Leucocytoses & leucopenia
Jo Caers Dept of Clinical Hematology [email protected] Bone marrow
Blood Granulopoiesis
Proliferation & 5 days maturation
Storage 1 day
Marginisation& Circulation 1 day
Tissues 1-2 days Granulopoiesis
Proliferation & 5 days maturation
Storage 1 day
Marginisation& Circulation 1 day
Tissues 1-2 days Granulopoiesis
Proliferation & 5 days maturation
Storage 1 day
Marginisation& Circulation 1 day
Tissues 1-2 days Lymphocytes Monocytes NORMAL BLOOD CELL COUNT
Hemoglobin 12.0 – 15.0 g/dl (F) 13.0 – 17.0 g/dl (M) Red Blood Cells 3.9 – 5.6 x 10 6/µl (F) 4.5 – 6.5 x 10 6/µl (M) Hematocrit 36 – 48% (F) 40 – 52% (M) Mean Corpuscular Volume 80 – 95µ³ Mean Hb Concentration 27 – 34 pg Conc corp mean Hb 30 – 35 g/dl Reticulocytes 0.5 – 20 % Leucocytes 4.0 – 10.0 x 10 3/µl ¨ Neutophils 1.8 – 7.5 Lymphocytes 1.5 – 3.5 Monocytes 0.2 – 0.8 Eosinophils 0.04 – 0.45 Basophils 0.01 – 0.1 Platelets 100 – 400 x 10 3/dl Hyperleucocytosis > 10.000 WBC/mm³
Normal Cells Abnormal cells or blastic cells
Infections ? Neutrophilia (> 7.500/mm³) Acute Leukemias Lymphocytosis (> 4.500/mm³) Chronic Myelomonocytic Leukemias Chronic Lymhocytic leukemia Chronic Myeloid Leukemia Non Hodgkin Lymphoma Chronic Monocytosis (> 800/mm³) … Inflammations? Eosinophilia (> 400/mm³) Basophilia (> 100/mm³) Leukoerythroblastic reaction
Cytopenia with immature RBCs (normoblasts) immature WBCs (agranular neutrophils, myelocytes, metamyelocytes ) Causes BM infiltration • Solid tumor or hematological malignancy • Myelofibrosis Strong BM stimulation • Infection, inflammation, hypoxia, trauma • Severe Hemolytic or megaloblastic anemia • Massive bleeding Leukemoid reaction
Leucocytosis ( > 50.000) similar to CML Causes - Infection (TB…) - Stress or infection in newborns - Intensive care Laboratory abnormalities - WBC > 50,000/µL - Formula deviated: immature WBC → hyposegmented neutrophils → métamyelocytes, myelocytes, promyelocytes, Neutropenia
Neutrophilcount Riskof infection 1.000-1.500 No significant increase in infection risk 0.500-1,000 Some increased risk in infection (can generally be treated as an outpatient) <0.500 Major increased infection risk (treat all fevers with broad spectrum IV antibiotics as an inpatient CASE 1: ♂ 26 years old
BLOOD CELL COUNT Differential Counts (%)
- Blasts 1.77 WBC (10 9/L) - Myélocytes 5.88 RBC(10 12 /L) - Métamyelocytes 16.8 Hb(g/dl) 44 Hct (%) - Non segmented 80.7 MCV (fl) 15 Neutrophils 28.4 CMH (pg) 74 Lymphocytes 34 CCMH (g/L) 11 Monocytes 9 MPV (fl) 0.0 Eosinophils 183 Platelets 0.0 Basophils Inherited - Benign familial or racial neutropenia (Africa) - Kostmann Syndrome - Chediak-Higashi - Shwachman-Diamond syndrome - Cyclic Neutropenia: cycles of 3-4 weeks Acquired - Infection * Sepsis * Viral (HIV, HC, CMV, influenza…) - Drug induced - Immune * Auto-immune (Ac anti-neutrophils) * Lupus * Felty = RA + neutropenia and splenomegaly * Chronic benign neutropenia - Hypersplénism - Idiopathic - Pancytopenia (AA, MF, MDS, hematological malignancies) Drug-induced
• Definitions - Neutropenia < 2,000 / µL - Agranulocytosis < 500 / µL
• Plusieurs mécanismes
