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CLS 3223 ADVANCED HEMATOLOGY DISORDERS
LEUKOCYTES AND THEIR PATHOLOGY
This part of the syllabus discusses abnormal and pathological conditions associated leukocytes. The narratives are arranged in objective form and in numerical order. All objectives are cognitive unless otherwise indicated. The student at the end of the instructional period is responsible for meeting these objectives by achieving a score of 70% or better on all problem sets, case studies, major exams, quizzes, and library assignments. The student, upon completion of this classroom component will be responsible to:
01 DISCUSS THE TWO CATEGORIES OF LEUKOCYTES: GRANULOCYTES AND NON-GRANULOCYTES
The granulocytes are the neutrophils, eosinophils, and basophils. These are formed in the bone marrow. The nongranulocytes are the monocytes and lymphocytes. Monocytes are formed in the bone marrow and the lymphocytes within the lymphatic system.
02 DISCUSS THE CELL MATURATION - STRUCTURE RELATIONSHIP OF DEVELOPING CELLS
All blood cells originate from an undifferentiated stem cell. In any cell series as it develops from its most immature form to the mature shape there is a series of infinite gradation in size, shape, and features. In the transformation procedure, several processes are occurring simultaneously. If everything is proceeding correctly, the system is synchronized. If abnormal hemopoiesis is occurring, then asynchronism occurs and atypical cells occur. The maturation process is characterized by three basic phenomenon as the cell matures from the immature (blast) cell to the mature cell. These are [1] cytoplasmic changes, [2] nuclear changes, and [3] reduction in cell size. The review of the maturation sequences in this objective are approached from a general perspective and there are a number of maturation steps that are common to all cells.
In the cytoplasmic and nuclear changes, the immature cell is characterized by some degree of basophilia. This basophilia will correlate to the cytoplasmic content of RNA. RNA is "lost" as the cell matures and with this loss, there is a change in cytoplasmic color.
Basophilia decreasing basophilia normal cell color
In the myeloid cell series (platelet, neutrophil, monocyte, basophil, eosinophil, and macrophage), cytoplasmic granules are present. The immature cell may have a few, coarse, reddish granules present. These change as the cell matures. The neutrophil series are characterized by three distinct sets of granules. The acidophilic granules of the eosinophil (red-orange color) increase in size, filling the cytoplasm. The basophilic granules of the basophil (blue-black) are fewer in number and not as large as the eosinophil. The purple colored primary granules of the neutrophil are much smaller, but not as large as the eosinophil. The lavender colored secondary granules of the neutrophil are much smaller and more numerous. In the monocyte, the azurophilic granules appear in the immature form and usually disappear as the cell matures.
Hemoglobin synthesis is a distinctive feature of the RBC line. In the earliest recognizable cell, the rubriblast, there is no visible evidence of hemoglobin synthesis. The cytoplasm is so basophilic that it masks out any hemoglobin present. Remember that the degree of basophilia in the cytoplasm is correlated to RNA. As the cytoplasmic RNA decreases, so does the basophilia and hemoglobin synthesis becomes visible. This is best observed in the rubricyte stage.
Nuclear maturation has some degree of consistency in all cell lines with some distinct difference for each cell line. In all cell lines there is a condensation of chromatin material. In the erythroid cell line, the nucleus and its chromatin condenses into a extremely pyknotic mass and is extruded. In the granulocyte line, the nucleus condenses and forms lobed structures with differences between the neutrophils, eosinophils, and basophils. The monocyte and lymphocyte condenses to a somewhat smaller form, but the chromatin patterns differ between the two cell lines. In the immature cell, regardless of the cell lines, there is a high nucleus to cytoplasm ratio and the nucleus is characterized by delicate, net-like or sponge-like nuclear chromatin. As the cell matures the chromatin condenses, becoming more coarse and clumped. The staining properties go for a purple or reddish-purple tint to a dense blue-black color. The nucleoli number varies with each cell line. They are present in the nucleus as islands of metabolic activity without a definite membrane. Their cytoplasmic mass compresses the surrounding chromatin to appear as membrane-like structures. The nucleolus consists of RNA, but is decreases as it is replaced by DNA. The nucleolus tends to stain blue in methylene blue and eosin stains. It function seems to be to synthesize cytoplasmic RNA. This ceases when the cell reaches maturity. The lymphocyte is the exception as its nucleolus remains viable in the mature stage.
Nuclear size and color changes
The nucleus of the immature cell has a greater affinity for eosinophilic dye which gives it a predominately reddish color. In the immature cell, the chromatin strands are loose, delicate, and spreading. As the nuclear chromatin condenses, the color changes to a predominating blue. As the chromatin condenses, it becomes more coarse and clumped. This is where variation occurs in the WBC’s. The nuclear material is ejected from the maturing RBC.
All cell lines change in shape and size. Cells tend to become smaller with the most striking changes seen in the thrombocytes. The greatest nuclear changes occur in the granulocyte cell line
03 DEFINE THE FOLLOWING TERMS
Hyperplasia. An increase in cell numbers because of the development of new cells. Hypertrophy. An increase in cell size. Dysplasia. Abnormal or atypical increase in cell number due to a pathological cause. Metaplasia. The change of one cell type to another type. This process may be benign or malignant. Neoplasia. Abnormal growth of tissue with progressive persistent growth. Synonym: tumors. Benign tumors. Slow growing, well differentiated cells that do not invade surrounding tissues. Malignant tumors. Cells expand into adjacent tissues, displacing normal cells. Progressively life threatening. Granulocytosis: A condition characterized by increased numbers of granulocytes in the circulating blood or tissues. Granulocytes includes neutrophils, eosinophils, and basophils. Sarcoma. Malignant tumors from mesenchymal tissues. Carcinoma. Malignant tumors from epithelial tissues. Myeloproliferative disorders (MPD). Uncontrolled growth of a cell clone into a leukemic disorder and involves any of the following cell lines: [1] granulocytic, [2] monocytic, [3] lymphoid, [4] erythroid, [5] histocytic, or [6] fibroblastic. Myelodysplastic syndromes (MDS). Blood cell precursors exhibit abnormal ineffective growth or maturation. Cytopenia is the rule and the marrow is hypocellular. Leukemogenic. Inducing the development of leukemia.
04 DISCUSS LEUKOPENIA
Leukopenia simply means a reduction in the white blood cell count below a value of 5,000 WBC’s per µL. Some labs may have a cut-off value or 4,500/µL. Leukopenia occurs much less frequently than anemia and can exist in several forms. Specific leukopenia disorders are [1] neutropenia, [2] lymphopenia, [3] eosinopenia, [4] basopenia, and [5] monocytopenia. Leukopenia may be induced by any substance that is toxic to the bone marrow. Examples of such substances are cytotoxic drugs, environmental chemicals, and industrial chemicals. Any chemical that can cause damage to the precursors of white blood cells can also damage red blood cells. If leukopenia occurs, regardless of the reason, the body’s defense against infections is compromised. Neutropenia can be marked by overwhelming infections, whereas a depletion of lymphocytes can result in viral, bacterial, fungal, and parasitic infections. If the leukopenia is short term phenomenon, medical intervention can prevent life threatening events, but if it is of a long term event, then it may be fatal. Leukopenia, if accompanied by aplastic anemia, is often fatal.
05 BRIEFLY DISCUSS LEUKOCYTOSIS
This is an increase in the number of circulating white blood cells in peripheral blood and represents counts greater that 12,000/µµL. Specific types of leukocytosis are as follows: [a] granulocytosis, [b] eosinophilic leukocytosis, [c] lymphocytosis, [d] basophilia, and [e] monocytosis. Leukocytosis, if a benign and reactive condition, will run a short course and require no medical intervention. If this problem persists, it may be an indicator of a leukocyte malignant disease.
06 DEFINE THE LEUKEMOID REACTION
This is a sudden and dramatic increase in neutrophilia, so that the elevated WBC
count will rise to 50,000 to 100,000/μL and appears to mimic leukemia. There
will be a shift-to-the-left and the presence of toxic granulation. Such
[2] presence of necrotic tissue [4] acute alcoholic hepatitis If this WBC "picture" resembles leukemia, it can be differentiated by Leukocyte Alkaline Phosphatase (LAP) stain. Elevated LAP scores are observed in leukemoid reactions, last trimester of pregnancy, neutrophilia (caused by infections), aplastic anemia, polycythemia vera, multiple myeloma, myelosclerosis, and obstructive jaundice. It is decreased in chronic myelogenous leukemia, sickle cell anemia, paroxysmal nocturnal hemoglobinuria, marked eosinophilia, and sideroblastic anemia. Normal LAP values range form 13 to 100, but may vary with the laboratory. A LAP score >100 is supportive of the leukemoid reaction. Anemia or thrombocytopenia are usually not associated with the leukemoid reaction.
07 DISCUSS NEUTROPHILIA
Also called neutrophilic leukocytosis. This is a condition in which there is an increase in the number of peripheral blood neutrophils. The normal absolute neutrophil range is between 2000 and 7000/μL (adults). Neutrophilia is diagnosed when the neutrophil count is >7,500/μL.
An intermediate form of neutrophilia (known as pseudoneutrophilia) occurs when there is a shift from the granulocyte pool into peripheral circulation. This shift consists of mature neutrophils only. This occurs during vigorous exercise, anesthesia, intense anxiety, convulsions, and epinephrine administration. Toxic granulation is absent and as a rule there is not a shift-to-the-left with an increase in the immature forms. No movement of neutrophils from the bone marrow occurs in this intermediate form.
The presence of acute neutrophilia is the consequence of a pathological stimulus. The most common cause is bacterial infections or bacterial toxins. This is characterized by a movement of neutrophils from the bone marrow and there will be a shift-to-the-left in the peripheral smear. The band count will be >6%. If the tissue demands for neutrophils is great, then metamyelocytes and possibly myelocytes will be present. The presence of toxic granulation is common. Look for large blue-back granules which are immune complexes of microbial antigens and reactive immunoglobulins. The WBC count will be between 12,000 and 20,000/μL. Counts as high as 70,000/μL has been reported. If a shift-to-the-left is present, look for eosinophilia. When the cause of neutrophilia ceases and the neutrophil count is decreasing, a transitory monocytosis may present, followed by a lymphocytosis, then finally eosinophilia.
08 DISCUSS CHRONIC NEUTROPHILIA
A chronic form of neutrophilia may develop following an acute occurrence of increased neutrophils. This may be due to the continued stimulus for the bone marrow continue to produce "segs". The peripheral blood film will demonstrate bands, metamyelocytes, and myelocytes. This type of neutrophilia is associated with chronic inflammation, such as chronic glomerulonephritis, rheumatoid arthritis, or rheumatic fever. In a few cases of chronic neutrophilia, an occasional promyelocyte and/or myeloblast may be observed.
09 DISCUSS THE DIFFERENT TYPES OF NEUTROPENIA
A reduction in neutrophils occurs when its absolute count (both "segs" and
bands) drops below 1,500/μL. If the count drops below 500/μL, then the condition
is called agranulocytosis. Causes for neutropenia are: B. Chemotherapy. C. Myelophthisis . . . . an infiltration of malignant cells and causing a wasting way of normal cells.
D. Radiation (x-rays)
B. Felty’s syndrome (a chronic rheumatoid arthritis characterized by
splenomegaly, anemia, and C. As a secondary problem to a primary disorder (as an autoimmune disease). Pseudoneutropenia represents a decrease in neutrophils that may be due to hypothermia, nutritional deficiencies or a shifting of the neutrophils from peripheral circulation into the marginal pools. This shifting is characterized by the neutrophils attaching to the walls of the blood vessels. In this case the other WBC’s may appear increased. For example if the lymphocytes appear increased due to a decrease in the neutrophil count, this would be called relative lymphocytosis.
A decrease in neutrophils, known as false neutropenia, occurs due to laboratory error. If a blood sample is allowed to stand for a period of time, the neutrophils will deteriorate at a faster rate than other WBC’s. This will result in a lower WBC count and decrease in the relative neutrophil count on a WBC differential. The neutrophil is more fragile in Chediak-Higashi anomaly. Laboratory manipulations may result in the rupture of neutrophils causing a reduced WBC count. If paraproteins are present (as in multiple myeloma), this may facilitate a clumping of neutrophils and in an automated procedure, the count will appear lower.
10 DISCUSS THREE ACQUIRED MORPHOLOGIC ABNORMALITIES OF WBC’s
DÖHLE BODIES. These are aggregates of rough endoplasmic reticulum (RNA), usually found near the inside edge of the neutrophil. These stain as light blue to light blue-gray oval masses. Döhle bodies (first reported in scarlet fever) are observed in aplastic anemia, burns, neoplasms, severe bacterial infections, and pregnancy. If you observe toxic granulation in the neutrophil, look for the presence of Döhle bodies. Do not confuse these with the cytoplasmic inclusions observed in May-Hegglin anomaly (See Objective 29). Döhle bodies are also observed in eosinophils.
CYTOPLASMIC VACUOLES. The presence of vacuoles may be due to the ingestion and phagocytosis of bacteria and other material. These vacuoles tend to be large and will be unevenly distributed in the cytoplasm. Vacuolization may be seen in self or auto-phagocytosis when the body is experiencing long term exposure to certain drugs, alcohol, and radiation. If the neutrophil is characterized by toxic granulation or Döhle bodies, then vacuoles are usually clinically significant.
TOXIC GRANULATION. This is the presence of large deep blue-black granules in the cytoplasm of neutrophils. These large granules are thought to be composed of immune complexes and reactive immunoglobulins or strands of aggregated endoplasmic reticulum. Toxic granulation is considered to be clinically significant since it may be an indicator of a more serious prognosis.
11 DISCUSS EOSINOPHILIA
Eosinophilic leukocytosis is observed in allergies, asthma, drug hyper-sensitivities, parasitic infections, terminal Hodgkin’s disease, chronic hepatitis., bacterial infections (leprosy, tuberculosis, scarlet fever), fungal infections, ulcerative colitis, and certain skin diseases. Counts >450/μL are required in the peripheral blood. When you are performing a differential count and you note the increased presence of eosinophils (EO), look for increased rupture of EO cytoplasmic membranes. Eosinophils tend to be more fragile when increased.
There is a hyper-eosinophilia in which the count will be >1,500/μL This highly elevated count is due to a systemic disorder such as polyarteritis (a disorder involving the medium sized arteries) or Löffler’s syndrome (an allergic response to helminth parasites). In hyper-eosinophilia, hepatosplenomegaly may be observed and also Charcot-Leyden crystals in exudates and tissues.
12 DISCUSS EOSINOPENIA
This condition is not easy to identify. Normal values in the peripheral blood are normally low. It is possible to perform a differential and not count any eosinophils (EO). An absolute count of 50/μL is considered to be eosinopenia. Causes of eosinopenia include [1] stress, [2] acute infections, [3] neoplasms, and [4] severe injuries (for example: burns). To determine if the patient has eosinopenia, use the 10X objective and scan the blood smear. If NO eosinophils are observed, then the patient may have eosinopenia. NOTE. If the blood levels of glucocorticoids are elevated for any reason, there will be most likely, a decreased peripheral concentration of EO’s.
13 DISCUSS LYMPHOCYTOSIS
Lymphocytosis is characteristic of viral infections, certain chronic infections,
and certain disorders. (Examples include: lymphocytic leukemia, tuberculosis,
pertussis, toxoplasma infection, and hyperthyroidism). A normal absolute
lymphocyte count (adult) ranges from 1,500 to 4,000/μL. In lymphocytosis, look
for absolute lymphocytes concentrations >4,000/μL in adults. In children, the
normal absolute count varies. Consider the following examples: b. 1 y/o = 4,000 to 10,500/μL c. 4 y/o = 2,000 to 8,000/μL d. 6 y/o = 1,500 to 6,500/μL An absolute lymphocyte count for lymphocytosis will be greater than the maximum values listed. Remember when determining absolute lymphocytosis, there will be an increase in the lymphocyte count along with an increase in the overall WBC count. Also there should be almost no smudge cells present as in CLL.
