Articles on Medical Diseases and Conditions

Category: Leukemia, Lymphomas, and Myeloproliferative Syndromes

  • 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

  • Acute Leukemia

    Acute leukemia comprises about half of all leukemias. Acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL) are about equal in overall occurrence, but differ considerably in age groups. About 80%-90% of acute leukemia in childhood is ALL, and about 85%-90% in adults is ANLL (most commonly acute myelogenous leukemia and myelomonocytic leukemia). Peak incidence in childhood is 3-10 years, whereas it is most common in adults after age 50. About 50% of childhood ALL cases occur between ages 3 and 7, whereas the age incidence of ANLL is more evenly distributed. Childhood ALL and ANLL occur predominantly (>80%) in whites. About 5% have central nervous system (CNS) involvement at the time of diagnosis, and the CNS is eventually involved in about 50% unless prophylactic therapy is given.

    Acute leukemia usually has more than 25% blasts in the peripheral blood and by FAB criteria must have more than 30% blasts in the bone marrow. Sometimes the peripheral blood has fewer than 25%, especially if there is a leukopenia or if the patient has monocytic leukemia. The peripheral blood WBC count typically is mildly to moderately elevated (15,000-50,000/mm3; 15-50 Ч 109/L). However, nearly one half of the patients either have WBC counts within the WBC reference range or have leukopenia. Also, about 10% have WBC counts more than 100,000/mm3 (100 Ч 109/L). Anemia is present in about 90% of patients and is generally of moderate to severe degree. If not present initially, it develops later. Thrombocytopenia is reported in 80%-85% of patients (range, 72%-90%); about 40% have a platelet count of 50,000/mm3 or less. Childhood acute leukemia may be associated with meningeal involvement in as many as 50% of patients.

    Lymphadenopathy, usually of mild degree, is present in about 50% of patients, and splenomegaly, also usually minimal or mild, is reported in about 65% (range, 50%-76%). Generally speaking, enlargement of visceral organs is related to the duration of leukemia, so that the chronic leukemias are usually much more likely than the acute leukemias to be associated with marked organomegaly or with adenopathy. A significant number of patients with acute leukemia develop ulcerative lesions in the oral mucous membranes or gums and occasionally elsewhere, as in the gastrointestinal (GI) tract. Hemorrhagic phenomena (petechiae or localized small hemorrhages) are frequent, due to thrombocytopenia. Superimposed infection is common and is probably the most frequent cause of death.

    French-American-British (FAB) classification of acute leukemias

    In 1976 a group of French, American, and British hematologists proposed a system for classification of acute leukemia based primarily on morphologic and cytochemical criteria. The FAB classification has been widely adopted as the basis for standardization of diagnosis and comparing results of therapy (Table 7-1). During this time there have been several minor modifications. The classification can be applied only before initial therapy is begun. There are two categories, acute lymphocytic leukemia (ALL, FAB prefix L) and acute non-lymphocytic leukemia (ANLL, FAB prefix M). The latter includes myelocytic, myelomonocytic, monocytic, erythroid, and megakaryocytic leukemia subcategories. The panel stated that great caution was required before diagnosing leukemia in hypocellular bone marrow aspirates. It is worth noting that using morphologic study alone, even experts reached complete agreement only in about 80% of cases submitted for diagnosis.

    French-American-British (FAB) classification of acute leukemia (modified)

    Table 7-1 French-American-British (FAB) classification of acute leukemia (modified)

    Cytochemical stains

    The FAB group found that cytochemical stains were extremely helpful in categorizing some cases of acute leukemia, especially those that are relatively undifferentiated. Results of the Sudan black B stain are usually positive in myelocytic and myelomonocytic leukemia but negative in lymphocytic or other types of monocytic leukemia. The myeloperoxidase stain gives results similar to Sudan black B but is more technique dependent and thus less reliable in many laboratories. Nonspecific esterase stains are used to diagnose the monocytic leukemias. Results of alpha-naphthylbutyrate esterase are positive only in monocytic cells, whereas NASD-acetate esterase is positive in both myeloid and monocytic cells but is inhibited by fluoride in monocytic but not in myeloid cells. In a few cases none of the special stains produce diagnostic results. In categories not supposed to display special stain reaction, up to 3% reactive cells is permitted.

