Articles on Medical Diseases and Conditions

Tag: WBC

  • Metastatic Carcinoma to Bone

    About 27% of all cancer patients have some metastases at autopsy. Any carcinoma, lymphoma, or sarcoma may metastasize to bone, although those primary in certain organs do so much more frequently than others. Prostate, breast, lung, kidney, and thyroid are the most common carcinomas. Once in bone they may cause local destruction that is manifested on x-ray film by an osteolytic lesion. In many cases there is osseous reaction surrounding the tumor with the formation of new bone or osteoid, and with sufficient degree of reaction this appears on x-ray films as an osteoblastic lesion. Prostate carcinoma is usually osteoblastic on x-ray film. Breast and lung carcinomas are more commonly osteolytic, but a significant number are osteoblastic. The others usually have an osteolytic appearance.

    Hematologic. About one half of the carcinomas metastatic to bone replace or at least injure bone marrow to such an extent as to give hematologic symptoms. This must be distinguished from the anemia of neoplasia, which appears in a considerable number of patients without direct marrow involvement and whose mechanism may be hemolytic, toxic depression of marrow production, or unknown. The degree of actual bone marrow replacement is often relatively small in relation to the total amount of bone marrow, and some sort of toxic influence of the cancer on the blood-forming elements has been postulated. Whatever the mechanism, about one half of patients with metastatic carcinoma to bone have anemia when first seen (i.e., a hemoglobin value at least 2 gm/100 ml [20 g/L] below the lower limit of the reference range). When the hemoglobin value is less than 8 gm/100 ml (80 g/L), nucleated red blood cells (RBCs) and immature white blood cells (WBCs) may appear in the peripheral blood, and thrombocytopenia may be present. By this time there is often extensive marrow replacement.

    Therefore, one peripheral blood finding that is always suspicious of extensive marrow replacement is the presence of thrombocytopenia in a patient with known cancer (unless the patient is on cytotoxic therapy). Another is the appearance of nucleated RBCs in the peripheral blood, sometimes in addition to slightly more immature WBCs. This does not occur in multiple myeloma, even though this disease often produces discrete bone lesions on x-ray film and the malignant plasma cells may replace much of the bone marrow.

    Alkaline phosphatase. Because of bone destruction and local attempts at repair, the serum alkaline phosphatase level is often elevated. Roughly one third of patients with metastatic carcinomas to bone from lung, kidney, or thyroid have elevated alkaline phosphatase levels on first examination. This is seen in up to 50% of patients with breast carcinoma and 70%–90% of patients with prostate carcinoma.

    Bone x-ray film. If an x-ray skeletal survey is done, bone lesions will be seen in approximately 50% of patients with actual bone metastases. More are not detected on first examination because lesions must be more than 1.5 cm to be seen on x-ray films, because parts of the bone are obscured by overlying structures, and because the tumor spread may be concealed by new bone formation. Almost any bone may be affected, but the vertebral column is by far the most frequent.

    Bone radionuclide scan. Bone scanning for metastases is available in most sizable institutions using radioactive isotopes of elements that take part in bone metabolism. Bone scanning detects 10%–40% more foci of metastatic carcinoma than x-ray film and is the method of choice in screening for bone metastases. A possible exception is breast carcinoma. Although bone scan is more sensitive for breast carcinoma metastasis than x-ray film, sufficient additional lesions are found by x-ray film to make skeletal surveys useful in addition to bone scanning. Also, in cases in which a single lesion or only a few lesions are detected by scan, x-ray film of the focal areas involved should be done since scans detect benign as well as malignant processes that alter bone (as long as osteoblastic activity is taking place), and the x-ray appearance may help to differentiate benign from malignant etiology. Bone scan is much more sensitive than bone marrow examination in patients with most types of metastatic carcinoma. However, tumors that seed in a more diffuse fashion, such as lung small cell carcinoma, neuroblastoma, and malignant lymphoma, are exceptions to this rule and could benefit from marrow biopsy in addition to scan.

