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NONMALIGNANT LEUKOCYTE DISORDERS. NONMALIGNANT LEUKOCYTE DISORDERS. Changes in leukocyte concentration and morphology often reflect disease processes and toxic challenge. The type of cell affected depends upon its primary function:

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nonmalignant leukocyte disorders1
NONMALIGNANT LEUKOCYTE DISORDERS
  • Changes in leukocyte concentration and morphology often reflect disease processes and toxic challenge.
  • The type of cell affected depends upon its primary function:
    • In bacterial infections, neutrophils are most commonly affected
    • In viral infections, lymphocytes are most commonly affected
    • In parasitic infections, eosinophils are most commonly affected.
nonmalignant leukocyte disorders2
NONMALIGNANT LEUKOCYTE DISORDERS
  • Neutrophil disorders
    • The peripheral neutrophil concentration depends upon
      • Bone marrow production and release
      • The rate of neutrophil movement into the tissues
      • The proportion of circulating to marginating neutrophils
      • Most benign quantitative abnormalities occur in response to physiologic or pathologic processes
    • Neutrophilia – an increase in neutrophils
      • Immediate – may occur without tissue damage or other pathologic stimulus.
        • Results from a simple redistribution of cells from the marginal pool to the circulating pool
nonmalignant leukocyte disorders3
NONMALIGNANT LEUKOCYTE DISORDERS
    • May occur after violent exercise, epinephrine administration, anesthesia, or anxiety
    • Is also called shift neutrophilia
  • Acute neutrophilia – this occurs 4-5 hours after a pathologic stimulus
    • Results from an increased flow of cells from the bone marrow to the peripheral blood
    • Bands and metamyelocytes may be seen
  • Chronic neutrophilia – this follows acute neutrophilia
    • The bone marrow starts to throw out younger and younger cells (a shift to the left)
nonmalignant leukocyte disorders4
NONMALIGNANT LEUKOCYTE DISORDERS
  • Conditions that are associated with neutrophilia are:
    • Bacterial infections (most common cause)
      • This usually causes an absolute neutrophilia (10-19 x109/L)
      • In severe infections, the bone marrow stores may be depleted and this can result in neutropenia (typically seen in typhoid fever and brucellosis)
    • Tissue destruction or drug intoxication (tissue infarctions, burns, neoplasms, uremia, gout)
nonmalignant leukocyte disorders5
NONMALIGNANT LEUKOCYTE DISORDERS
  • Leukemoid reaction – this is an extreme neutrophilia with a WBC count > 30 x 109/L
    • Many bands, metamyelocytes, and myelocytes are seen
    • Occasional promyelocytes and myeloblasts may be seen.
    • This condition resembles a chronic myelocytic leukemia (CML), but can be differentiated from CML based on the fact that in leukemoid reactions:
    • There is no Philadelphia chromosome
    • The condition is transient
    • There is an increased leukocyte alkaline phosphatase score (more on this later)
    • Leukemoid reactions may be seen in tuberculosis, chronic infections, malignant tumors, etc.
nonmalignant leukocyte disorders6
NONMALIGNANT LEUKOCYTE DISORDERS
  • Leukoerythroblastic reaction – in this condition nucleated RBCs and neutrophilic precursors are both found in the peripheral blood
