NONMALIGNANT LEUKOCYTE DISORDERS. Changes in leukocyte concentration and morphology often reflect disease processes and toxic challenge. The type of cell

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 processesNeutrophilia – 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


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)


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)


Leukemoid reaction – this is an extreme neutrophilia with a WBC count > 30 x 109/LMany bands, metamyelocytes, and myelocytes

are seenOccasional 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 chromosomeThe condition is transientThere 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


Leukoerythroblastic reaction – in this condition nucleated RBCs and neutrophilic precursors are both found in the peripheral bloodThe WBC count may be increased, normal, or

decreasedThis 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


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


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


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


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


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


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


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


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


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


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:ChemotaxisPhagocytosisRespiratory burst activationDegranulation

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


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


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


Lymphocyte disordersAcquired, 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


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


Cytomegalovirus infectionLeukocytosis with absolute lymphocytosis

Infectious lymphocytosisUnknown etiologyLeukocytosis with absolute lymphocytosis 60-97% normal appearing lymphocytesThe increased lymphocytes are mainly T lymphs

Bordetella pertussis infectionLeukocytosis with an absolute lymphocytosisDue to a redistribution of T lymphocytes from the

tissues to the circulationLymphocytes are small, normal appearing

lymphocytes

LYMPHOCYTOSIS WITH B. PERTUSSIS INFECTION


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


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


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


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


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

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NONMALIGNANT LEUKOCYTE DISORDERS. Changes in leukocyte concentration and morphology often reflect disease processes and toxic challenge. The type of cell