    Bone marrow examination. Bone marrow aspiration will demonstrate tumor cells in a certain number of patients with metastatic carcinoma to bone. Reports do not agree on whether there is any difference in positive yield between the sternum and iliac crest. Between 7% and 40% of the patients with tumor in the bone have been said to have a positive bone marrow result. This varies with the site of primary tumor, whether the marrow is tested early or late in the disease, and whether random aspiration or aspiration from x-ray lesions is performed. The true incidence of positive marrow results is probably about 15%. Prostatic carcinoma has the highest rate of yield, since this tumor metastasizes to bone the most frequently, mostly to the vertebral column and pelvic bones. Lung small cell (oat cell) carcinoma, neuroblastoma, and malignant lymphoma also have a reasonable chance of detection by bone marrow aspiration.

    Several studies have shown that marrow aspiration clot sections detect more tumor than marrow smears and that needle biopsy locates tumor more often than clot section. Two needle biopsies are said to produce approximately 30% more positive results than only one.

    The question often arises as to the value of bone marrow aspiration in suspected metastatic carcinoma to bone. In this regard, the following statements seem valid:

    1. It usually is difficult or often impossible to determine either the exact tumor type or the origin (primary site) of tumor cells from marrow aspiration.
    2. If localized bone lesions exist on x-ray film and it becomes essential to determine their nature, a direct bone biopsy of these lesions using a special needle is much better than random marrow aspiration or even aspiration of the lesion area. In this way, a histologic tissue pattern may be obtained.
    3. If a patient has a normal alkaline phosphatase level, no anemia, and no bone lesions on bone scan (or skeletal x-ray survey, if bone scan is not available), and in addition has a normal acid phosphatase level in cases of prostatic carcinoma, the chances of obtaining a positive bone marrow aspirate are less than 5% (exceptions are lung small cell carcinoma, lymphoma, and neuroblastoma).
    4. If a patient has known carcinoma or definite evidence of carcinoma and x-ray lesions of bone, chemical studies or bone marrow aspiration usually have little practical value except in certain special situations in which anemia or thrombocytopenia may be caused by a disease that the patient has in addition to the carcinoma.

  • Granulocytes (Neutrophils)

    WBC transfusions are being used for treatment of infections not responding to antibiotics in patients with severe leukopenia due to acute leukemia or bone marrow depression. The AABB recommends 500 granulocytes/mm3 (or per microliter) as the cutoff point defining severe leukopenia. Clinical improvement has been reported in some of these patients but not all. Most large blood banks have the equipment to offer granulocyte transfusion as a routine procedure. The granulocytes are usually collected by apheresis methods and stored at room temperature. The AABB recommends that granulocytes be transfused within 24 hours after collection. According to the AABB, a daily dose of at least 1 x 1010 functional granulocytes appears necessary. Each granulocyte concentrate dose also contains 3 x 1011 platelets. The same recommendations regarding irradiation noted above for platelet concentrates also applies to granulocytes.

  • White Blood Cell Antigens

    The RBC ABO surface antigens are found in most tissues except the central nervous system (CNS). Some of the other RBC antigens, such as the P system, may occur in some locations outside the RBCs. White blood cells also possess a complex antigen group that is found in other tissues; more specifically, in nucleated cells. This is called the human leukocyte-A (HLA) system and is found in one site (locus) on chromosome number 6. Each locus is composed of four subloci. Each of the four subloci contains one gene. Each sublocus (gene) has multiple alleles (i.e., a pool of several genes), any one of which can be selected as the single gene for a sublocus. The four major subloci are currently designated A, B, C, and D. There is possibly a fifth sublocus, designated DR (D-related), either close to the D locus or part of it.

