Submitting Author: Tandon, Bevan, MD
Institution: Division of Hematopathology, University of Pittsburgh School of Medicine
Additional authors:Lydia Contis, M.D.
Session: Erythroleukemia and megakaryoblastic AML and mimics

The patient is a 72 year old male with fatigue. Complete blood count (CBC) indicates pancytopenia with 1.8 x10E+9/L WBC; hemoglobin 8.6 g/dL; and platelet count 53.0 x10E+9/L. Laboratory studies also indicate mild vitamin B12 deficiency (186 pg/ml). Initial medical management included parenteral B12 administration, transfusion support, and weekly monitoring of the CBC. Due to persistence of the patient’s cytopenias, a bone marrow biopsy was performed.

Bone Marrow Adult

Differential Patient Mean Normal Range

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Blast 13.3% 1.0 (0.0 - 2.0)

Promyelocyte 3.5 % 3.0 (2.0 - 4.0)

Myelocyte 4.0 % 12.0 (8.0 - 16.0)

Metamyelocyte 1.0 % 17.0 (10.0 - 25.0)

Band 6.0 % 12.0 (9.0 - 18.0)

PMN 1.0 % 9.0 (7.0 - 14.0)

Eos Myelo/Meta 1.5 % 2.0 (1.0 - 4.0)

Eos Band 0.5 % 1.0 (0.0 - 3.0)

Eos Seg 0.3 % 1.0 (1.0 - 2.0)

Basophil 0.0 % 0.0 (0.0 - 0.2)

Monocytes 0.3 % 1.0 (0.0 - 2.0)

Pronormoblasts 0.8 % 1.0 (0.0 - 1.0)

Normoblasts 57.0% 24.0 (16.0 - 32.0)

Lymphocytes 8.8 % 16.0 (11.0 - 23.0)

Plasma Cells 2.3 % 2.0 (0.0 - 3.0)

Other 0.0 %

Myeloid/Erythroid(ratio) 0.5 2.4 (1.5 - 3.3)

Tot. # of Cells counted 400

The peripheral blood smear revealed pancytopenia with significant red blood cell anisopoikilocytosis including occasional red blood cell fragments, microcytes, and some abnormal appearing circulating nucleated red blood cells (Image 1). The bone marrow trephine biopsy (formalin fixed, posterior iliac crest) demonstrated hypercellularity for age (50%) (Image 2) with erythroid predominant trilineage hematopoiesis and increased marrow blasts by manual differential cell count (13.3%). The blasts exhibited intermediate size, an increased nuclear/cytoplasmic ratio, and dispersed chromatin (Image 3). The myeloid/erythroid ratio was 0.5; pronormoblasts and normoblasts comprised 57.8% of the overall cellularity. Significant dyspoietic changes were noted within the erythroid series including marked nuclear/cytoplasmic asynchrony, terminal dyspoiesis with prominent nuclear budding, and nuclear dyskaryorrhexis (Image 4). Myeloid maturation was sequential and complete and showed unremarkable morphology. Megakaryocytes included small, hypolobated forms, as well as some bizarre forms with multiple, discrete nuclei (Image 5). Moderate numbers of ring sideroblasts were identified on an iron stained marrow aspirate smear (17% of total erythroid precursors) (Image 6). A PAS stain performed on the marrow aspirate smear was negative for staining in erythroid precursors.

Flow cytometric studies performed on the bone marrow aspirate demonstrated a myeloblast population comprising approximately 7% of total cellular events with the following phenotype:

CD45 positive (dim), CD34 positive, CD117 positive, HLA-DR positive, CD13 positive, CD33 positive, CD36 negative, CD64 negative, CD15 negative, CD56 partial positive, and myeloperoxidase mostly negative (Images 7,8).

Immunohistochemical stains performed on the bone marrow core biopsy demonstrated increased numbers of CD34 positive blasts (Image 9), and otherwise mostly scattered cells with myeloperoxidase, CD117, and E-cadherin.

44~47,X,-Y,add(5)(q12),t(6;11)(p10;q10), -7,del(8)(p11.2p21),del(12)(p11.2p13),hsr(18)(q21),del(18)/(p11.2p11.2),-20,del(20)(q12q13.3),add (20)(q13.3),-22,+r,+mar1,+mar2x1~2,dmin[cp17]/46,XY[3]

Classical cytogenetic analysis demonstrated a complex karyotype (Image 10) including a missing Y chromosome; an abnormal chromosome 5 with various segments of chromatin of undetermined origin attached to the long arm resulting in a partial monosomy 5q; what appears to be a whole arm translocation between chromosomes 6 and 11; monosomy 7, what appears to be a deletion of the short arm of chromosome 8; a deletion of the short arm of chromosome 12; either an abnormal chromosome 18 with a deletion of the short arm in some cells, or what appears to be a homogeneously staining region (hsr) in the long arm of chromosome 18 in other cells; either monosomy 20 in some cells, or an abnormal chromosome 20 with a deletion of the long arm in other cells, or an abnormal chromosome 20 with chromatin of undetermined origin attached to the long arm in other cells; monosomy 22; a ring chromosome; one or two very small markers; and a double minute.

Molecular studies were not performed.

This case shows features typical of a high grade myelodysplastic syndrome (MDS), the precise classification of which is rendered difficult due to vitamin B12 therapy. Myeloblasts comprise 13.3% of the marrow cellularity, and there is prominent dysplasia involving the erythroid series and megakaryocytes. Ring sideroblasts are also increased (17%), and classical cytogenetic analysis demonstrated a complex karyotype. The case fulfills criteria for a diagnosis of erythroleukemia of erythroid/myeloid type: erythroid precursors comprise greater than 50% of nucleated cells in the marrow based on manual differential cell count, and blasts comprise >20% of the non-erythroid cell population. However, given the patient’s recent B12 therapy, it is uncertain whether the apparent erythroid hyperplasia represents a response to therapy. Distinguishing between a diagnosis of erythroleukemia and MDS-RAEB-2 is especially important given the significant differences in implications for management and prognosis.

Thus far, management has included 5 courses of 5-azacytidine administered over a six month period. Most recent CBC demonstrates persistent pancytopenia with overall white blood cell count of 3.2 x10E+9/L, hemoglobin 11.6 g/dL, and a platelet count of 38.0 x10E+9/L. Overall, the patient has remained clinically stable with reported improvement in fatigue related symptoms and transfusion requirements have been minimal.

Myelodysplastic syndrome: Refractory Anemia with Excess Blasts – 2 (RAEB-2). RAEB-2 is favored over a diagnosis of an erythroleukemia as the influence of vitamin B12 therapy on the degree of erythroid hyperplasia is uncertain. Despite the presence of a complex karyotype and -7, the percentage of blasts would not fulfill the criteria for a diagnosis of acute myeloid leukemia with myelodysplasia-related changes.

Erythroid predominant myeloid neoplasm (13% blasts):

Acute erythroid leukemia, erythroid/myeloid (WHO classification) versus refractory anemia with excess blasts-2, RAEB-2

Case 403