LEUKOCYTE DISORDERS MM Khan May 14, 2013

Lecture: [Path] Leucocytic disorders Objectives The objective of the lecture is to discuss leukocytosis, agranulocytosis, leucopenia, and leukemoid reactions; acute and chronic leukemia Learning Outcomes At the end of the lecture, students should be able to Explain the terms leukocytosis, leucopenia , agranulocytosis and leukemoid reactions List the causes of leukocytosis, , leucopenia , agranulocytosis and leukemoid reactions Define and classify leukemia Explain the etiopathogenesis and clinical manifestation of acute lymphoblastic(ALL) and chronic lymphocytic leukemia(CLL) Discuss the etiology, clinical manifestation, blood and marrow morphology of acute lymphoblastic and chronic lymphocytic leukemia Classify acute myelogenous leukaemia(AML) using the Revised FAB classification Discuss the etiology, clinical manifestation, blood and marrow morphology of acute myelogenous leukaemia(AML) and chronic myelocytic leukemia(CML)

Granulopoiesis-Myeloid series

Granulopoiesis-Lymphoid series

myeloblast promyelocyte metamyelocyte myelocyte eosinophil neutrophil Band form basophil

monoblast monocyte

Small lymphocyte lymphoblast Large lymphocyte

myeloblast promyelocyte metamyelocyte myelocyte Band form neutrophil eosinophil basophil monoblast monocyte lymphoblast lymphocyte

Morphology of mature leukocytes in PB

Normal white cell counts

Leukocyte disorders leukocytosis leukopenia neutrophilia neutropenia lymphocytosis lymphopenia eosinophilia basophilia monocytosis leukemoid reaction leukemia

LEUKOCYTE DISORDERS Changes in leukocyte count and morphology often reflect disease processes 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.

Neutrophil disorders Neutropenia Neutrophilia < 1500 /cu.mm. Viral infection Drug Aplastic anemia Cyclic neutropenia bacterial infection Inflammation Acute blood loss Acute hemolysis stress

Eosinophilia > 200 /cu.mm Causes: allergic reaction parasitic infestation skin diseases malignancy idiopathic

Basophilia > 100 /cu.mm. chronic myelocytic leukemia (CML) Polycythemia vera (PV) Chronic sinusitis

Lymphocyte Lymphopenia Lymphocytosis < 1500 /cu.mm. viral infection Chronic infection CLL immune deficiency Acute infection

Monocytosis > 950 /cu.mm chronic infection Hodgkin disease Acute monoblastic leukemia (AML) Chronic myelomonocytic leukemia (CML)

Neutrophil disorders Neutropenia Neutrophilia < 1500 /cu.mm. Viral infection Drug Aplastic anemia Cyclic neutropenia bacterial infection Inflammation Acute blood loss Acute hemolysis stress

Neutrophil disorders The peripheral neutrophil count depends upon Bone marrow production and release The rate of neutrophil movement into the tissues The proportion of circulating to marginating neutrophils Destruction or loss of neutrophils

Neutrophilia Physiological – may occur without tissue damage or other pathologic stimulus. Results from a simple redistribution of cells from the marginal pool to the circulating pool May occur after violent exercise, epinephrine administration, anesthesia, or anxiety Is also called shift neutrophilia

Neutrophilia Pathological neutrophilia are: 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)

Neutrophilia Leukemoid reaction – this is an extreme neutrophilia with a WBC count > 30 x 109/L Many bands, metamyelocytes, and myelocytes are 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

Neutropenia Neutropenia – this may result from Decreased bone marrow production 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

Neutropenia Increased cell loss Early in an infection there is a transient decrease due to increased movement of cells into the tissues Could be due to an immune mechanism such as production of anti-leukocyte antibodies Hypersplenism Pseudoneutropenia – alterations may occur in the circulating to marginating pools. This may be seen in: Viral infections Bacterial infections with endotoxin production Hypersensitivity reactions

Eosinophil disorders Eosinophilia may be found in 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

Basophil disorders Basophilia Is associated with chronic myeloproliferative disorders (discussed later) Inflammatory bowel disease Radiation exposure

Monocyte disorders Monocyte quantitative and qualitative disorders Associated with malignancies

Macrophage disorders Lipid storage diseases – the cells are unable to completely digest phagocytosed material 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

Lymphocyte disorders Acquired, quantitative 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

Lymphocyte disorders- Lymphocytosis Lymphocytosis – may be relative (secondary to neutropenia) or absolute (usually seen in viral infections); if absolute it may or may not be 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 IN IM

Lymphocytosis Cytomegalovirus infection Infectious lymphocytosis Leukocytosis with absolute lymphocytosis Infectious lymphocytosis Unknown etiology 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 in B. PERTUSSIS INFECTION

Lymphocytosis Lymphocytic leukemoid reaction – Peripheral smear shows increased lymphocytes with younger lymphocytes being seen Can occur with tuberculosis, chickenpox and the viral diseases discussed above

Lymphocytosis Plasmocytosis Plasma cells are rarely seen in the peripheral blood, but they may be found under conditions of intense immune stimulation

Lymphocytopenia Lymphocytopenia – caused by stress, drugs, irradiation, and some diseases

Causes of leukocytosis Neutrophilic leukocytosis (neutrophilia) Acute bacterial infections, especially pyogenic infections Sterile inflammation Tissue necrosis Myocardial infarction Burns Eosinophilic leukocytosis (eosinophilia) Allergic disorders Asthma Hay fever Drug allergies Allergic skin diseases Parasitic infections Some forms of malignancy Hodgkin's lymphoma Some forms of Non-Hodgkin lymphoma Systemic lupus erythomatouse (SLE) Basophilic leukocytosis Basophilia Chronic myelogenous leukemia Monocytosis Chronic infections Tuberculosis Bacterial endocarditis Rickettsiosis Malaria Inflammatory bowel diseases, e.g. ulcerative colitis Lymphocytosis Brucellosis Viral infections Hepatitis Cytomegalovirus infection Infectious mononucleosis Pertussis

CAUSES OF LWUKOPENIA Decreased production Drug-induced—alkylating agents (nitrogen mustard, busulfan, chlorambucil, cyclophosphamide); antimetabolites (methotrexate, 6-mercaptopurine, 5-flucytosine); noncytotoxic agents [antibiotics (chloramphenicol, penicillins, sulfonamides), phenothiazines, tranquilizers (meprobamate), anticonvulsants (carbamazepine), antipsychotics (clozapine), certain diuretics, anti-inflammatory agents, antithyroid drugs, many others] Hematologic diseases—idiopathic, cyclic neutropenia, Chédiak-Higashi syndrome, aplastic anemia, infantile genetic disorders, Tumor invasion, myelofibrosis Nutritional deficiency—vitamin B12, folate (especially alcoholics) Infection—tuberculosis, typhoid fever, brucellosis, tularemia, measles, infectious mononucleosis, malaria, viral hepatitis, leishmaniasis, AIDS Peripheral destruction Antineutrophil antibodies and/or splenic or lung trapping Autoimmune disorders—Felty’s syndrome, rheumatoid arthritis, lupus erythematosus Drugs as haptens—aminopyrine, α-methyldopa, phenylbutazone, mercurial diuretics, some phenothiazines Wegener’s granulomatosis Peripheral pooling (transient neutropenia) Overwhelming bacterial infection (acute endotoxemia) Hemodialysis Cardiopulmonary bypass