WBC Inclusions and Non-Malignant WBC Disorders PDF

WBC INCLUSIONS AND NON- MALIGNANT WBC DISORDERS Hematology 1 Lecture __________ ANGELO CHRISTIAN O. DE GUZMAN, RMT, SO1, CLSSYB, MSMTc, MBA (ip), MPA(ip), HIV Proficient School of Medical Technology Abnormal White Blood...

WBC INCLUSIONS AND NON- MALIGNANT WBC DISORDERS Hematology 1 Lecture __________ ANGELO CHRISTIAN O. DE GUZMAN, RMT, SO1, CLSSYB, MSMTc, MBA (ip), MPA(ip), HIV Proficient School of Medical Technology Abnormal White Blood Cells Smudge/Basket Cells Ruptured WBC with Bare Nucleus Artifactual (Smearing) / Disease (Leukemia) Due to improper, forceful smearing Large number may be seen in Leukemia (their presence indicated increased cell fragility or increased cell destruction) According to Steininger: Smudge – Nuclear remnants of Lymphocytes Appearance is similar to a thumbprint Basket – Nuclear remnants of Granulocyte cells with netlike chromatin pattern Abnormal White Blood Cells Hypersegmented Neutrophil Aka Macropolycyte: Neutrophils produced during accelerated Myelopoiesis Nucleus has > 5 lobes Usually found in Megaloblastic Anemia Abnormal White Blood Cells Vacuolated White Blood Cells With Holes or Vacuoles in the cytoplasm (Signs of Degeneration) May be found in normal blood smears if the smear is made from Oxalated Blood which is over 2 hours old. If seen in smears made from fresh blood, they should be counted and reported May be seen in severe infections, Chemical Poisonings, and Leukemia. Abnormal White Blood Cells Tart Cells First described in a patient named Tart A phagocytic WBC (usually a monocyte) with engulfed Nucleus of another cell. Seen in drug sensitivity Abnormal White Blood Cells Lupus Erythematosus (LE) Cell Lupus: Autoimmune Disorder A Phagocytic WBC (Usually a Neutrophil) that has ingested an altered, homogenous globular nuclear mass of a destroyed cell. Ingested nuclear material is redder than the usual color of unaltered chromatin. Kidneys – most infected Found in 80% of cases with disseminated Lupus Erythematosus Abnormal White Blood Cells Rieder Cells Lymphocytes with notched, lobulated, or segmented, or clover- leaf-like nucleus Seen in Chronic Lymphocytic or Lymphatic Leukemia Abnormal White Blood Cells Hairy Cells Seen in 80% of patients with cancer Fine, Hair-like, Irregular cytoplasmic projections Hairy Cell Leukemia Abnormal White Blood Cells Jordan Anomaly Genetic qualitative disorder with abundant sudanophilic inclusions (i.e. Lipids) Presence of multiple large vacuoles in all granulocytes and monocytes which stain positively for fat First associated in association with progressive muscular dystrophy and subsequently ichthyosis (skin is dry and scaly like a fish) Vacuoles are not found in Lymphocytes. Abnormal White Blood Cells Auer Bodies (Auer Rods) Rod-like bodies which stain reddish- purple in the Cytoplasm of Myeloblasts in acute Myelocytic Leukemia Linear projections of Primary (Azurophilic) granules Abnormal White Blood Cells Russell Bodies Results from the proteinaceous material produced by Immunoglobulins These bodies appear as grape-like structure. Sometimes the stain (red) is diffused and therefore these plasma cells are therefore called “Flame Cells” or “Flaming Plasma cell” Flame Cell: Increase Glycoproteins, Red Pyrorinophilic Bodies Abnormal White Blood Cells Lazy Leukocyte Syndrome A rare condition in which both random and directed movement of the cells are defective Bone Marrow reserves of granulocytes are normal, but release of cells from Bone Marrow to the Peripheral Blood is poor. Congenital Defects of Leukocyte Number and Function Severe Combined Immune Deficiency Gamma chain deficiency (X-linked SCID) – Most common SCID form Mutations in the IL2RG gene at Xq13.1 Codes for the common gamma chain in Leukocyte receptors Adenosine Deaminase (ADA) deficiency – 10-20% of SCID cases Mutation in the ADA gene at 20q13.12 ADA: Key component of the metabolic breakdown of ATP and RNA ADA Deficiency: intra- and extracellular accumulation of Adenosine (Lymphotoxic) Congenital Defects of Leukocyte Number and Function Wiskott-Aldrich Syndrome (WAS) Rare X-linked disease caused by one of >400 mutations in the WAS gene  