Submitting Author: La Fortune, Kristin Amber, MD, MS
Institution: University of Virginia Health System
Additional authors:Nadine Aguilera, M.D.
Session: Erythroleukemia and megakaryoblastic AML and mimics

The patient is a 35-year-old African American man in otherwise good health who presented to the emergency department with general fatigue and progressive shortness of breath. He endorsed fevers, night sweats and a weight loss of fifteen pounds over the past six weeks. Other symptoms included frequent headaches relieved with aspirin and chest tightness in the left hemithorax. He denied recent illness and use of tobacco, alcohol, and prescription medications. Past medical and family histories were non-contributory. Physical examination revealed pale mucous membranes and marked pallor of the lips and palms. Pertinent negatives included no palpable adenopathy, rashes, bruising or petechiae.

Initial laboratory results were significant for pancytopenia with macrocytic anemia, thrombocytopenia, and leukopenia (WBC 2.8, RBC 1.3, HB 4.2, HCT 12.7, MCV 101, MCHC 33, RDW 41, and PLT 70). The differential demonstrated absolute neutropenia (LYMPH 2.03, NEUT 0.67, MONO 0.03, EOS 0.0, and BASO 0.03). The percent of nucleated RBC was elevated at 8.3%.

Other pertinent laboratory findings included:

Reticulocyte count of 2.3% (Normal range 0.7-2.5%)

LDH 6651 (Normal range 125-250 U/L)

D-dimer 2097 (Normal range <305 ng/mL)

Haptoglobin <8 (Normal range 30-200 mg/dL)

Ferritin 345 (Normal range 20-275 ng/mL)

Serum iron 170 (Normal range 60-160 ug/dL)

Transferrin 192 (Normal range 190-315 mg/dL)

Percent transferrin saturation 62% (Normal range 16-48 %)

A Coombs’ direct antiglobulin test was negative. Viral serologies were negative for the hepatitis viruses, cytomegalovirus and HIV-1/HIV-2. Serologies for Epstein Barr Virus were consistent with remote infection.

The patient was transfused three units of red blood cells and treated empirically with antibiotics for neutropenic fever. He was transferred to the Hematology and Oncology Service for bone marrow evaluation and medical management.

A bone marrow core biopsy and aspirate were obtained from the left posterior iliac crest. The trephine biopsy underwent decalcification and formalin fixation. The core biopsy was stained with hematoxylin and eosin and the aspirate was stained with Wright Giemsa.

Examination of the peripheral smear revealed marked anisopoikilocytosis with dacrocytes and schistocytes, coarse basophilic stippling, and dysplastic nucleated red blood cells. White blood cells were decreased and showed a predominance of lymphocytes. Platelets were decreased.

Microscopic examination of the bone marrow aspirate revealed a marked increase in erythroblasts with prominent megaloblastic features and dyserythropoiesis. Conspicuous giant band forms within the granulocytic lineage were present. Due to the predominance of erythroblasts, the myeloid to erythroid ratio was significantly decreased (0.2:1). The core biopsy revealed a markedly hypercellular bone marrow with expansion of erythroblasts demonstrating prominent mitotic activity. There was a background of limited, orderly myeloid maturation. A reticulin stain revealed no increase in reticulin fibrosis. Storage iron appeared decreased on iron stain.

The bone marrow aspirate differential:

Blasts 0%

Promyelocytes 0%

Myelocytes 2%

Metamyelocytes 3%

Neutrophils 8%

Eosinophils 2%

Basophils 0%

Monocytes 0%

Lymphocytes 12%

Proerythroblasts 5%

Erythroblasts 67%

In situ hybridization for EBER was negative. PCR and immunohistochemistry for parvovirus B19 were negative. Flow cytometry of the bone marrow aspirate revealed a predominance of erythroid precursors with dim CD45 expression and strong expression of CD71 and Glycophorin A representing 52% of all events. Markers for B- and T-cells were negative. Myeloid blasts were not increased.

Cytogenetic analysis of the bone marrow revealed normal 46,XY karyotype.

Molecular cytogenetic analyses for EGR1(5q31), D7S486(7q31), PML/RARA(15;17) RUNX1/RUNX1T1, BCR/ABL(9;22), CBFB(inv16), and MLL(11q23) were normal.

The differential diagnosis included acute erythroid leukemia (pure erythroid leukemia) versus megaloblastic anemia. In response to the megaloblastic changes noted within the bone marrow, evaluation for vitamin B12 and folate deficiencies were investigated. Vitamin B12 was markedly decreased (34 pg/mL, normal reference range 210-815 pg/mL) and the patient received intramuscular vitamin B12. Folate was within normal range. A test for Intrinsic Factor Blocking Antibody (IFBA) was performed by Mayo Medical Laboratories and was positive, however the sample was submitted after the patient received an intramuscular vitamin B12 injection, which can lead to a false positive result.

Megaloblastic anemia.

Megaloblastic anemia

Case 56