Hematology 425 Qualitative Alterations of Leukocytes

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Hematology 425 Qualitative Alterations of
Leukocytes

• Russ Morrison
• November 27, 2006

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Leukocyte Alterations - Qualitative

• Changes in WBCs may be inherited or acquired
• Benign changes do not correlate with dysplasia or
  malignancy
• Inherited changes may be asymptomatic or life
  threatening
• Acquired changes are seen in response to
  circumstances and are interpreted as indicators
  of disease states

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Leukocyte Alterations - Qualitative

• Leukocyte alterations can be distinguished by
  many methods
• Mode of transmission (inherited or acquired)
• Frequency (common or rare)
• Location (nuclear or cytoplasmic)
• Microscopic manifestation (morphologic or
  nonmorphologic)

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Nuclear/Morphologic Alterations of Granulocytes

• Pelger-Huet Anomaly
• Common (1/6000) inherited nuclear aberration
• Hyposegmentation of the nucleus
• Clinically insignificant, no loss of cellular
  function
• Inherited as an autosomal dominant

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Nuclear/Morphologic Alterations of Granulocytes

• Identified by
• 1. Nuclei that are round, oval or bilobed with
  pinched appearance
• Clumping of chromatin
• Uniformity of appearance of most cells
• Cells sometimes confused with bands or metas
• Must be differentiated from pseudo-Pelger-Huet
  cells

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Nuclear/Morphologic Alterations of Granulocytes

• Pseudo-Pelger-Huet cells are found in high stress
  situations (burns, drug reactions, infections,
  myelodysplastic syndromes, CGL and acute
  leukemias
• If these cells are seen, report as mature cells
  resembling those of Pelger-Huet anomaly
• Genetic studies will verify the status

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Pelger-Huet Anomaly
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Hereditary Hypersegmentation of Granulocytes

• Hereditary hypersegmentation of granulocyte
  nuclei is clinically insignificant
• Autosomal diminant inheritance
• Must be distinguished from hypersegmentation seen
  in megaloblastic anemias (B12, folate deficiency)
  and from acquired hypersegmentation (twinning
  deformity)

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Hereditary Hypersegmentation of Granulocytes

• Twinning is a term that describes a nucleus that
  has axial symmetry
• Twinning is an acquired anomaly and is clinically
  significant in stress situations, malignancies
  and oncologic treatments
• Figure 26-4 shows hypersegmentation with
  increases in extrusions of nuclear material
• Extrusions are found in persons with trisomy some
  chromosomes, including X

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Hypersegmented Neutrophil
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Cytoplasmic Alterations of Granulocytes,
Alder-Reilly Anomaly

• Alder-Reilly anomaly results from a recessive
  disorder that causes deposition of
  mucopolysaccharides (lipids) in the cytoplasm of
  most cells
• The lipid deposits stain purple and are called
  Alder-Reilly bodies
• Commonly seen in patients with Hurlers and
  Hunters syndromes

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Cytoplasmic Alterations of Granulocytes,
Chediak-Higashi Syndrome

• Chediak-Higashi syndrome demonstrates large
  peroxidase-positive lysosomes in most cells of
  the body
• It is a rare autosomal recessive syndrome
• Large, fused granules also occurs in melanosomes
  of the sking and may lead to albinism
• C-H syndrome results in an increased rate of
  precursor cell death, causing neutropenia and
  thrombocytopenia

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Cytoplasmic Alterations of Granulocytes,
Chediak-Higashi Syndrome

• C-H syndrome results in increased susceptibility
  to infections and bleeding problems
• It progresses through peripheral neuropathy,
  pancytopenia, systemic infections,
  hepatosplemomegaly and lymphadenopathy to death

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C-H Syndrome, cytoplasmic inclusions
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Cytoplasmic Alterations of Granulocytes,
May-Hegglin Anomaly

• May-Hegglin anomaly is characterized by the
  presence of large Dohle body-like formations in
  all cells
• It is a rare autosomal dominant condition
• Patients are at risk for infections and bleeding
• Bleeding is due to thrombocytopenia and abnormal
  platelet function with short life span
• Most patients with M-H anomaly are asymptomatic,
  but bleeding episodes have been reported

