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Leukemias

Leukemias. Jan Żeromski Pathology 2010/2011. Definition and two main lineages. Malignant proliferation of white cells of the hematopoietic system with infestation of blood and usually bone marrow. Lymphoid and myeloid leukemias. Cell origin and pathogenesis.

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Leukemias

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  1. Leukemias Jan Żeromski Pathology 2010/2011

  2. Definition and twomainlineages • Malignant proliferation of white cells of the hematopoietic system with infestation of blood and usually bone marrow. • Lymphoid and myeloid leukemias

  3. Cellorigin and pathogenesis • Hematopoieticstemcellsdifferentiating to progenitorones, eithermyeloidorlymphoidlineage • Chromosomalabnormalities, most commonlytranslocations, • Inheritedgeneticdefects (Down syndrome, Bloomsyndrome, ataxiatelangiectasia • Someviruses: Epstein-Barr (EBV), herpesvirus -8, HTVL-1 etc. • Environmentalfactors: chronicinfection, Helicobacterpylori, radiationtherapy, chemotherapy

  4. Classification of lymphoidleukemias • Precursorleukemias - acutelymphoblastic l. - pro B - pre B (common) • Peripheralones - chroniclymphocytic l. - prolymphocytic l. - hairycell l. - plasmacellmyeloma • Precursor leukemias - acute lymphoblastic l. • Peripheral ones (T and NK) - chronic lymphocytic l. - large granular lymphocytic l. - Sezary syndrome - NK-cell leukemia B-cell origin T-cell origin

  5. Significance of cellimmunophenotype • Definition:the set of differentiationantigensexpressed on a givencelltype • Lymphoid and myeloidcellsubsetsinvariousstages of maturationhavedistinctimmunophenotype • Differentiationantigensareclassifiedaccordingto clusterdeterminants (CD) system • CD classificationcoversmorethan 300 antigenicepitopessearched by monoclonalantibodies • Each leukemia typehascharacteristic set of CD markers, whatconstitutesnowadayscurrentclassificationhematopoieticmalignancies and thebasis of diagnosis

  6. B cell lineage antigens differentiation

  7. Clonality – generearrangement • Clonality – crucialdifferencebetweenneoplastic and normallymphocytes • Uniquefeature of lymphocytes – antigen receptor • Antigen receptor generearrangementdetermines antigenspecificity of lymphocytes • Rearrangementprecedesneoplastictransformation • Thusdaughtercellsfrommalignantcellprogenitorexpressthe same antigen receptor (either T or B) – form identicalcell clone

  8. Acute Lymphoblastic Leukemia • Most cases are Tdt positive • Most express CD10 (common ALL antigen) • Most are “pre-B cell” phenotype • 15-20% T-cell lineage • 5% B-cell phenotype

  9. Acute Lymphoblastic Leukemia

  10. General division of myeloidneoplams • Acute myelogenous leukemias (8 types) • Myelodysplastic syndromes (MDS) • Chronic myeloprolifeative disorders: - chronic myelogenous leukemia - polycythemia vera - essential thrombocytosis - primary meylofibrosis

  11. FAB classification of acutemyelogenousleukemias • M0 AML – non-differentiated, incidence 2-3% • M1 AML – almostwithoutdifferentiation, 20% • M2 AML – myeloidmaturation of granuloc.30-40% • M3 AML – hypergranularpromyelocytes, 5-10% • M4 AML – cells of bothmyelocytic (min.20%) and monocyticorigin (<30%), 15-20% • M5 AML – Monoblasts (M5a) and monocytes (M5b), 10% • M6 AML – dysplasticerythroidprecursors and myeloblasts, 5% • M7 megakaryocytic leukemia – blasts of megakaryoc.lineagepredominate, 1% Number of blastsinall: < 20%

  12. Myeloid cell lineage antigens differentiation

  13. Significance of geneticabnormalities • Chromosomaltranslocationisfairlycommon and may be distinct for givensubtypesuch as t(15;17) in M3 AML • Someleukemias do no fit to currentclassifications and aredescribed on thebasis of severalcytogeneticdefectssuch as genefusion, deletion, insertion etc. • In lymphoidtumorsantigen receptor generearrangementisearlierthanneoplastictransformation. Thus, tumorousgene products (immunoglobulinsorT-cellreceptors) areidenticalincontrast to normallymphocytesexpressingplethora of variousantigenreceptors. Itturned out to be of diagnosticvalue.

  14. Clinicalfeatures of leukemias • General: symptomsaremoreevidentinacutethaninchronicforms , but do not differ much inlymphoidvs. myeloidleukemias, • In chronictypestheonsetisusuallyinsidious: mild anemia, weakness, easyfatigue, weightloss, anorexia • Enlargement of spleen iscommoninbothtypesoften associated withleftupperquadrantpain, • Acuteleukemias manifest by abruptstormyonset: fever, infection, bleeding, bonepain, hepatosplenomegaly, cnsmanifestationssuch a vomiting, headache, nervepalsies.

  15. Chronic Leukemia • Often discovered because of an abnormal lab or an abnormal physical examination • Severe cytopenias characteristic of acute leukemia are seldom present at time of diagnosis

  16. Prognosisinleukemias • FairlygoodinprecursorB-cellleukemiasinchildhood • In chronicB-cellleukemias life expectancymay be comparable to normal one, providedthatthereis no cnsinvolvement • Acutemyeloidleukemiashaveusuallyunfavourableprognosis (15-30% remainfree of disease for 5 years), • In chronicmyelogenous leukemia supplementation of blood and properchemotherapyallowfro 4-5 yearssurvival, but theendisalmostalwaysfatal.