Decreased levels of WASp protein (Cytoskeletal remodeling and nuclear transcription in hematopoietic cels) Decreased T Cells Dysfunctional cells: B Cells, T Cells, NK Cells, Neutrophils, Monocytes Leads to bacterial, viral, and fungal infections Leads to bleeding due to Thrombocytopenia and small abnormal platelets Congenital Defects of Leukocyte Number and Function 22q11 syndromes All disorders within the 22q11 deletion syndrome Classified as Combined Immunodeficiency DiGeorge Syndrome Autosomal Dominant Opitz GBBB Sedlackova syndrome Caylor Cardiofacial Syndrome Shprintzen syndrome Conotruncal Anomaly Face syndrome Congenital Defects of Leukocyte Number and Function Bruton Tyrosine Kinase Deficiency “Antibody Deficiency”, “X-linked Agammaglobulinemia”: Primary immunodeficiency disease characterized by reductions in all serum immunoglobulin isotypes, decreased or absent B cells Caused by a mutation in the gene encoding Bruton Tyrosine Kinase  Decreased production of BTK (B cell development) Congenital Defects of Leukocyte Number and Function Chédiak-Higashi Syndrome (Chédiak-Steinbrinck-Higashi Syndrome) Genetic disorder characterized by giant cytoplasmic granules in the phagocytes and lymphocytes Basic defect in the Golgi complex responsible for granule assembly Granules are believed to be round in content but abnormally packaged This syndrome affects at least 6 species: Man, Mink, Cattle, Mine, Cats, and Killer Whales Rare autosomal recessive disease of immune dysregulation Mutation in the CHS1 LYST gene on chromosome 1q42.1-2 (Protein regulating morphology and function of lysosome- related organelles) In severe form, all WBCs may be affected and contain giant Lysosomes of varying size up to 4 μm. Congenital Defects of Leukocyte Number and Function Chédiak-Higashi Syndrome (Chédiak- Steinbrinck-Higashi Syndrome) They stain variably as gray, blue, purple, or orange and are strongly Peroxidase positive Affected individuals display: More susceptible to a variety of common infectious agents (Leukocyte granule are affected) Have hemorrhagic tendencies (platelet granules are affected) Partial albinism – the Melanosomes (Melanocyte) are affected Congenital Defects of Leukocyte Number and Function Chédiak-Higashi Syndrome (Chédiak- Steinbrinck-Higashi Syndrome) Findings: Giant lysosomal granules in Granulocytes, Monocytes, Lymphocytes Pseudo-Chédiak-Higashi granules: cytoplasmic inclusions resembling fused lysosomal granules Reported in: Acute Myeloid Leukemia, Chronic Myeloid Leukemia, Myelodysplastic Syndrome (MDS) Congenital Defects of Leukocyte Number and Function Congenital Defects of Phagocytes Characteristics: Low Neutrophil count, Increased risk of infection, organ dysfunction, high rate of Leukemic transformation First year of life: Life-threatening recurrent fevers due to bacterial and fungal infections Treatment: Antibiotic prophylaxis, use of G-CSF Congenital Defects of Leukocyte Number and Function Leukocyte Adhesion Disorders (Defects of Motility) Inability of neutrophils and monocytes to move from circulation to the inflammation site (Extravasation) causing recurrent severe bacterial and fungal infections Treatment: Hematopoietic stem cell transplant Types: LAD I Mutation in ITGB2 encoding the CD18 subunit of β2 integrins  Necessary for adhesion to endothelial cells, bacterial recognition, and outside-in signaling High infant mortality rate Symptoms: Recurrent infections, skin and mucosal infections, lymphadenopathy, splenomegaly, and Neutrophilia Congenital Defects of Leukocyte Number and Function Leukocyte Adhesion Disorders (Defects of Motility) Types: LAD II Mutation in SLC35C1 coding for Fucose transporters moving Fucose from the Endoplasmic Reticulum to the Golgi region  Can’t produce selectins, defective Leukocyte recruitment  recurring infections Fucose: Needed for posttranslational Fucosylation of Glycoconjugates for selectin ligand synthesis Absence of Group H Antigen, Growth retardation, Neurologic defects Congenital Defects of Leukocyte Number and Function Leukocyte Adhesion Disorders (Defects of Motility) Types: LAD III Mutation in Kindlin-3 Kindlin-3 Protein + Kalin  Activation of β integrin and leukocyte