(1) Central : ↓ granulopoiesis : dose-response effect (2) Central : ineffective granulopoïesis : dose-response effect (3) Periphery: Ab-mediated destruction : no dose-response Central Peripheral
• production • destruction • Toxic • Immunologic • Dose-response effect • No dose-response effect • Progressive • Abruptly • Recovery: 2-4 weeks • Recovery: 1-2 weeks
eg : chemotherapy eg : phenylbutazone • Médicaments
- Rituximab delayed - Azathioprime, MMF C - Metamizol / amidopyrine / noramidopyrine 1/100 P - Phenylbutazone 1/100 P - Phenothiazine C - Thyroid (propylthiouracil , carbimazol) 1/100 C - Anti-epileptics (phenobarbital, DPH, mysoline, carbamazepine) C - Sulfonamides (cotrimoxazole , salazopyrine, chlorpropamide, dapsone) C/P - Indomethacine, diclofenac - Levamizole 2/100 P - Ticlopidine 2/100 P - Deferiprone 5/100 P - Clozapine 1/100 P - Antibiotics β-lactams P - Spironolactone - Procainamide CASE 1: ♂ 26 years old
• BM cytology: normal granulopoiesis (normal differentiation) and erythropoiesis • Ultrasound abdomen: nl • Nl iron and vitamin status
• Anti-nuclear antibodies: 1/1280 anti-SSA • Anca – • Rheumatoid factor - CASE 2 : ♂ 42 years old
Leukocytosis discovered during routine « check-up » Complaints of fatigue and flu-like syndrome Examination: mild splenomegaly CASE 2 : ♂ 42 years old
BLOOD CELL COUNTS DIFFERENTIAL (%) - Blasts 39.86 + WBC (10 9/L) 1+ Myelocytes 5.13 RBC (10 12 /L) 2+ Métamyelocytes 15.0 Hb (g/dl) Non segmented 44.6 Hct (%) + 86.9 MCV (fl) 84 Neutrophils 29.3 CMH (pg) 2- Lymphocytes 33.8 CCMH(g/L) 2 Monocytes 13.3 MPV (fl) - Eosinophils 695 + Platelets 9+ Basophils Neutrophilia • Etiologie - Infection - Inflammation (trauma, infarctus, vasculitis, rheumatology) - Drugs G-CSF, GM-CSF ( production & liberation) Corticosteroides (demargination ) Adrenalin (demargination ) - Tabac - Anesthesia, surgery - Exercice - Cold, heat stroke, burns, seizures - Cancer - Chronic stimulation of the BM (bleeding, hemolysis, iTP) - Post-splenectomy - Myéloproliferative disorders - Idiopathic MYELOPROLIFERATIVE NEOPLASMS CML MF PV ET
Hématocrit N ou ↑ ↓↓ ↑↑ N
Leucocytes ↑↑ ↑ ou ↑↑ ↑↑ ou N N
Platelets ↑↑ ou N N ou ↓ ↑ ou N ↑↑
Splénomégaly +++ +++ + +
LAP ↓ N ↑↑ N
Fibrosis N ou ↑↑ +++ N ou ↑↑ N ou ↑↑
Cytogénétics Phi + Jak2 Jak2 (95%) Jak2/CalR
Median Survival 12 1 –5 ans 10 + ans 10 + ans
Acute leukemia <20% ? 10% < 10% < 10% Basophilia
• Causes - Myeloproliferative neoplasms – CML – PV – TE – MF – Basophilic leucemia • Hypersensitivity reactions IgE–mediated • Inflammatory diseases (RA, RCUH, Crohn) Viral infections • Hypothyroidism • Hyperlipidemai • Oestrogens • Hyperlipidemia CASE 3: ♀ 45 years old
• Leucocytosis discovered during « check-up » for asthenia
• past History : unremarkable • Physical exam : Slenomegaly 2 cm below costal margin, No hepatomegaly, no lymphnodes. CASE 3: ♀ 45 years old
BLOOD CELL COUNT Differential Counts (%)
22 +++ WBC (10 9/L) - Blasts - Myélocytes 4.88 RBC(10 12 /L) - Métamyelocytes 14.8 Hb (g/dl) 44 Hct (%) - Non segmented 90 MCV (fl) 12.3 Neutrophils 30.3 CMH (pg) 85.9 + Lymphocytes 34 CCMH (g/L) 0.0 - Monocytes 9 MPV (fl) 0.9 Eosinophils 183 Platelets 0.9 Basophils Lymphocytosis > 4.500 Ly/mm³
Atypical lympocytes ?