  17. Chroniclymphocytic leukemia/lymphoma (CLL/SLL-B)

  18. CLL-B: flowcytometry

  19. HairyCell Leukemia (HCL) • Clinical – pancytopenia, normal lymph nodes and splenomegaly • Incidence –mostly middle age males (2% of lymphomas) • Origin – mature B cells but with peculiar projections best seen in phase-contrast microscope. They are pan B, CD5-, CD25+, CD11c+, CD103+ • Infiltration of spleen, bone marrow and liver • Accompanying infections common often with atypical mycobacteria

  20. Spleen- hairycell leukemia

  21. FAB classification of acutemyelogenousleukemias • M0 AML – non-differentiated, incidence 2-3% • M1 AML – almostwithoutdifferentiation, 20% • M2 AML – myeloidmaturation of granuloc.30-40% • M3 AML – hypergranularpromyelocytes, 5-10% • M4 AML – cells of bothmyelocytic (min.20%) and monocyticorigin (<30%), 15-20% • M5 AML – Monoblasts (M5a) and monocytes (M5b), 10% • M6 AML – dysplasticerythroidprecursors and myeloblasts, 5% • M7 megakaryocytic leukemia – blasts of megakaryoc.lineagepredominate, 1% Number of blastsinall: < 20%

  22. AcuteMyelogenous Leukemia (AML) • Incidence:middleage, olderadults and children • Bonemarrow: normalcellsarereplaced but undifferentiatedblastswithsomemyeloidfeatures. Theyhaveblockedmaturation, increasedsurvival and thereplicationratelowerthannormalmyeloidprogenitors, • Genetic:severalchromosomalrearrangementsdisruptinggenesencodingtranscriptionfactorsneeded for normalmyeloidmaturation, • Lab findings: anemia, neutropenia, thrombocytopenia

  23. AcuteMyelogenous Leukemia (AML) - 2 • Flowcytometry:due to poorcellgranularityblastshaveverylowsitescatter. Theyusually show myeloid-specificsurfacemarkers (CD13, CD33) and markers of progenitorcells (CD34, CD117), but variousdeparturesfromtheabovearecommon, • Clinical:fatigue, spontaneousbleedings, infections, oftencaused by opportunisticpathogenssuch as fungiorPseudomonas. Organomegaly of liver, spleen, infiltration of skin, gingiva by normalmonocytesisoftenseen.

  24. Organomegaly

  25. Platelet Coagulation Petechiae, Purpura Hematoma, Joint bl.

  26. AML-M0 - Undifferentiated:

  27. AML-M2 - with maturation

  28. AML-M3 - Auer Rods

  29. AML-M4 - Myelomonocytic

  30. AML-M5 - Gum Hypertrophy:

  31. AML-M6 : Erythroleukemia

  32. PURE ERYTHROID LEUKEMIA

  33. AML-M7 : Megakaryocytic

  34. Chronicmyelogenous leukemia (CML) • Disease of adults(25 – 60 yrs), morecommoninwomen, • Bonemarrow– highlycellular, mainlymaturinggranulocyteprecursors, increasednumbers of megakaryocytes • Molecular– translocation of BCR gene (chromosome 9) to ABL gene (on chromosome 22) TheresultantBCR-ABLfusiongeneencodes protein withtyrosinekinaseactivity. So-called Philadelphia chromosomeseeninkaryotypingstudiesisthereflection of (9;22) translocation • Clinical – slow progressionup to 5 years, afterwardssome 50% of patients enter „acceleratedphase” withappearance of blasts, resemblingacute leukemia.

  35. BCR-ABL translocation Chronic Myelogenous Leukemia

  36. BCR – ABL GENES DISRUPTED IN THE t(9;22) CHROMOSOMAL ABNORMALITY

  37. CHRONIC MYELOID LEUKEMIA IN BLAST PHASE

  38. PolycythemiaVera • Cellorigin: multipotentmyeloidstemcell • Bonemarrow: increasedproduction of erythroid, granulocytic and megakaryocyticmaturingcelltypes • Blood: erythrocytosis, granulocytosis, thrombocytosis, increasedhematocrit and red cell mass • Clinical:insidiousonsetinlatemiddleage (above 60 yrs). Patientssufferfromheadache, dizziness, hypertension, gastrointestinalabnormalities, goutdue to high cellturnover. Thrombosis episodesarecommon. • Finalfate: either „spentphase” leading to marrowmyelofibrosiswithextramedullaryhematopoesisor terminal AML

  39. POLYCYTHEMIA VERA

  40. POLYCYTHEMIA VERA – CELLULAR PHASE

  41. POLYCYTHEMIA VERA-LATE PHASE

  42. MyelodysplasticSyndromes (MDS) • Definition:clonalcelldisordersmarked by maturationdefects, ineffectivehematopoiesis and increasedrisk of AML (10-40%) • Twodistincttypes: idiopatic (primary) MDS inolderpeoplewithinsidiouscourse. Oftendiscoveredincidentally on routinetesting. therapy-related MDS, due to previouschemo-orradiationtherapy, usually 2 to 8 yearsafter, • Bonemarrow: severaldistortedcells of myeloidlineageshowingvariousabnormalities. Myeloblastsmay be increased, but below 20%. Ifhigher – itisalready leukemia, • Survival:primary MDS-9-29 mo, therapy-related – 4 to 8 mo.

  43. Thankyou for yourpatience and perseverance!

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