NOTE #1. If the increase in lymphocytes is due to small lymphocytes (with diameters of 6 to 8 μ and a small amount of cytoplasm) then it is most likely this is a benign response. Note. LESS THAN 10% of the total lymphocytes will be larger forms with increased cytoplasm and an "immature appearing" nucleus that may resemble a monocyte. Conditions in which this type of mature lymphocyte predominates are [1] hyperthyroidism, [2] pertussis, [3] disseminated tuberculosis, [4] acute infectious lymphocytosis (a children’s disorder), [5] early chronic lymphocytic leukemia, and [6] advance chronic lymphocytic leukemia.
NOTE #2. If the increase in lymphocytes is characterized by >10% of the total lymphocyte of the larger form with increased cytoplasm and an "immature appearing" nucleus that may resemble a monocyte, then you may be observing reactive lymphocytosis. This type of increase may due to any of the following viral infections: [1] infectious mononucleosis (Epstein-Barr virus), [2] cytomegalovirus infection, [3] viral hepatitis, [4] mumps, [5] measles, [6] upper respiratory infections, and [7] human immuno-deficiency virus.
Absolute lymphocytosis (due to an increase in lymphocytes) must be distinguished from relative lymphocytosis (which is due to a decrease in neutrophils)..
14 DISCUSS LYMPHOCYTOPENIA
Lymphocytopenia for the adult occurs when the absolute lymphocyte count drops
below 1,500/μL In the child, dependent on the age, the absolute count will be
<1,500 to 2,000/μL Causes for lymphocytopenia include
15 DISCUSS MONOCYTOSIS . Monocytosis occurs when the monocyte concentration is >800/μL. (Normal is an absolute count of 100 to 800/μL) In children up to 1 y/o, the normal absolute count may be up to 1,100/μL. Such increases are associated with [1] monocytic leukemia, [2] tuberculosis, [3] syphilis, [4] 62% of all malignancies, [5] chronic neutropenia, [6] hemolytic anemias, [7] polycythemia vera, [8] 25% of patients with Hodgkin’s disease, and [9] connective tissue diseases. Caution: When you are interpreting a Wright’s stained blood smear, do not confuse these cells with reactive lymphocytes that may be encountered in a variety of diseases.
16 DISCUSS MONOCYTOPENIA
Monocytopenia occurs when the absolute monocyte count drops below 50/μL. Decreased monocytes occur in [1] hairy cell leukemia, [2] massive infections, and [3] glucocorticoid (steroid) therapy. If monocytopenia occurs in a massive infection, it is probable that there is also neutropenia.
17 DISCUSS BASOPHILIA
Basophilia is diagnosed when the absolute basophil count is >100/μL. Another criterion for basophilia is that more than 2% of the total WBC count will be basophils. This increase will most often be observed in chronic myelogenous leukemia, colitis, polycythemia vera, myelofibrosis, nephrosis, radiation exposure, chronic hemolytic anemia, myxedema, and hypothyroid conditions.
Basophils are involved in inflammatory processes and hypersensitivity reactions. These cells synthesize and store histamine and other inflammatory mediator
chemicals. These biologically active materials when released will cause
[2] initiate smooth muscle contractions, [3] increase secretions, [4] exert an inhibitory effect upon certain parts of the coagulation mechanism. Basophils (and tissue basophils/mast cells) have receptors for IgE. If the appropriate antigens for IgE are present, then degranulation occurs with release of histamine with a clinical manifestation of a form of hypersensitivity is seen in [1] bronchial asthma, [2] urticaria, [3] allergic rhinitis, and [4] hyper-sensitivity to drugs, insect venom, and other antigens.
18 DISCUSS BASOPENIA
Basopenia is even more difficult to identify than eosinopenia. It is not unusual to perform a differential count and not record a basophil, even when counting 200 WBC’s. Use the same strategy as when screening for eosinopenia. If no basophils can be observed on a stained blood film, then that patient may have basopenia. Until the development of flow cytometry, with it capability of identifying the basophils in a population of 10,000 or more WBC’s, the identification of basopenia was a problem. Decreased basophils are observed in anaphylaxis and other allergic reactions, hemorrhage, stress, myxedema, myelofibrosis, chronic hemolytic anemia, glucocorticoid therapy, acute infections, neoplasms, polycythemia vera, colitis, and severe injuries (as in burns).
19 BRIEFLY EXPLAIN WHY BONE MARROW TESTING IS IMPORTANT IN IDENTIFYING WHAT IS GOING ON THE BLOOD OF A PATIENT
Bone marrow is often definitive because leukemic cells exhibit features such as chromosome abnormalities, Auer rods, and cell membrane markers that the normal blood cells lack when the cell count is increased due to an inflammatory and/or infectious process.
20 DISCUSS THE REACTIVE LYMPHOCYTE
This cell is also known as the [1] Downey cell, [2] stimulated lymphocyte, [3] transformed lymphocyte, [4] activated lymphocyte, [5] leukocytoid lymphocyte, [6] virocyte, and [7] atypical lymphocyte (a term which should be avoided).
The following precaution should be adhered to regarding reactive lymphocytes. They are very susceptible to the effects of time delays and EDTA anticoagulant. Reactive lymphocytes should be evaluated from fresh blood smears (withing 30 minutes of collection). The nuclear material of the reactive lymphocyte, when left too long in EDTA, will undergo morphology changes that cause it to resemble abnormal and malignant lymphocytes. Nuclear changes include [1] "cleft" nuclei, [2] mitotic forms, [3] necrobiotic cells, and [4] numerous deteriorating cells
NOTE: Reactive lymphocytes are normal and of a benign nature. Their appearance is due to their response to antigen stimulus. The Downey descriptions have no clinical value and are no longer used.
To identify the reactive lymphocyte, look for the following features in the:
When enumerating the "reactive" lymphocyte, follow the established laboratory criteria for your laboratory. It is normal for "normal" lymphocytes to have slight degrees of variation. It may be deemed to be wise policy to ignore the slight variations and have established criteria for more distinctive variations. Lymphocytes react readily to a variety of antigens in the blood and will "transform" according to the degree of stimulus. Because reactive and malignant lymphocytes may exhibit immature-appearing cells, remember that malignant lymphocytes are usually clonal and all abnormal cells should appear very similar to each other with consistency in appearance to its nucleus, cytoplasm, and size and shape. The "reactive" lymphocyte should present somewhat inconsistent, with variation in the appearance of its nucleus, cytoplasm, and size and shape.
21 DISCUSS INFECTIOUS MONONUCLEOSIS (IM)
This acute and contagious viral disorder was first described by Emil Pfeiffer as "glandular fever". It received it current name in 1920 by T.P. Sprunt and F.A. Evans when they associated the disease with the cellular morphology of the blood. The relationship to the Epstein-Barr virus was discovered in 1968. This disorder affects primarily young adults, preferably in the age range of 14 to 20 years. Eighty to ninety percent of the adults have antibodies to the virus and are immune. I. M. can be transmitted by saliva, hence its name "kissing disease".
Clinical symptoms include [a] pyrexia, [b] pharyngitis, [c] lethargy, [d] cervical lymph node enlargement, [e] splenomegaly (in 75% of the patients), [f] hepatomegaly (in 25% of the patients), [g] vomiting (in 20% of the patients), [h] headaches (in 20% of the patients), [i] jaundice (in 5% of the patients). If I. M. infects a child under ten years of age, that child will be heterophil negative. Infectious mononucleosis can be either heterophil negative or positive. Expected clinical laboratory findings include: [1] WBC count = 12,000 to 25,000/μL [2] The stained blood film will contain >10% reactive lymphocytes and >50% of the WBC’s are lymphocytes. [3] Platelet count will be decreased but seldom <1.0 X 105/μL
[4] About heterophil testing: If the test is negative repeat in 7 to 10 days.
Heterophil antibodies are not [5] The liver function tests will be abnormal: A. Bilirubin = upper limits of normal is the rule, B. AST (SGOT) = >30 IU/L (look for values eight times normal) C. ALT (SGPT) = >30 IU/L (look for values up to three times normal) D. RBC, Hct, Hgb, MCV, MCH, MCHC = usually within normal parameters. E. Coomb’s test = negative 22 DISCUSS LYMPHOCYTOSIS
Infectious lymphocytosis is a disease of young children with an unknown etiology. Clinical symptoms include [1] diarrhea, [2] gastrointestinal distress, [3] headache, [4] respiratory infection, [5] vertigo, [6] fever, [7] lymphadenopathy is not present. Expected laboratory findings include: [1] WBC count = 40,000 to 50,000/μL. [2] Sixty to ninety percent of the WBC’s seen on the stained blood film are small, normal-like lymphocytes. Reactive lymphocytes are not the rule. As the leukocytosis recedes, the eosinophil count tends to increase, with absolute values up to 3,000/μL being reported. [3] Other hematology parameters are normal.
23 DESCRIBE CHÉDIAK-STEINBRINCK-HIGASHI SYNDROME
This is an autosomal recessive disorder, more apt to be referred to as Chédiak-Higashi Syndrome. It is a hereditary anomaly of neutrophils with a very poor prognosis. It appears in infancy and most children die before their tenth year of life. Clinical symptoms include hepatosplenomegaly and partial albinism (seen in the hair, eyes, and skin). These patients tend to bleed easily and have low resistance to infections (infections tend to be overwhelming and are the usual cause of death). If the affected individual lives into their teen years, the condition will develop into a fatal lymphoma. Expected laboratory findings include: [1] WBC = 2,000 to 3,000/μL (leukocytopenia). There is a persistent and mild granulocytopenia. [2] The stained peripheral blood smear is characterized by:
A. giant cytoplasmic lysosomes which are defective and peroxidase
positive. They are the result of B. granulocytes are irregular in size and shape. C. eosinophils have over-large granules. D. monocytes have large cytoplasmic granules E. lymphocytes may have large cytoplasmic granules (not peroxidase positive). [3] Decreased platelet count.
[4] Bleeding time is prolonged due to thrombocytopenia. Other coagulation tests
are usually normal. 24 DISCUSS CHRONIC GRANULOMATOUS DISEASE (CGD)
This is a lethal sex-linked disorder, predominate in males. There is a form that is transmitted by autosomal recessive genes. The abnormality for this disorder lies in the following loss of neutrophilic functions:
The prognosis for this patient is very poor. These individuals are subjected to repeated infections. The recurring problem are [1] pneumonia, [2] osteomyelitis, [3] lymphadenitis, and [4] liver abscesses. Death usually occurs in the first or second decade. Two distinctive clinical features are eczema (with papules, vesicles, pustules, scales, crusting, and scabs; in combination or alone) and hepatosplenomegaly.
Expected laboratory findings reveals no obvious/visible morphological abnormalities on the stained blood film. Other laboratory tests are usually normal. The one distinctive diagnostic test is the Nitroblue Tetrazolium (NBT) test. This detects the abnormal oxidase activity in the neutrophils. It requires that NBT be mixed with heparinized whole blood and incubated for 20 minutes. Thick blood films are made and stained with Wright’s stain. Examine the slide for neutrophils that contain "formazin". The presence of black "formazin" indicates normal oxidase activity and healthy neutrophils. The absence of "formazin" is suggestive of chronic granulomatous disease type neutrophils since the dye NBT is not reduced and retains it yellow color. 25 DISCUSS MYELOPEROXIDASE DEFICIENCY Myeloperoxidase (MPO) deficiency is a benign, autosomal recessive disorder with very few symptoms. The enzyme myeloperoxidase is absent in primary granules of neutrophils and monocytes. Eosinophils contain normal myeloperoxidase. This enzyme catalyzes H2O2 into HOCl, an efficient oxidizing radical that is toxic to microorganisms. The patient demonstrates effective killing of bacteria through other mechanisms but is susceptible to fungal infections caused by Candida and Aspergillus Laboratory tests, including the WBC differential are normal.
26 DISCUSS ALDER-REILLY ANOMALY
This is an autosomal recessive trait that expresses itself in association with a group of mucopolysaccharide storage disorders. This anomaly is a morphological aberration of all leukocytes in which there is a decreased degradation of mucopolysaccharides and the subsequent aggregation within the WBC to form deposits of mucopolysaccharides and glycogen. When the WBC is stained with toluidine blue O stain, this granule-like material will stain varying shades of purple-red. These stained inclusions found in the neutrophils are metachromic granules, known as Alder-Reilly bodies. They are larger than toxic granules and are seen in all leukocytes. The eosinophils and basophils contain such bizarre granules that they cannot be distinguished except by the peroxidase reaction. Eosinophils are peroxidase positive where basophils are negative. Note: Alder-Reilly bodies are positive for leukocyte alkaline phosphate where toxic granules are not as positive. Also toxic granules do not demonstrate metachromic coloration.
Alder-Reilly cells can be observed in Huler’s syndrome, Hunter’s syndrome, and Sanfilippo’s syndrome. These cells may be observed in peripheral blood smears, but are more likely to be found in bone marrow studies. If the metachromic granules are found in lymphocytes, then they may be called Gasser’s cells and in monocytes, they are Berhot’s cells.
27 DISCUSS PELGER-HUET ANOMALY
Pelger-Huet anomaly is a benign, autosomal dominant trait, actually a clinical oddity. It is a morphological anomaly where the leukocytes are not othe homozygous individual, the nuclei are usually "bi-lobed", however a few may not contain lobes. These neutrophils are also known as "dumb-bell" or "pince-nez" cells. The band has a peanut-shaped nucleus. If the individual is heterozygous, then from 70% to 90% of the neutrophils will have a bi-lobed appearance.
28 DESCRIBE PSEUDOPELGER-HUET ANOMALY
This is a acquired anomaly that is commonly associated with a malignant myeloproliferative disorder. The pseudo-Pelger-Huet cell can be observed in pre-leukemic conditions, burns, myelodysplastic disorders, tumors that have metatasized to bone, toxic chemotherapy, Fanconi’s anemia, drug reactions, infections, infectious mononucleosis, chronic granulocytic leukemia, and malaria.
29 DISCUSS MAY-HEGGLIN ANOMALY
This is more of a platelet disorder than it is of neutrophils. It is an autosomal dominate disorder that is of rare occurrence. The peripheral blood smear presents with thrombocytopenia and the presence of giant agranular platelets. Some of the platelets may have bizarre appearances. If the thrombocytopenia is significant, the patient will have bleeding problems. The clot retraction test will be prolonged and the capillary fragility test will be positive.
This patient tends to present with mild neutropenia and the granulocytes are characterized by the presence of blue staining Döhle-like bodies in the cytoplasm. These bodies are composed of glycogen and RNA material. These bodies stain best with methyl green pyronin stain but appear as blue-grey structures with Wright’s stain.. These spindle-shaped bodies may be observed in lymphocytes and monocytes. These presence of these inclusions do not appear to seriously impair WBC functions as most persons are found to be in good health and asymptomatic.
30 DISCUSS JORDAN’S ANOMALY
Jordan’s anomaly is familial disorder observed in two primary diseases: muscular dystrophy and xeroderma (ichthyosis). It is a familial oddity. The clinical laboratory observations are limited to the monocytes and lymphocytes which contain fine vacuolation. When these are observed, a lipid stain should be performed to help identify this abnormality. Sudanophilic inclusions have been observed in granulocytes, monocytes, and lymphocytes of peripheral blood. These inclusion have been observed in bone marrow progranulocytes, myelocytes, metamyelocytes, and plasma cells. There are no known functional defects known in these cells.