    HLA-A, B, and C are known as class I antigens. They have similar structure, including one polypeptide heavy chain, and can be identified using standard antiserum (antibody) methods. The class II antigen HLA-D is identified by the mixed lymphocyte culture test in which reagent lymphocytes with HLA-D antigen fail to stimulate proliferation of patient lymphocytes when patient lymphocytes havethe same HLA-D antigen but will stimulate proliferation if the patient HLA-D antigens are not compatible. HLA-DR is classified as a class II antigen with a structure that includes two polypeptide heavy chains. It includes a group of antigens found on the surface of B-lymphocytes (B antigen) and also in certain other cells such as monocytes but not in most T-lymphocytes. HLA-DR is currently tested for by antibody methods using patient lymphocytes and antibody against DR antigen (microcytotoxicity test). Two other antigen groups, MB and MT, which are closely associated with HLA-DR, have been described.

    The four subloci that form one locus are all inherited as a group (linked) in a manner analogous to the Fisher-Race theory of Rh inheritance. Again analogous to Rh, some HLA gene combinations are found more frequently than others.

    The HLA system has been closely identified with tissue transplant compatibility to such a degree that some refer to HLA as histocompatibility leukocyte-A. It has been shown that HLA antigens introduced into a recipient by skin grafting stimulate production of antibodies against the antigens that the recipient lacks, and that prior sensitization by donor leukocytes produces accelerated graft rejection. In kidney transplants from members of the same family, transplant survival was found to correlate with closeness of HLA matching between donor and recipient. On the other hand, there is evidence that HLA is not the only factor involved, since cadaver transplants frequently do not behave in the manner predicted by closeness of HLA typing using HLA-A and B antigens. There is some evidence that HLA-D, DR, and MB antigens may also be important in renal transplant compatibility.

    Platelets contain HLA antigens, and patients who receive repeated transfusions of platelets may become refractory to such transfusions due to immunization against HLA antigens. Transfusion of HLA-A and B compatible platelets improves the success rate of the platelet units. However, about one third of platelet transfusion units containing well-matched HLA-A and B platelets will not be successful once the patient is sufficiently immunized.

    HLA antigens on each chromosome are inherited as a unit in a mendelian dominant fashion. Therefore, HLA typing has proved very useful in paternity case investigations.

    Besides their association with immunologic body defenses, certain HLA antigens have been found to occur with increased frequency in various diseases. The B27 antigen is associated with so-called rheumatoid arthritis (RA) variants (Chapter 23). In ankylosing spondylitis, Reiter’s syndrome, and Yersinia enterocolitica arthritis, HLA-B27 occurs in a very high percentage of cases. The incidence of HLA-B27 in ankylosing spondylitis is 90%-95% (range, 83%-96%) in Europeans and approximately50% in African Americans. In Reiter’s syndrome the incidence is 80%-90% (range, 63%-100%) in Europeans and approximately 35% in African Americans. In juvenile rheumatoid, psoriatic, and enteropathic (ulcerative colitis and Crohn’s disease) arthritis, the incidenceof HLA-B27 depends on the presence of spondylitis or sacroiliitis. In all RA-variant patients, those with spondylitis or sacroiliitis have B27 in more than 50% of cases (some report as high as 70%-95%); without clinical disease in these locations, B27 is found in less than 25%. Increased frequency of the B27 antigen was also reported in close relatives of patients with ankylosing spondylitis.

    An increased incidence of certain other HLA antigens has been reported in celiac disease (HLA-B8), chronic active hepatitis, and multiple sclerosis (as well as in various other diseases) but with lesser degrees of correlation than in the RA variants. The significance of this is still uncertain, and verification is needed in some instances.

  • Leukemoid Reaction

    Leukemoid reaction is an abnormally marked granulocytic response to some bone marrow stimulus, most commonly infection. Leukemoid reaction is basically the same process as an ordinary leukocytosis except in the degree of response. The expected peripheral blood WBC count response is even more marked than usual and may reach the 50,000-100,000/mm3 (50-100 x 109/L) range in some cases. Instead of the mild degree of immaturity expected, which would center in the band neutrophil stage, the immature tendency (“shift to the left”; see Chapter 6) may be extended to earlier cells, such as the myelocyte. The bone marrow may show considerable myeloid hyperplasia with unusual immaturity. However, the number of early forms in either the peripheral blood or bone marrow is not usually as great as in classic CML. There is no basophilia, although the increased granulation often seen in neutrophils during severe infection (“toxic granulation”) is sometimes mistaken for basophilia. The bone marrow in leukemoid reaction is moderately hyperplastic and may show mild immaturity but, again, is not quite as immature as in CML. Splenomegaly and lymphadenopathy may be present in a leukemoid reaction due to the underlying infection, but the spleen is usually not as large as in classic CML.

