BHS PG seminar # 9 Non Malignant Hematology November 8, How to approach LEUCOCYTOSIS. Prof. Dominique BRON Inst J Bordet- (ULB) -Hop Erasme

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1 BHS PG seminar # 9 Non Malignant Hematology November 8, 2014 How to approach LEUCOCYTOSIS Prof. Dominique BRON Inst J Bordet- (ULB) -Hop Erasme

2 NORMAL BLOOD CELL COUNT Hémoglobin g/dl (F) g/dl (H) Red Blood Cells Hematocrit x 10 6 /µl (F) x 10 6 /µl (H) 36 48% (F) 40 52% (H) Mean Corpuscular Volume 80 95µ Mean Hb Concentration Conc corp mean Hb pg g/dl Reticulocytes % Leucocytes Neutophils Lymphocytes Monocytes Eosinophils Basophils Platelets x 10 3 /µl x 10 3 /dl

3 Reference values /µl of leucocytes in absolute values! Total leucocytes Neutrophiles Eosinophiles Basophiles Monocytes Adult lymphocytes

4 CAS # 1 M 45yo 70 kg / 172 cm Leucocytosis discovered with a routine «check-up» Past History : Complaints : none unremarkable Physical exam : Slenomegaly 2 cm below costal margin, No hepatomegaly, no lymphnodes.

5 CAS # 1 BLOOD CELL COUNT 22 + WBC (10 9 /L) 4.88 RBC(10 12 /L) 14.8 Hb (g/dl) 44 Hct (%) 90 MCV (fl) 30.3 CMH (pg) 34 CCMH (g/l) 9 MPV (fl) 183 Platelets Differential Counts (%) - Blasts - Myélocytes - Métamyelocytes - Non segmented 12.3 Neutrophils Lymphocytes Monocytes 0.9 Eosinophils 0.9 Basophils 10 Reticulocytes ( )

6 Hyperleucocytosis > WBC/mm³ Normal Cells Abnormal or blastic cells Infections? Neutrophilia (> 7.500/mm³) Acute Leukemias Lymphocytosis (> 4.500/mm³) Chronic Myelomonocytic Leukemias Chronic Lymhocytic leukemia Or Chronic monocytosis (> 800/mm³) Chronic Myeloid Leukemia Inflammations? Eosinophilia (> 400/mm³) Non Hodgkin Lymphomas basophilia (> 100/mm³).

7 + - Infectious mononucle osis (T8, T4/T8 ) Lymphocytosis > Ly/mm³ + EBV serology Atypical lymphocytes Bone biopsy + marrow smear CMV serology (T8 ) Hepatitis (T8 ) Toxoplasmosis HIV serology (T4 ) + - B monoclonal CLL / HCL / NHL ALL (blasts +) MM (Ig intrac) OR T monoclonal ATCL/LGL T NHL Sezary S. (T4 ) A Chr (morpho, caryo, cult, mol biol) No monoclonolity Virosis Brucellosis Mycoplasma Pertussis Tuberculosis MAI Sarcoïdosis Wegener Syphilis III Thyreotoxicosis adrenal insufficiency

8 Pereira I et al Atlas of Peripheral Blood,2012.

9 B-polyclonal Lymphocytosis related to heavy smoking Young ladies Binucleated Lymphocytes Polyclonal lymphocytes population Splenomégaly : +/- polyclonal IgM Association with HLA-DR7 Begnin Evolution Leukemia Lymphoma 1996:

10 Phenotype of Peripheral Blood LYMPHOCYTES T = CD3: 60à 85% CD4: 40 à 60% CD8: 20 à 40% CD4/CD8: 1.5 à 3 B = CD19: 5 à 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

11 DIFFERENTIAL DIAGNOSIS OF B- LYMPHOCYTOSIS Chronic lymphocytic LK CLL Hairy cell LK HCL Prolymphocytic LK PLL F Follicular Lymphoma F NHL Mantle Cell Lymphomas MCL* Splenic vilous lymphomas SVL lympho Spleen +/ /- +/- +++ CD CD / CD /+ - - CD CD11c +/ FMC CD103/ /+

12 DIFFERENTIAL DIAGNOSIS OF B- LYMPHOCYTOSIS Chronic lymphocytic LK CLL Hairy cell LK HCL Prolymphocytic LK PLL F Follicular Lymphoma F NHL Mantle Cell Lymphomas MCL* Splenic vilous lymphomas SVL lympho Spleen * +/ /- +/- +++ CD19 * CD / CD /+ - - CD CD11c * +/ FMC CD103/25 * /+

13 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 Mature T-cell lymphoproliferative disorders Marker T-LGLL NK-LGLL T-PLL ATLL SS TdT* CD CD CD / CD CD7 -/ /+ CD /+ - - CD CD / CD56 -/ Other CD11b+ CD16+ CD57+ HTLV1+