31 EXPLAIN THE WBC MOVEMENT DISORDER, JOB’S SYNDROME
This is a defect that is characterized by the neutrophil’s poor directional motility and some impairment in their ability to undergo a respiratory burst to destroy an antigen or bacteria. Job’s syndrome is also known a hyperimmunoglobulin E syndrome. The mode of inheritance is unknown. The WBC’s do not respond well to chemical stimulus (chemotaxis). Because of slow response time and poor directional movements, these cells will arrive at an infection site late. This gives microorganisms more time to increase in the tissues creating problems. Such patients tend to present with recurring mucous membrane infections and boils. One characteristic of this patient is the elevated levels of IgE.
32 BRIEFLY DESCRIBE LAZY LEUKOCYTE SYNDROME.
This is a rare occurring condition (reported in 1971) that affects the random movements of neutrophils and also their directional movement. It is thought that the actin filaments in the neutrophil is defective. Like Job’s syndrome, patients with this disorder then to have recurrent infections, but involvement seems to focused in the areas of the mouth, gums, and ears. These patients have low grade fever and may not have any significant clinical symptoms. Bone marrow studies indicate normal reserves of neutrophils, but the release mechanism from bone marrow to peripheral blood is poor. One consistent clinical lab finding is neutropenia.
33 DESCRIBE WISKOTT-ALDRICH SYNDROME
Wiskott-Aldrich syndrome (designated as a congenital immunodeficiency disorder) is a sex-linked, recessive disorder characterized by a decrease in T-lymphocytes and normal B-lymphocytes. This patient has a poor prognosis because of their inability to generate an appropriate T-lymphocyte response. Affected boys present with bleeding problems in infancy and most do not survive beyond ten years of age, dying of bleeding complications, infections, or lymphoreticular malignancy. Transplantation of histocompatible bone marrow from a normal donor has corrected this syndrome anomaly. The problem appears to lie in the inability of the antibody system to synthesize antibodies to the polysaccharide antigens. Clinical symptoms include: eczema, susceptibility to infections, and bleeding tendencies. Clinical laboratory findings include: [1] thrombocytopenia, [2] normal lymphocyte counts, and [3] decreased serum IgM. The platelets are structurally abnormal, with deficiencies in alpha and dense granules. The platelets tend to be small.
34 DESCRIBE DiGEORGE SYNDROME
This syndrome (considered to be an immune deficiency disease) is also known as Congenital Thymic Hypoplasia (or aplasia) and occurs in both males and females.. This is a T-lymphocyte deficiency and results from maldevelopment of the thymus and parathyroid glands. It is not known to be an inherited disorder. The degree of thymic aplasia varies. Those with some degree hypoplasia may have little trouble with infections, but those with aplasia are susceptible to infections with low-grade or opportunistic pathogens. These patients are characterized by retarded growth, short life-spans, wasting, and diarrhea. They are also susceptible to a high incidence of malignancy. Patients diagnosed with DiGeorge’s syndrome will die in their first year of life. Clinical lab findings include: [1] decreased T-lymphocytes (if a true thymic aplasia, then no T-lymphocytes), [2] increased B-lymphocytes, [3] decreased IgG, and [4] increased IgE. Correction of this abnormality has been attempted with embryonic thymic transplants. The value of this therapeutic strategy is unclear.
35 DISCUSS SEVERE COMBINED IMMUNE DEFICIENCY (SCID) SYNDROME
Severe Combined Immune Deficiency (SCID) syndrome (lymphopenic agammaglobulinemia, Nezelof’s syndrome, thymic alymphoplasia) is a gross functional impairment of both humoral (implies circulating antibodies) and cellular immunity. It affects both the B- and T-lymphocytes and plasma cells. It can be inherited as either a sex- or autosomal-linked recessive disorder. Affected infants are susceptible to all types of infections and rarely survive beyond their first year. Infections with common organisms as measles virus, Candida albicans, Pneumocystis carinii, cytomegalovirus, varicella (varicella-herpes virus), and vaccinia (pox virus) are likely to result in death. Transplantation of histocompatible bone marrow has proven to be a successful form of therapy. Clinical symptoms include: retarded growth, frequent infections, wasting, and diarrhea. Clinical laboratory findings include: [a] decreased T-lymphocytes, [b] decreased or absence of gamma globulins, [c] decreased B-lymphocytes, and [d] absence of plasma cells. CAUTION: It is important that this disorder be identified early. If an infant should be given a blood transfusion, it may result in fatal graft-versus-host disease.
36 DISCUSS ATAXIA TELANGIECTASIA
Ataxia telangiectasia is a rare, autosomal recessive genetic disorder. This is a complex disorder involving abnormalities in the nervous, immunological, hepatic, endocrine, and cutaneous systems. This disorder begins to express itself about the third year of life. It is a progressive disease with the patient becoming confined to the wheel chair at about the age of ten. There is no known treatment that will reverse this disorder. Only symptomatic treatment is available. The most frequent causes of death are chronic pulmonary disease (due to decreased IgA) and malignancy. Expected laboratory findings include: [a] absence of serum IgA (in up to 80% of the patients), [b] decreased serum IgG, [c] decreased serum IgE, and [d lymphopenia. IgM and IgD are usually normal.
37 BRIEFLY PROVIDE AN OVERVIEW OF THE LIPID STORAGE DISORDERS
Lipid storage disorders are also called lysosomal storage diseases. These are rare occurring, autosomal recessive traits that express early in childhood. They are due to defects in lipid enzymes and are characterized by the accumulation of unmetabolized material in the lysosomes of a variety of cells. Lysosomes are a type of intracellular digestive tract and breakdown selected macromolecules. The cells responsible for much of this digestive activity are the monocytes and macrophages. When such an enzyme deficiency occurs, there is a subcellular accumulation of undigested lipids. Designated as lipid storage diseases, these phagocytic cells will infiltrate the bone marrow and replace the normal cells causing depressed organ function. Other organs affected are the spleen and liver. Diagnosis is dependent upon identifying an enzyme deficiency or a clinically distinct cell. The three best known of these disorders are [a] Gaucher’s disease, [b] Niemann-Pick disease, and [c] Tay-Sachs disease. These three disorders have a predilection for Jewish people. Therapy strategies include bone marrow transplantation, which has been considered to be successful in some cases. These disorders may be referred to as a non-malignant WBC disorder.
38 DISCUSS GAUCHER’S DISEASE
Gaucher’s disease is a glucosylceramide lipidosis due to a deficiency in the enzyme glucosylceramidase. It is characterized by hepatomegaly and is a progressive neural disorder that terminates in death. It is the most common of the lysosomal storage diseases. The source of glucocerebrosides are the neutral glycolipid of neutrophils and the stroma of erythrocytes. If the macrophage enzymes are normal, these glycolipid wastes of neutrophils and erythrocytes are readily degraded. These macrophages are found in the bone marrow, liver, and lymphoid tissues. There are three types of Gaucher’s disease.
Type I. Adult form. This is the most common and can appear at any age. It will most often manifest in childhood or early adulthood. Liver function will deteriorate as the liver macrophages interfere with liver circulation. Diagnosis usually occurs with finding splenomegaly, anemia, thrombocytopenia, and/or leukopenia. Type II. Infantile form. This is an acute or malignant neuropathic type. It onsets in the first year of life. It is progressive with death occurring before two years of age. It affects the brain stem, bringing on rapid neurological death. Type III. Juvenile or subacute neuropathic type. This appears in childhood (from one y/o to eight y/o). It is characterized by rapid hepatosplenomegaly. Bone destruction is common with pain. Death occurs in late childhood or adolescence.
Clinical lab findings include:
39 DISCUSS NIEMANN-PICK DISEASE
Niemann-Pick disease is the second most commonly occurring lipid disorder with a defect in the enzyme sphingomyelinase. Common clinical manifestations are hepatosplenomegaly and impaired mental development. It affects girls more than boys, with death occurring before the third year of life. The defective enzyme allows the macrophage to accumulate unmetabolized sphingomyelin and cholesterol, constituents of the cell membrane. This lipid-laden, foamy-like macrophages are readily found in the bone marrow, liver, lungs, lymph nodes, spleen, and other tissues.
The lipid filled macrophage is known as a Niemann-Pick cell. It is diagnostic for this disease. Enzyme analysis of leucocytes and fibroblasts for the absence of sphingomyelinase is diagnostic. The Niemann-Pick cell measures from 20 μ to 90 μ in diameter. Wright’s stain will cause the lipids (appearing as droplets due to the lipid filled vacuoles) in the cell to take on a very pale to light blue color. The nucleus takes on a purplish-red to darker blue coloration. This cell reacts positively with Sudan black B, luxol fast blue, acid phosphatase, nonspecific esterase, and oil red O stains. The myeloperoxidase stain is negative. NOTE: No treatment is available.
There are five variations of this disorder. This information is compiled from medical textbooks. [1] Type A: Infantile or classic Niemann-Pick disease. The most common and severest form, making up to 85% of the known cases. It onsets as early as three months and is progressive with marked liver and nerve dysfunction, resulting in death within one to four years. [2] Type B: Similar to Type A, but without nervous system involvement. The disease is less severe. Life threatening risks are primarily from pulmonary infections and hypersplenism. A reasonable life span is possible with medical intervention. [3] Type C: This disorder onsets in childhood and then presents with neurological disorders (seizures, behavioral disorders, and/or mental retardation). Hepatosplenomegaly and/or hypertelorism (abnormal distance between paired organs) may occur. This is a progressive disorder and is fatal. [4] Type D: Rare. Known to occur only in a Nova Scotian population. It resembles Type C. [5] Type E. Known to not involve the nervous system and does not have a sphingomyelinase deficiency. Its biochemistry is not understood. Other clinical laboratory findings include:
40 DISCUSS TAY-SACH’S DISEASE
Also known as amaurotic infantile idiocy and GM2 gangliosidosis. It is similar to Sanhoff’s disease. This disease onsets early in childhood (about sixth month) and is progressive, with death occurring by the fourth year. This disease is devastating to the nervous system and eyes. The first symptoms are the startle reflex, where there is exaggerated responses to noise. The affected infant will demonstrate failure to thrive, macrocephaly, seizures, paralysis, weakness (hypotonia), decreased attentiveness, deafness, and blindness. One distinguishing feature is the presence of a cherry red spot on the macula of each eye. This disorder has a predilection for the Ashkenazi Jews. It is estimated that in this high risk group, about one in thirty is a carrier.
Tay-Sach’s disease is a lipid metabolism disorder of neurons characterized by a deficiency of β-hexosaminidase A. This deficiency allows for the accumulation of mucopolysaccharides, gangliosides, and other glycolipids within the tissues. The accumulation of the GM2 ganglioside has a unsafe effect upon the CNS and eye. The neurons will accumulate the ganglioside within its cytoplasm. NOTE: No treatment is available.
Clinical laboratory testing strategy is to test for enzyme deficiency in the serum or plasma, WBC’s, or fibroblasts. The only peripheral blood finding of any significance is the presence of vacuolated lymphocytes. These lymphocytes are also seen in Niemann-Pick’s disease and leukemias, hence is not diagnostic. If the bone marrow is examined, vacuolated or foamy appearing macrophages are not observed. The absence of these macrophages can be an indirect means of affirming diagnosis.
41 DISCUSS FABRY’S DISEASE
Fabry’s disease, also called glycosphingolipidosis is a sex-linked, lipid storage disease, fully manifesting in the male. The female will exhibit an attenuated form of this disease. Clinically the patient will present with skin lesions, hypohidrosis (9 perspiration), corneal opacity, pain, fever, renal failure, and disturbances of the cardiovascular, gastrointestinal, and central nervous systems. The distinctive feature is intense pain (lasting from minutes to days) in the extremities, then suddenly disappears. This expression of pain is referred to as a Fabry’s crisis.
The biochemical defect is an accumulation of a ceramide trihexoside (galactosylglactosylgluccosylceramide) due to a deficiency of α-galactosidase A. This substance accumulates in all areas of the body, especially in the smooth muscle cells of the blood vessels.
Clinical laboratory testing strategy consist of demonstrating a deficiency of the enzyme in plasma, serum, leukocytes, biopsied renal tissue or fibroblasts. Stained blood films may present vacuolated leukocytes (due to the deficient enzyme)..
Kidneys are vulnerable to lipid deposition and this leads to renal failure which causes death in mid- life (around 41 y/o). Kidney transplants are an acceptable treatment strategy.
42 BRIEFLY DISCUSS WOLMAN’S DISEASE
Wolman’s disease is a rare and fatal disease that resembles Niemann - Pick disease. Also called cholesterol ester storage disease, it is a autosomal recessive disorder. Macrophages will accumulate triglycerides and cholesterol presenting with a foamy appearance. Hepatosplenomegaly is the characteristic symptom. Lab findings are characterized by elevated serum levels of cholesterol and fatty acids. Death often occurs in early infancy. There are no specific findings in the peripheral blood.
43 DISCUSS HISTOCYTOSIS
Also known as Sea-Blue Histocyte Syndrome and Ceroid Histocytosis. This is an autosomal-recessive benign genetic disorder that generally occurs in adults under 40 y/o. The patient presents with hepatomegaly and splenomegaly. There is a tendency for bleeding (epistaxis, purpura, and gastrointestinal bleeding). The younger the affected individual, the more severe the disease. There is a medical opinion that Histocytosis is an adult form of Neimann-Pick disease.
Clinical laboratory findings include: [a] thrombocytopenia (common finding), [b] normal liver function tests in most cases, [c] WBC counts = normal or decreased, [d] other lab tests (includes the lipids) are within normal limits. Bone marrow biopsy is required for diagnosis. The diagnostic cell is a bright sky-blue Wright’s stained macrophage with an eccentric nucleus and the blue cytoplasm containing blue or blue-green lipid rich granules. The diagnostic cells will stain positive with PAS, Sudan Black B, Oil Red O, and acid-fast stains. The diameter of these cells range from 50 μ to 60 μ and can also be found in the liver and spleen.
44 BRIEFLY DISCUSS EOSINOPHILIC GRANULOMA
Eosinophilic granuloma is a type of histocytosis that affects all age groups but has a predilection for adolescents and young adults. Spontaneous remissions are common. The peripheral blood smear presents with normal eosinophils. Eosinophilia and histocytosis in the bone marrow is the rule.
45 BRIEFLY DISCUSS HAND-SCHULLER-CHRISTIAN DISEASE
This disorder is a chronic and benign form of histocytosis. The disease has a predilection for children under 5 y/o. Fifty percent of the affected children recover spontaneously with the remainder requiring chemotherapy for recovery. Clinical laboratory findings may include anemia. This disorder affects prolactin, ADH, and growth hormones.
46 BRIEFLY DISCUSS LETTERER-SIWE DISEASE
This is an acute systemic disease (histocytosis) of infants and children (up to 3 y/o) which is responsive to aggressive chemotherapy. If treatment is not implemented, death occurs in a few months. Clinical laboratory findings are a general pancytopenia.
47 DISCUSS MUCOPOLYSACCHARIDOSES (MPS)
Mucopolysaccharidoses (MPS) is a group of closely related syndromes characterized by the accumulation of unmetabolized mucopolysaccharides in the lysosomes of a variety of cells throughout the body, including leukocytes. They are lysosomal storage diseases caused by an enzyme deficiency. They are autosomal recessive inherited disorders with the exception of the Hunter’s syndrome, which is sex-linked. The unmetabolized mucopolysaccharides are [1] keratin sulfate, [2] heparan sulfate, [3] dermatan sulfate, and [4] chondroitin sulfate. There are several categories of MPS.