EBV serology monoclonality
pos neg B monoclonality T monoclonality
Infectious CMV (T8↑) CLL / HCL / NHL mononucleosis Hepa s (T8↑) ATCL/LGL MM (Ig intraC) (T8↑, T4/T8↓) Toxoplasmosis T NHL HIV (T4↓) Sezary S. (T4↑) Lymphocytosis > 4.500 Ly/mm³
Atypical lympocytes Normal lympocytes
No monoclonolity EBV serology monoclonality Viral Acute Brucellosis Mycoplasma B monoclonality T monoclonality Pertussis
Chronic Tuberculosis Infectious CMV serology ATCL/LGL CLL / HCL / NHL mononucleosis (T8↑) T NHL Sarcoïdosis MM (Ig intraC) (T8↑, T4/T8↓) Hepa s (T8↑) Sezary S. (T4↑) Wegener Toxoplasmosis Syphilis III HIV serology (T4↓) Thyreotoxicosis adrenal insufficiency Pereira I et al Atlas of Peripheral Blood, 2012. B-polyclonal Lymphocytosis related to heavy smoking
• Young ladies • Binucleated Lymphocytes • Polyclonal lymphocytes population • Splenomégaly : +/- • ↑ polyclonal IgM • Association with HLA-DR7 • Benign Evolution
Leukemia – Lymphoma 1996: 275-279 Phenotype of Peripheral Blood LYMPHOCYTES
T = CD3: 60 - 85% CD4: 40 - 60% CD4/CD8: 1.5 - 3 CD8: 20 - 40%
B = CD19: 5 - 15% κ/λ : 1.5 à 2
Values in our patient :
• Phenotype : 45% of B- lymphocytes (IgM, λ) , CD5 - CD23 - FMC7 +, CD25 + • CRP : < 0.5 mg/dl , LDH : NL , Viral Serology : NL DIFFERENTIAL DIAGNOSIS OF B- LYMPHOCYTOSIS F Chronic Hairy cell LK Prolymphocytic Follicular Mantle Cell Splenic vilous lymphocytic LK LK Lymphoma Lymphomas lymphomas CLL HCL PLL F NHL MCL* SVL
↑↑ lympho ++ + +++ + + +++
Spleen +/- ++ ++ +/- +/- +++
CD19 + + ++ ++ ++ ++ ++
CD5 ++ - -/+ - ++ -
CD23 + - - -/+ - -
CD10 - - + - -
CD11c +/- ++ - - - -
FMC7 - - ++ + + +
CD103/25 - + - - - -/+ Mature T-cell lymphoproliferative disorders
Marker T-LGLL NK-LGLL T-PLL ATLL SS TdT* ----- CD2 + + + + + CD3 ++ - ++ ++ ++ CD4 - - +/- ++ ++ CD5 + + + + + CD7 -/+ - +++ - -/+ CD8 ++ - -/+ - - CD16 + + - - - CD25 - - -/+ ++ -- CD56 -/+ + - - - Other CD11b+ HTLV1+ CD16+ CD57+
T-LGLL, T-cell large granular lymphocyte leukemia; NK-LGLL, NK-cell large granular lymphocyte leukemia; T- PLL, T cell prolymphocytic leukemia; ATLL, adult T cell leukemia/lymphoma; SS, Serazy syndrome. *TdT : terminal deoxynucleotidyl transferase differentiates these cells from lymphoblasts of ALL CASE 4: ♂ 23 years old
Back from a stay in China for professional reasons
