Nonmalignant Leukocyte Disorders PDF

29/09/2023 Nonmalignant Prepared by: Hazel B. Velasco, RMT, DTA, Leukocyte Disorders MLS(ASCPi)cm Rodak 6th Ed, Chapter 26, pg. 445 1 ...

29/09/2023 Nonmalignant Prepared by: Hazel B. Velasco, RMT, DTA, Leukocyte Disorders MLS(ASCPi)cm Rodak 6th Ed, Chapter 26, pg. 445 1  29/09/2023 Important Topics in this Chapter: Congenital Defects of Leukocyte Number Morphologic Abnormalities of Leukocytes and Function 1. Severe Combined Immune Deficiency 1. Pelger-Huët Anomaly 2. Wiskott-Aldrich Syndrome 2. Pseudo- or Acquired Pelger-Huët Anomaly 3. 22q11 Syndromes 3. Neutrophil Hypersegmentation 4. Bruton Tyrosine Kinase Deficiency 4. Alder-Reilly Anomaly 5. Chédiak-Higashi Syndrome 5. May-Hegglin Anomaly 6. Leukocyte Adhesion Disorders 6. Lysosomal Storage Diseases Prepared by: Hazel B. Velasco, RMT, DTA, 7. Defects of Respiratory Burst: Chronic Granulomatous Disease 8. WHIM Syndrome Quantitative Abnormalities of Leukocytes Secondary Morphological Changes 1. Neutrophils 1. Neutrophils MLS(ASCPi)cm 2. Eosinophils 2. Eosinophils and Basophils 3. Basophils 3. Monocytes 4. Monocytes 4. Lymphocytes 5. Lymphocytes Infectious Mononucleosis 2  Number and Function Congenital Defects of Leukocyte Prepared by: Hazel B. Velasco, RMT, DTA, 29/09/2023 3 MLS(ASCPi)cm  29/09/2023 Severe Combined Immune Laboratory Deficiency Findings - Gamma chain deficiency/X-linked SCID – most common form of SCID; due to a mutation in IL2RG gene which codes for the - Nearly absent circulating T and common y chain in leukocyte receptors the bind with IL-2, 4, NK cells 7, 9, 15, and 21. - Autosomal recessive adenosine deaminase deficiency - - Adequate B cells but are represents 10 to 20% of SCID cases; due to a mutation in the dysfunctional. ADA gene (results in accumulation of adenosine, which is lymphotoxic , leading to a decrease in T, B, or NK cell. Prepared by: Hazel B. Velasco, RMT, DTA, - IL-2, 4, 7, 9, 15, and 21 – provides growth, differentiation, and survival signals for B, T, and NK cells. Clinical Findings MLS(ASCPi)cm - Patients become symptomatic between 3 to 6 months of age (due to depletion of protective maternal immunoglobulins) - Absence of tonsils or lymph nodes, and severe life-threatening recurring infections. ADA deficiency: Recurring bacterial, viral, and fungal infection in addition to skeletal abnormalities, neurologic deficits, and skin rashes. 4  29/09/2023 Wiskott-Aldrich Syndrome - Rare X-linked disease caused by a mutation in the WAS gene, resulting in decreased levels of WASp protein. - WASp protein – important in cytoskeletal remodeling and nuclear transcription of HSC cells. Prepared by: Hazel B. Velasco, RMT, DTA, - Triad of: Immunodeficiency, Thrombocytopenia, and Eczema Findings: - Decreased T cells MLS(ASCPi)cm - Dysfunctional T cells, B cells, NK cells, Neutrophils, and monocytes 5  29/09/2023 22q11 Syndromes - Includes DiGeorge syndrome, autosomal dominant Opitz GBBB, etc. - Variable degrees of immunodeficiency bec Prepared by: Hazel B. Velasco, RMT, DTA, of the absence or decreased thymus size and low numbers of Tcells. - Due to microdeletion in chromosome band 22q11.2 that is assoc with cardiac defects, palatal abnormalities, distinctive facial features, developmental delays, psychiatric disorders, short stature, kidney disease, MLS(ASCPi)cm and hypocalcemia 6  29/09/2023 Bruton Tyrosine Kinase Deficiency - Aka X-linked Agammaglobulinemia – reductions in ALL serum immunoglobulin isotypes and profoundly decreased or absent B cells. Prepared by: Hazel B. Velasco, RMT, DTA, - mutation in the gene encoding Bruton tyrosine kinase; an impt factor for B cell development, differentiation, and signaling. - Due to inability to produce antibodies once maternal antibodies have cleared, MLS(ASCPi)cm recurring bacterial infection ensues. - Normal T cell function thus, low risk of viral and fungal infection. 