Hurlers Syndrome (Type I H MPS). This may be considered as typical of the mucopolysaccharidoses. Clinical symptoms appear around six months of age. The prognosis is poor with the patient dying in the first decade of life. The patient will develop coarse facial feature (sometimes called gargoylism), with clouding of the corneas and mental retardation. There will be heart damage and deafness. Hepatosplenomegaly occurs. Arms and legs are abnormal. Lordosis occurs with a distended abdomen. Clinical laboratory diagnosis is made by performing enzyme assays using leukocytes or fibroblasts. The leukocytes may demonstrate Alder-Reilly bodies. A urine spot test for MPS [using 5% cetyltrimethyl ammonium bromide, CTAB, reagent in citrate buffer] may be performed (with a about of 32% of the tests yielding a false negative result). Two mucopolysaccharides are known to accumulate in this disorder (dermatan sulfate and heparan sulfate).
Schele’s Syndrome (Type 1 S MPS). This is very similar to Hurlers syndrome with this exception, mental retardation is absent. It runs a milder course even though dermatan sulfate and heparan sulfate accumulate in the lysosomes of cells.
Hunter’s Syndrome (Type II MPS). This resembles Hurler’s syndrome without the
clouding of the cornea’s. It is a less severe disorder with most patient’s
having a normal life expectancy. Mental retardation is milder. Dermatan sulfate
and heparan sulfate accumulate in the cells lysosomes Sanfillippo’s Syndrome (Type III MPS) is characterized by four subgroups. In each subgroup, only heparan sulfate accumulates in the lysosomes. Mental retardation is the rule and death occurs in the second or third decade of life.
Morquiois Syndrome (Type IV MPS). Mental retardation is absent, but marked bone dystrophy complicates this disorder. Keratan sulfate accumulates. Death may occur as early as the third decade of life.
Maroteaux-Lamy (Type VI MPS). Mental retardation is absent. There is osseous involvement and corneal clouding. Dermatan sulfate accumulates. Death usually occurs in the second decade of life.
48 LIST AND BRIEFLY DESCRIBE EIGHT CYTOCHEMICAL STAINING STRATEGIES FOR LEUKEMIA STUDIES
Myeloperoxidase stain. This is dependent upon the peroxidase enzyme found in the primary granules of granulocytes, eosinophils, and (to a lesser degree) in monocytes. In the granulocyte cell line, this enzyme is found in the promyelocyte and subsequent stages. This enzyme should be designated as myeloperoxidase (MPO) to differentiate it from other cellular peroxidases. The neutrophil line of cells will give the strongest peroxidase reaction. The value of this stain lies in differentiating acute myeloid leukemia (FAB type M1, M2, and M3) from acute lymphocytic leukemia. As a rule, more than 80% of the myeloid blast cells will be peroxidase positive. Auer rods are also emphasized with this stain. Lymphocytic blasts are negative, that is <3% of the blast cells demonstrate some degree of peroxidase activity. Monocytes will be weakly or diffusely positive. The fact that the more mature granulocytes are peroxidase positive does not contribute to the diagnosis. It is the immature forms that are diagnostic. Look for a blue-black precipitate that is identified as coarse granulation in the cytoplasm of cells. Note: Early myeloblasts, rubriblasts, lymphoblasts, mature basophils, and plasma cells are myeloperoxidase negative.
Sudan Black B stain. Sudan Black B (SBB) stain is a lipid soluble dye. Cells that stain with SBB are designated as sudanophilic, The lipids are found in the primary, secondary, and tertiary granules of the granulocytes. Lipids are found in the lysosomal granules of monocytes and macrophages, but to a lesser extent. Myelocytic cells stain most strongly and monocytes are weakly or diffusely staining. Early myeloblasts, lymphocyte series, erythrocyte series, mature basophils, and platelets are negative for the SBB stain. Note: Burkitt’s lymphoma cells have been found to be sudanophilic. The presence of brown-black granules in the cytoplasm is positive for SBB stain. This procedure is useful to differentiate acute myelocytic leukemia form acute lymphocytic leukemia.
Periodic Acid-Schiff stain. The periodic acid-Schiff (PAS) stain or reaction is specific for glycogen. The periodic acid converts glycogen (also mucoproteins and other polysaccharides) to aldehydes. The staining pattern is dependent upon the quantity and distribution of aldehydes liberated by the periodic acid. The Schiff reagent (colorless) will react with the aldehyde to form a distinctive magenta color. This test is easy to mis-interpret since results can be variable. Consider how the cells stain:
How is this test useful? It is not very useful. It has been replaced with other testing procedures. It can be helpful in diagnosing M6 acute erythroleukemia and L3 (Burkitt type) acute lymphocytic leukemia. M6 presents erythroid precursors as PAS positive and L3 (Burkitt type) is PAS negative.
α-Naphthol AS-D Esterase stain. Also designated as specific esterase
(SE) stain, this reagent stain is specific for early myeloid cells. It
advantage lies in identify precursor cells in myelogenous leukemia. It is used
it identify M1, M2, M3, and M5 acute leukemias. The myeloblasts usually stain
positive. The dye stains the neutrophil line strongly, but the monocyte line is
weakly or diffusely stained. Auer rods are well stained by this technique.
α-Naphthol butyrate stain. Also designated as nonspecific esterase (NSE) stain, this reagent stain is less sensitive than α-naphthol AS-D stain, but it is more specific. Its value lies in identifying early monocytes and macrophages if used with a sodium fluoride inhibition step. Macrophages, plasma cells, monocyte, and megakaryocytes are NSE positive. Granulocytes tend to be NSE negative. If the sodium fluoride step is added, the macrophages and monocytes become NSE negative, but the other NSE positive cells remain positive. This stain is advantageous in identifying M4 and M5 acute leukemias. Caution is to be used in interpreting this stain. T-lymphocytes can stain positive.
Leukocyte alkaline phosphate (LAP) stain. The enzyme, leukocyte alkaline phosphatase, is found in the tertiary granules of neutrophils, bands and metamyelocytes. LAP activity is low in the metamyelocyte, but is increased in the band and even more so in the neutrophil. The advantage of this procedure is for the differentiation of chronic granulocytic leukemia from neutrophilic leukemoid reactions. This procedure depends upon visually evaluating 100 neutrophils and bands, then assigning each cell a grade of 0 to 4+ as follows:
The color of the precipitate is dependent upon the dye used. Normal values range from 13 to 100. LAP scores <13 are observed in paroxysmal nocturnal hemoglobinuria, sickle cell anemia, marked eosinophilia, sideroblastic anemia, and chronic myelogenous leukemia. LAP score >100 are observed in the third trimester of pregnancy, leukemoid reaction, polycythemia vera, corticosteroid therapy, aplastic anemia, multiple myeloma, infections with neutrophilia, myelosclerosis, and obstructive jaundice.
Terminal Deoxynucleotidyl Transferase. Terminal deoxynucleotidyl transferase (TdT) is a nuclear enzyme that is present in immature (precursor) B- and T-lymphocytes and stem cells. It is an immunocytochemical or immunofluorescent technique to distinguish acute lymphocytic leukemia from acute myelogenous leukemia. A positive test is indicated by a staining pattern of the nucleus.
Research, using monoclonial antibodies to evaluate the presence of cell
membrane surface markers, has identified multiple antigens. The following
lineage of cells is presented with their distinctive cell membrane markers. The WHO
Classification system is changing with new technology in genetic and molecular
diagnostic analysis that in order to keep current, one will have to frequently
peruse journals and other frequently published literature. This is a field of study in which chromosome defect are studied. Defects include deletions, ring formation, inversions, trisomies, and polyploidy. There are two general types of defects: [1] an abnormal number of chromosomes and [2] chromosomal structural changes. Karyotype: The chromosome characteristics of an individual cell or of a cell line, usually presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Syn: idiogram, karyogram.
Aneuploidy is the number of chromosomes which is not a multiple of the haploid number (23) of chromosomes. An example of aneuploidy is trisomy, which is the addition of an extra chromosome. Down’s syndrome is an example of trisomy in which there are three #21 chromosomes. This may be referred to as trisomy 21. Edward’s syndrome is a trisomy 18 (three #18 chromosomes).
The normal chromosome number of a person is 46 and is designated as diploidy, having the correct haploid sets of chromosomes. Polyploidy is an abnormality in which the chromosome number is a multiple of 23 (the haploid chromosome number). Triploidy is a karyotype containing 69 chromosomes (23 + 23 + 23). Tetraploidy would contain 92 chromosomes (23 + 23 + 23 + 23).
Chromosomal structural changes that are of a principle concern in this course are the breakage of one chromosomal part with its loss or its being joined to another chromosome to form an abnormal chromosomal structure (called a translocation). Translocations can be balanced when there is no loss or gain of genetic material/information. It is unbalanced if there is gain or loss of genetic material/information. Consider the Philadelphia chromosome as a typical example of an unbalanced translocation. The long arm of chromosome 22 breaks away and relocated onto the long arm of chromosome 9. This translocation is technically written as t(9q+ @ 22q-). Note that "t" implies a transfer. "q" refers to the long arm of the chromosome. The lower chromosome number is always written first. Placement of the numbers do not indicate which is receiving or losing the chromosomal part. Note the superscript signs (+ and &); "+" implies the location to the chromosome and "&" implies that there is loss for that chromosome. If you see the translocation written as t(9;22), then you know that a translocation involves chromosomes 9 and 22, but the genetic shorthand formula does not indicate which chromosome gains or loses. Note: If "p" replaces "q" then it is the short arm of the chromosome that gains or loses.
If two genes fuse together, then this known as fusion. This is seen in [1] Acute Lymphocytic Leukemia, [2] Acute Myelocytic Leukemia, [3] Acute ProMyelocytic Leukemia, [4] B-Cell Lymphoma, [5] Chronic MonoMyelocytic Leukemia, [6] Chronic Myelocytic Leukemia, and Non-Hodgkins Lymphomas. If the intact gene move near each other but do fuse, this is known as nonfusion. This is seen in [1] Acute Lymphocytic Leukemia, [2] B-Cell Lymphoma, [3] Burkitt's Lymphoma, [4] Non-Hodgkins lymphoma, and [5] ProLymphocytic Leukemia.
51 DISCUSS THE CONCEPT OF LEUKEMIA
Leukemia (a generic term) is a malignant disease of white blood cells. Leukemias can involve any of the white blood cells in all of their varying stages of maturity. All leukemias have three complications in common. [1] Leukemias always infiltrates the bone marrow. For this reason physicians will request a bone marrow biopsy to confirm the diagnosis of leukemia. [2] Peripheral blood will contain increased leukocytes and may contain an increased number of immature cells. [3] The three following complications are common: anemia, recurring infections, and bleeding.
As leukemia progresses, it infiltrates (with uncontrolled proliferation) the body organs and replaces the precursors of normal leukocytes, erythrocytes, and thrombocytes. As the liver cells are overwhelmed, coagulation factor productions is suppressed which causes the patient to have a bleeding tendency. Massive infections are often the major cause of death in leukemic patients. Leukemia can occur at any age and in any population of people. Certain forms of leukemia may have predilection for age groups, genders, or race. Leukemias that present in children are often of the acute form (up to 85%). The adult populations contend with the chronic forms of leukemia.
Consider the following four leukemias: [1] Acute lymphoblastic leukemia (ALL) is the most common form of leukemia in children and is increased in older adults. It occurs twice as often in whites as it does in blacks. About 20% of the total leukemias are of this type. [2] Acute myelogenous leukemia (AML) occurs in all age groups, but is most common in the older individual. About 40% of all leukemias are of this type. [3] Chronic myelogenous leukemia (CML) rarely occurs before adolescence, affect the older person. About 15% of all leukemias are of this type. [4] Chronic lymphocytic leukemia (CLL) Is rarely diagnosed in individuals under 40 years of age,. It incidence in adults increases as the adult ages. About 25% of all leukemias are of this type.
52 LIST SEVERAL FACTORS ASSOCIATED WITH THE ETIOLOGY OF LEUKEMIA AND BRIEFLY DISCUSS EACH ONE
The causes of leukemia are not clearly understood. There are several factors that have been identified that are associated with the risk of leukemia. The term host factor implies those conditions that predispose a person for increased risk of leukemia. [1] HEREDITY. There is no hard evidence that leukemia can be inherited. What appears to be the problem is that mutations and alterations in genetic expression are the origins of leukemia. What is known is that certain unique and recurring chromosomal abnormalities do predispose a person for a malignancy. If a family line has a recurring history of a certain disease, the risk or incidence is increased for that family. [2] CHROMOSOME ABNORMALITIES. The statistical data supports chromosome abnormalities to be linked to an increased risk for leukemia.
[3] CONGENITAL IMMUNODEFICIENCY. Hereditary linked immunodeficiencies have been statistically linked to malignant disorders.
[4] CHRONIC MARROW DYSFUNCTION. Statistical data for patients with the following disorders indicated a significant risk for the development of acute leukemia.
[5] IONIZING RADIATION. This is an environmental influence in which there is a statistical relation-ship of leukemia developing to exposure to ionizing radiation.
[6] CHEMICALS AND DRUGS. This is an environmental influence. Two chemicals known to have high carcinogenic potential are [a] benzene and [b] benzidine (extremely carcinogenic). Other chemicals include:
[7] VIRUSES. Evidence for viral causes of leukemia is not conclusive, although the link has been established. Feline leukemia has be proven to be caused by a virus designated as FeLV.
53 DESCRIBE THREE GENERAL CLASSIFICATION STRATEGIES FOR LEUKEMIA
[1] W. Ebstein (1888-1889) classified leukemia into two categories: [1] acute and [2] chronic. This system is popular and in continued use. Acute implies a disorder with a predominance of immature cells and chronic infers a predominance of mature cells. [2] The medical profession tends to categorize leukemias into two predominant cell types. The lymphoid and myeloid or non-lymphoid. In this form of classification, the acute stages tend to be very difficult to differentiate. [3] Another classification scheme is on the basis of duration. Those with the acute type have a short life expectancy, up to six months. Those diagnosed with the chronic tn 12 re have been some who have employed the term subacute to describe a life expectancy between the acute and chronic types. The subacute stage is not popular because it is difficult to define. [4] A fourth method is on the basis of the leukocyte count and morphology in the peripheral blood. This method classifies leukemia as [1] leukemic, [2] subleukemic, and [3] aleukemic.
54 LIST THREE REASONS FOR CLASSIFYING LEUKEMIAS
[1] A mechanism is provided to allow the comparison of different therapeutic [2] A system to identify and compare clinical features and laboratory findings. [3] Permits association of cytogenic abnormalities with the disease.
55 BRIEFLY DESCRIBE GENERAL LABORATORY FINDINGS AND STRATEGIES TO IDENTIFY LEUKEMIA
A laboratory work-up is reqired to identify the type of leukemia. Anemia will be a consistent finding. Thrombocytopenia will (as a rule) be present. The WBC count will range from decreased to significantly increased values. The peripheral blood smear will demonstrate "blasts" and other immature forms. When evaluating the peripheral blood morphology, it is best to use non-anticoagulant blood. A finger-stick prepared smear is an appropriate specimen. Caution is to be exercised if using EDTA anticoagulant treated blood. A smear made immediately will be suitable for a cellular evaluation. EDTA is capable of causing morphological artifacts of nucleated cells and platelets. If the blood is allowed to "stand" in the anticoagulant for >30 minutes, the following will likely be observed: [a] artifactual vacuolation of monocytes and neutrophils, [b] induced aberrant nuclear shape changes, [c] cellular swelling, and [d] platelet degranulation.