    Terminal deoxynucleotidyl transferase (TdT) enzyme reaction is normally present (positive reaction) only in lymphocytes, predominately in nuclei of thymus-derived cells (T-lymphocytes) and a few bone marrow lymphocytes. It is usually not present in B-lymphocytes or B-lymphocytic malignancies (e.g., CLL, well or poorly differentiated lymphocytic lymphoma, or myeloma. However, one very early B-cell malignancy called Pre-B-cell ALL is TdT positive. TdT enzyme activity is present in 90% or more (88%-95%) of ALL patients, comprised mostly of T-cell and non-B, non-T phenotypes. The equivalent malignant lymphoma category (T-cell/lymphoblastic lymphoma) is also TdT positive. Therefore, TdT positivity has been used to differentiate ALL from ANLL. However, there are exceptions; FAB L3 ( B-cell ALL) and the equivalent malignant lymphoma (Burkitt’s lymphoma) are usually TdT negative. About 5%-10% of AML are reported to be TdT positive. About one third of patients in the blast crisis of CML may have a positive TdT reaction, even some who have the Philadelphia chromosome.

    Chromosome studies

    A considerable number of leukemia patients have chromosome abnormalities; and some leukemia subgroups have one particular abnormality that occurs more frequently than all others. In some cases the chromosome abnormality is diagnostic of an acute leukemia subgroup and in some cases it gives prognostic information. The most well-known examples is the Philadelphia chromosome abnormality of CML.

    FAB phenotype in ANLL

    In adults, approximately 80% of acute leukemia cases are the ANLL type. Of the adult ANLL cases, almost 30% each are FAB-M1, M2, or M4. About 5% are FAB-M3, known as acute progranulocytic leukemia. This category, especially the so-called hypergranular variant, is associated with an unusually high incidence of coagulation disorders, particularly disseminated intravascular coagulation (DIC). In childhood, about 20% of the acute leukemias is ANLL; roughly 60% of these are M4 and about 25% are M1 or M2.

    FAB phenotype in ALL

    About 20% of adult acute leukemia is ALL; of these patients, about 65% are FAB-L2. About 80% of children with acute leukemia have ALL, and about 15% have the nonlymphocytic form. About 80% of childhood ALL cases are the FAB-L1 type. About 2% of childhood cases and less than that of adult cases are FAB-L3. Morphologically, FAB-L3 leukemia resembles the malignant lymphoma known as Burkitt’s lymphoma and currently has the worst prognosis of the ALL categories.

    Immunologic classification of acute lymphocytic leukemia

    Both ALL and the non-Hodgkin’s malignant lymphomas have been classified according to the immunologic type of lymphocyte involved (see Table 37-7 and Table 7-4). Acute lymphocytic leukemia has been subdivided by immunologic techniques into three categories: B-cell, T-cell, and non-B, non-T (most of these are actually Pre-Pre-B or Pre-B-lymphocytes). Immature B-cell ALL displays surface immunoglobulin production and comprises about 2% (range 1%-5%) of ALL cases. Morphology is usually FAB-L3 and resembles Burkitt’s lymphoma. T-cell ALL demonstrates a positive spontaneous E rosette test. Two categories of T-cell ALL have been reported; the “idiopathic” type and the “endemic” type. The idiopathic type is derived from Pre-T- cells or early (subcapsular) T-cells and comprises about 20% (10%-28%) of ALL in the United States. It tends to occur in later childhood or in adolescents and has male predominance. Approximately 75% have a mediastinal mass due to lymphadenopathy; this group resembles the type of malignant lymphoma called lymphoblastic in the Rappaport classification. The endemic type is most frequent in Japan and the Caribbean islands and is apparently caused by human T-cell leukemia virus-I (HTLV-I) retrovirus infection. This type is more frequent in adults, has about equal male-female incidence, does not have a high incidence of prominent mediastinal lymphadenopathy, has leukemic cells with convoluted nuclei, and has a relatively high incidence of skin involvement and also of hypercalcemia (about 25% of cases, but ranging up to 70% in some series). Pre–pre-B and Pre-B ALL (formerly called non-T, non-B ALL) comprises about 70%–80% of ALL patients; these patients have blasts that do not possess surface immunoglobulins and have a negative E rosette test result. However, most have immunologic or DNA probe evidence of early B-cell lineage. These can be further subdivided into four groups. About 75%-80% (range, 65%-90%) of these patients, constituting about 65% (range, 50%-76%) of all ALL cases, have blasts with a surface antigen that reacts with antibody prepared against non-B, non-T lymphocytes (common ALL antigen or CALLA). This group is often designated “common” ALL. Another subset of about 10%-20% (constituting about 10%-15% of all ALL cases) demonstrate intracytoplasmic immunoglobulin production but not surface (membrane) immunoglobulin and are said to have pre-B-cell ALL. A few patients have blasts that react with antisera to T-lymphocyte surface antigens but that have negative B-cell test results. These patients are said to have pre-T-cell ALL. Finally, there are a few patients with blasts that do not react with any of the tests mentioned. These patients are said to have null cell ALL.