7  29/09/2023 Chédiak-Higashi Syndrome - assoc with a mutation in the CHS1 LYST gene (encodes for a protein that regulates morphology and function of lysosome-related organelles. - Characterized by GIANT Prepared by: Hazel B. Velasco, RMT, DTA, LYSOSOMAL GRANULES that are dysfunctional found in granulocytes, monocytes, and lymphocytes. Abnormal dense granules in platelets resulting to increased bleeding. Clinical manifestations: MLS(ASCPi)cm - Partial albinism, severe recurrent bacterial infections. 8  29/09/2023 Leukocyte Adhesion Disorders (Defects of Mobility) - Results in the inability of neutrophils and monocytes to move to the site of inflammation. LAD I LAD II LAD III – caused by a mutation in - Normal ϐ2 integrin, but - Mutations in Kindlin-3 that ITGB2 which encodes for the defective SLC35C1 (codes for is required for ϐ integrin CD18 subunit of ϐ𝟐 integrin fucose transporter. Fucose is activation and leukocyte (necessary for adhesion to needed for proper synthesis rolling. Prepared by: Hazel B. Velasco, RMT, DTA, endothelial cells, bacterial of selectin ligands. - Normal expression of recognition, and outside-in integrins but failure to signaling. *Selectin ligands – important in response to external signals - High infant mortality leukocyte homing. that normally results in leukocyte activation. Patient suffers from recurrent Recurrent infections, Mild LAD I-like MLS(ASCPi)cm (most commonly mucosal and neutrophilia, growth immunodeficiency. skin) infections. retardation, coarse face, and other physical deformities. Additionally, there is decreased GPIIbIIIa resulting bleeding, similar with Glanzmann's thrombasthenia. 9  29/09/2023 Defects of Respiratory Burst Chronic Granulomatous Disease (CGD) – rare condition caused by inability of neutrophils to undergo respiratory burst after phagocytosis of foreign organisms. - Caused by mutations that code for the reduced form of nicotinamide adenine Prepared by: Hazel B. Velasco, RMT, DTA, dinucleotide phosphate (NADPH) oxidase. Clinical manifestations: Life-threatening, catalase positive bacterial and fungal infections. MLS(ASCPi)cm Diagnose with: Test that uses fluorescent probe dihydrorhodamine to measure intracellular production of reactive oxygen species. 10  29/09/2023 WHIM Syndrome - WHIM(warts, hypogammaglobulinemia, infections, and myelokathexis syndrome) results in mutations in the CXCR4 gene. Prepared by: Hazel B. Velasco, RMT, DTA, - CXCCR4 regulates WBC movement between the BM and peripheral blood. - Neutrophilis accumulate in the BM (myelokathexis) resulting in low numbers of circulating neutrophils. MLS(ASCPi)cm - Patients are highly susceptible to to HPV (human papillomavirus) infection leading to warts. 11  29/09/2023 Morphologic Abnormalities of Leukocytes without associated Prepared by: Hazel B. Velasco, RMT, DTA, Immunodeficiency MLS(ASCPi)cm 12  Pelger-Huët Anomaly 29/09/2023 - Aka True or Congenital PHA - an autosomal disorder characterized by decreased nuclear segmentation and distinctive coarse chromatin clumping pattern. - Due to a mutation in the Lamin ϐ-receptor gene which plays a role in leukocyte nuclear shape changes that occur during normal maturation. - Pelger-Huët (PH) nuclei may appear round, ovoid, or peanut shaped. Bilobed forms— the characteristic spectacle-like (“pince- nez”) morphology with the nuclei attached by a thin filament can Prepared by: Hazel B. Velasco, RMT, DTA, also be seen. - Normal neutrophil PHA function Pseudo- or Acquired Pelger- Huët Anomaly MLS(ASCPi)cm -Seen in patients with MDS, acute myeloid leukemia, and myeloproliferative neoplasm. - May be induce by drugs such as valproate, fluconazole, ganciclovir, etc. - classified as segmented neutrophil. 13  29/09/2023 Neutrophil Hypersegmentation - Normal neutrophils contain three to five lobes that are separated by filaments. Prepared by: Hazel B. Velasco, RMT, DTA, - Associated with megaloblastic anemia but can also be seen in MDS as a form of dysplasia. - Less often, it can also be found in hereditary hypersegmentation but are asymptomatic and have no signs of MLS(ASCPi)cm megaloblastic anemia. 