1. 24/2/2013leuke.ppt1 Neoplastic proliferation arising from white blood cells Lymphoproliferative and myeloproliferative diseases and syndromes  Oliver Rácz, 2012/13

2. 24/2/2013leuke.ppt2 Introductory remarks „ Leukemia“ and „lymphoma“are old descriptive terms On the other side the new classification is also descriptive and not fully rational. High number of subtypes in most group. Typisation is based on new knowledge – histology, surface antigens (imunochemistry, flow cytometry) and genetics Not without purpose – different treatment regimes

3. 24/2/2013leuke.ppt3 Classification „LYMPHOID NEOPLASMS Hodgkin, non-Hodgkin ALL, CLL CHAOS TILL 1994 – REAL, 1997 WHO Immunochemical and genetic characteristics MYELOID NEOPLASMS AcuteAML ChronicCML Myelodysplastic syndromes

4. 24/2/2013leuke.ppt4 LYMPHOID NEOPLASMS, B;T; HODGKIN 1.Precursor B cell neoplasms (1) 2.Peripheral B cell neoplasms (12) why? Hairy cell leukemia, plasmocytoma, Burkitt lymphoma 3.Precursor T cell neoplasms (1) 4.Peripheral T and NK cell neoplasms (12) why? 5.Hodgkin lymphoma (5 subtypes)

5. 24/2/2013leuke.ppt5 LYMPHOID NEOPLASMS, B;T; HODGKIN 1.Precursor B cell neoplasms (1) 2.Peripheral B cell neoplasms (12) why? Hairy cell leukemia, plasmocytoma, Burkitt lymphoma 3.Precursor T cell neoplasms (1) 4.Peripheral T and NK cell neoplasms (12) why? WHY 1:12? There is only one precursor but many development stages

6. 24/2/2013leuke.ppt6

7. 24/2/2013leuke.ppt7 LYMPHOID NEOPLASMS, B;T; HODGKIN 1.Precursor B cell neoplasms (1)NHL 2.Peripheral B cell neoplasms (12) NHL 3.Precursor T cell neoplasms (1)NHL 4.Peripheral T and NK cell neoplasms (12)NHL 5.Hodgkin lymphoma (5 subtypes)HL CLINICAL PICTURE NODAL ENLARGEMENT IN 80% NHL, ALL HL SUPRESSION OF NORMAL HEMATOPOIESIS SPLEEN AND LIVER INFILTRATION IMMUNE SYSTEM DYSFUNCTION SPECIFIC OR also NOTHING

8. 24/2/2013leuke.ppt8 LYMPHOID NEOPLASMS, B;T; HODGKIN 1.Precursor B cell neoplasms (1) NHL 2.Peripheral B cell neoplasms (12) NHL 3.Precursor T cell neoplasms (1)NHL 4.Peripheral T and NK cell neoplasms (12)NHL 5.Hodgkin lymphoma (5 subtypes)HL LABORATORY PICTURE PERIPHERAL BLOOD NEOPLASM BIOPSY ANTIGEN RECEPTORS AND OTHER SURFACE PROTEINS (CD1 – 79) PRESENT ALSO ON NORMAL CELLS – FLOW CYTOMETRY CHROMOSOME AND GENE ANALYSIS

9. 24/2/2013leuke.ppt9 Hodgkin: Reed-Sternberg cells

10. 24/2/2013leuke.ppt10 Hodgkin: Reed-Sternberg cells Size between 20 - 50 microns; Amphofilic, finely granular/homogenous cytoplasm; Two mirror-image nuclei ("owl eyes") each with an eosinophilic nucleolus and a thick nuclear membrane (chromatin is distributed on the inner surface of the nuclear membrane, generating a halo image around the nucleolus).

11. 24/2/2013leuke.ppt11 Hodgkin: Clinical picture 5 subtypes according Ly morphology and tumor histology, 1 – 4 is the same, 5 (nodular lymphocyte predominant Hodgkin disease; NLPHD) is a separate disease Enlargement of one ore more lymphatic nodes, without pain, mostly in the cervical or mediastinal region Fever, sweat, quiver, weight loss (or no) Later dissemination to other organs

12. 24/2/2013leuke.ppt12 The Reed-Sternberg cells affect the immune system !

13. 24/2/2013leuke.ppt13 Non-Hodgkins: More frequent B >> T (80-85 vs 15-20 %) Associated with (cause ???) Epstein – Barr virus (Africa, Burkitt) HTLV – human T-cell Lymphotropic (Japan) HIV Posttransplantation (immunosupression?) Helicobacter – MALT lymphoma?

