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CASE HISTORY • Part 1
A 65-year-old woman seen for a routine checkup reports a decrease in exercise tolerance, especially during routine workouts at the gym. She denies other recent illness. Review of systems is positive, however, for a history of Hodgkin lymphoma, stage IA, diagnosed at age 25 and treated successfully with mantle radiation. Physical examination reveals a well-developed white female looking younger than her stated age. Conjunctiva may be somewhat pale. No evidence of lymphadenopathy or hepatosplenomegaly. No recent weight loss.
CBC: Hemoglobin/hematocrit - 10 g/dL/30%
MCV - 99 fL MCH - 32 pg MCHC - 33 g/dL
RDW-CV - 16%
White blood cell count – 4,900/μL
SMEAR MORPHOLOGY Slightly macrocytic, normochromic with 1+ aniso- and poikilocytosis. Few if any polychromatic macrocytes observed. Leukocytes are normal except for occasional bilobed cells (Pelger-Huët anomaly). Platelets appear somewhat pale—poorly granulated.
Reticulocyte count/index - 1.2%/<1.0
Questions
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The dysplastic and sideroblastic anemias are primary stem cell disorders, many of which eventually result in progressive bone marrow failure or evolve to acute leukemia. Clinical recognition and differential diagnosis of these disorders revolves around characteristic changes in blood film and marrow morphology. The dysplastic anemias (myelodysplasia) present with varying combinations of anemia, leukopenia, and thrombocytopenia together with macrocytosis, distorted marrow precursor maturation, and ineffective erythropoiesis. Sideroblastic anemias are defined by the distinctive appearance of ringed sideroblasts on the Prussian blue stain of the marrow. The overall incidence of these disorders is said to be low, only 1–3:100,000 population. However, the incidence increases with age, rising to 15–50: 100,000 in older populations.
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The pathophysiology of myelodysplasia is complex. There is evidence for impairments in stem cell growth, progenitor maturation, and both growth factor production and progenitor responsiveness. The presence of ineffective hematopoiesis (increased apoptosis of maturing marrow precursors) is a hallmark of myelodysplasia. It appears to correlate in part with CD95 expression and persistent high levels of Fas receptor, resulting in increased fas-ligand apoptosis. Upregulation of the cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) also may play a role in promoting apoptosis of long-term hematopoietic stem cells (LT-HSC) and committed precursors in myelodysplastic marrows. Vascular endothelial growth factor (VEGF) overproduction is thought to be involved in the promotion of myeloblastic elements, and perhaps the evolution to acute myeloid leukemia (AML).
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The level of apoptotic activity varies with the stage and progression of the dysplastic disorder. Lower-risk patients (refractory anemias with few if any blasts) generally have higher levels of apoptosis (ineffective hematopoiesis). With evolution to more advanced disease, the apoptotic index decreases and the number of myeloblasts in the marrow increases. Possible reasons for this include an upregulation of BCL2/BCLXL, loss of the p15 proto-oncogene, ...