Articles on Medical Diseases and Conditions

Tag: Leukemia

  • Myelodysplastic Syndromes

    The myelodysplastic syndromes are a group of disorders with a varying number of features that may raise the question of early, borderline, or atypical acute leukemia but that do not satisfy FAB criteria for leukemia (especially, the FAB cutoff level of 30% blasts in the bone marrow). The disorders included in this category by the FAB group have certain common features: insufficient blasts in bone marrow to be diagnosed as acute leukemia; some degree of abnormality in at least two cell lines (RBC, WBC, or platelets), a high incidence of pancytopenia or cytopenia of less than three cell lines, frequent normocellular or hypercellular bone marrow in spite of peripheral blood pancytopenia, and a relatively high rate of progression to acute nonlymphocytic leukemia (roughly 15%-45%, depending on the particular subgroup of the FAB classification). Some or all of these disorders were previously considered a subgroup of Di Guglielmo’s syndrome by some investigators and were called “preleukemia” by others. Some believe that these disorders represent a leukemic cell clone or clones that for some reason have a relatively slow or variable progression. These syndromes can be idiopathic or preceded (and presumably induced) by bone marrow injury from toxins or radiation. The myelodysplastic syndrome occurs predominantly in persons over age 50 (reported mean ages varying between 60 and 80). Men are affected more frequently than women in some studies but not in others. Chromosome abnormalities have been reported in 35%-50% of cases, with the most common being monosomy 7 (loss of one chromosome 7) or 7q- (loss of a chromosome 7 long arm).

    The peripheral blood frequently contains some abnormal cells such as oval macrocytes; moderate anisocytosis and poikilocytosis; a few nucleated RBCs; myeloid cells with Pelger-Huлt nuclear changes, abnormal granulation, or abnormal granules; and abnormal platelets. There may be a few blasts, but less than 5%. Bone marrow shows various combinations of myeloid immaturity (but <30% blasts), increased monocytes, megaloblastic, or megaloblastoid RBC precursor change, ring sideroblasts, and abnormal megakaryocytes in addition to changes similar to those of the peripheral blood. Table 7-2 lists the major differences between subgroups of the myelodysplastic syndrome.

    French-American-British classification of myelodysplastic syndromes

    Table 7-2 French-American-British classification of myelodysplastic syndromes

  • Leukemia

    Malignancy may occur at each major stage in the development sequence of the blood cells. In general, the earlier the stage at which the cell is involved by malignancy, the worse the prognosis. Thus, a leukemia whose predominant cell is the myeloblast has a much worse prognosis (if untreated) than one whose predominant cell is the myelocyte.

    Leukemia is a term that denotes malignancy of WBCs, although its definition is often extended to include malignancy of any type of blood cell. In many patients with leukemia (including the majority of those with the chronic leukemias), the total number of WBCs in the peripheral blood is increased above the reference range. Acute leukemia was originally defined as a leukemia that, if untreated, would be expected to permit an average life span of less than 6 months. The predominant cell is usually the blast (or closely related cells such as the promyelocyte). In most cases there are more than 25% blasts in the peripheral blood, and for many years this criterion was the usual basis for suggesting the diagnosis of acute leukemia. The major exception was monocytic leukemia, which behaves like acute leukemia even though the number of monoblasts may be very low. Definitive diagnosis was usually made by bone marrow aspiration; this is a necessity when using the French-American-British classification system (discussed later). Chronic leukemia is a leukemia that, if untreated, would be expected to permit an average life span of more than 1 year. The predominant cell forms are more mature; generally, the prognosis is best for chronic leukemias involving the most mature forms. Thus, chronic lymphocytic leukemia (CLL) has a better prognosis than chronic granulocytic (myelocytic) leukemia (CGL).

    Subleukemic leukemia is sometimes used to refer to a leukemia in which the total peripheral blood WBC count is within the reference range but a significant number of immature cells (usually blasts) are present.

    Aleukemic leukemia is the term used when the peripheral blood WBC count is normal (or, more often, decreased) and no abnormal cells are found in the peripheral blood. The diagnosis of subleukemic or aleukemic leukemia is made by bone marrow examination. More than 30% blasts in the bone marrow usually means leukemia; 10%-30% suggests the myelodysplastic syndrome (discussed later).

