NONMALIGNANT LEUKOCYTE DISORDERS Dr.Ghorbani

Dr.Ghorbani NONMALIGNANT LEUKOCYTE DISORDERS Dr.Ghorbani

Dr.Mahdi Ghorbani AJA university NONMALIGNANT LEUKOCYTE DISORDERS

 Changes in leukocyte concentration and

morphology often reflect disease processes Dr.Ghorbani 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 Dr.Ghorbani 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 Dr.Ghorbani 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: Dr.Ghorbani 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 Dr.Ghorbani 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 Dr.Ghorbani

LEUKEMOID REACTION Dr.Ghorbani NONMALIGNANT LEUKOCYTE DISORDERS

 Leukoerythroblastic reaction – in this condition nucleated RBCs (NRBC) and neutrophilic precursors are both found in

the peripheral blood Dr.Ghorbani  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 Dr.Ghorbani NONMALIGNANT LEUKOCYTE DISORDERS

 Neutropenia this may result from

 Decreased bone marrow production Dr.Ghorbani  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 Dr.Ghorbani 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 DISORDERS

 Periodic or cyclic – is an inherited autosomal dominant disorder in which every 21-30 days there

are several days of neutropenia with Dr.Ghorbani accompanying infections. This is followed by asymptomatic periods.

 Familial – this is benign, chronic, and mild with rare clinical symptoms

 Infantile genetic agranulocytosis (Kostmann syndrome)– 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 Dr.Ghorbani  Acquired, morphologic – these are reactive, transient changes accompanying infectious states. They include

 Toxic granulation

 Dohle bodies

 Cytoplasmic vacuoles

 May also see ingested microorganisms Toxic granulation is found in severe inflammatory states. The toxic granules are azurophilic, usually found in the promyelocyte, metamyelocyte, band, and segmented stages. The toxic granulation is thought to be due to impaired cytoplasmic maturation,in the effort to rapidly

generate large numbers of granulocytes. Dr.Ghorbani

TOXIC GRANULATION Dr.Ghorbani MORPHOLOGIC NEUTROPHIL

CHANGES Dr.Ghorbani

Toxic granulation Dohle bodies are single or multiple blue cytoplasmic inclusions. They represent remnants of rough endoplasmic reticulum from earlier maturational stages. They are associated with myeloid "left shifts" and are seen in

conjunction with toxic granulation. Dr.Ghorbani

DÖHLE BODIES Dr.Ghorbani

DOHLE BODIES Dr.Ghorbani NONMALIGNANT LEUKOCYTE DISORDERS

 Inherited functional and/or morphological

abnormalities Dr.Ghorbani  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 Dr.Ghorbani

PELGER HUET ANOMALY Dr.Ghorbani

PELGER-HUET OR BAND? Dr.Ghorbani

PELGER HUET Dr.Ghorbani

VARIATIONS IN PELGER HUET Dr.Ghorbani

PSEUDO PELGER-HUET ANOMALY Dr.Ghorbani

Note nuclear maturity NONMALIGNANT LEUKOCYTE DISORDERS

Alder-Reilly Anomaly – in this disorder all

leukocytes contain large, purplish granules Dr.Ghorbani (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 The Alder-Reilly anomaly is associated with the genetic mucopolysaccharidoses. Patients with mucopolysaccharidoses lack the lysozymal enzymes necessary to break down mucopolysaccharides. Dense azurophilic granules, resembling toxic granulation in

neutrophils, are seen in all leukocytes. Most characteristic ofDr.Ghorbani these disorders are the metachromatic granules surrounded by a clear zone seen in lymphocytes.

ALDER REILLY SYNDROME Dr.Ghorbani HURLER’S SYNDROME

Note the

granules Dr.Ghorbani Alder-Reilly Anomaly Prominent red-purple

granules in neutrophils. Dr.Ghorbani

Pelger-Hüet Anomaly Bilobed or monolobed granulocytes; autosomal dominant inheritance.

Unsegmented eosinophil NONMALIGNANT LEUKOCYTE DISORDERS

Chediak-Higashi Anomaly

 This is a rare autosomal recessive Dr.Ghorbani 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 syndrome is a rare autosomal recessive condition associated with abnormally large leukocyte granules resulting from fusion of lysozymes. This disorder may affect granulocytes, leukocytes, and monocytes. Chemo taxis and phagocytosis is defective. Platelets lack dense granules and platelet function is abnormal. Giant melanosomes in ocular and skin tissues result in hypo Dr.Ghorbani pigmentation.

