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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:



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
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
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
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
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.
LEUKEMOID REACTION
LEUKEMOID REACTION
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

LEUKOERYTHROBLASTIC
REACTION
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
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:



Viral infections
Bacterial infections with endotoxin production
Hypersensitivity reactions
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
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
DOHLE BODIES
MORPHOLOGIC NEUTROPHIL
CHANGES
Vacuolated cell
MORPHOLOGIC NEUTROPHIL
CHANGES
Toxic
granulation
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
PELGER-HUET ANOMALY
PSEUDO PELGER-HUET ANOMALY
Note nuclear
maturity
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
Note the
granules
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
Note abnormal lysosomes
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
MAY-HEGGLIN ANOMALY
Basophilic
inclusions
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
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
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
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
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
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
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
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
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
ATYPICAL LYMPHOCYTE SEEN IN
IM
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

LYMPHOCYTOSIS WITH B.
PERTUSSIS INFECTION
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
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
DISORDERS

Wiskott-Aldrich Syndrome
 Is a sex-linked progressive disorder characterized by





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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
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
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