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May-Hegglin Anomaly
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Cytoplasmic Alterations - Acquired

• In addition to the genetic alterations already
  discussed, a number of acquired cytoplasmic
  changes have been described
• Toxic granulation demonstrates dominant primary
  granules as a result of stress
• The stress response is usually the result of
  infection or inflammation
• Cellular stimulation of young neutrophils causes
  membrane alteration which causes granules to
  appear larger and darker than normal in common
  staining methods

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Toxic Granulation

• Toxic granulation is felt to be clinically
  significant as it appears to reflect a poorer
  prognosis when identified
• It is not significant in patients being treated
  with granulocyte monocyte colony-stimulating
  factor (GM-CSF)
• May look like an artifact produced with poor
  staining, but TG will be uniform throughout all
  WBCs, while real TG is unevely spread throughout
  the cytoplasm of certain cells

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Toxic Granulation
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Dohle Bodies

• Dohle bodies develop in the cytoplasm of
  granulocytes of patients with infections
• Dohle bodies are composed of parallel rows of
  ribosomal RNA
• When stained, they are gray to light blue
• Mechanism of development is unknown, but
  associated with burns, infections, surgery,
  pregnancy and use of GM-CSF

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Dohle Bodies
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Vacuolization

• Phagocytic vacuoles are found in neutrophils as a
  result of various situations
• Autophagocytosis (phagocytosis of self) is seen
  with prolonged drug exposure (antibiotics) and
  toxins (alcohol and radiation)
• Ingestion of bacteria or fungi
• Jordan anomaly is a familial disorder with
  vacuoles filled with lipids, in the cytoplasm of
  granulocytes, lymphocytes and monocytes

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Necrobiosis

• Large numbers of dead granulocytes in the PBS
  indicate severe strain in granulocyte development
  pools
• Figure 26-8 shows a necrobiotic cell, typical of
  dead or dying white blood cells
• Box 26-2 summarizes the acquired granulocyte
  anomalies

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Cytoplasmic Alterations of Granulocytes -
nonmorphologic

• Chronic granulomatous disease (CGD) of childhood
  is a group of genetic disorders where the
  intracellular kill mechanism of the granulocyte
  is defective
• The two most common forms of CGD are sex linked
  and autosomal recessive
• Victims have chronic pyogenic infections of all
  systems
• Secondary anemia of chronic disease is often
  present

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Miscellaneous Deficiencies

• Other manifestations of neutrophilic dysfunction
• Congenital C3 deficiency
• Disorders of neutrophilic movement
• Myeloperoxidase deficiency
• WHO cluster of poor leukocyte adherence syndromes

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Cytoplasmic changes of Monocyte/Macrophage

• Cells of the monocyte/macrophage system are quite
  rich in lysosomes that contain hydrolytic enzymes
• These enzymes normally break down products of
  cellular metabolism
• Monocytes/macrophages store materials that are
  not degraded satisfactorily
• The breakdown of cellular structures requires a
  series of functioning enzymes

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Cytoplasmic changes of Monocyte/Macrophage

• Hereditary absence or dysfunction of these
  enzymes causes an increase in substrate
  concentration and a decrease or absence of the
  product
• These conditions are commonly known as storage
  cell diseases
• Table 26-1 summarizes some of the more common
  storage cell diseases

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Cytoplasmic changes of Monocyte/Macrophage

• The most common lipid storage disorder is Gaucher
  disease, in which there is an inability to
  degrade glucocerbroside due to a deficiency of
  glucocerebrosidase
• Glucocerbroside accumulates in the
  monocyte/macrophage system of the BM, spleen and
  liver
• Neurons of the CNS may also be affected
• Gaucher disease is an autosomal recessive trait
  with more than 65 mutations known to cause the
  disease

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Cytoplasmic changes of Monocyte/Macrophage

• Gaucher disease occurs in three types
• Chronic adult type (type 1)
• Acute infantile neuronopathic type (type 2)
• Less defined subacute neuronopathic type (type 3)
• Characteristics of the three types of Gaucher
  disease are listed in Table 26-2

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Cytoplasmic changes of Monocyte/Macrophage

