Myeloid Cells


Pluripotent hematopoietic stem cells (HSC) in the marrow differentiate into all of the different circulating blood cells. HSCs commit to the myeloid or lymphoid lineage under the influence of cytokines & growth factors, generating myeloid or lymphoid stem cells. Mature myeloid cells include neutrophils, basophils, eosinophils, and monocytes. Red blood cells (RBC) and platelets are also derived from a common myeloid progenitor but diverge soon thereafter. This process of hematopoiesis is illustrated in the following diagram.


Neutrophil Differentiation

Representative photographs of actual differentiating myeloid cells in the neutrophil lineage are shown here.

Differentiation of Neutrophils
Differentiation of Neutrophils

Note that blasts tend to be large cells with a high nucleus-to-cytoplasm ratio, and they often contain large pale circular areas in the nucleus that represent prominent nucleoli.

Blood Cell Count Terminology

In evaluating blood cells, the following terminology is used to describe variations in cell number. Elevations in cell count are labeled with the suffix "-osis" or "-ilia", e.g., leukocytosis, neutrophilia, lymphocytosis, eosinophilia, or thrombocytosis. Reductions in cell count are labeled with the suffix "-penia", e.g., leukopenia, neutropenia, lymphopenia, or thrombocytopenia. The exceptions to this rule are for the RBC lineage, where an elevation in hemoglobin or hematocrit leading to an increased red cell mass is termed "polycythemia", while a reduction in hemoglobin is termed "anemia.

Evaluating Blood Cell Counts

In approaching a patient with an elevated blood cell count, the first step is to determine what type of blood cell is affected. The next step is to categorize the elevation in cell count as primary vs. secondary. Primary abnormalities are those that arise from a primary hematologic problem, often due to a bone marrow disorder. Secondary abnormalities are those in which bone marrow function and hematopoiesis are intact, but there is a stimulus exogenous to the marrow that is driving forth increased hematopoietic activity.

As an example, consider a patient with a WBC count of 24,000/µn;L (normal 4-10,000) and the following blood smear.

Blood Smear
Blood Smear

The first step in evaluating this patient's leukocytosis is to determine which blood cell type is elevated - in this case, neutrophils. The second step is to determine whether the neutrophilia seen here is due to a primary or secondary cause. Primary causes of neutrophilia arise when there is a primary hematologic or bone marrow problem giving rise to a high neutrophil count. A primary neutrophilia might result from a hematopoietic defect due to clonal overproduction of neutrophils, which can be seen in some types of leukemias or similar disorders known as myeloproliferative neoplasms. By contrast, secondary neutrophilia arises when there is an exogenous stimulus that promotes normal albeit accelerated neutrophil production and release from the bone marrow, or that increases intravascular demargination of neutrophils. The major causes of secondary neutrophilia are infections (which tend to give rise to not only an increase in mature circulating neutrophils, but also a rise in circulating bands, a.k.a. "bandemia") or medications, particularly steroids (which increase neutrophil demargination from the vascular wall) or lithium (which causes increased levels of granulocyte colony stimulating factor (G-CSF)).

Here are some additional examples of how to approach elevations in different myeloid cell counts.

  • A patient with eosinophilia might have incurred this as a result of a primary problem in the bone marrow, e.g., hypereosinophilic syndrome (due to a gene translocation involving PDGFR and FIP1L1 genes), or a secondary process such as an allergic reaction or a parasitic infection.
  • A patient with monocytosis might have a primary problem in the bone marrow such as chronic myelomonocytic leukemia (defined as an unexplained, persistent monocytosis over a 3 month period), or a secondary process such as an infection (e.g., tuberculosis), an autoimmune or inflammatory disease (e.g., sarcoidosis), splenectomy, or a bone marrow that is recovering from a prior aplastic insult (e.g., from recent chemotherapy).
  • Basophilia is generally considered abnormal and often raises suspicion for a primary problem in the bone marrow, most commonly a myeloproliferative neoplasm such as polycythemia vera or chronic myeloid leukemia.

Lastly, in order to understand some aspects of this lab, and as a preview for the clinicopathologic conferences (CPC) that will comprise the bulk of the malignant hematology lectures, we should discuss a few key concepts that underlie the myeloid cancers in hematology.