    • The WBC count may be increased, normal, or decreased
    • This is associated with myelopthesis (proliferation of abnormal elements in the bone marrow)
  • Reactive states
    • With hemorrhage or hemolysis of RBCs, there is increased production of RBCs in the bone marrow and sometimes the granulocyte production also increases.
  • Corticosteroid therapy
nonmalignant leukocyte disorders7
NONMALIGNANT LEUKOCYTE DISORDERS
  • Neutropenia – this may result from
    • Decreased bone marrow production
      • The bone marrow will show myeloid hypoplasia with a decreased M:E ratio
      • The bone marrow storage pool, and peripheral and marginating pools are all decreased
      • Immature cells may be thrown into the peripheral blood and those younger than bands are ineffective at phagocytosis. This can lead to overwhelming infections.
      • This may be due to stem cell failure, radiotherapy, chemotherapy, or myelopthesis.
    • Ineffective bone marrow production
      • The bone marrow will be hyperplastic
      • Defective production is seen in megaloblastic anemias and myelodysplasic syndromes where the abnormal cells are destroyed before they are released from the bone marrow
nonmalignant leukocyte disorders8
NONMALIGNANT LEUKOCYTE DISORDERS
  • Increased cell loss
    • Early in an infection there is a transient decrease due to increased movement of cells into the tissues
    • Could be due to an immune mechanism such as production of anti-leukocyte antibodies or PNH
    • Hypersplenism
    • Pseudoneutropenia – alterations may occur in the circulating to marginating pools. This may be seen in:
      • Early in any infection:
      • Viral infections
      • Bacterial infections with endotoxin production
      • Hypersensitivity reactions
nonmalignant leukocyte disorders9
NONMALIGNANT LEUKOCYTE DISORDERS
  • Periodic or cyclic – is an inherited autosomal dominant disorder in which every 21-30 days there are several days of neutropenia with accompanying infections. This is followed by asymptomatic periods.
  • Familial – this is benign, chronic, and mild with rare clinical symptoms
  • Infantile genetic agranulocytosis – this is a rare, congenital, and often fatal disorder in which there is defective bone marrow production of neutrophils.
  • False – blood drawn into EDTA in which the cells stick to the side of the tube; disintegration of cells due to age from sitting in a tube for too long; cell clumping
nonmalignant leukocyte disorders10
NONMALIGNANT LEUKOCYTE DISORDERS
  • Morphologic and functional abnormalities of neutrophils
    • Acquired, morphologic – these are reactive, transient changes accompanying infectious states. They include
      • Toxic granulation
      • Dohle bodies
      • Cytoplasmic vacuoles
      • May also see ingested microorganisms
nonmalignant leukocyte disorders11
NONMALIGNANT LEUKOCYTE DISORDERS
  • Inherited functional and/or morphological abnormalities
    • Pelger- Huet Anomaly – this is a benign, inherited, autosomal dominant abnormality in which the neutrophil nucleus does not segment beyond the bilobular stage (“Prince-nez cells”).
      • The cells may sometimes resemble bands, but the chromatin is more condensed (mature).
      • The cells function normally.
      • Acquired or pseudo Pelger-Huet Anomaly is seen in myeloproliferative and myelodysplastic states
pseudo pelger huet anomaly
PSEUDO PELGER-HUET ANOMALY