56 DISCUSS IN GENERAL TERMS, THE EFFECT OF ACUTE LEUKEMIA UPON THE BODY
Clinical features include an invasion of the bone marrow that is unchecked will result in displacement of the normal cells, which leads to organ failure and eventually death. The bone marrow will undergo a series of changes due to the sequella (conditions and effects that result from a disease) of invasion that is characterized by [a] anemia, [b] thrombocytopenia, and [c] granulocytopenia. Because of the aggressiveness of acute leukemia, the symptoms appear suddenly. The patient notices that they are weak, easily fatigued. They complain of flu-like symptoms and if they wound themselves, they notice that it takes longer for the bleeding to stop. The find that infections that at one time did not deter them, now causes problems. These patients are likely to die of infections or bleed to death before the leukemia kills them. Other disorders that causes death are hepatic, renal, pulmonary, and cardiac failures. Such failures is due the invasive nature of the leukemia and the overwhelming leukemic infiltration of the organ causes it to cease functioning and death occurs. The uncontrollable proliferation of WBC’s causes an increase in blood viscosity that results in "sludging" with causes infarction or organ rupture leading to hemorrhage.
57 LIST THE THREE TYPES OF ACUTE LYMPHOBLASTIC LEUKEMIAS AND DESCRIBE THEIR GENERAL CHARACTERISTICS ACCORDING TO THE FAB CLASSIFICATION
[1] L1 or acute lymphoblastic leukemia (with small blasts). A. There is a uniform population of small lymphocytic blasts with scanty cytoplasm. B. The nucleus tends to be regular shaped and nucleoli are not conspicuous. C. Chromatin material tends to be homogenous.
D. Cytoplasmic vacuolation may be present. [2] L2 or acute lymphoblastic leukemia (with heterogenous blasts). A. Lymphoblasts are variable in size, cytoplasmic mass, and nuclear mass. B. Nucleus may be cleft or indented. C. Nucleoli may be prominent and very large. Is not uncommon to have more than one. D. Cytoplasm is likely to be abundant in many cells.
A. Lymphoblasts are large with moderate to abundant cytoplasm. B. Cytoplasm tends to stain basophilic and is often vacuolated. C. Nucleus is round to oval, characterized by one or more prominent nucleoli.
D. Nuclear chromatin is homogenous. 58 DISCUSS ACUTE LYMPHOBLASTIC LEUKEMIA
Overview: This type of leukemia (designated as ALL) is characterized by a massive invasion of the bone marrow with small to large immature blast cells. There is a corresponding spillage into the peripheral blood containing a significant increase in immature lymphoid cells. The etiology of this malignancy is not known. This disease has a rapid course and the patient is afflicted with recurring infections, weakness, and bleeding. Lymph nodes are enlarged and splenomegaly and hepatomegaly are present.. Without medical intervention, ALL is fatal within six months. Current chemotherapy is producing a cure rate in about 60% of those treated with children having a better prognosis than adults. Females have a better survival rate than males. About 90% of all patients treated can expect a full remission.
Acute lymphoblastic leukemia can be separate into three FAB morphological groups as follows: L1. This leukemia is characterized by small, uniform lymphoblasts. The nucleus is round with an indistinct/inconspicious nucleolus. The cytoplasm is scanty and stains blue. Some basophilia may be seen. Cytoplasmic vacuoles may or may not be present. This "blast" cell will be about up to 2.5 times larger than the normal small lymphocyte. The cell is fairly homogenous, consistent in its appearance. 71% of the ALL cases will be of this type. This disorder tends to occur in individuals >15 y/o. This has the best prognosis of the three types. The age groups of 2 to 10 have the best prognosis and if the patient is under 1 y/o, then they have the poorest prognosis.
L2. This form tends to appear most often in adults. The predominate lymphoblast is from 2 to 3 times larger than the small lymphocyte. Cell size is not consistent, it has a degree of variability. It has a mod of cytoplasm surrounding a nucleus with a irregular nuclear membrane. One or more nucleoli are visible and large. The nucleus tends to be irregular with clefting or indenting. Cytoplasmic vacuolation and some basophilia may be present.
L3. This leukemia affects all age groups equally and has the worst
prognosis. The lymphoblast is large, with a nucleus containing from 3 to 5 nucleoli.
The nucleus is round to oval, not given to clefting or indenting. The cytoplasm
is abundant and very basophilic. The cytoplasm has prominent vacuolation. This
type is a B-cell malignancy arst prognosis. Vacuoles will stain
with Oil Red O which helps to identify this type ALL. The lymphocyte is
designated as a Burkitt type-lymphocyte.
The acute leukemic lymphoblast can be identified immunologically by the presence of certain lymphocyte leukemic antigens present on the membrane. There are six immunological subtypes of acute lymphoblastic leukemia based upon these antigens. [1] B ALL . . . . corresponds to L3.
[2] cALL . . . . corresponds to L1/L2.
[3] pre-B ALL . . . . corresponds to L1/L2.
[4] pre-T ALL . . . . corresponds to L1/L2.
[5] T ALL . . . . corresponds to L1/L2.
[6] uALL . . . . corresponds to L1/L2.
Prognosis indicator for ALL are as follows:
General clinical symptoms include [a] fatigue, [b] pallor, [c] pyrexia (an infection may be present), [d] weight loss, [e] anorexia, [f] bone pain in 80% of the cases, [g] petechiae and/or ecchymoses in 50% to 60% of the cases, [h] cephalalgia, [i] splenomegaly, [j] lymphadenopathy, [k] hepato-megaly, and/or [l] vomiting.
Expected clinical laboratory findings for ALL include: [1] WBC count may be aleukemic (decreased), subleukemic (normal range) and a few blasts may be present, or leukemic (increased)and blasts will be present. [2] Thrombocytopenia (<150,000/μL). [3] RBC: normocytic, normochromic anemia is the rule. Anisocytosis, poikilocytosis, and NRBC/s are not usually present. [4] If the CBC results support pancytopenia, this is the aleukemic stage. [5] If there is a hyperleukocytosis, then hyperkalemia, hypocalcemia, and hyperphosphatemia is most likely to be present. [6] Chromosome anomaly may be present:
[7] Bone marrow is hypercellular and infiltrated with lymphocytic cells.
59 DISCUSS CHRONIC LYMPHOCYTIC LEUKEMIA
OVERVIEW. Chronic lymphocytic leukemia (CLL) is a malignant disease of lymphoid cells in which there is a clonal proliferation of immunologically immature and functionally inadequate small B-type lymphocytes. The CLL lymphocyte is strikingly similar to the normal lymphocyte. As this disease progresses the lymphocytes will invade the lymphatic system, causing enlargement of the spleen and lymph nodes. There may some hepatomegaly. There follows and invasion of the bone marrow. The increase in abnormal cells gradually replaces normal tissues compromising normal functions. CLL is an indolent or sluggishly progressing disorder that takes years to effect death in the patient. Because of the slow nature of this disorder, chemotherapy treatment is not satisfactory and is not offered to the patient.
Clinically, diagnosis is confirmed by a WBC count that indicates lymphocytosis with an absolute lymphocyte count of 15,000/mm3 or more. As the disease progresses, severe anemia, thrombocytopenia, and neutropenia are characteristic. The patient complains of tiredness and absence of endurance (these are the earliest symptoms). Other symptoms include splenomegaly (in 50% of the patients), hepatomegaly, anorexia, weight loss, low grade fever, night sweats, lymphadenopathy, and is prone to infections. Discrete lymph nodes are easily palpable in about 75% of the patients. The prognosis is variable. Some patients live as few as two years and others may survive for 20 years and longer. Most patients die in about eight years from recurring infections, uncontrolled progressive leukemic infiltration of vital organs, bleeding, or extreme inanition (inability of the body to use food for whatever reason and the body starves to death).
The disease rarely occurs in individuals under 40 y/o. 90% of the patients are >50 y/o and 66% of the these are over 60 y/o. Men are affected more than women by a 2 to 1 ratio. It has been estimated that about 25% of the patients diagnosed with CLL are discovered at the physician’s office when they are there for some other reason. There are no known characteristic chromosome abnormalities described. The chromosome aberrations have been observed in CLL: [a] an extra chromosome 12 to form a trisomy, [b] deletion of the long arms on chromosome 6, and [c] translocation to the long arm of chromosome 14 from some other chromosome.
There are five stages in the development and clinical course of CLL. STAGE O. Look for an absolute lymphocytosis with a WBC count >15,000/μL. Lymph nodes will appear normal. The prognosis at this stage is from 12 to 15 years.
STAGE I. Look for absolute lymphocytosis with a WBC count >15,000/μL. Lymph nodes are enlarged. The prognosis is from 5 years to 11 years. The spleen and liver begin to enlarge during this stage.
STAGE II. There is the presence of absolute lymphocytosis with hepatomegaly and/or splenomegaly. Lymph node enlargement is continued. The prognosis is from 4 to 9 years.
STAGE III. Absolute lymphocytosis is well established. The patient is anemic with a hemoglobin <11 g/dL. Hepatosplenomegaly is continued. Prognosis is from 1 to 3.5 years.
STAGE IV. This stage is a continuation of STAGE III, but with thrombocytopenia (<100,000/μL). Prognosis does not change.
Expected laboratory findings: [1] WBC counts may go as high as 1.0 X 106/μL (higher values have been reported). [2] Absolute lymphocytosis. This may range for 10,000 to 150,000/μL. Lymphocytes are always increased and may represent >97% of the total WBC count. [3] Anemia [4] Smudge cells (fragile lymphs) are typical for CLL. The number of smudge cells per 100 WBC’s on a stained blood film may equal or exceed the number of WBC’s counted. (Note: if it is necessary to demonstrate that the smudge cells are lymphocytes, then add a few drops of 22% bovine albumin to a few drops of patient's blood and make a blood smear and stain when dry. The albumin will help prevent the lymphocyte from forming into smudge cells. [5] As CLL advances the following parameters appear
[6] A bone marrow biopsy is generally not required to diagnose this type of leukemia. Immunological markers for CLL include: weak sIg (surface Immunoglobulin), HLA-DR, CD5, CD19, CD20, CD24, CD2, CD3, CD8, T-cell CLL.
60 DISCUSS HAIRY CELL LEUKEMIA (HCL)
Also known as leukemic reticuloendotheliosis or reticulum cell leukemia. It was first described in 1923 by O. Ewald (Germany). It represents about 2% of all leukemias and occurs about 4 time more often in men than women. It onsets in the middle-aged individual (average age is about 50). Clinical findings includes [1] Splenomegaly, in up to 90% of the patients, [2] hepatomegaly, in up to 40% of the patients, [3] pancytopenia in up to 66% of the patients, and the presence of petechiae, indicating the presence of thrombocytopenia. Hairy cell leukemia (HCL)tends follow an indolent course in most patients. Patients have been reported as living 27 years. The usual prognosis is about 7 years for most patients. HCL is a chronic lymphoproliferative leukemic disorder. What is the hairy cell in this form of leukemia? It is a medium size to large lymphocyte that has the appearance of a reticuloendothelial cell that has multiple cytoplasmic projections from the cell membrane that resembles hairs. They are B-lymphocytes. They are larger than the normal, small lymphocyte with a cytoplasm that stains from clear to sky blue. Azurophilic granules may be present and if vacuoles are present, they are most likely to be small. The nucleus may be round, reniform, or oval in shape. Nuclear shapes that are folded or dumb-bell in appearance have been reported. Its chromatin resembles that of the medium size lymphocyte. Nucleoli are usually absent. If a nucleolus is present, it will be single and small. The hairy cell is rich in type 5 tartrate-resistant acid phosphatase. Note the presence of a hairy cell is not sufficient for a diagnosis
Cytochemical staining is not helpful in differentiating HCL The hairy cell cytoplasm tend to fragment and such fragments may be confused as platelets. The bone marrow biopsy is useful in diagnosing HCL. It is always involved. Bone marrow aspirates are often fibrotic, designated as a "dry tap", and are characterized by the presence of lots of reticulum (produced by the tumor cells). If a reasonable bone marrow tap is procured, then the stained smear should contain widely spaced cells that do not overlap or touch each other. Mitotic figures are not likely to be observed. The cells will be well defined with a clear cytoplasm and "bland" nucleus.
Expected clinical laboratory findings include [a] granulocytopenia, [b] possible monocytopenia, [c] abnormal platelets, [d] absence of hairy cells in other body fluids (unusual in that most leukemic cells tend to infiltrate all body fluids), [e] anemia.
Immunological markers include: HLA-DR, CD19, CD20, CD22, CD24, CD25, CD103, sIg (surface immunoglobulin).
61 DISCUSS HODGKIN’S DISEASE
Hodgkin’s disease (HD)is a unique malignancy that originates in the lymphoid tissue. The distinguishing cell that confirms diagnosis of this disorder is the Reed-Sternberg cell (a large binucleated containing large eosinophilic nuclei). The cause of HD is unknown and strikes more men than women and more whites than blacks. HD can occur at any age. It is bimodal because it has a predilection for patient in the 20 to 30 and 50 to 60 age ranges. Statistically [1] infectious mononucleosis patients seem to be more disposed to HD, [2] early exposure to infectious agents appear to confer a type of immunity against HD, [3] few childhood playmates appear to increase the risk of HD, where many playmates tend to decrease the risk, and [4] a one sibling family is at greater risk for HD that a multiple sibling family. It has been described as a malignant neoplasm, but not an immunologic disorder. The patient when diagnosed with HD will have experienced for about six months [1] low-grade fever, [2] night sweats, [3] 10% weight loss, and [4] pruritus. The disease presents itself as a peripheral adenopathy, affecting the cervical and mediastial lymph nodes. If untreated, the prognosis is fatal, with 99% of the patients dying in less than ten years.
There are four subtypes of Hodgkin’s disease. [1] Lymphocyte-predominate (subtype I) characterized by the presence of small lymphocytes. Occurs with <15% frequency. This is an indolent or sluggish disease affecting four times more men than women. Reed-Sternberg cells are rarely seen. Men under 35 are most often affected. This disease has a good prognosis, with a cure rate of 90%. [2] Mixed cellularity type characterized by [a] numerous Reed-Sternberg cells, [b] lymphocytes, and [c] a significant number of eosinophils and neutrophils. Plasma cells are also reported. Reed-Sternberg cells are numerous with both single- and multi-nucleate varieties. The predilection is for adults between the ages of 25 to 35. Frequency of occurrence is from 20% to 40%. The cure rate is about 75%. [3] Lymphocyte-depleted type without a significant number of lymphocytes, eosinophils, and neutrophils. This is a clinically aggressive disorder with an adenopathy that affects the spleen, liver, and bone marrow. This type of Hodgkin’s disease affects middle aged males. Frequency of occurrence is <15%. Patients are apt to develop a profound immunodeficiency and death is likely to result from overwhelming infections. Few to many Reed-Sternberg cells may be observed and bizarre forms of RS cells are present. Few lymphocytes are seen. The recover rate is up to 50%, having the poorest prognosis. [4] Nodular sclerosis type (subtype II) with numerous Reed-Sternberg cells and broad bands of dense collagen. The lymph node will demonstrate Reed-Sternberg cells. The lacunar cell is present. This cell is a variant of the RS cell and occupies a lacunae (an abnormal space between cells). The lacunae cell contains a centric nucleus in clear cytoplasm. The nucleus may indented or lobed. The bands of collagen that transverse the node contains packets of normal and abnormal tissue This disorder affects mostly female between the ages of 15 to 34 years of age. The frequency of occurrence is from 35% to 75%. The medical prognosis is good, with a cure rate of up to 85%.
To facilitate treatment of the disease, it is important to determine at what stage the disease has progressed to. This will also establish a reasonable prognosis. The physician has to determine how much of the body is involved. This is done by biopsies of the lymph nodes, liver, spleen, and/ or bone marrow. The following are the four stages of Hodgkin’s disease.