rolling Leukocytes and platelets have normal expression of integrins with failure in response to external signals resulting in Leukocyte activation Symptoms: Mild LAD I-like immunodeficiency with recurring infections, Decreased GP IIb/IIIa (Bleeding) Congenital Defects of Leukocyte Number and Function Defects of Respiratory Burst: Chronic Granulomatous Disease (CGD) Decreased ability of Neutrophils to undergo respiratory burst after Phagocytosis of foreign organisms ~60% are X-linked recessive, ~40% are autosomal recessive X-linked recessive has more severe disease course with shorter lifespans than autosomal recessive Mutations in genes for production of NADPH oxidase Can cause life-threatening catalase-positive bacterial and fungal infections Diagnosis: Fluorescent Probe Dihydrorhodamine (measures intracellular production of reactive oxygen species) Congenital Defects of Leukocyte Number and Function WHIM Syndrome (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) Defect in the intrinsic and innate immunity Mutations in the CXCR4 gene located at 2q22 Normal CXCR4 protein: regulates WBC movement between BM and peripheral blood Myelokathexis: Accumulation of Neutrophils in the Bone Marrow  Low number of circulating Neutrophils Findings: Neutropenia, Lymphopenia, Monocytopenia, Hypogammaglobulinemia Patients experience recurrent bacterial infections, high susceptibility to HPV (Warts) Treatment: Antibiotic Prophylaxis, Immunoglobulin replacement therapy, G-CSF Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Pelger-Huët Anomaly (True or Congenital PHA) Autosomal Dominant, Decreased Nuclear segmentation with distinctive coarse chromatin clumping pattern Mutation in the lamin β-receptor gene (Major role in Leukocyte nuclear shape changes during normal maturation) “Pince-Nez” morphology – Spectacle-like nuclei Neutrophils with normal function Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Pseudo or acquired Pelger-Huët Anomaly Associated with severe bacterial infections, HIV, tuberculosis, and mycoplasma pneumonia Induced by drugs: Immunosuppressants, chemotherapies, valproate, sulfisoxazole, fluconazole, ganciclovir, hematopoietic growth factors, ibuprofen Pseudo-PHA cells exhibit hypogranularity in MDS TRUE PHA PSEUDO PHA Affected cells > 68% 5 Lobes, associated with MBA Hypersegmented Neutrophils usually larger than normal Also seen in MDS, representing a form of dysplasia Hereditary Hypersegmented Neutrophils: Asymptomatic, no signs of MBA Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Alder-Reilly Anomaly Rare inhibited disorder, granulocytes with large, darkly staining metachromatic cytoplasmic granules Characterized by dense azurophilic granulations in all types of Leukocytes Granules are larger than toxic granules tend to cover the nucleus AR bodies in Neutrophils: resemble heavy toxic granulation Reilly bodies present in Monocytes and Lymphocytes Toxic granulations only present in Neutrophils Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Alder-Reilly Anomaly Initially reported in patients with Gargoylism Reilly bodies: Characteristic granulation found in Mucopolysaccharidoses (MPSs) Contains partially-digested mucopolysaccharides Granulation usually results from an abnormal deposition and storage of Mucopolysaccharides. Alder’s Bodies are associated with Skeletal Dystrophy Cytoplasmic granulation is not transient or related to an infection as it is with toxic granulation Alder-Reilly Bodies generally are distributed throughout the cell and all cells tend to be affected equally. Morphologic Abnormalities of Leukocytes without associated Immunodeficiency May-Hegglin Anomaly Rare, Autosomal Dominant disorder with variable thrombocytopenia, giant platelets, and large Dohle body-like inclusions in Neutrophils, Eosinophils, Basophils, and Monocytes. Neutrophil and Giant Platelet from a Caused by a mutation in MYH9 gene on Chrom 22q12-13 Patient with May- Pale blue, spindle-shaped inclusions (Larger [2-5μm]) Hegglin Anomaly With disordered production of myosin heavy chain type IIA: Affects Megakaryocyte maturation and platelet fragmentation (Large, Hypogranular Platelets seen) Basophilic Dohle body-like