Note nuclear maturity

nonmalignant leukocyte disorders12
NONMALIGNANT LEUKOCYTE DISORDERS
  • Alder-Reilly Anomaly – in this disorder all leukocytes contain large, purplish granules (due to partially degraded protein-carbohydrates) in the cytoplasm, but the cells function normally.
    • This is seen in Hurler’s and Hunter’s syndromes in which there is an incomplete breakdown of mucopolysaccharides
hurler s syndrome
HURLER’S SYNDROME

Note the granules

nonmalignant leukocyte disorders13
NONMALIGNANT LEUKOCYTE DISORDERS
  • Chediak-Higashi Anomaly –
    • This is a rare autosomal recessive disorder in which abnormal lysosomes are formed by the fusion of primary granules. These are seen as grayish-green inclusions
    • The cells are ineffective in killing microorganisms and affected individuals often die early in life from pyogenic infections.
chediak higashi anomaly
CHEDIAK-HIGASHI ANOMALY

Note abnormal lysosomes

nonmalignant leukocyte disorders14
NONMALIGNANT LEUKOCYTE DISORDERS
  • May-Hegglin Anomaly
    • This is a rare, autosomal dominant disorder in which the leukocytes contain large basophilic inclusions containing RNA that look similar to Dohle bodies.
    • It can be differentiated from an infection because toxic granulation is not seen.
    • The patients also have giant platlets that have a shortened survival time. Because of this, patients may have bleeding problems, but they usually have no other clinical symptoms
nonmalignant leukocyte disorders15
NONMALIGNANT LEUKOCYTE DISORDERS
  • Chronic granulomatous disease
    • This is a lethal, sex-linked disorder affecting the function of the neutrophil
    • The neutrophil can function in phagocytosis, but it cannot kill microorganisms because the cells have a defect in the respiratory burst oxidase system.
    • Affected individuals have chronic infections with organisms that do not normally cause infections in normal individuals
  • Myeloperoxidase deficiency
    • This is a benign, autosomal recessive disorder characterized by a lack of myeloperoxidase in the neutrophils
nonmalignant leukocyte disorders16
NONMALIGNANT LEUKOCYTE DISORDERS
    • Affected individuals may have occasional problems with Candida infections, but usually they have no problems with infections because they have other mechanisms to kill microorganisms
  • Leukocyte adhesion deficiency
    • This is a rare, autosomal recessive disorder characterized by the absence of leukocyte cell surface adhesion proteins
    • Because of the lack of the adhesion molecules, the leukocytes have functional defects in:
      • Chemotaxis
      • Phagocytosis
      • Respiratory burst activation
      • Degranulation
    • Affected individuals have frequent bacterial and fungal infections and mortality in childhood is high.
nonmalignant leukocyte disorders17
NONMALIGNANT LEUKOCYTE DISORDERS
  • Eosinophil disorders
    • Eosinophilia may be found in
      • Parasitic infections
      • Allergic conditions and hypersensitivity reactions
        • Eosinophils have low affinity IgE Fc receptors and may be important in modulating immediate hypersensitivity reactions
      • Cancer
      • Chronic inflammatory states
nonmalignant leukocyte disorders18
NONMALIGNANT LEUKOCYTE DISORDERS
  • Basophil disorders
    • Basophilia
      • Is associated with chronic myeloproliferative disorders (discussed later)
      • Inflammatory bowel disease
      • Radiation exposure
  • Monocyte quantitative and qualitative disorders
    • Associated with malignancies
nonmalignant leukocyte disorders19
NONMALIGNANT LEUKOCYTE DISORDERS
  • Inherited abnormalities of neutrophils are also seen in monocytes because they originate from a common stem cell:
    • Chronic granulomatous disease (defective respiratory burst)
    • Chediak Higashi (abnormal lysosomes caused by fusion of primary granules)
    • Alder Reilly Anomaly (large purple-blue granules)
nonmalignant leukocyte disorders20
NONMALIGNANT LEUKOCYTE DISORDERS
  • Macrophage disorders
    • Lipid storage diseases – the cells are unable to completely digest phagocytosed material
      • Gaucher’s disease – is a recessive autosomal disorder with a deficiency of glucocerebroside
        • There is an accumulation of lipid in macrophages in lymphoid tissue
        • This leads to liver and spleen enlargement and destructive bone marrow lesions
        • Death occurs early in life
nonmalignant leukocyte disorders21
NONMALIGNANT LEUKOCYTE DISORDERS
  • Niemann-Pick Disease – This is an autosomal recessive disorder with a defect in sphingomyelinase