CHEDIAK-HIGASHI SYNDROME Dr.Ghorbani CHEDIAK-HIGASHI ANOMALY

Note abnormal lysosomes Dr.Ghorbani NONMALIGNANT LEUKOCYTE DISORDERS

May-Hegglin Anomaly

This is a rare, autosomal dominant disorder Dr.Ghorbani 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 platelets 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

 Triad of giant platelets, thrombocytopenia, and

leukocyte inclusions Dr.Ghorbani  Absent to moderate bleeding diathesis  Normal platelet function  Autosomal dominant inheritance  Related syndromes: Sebastian (variant inclusions) and Fechtner (features of Alport) MAY-HEGGLIN ANOMALY

 Medical and genetic history assessment including

bleeding diathesis, hearing loss, kidney dysfunction, Dr.Ghorbani cataract formation  Affection status determined by automated CBC and review of Wright-stained peripheral blood film  DNA isolated from peripheral blood used for genetic analysis of MYH9 by RFLP &/or sequencing MAY-HEGGLIN ANOMALY

 MHA results from MYH9 mutation in diverse ethnic

groups Dr.Ghorbani  MYH9 mutations associated with MHA are highly penetrant  Two MYH9 mutations account for large majority of MHA  Automated platelet counts are lower in R1933Ter mutations, possibly due to larger platelet size May-Hegglin Anomaly RNA in granulocytes and monocytes; thrombocytopenia

with giant platelets; autosomal dominant inheritance. Dr.Ghorbani

Giant platelets

May-Hegglin anomaly (arrow indicates neutrophil inclusion) Dr.Ghorbani

Diagnosis of the Blood Smear, N Engl J Med 2005;353:498-507

MAY-HEGGLIN ANOMALY Dr.Ghorbani NONMALIGNANT LEUKOCYTE DISORDERS

 Chronic granulomatous disease  This is a lethal, sex-linked disorder affecting the function of the neutrophil Dr.Ghorbani  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

 Eosinophil disorders

 Eosinophilia may be found in Dr.Ghorbani 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

EOSINOPHILIA Dr.Ghorbani

EOSINOPHILIA Dr.Ghorbani NONMALIGNANT LEUKOCYTE DISORDERS

 Basophil disorders

 Basophilia Dr.Ghorbani  Associated with chronic myeloproliferative disorders  Inflammatory bowel disease  Radiation exposure  Monocyte quantitative and qualitative disorders  Associated with malignancies

BASOPHILIA Dr.Ghorbani NONMALIGNANT LEUKOCYTE DISORDERS

 Inherited abnormalities of neutrophils are also seen in monocytes because they originate from a common stem cell: Dr.Ghorbani

 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 Dr.Ghorbani  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 Dr.Ghorbani  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 Dr.Ghorbani

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 Dr.Ghorbani 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 Dr.Ghorbani

MONOCYTE Dr.Ghorbani

ATYPICAL LYMPHOCYTES - PERIPHERAL BLOOD Dr.Ghorbani

ATYPICAL LYMPHS V. MONOCYTES Dr.Ghorbani

 Cytomegalovirus infection

 Leukocytosis with absolute lymphocytosis Dr.Ghorbani  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 Dr.Ghorbani NONMALIGNANT LEUKOCYTE DISORDERS

 Lymphocytic leukemoid reaction –  Peripheral smear shows increased lymphocytes with younger

lymphocytes being seen Dr.Ghorbani  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

 Plasma cells have also been recorded in the blood of patients with viral disorders, including rubella, measles, chickenpox and mumps.

 In the marrow, an average of 1%–2% of plasma cells are present in adults.

 Increases of up to 20% of plasma cells may be found in a variety of conditions other than multiple myeloma, including metastatic carcinoma, chronic granulomatous infection, conditions linked with hypersensitivity, and following administration of cytotoxic drugs.  Lymphocytopenia – caused by stress, drugs, irradiation, impaired lymphopoiesis 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 Dr.Ghorbani

 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 Dr.Ghorbani  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 Dr.Ghorbani  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 Dr.Ghorbani (HIV)

Viral infection results in a selective depletion of T helper cells resulting in opportunistic infections