1. LEUKOCYTE DISORDERS
MM Khan
May 14, 2013

2. 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)

4. Granulopoiesis-Myeloid series

5. Granulopoiesis-Lymphoid series

6. myeloblast
promyelocyte
metamyelocyte
myelocyte
eosinophil
neutrophil
Band form
basophil

7. monoblast
monocyte

8. Small lymphocyte
lymphoblast
Large lymphocyte

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

10. Morphology of mature leukocytes in PB

11. Normal white cell counts

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

13. 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.

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

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

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

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

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

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

20. 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

21. 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

22. 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)

23. 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.

24. LEUKEMOID REACTION

26. 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

27. 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

28. 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

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

30. Monocyte disorders Monocyte quantitative and qualitative disorders
Associated with malignancies

31. 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

32. 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

33. 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

34. ATYPICAL LYMPHOCYTE IN IM

35. 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

36. LYMPHOCYTOSIS in B. PERTUSSIS INFECTION

37. 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

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

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

40. 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

41. 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