Benign White blood cell (WBC) Disorders

Benign White blood cell (WBC) Disorders

1. White Blood Cell (WBC) Disorders By Dr . Varughese George

2. Introduction Disorders of white cells include Proliferations ( leukocytosis ) reactive neoplastic . Deficiencies ( leukopenias ) Reactive proliferation of WBCs in response to an underlying primary, often microbial, disease is fairly common. Neoplastic disorders, though less common, are more ominous & cause approximately 9% of all cancer deaths in adults and a staggering 40% in children younger than 15 years. In this session, we ll discuss about non-neoplastic disorders of white cells.

3. Quantitative WBC Disorders Leukocytosis An increase in the number of white blood cells is common in a variety of inflammatory states caused by microbial & non-microbial stimuli. Leukocytoses are relatively non-specific & are classified according to the particular white cell series that is affected. In some cases reactive leukocytosis may mimic leukemia . Such “ leukemoid ” reactions must be distinguished from true white cell malignancies. Infectious mononucleosis merits separate consideration because it gives rise to distinctive syndrome associated with lymphocytosis .

4. Quantitative WBC Disorders Refers to an absolute neutrophil count >7500 /mm³. Causes include: Bacterial infections. Tissue damage or necrosis: e.g. surgery, burns, trauma, hyperthermia, myocardial infarction and other tissue necrosis . Inflammatory disorders: e.g. acute appendicitis, acute pancreatitis, colitis, vasculitis , rheumatoid arthritis. Acute stress or physical exertion, pregnancy, seizures Acute hemorrhage . Hemolysis : acute or chronic Metabolic disorders: diabetic ketoacidosis, uraemia, toxins, gout, Medications : e.g. lithium , corticosteroids, epinephrine, hematopoietic growth factors. Physiological: newborns , pregnancy, stress, exercise Haematological malignancies: myeloproliferative neoplasms, chronic myelomonocytic leukaemia, acute myeloid leukaemia Conditions like chronic idiopathic neutrophilia & hereditary neutrophilia . Neutrophilic leukocytosis

5. Quantitative WBC Disorders Pathogenesis Cytokines stimulate increased bone marrow production and/or early release of segmented neutrophils/bands in response to inflammation/infections. Decreased activation of neutrophil adhesion molecules Fewer neutrophils adhere to endothelial cells and become part of the circulating pool of neutrophils. Agents that decrease activation of neutrophil adhesion molecules include corticosteroids , catecholamines & lithium Neutrophilic leukocytosis

6. Quantitative WBC Disorders The most common cause of neutrophilic leucocytosis is bacterial infections particularly by Gram-positive cocci (Staphylococci) Bacterial infections are frequently associated with following alterations in peripheral blood — Neutrophilic leucocytosis with shift to left Toxic granules Döhle inclusion bodies : Cytoplasmic vacuoles: Neutrophilic leukocytosis

7. Quantitative WBC Disorders Neutrophilic leucocytosis with shift to left Normally neutrophils with 3 lobes predominate, while some have 4 lobes & only a few have 2 or 5 lobes. In mild to moderate left shift, immature cells are limited to band forms & metamyelocytes . In severe left shift, immature cells like myeloblast , promyelocytes & myelocytes are also seen Neutrophilic leukocytosis

8. Quantitative WBC Disorders Toxic granules These are dark blue or purple granules in the cytoplasm of segmented neutrophils, band forms,and metamyelocytes . They represent azurophil granules Toxic granules probably result from impaired cytoplasmic maturation while generating large number of neutrophils. Neutrophilic leukocytosis

9. Quantitative WBC Disorders Döhle inclusion bodies: These are small, pale blue inclusion bodies in the periphery of cytoplasm of neutrophils. They represent rows of rough endoplasmic reticulum Neutrophilic leukocytosis

10. Quantitative WBC Disorders Neutrophilic leukocytosis Cytoplasmic vacuoles: Cytoplasmic vacuoles are indicative of phagocytosis.

11. Quantitative WBC Disorders Neutrophilic leukocytosis There is neutrophilia with neutrophils constituting 88% of the differential leucocyte count. The patient had bronchopneumonia Band forms in peripheral blood Band forms of neutrophils are preponderant in children with bacterial infections. Note the cytoplasmic vacuoles and toxic granules in these cells.