Complaints : Fatigue, NS, subT ° , Weight loss +/- 2kg, No pruritus , no diarrhea. Past history : unremarkable Treatment : none Alcohol / tabacco : moderate Phys Exam : 5 cm diameter left Sub-clavicular LN CASE 4: ♂ 23 years old
Differential (%) BLOOD CELL COUNT - Blasts 19.6 + WBC (10 9/L) - Myelocytes 12 4.3 RBC (10 /L) - Métamyelocytes 12.8 Hb (g/dl) - Non segmented 37.7 Hct (%) + 88.5 MCV (fl) 66.2 Neutrophils 29.6 MCH(pg) 7.9 Lymphocytes 33.9 MCCH (g/L) 7.3 + Monocytes 6.6 MPV (fl) 18.3 + Eosinophils 473.000 + Platelets 0.6 Basophils Causes of Eosinophilia Mild > 500, Moderate >1500, high >5000/ul
• Allergies (industrialised countries) – atopia – Drug (Il-2 treatment) • Parasitosis (especially in developing countries) • Neoplasia – Hematological – - clonal eosinophilia in myeloid pathologies – - Polyclonal paraneoplasic eosinophilia in lymphoid pathologies – Solid tumors (uterus, lung, colon) • Idiopathic (SHE, GI eosinophilia, Eos pneumonia, Eosinophilic Fasceitis ) • AI Diseases (Churg-Strauss Vasculitis , Crohn, RA, Psoriasis….) Myeloproliferative disorders
« clonal » hyperéosinophilie • Chronic myelomonocytic leucemia (CMML) • Chronic myeloid leukemia (Caryotype, B12) • Systemic mastocytosis • Chronic eosinophilic leucemia – Mature eosinophils in chronic fase – Specific cytogenetic abnormalities (FIP1L1/PDGF RA) – Blastic transformation non-myeloid disorders
« polyclonal » reactive hypereosinophilia
(non) Hodgkin lymphoma –T cell lymphoma (TCR rearrgt, FACS, IgE) –Skin lymphoma (CD4+), ATLL (HTVL1+) CASE 4: ♂ 23 years old Reed- Sternberg cell
Diagnosis : Hodgkin’s Lymphoma CASE 5: ♂ 72 years old
Complaints : fatigue, anorexia, max 37 7 (evening ) Past history : Controlled hypertensive cardiomyopathy Phys. Exam. : BP : 15/9 – HR : 90 ’ rég, GGL 0, Liver N, sensitive spleen without clinical SM CASE 5: ♂ 72 years old Differential (%)
- Blasts BLOOD CELL COUNTS - Myélocytes 12.4+ WBC (10 9/L) - Métamyélocytes 3.30 RBC (10 12 /L) - Non segmented 11.6- Hb (g/dl) 16 - Neutrophils 34.3 Hct (%) 43 Lymphocytes 104+ MCV(fl) 39 + Monocytes 35.2 MCH (pg) 2 Eosinophils 33.8 CCMH (g/L) 0 Basophils 7 MPV (fl) 141- Platelets 8 Réticulocytes (‰) Monocytosis > 800/mm³ > 1.000 µL Etiologie Medullar aspiration / - MDS/MPN biopsy CMMC JMML - Infections Malaria Trypanosomiase Chronic Myelo-Monocytic Typhus Leukemia (CMML) TB Endocarditis Brucellosis - Recovery after chemotherapy/transplant - GM-CSF > G-CSF - Cancers Lymphoma AML (types M4 & M5) Tracy I Georges, ASH 2012