1. NONMALIGNANT LEUKOCYTE DISORDERS

2. 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.

3. 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

4. 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)

5. 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)

6. 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.

7. LEUKEMOID REACTION

8. LEUKEMOID REACTION

9. 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

10. LEUKOERYTHROBLASTIC REACTION

11. 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

12. 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

13. NONMALIGNANT LEUKOCYTE DISORDERS
Periodic or cyclic – is an inherited autosomal dominant disorder in which every 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

14. 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

15. DOHLE BODIES

16. MORPHOLOGIC NEUTROPHIL CHANGES
Vacuolated cell

17. MORPHOLOGIC NEUTROPHIL CHANGES
Toxic granulation

18. 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

19. PELGER-HUET ANOMALY

20. PSEUDO PELGER-HUET ANOMALY
Note nuclear maturity

21. 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

22. HURLER’S SYNDROME
Note the granules

23. 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.

24. CHEDIAK-HIGASHI ANOMALY
Note abnormal lysosomes

25. 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

26. MAY-HEGGLIN ANOMALY

27. 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

28. 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.

29. 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

30. 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

31. 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)

32. 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

33. 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

34. 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

35. 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

36. ATYPICAL LYMPHOCYTE SEEN IN IM

37. NONMALIGNANT LEUKOCYTE DISORDERS
Cytomegalovirus infection
Leukocytosis with absolute lymphocytosis
Infectious lymphocytosis
Unknown etiology
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

38. LYMPHOCYTOSIS WITH B. PERTUSSIS INFECTION

39. 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

40. 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

41. 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

42. 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

43. 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