• A characteristic Gaucher cell is large with an
  eccentric nucleus and a cytoplasm that has been
  described as chicken scratch
• Many patients with Gaucher disease have a normal
  life span, but the clinical span is large from
  asymptomatic to severely incapacitated

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Gaucher Cell
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Niemann-Pick disease

• N-P disease is another type of storage cell
  disease caused by a deficiency of
  sphingomyelinase
• This deficiency allows sphingomyelin to
  accumulate in the spleen, liver, lungs, BM and
  sometimes the brain
• Cholesterol and other lipids accumulate as well
  along with a decrease in ceramides
• Inheritance is autosomal recessive. Genetic locus
  is C18

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Niemann-Pick disease

• N-P disease is described in 4 types with a broad
  range of symptoms
• Many of the patients eventually exhibit symptoms
  related to brain damage
• Presentation with difficulty of motor functions
  (swallowing, walking talking) is typical
• Progressive dementia and psychosis leading to a
  nonambulatory vegetative state may result

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Niemann-Pick disease

• The typical N-P Cell is large with an accentric
  nucleus and foamy cytoplasm
• The cytoplasm is filled with uniformly sized
  droplets of accumulated lipid
• The N-P cell is not unique to N-P disease, but
  may be seen in other lipid storage diseases
• There is no successful treatment

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Neimann-Pick Cell
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Other Storage Cell Diseases

• Other inherited storage cell diseases do not have
  significant hematologic implications
• These include gangliosidosis, Tay-Sachs disease
  and Fabry disease
• Acquired hyperlipidemias occur when a condition
  produces too much lipids for monocyte/macrophage
  cells to process
• May be primary disease (hypercholesterol-emia),
  or secondary (diabetes or chronic leukemia)

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Morphologic Alterations of Lymphocytes

• Morphologic variations in lymphocytes are not as
  frequent or as potentially debilitating as those
  seen I neutrophils
• Lymphocyte changes are most often directly
  related to antigenic stimulation and are
  considered normal
• Lymphocytes demonstrating these normal changes as
  a result of stimulation are termed reactive,
  stimulated or committed

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Reactive Lymphocytes

• Stimulated B cells undergo morphologic changes to
  both the nucleus and cytoplasm
• Once proliferation begins, the cells mature into
  plasma cells that synthesize and secrete large
  quantities of immunoglobulin whose binding
  specificity is the same as the one from the
  initially stimulated cell
• These changes progress and regress over time
• T cells also undergo reactive changes as a
  result of clonal expansion

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Reactive Lymphocytes

• Characteristics of reactive lymphocytes
• Vacuolated cytoplasm
• Radial basophilia
• Cytoplasm indented by adjacent cells
• Peripheral basophilia
• Large azurophilic granules
• Nucleoli may be present
• Chomatin appears finer and dispersed
• Cytoplasm may be deeply basophilic

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Reactive Lymphocytes

• Infectious mononucleosis is an example of a viral
  illness that exhibits reactive lymphocytes
• Infectious mononucleosis is caused by two strains
  of the Epstein Barr virus EBV-1 (type A) and
  EBV-2 (type B)
• Childhood forms seem to be less severe that that
  seen in teenagers
• IM is also known as kissing disease as the
  virus is found in body fluids, especially saliva,
  and can directly transmitted through sharing of
  body fluids

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Reactive Lymphocytes
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Lymphocyte Nuclear Abnormalities

• Nuclear abnormalities associated with lymphocytes
  will be discussed in chapter 36 and include
  clefting (Butt Cells) and Sezary Cells seen with
  Sezary syndrome.

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Lymphocyte Cytoplasmic Abnormalities

• Vacuolization of the cytoplasm is seen in
  mucopolysaccharidoses, Gaucher disease and
  others.
• Azurophilic granulation can be seen in response
  to antigenic stimulation and in Hunters syndrome
• Increased amounts of non-staining materials may
  also be seen
• Box 26-3 summarizes morphologic alterations in
  lymphocytes

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Nonmorphologic Alterations of Lymphocytes

• Most of the nonmorphologic changes of lymphocytes
  are seen in diseases of immunologic function
• The alteration results from a lack of the
  specific cell type or from failure of a cell to
  act in a mature manner
• B cell alterations include hypogammaglobulin-emias
  , agammaglobulinemias and dysgamma-globulinemias
  (qualitative and quantitative)
• T cell alterations can be described by cell
  marker phenotypes