    • It is often fatal by the age of 3
  • Tay Sachs and Sandhoffs diseases – these are autosomal recessive disorders with deficiencies in - hexosaminidase and  and - hexosaminidase, respectively
    • Gangliosides and other glycolipids and mucopolysaccharides accumulate in tissues, especially in the CNS.
    • This is usually fatal by the age of 4
  • Fabry’s, Wolman’s, and Tangier are examples of other lipid storage diseases
nonmalignant leukocyte disorders22
NONMALIGNANT LEUKOCYTE DISORDERS
  • Lymphocyte disorders
    • Acquired, quantitative
      • Is usually a self-limited reactive process to infection or inflammation
      • Both B and T cells are affected
      • Function is normal, though the morphological process may be heterogenous
      • With intense proliferation, may have lymphadenopathy or splenomegaly
nonmalignant leukocyte disorders23
NONMALIGNANT LEUKOCYTE DISORDERS
  • Lymphocytosis – may be relative (secondary to neutropenia) or absolute (usually seen in viral infections); if absolute it may or may not be accompanied by a leukocytosis
    • Infectious mononucleosis (IM) –
      • This is caused by Epstein-Barr virus infecting B lymphocytes.
      • The infected B cells may eventually be killed by cytotoxic T cells, though some will continue to harbor the virus in a latent infection.
      • The reactive lymphocytes seen in the peripheral smear are cytotoxic T cells
      • The lymphocytosis is accompanied by a leukocytosis
nonmalignant leukocyte disorders24
NONMALIGNANT LEUKOCYTE DISORDERS
  • Cytomegalovirus infection
    • Leukocytosis with absolute lymphocytosis
  • Infectious lymphocytosis
    • Unknown etiology
    • Leukocytosis with absolute lymphocytosis
    • 60-97% normal appearing lymphocytes
    • The increased lymphocytes are mainly T lymphs
  • Bordetella pertussis infection
    • Leukocytosis with an absolute lymphocytosis
    • Due to a redistribution of T lymphocytes from the tissues to the circulation
    • Lymphocytes are small, normal appearing lymphocytes
nonmalignant leukocyte disorders25
NONMALIGNANT LEUKOCYTE DISORDERS
      • Lymphocytic leukemoid reaction –
        • Peripheral smear shows increased lymphocytes with younger lymphocytes being seen
        • Can occur with tuberculosis, chickenpox and the viral diseases discussed above
  • Plasmocytosis
    • Plasma cells are rarely seen in the peripheral blood, but they may be found under conditions of intense immune stimulation
    • Lymphocytopenia – caused by stress, drugs, irradiation, and some diseases
nonmalignant leukocyte disorders26
NONMALIGNANT LEUKOCYTE DISORDERS
  • Congenital qualitative or quantitative disorders – may affect both T and B cells or only one cell type. Most will severely compromise the immune system
    • Severe combined immunodeficiency system (SCIDS)
      • This is a heterogenous group of disorders in which both B and T cells are profoundly deficient
      • In some cases there is no rearrangement of the B cell and T cell receptor genes to produce immunocompetent cells
      • A bone marrow transplant or gene therapy are the only effective treatments
nonmalignant leukocyte disorders27
NONMALIGNANT LEUKOCYTE DISORDERS
  • Wiskott-Aldrich Syndrome
    • Is a sex-linked progressive disorder characterized by
      • Eczema
      • Thrombocytopenia
      • Immunodeficiency due to progressive decrease in T cell immunity
      • There is also an intrinsic B lymphocyte abnormality resulting in an inability to respond to polysaccharide antigens
      • Most children die before the age of 10 from bleeding and infections
      • Treatment is a bone marrow transplant
nonmalignant leukocyte disorders28
NONMALIGNANT LEUKOCYTE DISORDERS
  • DiGeorge syndrome
    • This is characterized by absence or aplasia of the thymus and parathyroid gland
    • This results in decreased T lymphocytes and death in the first year without thymic grafts
  • X linked agammaglobulinemia
    • This is characterized by a block in B lymphocyte maturation leading to a decrease in B lymphocytes and no plasma cells
    • There is decreased IgM, IgA, and IgG
    • Treatment is monthly injections with gammaglobulin to prevent infections
  • Ataxia telangiactasia
    • This is a cell mediated immune defect with thymic hypoplasia or dysplasia and depletion of T cells
nonmalignant leukocyte disorders29
NONMALIGNANT LEUKOCYTE DISORDERS
  • Acquired immune deficiency syndrome (AIDS)
    • Caused by human immunodeficiency virus (HIV)
    • Viral infection results in a selective depletion of T helper cells resulting in opportunistic infections