Comment: Patients diagnosed in stage 1 and 2 have a good prognosis with medical intervention.
As the disease progresses, the following symptoms develop: [a] pulmonary problems with pleural effusions, infections, and/or lesions; [b] superior vena cava obstruction, [c] bone pain, [d] hepatomegaly with liver dysfunction, and [e] splenomegaly.
Expected clinical laboratory findings:
[1] Normocytic/normochromic anemia that is from mild to moderate in nature.
[2] increased ESR [3] normal reticulocyte count is the rule, but may be decreased in some patients. [4] reactive lymphocytes may be encountered on the smear in the early stages.
[5] Neutrophilic leukocytosis is moderated to marked (Normal = 2000 to
B. Toxic granulation may be present. [6] Large monocytes, with vacuolation, may be present. [7] Lymphocytopenia seen in <15% of patients (<1000/μL). [8] Eosinophilia (mild form) is usually present. [9] Thrombocytosis with bizarre forms present.
[10] AHG Test: usually negative. If the patient develop autoimmune
[11] If the liver is involved, then liver function tests will be positive. [12] The Epstein-Barr virus titer is usually elevated. [13] The bone marrow biopsy tends to reveal little useful data. [14] Plasma cells may be observed in the peripheral blood smear.
62 DISCUSS PROLYMPHOCYTIC LEUKEMIA
Prolymphocytic leukemia is a lymphoproliferative disorder that has a predisposition for men over the age of 60. It onset is sudden and is characterized by fatigue, weakness, weight loss, sweating, and pyrexia. The prognosis for this disorder is more serious than for CLL. Lymphadenopathy is not a problem, but there is a marked enlargement of the liver and spleen. Clinical laboratory findings include: [1] WBC count = 2.5 X 104/μL to 1.0 X 106/μL. [2] Normocytic/normochromic anemia. [3] Thrombocytopenia. [4] Peripheral blood smear: A. immature granulocytes B. Nucleated RBC’s with rubriblasts. C. Monocytosis (Note: An absolute count may be >800/μL.) The prolymphocytes is the predominate cell and can totally replace the bone marrow by aggressive infiltration. This cell is a large mononuclear lymphocyte with a round to oval nucleus. Chromatin is coarse in appearance. The nucleus may present with one or more large nucleoli. The cytoplasm is agranular and basophilic. Immunological markers are: strong sIg (surface Immunoglobulin), HLA-DR, CD22, CD19, CD20, CD 24, CD2, CD3, CD4, CD5, CD7. CD10 and CD8 may or may not be present.
63 BRIEFLY DISCUSS SÉZARY’S SYNDROME
This is a rare cutaneous T-helper cell lymphoma of skin. The Széary cell is a neoplastic cell that is produced in the lymphatic tissue after which it migrates to the skin. This disorder has a predilection for middle age or elderly males. The first symptoms is pruritus. As the condition progresses, the lymph nodes are invaded, followed by the liver, spleen, and lungs. A leukemic phase appears in the blood. The skin undergoes changes, becoming thickened, reddish, and wrinkled. The condition is referred to as generalized erythroderma. In this erythrodermal state, 90% of these patients will demonstrate a distinctive lymphocyte in the blood in which case it is designated as Széary's syndrome. If the distinctive lymphocyte does not appear in the blood, then the condition is designated as mycosis fungoides. This cell is larger than normal with scanty cytoplasm. The nucleus is large and may appear convoluted/cerebriform or folded. The nuclear chromatin appears fine and delicate. In most cases, there will be no condensing of chromatin. Nucleoli may or may not be visible. The large cell will measure from 15 to 20 μ in diameter. In the early development of this disorder, before the cell can be observed in the peripheral blood, this condition is known as mycosis fungoides, even though no fungi can be isolated. When the abnormal lymphocyte appears in the peripheral blood, it is then known as Sézary’s syndrome. This is an indolent and progressive lymphoproliferative disease. Prognosis is poor when other organs are involved, with the survival rate measured in months. Note: Some medical sources describe mycosis fungoides as a similar but rare T-cell lymphoma malignancy of the skin and is a related disorder to Sézary’s syndrome.
64 BRIEFLY DESCRIBE BURKITT’S LYMPHOMA
Burkitt’s lymphoma is a disorder small malignant lymphoid cells. It is usually seen in children but may appear in adults. Burkitt’s lymphoma is endemic to Africa, but is found worldwide. The disease has a predilection for males. There are clinical variations of this malignancy, but all variations are characterized by diffuse proliferation of small neoplastic lymphoid cells that are interspersed with histocytes (that stains lightly compare to the darker staining lymphoid cells). This results in a microscopic view described as a "starry sky" pattern that consists of benign macrophages interspersed among the B-lymphocyte tumor cells. The Burkitt lymphoid cell presents with a round and noncleaved nucleus containing clumped chromatin, multiple nucleoli, and mitotic patterns. Nucleoli are present. There is scanty basophilic cytoplasm containing lipid filled vacuoles. The Burkitt cell is described as being monotonously uniform. Diagnosis is made using histological and cytoimmunological techniques of lymph nodes and affected tissues.. Chromosomal studies demonstrate t(8;14), t(2;8), and t(8:22) translocations.
65 DESCRIBE THE NONMALIGNANT LYMPHOCYTE DISORDER: AIDS
This
is a lethal immunodeficiency disease that is characterized by a decrease in CD4
T lymphocytes (helper-inducer cells). It is known as acquired
immune deficiency syndrome (AIDS). It was first described in 1981 and
initially given the name of gay-related
immunodeficiency disease (GRID), but later changed. The destruction
of the CD4 T lymphocytes immulogically compromises the host and they become very
susceptible to a wide variety of opportunistic pathogens. The following is
a partial listing of such pathogens:
Mycobacterium intracellulare
Cytomegalovirus (CMV) It is a three stage disease where the first stage is asymptomatic carrier stage, which give way to the AIDS-related complex (ARC) stage where mild symptoms are evident. The third stage is the symptomatic AIDS stage.
Laboratory evidence of a patient having AIDS is the presence of serological antibody tests positive for the AIDS virus (human immunodeficiency virus type (HIV-1). This includes:
[1]
Positive HIV nucleic acid (either DNA or RNA).
The clinical laboratory should watch for the following findings when testing patient with AIDS. [1] Anemia will onset early in most patients and will become progressively
worse as the disease progresses. Opportunistic infections
facilitate the [2]
Pancytopenia develops as the disease progresses. [4]
Many patients will develop immune thrombocytopenia which is
66 DISCUSS ACUTE MYELOID LEUKEMIA
Acute myeloid leukemia (AML), also known as acute myelogenous leukemia represents a heterogenous group of diseases arising from a neoplastic transformation of the multipotential hemopoietic stem cell that can express it consequences in granulocytes, monocytes, erythrocytes, or megakaryocytes. This neoplastic cell does not mature beyond the blast stage and will spill its immature forms into the peripheral circulation. There are seven variant forms of AML as designated by the French-American-British (FAB) system (see the next objective).
AML is a rapidly fatal disease is not treated. The remission rate is low, with some patients surviving more than 15 years with supportive chemotherapy intervention. It is estimated that if the patient is younger (under 60 years of age) remission for up to three years can be obtained in 70% of the patients treated. Long term remissions are low. Few patients live beyond five to six years. Treatment consists of aggressive chemotherapy and high-dose radiation.
Acute myelogenous leukemia shares several clinical features with acute lymphocytic leukemia. In both types, the initial symptoms are present within three months. A sample listing of similarities include the following: [1] pancytopenia without circulating blasts. [2] normal leukocyte count or a marked increased leukocyte count. [3] Leukostasis when the blast count exceeds 100.0 X 109/L (1.0 X 105/μL). This marked number of blasts causes hypofusion of vital organs and occlusion of their micro-circulation. Infarcts may occur. [4] Anemia [5] Dyspnea and fatigability on mild exertion or exercise. [6] Laboratory analysis of glucose, potassium, and blood gases will be altered. [7] Thrombocytopenia with bleeding and coagulation defects. [8] Infection is a frequent and a serious complication as the disease progresses. Gram-negative bacteria, gram-positive cocci, and Candida species are common pathogens for the compromised acute leukemia patient. [9] Hepatomegaly and splenomegaly varies with the type of acute leukemia. [10] Bone pain and sternal tenderness are symptoms in about ½ of the patients. [11] Hyponatremia, hypokalemia, increased LDH, and hyperuricemia result from metabolic abnormalities. [12] Cerebrospinal fluid (CSF) demonstrates presence of blast cells, increased total protein, decreased glucose, and may contain blood.
67 BRIEFLY DESCRIBE THE FRENCH-AMERICAN-BRITISH (FAB) CLASSIFICATION SYSTEM FOR ACUTE MYELOBLASTIC LEUKEMIAS (AML) AND LIST SEVERAL CHARACTERISTICS FOR EACH TYPE
This is a classification system (proposed in 1976) that assumes to categories of acute leukemia: lymphoblastic and myeloblastic. This classification is based upon the basis of the morphology of the cells from bone marrow and peripheral blood smears using Romanovsky stain along with cytochemical stains (myeloperoxidase, Sudan Black B, periodic acid Schiff, , naphthol AS-D chloroacetate (specific), α-naphthyl acetate esterase (non-specific), α-naphthyl butyrate esterase (non-specific), and leukocyte alkaline phosphatase. Cell markers for B- and T-lymphocytes, Terminal DNA nucleotidyltransferase testing, and membrane immunoglobulin testing are examples of testing strategies to classify acute leukemias.
[1] M1 or acute myeloblastic leukemia (without maturation).
A. 3% of blasts will stain positive with Sudan Black B, myeloperoxidase,
B. <20% of the blasts must stain positive with non-specific esterase stain.
C. The predominate marrow blast cells (>90% ) are poorly differentiated
D. Few (if any) Auer rods are present.
E. Primarily seen in adults and infants (<1 y/o). [2] M2 or acute myeloblastic leukemia (with maturation), one of the two most common subtypes. A. Promyelocytes will make up 10% of the "mature" cells
B. >50% of the mature cells will be myeloperoxidase, Sudan Black B
C. Auer rods are common.
D. Blast cells make up from 30% to 90% of the bone marrow cell
E. Look for eosinophilia, basophilia, and increased numbers of plasma
F. False Pelger-Huet is likely to be present.
G. A disorder primarily of adults making up about 30% of the acute myelocytic
leukemias (AML) cases.
In the WHO classification, an acute
myeloid leukemia (whose cytochemistry and morphology could place some of these
into the M2 FAB classification) is found in young adults and children and makes
up f rom 5% to 12% of all AML cases. The following distinguishes this form of
leukemia:
[3] M3 or acute promyelocytic leukemia. The following distinguishes
A. Also designated as "hypergranular promyelocytic leukemia". The
a. The promyelocyte may have a disrupted appearance. B. Auer rods are frequently seen in the cells in peripheral blood.
a. These rods are often seen in
bundles, in which case, the cell
C. Almost 100% of the cells stain positive with the cytochemistry
D. Nucleus is variable in size and shape. Bi-lobed shapes seen.
E. Leukocyte counts up to 200,000/μL reported although decreased
F. A chromosomal aberration reported in 90% of M3 cases. It involves
G. There is an increased incidence of Disseminated Intravascular
H. Makes up between 5% and 10% of AML’s and affects all age
A. The granules in the promyelocyte are so small that they cannot be
B. The nucleus is often reniform or bilobed. Its cytochemistry is similar
C. This type has been confused the M5 (acute monocytic leukemia). D. There is also an increased incidence of DIC.
E. Auer rods may be observed, sometimes in multiple forms (fagot cell). [5] M4 or acute myelomonocytic leukemia, one of the two most common subtypes. A. Both immature monocytic and granulocytic forms present.
B. 20% to 80% of the immature cells stain positive with myeloperoxidase,
C. False Pelger-Huet cells present. D. Serum or urine lysozyme levels is three times over normal.
E. Makes up to 30% of AML’s and is also known as Naegeli monocytic
F. Unlike other AML’s, this type also infiltrates the soft tissues.
G. The bone marrow must contain more than 30% blast forms with more
H. Monoblasts, promonocytes, and monocytes along with hypogranular
I. This disorder has a predilection for adults >50 y/o. Note: Refer to Objective 74 for more information. [6] M4E or Acute myelomonocytic leukemia with bone marrow eosinophilia.
A. Similar to M4 except abnormal and immature eosinophils are present
B. Chromosome 16 has an abnormal inversion
C. This subtype has a better remission rate that M4. [7] M5a or acute monocytic leukemia, poorly differentiated.
A. >80% of the bone marrow cells are monoblasts with delicate
B. The remaining cells tend to be monocytes. Note that a distinguishing
C. This cell tends to be confused with M1 type acute leukemia. D. M5a is observed most often in the young adult (median age of 16).
[8] M5b or acute monocytic leukemia, well differentiated.
B. The cytoplasm is abundant and of a translucent gray color with fine
C. This form of leukemia appears most often in the middle aged adult.
[9] M6 or acute erythroleukemia.
A. >49% of the marrow cells will be erythroid series and bizarre
B. Erythroblasts’s cytoplasm will feature budding and vacuolation. C. PAS staining positive in erythroid cells.
D. It is not uncommon to find erythroblasts on the peripheral blood
E. Howell-Jolly bodies and ringed sideroblasts are present along
F. Myeloblasts and promyelocytes will make up >30% of the marrow
G. Makes up to 5% of all AML’s and has a predilection for adults >50 y/o. H. This leukemia may progress to the M1, M2, or M4 leukemia
[10] M7 or acute megakaryocytic leukemia.
B. This is a rare leukemia (< 1% of AML cases) and presents with small,
C >30% of the blast cells in the marrow must be of the small
D. Prominent nucleoli are present.
E Stains positive with α-naphthol acetate esterase (non-specific), but if
F. The peripheral blood smear is characterized by pancytopenia.
G. The enzyme acid phosphatase can be a cell marker for the immature
J. This is a serious disease and is often refractory to treatment.
67 DISTINGUISH BETWEEN ACUTE AND CHRONIC LEUKEMIAS IN GENERAL TERMS.
Presentation Acute Chronic Age Affects all ages Predilection for adults Clinical Onset Sudden Slow and insidious Prognosis (untreated) < 6 months < 6 years Leukemic cell type immature forms predominate mature forms predominate Anemia prominent mild, less prominent Thrombocytopenia prominent mild, less prominent WBC count variable elevated Lymphadenopathy mild, less prominent present Splenomegaly mild, less prominent present Hepatomegaly mild, less prominent present
68 DISTINGUISH A LEUKEMOID REACTION FROM CHRONIC MYELOGENOUS LEUKEMIA
CONDITION LEUKEMOID RX CML Anemia not present normocytic/normochromic Toxic Vacuoles 2+ to 4+ 0 to 1+ Toxic Granules 2+ to 4+ 0 to 1+ Döhle Bodies frequent rare Eosinophilia absent 1+ to 3+ Basophilia absent 1+ to 3+ Pseudo-Pelger Huet 0 to 1+ occasional Karyorrhexis 0 to 1+ 1+ to 2+ Giant Bizarre Nuclei 0 to 1+ 1+ to 3+ LAP Score >100 <13 Ph1 Chromosome absent found in 85% to 95% of cases Splenomegaly absent present Platelet Count 2.0 to 4.0 X 105/μL 1.0 to 6.0 X 105/μL NRBC 0 to 1/100 WBC 0 to 5/100 WBC WBC count 5.0 X 104/μL up to 1.0 x 106/μL Blasts seldom up to 15%
69 DISCUSS CHRONIC MYELOGENOUS LEUKEMIA
Chronic myelogenous leukemia (CML) is a malignant disease of myeloid cell precursors, generally limited to the granulocyte cell line. Synonyms are [1] chronic myeloid leukemia and [2] chronic granulocytic leukemia. Patients, diagnosed with CML generally present with immature granulocytes (myeloblasts, promyelocytes myelocytes, and metamyelocytes), basophilia, anemia, thrombocytosis, splenomegaly, and hepatomegaly. Immature granulocytes are found in the peripheral blood and WBC counts will exceed 100,000/mm3. This disease onsets insidiously, the patient may see the physician for other reasons and in the medical evaluation discover the presence of CML. If platelet defects are present, the patient bruises easy and hemorrhagic episodes may occur. CML patients exhibit tiredness, lack endurance, and are prone to infections. This disorder is designated as a chronic myeloproliferative disorder and account for about 15% of all leukemias (There are statistical sources that state CML accounts for up to 20% of all leukemias). It affect adults between the ages of 25 to 60 y/o. The peak occurrence of CML is between 35 and 45 y/o. It is seen occasionally in adolescents and rarely in infancy.
