[Megaloblastic anemia]. The bone marrow findings in megaloblastic anemia are very characteristic that help differentiate this disorder from pure erythroid leukemia and myelodysplasia. In moderate to severe cases, the marrow is almost always hypercellular with brisk erythroid hyperplasia (small black arrows). Very early erythroid precursors (proerythroblasts & basophilic erythroblasts) predominate over late precursors (polychromatophilic & orthochromatophilic erythroblasts) because of ineffective erythropoiesis which limit the number of early precursors maturing into later stages. The yellow arrow indicates a proerythroblasts in a mitotic prophase. Dysplasia of red cell precursors manifested by nuclear shape abnormalities is also a constant feature in moderate to severe cases (arrowhead).
[Megaloblastic anemia]. Although the bone marrow picture is dominated by early erythroid precursors, late erythroid precursors including polychromatophilic and orthochromatophilic erythroblasts show the most dramatic megaloblastic changes. A polychromatophilic erythroblast (shown with yellow arrow) shows open chromatin when it should be condensed for that stage of maturation. Four precursors of later orthochromatophilic erythroblast stage (four arrowheads) show more than normal amount of cytoplasm. This is because of nuclear cytoplasmic asynchrony whereby nuclear maturation is delayed or incomplete but the cells continue to accumulate cytoplasm. This gives rise to the essential “megaloblastic” appearance of erythroid cells.
[Megaloblastic anemia]. The basic abnormality in megaloblastic anemia is the functional lack of vitamin B-12 or folic acid, both of which are needed for DNA synthesis. In deficiency of either or both, cells cannot synthesize enough DNA, which results in cells being caught up in mitoses (three arrowheads) for longer than usual and may not be able to complete the mitotic phase. Cells which cannot complete mitoses because of the lack of DNA synthesis ultimately die within marrow (ineffective erythropoiesis) causing deficiency of normal red cell production. A yellow arrow on the top shows a giant twisted band neutrophil.
[Megaloblastic anemia]. This micrograph shows a dividing red cell precursor with an incomplete cell division (two arrows). Note that the cytoplasmic quality is that of an orthochromatophilic erythroblast stage but the cell is hung up in mitosis. Red cell precursors beyond basophilic erythroblast stage (polychromatophilic & orthochromatophilic erythroblasts) do not undergo mitosis but accumulate hemoglobinized cytoplasm and extrude nucleus for final maturation and journey to the peripheral blood. The cytoplasmic quality of this cell shows nicely the nuclear-cytoplasmic asynchrony that is so characteristic of these cells.
Megaloblastic anemia. This image shows several abnormalities characteristic of megaloblastic erythropoiesis, including giant proerythroblasts (big yellow arrow in the center), an abnormally dividing red cell precursor (black arrow), and a megaloblastic orthochromatophilic erythroblast with numerous coarse basophilic stippling. Note the cell depicted with the black arrow shows an abnormal mitosis with remnants of mitotic spindle and nuclear fragments in the cytoplasm (shown with a small yellow arrow).
Megaloblastic anemia. Red cell precursor dysplasia is often a prominent feature in severe cases but it may be absent to minimal in mild cases. The dysplasia is manifested by nuclear budding, nuclear contour abnormalities, and bizarre shaped nuclei (arrowheads). Nuclear fragments in the form of Howell-Jolly bodies (long yellow arrow at the bottom) can often be found. Red cell dysplasia is also a feature of primary or secondary myelodysplasia, erythroid leukemia, and congenital dyserythropoietic anemia.
Megaloblastic anemia. Since vitamin B-12 and folic acid are needed for DNA synthesis, the findings are not specific to red cell nuclear maturation but affect all bone marrow precursor cells. In fact, DNA synthesis in all cells of the body is affected but changes are most marked and obvious in cells which are rapidly proliferating such as bone marrow cells. In white cell precursors, abnormal DNA maturation is manifested by giant sized nuclei of metamyelocytes and band neutrophils (arrow). Segmented neutrophils show nuclear hypersegmentation.
[MEGALOBLASTIC ANEMIA]. Bone marrow aspirate showing a close-up view of giant twisted bands (two arrows) and a giant metamyelocyte (arrowhead). Notice abundant normal granulation indicating normal cytoplasmic maturation
[MEGALOBLASTIC ANEMIA]. Nuclear hypersegmentation of neutrophils (arrow) is a diagnostic feature of megaloblastic anemia when found in many cells in conjunction with other characteristic findings. Cells with six or more nuclear lobes are commonly found in severe cases. Hypersegmentation reflects the same abnormality as in red cell precursors, i.e., delayed or incomplete nuclear maturation. It should be noted that in acquired deficiency of vitamin B-12 or folic acid ONLY a proportion of cells are affected whereas others may be normal and the proportion of affected cells depends on the severity of lack of these substrates.
[MEGALOBLASTIC ANEMIA]. Megakaryocytes also show abnormal nuclear maturation but the abnormality takes the form of small and hypolobated nuclei (arrowhead) rather than hypersegmentation as noted in neutrophils. Megakaryocytes contain the most amount of DNA than any other cell in the body and thus are affected severely by moderate to severe deficiency. Lack of DNA synthesis leads to small and hypolobated megakaryocytes which contain less amount of cytoplasm and hence fewer platelets are shed resulting in thrombocytopenia.
[MEGALOBLASTIC ANEMIA]. The bone marrow core biopsy in severe cases of megaloblastic anemia is markedly hypercellular due to ineffective erythropoiesis. The majority of the hypercellularity is caused by very early erythroid precursors, which may constitute more than 80% of all nucleated bone marrow cells. A cursory look at low magnification may give an impression of a malignancy but careful examination confirms the correct diagnosis. In fact, an acute leukemia, especially erythroleukemia (AML-M6), must be excluded.
[MEGALOBLASTIC ANEMIA]. Ineffective erythropoiesis may also lead to prominent hemophagocytosis with macrophages clearing up dead cell debris. The larger cells with abundant pale cytoplasm and large euchromatic nuclei represent macrophages dispersed among early erythroid precursors.
[MEGALOBLASTIC ANEMIA]. In core biopsy sections, erythroblasts appear as large cells (arrows) with moderate amounts of amphophilic cytoplasm and round nuclei with open chromatin and distinct round to comma-shaped nucleoli.
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