14  29/09/2023 Alder-Reilly Anomaly - Rare inherited disorder characterized by granulocytes with large, darkly staining metachromatic cytoplasmic granules. Prepared by: Hazel B. Velasco, RMT, DTA, - Initially reported in patients with gargoylism. - Reilly bodies – characteristic granulation seen and is also found in mucopolysaccharidoses. MLS(ASCPi)cm - Normal leukocyte function. 15  29/09/2023 May-Hegglin Anomaly - Rare, autosomal dominant disorder characterized by variable thrombocytopenia, giant platelets, and large Döhle body-like inclusions in neutrophils, eosinophils, Prepared by: Hazel B. Velasco, RMT, DTA, basophils, and monocytes. - caused by a mutation in the MYH9 gene; leading to a disordered myosin heavy chain IIA production which affects megakaryocyte maturation and platelet fragmentation. MLS(ASCPi)cm - Most indiv are asymptomatic, but few may have mild bleeding tendencies related to the degree of thrombocytopenia. 16  29/09/2023 Mucopolysaccharidoses - Family of inherited disorders of mucopolysacchari de or glycosaminoglyca n (GAG) degradation. - Each MPS is caused by Prepared by: Hazel B. Velasco, RMT, DTA, deficient activity of an enzyme necessary for the degradation of dermatan sulfate, heparan sulfate, keratan sulfate, and/or chondroitin sulfate. MLS(ASCPi)cm - Presence of metachromatic Reilly bodies  17  29/09/2023 Sphingolipidoses - Inherited disorders in which lipid catabolism is defective. Two (2) most commonly assoc disorders: 1. Gaucher disease 2. Neimann-Pick disease Prepared by: Hazel B. Velasco, RMT, DTA, Gaucher disease - At least 1 in 17 Ashkenazi Jews are carriers. - There are three types of Gaucher disease; the - Most common lysosomal lipid storage most common is Type I. MLS(ASCPi)cm disease. - BM replacement by GAUCHER CELLS - Caused by a defect or deficiency in the contribute to anemia and thrombocytopenia. catabolic enzyme β-glucocerebrosidase. - GAUCHER CELLS – distinctive macrophages, - Accumulation of unmetabolized single or in clusters, exhibiting abundant fibrillar substrate sphingolipid blue-gray cytoplasm with a striated or wrinkled glucocerebroside in macrophages. appearance (onion skin-like). 18  29/09/2023 Niemann-Pick Disease - Accumulation of fat in cellular lysosomes of vital organs. Has three subtypes: Type A and B: mutations in SMPD1 Prepared by: Hazel B. Velasco, RMT, DTA, gene resulting in the deficiency of lysosomal hydrolase enzyme acid SPHINGOMYELINASE. Type C: mutation in NPC1 and NP2 gene; poor prognosis. MLS(ASCPi)cm Pathognomonic cell seen: FOAM CELLS and SEA-BLUE HISTIOCYTES. 19  Leukocytes Quantitative Abnormalities of Prepared by: Hazel B. Velasco, RMT, DTA, 29/09/2023 MLS(ASCPi)cm 20  29/09/2023 Neutrophils Bands + Segmented forms: Approx 50% to 70% Neutrophilia: Increased in neutrophils Neutropenia: Decreased in Prepared by: Hazel B. Velasco, RMT, DTA, neutrophils Leukemoid reaction: refers to a reactive neutrophilic leukocytosis greater than 50 x 109 /L with a shift to the left; must be differentiated with Chronic Myelogenous Leukemia. MLS(ASCPi)cm Leukoerythroblastic reaction: simulataneous presence of immature neutrophils, nucleated red blood cells, and teardrop RBCs. 21  29/09/2023 Eosinophils Eosinophilia – absolute eosinophil count Basophils greater than 0.4 x 109 /L; assoc with Basophilia – absolute basophil count parasitic infections, especially helminths and greater than 0.15 x 109 /L; assoc with allergic reactions. chronic myeloid leukemia, hypersensitivity, bee stings, etc. Eosinopenia – defined as an absolute eosinophil count less than 0.09 x 109 /L; Prepared by: Hazel B. Velasco, RMT, DTA, usually due to marrow hypoplasia, stress, sepsis, and autoimmune disorders. Monocytes Lymphocytes Monocytosis – defined as an absolute monocyte count greater than 1.0 x 109 /L in MLS(ASCPi)cm adults; assoc with acute and chronic Lymphocytosis - defined as a count greater inflammation, immunologic conditions, than 5.0 𝑥 109 /L; accompanied by a change in hypersensitivity reactions, and tissue repair. morphology. Monocytopenia – very rare condition, may Lymphocytopenia – may be due to an inherited signify a condition that causes cytopenia/ or acquired nonmalignant cause. 