    Table 7-4 Clinical staging of the malignant lymphomas*

    Clinical staging of the malignant lymphomas

    Monocytic leukemia

    Monocytic leukemia has the clinical and laboratory aspects of acute leukemia and is included in the FAB classification of acute leukemia as categories M4 and M5. In monocytic leukemia, however, the number of actual blasts may be low in both the peripheral blood and bone marrow. Instead of blasts there are cells resembling monocytes. In FAB category M4 the cells have a monocytic nucleus but cytoplasm containing granules resembling those found in granulocytes rather than those of monocytes (myelomonocytic leukemia, originally known as monocytic leukemia of Naegeli). In FAB category M5 the cells have both nucleus and cytoplasm resembling a monocyte (“pure” monocytic leukemia, originally known as monocytic leukemia of Schilling). Diagnosis of M5 requires 80% or more of the nonerythroid nucleated cells in the bone marrow to be monocytes, promonocytes, or monoblasts. There are two FAB subdivisions: 5A, in which more than 80% of the marrow monocytic cells are monoblasts, and 5B, in which less than 80% of the marrow monocytic cells are monoblasts.

    Myelomonocytic leukemia is by far the most frequent type of monocytic leukemia. It actually is a form of myelogenous leukemia in which the leukemic cells have cytoplasmic features of the more differentiated myeloid line and nuclear characteristics of the more primitive histiocytic precursors of the myeloid cells. There may be accompanying myeloid cells that are nonmonocytic, less immature forms; if so, this helps suggest the diagnosis. Sometimes the monocytic cells are indistinguishable from those of pure monocytic leukemia (Schilling type), but eventually some of them develop myeloid cytoplasmic features. If Auer rods are found, this establishes the myeloid derivation of the cells. According to the revised FAB criteria, if there is peripheral blood absolute monocytosis, M4 can be diagnosed if more than 20% of the bone marrow nucleated cells are monocytic. Cytochemical tests for monocytes may be needed. If peripheral blood monocytes are not increased, more than 20% of the bone marrow nucleated cells must be monocytic either confirmed by cytochemical stains or by elevated serum lysozyme (an enzyme associated with histiocytes or monocytes).

    Diseases accompanied by peripheral blood monocytosis sometimes raise the question of monocytic leukemia. Bone marrow aspiration provides the differentiation. The most common of these diseases are subacute bacterial endocarditis, typhoid fever, and tuberculosis.

    Erythroleukemia

    Erythroleukemia (FAB M6) was formerly known as Di Guglielmo’s syndrome. Some considered Di Guglielmo’s a single entity (erythroleukemia) and others included at least two categories: erythroleukemia and a syndrome comprising one or more disorders now included in myelodysplasia (discussed later). Erythroleukemia constitutes about 8% (range, 3.3%-13%) of acute leukemia cases. Sixty-five percent to 71% of patients are male. The mean age at diagnosis is in the forties and fifties, but patients from age 2-85 have been reported. Splenomegaly is reported in 18%-23% of patients, hepatomegaly in 0%-18%, and lymphadenopathy in 2%-43%. Various cytogenetic abnormalities have been found in about 60% of cases. At the time of diagnosis, all patients have anemia, most often moderate or severe, either normocytic or macrocytic. Leukopenia is reported in 25%-86% of cases, and thrombocytopenia is found in about 75%. Occasionally a monocytosis may be present in patients.

    The disease is reported to progress in three bone marrow stages: (1) an erythroproliferative phase with abnormalities largely confined to the erythroid line, (2) a mixed erythroid-myeloid dysplastic phase, and (3) a transition to ANLL. Therefore, in erythroleukemia there is abnormality in both the RBC and the myeloid precursors. The peripheral blood typically contains varying numbers of nucleated RBCs and immature granulocytes. In classic cases there are some peripheral blood myeloblasts and rubriblasts (pronormoblasts), but in some patients there are only a few nucleated RBCs, and rubriblasts are not seen. There may be increased numbers of monocytes. There is most often leukocytosis, but the WBC count may be normal or decreased. A normocytic (or slightly macrocytic) and normochromic anemia is present with considerable RBC anisocytosis and often with some oval macrocytes. The platelet count may be normal or decreased. The bone marrow shows overall increase in cellularity with hyperplasia of both the granulocytic and the erythroid series. The erythroid hyperplasia usually predominates, typically producing a reversal of the myeloid to erythroid (M/E) ratio (the normal M/E ratio is 3:1 or 2:1). The erythroid precursors are usually megaloblastic or, at least, megaloblastoid, are often bizarre in appearance, and may exhibit erythrophagocytosis (40%-50% of patients); frequently there are increased (>2%) numbers of multinucleated RBC precursors. Ringed sideroblasts are usually present. The FAB criteria for M6 diagnosis are nucleated RBCs comprising more than 50% of all marrow nucleated cells, and at least 30% of the nonerythrocytic nucleated cells must be blasts. In most patients the marrow picture eventually progresses to ANLL of the M1, M2, or M4 type.