12. Quantitative WBC Disorders Leukopenia Results most commonly from a decrease in granulocytes. Neutropenia For children from 1 month - 10 years old, neutropenia is defined as a absolute neutrophil count < 1500 / mm³ . For individuals older than age 10 years, neutropenia is defined as a absolute neutrophil count ≲ 1800 / mm³ . Agranulocytosis literally means a complete absence of blood granulocytes. indicates severe neutropenia, i.e , counts < 500 / mm³ . serious consequence of making individuals susceptible to bacterial and fungal infections.

13. Causes of neutropenia Inadequate or ineffective granulopoiesis Suppression of Hematopoietic stem cells (e.g. aplastic anemia) Infiltrative marrow disorders (tumors, granulomatous disease ). Suppression of committed granulocytic precursors (e.g., after drug exposure ). Disease states characterized by ineffective granulopoiesis in conditions such as m egaloblastic anemias [vitamin B12 deficiency] & m yelodysplastic syndromes [MDSs ] Rare inherited conditions ( e.g. Kostmann syndrome) impairing differentiation. Accelerated removal or destruction of neutrophils Neutrophil injury caused by immunologic disorders (e.g. systemic lupus erythematosus ) or drug exposures. Splenic sequestration as a result of splenomegaly. Increased peripheral use in overwhelming infections

14. Causes of neutropenia Drug toxicity Immune mediated destruction of neutrophils by drugs like aminopyrine , penicillin, gold and antithyroid drugs. Circulating immune complexes are formed in response to the inducing drug, which in turn bind to the neutrophils destroying them. Dose dependent direct toxic effect on granulopoiesis by drugs such as β lactam antibiotics, chlorpromazine,procainamide , clozapine, dapsone , sulfonamides, phenytoin, indomethacin & diclofenac , which are toxic to neutrophils, microenvironment of the bone marrow & myeloid precursors.

15. Morphology in neutropenia Marrow anatomic alterations depend on the underlying cause. Hypocellularity occurs with agents that suppress granulocyte progenitor cell growth and survival. these may be granulocyte specific or can potentially affect erythroid and megakaryocytic progenitors , leading to pancytopenia and aplastic anemia ( empty marrow ). Hypercellularity occurs in conditions with ineffective granulopoiesis (MDSs) or when there is increased peripheral destruction of neutrophils . Need to rule out other causes of neutropenia like subleukemic / aleukemic leukemia , megaloblastic anemia & aplastic anemia .

16. Morphology in neutropenia Note the characteristic maturation arrest at the stage of promyelocyte / myelocyte in the bone marrow smear from the severe congenital neutropenia patient. In contrast, immature and mature forms of neutrophils are found in a bone marrow smear from a healthy control. Bone marrow smear from a patient with neutropenia & a healthy person

17. Clinical features in neutropenia Symptoms & signs relate to intercurrent infections include malaise , chills & fever , often with marked weakness & fatigability . Serious infections are most likely when the neutrophil count ≤ 500cells/ mm³ . Ulcerating necrotizing lesions of the gingiva , buccal mucosa, or pharynx are characteristic. Severe , life-threatening, invasive bacterial or fungal infections can occur in the lungs , kidney or urinary tract. Neutropenic patients are at high risk for deep Candida/ Aspergillus infections. Infections are often fulminant. Neutropenic patients are therefore treated with broad-spectrum antibiotics at the first sign of infection. Granulocyte colony–stimulating factor therapy decreases the duration & severity of the neutrophil nadir caused by chemotherapeutic drugs .

18. Quantitative WBC Disorders Lymphocytosis Refers to an absolute lymphocyte count >5000 cells/ mm³ in adults or >8000 cells/ mm³ in children. Causes include: Infections Predominantly viral (e.g. infectious mononucleosis, dengue) Occasionally bacterial (e.g. pertussis and chronic infections like tuberculosis) Unusually parasites (e.g. babesiosis ) Stress and Postsplenectomy Hypersensitivity Reactions Autoimmune Disorders (e.g. Grave’s disease) Thymoma Clonal Monoclonal B cell lymphocytosis Lymphoproliferative disorders especially chronic lymphocytic leukaemia & lymphomas

19. Quantitative WBC Disorders Lymphocytosis Pathogenesis Decreased entry of lymphocytes into the lymph nodes. e.g . lymphocytosis-promoting factor produced by Bordetella pertussis (whooping cough ) Increased production of lymphocytes ( e.g. CLL).

