B e n i g n L e u k o c y t o s e s
Normal neutrophil physiology
Myeloid cell growth and differentiation
Neutrophil Pools
1. Marrow (95%)
• dividing = 25%
• storage = 75%
2. Blood (5%)
• marginal = 50%
• circulating = 50%
Neutrophil Count
1. Normal range = 2.0 - 8.0 x 10 /L
2. Physiologic variations:
a. Hormone-related
• Women between 20 and 49 (increased count)
• Pregnancy (increased count)
• Menstruation (increased count)
• Post-menopausal state (increased count)
• Strenuous exercise (increased count)
b. Race (blacks show greater range in counts than whites)
c. Diurnal variation (evening > morning)
d. Miscellaneous
• Stress (increased count)
• Cigarette smoking (increased count)
• Alcohol use (increased count)
Mechanisms of the Neutrophil Response
• Demargination
• Mobilization
• Increased production
• Increased transit time in blood
Stimulators of the Neutrophil Response
• Colony-stimulating factor (CSF)
• Catecholamines
• Steroids
• Endotoxins
• Bone destruction
Neutrophilic Leukocytoses
Proliferation of Mature Neutrophils
1. Infection. Often see toxic changes in neutrophils in infection:
• Toxic granulation
• Döhle bodies
• Cytoplasmic vacuolization
2. Inflammation
3. Malignant disease
4. Metabolic disease
5. Redistribution
Proliferation of Immature Neutrophils
1. Left shift
a. Definition: Increased early neutrophil precursors in blood.
(Officially: should see at least 2 metamyelocytes, 1 myelocyte, or
1 promyelocyte per 100 WBCs.)
b. Causes:
• Infections. Remember: look for toxic changes!
• Inflammation/necrosis.
• Brisk hemolysis or hemorrhage.
• Space-occupying lesions in marrow, such as granulomas or cancer.
2. Leukemoid reaction (Bad term! Don’t use!)
a. Definition: Very high neutrophil count with or without marked left shift
(leukemia-like blood picture in absence of leukemia).
b. Causes:
• Chronic infections. Remember: look for toxic changes!
• Malignancies.
• Severe stresses: metabolic, inflammatory, infectious.
3. Leukoerythroblastotic reaction (LEBR)
a. Definition: Very early neutrophil precursors and erythroid precursors
in blood.
b. Causes:
1. Malignant (2/3 of cases)
• Carcinoma
• Lymphoma
• Leukemia
2. Benign (1/3 of cases)
• Anemia
• Sepsis. Remember: look for toxic changes!
Normal Lymphocyte Physiology
Lymphocyte Growth and Differentiation
• Most lymphoid stem cells in adults are in bone marrow.
• Growth factors (including IL-2) induce differentiation into T, B, and NK cell
precursors which then travel to different organs (e.g., lymph nodes, spleen,
thymus, mucosa-associated lymphoid tissue) for further processing.
Lymphocyte Count
1. Normal range varies with age.
• Highest in infants (at 2 weeks: 2.0 - 17.0 x 10 /L)
• Intermediate in children (at age 4: 2.0 - 8.0)
• Lowest in adults (by age 18: 1.0 - 4.0)
2. Normal immunophenotype of blood lymphocytes:
• T cells: 60 - 80%
• B cells: 10 - 20%
• NK cells: 5 - 10%
Lymphoid Leukocytoses
Proliferation of Mature Lymphocytes
• Infectious lymphocytosis (note: lymphocyte count = 35 – 100)
• Whooping cough (Bordetella pertussis) (note: lymphocyte count = 10 – 55)
• Transient stress lymphocytosis (note: lymphocyte count = 6 – 8)
Proliferation of Reactive Lymphocytes
1. Types of reactive lymphocytes
• Downey I lymphocytes (small cells with lobed nuclei and scant,
compact cytoplasm)
• Downey II lymphocytes (large cells with copious cytoplasm
containing radial striations)
• Downey III lymphocytes (large cells with reticular chromatin)
• Plasmacytoid lymphocytes
• Plasma cells and their precursors (immunoblasts and proplasmacytes)
2. Causes of reactive lymphocytosis
• Infectious mononucleosis (IM)
• Lymphocyte count = 10 – 30
• Downey lymphocytes
• Pediatric viral infections (rubella, rubeola, mumps, chickenpox)
• Lymphocyte count = 4 – 10
• Downey I lymphocytes
• Proplasmacytes and plasma cells
• Viral hepatitis
• Lymphocyte count = 4 – 10
• Proplasmacytes and plasma cells
• Immune disorders (autoimmune diseases, drug reactions, immunization)
• Immunoblasts
Differentiating Benign from Malignant Leukocytoses
Neutrophilic Leukocytoses
1. Left shift
• Fewer immature cells than in CML.
• Toxic changes present, if infectious cause.
• No basophilia.
• LAP normal or increased.
• Very high WBC (50,000 - 100,000) with marked left shift and
"bulges" at the myelocyte and segmented neutrophil stages.
• Concurrent basophilia.
• LAP (leukocyte alkaline phosphatase) decreased or absent.
Lymphoid Leukocytoses
1. Reactive lymphocytosis
• Increased number of atypical lymphocytes.
• Most commonly occurs in young patients (<40).
2. Mature lymphocytosis
• Increased number of mature lymphocytes.
• Most commonly occurs in very young patients (<14).
• Monomorphous population of mature-appearing lymphocytes.
• Generally occurs in older patients (>40).
Other Leukocytoses
Monocytosis
• Normal = 0.3 - 0.5 x 10 /L
• May be associated with malignancies, autoimmune disease, and infection.
Basophilia
• Normal = 0.01 - 0.1 x 10 /L
• Always rule out CML!
• May see a slight basophilia in severe iron deficiency anemia or renal failure.
Eosinophilia
• Normal = 0.05 - 0.3 x 10 /L
• Frequent causes:
• Drug allergies
• Bronchial asthma
• Skin diseases
• Occasional causes:
• Intestinal parasitism
• Chronic ulcerative colitis
• Chronic active hepatitis
• Sarcoidosis