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Quantitative Alterations of Leukocytes

• Alterations of leukocyte numbers must be
  determined using the absolute leukocyte count
• Absolute counts may be provided by auto-mated
  equipment or may be calculated by multiplying the
  total WBC count by the percentage of the
  population on the differential
• 10.0 x 109/L (WBC) x 0.4 ( neutrophils) 4.0 x
  109/L neutrophils

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Quantitative Alterations of Leukocytes

• WBC count is dependent on several factors
• Age of the patient
• Ethnicity
• Granulocyte kinetics are influenced by
• Input from bone marrow pools
• Changes in proportion of marginating to
  circulating pools
• Changes caused by disease

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Quantitative Alterations of Leukocytes

• Spuriously elevated granulocyte counts may be
  seen when the marginating pool is decreased,
  increasing the circulating pool
• Decreased counts can occur when a large number of
  granulocytes are in the storage pool
• Causes of both leukocytosis and leukopenia are
  many and the causes for both may be the same

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Alterations in Granulocyte Number

• Neutrophilia
• Acute infections
• Hemorrhage/hemolysis
• Inflammatory changes
• Intoxications/poisons
• Medications
• Myeloproliferative disorders
• Malignancy
• Physiologic response to stress

• Neutropenia
• Acute infections
• Hemodialysis
• Overwhelming inflammation/infection
• Medications
• Physical agents (x-rays)
• Secondary to autoimmune disorders
• Aplastic/hypoplastic states

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Alterations in Eosinophil Number

• Eosinophilia is definced as gt0.5 x 109
  eosinophils per Liter
• Conditions associated with eosinophilia
• Allergic responses
• Medication usage
• Skin diseases, dermatitis
• Parasitic infestations
• Some autoimmune disorders
• Some malignancies
• Eos may be reduced in response to
  adrenocorticotropic hormone (ACTH) and emotional
  stress

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Alterations in Basophil Number

• Basophilia (gt0.15 x 109/L) is seen in patients
  with hypoactive thyroid conditions, ulcerative
  colitis and some types of nephrosis as well as
  certain malignancies (CML)
• Increases in tissue basophils are seen in
  patients with contact dermatitis and delayed
  hypersensitivity reactions
• Basophil counts may be low in patients with
  hyperthyroidism and stress

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Alterations in Monocyte/Macrophage Number

• Monocytosis (gt 0.8 x 109/L) is seen whenever
  there is an increased amount of cell damage
• Conditions causing monocytosis include active TB,
  subacute bacterial endocarditis, syphilis,
  parasitic and rickettsial infections, some
  autoimmune diseases and truama
• Monocytes are also increased during recovery from
  acute infections

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Alterations in Lymphocyte Number

• Normal lymphocyte range in adults is 34 of WBCs
  or 0.6 to 5.5 x 109/L
• The value is higher in children at 70 or 2.0-7.0
  x 109/L
• Lymphocytosis is present in an adult when the
  absolute lymphocyte count is higher than 5.5 x
  109/L

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Alterations in Lymphocyte Number

• Relative lymphocytosis can be seen in patients
  with skin rashes from viral diseases such as
  measles and mumps
• It is also seen in patients with thyrotoxicosis
  and those convalescing from acute infections
• Lymphocytosis is rare in children with the
  exception of pertussis infection

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Alterations in Lymphocyte Number

• Causes of Reactive Lymphocytosis
• Beta-streptococcus
• CMV
• Drugs
• EBV (IM)
• Syphilis
• Toxoplasmosis
• Vaccination
• Viral hepatitis

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Alterations in Lymphocyte Number

• Relative lymphopenia may be seen in patients with
  heart failure, uremia, SLE and malaria, among
  other causes
• Absolute lymphopenia (lt0.6 x 109/L) may be seen
  in infectious hepatitis, secondary to
  malignancies, some Hodgkin lymphomas, active TB,
  SLE or endocrine disorders, also as a result of
  drug exposure
• It may also be seen in the elderly with bone
  marrow depletion