Approximately 90% of the patients diagnosed with CML will demonstrate a Philadelphia (Ph1) chromosome. A fragment (the c-abl proto-oncogne) of chromosome 9 breaks off and is relocated to chromosome 22, attaching to the break point cluster (bcr) region. This new chromosome region then causes the production of an aberrant protein with elevated tyrosine kinase activity. This chromosome can be demonstrated in neutrophils, monocytes, RBC, thrombocyte, and basophil precursors. It has been isolated in the B-lymphocyte. The presence of the Ph1 chromosome is considered to be diagnostic of CML. On an average, about three males are affected by this disorder for every two females.. Once diagnosed with CML the patient will live for about 3 to 4 years in the chronic phase. In approximately 66% of the CML patients, the initial or stable phase will revert to an accelerated phase known as the blast stage. The blast stage tends to be refractive and is a signal that death is soon pending. It is estimated that 50-60% of CML patients will convert to the blast stage. It is interesting to note that up to 30% of the CML patients will demonstrate lymphoblastic morphology NOT myeloblastic morphology. This would infer that the pluripotential stem cell is involved and holds some degree of "uncommitment". The mechanism for this is not known.
Clinical symptoms known to manifest are: [a] malaise, [b] fatigue, [c] pyrexia, [d] sweating, [e] loss of weight, [f] bone pain, [g] hepatospelnomegaly (causes fullness in abdomen), [h] recurring headaches, [i] unusual infections, [j] ankle edema, [k] priapism (males only), [l] gouty arthritis, with elevated uric acid, [m] peripheral vascular insufficiency, and [n] hemorrhage manifestations (petechiae, hematuria, ecchymosis, and retinal hemorrhages).
Expected laboratory findings include:
[1] leukocytosis with an average range of 2.0 X 105/μL to 5.0 X 105/μL.
Counts
[2] thrombocytopenia is uncommon in CML. Counts range from 1.0 X 105/μL
[3] RBC count = 2.0 to 3.0 X 106/μL. Anemia will be normocytic/normochromic
[4] Hemoglobin in the asymptomatic stage will range from 9 to 13 g/dL. As CML
[5] The peripheral blood smear presents a distinct shift-to-the-left. The
myeloblasts = 1% (both myeloblasts and promyelocytes will not exceed
20% of the total count) myelocytes = 6% (can be up to 50% of the total count) metamyelocytes = 4% (can be up to 25% of the total count) bands = 6% neutrophils = 55% lymphocytes = 6% (are usually increased) eosinophils = 5% (can be 7% to 8% of the total count)
basophils = 9% (can be >20% of the total count if in the blast stage.
Note NRBC = may range from 4 to 12 per 100 WBC’s Pseudo-Pelger Huet anomaly may be demonstrated. [6] Other laboratory findings are: LAP score = decreased (<13) Anisocytosis may present toward the end of stage 2. Reticulocyte count = up to 3% LDH = >200 IU/L Uric acid = >8.0 mG/dL Total serum B12 = >950 pG/mL
[7] Bone marrow demonstrates intense cellularity. The myeloid:erythroid ratio
The clinical course of this disease transverses through three stages: STAGE 1: the asymptomatic and proliferative stage. [1] It may take up to eight years for CML to develop any symptoms. [2] This is the pre-leukemic stage, chronic stage.. [3] Ph1 chromosome can be identified in the bone marrow cells. [4] WBC count is normal.
STAGE 2. The symptomatic stage with hyperproliferation. [1] Occurs about 6.3 years after the appearance of the Ph1 chromosome.
[2] Immature granulocytes may be found in the peripheral blood, the [3] WBC count begins to elevate indicating that the disease is accelerating.
[4] After the onset of leukocytosis, then about 19 months will lapse before
[5] Diagnosis is often made in this stage. [6] Patients, once diagnosed in this stage, will live only 3 to 4 years.
STAGE 3. Accelerated stage with uncontrolled hyperproliferation.
[1] Once the blast stage manifests, then the chronic form becomes the acute
[2] There is a rapid and inexorable progression to death. [3] This stage is refractory to any treatment.
70 DESCRIBE EOSINOPHILIC LEUKEMIA
Eosinophilic leukemia is thought to be a variation of Chronic Myelocytic Leukemia (CML) and is generally NOT included as a topic item in some textbooks. It is usually so diagnosed by excluding other forms of chronic leukemia. The criteria for diagnosing this disorder are: A. Less than 5% blasts in the bone marrow. B. There will be a shift-to-the-left with an increase in eosinophilic myelocytes. C. The bone marrow will be fibrotic. D. There will be tissue infiltration by eosinophils. E. Persistent eosinophilia with immature forms making up to 70% of the total WBC count. F. There is accompanying anemia and thrombocytopenia.
Patients usually demonstrate a WBC count over 30,000/µL. The LAP score is usually in the normal range. The serum B12, uric acid, and muramidase tests tend to be elevated. The Philadelphia chromosome has been demonstrated in this leukemia but is not the rule. It has a predilection for middle aged males and the prognosis is very poor as it is refractory to treatment. Once it is diagnosed, the patient seldom lives beyond one year. Many patients die of congestive heart failure which may be due to the disintegrating products of the eosinophil. The eosinophilic degradation products have tissue injury properties.
71 DESCRIBE BASOPHILIC LEUKEMIA
This is the rarest of the chronic myelocytic leukemia and like chronic eosinophilic leukemia, it occurs more often in middle-aged males. This disorder can be confused with basophilia that can follow a blast-crisis or basophilia that accompanies othre myeloproliferative disorders. The Philadelphila chromosome has not been observed in this leukemia.
The disease appears suddenly and resembles CML. The patient tends to demonstrate the symptoms of diarrhea, edema in the appendages, pruritis, urticaria, and wheezing which are symptoms of patients diagnosed with hyperhistaminemia.
Laboratory findings include an increased WBC count with basophilia between 40% to 80%. Immature forms can be demonstrated. The increased numbers of basophils also means increased basophilic granules with increased histamine substance. Patients do not respond well to traditional therapy as this usually triggers an mass release of granules producing shock and/or disseminated intravascular coagulation. Also observed are abnormal neutorphils, monocytes, and eosinophils. The LAP score will be normal or sometimes low. Serum and urine histamine levels are elevated, as much as 10 to 15 times greater than normal.
72 DESCRIBE NEUTROPHILIC LEUKEMIA
Neutrophilic leukemia is describe as a rare disorder that differs from CML in that the Philadelphia chromosome is absent and there is a sustained leukocytosis without immature myeloid precursors. The peripheral blood has a high neutrophilic count and there is significant tissue infiltration by neutrophils. The LAP score is increased. Anemia is present with nucleated red blood cells present. The platelet count is usually normal but may be low in some patients. A bone marrow biopsy demonstrates hypercellularity with granulocyte hyperplasia. This disorder affects either gender over 50 years and an enlarged spleen is a typical finding. The disease does not proceed to a blast phase but may evolve into a different myeloproliferative disorder. The disease progresses slowly and is characterized by organomegaly. The survival rate varies.
73 DISCUSS MYELOMONOCYTIC LEUKEMIA
This is a M4 variant (also known as Naegeli type of myelomonocytic leukemia) of the acute myeloid leukemias and is characterized by an increase in leukemic monocytic cells in bone marrow and/or peripheral blood. Because it can comprise up to 30% of the acute myelocytic leukemias (AML) cases, it is the most commonly occurring leukemia in the AML group. The increased monocyte proliferation is characterized by an increase in the levels of muramidase (lysozyme) levels in blood and urine.
Diagnosing this type of leukemia requires that the bone marrow present with >20% monocytic cells (includes monoblasts, promonocytes, and monocytes), but less that 80%. If the monocyte line accounts for >80%, then it is a leukemia of the M5 type. The peripheral blood will contain >20% of the monocyte line. This type of leukemia is to be confirmed with the following tests according to the FAB criteria. [1] Sudan Black B stain: positive [2] Peroxidase stain: positive [3] Naphthol AS-D chloroacetate esterase stain: positive[4] α-Naphthol AS-D acetate esterase stain: positive [5] increased levels (3X normal) of muramidase levels in blood and/or urine.
Monoblasts (myelomonocytic) = 22% Promonocytes (myelomonocytic = 43% Monocytes = 2% Progranulocytes = 4% Myelocytes (neutrophilic) = 2% Myelocytes (basophilic/EO) = <2%
Metamyelocytes (neutrophilic) = <1%
A typical CBC (on discovery of this disease) may be as follows: RBC count = 2.7 X 106/μL Hgb = 8.2 g/dL Hct = 25% Platelet count = 22,000/μL WBC count = 31,000/μL WBC Differential: Monoblasts = 87% Promonocytes = 12%
Neutrophils = 1% With this type of leukemia, it is possible for a person to be feeling well and a history of good health, then suddenly demonstrate symptoms of weakness, malase, anorexia, and pyrexia (temperatures up to 101 0F). This disease can be progressive and refractory to treatment, death occurring within a few days or weeks of diagnosis.
74 MYELOFIBROSIS (IDIOPATHIC MYELOFIBROSIS)
Synonyms: Agnogenic Myeloid metaplasia, primary myelofibrosis, aleukemic myelosis, splenomegalic myelophthisis, and leukoerythroblastic anemia. Myelofibrosis is a chronic myeloproliferative disorder characterized by an unchecked proliferation of hemopoietic elements. Involvement may include one, two, or three cell lines (erythrocytes, granulocytes, and/or platelets). Usually only one or two cell lines are involved. This is a progressive bone marrow fibrosis that occurs secondary to the abnormal cell line. It can be very severe. Fibroblasts appear and give rise to reticulin (type III collagen) and other collagen fibers. Splenic enlargement occurs due to the spleen assuming an extramedullary role in hemopoiesis. Islands of proliferating erythroid, myeloid, and megakaryocyte elements appear. This is seen in 85% of the cases. Hepatomegaly occurs for the same reason and is observed in 50% of the cases.
This disorder occurs in middle aged or older adults. 60% of the cases appear in individual between 50 to 70 years of age. There is no gender preference. When the disease onset, the following symptoms appear over time and cause the patient to seek the assistance of the physician: [1] gouty arthritis, [2] increased abdominal girth due to hepatosplenomegaly, [3] bone pain, [4] petechiae (seen in 25% of patients), [5] jaundice (about a 15% occurrence), [6] ascites (about 15% occurrence), [7] weight loss, and [8] pallor. Expected laboratory findings include:
75 DISCUSS MULTIPLE MYELOMA (MM)
Synonyms: Plasma cell myeloma, Kahler’s disease, Huppert’s disease, myelomatosis multiplex, myelopathic albuminosuria, lymphadenia ossea, multiple plasmacotoma of bone, and multiple myelomatosis. This is a malignant disease involving mutated plasma cells. Multiple myeloma (MM) is designated as a plasma cell neoplasm involving the B-type lymphocytes. These lymphocytes may appear morphologically normal, but are defective. The cells will invade the body organs, replacing normal cells and fat. MM makes up about 10% of all hematologic malignancies and is characterized by a multifocal infiltration of malignant plasma cells into the bone marrow. This multifocal infiltration is characterized by numerous (multifocal) lesions of the bone with demineralization. The neoplastic cells secrete a homogeneous, complete or incomplete (partial) immunoglobulins designated as paraproteins, which can be secreted by the kidneys. There are several risk factors for this disorder. Four are listed as follows: [1] Genetic predisposition. Families which have MM diagnosed relatives have a higher risk of presenting with this disease. [2] Ionizing radiation. Medical follow up of the victims of the Hiroshima and Nagasaki atomic bombings statistically has a fivefold increase in this disease. [3] Chronic infections. Chronic infections (examples: osteomyelitis and rheumatoid arthritis) have been statistically linked to an increased risk to presenting with MM. [4] Chromosome abnormalities. Chromosome studies in some MM patients have demonstrated translocations, trisomy, and monsomy (absence of one chromosome of a chromosome pair).
In the clinical diagnosis of this disease, the following features have been presented: [1] Diffuse sheets or nodular aggregates of plasma cells in the bone marrow. [2] Presence of monoclonal serum M-component paraproteins. [3] Radiological demonstration of bone lesions in the skull, spine, ribs, and other flat bones. [4] Bone pain in the vertebrae and ribs. [5] Anemia, hypercalcemia, and renal insufficiency. [6] Amyloidosis (metabolic disorder with amyloid, a protein-polysaccharide complex, being deposited in the tissues. [7] Bence-Jones protein demonstrated in the urine. [8] Decreased levels of normal serum immunoglobulins due the suppression of normal B-lymphocytes and an increase in the catabolic rate of IgG, in other words, an immunodeficiency. [9] Clotting disorders, indicating a serious risk for bleeding/hemorrhage.
Multiple myeloma (MM) is refractory to treatment, hence it is an incurable disease. With the best of medical care, the patient may survive up to 3 years. Without medical intervention, the patient will die in six months or less. Death usually comes because of infection or kidney failure.
There are several type of multiple myeloma: [1] Smouldering myeloma. An inactive, sluggish form of the disease, that in its early stages, it appears to be of uncertain significance. It will take several years for this stage to develop into a "full-blown" case of MM. [2] Non-secretory myeloma. Multiple myeloma cells are present and are highly undifferentiated (they are primitive, embryonic, without distinct morphology). o have invasive capability and can cause bone lesions. [3] Plasma cell leukemia. See the next objective. This disorder, though included as a subtype of multiple myeloma is considered by some to be a separate disease. It is suggested that plasma cell leukemia is the fulminant conclusion of multiple myeloma. Multiple myeloma has a predilection for the middle aged and elderly. The median age is about 60 y/o. It occurs in the black population more often than the white. It is rarely observed in patients under 40 y/o. It make up about 1% of all cancers and about 10% of hematologic malignant tumors.
Clinical symptoms: [1] bone pain (major symptom in about 60% of the patients), [2] renal insufficiency (in about 25% of the patients), [3] infections (in about 10% of patients, [4] bleeding disorders, [5] constipation, [6] back pain, [7] amyloidosis (about 15% of patients).