    One other phenomenon that could be confused with CML is the so-called leukoerythroblastic marrow response (Chapter 6) seen with moderate frequency in widespread involvement of the bone marrow by metastatic cancer and occasionally in diseases such as severe hemolytic anemia, severe hemorrhage, and septicemia. Anemia is present, and both immature WBCs and nucleated RBCs appear in the peripheral blood.

  • 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.

  • Neonatal Leukocytosis

    At birth, there is a leukocytosis of 18,000-22,000/ mm3 (18-22 Ч 109/L) for the first 1-3 days. This drops sharply at 3-4 days to levels between 8,000 and 16,000/mm3. At roughly 6 months, approximately adult levels are reached, although the upper limit of normal is more flexible. Although the postnatal period is associated with neutrophilia, lymphocytes slightly predominate thereafter until about age 4-5 years, when adult values for total WBC count and differential become established (see Table 37-1). Capillary (heelstick) blood WBC reference values are about 20% higher than venous WBC values on the first day of life and about 10% higher on the second day.

  • White Blood Cell Maturation Sequence

    Normal WBC maturation sequence begins with the blast form, derived from hematopoietic stem cells that, in turn, are thought to be derived from tissue reticulum cells (Fig. 6-1). In the myelocytic (granulocytic or neutrophilic) series, the blast is characterized by a large nucleus with delicate very uniform-appearing light-staining chromatin and with one or more nucleoli. Typically, a blast has relatively scanty basophilic cytoplasm without granules,* but the French-American-British (FAB) group (Chapter 7) describes a category of blasts with cytoplasm that may contain a few “azurophilic” granules. Next in sequence is the progranulocyte (promyelocyte), which is similar to the blast but has a variable number of cytoplasmic granules. The promyelocyte gives rise to the myelocyte. Myelocyte nuclear chromatin is more condensed, there is no nucleolus, and the nucleus itself is round or oval, sometimes with a slight flattening along one side. The cytoplasm is mildly basophilic and is granular to varying degrees, although sometimes granules are absent. Often there is a small, localized, pale or clear area next to the flattened portion (if present) of the nucleus, called the myeloid spot. Next, the nucleus begins to indent; when it does, the cell is called a metamyelocyte (juvenile). As the metamyelocyte continues to mature, the nucleus becomes more and more indented. The nuclear chromatin becomes more and more condensed, clumped, and darkly stained, and the cytoplasm becomes progressively less basophilic. The entire cell size becomes somewhat smaller, with the nucleus taking up increasingly less space. Finally, the band (stab) neutrophil stage is reached. There is some disagreement as to what constitutes a band as opposed to a metamyelocyte or band as opposed to an early mature polymorphonuclear leukocyte. Basically, a band is distinguished from a late metamyelocyte when the nucleus has indented more than one half its diameter and has formed a curved rod structure that is roughly the same thickness throughout. As the band matures, nuclear indentation continues and may also occur in other areas of the nucleus. When at least one area of nuclear constriction becomes a thin wire, the cell has reached the final stage of maturity, called the polymorphonuclear (poly) or segmented neutrophil. The nucleus has segmented into two or more lobes, at least one of which is connected only by a threadlike filament to the next. The nuclear chromatin is dense and clumped. The cytoplasm is a very slightly eosinophilic color, or at least there is no basophilia. There usually are small irregular granules, which often are indistinct.

