Neoplastic proliferation arising from white blood cells Lymphoproliferative

Neoplastic proliferation arising from white blood cells Lymphoproliferative and myeloproliferative diseases and syndromes Oliver Rácz, 2012 -2019 24/2/2019 leuke 19. ppt 1

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 24/2/2019 leuke 19. ppt 2

Classification „LYMPHOID NEOPLASMS Hodgkin, non-Hodgkin ALL, CLL CHAOS TILL 1994 – REAL, 1997 WHO Immunochemical and genetic characteristics MYELOID NEOPLASMS Acute AML Chronic CML Myelodysplastic syndromes 24/2/2019 leuke 19. ppt 3

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) 24/2/2019 leuke 19. ppt 4

LYMPHOID NEOPLASMS, B; T; HODGKIN 1. 2. Precursor B cell neoplasms (1) Peripheral B cell neoplasms (12) why? Hairy cell leukemia, plasmocytoma, Burkitt lymphoma 3. 4. Precursor T cell neoplasms (1) Peripheral T and NK cell neoplasms (12) why? WHY 1: 12? There is only one precursor but many development stages 24/2/2019 leuke 19. ppt 5

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LYMPHOID NEOPLASMS, B; T; HODGKIN 1. 2. 3. 4. 5. Precursor B cell neoplasms (1) Peripheral B cell neoplasms (12) Precursor T cell neoplasms (1) Peripheral T and NK cell neoplasms (12) Hodgkin lymphoma (5 subtypes) CLINICAL PICTURE NHL NHL HL NODAL ENLARGEMENT IN 80% NHL, ALL HL SUPRESSION OF NORMAL HEMATOPOIESIS SPLEEN AND LIVER INFILTRATION IMMUNE SYSTEM DYSFUNCTION SPECIFIC OR also NOTHING 24/2/2019 leuke 19. ppt 7

New data – 2018* Diffuse large B cell lymphoma – DLBCL Incidency cca 7/100 000 Nonspecific symptoms (infection? ) quick progression Therapy R-CHOP (4 chemo+rituximab), 75% pacients in remission ¼? More agressive chemo or CAR-T DIAGNOSTICS AND MONITORING THROUGH ct. DNA (liquid biopsy), fragments of tumor DNA *NATURE OUTLOOK 2018 23/2/2018 leuks 19. ppt 8

New data - 2018 Diffuse large B cell lymphoma – DLBCL Incidency cca 7/100 000 DIAGNOSTICS AND MONITORING THROUGH ct. DNA (liquid biopsy), fragments of tumor DNA Excellent marker of remission – relaps Deep sequencing of the fragments – which mutations? , new mutations? Therapy according to mutations! THE SAME ALSO FOR OTHER MALIGNANCIES 23/2/2018 leuks 19. ppt 9

New data - 2018 CAR-T chimeric antigen receptor T-cell therapy (from 2017 FDA approval) Genetically modified. T lymfocytes against B ly Isolatoion of T lymfocytes of pacient Gene transfer against CD 19 (normal antigen B of lymfocytes, a i. v. applicatiosn T lymphocytes kill the B lymphocytes Only for patients after failure of standard therapy. The results are good Price cca 400 00 eur, sever complications (cytokine storm, neurotoxicity) 23/2/2018 leuks 19. ppt 10

Our friends, too Treated by chemo. Helpful for research. Why? Inbreeding? 23/2/2018 leuks 19. ppt 11

LYMPHOID NEOPLASMS, B; T; HODGKIN 1. 2. 3. 4. 5. Precursor B cell neoplasms (1) Peripheral B cell neoplasms (12) Precursor T cell neoplasms (1) Peripheral T and NK cell neoplasms (12) Hodgkin lymphoma (5 subtypes) LABORATORY PICTURE NHL NHL HL PERIPHERAL BLOOD NEOPLASM BIOPSY ANTIGEN RECEPTORS AND OTHER SURFACE PROTEINS (CD 1 – 79) PRESENT ALSO ON NORMAL CELLS – FLOW CYTOMETRY CHROMOSOME AND GENE ANALYSIS 24/2/2019 leuke 19. ppt 12

Hodgkin: Reed-Sternberg cells 24/2/2019 leuke 19. ppt 13

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). 24/2/2019 leuke 19. ppt 14

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 24/2/2019 leuke 19. ppt 15

The Reed-Sternberg cells affect the immune system ! 24/2/2019 leuke 19. ppt 16

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? 24/2/2019 leuke 19. ppt 17

Non-Hodgkins B >> T (80 -85 vs 15 -20 %) V(D)J recombinations and regulated somatic hypermutations – higher possibility of mistakes 24/2/2019 leuke 19. ppt 18

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 CD 20 (B) with 90 Y Transplantation of stem cells or bone marrow 24/2/2019 leuke 19. ppt 19

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 24/2/2019 leuke 19. ppt 20

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) 24/2/2019 leuke 19. ppt 21

Philadelphia chromosome, chronic myeloid leukemia (CML) 9 22 bcr abl-bcr hybrid gene p 210 tyrosinkinase with increased activity abl 24/2/2019 leuke 19. ppt 22

Neurofibromatosis 1 Recklinghausen (and Genersich) Tumor supressor gene on 17 th ch. (NF 1) Risk of other malignities, too AD, 1/2500 - 4000 24/2/2019 leuke 19. ppt 23

Acute lymphatic leukemia Children, boys > girls Whites > nonwhites (2 x) pre. B > > pre. T, B earlier, T later Blood cell morphology makes possible differential dg of. ALL and AML, further immunophenotypisation Chromosomes: hyperploidia (> 50), polyploidia, Philadelphia and other translocations Microchip technology – specific patterns of abnormal gene expression 24/2/2019 leuke 19. ppt 24

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 24/2/2019 leuke 19. ppt 25

Chronic lymphatic leukemia, CLL Most frequent from all Manifestation in age over 50, M > W Ly > 4000/ml, sometimes 20 000/ml 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 24/2/2019 leuke 19. ppt 26

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 24/2/2019 leuke 19. ppt 27

AML Mostly in young adults The maturation is blocked !!! „Blasts“ 10 000 – 100 000/ml Frequent chromosomal aberrations (up to 90 % with modern technology) The prognosis is not very good 24/2/2019 leuke 19. ppt 28

AML Classification M 0 – M 7, mostly 1 and 2, AML without and with maturation, but also erytro. . . (M 6) a megakaryo. . . (M 7) M 3 often associated with DIC (acute promyelocyte L) WHO classification according to chromosomal aberrations 24/2/2019 leuke 19. ppt 29

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 24/2/2019 leuke 19. ppt 30

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 24/2/2019 leuke 19. ppt 31

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 24/2/2019 leuke 19. ppt 32

Myelodysplastic syndromes Pimary or in association with therapy of other leukemias After 60 Ineffective and abnormal haematopoesis, apoptosis Pancytopenia Transformation into AML 24/2/2019 leuke 19. ppt 33

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 24/2/2019 leuke 19. ppt 34

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References Robbins – Cotran: Pathologic basis of disease, 7 th Ed. (Kumar-Abbas-Fausto) Elsevier 2005 Aster: Diseases of white blood cells… Porth: Essentials of Pathophysiology, 2 nd Ed. , Lippincott 2007 Gaspard: Disorders of white blood cells and lymphoid tissues 24/2/2019 leuke 19. ppt 36