Expected clinical laboratory findings: [1] There are two hallmark features:
A. Erythrocyte sedimentation rate = very high (100 mm/hr has been
B. Rouleaux formation on stained blood films. [2] The stained blood film of the peripheral smear usually has a bluish background due to the excess abnormal plasma proteins. [3] Hemoglobin is usually <10 g/dL. Ranges reported to be 7.0 to 12 g/dL. [4] WBC count: at the initial presentation of the disease, the count is usually normal. As the disease progresses, neutropenia may be observed. [5] Platelet count: usually normal at onset but can progress to thrombocytopenia as the disease progresses. [6] Plasma cells are occasionally seen. As a rule they will represent <10% of the total cells seen. [7] The peripheral blood smear tends to yield a leukoerythroblastic (presence of immature granulocytes and erythrocytes) picture. [8] Electrophoresis:
A. MM results in the production of massive amounts of immunoglobulins
B. The typical MM electrophoresis peak is illustrated below with a
[9] Bone marrow is marked by hypercellularity due to plasma cell proliferation. The plasma cell is a large mono- or bi-nucleated cell with prominent nucleoli. The nuclear chromatin can be fine or coarse. The nucleus can stain with differing intensity. There is abundant cytoplasm with the degree of basophilia determined by the amount of RNA present. Bizarre plasma cells may be present which confuses the evaluation. Two intracellular inclusion are noted in the MM cell:
Multiple myeloma is not a curable disease. Death usually occurs in less than two years. The following are the most important diagnostic criteria for MM: [1] More than 30% of the cells in the bone marrow are plasma cells.
[2] Presence of a monoclonal (M) spike on the electrophoresis test that
[3] Multiple bone lesions.
76 DISCUSS PLASMA CELL LEUKEMIA
Plasma cell leukemia is diagnosed when a significant number (>10% of the total cells or 2,000/μL) of plasma cells appear in peripheral blood. It is an unusual disease with leukocytosis. These neoplastic cells are found in advanced stages of multiple myeloma. Plasma cells will diffuse throughout the body, infiltrating and aggregating in the liver, spleen, bone marrow, and lymph nodes. The "blood picture" is leuko-erythroblastic (presence of both immature granulocytes and erythrocytes). This patient will present with one or more of the following: [1] lymphadenopathy, [2] proteins with m-component, [3] bone lesions, and [4] hepatosplenomegaly. As this stage progresses, the following is typical:
Plasma cell leukemia is refractive to therapy and the patient dies in a few months from a blast crisis. Plasma cell leukemia is considered to have clinicopathological differences with multiple myeloma, but may only represent a phase of multiple myeloma.
77 DESCRIBE WALDENSTRÖM’S MACROGLOBULINEMIA
Waldenström’s macroglobinemia is a immuno-lymphproliferative disorder that has features of both malignant lymphoma and multiple myeloma. This is a disease of older adults, usually men with a median age of around 60. Clinical symptoms are [1] weight loss, [2] fatigue, [3] blurred vision, [4] epistaxis and other bleeding episodes. Clinical laboratory findings include:
78 DESCRIBE A MYELODYSPOIETIC DISORDER
Also known as myelodyspoietic syndrome (MDS), it was first described in 1949. It pathology is not well understood, but it is known to be the growth of an abnormal clone of cells. It does involve the pluripotential stem cell. The problem is demonstrated in both peripheral blood and bone marrow. The findings are heterogenic in nature and affect all cell lines. There is a progressive cytopenia in the erythroid, myeloid, and/or megakaryoblastic cell lines.
Other synonyms are hematopoietic dysplasia, subacute leukemia, myelodysplasia, smoldering leukemia, atypical chronic myelocytic leukemia, sideroblastic anemia, and refractory anemia. Because this disorder can be progressive, lead to aggravation of the cytopenia, and had the potential to develop into an acute leukemia condition, it was considered to be a preleukemic condition. This group of disorder usually occurs in the fifty or older population. There are five groups of myelodysplastic syndromes.
There are two common findings in all type of MDS. First is the presence of a progressive cytopenia and second, a dyspoiesis in one or more cell lines.
79 DIFFERENTIATE BETWEEN DYSPOIESIS IN THE THREE CELL LINES IN MDS
Dyserythropoiesis Dyserythropoiesis is commonly characterized by the presence of oval macrocytes in the peripheral blood. Also found are target cells. Abnormal erythrocyte development will feature anisocytosis, basophilic stippling, cytoplasmic vacuoles, Howell-Jolly bodies, nucleated RBC’s, poikilocytosis, reticulocytopenia, sideroblasts, and/or siderocytes. Hemoglobin F is usually increased up to 6%. Other anomalies reported are the presence of Hemoglobin H, altered A, B, and/or I membrane antigens, and membrane changes that resemble that of proximal nocturnal hemoglobinuria.
In the bone marrow, erythrocyte precursors will contain abnormal nuclear shapes and/or multiple nucleoli. Giant forms can be found. Karyorrhexis, nuclear budding and/or lobes will be observed. Ringed sideroblasts are a common finding. The vitamin B12 and folic acid serum values will be normal, yet there will be megaloblastoid features in the developing erythrocytes. The bone marrow may demonstrate either hypoplasia or hyperplasia in the erythrocyte line.
Whether in the peripheral blood or bone marrow, irregular staining properities will manifest. Cytoplasmic borders of erythrocytes may be indistinct or ragged. A dimorphic RBC population of hypochromic and normochromic cells is the rule.
Dysmyelopoiesis This abnormality is considered to be more subtle that the other two forms. One distinctive feature of this disorder is a persistent basophilia. Other distinctive peripheral blood findings are abnormal granulation (either hypogranular or agranularity) of the neutrophils. Granules present may be larger than normal. The neutrophil line may be characterized by peripheral basophilia and/or hypersegmentation. Abnormal granulation is common in the leukocytes and includes agranulation.
In the bone marrow the promyelocyte may be void of primary granules or have overly large granules. This is a primary finding for this anomaly. Both myelocytes and promyelocytes tend to have a central nucleus and may be agranular or hypogranular. (Agranular promyelocytes may be mistaken for blasts.) Auer rods may sometimes be seen. The myelocyte line is characterized by nuclear/cytoplasmic asynchrony. Nuclear anomalies include false Pelger-Huët cells and twinning defomity. Twinning is represented by an abnormal large tetraploid cell. Low CD4 helper T-type lymphocyte counts may be observed in the bone marrow.
Dysmegakaryopoiesis The megakaryocyte population in the bone marrow may display abnormal morphology as large mononuclear megakaryocytes, micromegakaryoblasts, and/or micromegakaryocytes. Look for nuclei in these cells to be either bilobed or have numerous small separated nuclei. In the peripheral blood, look for large and/or bizarre platelets. Other atypical platelets may have balloon-like buldging of the membranes. Numbers may be decreased, increased, or normal.
80 DESCRIBE ANY KNOWN CHROMOSOMAL PATHOLOGY ASSOCIATED WITH MDS
Known karyotype abnormalities with MDS involve mainly chromosomes 5, 7, and 8. Chromosomal anomalies may be monosomy, trisomy, or involve partial or total chromosomal alterations. There is usually no translocations occurring, but a loss of chromosomal material. The most frequent aberration is a monosomy 5 or loss from it short arm. Chromosome 7 abnormalities are monosomy, loss of the long arm, or rearrangement. Chromosome 8 problems are monosomy or rearrangement. Karyotyping has shown that other chromosomes (1, 3, 4, 9, 12, 17, 20, and X) have been implicated. In children, the most frequent anomalies are 8 trisomy, 7 monosomy, and deletions in 20 and X.
81 DISCUSS THE ROLE OF BLASTS IN CLASSIFYING THE MYELODYSPLASTIC SYNDROME
The blast count and identification is an important prognostic indicator for this disorder. The diagnosis of MDS is limited to less than 30 % blasts. If the percentage is higher, then the diagnosis will be that of an acute leukemia. The dysgranulopoiesis of the blast cells affects principally the primary azurophilic granules. A normal blast is classified as having a central nucleus composed of fine chromatin material, high nuclear to cytoplasm ratio, very basophilic cytoplasm, and an agranular cytoplasm. There are three types of blasts to be recognized in MDS.
First is Type I which includes the classic myeloblast and the unclassified immature cells. Prominent nucleoli (1 to 5 in number) are scattered among the nuclear chromatin in a round to oval nucleus. The nuclear to cytoplasm ratio tends to be variable, usually averaging a ration of 4:1. Granules are absent in the cytoplasm. The Type II blast also has a centrally located nucleus and somewhat resembles the Type I blast. Its cytoplasm will contain less than 20 azurophilic primary granules. The usual number of granules is from 1 to 6. The nuclear to cytoplasmic ratio is shifted so there is slightly more cytoplasm than nucleus. The Type III blast resembles the Type II blast but will have more than 20 azurophilic primary granules in the cytoplasm.
The promyelocyte is characterized by an eccentric nucleus containing more condensed chromatin material. A clear area (hof) is located adjacent to the nucleus and represents the Golgi body. Increased cytoplasm gives a smaller nuclear to cytoplasm ratio. The cytoplasm is characterized by many azurophilic primary granules. The promyelocyte is not included in the blast count when diagnosing MDS.
82 DISCUSS REFRACTORY ANEMIA
This is the mildest of all the myelodysplastic syndromes. The primary clinical finding is anemia with reticulocytopenia. This anemia is nonresponsive to medical therapy. Clinical findings in the bone marrow include less than 5% blasts (erythroid), erythroid hyperplasia with dyserythropoiesis, megablastoid appearing erythrocyte precursors, and less than 15% sideroblasts (included in the erythroid count)
In the peripheral blood, clinical findings include less than 1% blasts, ovalomacrocytes, less than 15% siderocytes, NRBC’s, and reticulocytopenia. Hemoglobin levels tend to be decreased. A dimorphic blood picture may sometimes be noted. Prognosis is generally good for these patients. The peripheral blood count must contain less than 1% Type I, II, and III blasts.
83 DESCRIBE REFRACTORY ANEMIA WITH RINGED SIDEROBLASTS (RARS)
Also called idiopathic acquired sideroblastic anemia (IASA), this clinical syndrome has the same symptoms as refractory anemia. It differs in the bone marrow by the presence of more than 15% ringed sideroblasts. These blast cells tend to form clusters. The bone marrow is hypercellular with megaloblastoid dyserythropoiesis. Less than 5% Type I, II, and III blasts (myeloid) are found in the bone marrow.
The peripheral blood presents with reticulocytopenia, leukopenia, and a dimorphic population of hypochromic and normochromic erythrocytes. Sideroblasts and siderocytes may be found in the peripheral blood smear. Less than 1% Type I, II, and III blasts are found in peripheral blood. As this disease progresses there is an increase in ringed sideroblasts, medullary iron, and serum ferritin. A few patients have been known to progress to hemochromatosis. About 40% of these patients will be blood transfusion dependent.
84 DISCUSS REFRACTORY ANEMIA WITH EXCESS BLASTS (RAEB)
This type of MDS is the most frequent of this class of disorders and resembles acute nonlymphocytic leukemia. Dysgranulocytopoiesis is more pronounced. The peripheral blood picture is characterized by qualitative abnormalities in the erythroid, myeloid, and megakaryocyte cell lines. Poorly granulated neutrophils, false Pelger-Huët cells, macrocytic anemia with hypochromic and normochromic cells, platelets with an abnormal number of granules along with size anomalies, oval macrocytes, ring-shaped nuclei in the neutrophils, reticulocytopenia, decreased platelet count, and micromegakaryocytes may be seen in the peripheral blood smear. There must be less than 5% of Type I, II, and III blasts in the peripheral blood. Promyelocytes may also be seen.
The bone marrow tends to be hypercellular and must demonstrate a number of ringed sideroblasts that make up more than 15% of the nucleated RBC’s. Type I, II, and III blasts make up from 5% to 20% of the bone marrow population. Abnormal promyelocytes may be seen. Those diagnosed with 5% to 10% blasts have a better prognosis than if 11% to 20% are present. Dyspoiesis in three cell lines are present.
There is a MDS variation of RAEB designated as "refractory anemia with excess blasts in transformation (RAEB-T). This variation has the same peripheral findings as RAEB, but differs in the bone marrow in the following ways. There are more than 5% circulating blasts in the peripheral blood and from 20% to 30% blasts in the bone marrow. Auer rods may be seen in the blasts. There is an absolute monocytosis. This form of MDS may be difficult to differentiate from acute myelocytic leukemia. A patient diagnosed with RAEB-T almost always progresses to acute leukemia and this disorder has the poorest prognosis.
85 DISCUSS CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AS A MDS DISORDER
This disorder can present with any of the dyspoietic features of the other MDS disorders and it is definitely a leukemic condition. Synonyms for CMML are subacute myelomonocytic leukemia and chronic erythromonocytic leukemia. This condition may manifest with leukocytosis but an absolute monocytosis is always present. The peripheral WBC count may be 100,000/μL or greater. The monocytosis will be at least 1,000/μL. Usually less than 5% blast cells are seen in the peripheral blood smear. RBC’s, platelets, and reticulocytes are decreased. Oval macrocytes are present in a normocytic and macrocytic anemia. Platelets can be giant forms and hypogranular. An important chemistry finding in serum and urine is an elevated lysozyme. Serum uric acid is usually elevated. More than 50% of the patients may present with a polyclonal hypergammaglobinemia.
The bone marrow demonstrates a granulocytic hyperplasia and the mature neutrophils tend to be agranular or hypogranular. Abnormal myelocytes tend to proliferate. At least 20% of the bone marrow cells will be monocytic with an increase in the number of promonocytes. The total blast cell count will make up between 5% and 20% of the nucleated cells. Erythroblasts are abnormal with multiple nuclei and megaloblastoid features. It is recommended that in diagnosing this type of disorder that both specific and nonspecific esterase stains be used. The Philadelphia chromosome will be absent.
Note: This form of disorder will most likely transform into a M4 or M5 acute leukemia.
86 DESCRIBE THE PROGNOSIS FOR PATIENTS DIAGNOSED WITH MDS
Prognosis is poor with life expectancy varying from 1 to 6 years. The average survival time is between 18 and 20 months. Acute leukemia is the usual sequela for MDS. Patients with RA survive about 32 months and about one-fourth die of infection. RARS patients can survive up to 76 months. The prognosis is somewhat poorer for RAEB. These patients have a mean survival time of about 11 months. Thirty percent of these patients will convert to acute leukemia.
The CMML diagnosis sees patients who will survive about 22 months. The worst prognosis is with a diagnosis of RAEB-T with a survival time of about 5 months.
87 DISCUSS THE VARIANT FORMS OF MYELODYSPLASTIC DISORDERS
There is a significant difference in the peripheral and bone marrow findings to prevent classification under the standard five FAB classifications of MDS disorders that they are designated as variants of MDS.
Hypoplastic MDS is characterized by a hypocellular bone marrow of less than 30% or 20% of normal if the patient is over 60 y/o. This disorder resembles aplastic anemia and hypoplastic acute myeloid leukemia which requires careful diagnosis to assure the correct therapy regime. MDS that presents with fibrosis in the bone marrow must be distinguished from myelofibrosis, chronic myeloid leukemia, and acute megakaryocytic leukemia. Mild to moderate fibrosis is observed in 50% of MDS patient and in a few cases the fibrosis is severe. The correct diagnosis is required for successful therapy.
About 10% of the MDS cases cannot be classified according to the FAB criteria for diagnosis. This is considered to be due to the overlapping symptoms and features of the types of MDS. There is difficulty is classifying this type of MDS because the blast percentages and dysplasia of cell lines do not conform to FAB criteria. This 10% grouping of MDS is designated as unclassified MDS.
88 DESCRIBE THE FORMS OF THERAPY FOR PATIENTS DIAGNOSED WITH MDS
There are no specific and accepted forms of therapy. There are a variety of treatments that include the following:
When supportive therapy is employed it consists of transfusions and antibiotics. RBC transfusions treat anemia, platelet transfusions are used in bleeding episodes, and granulocyte transfusions are required when neutropenia occurs. Antibiotics help counter the problem of infections in neutropenic patients.
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This web site is maintained by Whitney Williams, wwilliam@astate.edu This page last updated 07/28/08 |