22  Secondary Morphological Changes Prepared by: Hazel B. Velasco, RMT, DTA, 29/09/2023 MLS(ASCPi)cm 23  29/09/2023 Neutrophils Neutrophils may exhibit changes in morphology such as toxic granulation, Döhle bodies, and cytoplasmic vacuoles. 1. Toxic granulation - appears as dark, blue-black granules in the cytoplasm of neutrophils, usually in segmented and band forms. - Suggestive of inflammation (positive correlation with CRP) 2. Döhle bodies Prepared by: Hazel B. Velasco, RMT, DTA, - are cytoplasmic inclusions consisting of remnants of ribosomal ribonucleic acid (RNA) arranged in parallel rows that are typically found in band and segmented neutrophils. - intracytoplasmic, pale blue round or elongated inclusions between 1 and 5 mm in diameter. - presence is assoc with wide range of conditions, including bacterial infections, sepsis, and pregnancy. MLS(ASCPi)cm - Döhle-like bodies can also be seen in May-Hegglin anomaly; differs in that inclusions may also be present in eosinophils, basophils, and monocytes for MHA. 3. Cytoplasmic vacuolation - Reflects phagocytosis; may be due to the presence of a bacteria, exposure to radiation, acute alcoholism, and etc. 24 4. Ehrlichiosis and anaplasmosis 29/09/2023 - Ehlichia and Anaplasma are small, obligate, intracellular bacteria transmitted by ticks to humans. - Common findings include: Leukopenia, thrombocytopenia, anemia, and elevated liver enzymes. - Intracellular aggregates of purple colored particles (morulae) in neutrophils or monocytes - PCR is required to confirm case 5. Pyknotic nuclei - Indicates cell death 6. Necrotic nuclei - Found in dead neutrophils characterized by rounded nuclear fragments Prepared by: Hazel B. Velasco, RMT, DTA, with no filaments and no chromatin pattern. MLS(ASCPi)cm 25  29/09/2023 Eosinophils and Basophils Hypogranular eosinophils - Assoc with ALL, and hypereosinophilic syndrome; may be due to in vitro disruption of the cellular membrane. - Recommended to still count fractured Prepared by: Hazel B. Velasco, RMT, DTA, eosinophils to promote accuracy in the WBC differential. Basophil granules MLS(ASCPi)cm - Are water soluble, and may partially or completely washed away during staining. 26  29/09/2023 Monocytes Reactive changes are an uncommon finding. Have been associated with infection, recovery from myelosuppression, and GM-CSF administration. Lymphocytes Prepared by: Hazel B. Velasco, RMT, DTA, Have been classified using various terms: Reactive, variant, atypical, transformed, effector, plasmacytoid, Turk cells, Downey, and immunoblasts. The International Council for Standardization in Hematology (ICSH) recommends using REACTIVE when the lymphocyte exhibits morphology consistent with a benign etiology and ABNORMAL when lymphocyte morphology suggests a malignant or clonal etiology. MLS(ASCPi)cm Reactive changes occur when lymphocytes are stimulated when reacting with antigens. Plasmacytoid lymphocyte – a type of reactive lymphocyte that has morphologic features of plasma cells. - Increased in Lymphoma or Waldenstrom's macroglobulinemia. 27  Infectious Mononucleosis Prepared by: Hazel B. Velasco, RMT, DTA, 29/09/2023 MLS(ASCPi)cm 28  29/09/2023 Infectious Mononucleosis - Caused by Epstein-Barr virus. - Infects the B-cell; most of the circulating reactive lymphocytes represent activated T cells. Prepared by: Hazel B. Velasco, RMT, DTA, Common clinical manifestations: Sore throat, dysphagia, fever, chills, cervical lymphadenopathy, fatigue, and headache. Laboratory findings: MLS(ASCPi)cm 1. Absolute lymphocytosis (with up to 50% or more REACTIVE FORMS). 29  29/09/2023 ASSIGNED READING: Introduction to Prepared by: Hazel B. Velasco, RMT, DTA, Hematologic Neoplasms Rodak 6th Ed, Ch. 27, pg. 466 MLS(ASCPi)cm 30