inclusions in MHA: contain precipitated myosin heavy chains **True Dohle bodies contain lamellar rows of rough endoplasmic reticulum Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Lysosomal Storage Diseases (LSDs) Mutations in genes coding for production of lysosomal enzymes  Flawed degradation of phagocytized material and buildup of undigested substrates within lysosomes Causes cell dysfunction, cell death Diseases: Sphingolipidoses Oligosaccharidoses Mucolipidoses Mucopolysaccharidoses (MPS) Lipoprotein Storage Disorders Lysosomal transport defects Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Lysosomal Storage Diseases (LSDs) Mucopolysaccharidoses Inherited disorders of Glycoaminoglycan (GAG) degradation Deficient activity of enzyme necessary for degrading dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate  Lysosome buildup  Physical and cognitive problems with shortened survival Treatment: Enzyme replacement therapy, Hematopoietic stem cell transplantation (Hurler patients only), Improved anti-inflammatories, gene therapy, nanoparticles, substrate reduction therapy Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Lysosomal Storage Diseases (LSDs) Sphingolipidoses: Inherited disorders with defective lipid catabolism Gaucher Disease Most common lysosomal LSD Autosomal recessive, defect/deficient β-glucocerebrosidase (gene at 1q21-q22)  necessary for glycolipid metabolism  Accumulation of unmetabolized substrate sphingolipid glucocerebrosides in macrophages 1 in 17 Ashkenazi jews are carriers Three types of Gaucher Disease Most common: Type I Key factor for differentiation: Neurologic symptoms Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Lysosomal Storage Diseases (LSDs) Sphingolipidoses: Inherited disorders with defective lipid catabolism Gaucher Disease Gaucher cells: Stain (+) with Trichrome, Aldehyde Fuchsin, PAS, Acid Phosphatase Diagnosis confirmation: β-glucocerebrosidase test Diagnostic for Ashkenazi Jews: Screen for mutations in N370S, 84GG, IVS2 + 1G>A, L444P Treatment: Enzyme replacement with recombinant glucocerebroside Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Lysosomal Storage Diseases (LSDs) Sphingolipidoses Niemann-Pick Disease (NP) Accumulation of fat in cellular lysosomes of vital organs  function impairment Three subtypes: Type A and B: Recessive mutations in SMPD1 gene in chromosome 11p15.4 (Deficiency of lysosomal hydrolase enzyme acid sphingomyelinase (ASM) Seen in the Bone Marrow: Foam cells: Macrophages with cytoplasm with lipid-filled lysosomes appearing as vacuoles (foam) after staining Sea-blue histiocytes: Macrophags with Lipofuchsin-, Glycophospholipid-, and Sphingomyelin contained in cytoplasmic granules (1-3 um in diameter) Morphologic Abnormalities of Leukocytes without associated Immunodeficiency Lysosomal Storage Diseases (LSDs) Sphingolipidoses Niemann-Pick Disease (NP) Three subtypes: Type A (Acute Neuronopathic form): Affects European Jews Presents in infancy, associated with failure to thrive, Lymphadenopathy, Hepatosplenomegaly, vision problems, rapid neurodegenerative decline (death ~4 years old) Only with 7 x x109 /L (Adults); >8.5 x x109 /L (Children) Results from: Catecholamine-induced shift from the marginal pool to the circulating pool Increase in BM production of Neutrophils Transfer of Neutrophils from BM pool to the circulating pool Always accompanied by a left shift Quantitative Abnormalities of Leukocytes Neutrophils Neutrophilia Leukemoid Reaction Reactive Neutrophilic Leukocytosis (>50 x x109 /L), shift to the left Caused by: Acute and Chronic Infections Metabolic Diseases Inflammation in response to malignancy Always rule out with Chronic Myelogenous (Myeloid) Leukemia Quantitative Abnormalities of Leukocytes Neutrophils Neutrophilia Leukoerythroblastic Reaction Simultaneous presence of immature Neutrophils, nRBCs, and Dacryocytes Accompanied by Neutrophilia If present, suggests: Space-occupying lesion in the BM (Metastatic tumor, Fibrosis, lymphoma, Leukemia) Marked increase in one of the normal marrow cells (Erythroid Hyperplasia) Primary Myelofibrosis Quantitative Abnormalities of Leukocytes Neutrophils Neutropenia Decreased ANC (