20. Quantitative WBC Disorders Lymphocytosis Mature lymphocytes are increased in a case of tuberculosis

21. Quantitative WBC Disorders Lymphopenia Refers to absolute lymphocyte count of <1500 cells/ mm³ in adults or <3000 cells/mm³ in children Causes include: Human immunodeficiency virus (HIV )- AIDS caused by deficiency of CD4 T helper cells. Immunodeficiency disorders e.g. DiGeorge syndrome (T-cell deficiency), Severe combined immunodeficiency (SCID; B- and T-cell deficiency ), Bruton agammaglobulinemia (B-cell deficiency ), Wiskott Aldrich Syndrome. Infectious e.g . viral hepatitis, influenza, typhoid fever. Drugs e.g . Corticosteroids ,Cyclophosphamide, Cytotoxic chemotherapy Ionizing radiation. • Lymphocytes are the most sensitive cells to destruction by radiation

22. Quantitative WBC Disorders Eosinophilia Refers to an absolute eosinophil count of >400 cells/ mm³ in the peripheral blood. Causes include: Allergic Disorders Allergic rhinitis, asthma and atopic dermatitis. Gastrointestinal disorders – may be associated with tissue eosinophilia rather than peripheral blood eosinophilia. Drug reactions including the DRESS syndrome (drug reaction with eosinophilia and systemic symptoms). Parasitic Infections – especially with helminthic infestations Immunodeficiency Disorders Hyper IgE (Job) syndrome. Autoimmune lymphoproliferative syndrome. Graft-versus-host disease. Connective tissue/rheumatology disorders Neoplastic Diseases Primary/neoplastic hypereosinophilia , e.g. associated with FIP1L1-PDGFRA fusion gene . Myeloproliferative neoplasms such as chronic myeloid leukaemia & systemic mastocytosis Acute or chronic eosinophilic leukaemia . Reactive to other neoplasms, e.g. to B- or T-cell lymphoma or leukaemia or solid tumor.

23. Quantitative WBC Disorders Eosinophilia Pathogenesis : Caused by the release of eosinophil chemotactic factor (ECF) from mast cells Type I Hypersensitivity reactions Eosinophils in lymph nodes are not sequestered; hence, more eosinophils are circulating in the blood. e.g. hypocortisolism

24. Quantitative WBC Disorders Eosinophilia Eosinophilia in a case of tropical eosinophilia Some of the eosinophils show degranuation which are visible as clear vacuole like spaces (arrow ) Eosinophifia bone marrow biopsy shows eosinophils & their precursors are prominent in a case of eosinophilia (arrow )

25. Quantitative WBC Disorders Eosinopenia Refers to a decrease in the total number of circulating eosinophils in the peripheral blood. Hypercortisolism (Cushing syndrome, corticosteroids) is the most common cause of eosinopenia . Corticosteroids sequester eosinophils in lymph nodes and trigger apoptosis.

26. Quantitative WBC Disorders Basophilia Refers to an absolute basophil count > 110 cells / mm³ Causes include: Chronic myeloproliferative disorders Chronic myelogenous leukemia (CML) Polycythemia vera Allergic reactions Varicella infections. Rare cases like Acute basophilic leukemia

27. Quantitative WBC Disorders Basophilia Peripheral blood film from a case of CML shows immature myeloid precursors with 2 basophils (arrows) having coarse basophilic granules covering the nuclei. Pericellular pinkish halo is useful In identifying basophils in the peripheral smear and in bone marrow smears.

28. Quantitative WBC Disorders Monocytosis Refers to an absolute monocyte count > 800 cells / mm³ . Causes include: Chronic infections/inflammation: e.g. Tuberculosis, subacute bacterial endocarditis, syphilis, rickettsia, malaria, typhoid , kala-azar Haematological malignancies : e.g. Acute myelomonocytic leukaemia (AML M4), acute monocytic leukaemia (AML M5), myeloproliferative neoplasms, chronic myelomonocytic leukaemia, myelodysplastic syndrome, Others : e.g. Sarcoidosis , ulcerative colitis, regional enteritis, carcinomas Pathogenesis: Immune response to chronic inflammation, autoimmune or malignancy

29. Quantitative WBC Disorders Monocytosis Peripheral blood film demonstrates increased monocytes

30. Quantitative WBC Disorders Unusual benign leukocyte reactions Leukemoid reaction Refers to an absolute leukocyte count that is usually > 50,000 – 1,00,000 cells/mm ³ . It is caused by normal bone marrow response to cytokines released by cells (e.g., lymphocytes, stromal cells, macrophages) to severe infection (most common), trauma , burns , malignancies (especially with bone marrow metastases), myelofibrosis , hemorrhage / hemolysis & eclampsia . The triggering factors induces proliferation of precursors in the bone marrow caused by increased production of colony-stimulating factors and thus compensates for the loss of these cells in the inflammatory reaction . The reaction can be predominantly granulocytic that includes prdominantly mature / segmented neutrophils followed by few bands & metamyelocyte ; lymphocytic as seen in children with e.g. whooping cough & o ccasionally monocytic .