    Maturation sequence of granulocytic (myelocytic) series

    Fig. 6-1 Maturation sequence of granulocytic (myelocytic) series. A, Blast; B, promyelocyte; C, myelocyte (top, early stage; bottom, late stage); D, metamyelocyte (top, early stage; bottom, late stage) E, band granulocyte (top, early stage; bottom, late stage) F, segmented granulocyte (top, early stage; bottom, hypersegmented late stage).

    Terminology of blood cells

    Table 6-1 Terminology of blood cells

    In some cases there may be a problem differentiating bands from segmented neutrophils when a bandlike nucleus is folded over itself in such a way as to hide the possibility of a thin wirelike constricted area (Fig. 6-2). The majority of investigators classify this cell as a segmented form. However, many laboratorians consider these cells bands; unless the reference range takes into account the way these cells will be interpreted, the number of bands reported can differ considerably between persons or between laboratories and could lead to incorrect diagnosis. When there is multiple nuclear segmentation and the lobes connected only by a thin wire number more than five, the cell is termed hypersegmented. Some investigators believe that hypersegmentation is present if more than 5% of the neutrophils have five lobes. Naturally, there are transition forms between any of the maturation stages just described (Fig. 6-1).

    Folded segment versus folded band

    Fig. 6-2 Folded segment versus folded band. A, One end folded (“mushroom” effect). B, Nuclear fold closer to center. a, True band; b, segment with hidden constriction.

    Monocytes are often confused with metamyelocytes or bands. The monocyte tends to be a larger cell. Its nuclear chromatin is a little less dense than chromatin of the myeloid cell and tends to have a strandlike configuration of varying thickness rather than forming discontinuous masses or clumps. The nucleus typically has several pseudopods, which sometimes are obscured by being superimposed on the remainder of the nucleus and must be looked for carefully. Sometimes, however, a monocyte nuclear shape that resembles a metamyelocyte is found. The monocyte cytoplasm is light blue or light gray, is rather abundant, and frequently has a cytoplasm border that appears frayed or has small irregular tags or protrusions. The granules of a monocyte, when present, usually are tiny or pinpoint in size, a little smaller than those of a neutrophil. In some cases, the best differentiation is to find undisputed bands or monocytes and compare their nucleus and cytoplasm with that of the cell in question.

    The reference range for peripheral blood WBCs is 4,500-10,500/mm3 (4.5-10.5 Ч 109/L). Most persons have WBC counts of 5,000-10,000/mm3, but there is significant overlap between normal and abnormal in the wider range, especially between 10,000 and 11,000/mm3. The mean WBC count in African Americans may be at least 500/mm3 (0.5 Ч 109/L) less than those in Europeans, with some investigators reporting differences as much as 3,500/mm3. This difference would be important, since it would produce a greater than expected incidence of apparent leukopenia and less than expected leukocyte response to infection and inflammation. However, not all reports agree that there is a consistent difference between the two racial groups. Normal WBC differential values are listed here:

    The value for each cell type traditionally is known as the cell “count” (i.e., band count), although the findings are expressed as a percentage of 100 WBCs rather than the actual cell number counted.

    Some investigators report a diurnal variation for neutrophils and eosinophils. Neutrophil peak levels were reported about 4 P.M. and lowest values reported about 7 A.M., with an average change of about 30%. Eosinophil levels roughly paralleled serum cortisol levels, with highest values about 7 A.M. and lowest values about 4 P.M. The average change was about 40%. The remainder of this chapter describes anomalies of WBC morphology or count and associated disease states.

  • White Blood Cells

    White blood cells (WBCs, leukocytes) form the first line of defense of the body against invading microorganisms. Neutrophils and monocytes respond by phagocytosis; lymphocytes and plasma cells primarily produce antibodies. In addition to a nonspecific response to bacterial or viral infection, there are alterations in the normal leukocyte blood picture that may provide diagnostic clues to specific diseases, both benign and malignant. Nonneoplastic leukocyte alterations may be quantitative, qualitative, or both; qualitatively, leukocytes may demonstrate an increased degree of immaturity, morphologic alteration in cellular structure, or the increased production of less common types of WBCs.