    Stem cell leukemia or acute blastic leukemia are terms often applied when nearly all the WBCs are blasts and no definite differentiating features are present. Myeloblasts and lymphoblasts are morphologically very similar on peripheral blood smears, and reliable differentiation by morphologic appearance alone is sometimes not possible even by experts. In some cases differentiation is made on the basis of other information, such as the age of the patient and the types of cells accompanying the blasts. Cytochemical stains, monoclonal antibodies, and perhaps chromosome analysis are very helpful. Auer rods are small rod-shaped structures that sometimes are present in the cytoplasm of blasts. Auer rods are diagnostic of myeloid cells, either myeloblasts or the myelomonocytic form of monocytic leukemia.

    Both the lymphocytic leukemias and the malignant lymphomas are derived from lymphocytes or lymphocyte precursors; but the leukemias originate in bone marrow, whereas the lymphomas originate in lymphoid tissue outside the marrow, most often in lymph nodes. The lymphomas and their close relative, Hodgkin’s disease, will be discussed later.

  • Identification of Granulocytes

    Granulocyte and monocyte identification and phenotyping relies more heavily on morphology than is possible with lymphocytes. Light microscopic appearance can, if necessary, be supplemented by a limited number of cytochemical stains and enzyme tests, and in some cases by immunologic tests for CD antigens. In some cases phenotyping may require chromosome analysis using standard methods (e.g., the Philadelphia chromosome in chronic myelogenous leukemia [CML]), nucleic acid probe methods (e.g., breakpoint cluster region (BCR) gene rearrangement in CML), or immunologic tests for certain CD antigens. The morphologic and cytochemical approach is best seen in the French-American-British (FAB) classification of acute leukemias.

  • White Blood Cell Identification and Phenotyping

    WBC identification is usually done by Wright-stained peripheral blood smear examination. However, this approach creates problems due to the statistically small number of cells counted (usually 100), nonuniform cell distribution on the smear, and the need for subjective interpretation that can produce differences in cell counts in the same smear by the same technologist or between different technologists. Automated cell differential machines can improve the situation somewhat but currently still have problems with individual cells that are transitional between classification categories, atypical, or abnormal. In addition, neither a manual or machine differential can subtype normal or abnormal cells.

    Flow Cytometry

    Another approach to WBC counting is flow cytometry. Various WBC types and subtypes contain one or more antigens that are unique or are shared by a limited number of other cells. These antigens can be detected by specific monoclonal antibodies that can be tagged with a fluorescent molecule. A flow cytometer is able to activate the fluorescent molecule and detect, differentiate, and identify light wavelengths being produced. This permits detection, identification, and quantitation of the cells that possess the antigens being searched for. Usually an algorithmic approach is used in which one or two antibodies are tried, followed by one or two others depending on the initial results, and so on until final identification.

    One problem (still present to some extent) was confusion because different manufacturers developed antibodies against the same or closely related cell antigens, but used different names for their antibody. Therefore, a standard nomenclature called cluster designation (CD) was developed in which each WBC antigen was given a CD number and the various antibodies (antibody “cluster”) that reacted with the same WBC antigen were assigned the corresponding CD number or numbers. That way, antibodies from various manufacturers, beside the proprietary brand name, could also be given a CD number that would indicate what antigen the antibody reacts with. Each antigen corresponds to a WBC category or subgroup. However, more than one CD antigen may be present on cells of the same WBC category or subgroup. For example, CD-4 antigen is found on the lymphocyte T-cell helper subgroup and CD-8 antigen on the lymphocyte T-cell suppressor subgroup. However, both CD-2 and CD-7 antigen are found on the lymphocyte T-cell natural killer subgroup. Certain platelet and megakaryocyte antigens are also included in the CD system.

  • Leukemia, Lymphomas, and Myeloproliferative Syndromes

    A consideration of the origin and maturation sequence of white blood cells (WBCs) is helpful in understanding the classification and behavior of the leukemias and their close relatives, the malignant lymphomas. Most authorities agree that the basic cell of origin is the fixed tissue reticulum cell. Fig. 7-1 shows the normal WBC development sequence. In the area of hematologic malignancy, those of lymphocytic origin predominate since they produce nearly all of the malignant lymphomas as well as over half of the leukemias.

    Normal WBC maturation sequence (some intermediate stages omitted)
    Fig. 7-1 Normal WBC maturation sequence (some intermediate stages omitted).