31. Quantitative WBC Disorders Unusual benign leukocyte reaction s Leukemoid reaction Neutrophil leukemoid reaction in the peripheral blood. Note the great number of segmented and band neutrophils as well as metamyelocytes (red arrow) . This smear would be difficult to distinguish from chronic myelogenous leukemia without chromosome studies.

32. Parameters Leukemoid reaction Leukemia Clinical features As per underlying disease Splenomegaly Total white cell count Increase usually only moderate; seldom exceeds 1,00,000 cells/mm ³ Can exceed 1,00,000 cells/mm ³ Proportion of immature cells Usually small or moderate. Myelocytes seldom exceed 5-15% & blasts 5 % Usually numerous White cell morphology Toxic changes may be seen in infective cases Cells often atypical & immature. Toxic changes uncommon. Bone marrow White cell hyperplasia may be present but seldom to same degree as in leukaemia Hyperplastic with potentially large proportion of immature cells Neutrophil Alkaline Phosphatase Score Normal or increased Low Genetic analysis Normal Abnormal ( eg Philadelphia Chromosome) LEUKEMOID REACTION V/S LEUKEMIA

33. Quantitative WBC Disorders Unusual benign leukocyte reactions Leukoerythroblastosis ( leukoerythroblastic reaction ) Refers to the presence of immature myeloid & nucleated red blood cells ( normoblasts ) in the peripheral blood, irrespective of the total leukocyte count. It often occurs as a consequence of disturbance of the bone marrow architecture by abnormal tissue. Example of a leukoerythroblastic reaction with a normal bone marrow severe acute hemolytic anemia (e.g., sickle cell disease ).

34. Quantitative WBC Disorders Leukoerythroblastosis ( leukoerythroblastic reaction ) Examples of a leukoerythroblastic reaction with an abnormal bone marrow include : bone marrow infiltrative disease (e.g., amyloidosis), metastatic malignancy (e.g., breast cancer). granulomatous disease (e.g., tuberculosis [TB], systemic fungal disease, sarcoidosis ). hematologic malignancies (e.g., acute leukemia , multiple myeloma) chronic myeloproliferative diseases (e.g., primary myelofibrosis ). Other causes include massive trauma with multiple fractures, Paget disease of bone & extramedullary hematopoiesis (EMH). Unusual benign leukocyte reactions

35. Quantitative WBC Disorders Leukoerythroblastosis ( leukoerythroblastic reaction) The blue arrow shows a teardrop red blood cell (RBC). Immature myeloid cells are also present . A nucleated RBC (red arrow ) . Unusual benign leukocyte reactions

36. Quantitative WBC Disorders Unusual benign leukocyte conditions Infectious mononucleosis Disease of the young (15-25 years of age) caused by Epstein-Barr Virus (EBV ). Characterized by fever, sore throat ,cervical lymphadenopathy & splenomegaly. There is a response of cytotoxic T-lymphocytes (CD8+) subset reflected by the presence of atypical/reactive (transformed ) lymphocytes in the peripheral blood to infected B-lymphocytes present especially in the tonsils. Atypical / Reactive lymphocytes

37. Quantitative WBC Disorders Atypical / Reactive lymphocytes Unusual benign leukocyte conditions Infectious mononucleosis There is moderate degree of leucocytosis with a TLC of 10000 - 25000 cells/mm³ . Reactive lymphocytosis > 50% is present . Besides the presence of mature lymphocytes, there are large number of atypical lymphocytes and should be > 10%. These cells appear on 3rd -4th day of fever and persist for several months.

38. Quantitative WBC Disorders Atypical / Reactive lymphocytes Unusual benign leukocyte conditions Transformed benign lymphocytes as a result of antigen stimulation. There is marked variation in cell size and morphology. Cells are large with abundant pale blue cytoplasm. The nuclei may be round,oval , tabulated or eccentric and few may have open nuclear chromatin ( blastoid ). Some cells with foamy basophilic cytoplasm and kidney shaped nucleus ( monocytoid cells). Some cells have eccentric nuclei with pale basophilic cytoplasm ( plasmacytoid cells ). Some cells have irregular nuclei with cytoplasmic vacuulation . These are not pathognomonic for IM since similar cells are observed in other viral infections also.

