increasing the risk of leukemia appears to be the amount of melphalan the patients received. Patients who received cyclophosphamide had a lower incidence of secondary leukemia, without any relationship with the dose of cyclophosphamide.

In the setting of multiple myeloma, acute myelomonocytic leukemia is the most common type of secondary acute leukemia, and acute erythroid leukemia is relatively rare.3 In most cases, multiple myeloma appears to be in remission when acute leukemia is diagnosed. Most patients have a transient period of myelodysplastic syndrome before fully developing acute erythroid leukemia.3 Once leukemia fully develops, the patient's condition usually deteriorates quickly and leads to death in less than a year. In the current case, the patient was treated with idarubicin and cytarabine for leukemia, but he developed fever and pulmonary edema shortly after admission. The edema was successfully treated with diuretics, but he remained febrile while receiving antibiotics and had a rapidly rising serum lactate dehydrogenase and increasing number of immature cells in the bone marrow. He expired 1 month after admission.

Acute erythroid leukemia is a subtype of acute myeloid leukemia that is characterized by proliferation of predominantly neoplastic erythroid cells.2 Acute erythroid leukemia constitutes approximately 3% of all cases of acute leukemia and is rare in children.4 Two subtypes of acute erythroid leukemia are described in the current World Health Organization classification: erythroleukemia (erythroid/ myeloid) and pure erythroid leukemia.2 In erythroleukemia (M6A), the neoplastic population is composed of a mixture of erythroid precursors that represent at least 50% of the nucleated cells, and myeloblasts that represent 20% or more of the nonerythroid cell population. In pure erythroid leukemia, the neoplastic cells are predominantly erythroid in origin and represent more than 80% of the overall cellularity. According to the classification system proposed by Mazzella et al5 and Kowal-Vern et al,6 3 subtypes of erythroid leukemia (M6A, M6B, and M6C) are described and the percentage of proerythroblasts is taken into consideration. For example, in M6B the erythroid population comprises 50% or more of the total cells, and proerythroblasts comprise 30% or more of the erythroid population. The proerythroblasts also comprise 30% or more of the erythroid population in M6C. However, in M6C the myeloblasts comprise 30% or more of the nucleated cells, as opposed to M6B, in which the myeloblasts comprise less than 30% of the nucleated cells. In the current case, the erythroid precursors and myeloblasts accounted for 86% and 2% of the nucleated cell population, respectively. The proerythroblasts comprised approximately 50% of the total cells. Therefore, our case meets the criteria for pure erythroid leukemia (M6B).

The diagnosis of acute erythroid leukemia developing in the setting of multiple myeloma may be morphologically challenging. Cytologically, the proerythroblasts may look like anaplastic or blastic plasma cells. Therefore, these blast cells may be overlooked as atypical plasma cells. The correct diagnosis of acute erythroid leukemia in the course of multiple myeloma relies on the pathologist's awareness of this possibility as well as immunophenotypic and histochemical studies. The erythroid blasts usually express glycophorin A and hemoglobin A.2 Periodic acid-Schiff stain of the neoplastic cells demonstrate cytoplasmic globular positivity, a typical feature of proerythroblasts. Markers for plasma cells such as CD38, CD138, and ? and ? immunoglobulin light chains may be used to rule out the presence of a clonal plasma cell population.

In summary, we describe a patient with multiple myeloma who subsequently developed pure erythroid leukemia (M6B). We call attention to this rare occurrence because it may pose a diagnostic dilemma.

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