    It is now possible to differentiate most malignant lymphoid tumors from benign tumorlike proliferations and to evaluate the degree of lymphoid cell maturation (which in lymphoid malignancies may have prognostic or therapeutic importance) by means of immunologic tests that demonstrate cell antigens or structural arrangements found during different stages of lymphocyte maturation. Before discussing this subject it might be useful to briefly review the role of the lymphocyte in the immune response to “foreign” or harmful antigens. Considerably simplified, most lymphocytes originate from early precursors in the bone marrow; some mature in the bone marrow (B-lymphocytes, although later maturation can take place in the spleen or lymph nodes) and others mature in the thymus (T-lymphocytes). The T-lymphocytes first develop an antigen marker for T-cell family called CD-2 (the CD system will be discussed later), then a marker for T-cell function (CD-4, helper/inducer; or CD-8, cytotoxic/suppressor) and a surface marker for specific antigen recognition (CD-3). All nucleated body cells have elements of the Major Histocompatibility Antigen Complex (MHC; also called Human Leukocyte Antigen system, or HLA) on the cell surface membrane; this consists of MHC class I antigen (HLA-A, B, or C antigen) for all cells except brain glial cells. Some cells (including macrophages and B-lymphocytes but not CD-8 cytotoxic or suppressor T-lymphocytes) also have surface MHC class II antigen (HLA-D or DR).

    In the primary (first contact) immune response, certain cells known as antigen-presenting cells (usually macrophages) ingest the harmful or foreign antigen, partially digest (“process”) the antigen, and attach certain antigenic portions (epitopes) of it to an area on the macrophage surface membrane that contains the MHC Class II complex. The antigen-presenting cell (APC) then must meet a T-lymphocyte of the CD-4 helper category that has a surface receptor specific for the foreign/harmful antigen held by the APC. The two cells link together at the MHC-II complex area of both cells. The APC then releases a hormonelike substance known as a cytokine; more specifically, a category of the cytokines called interleukins; and specifically, a subgroup of the interleukins called interleukin-1 (IL-1). This substance (factor) stimulates the helper T-lymphocyte into activity. The activated T-cell secretes another interleukin called interleukin-2 (IL-2) that causes the helper T-cell to replicate itself with the same specific antigen receptor as the parent cell.

    The newly formed helper T-cells in turn can affect CD-8 cytotoxic/suppressor T-lymphocytes and B-lymphocytes. CD-8 cytotoxic lymphocytes recognize the original unaltered foreign or harmful antigen in the body by means of specific receptor and MHC Class I surface antigen complex, after which the cytotoxic T-lymphocyte attaches to the foreign antigen, develops IL-2 receptors, and tries to destroy the antigen by producing toxic chemicals. If helper T-cell IL-2 reaches the activated cytotoxic T-cell, the cytotoxic T-cell is stimulated to replicate itself to generate more cytotoxic cells that can find and destroy more of the same antigen. The helper T-cell IL-2 is also thought to activate other CD-8 T-lymphocytes that have a suppressor function to keep the antiantigen process from going too far and possibly harming normal body cells.

    B-lymphocytes are also affected by activated helper T-cells. B-lymphocytes have surface antibody (immunoglobulin) rather than CD-3 antigen-recognition receptor, but the surface immunoglobulin (Ig) recognizes a single specific antigen in similar manner to the CD-3 receptor. B-lymphocytes can recognize and bind cell-free antigen as well as antigen bound to the surface of other cells, whereas T-cells require cell-bound antigen. A B-lymphocyte with the appropriate antigen-recognition Ig attaches to APC macrophages with foreign/harmful antigen at a MHC antigen-binding complex site. If an activated helper T-cell is also bound to the macrophage, the B-lymphocyte attaches simultaneously to it also. IL-2 from the activated helper T-cell stimulated the B-cell to replicate (clone) itself exactly. In addition to IL-2, the helper T-cell can secrete a B-cell differentiation factor that causes some of the newly cloned B-lymphocytes to differentiate into plasma cells (either through an intermediate immunoblast stage or more directly) and some become memory cells, able to reactivate when encountering the same antigen months or years later. Plasma cells secrete specific immunoglobulin antibodies that can attack the specific antigen originally recognized by the parent B-lymphocyte. The first antibodies are IgM; later, production usually changes to another Ig type such as IgG, A, or E, at least partially under the influence of certain interleukins produced by the helper T-cell. Activated B-lymphocytes may on occasion become APC, processing and presenting antigen to T-lymphocytes similar to the activity of macrophages.

    Finally, there is a group of lymphocyte-like cells known as natural killer cells (NKC) that does not have either T-lymphocyte marker antigens or B-lymphocyte surface Ig. These cells can chemically attack foreign or cancer cells directly without prior sensitization or the limitation (restriction) of needing the MHC receptor. Of peripheral blood lymphocytes, 75%-80% (range, 60%-95%) are T-cells; 10%-15% (range, 4%-25%) are B-cells; and 5%-10% are NKCs. Of the T-cells, about 60%-75% are CD-4 helper/inducer type and about 25%-30% are CD-8 cytotoxic/suppressor type.