39. Quantitative WBC Disorders Atypical/Reactive Lymphocyte Peripheral blood smear showing monocytoid atypical/reactive lymphocytes. The lymphocytes are large and have abundant blue-gray cytoplasm. Nuclei are irregular and have dark chromatin with inconspicuous nucleoli . Peripheral blood smear showing plasmacytoid atypical/reactive lymphocytes which are T cells in response to B cells infected by Epstein-Barr Virus. There is variation in the cell size and morphology.

40. Quantitative WBC Disorders Atypical/Reactive Lymphocyte Reactive lymphocytes are also referred to as Downey cells . There are three types of Downey cells: ■ Type I: Small cells with minimum cytoplasm, indented nucleus/ irregular nuclear membrane, and condensed chromatin. ■ Type II: Larger cells with abundant cytoplasm; the lymphocyte cytoplasm seems to hug the red cells. Type II is the most common type of Downey cell. ■ Type III: Cells with large moderate basophilic cytoplasm and nucleus with coarse chromatin. Nucleoli are apparent Type I Type II Type III

41. Quantitative WBC Disorders Atypical/Reactive Lymphocyte Ballerina Skirt Cells - Characterisitic appearance of atypical lymphocytes in Infectious Mononucleosis. These are Downey Type II cells which are large cells  with abundant agranular pale cytoplasm and indented by surrounding red blood cells.

42. Qualitative WBC Disorders Rare familial disorders which manifest morphologic and functional changes in the leucocytes. Few disorders are picked up while examining the peripheral smear and/or bone marrow. Pelger-Huet Anomaly Alder-Reilly Anomaly May- Hegglin Anomaly. Chediak - Higashi Anomaly Chronic Granulomatous Disease of Childhood Myeloperoxidase deficiency Leucocyte adhesion defect Hyper IgE / Jotfs syndrome Catalase deficiency CARD 9 deficiency Giant neutrophils

43. PELGER-HUET ANOMALY A benign autosomal dominant anomaly of leukocytes. Neutrophils demonstrate lack of segmentation of nuclei with bilobed /band forms/dumb-bell shaped/smooth rounded small nuclei in > 70 % of neutrophils. < 25% band forms are present in peripheral blood. The nuclear chromatin is coarse . Confused with leukemoid reaction. A similar morphological appearance of neutrophils (Acquired or pseudo- Felger Huet anomaly) is seen in MDS . AML, CML and multiple myeloma.

44. ALDER REILLY ANOMALY An autosomal recessive disorder Neutrophils demonstrate large, darkly staining metachromatic cytoplasmic granules composed primarily of partially digested mucopolysaccharides referred to as Alder-Reilly bodies. Similar inclusions are also seen in lymphocytes and monocytes. Observed in Hurler syndrome & Hunter syndrome and the cell function is normal. Note the dark granules present in both cells in two neutrophils from a patient with Alder-Reilly anomaly.

45. MAY-HEGGLIN ANOMALY A rare autosomal dominant disorder characterised by the presence of basophilic inclusions in neutrophils, eosinophils , basophils and monocytes . This is associated with giant platelets and variable thrombocytopenia. A neutrophil and a giant platelet from a patient with May- Hegglin anomaly. Note the large, elongated, bluish inclusion in the neutrophil cytoplasm (arrow)

46. CHEDIAK HIGASHI ANOMALY This as an autosomal recessive disease characterized by partial cutaneous and ocular albinism, increased susceptibility to pyogenic infections and bleeding tendency due to abnormal platelet function . It is due to the defect in the leukocyte NADPH oxidase-respiratory burst, oxidase . Neutrophils and their precursors demonstrate inclusion like large single/multiple lysosomal granules (arrows). As the disease progresses, there is progressive anemia, neutropenia & thrombocytopenia .

47. CHEDIAK HIGASHI ANOMALY Large rounded granules are also seen in lymphocytes, monocytes & eosinophils . These granules are myeloperoxidase positive

48. CHRONIC GRANULOMATOUS DISEASE OF CHILDHOOD characterized by morphologically normal leucocytes which fail to generate superoxide and hydrogen peroxide & therefore phagocytosis and killing of organisms is impaired. These cases are susceptible to infections by organisms of low pathogenicity . A second hallmark feature is the development of inflammatory granulomas . Clinical features include recurrent, infections of skin, lungs and epithelial surfaces and hepatosplenomegaly . Management includes bone marrow transplantation & gene therapy.