14. 24/2/2013leuke.ppt14 Non-Hodgkins B >> T (80-85 vs 15-20 %) V(D)J recombinations and regulated somatic hypermutations – higher possibility of mistakes

15. 24/2/2013leuke.ppt15 Non-Hodgkins: Symptoms, prognosis More generalized as HL Enlarged L.N., no pain Many types, for general medicine is enough Low grade Aggressive Very aggressive (but radio-chemosenzitive) During disease the aggresivity can increase Therapy with monoclonal antibodies – rituximab against CD20 (B) with 90 Y Transplantation of stem cells or bone marrow

16. 24/2/2013leuke.ppt16 Lymphoid and myeloid leukemias ABNORMAL PROLIFERATION OF CELLS, CIRCULATING IN BLOOD, INFILTRATING ORGANS IN AGE 1 – 14 YEARS LEADING CAUSE OFMORTALITY, DESPITE THE FACT THAT LEUKÉMIA IS 10-TIMES MORE REQUENT IN ADULTS ALL children, 2 – 4 y. CLL older, m > w AML adults CML 30 – 50, and also children

17. 24/2/2013leuke.ppt17 Etiology in general Radiation – Hiroshima, Tchernobyl and ? Aromatic substances Antitumor drugs !!! Down (RR  10), Recklinghausen, Fanconi, Bloom > 500 different translocations and other chromosomal aberrations (Philadelphia)

18. 24/2/2013leuke.ppt18 Philadelphia chromosome, chronic myeloid leukemia (CML) abl bcr abl-bcr hybrid gene p210 tyrosinkinase with increased activity 9 22

19. 24/2/2013leuke.ppt19 Neurofibromatosis 1 Recklinghausen (and Genersich) Tumor supressor gene on 17th ch. (NF1) Risk of other malignities, too AD, 1/2500 - 4000

20. 24/2/2013leuke.ppt20 Acute lymphatic leukemia Children, boys > girls Whites > nonwhites (2x) preB > > preT, B earlier, T later Blood cell morphology makes possible differential dg ofALL and AML, further immunophenotypisation Chromosomes: hyperploidia (> 50), polyploidia, Philadelphia and other translocations Microchip technology – specific patterns of abnormal gene expression

21. 24/2/2013leuke.ppt21 Symptoms (common for ALL, AML) Rapid onset of symptoms (weeks) Anaemia, fatigue, fever, bleeding Bone pain Generalised lymphadenopatia, splenomegaly, hepatomegaly ALL > AML, sometimes testes (ALL) Headache, cramps (ALL) THE PROGNOSIS IS IMPROVING

22. 24/2/2013leuke.ppt22 Chronic lymphatic leukemia, CLL Most frequent from all Manifestation in age over 50, M > W Ly > 4000/  l, sometimes 20 000/  l Prolymphocytes in LN, high number of mitoses In blood small Ly, small amount of cytoplazma, fragile „smudge“ cells. Ly in bone marrow and other tissues Special immunophenotype Low number of chromosomal abnormalities Often asymptomatic Danger of increase in degree of malignancy

23. 24/2/2013leuke.ppt23 Myeloid neoplasma types in general From developmemtal stages of these cells Less infiltrate spleen, liver and L.N. AML – cells are nondifferentiated, haematopoesis blocked CML – differentiated cells Myelodysplastic syndromes Danger of transformation towards more agressive forms

24. 24/2/2013leuke.ppt24 AML Mostly in young adults The maturation is blocked !!! „Blasts“ 10 000 – 100 000/  l Frequent chromosomal aberrations (up to 90 % with modern technology) The prognosis is not very good

25. 24/2/2013leuke.ppt25 AML Classification M0 – M7, mostly 1 and 2, AML without and with maturation, but also erytro... (M6) a megakaryo... (M7) M3 often associated with DIC (acute promyelocyte L) WHO classification according to chromosomal aberrations

26. 24/2/2013leuke.ppt26 Symptoms (common for ALL, AML) Rapid onset of symptoms (weeks) Anaemia, fatigue, fever, bleeding Bone pain Generalised lymphadenopatia, splenomegaly, hepatomegaly ALL > AML, sometimes testes (ALL) Headache, cramps (ALL) THE PROGNOSIS IS IMPROVING

27. 24/2/2013leuke.ppt27 Chronic myeloid leukemia, CML Philadelphia chromosome in 90 %, with special methods the hybrid gene can be identified also in the remaining 10 % Uncontrolled proliferation of cells, inhibition of apoptosis Bone marrow is 100 % cellular (n: 50%) Peripheral blood up to 100 000 granulocytes, myelocytes, metamyelocytes Often high number of eosinophiles and bazophiles Thrombocytosis Extramedullan haematopoesis

28. 24/2/2013leuke.ppt28 Chronic myeloid leukemia, CML Slow nonspecific onset Fatigue, anorexia, weight loss Splenomegaly Cca after 3 years often acceleration New chromosomal abnormalities Blast crises Therapy: Inhibition of BCR-ABL kinase Bone marrow transplantation

29. 24/2/2013leuke.ppt29 Myelodysplastic syndromes Pimary or in association with the therapy of other leukemias After 60 Ineffective and abnormal haematopoesis, apoptosis Pancytopenia Transformation into AML

30. 24/2/2013leuke.ppt30 Other Polycytaemia vera Also platelets increased, ht up to 60 Flebotomy as therapy Essencial thrombocytosis (up to 600 000) Primary myelofibrosis – cytopenia and compensatory extramedullar haematopoesis

31. 24/2/2013leuke.ppt31

32. 24/2/2013leuke.ppt32 References Robbins – Cotran: Pathologic basis of disease, 7th Ed. (Kumar-Abbas-Fausto) Elsevier 2005 Aster: Diseases of white blood cells… Porth: Essentials of Pathophysiology, 2nd Ed., Lippincott 2007 Gaspard: Disorders of white blood cells and lymphoid tissues