    Differential diagnosis of acute leukemia

    Several diseases can simulate part of the clinical or laboratory picture of acute leukemia.

    Infectious mononucleosis is frequently a problem because of the leukocytosis (or initial leukopenia) plus atypical lymphocytes. However, infectious mononucleosis is almost never associated with anemia and only rarely with thrombocytopenia. The bone marrow of infectious mononucleosis is normal and is not infiltrated by significant numbers of atypical lymphocytes. Results of the Paul-Bunnell test for heterophil antibodies (chapter 17) are positive with infectious mononucleosis but negative in leukemia.

    Pancytopenia or other peripheral blood cytopenias (Chapter 6) may raise the question of possible acute leukemia, since acute leukemia may present in this way. Aplastic anemia is one of the more frequent causes for concern. The bone marrow, however, is usually hypoplastic, and the number of blasts is not significantly increased. Patients with agranulocytosis have leukopenia and often have mouth lesions, thereby clinically simulating monocytic leukemia, but do not have anemia or thrombocytopenia or increased number of blasts in their bone marrow.

    Certain viral diseases, such as mumps, measles, and pertussis, are occasionally associated with considerably elevated WBC counts. There may be occasional atypical lymphocytes. There is no anemia or thrombocytopenia. A disease called infectious lymphocytosis occurs in children but is uncommon. WBC counts may be 40,000-90,000, with most WBCs being mature lymphocytes. This condition lasts only a few days. There are no abnormal cells and no anemia or thrombocytopenia, and the bone marrow is normal.

    Overwhelming infection may cause immature cells and even a few blasts to appear in the peripheral blood of infants and young children, and sometimes other toxic bone marrow stimulation has the same effect. Anemia is frequent, and sometimes there is thrombocytopenia. Bone marrow aspirates may be hypercellular and show marked myeloid hyperplasia but do not usually contain the number of blasts found in leukemia. There are usually less than 5% blasts in the peripheral blood. They decrease in number and disappear when the underlying disease is treated.

  • 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.

  • Identification of T-Lymphocytes and B-Lymphocytes

    Mature T-lymphocytes are usually identified by monoclonal antibody detection of CD-2 antigen and mature B-lymphocytes by demonstration of surface Ig (usually by flow cytometry methods). The earliest B-cell stages are now identified by nucleic acid probes demonstrating characteristic rearrangement of intracellular genes for each component part of the Ig receptor molecule heavy chains and kappa and lambda light chains. The genetic material necessary to construct one type of chain is located in one chromosome, but the genetic material for other types of chains is located on different chromosomes. Each type of chain is constructed separately and sequentially, finally being united to form the Ig receptor at the surface of the B-lymphocyte in later stages of cell maturation. There is a similar T-cell gene rearrangement sequence to form the component parts of the T-cell surface receptor (TCR), although the TCR is not an Ig molecule. The sequence of gene rearrangement and Ig or T-cell receptor construction can be followed by nucleic acid probe techniques. Later-stage T-cells can also be identified by the classic erythrocyte (E) rosette technique in which sheep red blood cells (RBCs) spontaneously aggregate around the T-cell to form a “rosette.” The classic procedure for measuring T-cell function is the migration inhibition factor (MIF) assay.

    The same principles and technology can be applied to the non-Hodgkin’s lymphomas. Demonstration that almost all cells of a lymphocytic proliferation have the same (clonal) Ig or TCR rearrangement stage gives strong evidence for neoplasia (lymphoma or myeloma). There are some uncommon nonmalignant clonal lymphocyte-associated conditions such as angioimmunoblastic lymphadenopathy, posttransplant lymphoid proliferation or pseudotumor, and so-called monoclonal gammmopathy of undetermined significance. However, some patients with these conditions later go on to malignancy. The type of receptor gene rearrangement differentiates B- and T-cell lineage; Ig clonal light chain rearrangement is diagnostic for B-cell tumors, and clonal TCR rearrangement without light chain rearrangement is diagnostic of T-cell tumors.

  • 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.