CHAPTER 28 MORPHOLOGIC AND DISTRIBUTIVE LEUKOCYTE DISORDERS I.

DISTRIBUTIVE LEUKOCYTE DISORDERS Absolute WBC counts are more informative than relative percentages when determining whether there is a significant increase or decrease in a cell type Profiling instruments => relative and absolute values (total number per 109 / L) Absolute value = total WBC count x relative value -

REFERENCE RANGE: Total circulating WBC count is 4.5 to 11.5x109/L Newborns = Pedia = slight Adult = N Geriatric = Granulocyte kinetics = influenced by input from the bone marrow, changes in the proportion of marginating to circulating pools and changes caused by disease Transient elevated counts = seen when granulocytes leave the marginating pool, increasing the circulating pool Transient decreased periph blood WBC counts = seen when granulocytes move to the marginating or storage pool

ALTERATIONS IN GRANULOCYTE COUNT AND MATURITY Neutrophilia = absolute count; > 8.6 x 109/L o Accompanied by bm myelocytic hyperplasia Benign neutrophilia = occurs in stress, tachycardia, fever, labor, strenuous exercise and epinephrine and cortisone therapy Pathologic causes of neutrophilia: o Inflammatory states (acute infection, trauma, diabetes mellitus) o Intoxications (uremia) o Acute hemorrhage o Hemolysis o Malignancy

Leukoerythroblastic (presence of nRBCs) Leukemoid reaction = WBC count > 50x109/L o Exaggerated response to an infection o LAP (Leukocyte Alkaline Phospatase) stain = used to differentiate a leukemoid rxn from chronic myelogenous leukemia (CML) Left shift = immature granulocyte count Neutropenia = absolute count; <2.3x109/L Transient neutropenia = seen after exposure to certain medications, such as tranquilizers, sedatives, antimicrobial agents and procedures such as hemodialysis Cyclic neutropenia = peripheral blood count I a 21-day periodicity o Reflect autosomal dominant mutations in the ELA2 gene that codes for neutrophil elastase o Nadir = reaches 0, rendering the patient susceptible to infection o Kostmann neutropenia (severe congenital neutropenia) o Hermansky-Pudlak syndrome Neutropenia with fully mature granulocytes arises from: o Vit b12 or folate deficiency o Ingestion of medications o Job syndrome o (all suppress the mitotic pool) o Myelocytic suppression = seen with antimicrobials and calcium channel blockers o morbidity and mortality Rare immune neutropenia o Neutrophils are destroyed in the spleen or portal circulation as a result of autoantibodies o Autoantibodies to neutrophils arise following childhood infection as a complication in SLE and in Felty syndrome in conjunction with rheumatoid arthritis

Autoinfection = neutrophil count < 1x109/L or <0.5x109/L Neutrophilia with predominantly mature forms may have a better prognosis than with immature forms Immaturity = implies a diminution of storage pools and maturation pool stress VALUES >0.5x109/L CAUSES/ASSOCIATION S: allergic responses and dermatitis, parasitic infections, some autoimmune disorders and some malignancies in response to adrenocorticotropic hormone hypoactive thryroid conditions, ulcerative colitis, some types of nephrosis, and certain malignancies, including chronic myelogenous leukemia strenuous exercise, active tuberculosis subacute bacterial endocarditis, syphilis, parasitic and rickettsial infections, certain autoimmune diseases and trauma; recovery from acute infections after glucocorticoid admininstration Exanthems (skin rashes) from viral diseases such as measles and mumps Thyrotoxicosis Patients recovering from certain acute infections Rare in children with bacterial infection except w/ Bordetella

ALTERATIONS EOSINOPHILIA

LYMPHOPENIA

<0.6x109/L

EOSINOPENIA

BASOPHILIA

>0.15x109/ L

pertussis infection Hepa A, IM, CMV, EBV, T.pallidum, infectious lymphocytosis Congenital and secondary-stage syphilis ad brucellosis Beta streptococcus T. gondii Vaccination Heart failure Uremia SLE Malaria Assoc. with leukoerythroblastic picture Elderly = bm depletion Infectious hepatitis Hodgkin lymphoma Active tuberculosis Endocrine disorders Post-stem cell transplant HIV Drug exposure

MONOCYTOSIS

>0.8x109/L

II.