  • Myelodysplastic syndrome (MDS) is a diagnosis that is based on morphology of blood and bone marrow cells, in conjunction with circulating cell numbers. The diagnostic criteria require that ≥ 10 of cells have dysplasia - which means that the cells "look funny". Many patients with MDS will also have an increase in the number of myeloid blasts in the bone marrow. The major complications of MDS are the consequences of cytopenias (e.g. neutropenia, which can give rise to increased infections; anemia, leading to fatigue and debilitation; and thrombocytopenia, leading to increased bleeding). In addition, MDS is a clonal disorder, meaning that if one analyzes the DNA from the bone marrow of a patient with MDS, an increased representation of certain DNA mutations specific to that patientŐs MDS will be identified, indicating that the bone marrow cells have largely arisen from a an progenitor cell. Because it is a clonal disorder, MDS carries an increased risk of transformation into acute myeloid leukemia, which is defined by the presence of ≥ 20% myeloid blasts in the blood or bone marrow. Interestingly, MDS can sometimes be hallmarked by the presence of circulating myeloid cells known as Pelger-Huet cells, which have a bilobed nucleus with a thin piece of nuclear material connecting the two nuclear lobes, resembling pince nez glasses, as follows:
    Pelger-Huet Cells
    Pelger Huet Cells
    Note that the original Pelger-Huet anomaly was first described as an inherited autosomal dominant condition sometimes be associated with certain anatomic abnormalities. Hence, most clinicians refer to the Pelger-Huet cells of MDS as "pseudo"-Pelger Huet cells to distinguish them from the true Pelger-Huet anomaly.
  • Myeloproliferative neoplasms (MPN) are a heterogeneous group of disorders characterized by excessive proliferation of different hematopoietic cell types. There are four MPNs:
    • Polycythemia vera (PV) is characterized by an increase in hemoglobin and hematocrit with an increase in red cell mass.
    • Essential thrombocytosis (ET) is characterized by an increase in platelet count. A typical CBC and blood smear in ET will show thrombocytosis, with all other secondary causes of thrombocytosis being ruled out (e.g., infection, inflammation, or iron deficiency).
    • Primary myelofibrosis (PMF) is characterized by an increase in fibrosis (scar tissue) in the marrow, leading to extramedullary hematopoiesis (i.e., hematopoiesis at sites other than the bone marrow, most commonly the spleen and/or sometimes the liver) and consequent splenomegaly +/- hepatomegaly. A typical CBC and blood smear in PMF will show a large number of early granulocyte forms including blasts and early RBC forms including nucleated red blood cells, referred to as a "leukoerythroblastic" picture, along with red cells that have a teardrop shape (a.k.a. "dacrocytes""), owing to copious scar tissue in the marrow, which limits normal hematopoietic potential and alters the types and morphologies of cells released from the marrow. Incidentally, leukoerythroblastosis tends to be seen in just a few clinical conditions, one being myelofibrosis, another being myelophthisis (defined as the infiltration of the bone marrow by another cell type that should not be there), or severe physiologic strain (e.g., severe infection or sepsis).
    • Chronic myeloid leukemia (CML) is characterized by an increase in representation of myeloid cells at all stages of myeloid differentiation.
    At least two major molecular mutations underlie the different MPNs. PV, ET, and PMF are associated with a mutation in a tyrosine kinase known as the JAK2 V617F mutation, which is seen in about 98% of PV cases and 40-50% of ET and PMF. CML develops because of an abnormal tyrosine kinase known as Bcr-Abl, which arises from a translocation between the abl gene on chromosome 9 and the bcr gene on chromosome 22, a.k.a. the "Philadelphia chromosome", or t(9;22). Treatment of CML was revolutionized a number of years ago by the development of an inhibitor to Bcr-Abl known as imatinib (Gleevec®), which heralded the dawn of the molecular therapeutics in cancer.
  • Acute myeloid leukemia (AML) is a diagnosis that is based on the finding of more than 20% myeloid blasts in the blood or bone marrow. AML is treated with intensive chemotherapy in many cases, with consideration of hematopoietic stem cell transplant in high-risk patients.