14 CAS # 3 M. 72 yo 85 kg / 180 cm 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

15 CAS # 3 BLOOD CELL COUNTS WBC (10 9 /L) RBC (10 12 /L) Hb (g/dl) Hct (%) MCV(fl) MCH (pg) CCMH (g/l) Differential (%) - Blasts - Myélocytes - Métamyélocytes - Non segmented 16 - Neutrophils 43 Lymphocytes 39 + Monocytes 2 Eosinophils 0 Basophils MPV (fl) Platelets 8 Réticulocytes ( )

16 Monocytosis > 800/mm³ + Infections Bact (brucellosis, tuberculosis, leprosy, subacute endocarditis) Protooz (malaria), Rickettsia (Typhus, Mont Roch fever) Collagenosis rheumatoid arthritis, SLE, polyarteritis Myeloproliferative syndroms Myelodysplasia, Acute Leukemia Multiple Myeloma Gastro-intestinal disorders Diarrhea, colitis ulcerosa Histiocytosis Crohn s Disease Benign hemopathies PTI, post splenectomy, post neutropenia Post hemolysis Neoplasia Inflammation of unknown origin / sarcoidosis > µl Medullar aspiration / biopsy Chronic Myelo-Monocytic Leukemia (CMML)

17 CAS # 4 M 42 yo Leukocytosis discovered by chance with a routine «check-up» Complaints : fatigue and Flu-like syndrome Physical Examination: mild splenomegaly

18 CAS # 4 BLOOD CELL COUNTS WBC (10 9 /L) 5.13 RBC (10 12 /L) 15.0 Hb (g/dl) 44.6 Hct (%) 86.9 MCV (fl) 29.3 CMH (pg) 33.8 CCMH(g/L) 13.3 MPV (fl) Platelets DIFFERENTIAL (%) - Blasts 1 + Myelocytes 2 + Métamyelocytes Non segmented 84 + Neutrophils 2 - Lymphocytes 2 Monocytes - Eosinophils 9 + Basophils - Réticulocytes ( )

19 Neutrophilia > 7.500/mm³ < /mm³ LAP or NL > /mm³ LAP or BRC/ABL?? Acute infection Leukemoid reaction Tumoral necrosis Medullar infiltration Post excercices Pregnancy Stress, tobacco Inflammation Necrosis (MI, tissular necrosis, tumor, AID) Drugs (corticoids!!!, heparin, epinephrin, histamin, G-CSF) Post-splenectomy, post hemorrhage ou hemolysis Myeloproliferative syndrom (myelofibrosis, CML, MPN) Chronic Myeloid Leukemia (Ph+) Myeloproliferative neoplasm (Ph-)

20 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 ans 1 5 ans 10 + ans 10 + ans Acute leukemia <20%? 10% < 10% < 10%

21 CAS # 5 - eosinophilia M 23 yo, ingenieur, 65 kg/178 cm, Back from a stay in China for professional reasons Comlaints : fatigue, NS, subt, Weight loss +/- 2kg, N pruritus, no diarrhea. Past history : unremarkable Treatment : none Alcohol / tabacco : moderate Phys Exam : 5 cm diameter left Sub-clavicular LN

22 CAS #5 Differential (%) - Blasts BLOOD CELL COUNT WBC (10 9 /L) 4.3 RBC (10 12 /L) 12.8 Hb (g/dl) 37.7 Hct (%) 88.5 MCV (fl) 29.6 MCH(pg) 33.9 MCCH (g/l) 6.6 MPV (fl) Platelets - Myelocytes - Métamyelocytes - Non segmented Neutrophils 7.9 Lymphocytes Monocytes Eosinophils 0.6 Basophils 8.5 Réticulocytes ( )

23 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 Solids (uterus, lung, colon) Idiopathic (SHE,..GI eosinophilia, Eos pneumonia, Eosinophilic Fasceitis) AI Diseases (Churg-Strauss Vasculitis, Crohn, RA, Psoriasis.)

24 Hémopathies «myéloprolifératives» Hyperéosinophilie «clonale» leucémie myélomonocytaire FAB M4 (cytopénie, SM) leucémie myéloïde chronique (Caryotype, B12) mastocytose systémique leucémie chronique à éosinophiles éosinophiles matures en phase chronique anomalies cytogénétiques spécifiques (FIP1L1/PDGF RA) transformation blastique

25 Hémopathies «non-myéloïdes» Hyperéosinophilie réactionnelle, «polyclonale» Lymphome de Hodgkin Lymphomes non-hodgkiniens lymphomes T +++ (IgE,Phénotype, TCR rearrgt +) lymphomes cutanés( CD4+), ATLL(HTLV1+)

26 CAS # 5 Reed- Sternberg cell Diagnosis : Hodgkin s Lymphoma

27 Tracy I Georges, ASH 2012