49. CHRONIC GRANULOMATOUS DISEASE OF CHILDHOOD Normal neutrophils, when stimulated reduce the yellow water-soluble nitroblue tetrazolium to a dark blue insoluble formazan . In the nitroblue tetrazolium reduction test Neutrophils in chronic granulomatous disease CANNOT perform this reduction

50. MYELOPEROXIDASE DEFICIENCY It is the most common hereditary neutrophil function defect. There is absence of myeloperoxidase (MPO) enzyme in the neutrophils & monocytes, however, the cell morphology is normal on peripheral smear. The intracellular killing of microorganisms is slower than normal PMNs but it is eventually achieved  so infections are not a major complication. But there is an increased susceptibility to Candida & staphylococcal infections. Diagnosis is confirmed by MPO stain of the blood smear that demonstrates a lack of peroxidase in the neutrophils. Peroxidase activity in polymorphonuclear neutrophils (PMN) from a healthy subject (Normal PMN) & an individual with myeloperoxidase (MPO) deficiency (as indicated). Panel at far right indicates normal peroxidase activity in an eosinophil isolated from an individual with MPO deficiency as eosinophil peroxidase is encoded by another gene than MPO.

51. LEUCOCYTE ADHESION DEFICIENCY It is a rare autosomal recessive disorder, characterised by absence of leucocyte cel ! surface adhesion proteins CD11/CD1 8 . These surface glycoproteins play an important role in the cell's ability to kill microorganisms. Neutrophils with LAD are morphologically normal, but have multiple functional abnormalities related to adhesion, motility ( chemotaxis ), phagocytosis, degranulation and respiratory burst activation. Patients present with recurrent bacterial and fungal infections with persistent leucocytosis . Diagnosis can be established by flow cytometric analysis of CD11/GD18 levels in neutrophils using monoclonal antibodies. These patients require prophylactic antibiotics and prompt treatment of infections .

52. HYPER IgE /JOB SYNDROME It is a rare congenital disorder, characterized by defective neutrophil chemotaxis . Patients present, with recurrent bacterial , fungal and viral infections. The most common pathogens are Staphylococcus aureus and Candida species. The most common laboratory findings are blood eosinophilia & raised IgE levels. This infant with markedly elevated IgE experienced early onset of a pruritic dermatitis that shared clinical features with both seborrhea and atopic dermatitis. The perinasal crusting caused by Staphylococcus aureus infection .

53. CATALASE DEFICIENCY The catalase enzyme plays a crucial role in protecting neutrophils from products of NADPH oxidase by converting H 2 2 to H 2 and 0 2 . In catalase deficiency, the surface of neutrophil becomes very susceptible to damage by H 2 2 . However, these patients do not manifest with very severe infections.

54. CARD 9 (CASPASE ASSOCIATED RECRUITMENT DOMAIN) DEFICIENCY Caspase recruitment domain-containing protein 9 deficiency is a rare immunologic disorder because of mutation in CARD 9 gene &results in defective defence against pathogen fungi like Candida. CARD 9 protein plays a role in apoptosis. Mucocutaneous candidiasis is associated with CARD9 deficiency .

55. GIANT/HYPERSEGMENTED NEUTROPHILS Giant neutrophils are larger & hypersegmented ( macropolycytes ) found in the peripheral blood of individuals with Vitamin B12 & folic acid deficiency. Seen rarely in families as an inherited condition & observed in AIDS cases . Giant neutrophils, large myeloid precursors and few binucleate promyelocytes are also seen in bone marrow and peripheral blood following G-CSF therapy. The granulopoiesis is ineffective, accelerated & skipping of 1 or 2 mitotic divisions without cytoplasmic division may result in morphologically abnormal giant neutrophils. Neutrophils have 6 to 10 nuclear segments & are > 5% of all the peripheral blood neutrophils.

56. GIANT/HYPERSEGMENTED NEUTROPHILS These are larger & hypersegmented neutrophils ( macropolycytes ). They are found in peripheral smear of patients with Vitamin B 12 & folic acid deficiency. These are also seen rarely in families as an inherited condition & in AIDS. Giant neutrophils, large myeloid precursors & few binudeate promyelocytes are also seen in bone marrow & peripheral blood following G-CSF therapy. The granulopoiesis is ineffective but accelerated & skipping of one or two mitotic divisions without cytoplasmic division may result in morphologically abnormal giant neutrophils. Neutrophil hypersegmentation can be defined as the presence of neutrophils ≥ 6 lobes or the presence of more than 3% of neutrophils with at least 5 lobes.