MORPHOLOGIC ALTERATIONS

NON-FUNCTIONAL/MORPHOLOGIC 1. NUCLEI A. Pleger-Huet Anomaly - Autosomal dominant neutrophil nuclear hyposegmentation - Nuclear matrix proteins are abn - Nuclei = round, oval or bilobed w/ a characteristic pinched or pince-nez appearance - Chromatin = clumped and overly mature; dense heterochromatin - True homozygote = skeletal and neurologic abnormalities - Pseudo-Pelger Huet = acquired o Nuclei = less dense o Hypogranular cytoplasm o Burns, drug reactions, infections, myelodysplastic syndromes, chronic

MONOCYTOPENI A LYMPOCYTOSIS Children: 2 to 7x109/L Adult: >5.5x109/L

myelogenous leukemia, acute leukemia, chemotherapy B. Hereditary Hypersegmentation, Twinning and Drumsticks - Autosomal dominant neutrophil hypersegmentation - Must be diff from megaloblastic anemias and from twinning deformity - Twinning = nucleus with axial symmetry (mirror image); acquired in malignancies and chemotherapy - drumsticks - Small chromatin extensions - Trisomy of group E chromosomes - Extra X chromosomes - Aneuploid states 2. CYTOPLASM A. Alder-Reilly Anomaly - Recessive - mucopolysaccharide degradation deposition of mucopolysaccharides in the cytoplasm - Structural abnormality of myeloperoxidase gene - Stained: Alder-Reilly bodies o metachromatic (deep purple to lilac) granules; o difficult to dist. From toxic granulation - extreme manifestation: eo and baso may possess unusual granulation (makes it difficult to dist. Bet. Them) - commonly seen in patients w/ Hurler and Hunter syndromes B. Chediak-Steinbrinck-Higashi Syndrome - Rare autosomal recessive state - Abnormally large peroxidase-positive lysosomes - Fusion of granules seen in melanosomes (albinism) - Uncontrolled act of granular membrane primary, secondary granules - susceptibility to infections o precursor death in bm o Moderate periph bld neutropenia o Slowed bactericidal function

Patients exhibit mucocutaneous hemorrhage (caused by thrombocytopenia) Large platelet granules Bleeding time = prolonged Platelet aggregation reduced response May progress to peripheral neuropathy, pancytopenia and systemic infections assoc. with lymphocytic prolif, hepatosplenomegaly and lymphadenopathy to death C. May-Hegglin Anomaly Rare autosomal dominant Patients are at risk for infections and mucocutaneous hemorrhage Assoc. w/ a mutation in MYH9 (encodes nonmuscle myosin heavy chain A) Characterized by presence of large Dohle bodylike formations in all cells, thrombocytopenia, and giant plts w/ function and shortened life span Dohle body-like formations = combination of rods and granules that are ribosomal in origin Inclusions are larger, more spindle shaped than oval, permanent and are found in monocytes and lymphocytes (unlike Dohle bodies) Asymptomatic D. Toxic Granulation Abnormally large or dominant primary granules Stress response to infection or inflammation Reflect a poorer prognosis Cellular stimulation (younger cells) may cause alteration in granulocyte membrane granules appear visibly larger and darker (Wright stain) Not a poor prognosis: toxic granulation pattern seen in granulocyte-monocyte colonystimulating factor treatment o Stimulation speed up devt and shorten marrow transit time younger cells w/ dark granules (functionally normal) Artifactual heavy granulation (poor staining) = seen homogeneously spread within each cell and in all granulocytes Toxic granulation = unevenly spread throughout the cytoplasm of certain cells

E. Dohle Bodies Round to oval neutrophil accumulation of rRNA 1-5 um in diameter Gray to light blue (Wright stain) Burns, infections, surgery, pregnancy, use of granulocye-macrohage colony-stimulating factor Appear shortly after the stimulating event First appear in storage pool cells F. Vacuolization Form by ingestion and degradation of bacteria or fungi Unevenly distributed Clinically significant when assoc w/ toxic granulation, degranulation, or Dohle bodies Autophagocytosis = seen with prolonged exposure to drugs such as antimicrobial agents and alcohol or radiation o Vacuoles are smaller and more evenly spaced o Jordans anomaly = familial disorder in w/c vacuoles are present in cytoplasm of granulocytes, monocytes and lymphocytes No apparent disease correlation Special staining: vacuoles are filled w/ lipids G. Necrobiosis Dead granulocytes Cells appear to have exploded nuclei and pale or nongranular cytoplasm