Leukemia. Lymphomas. (WHO classification) Markéta Hermanová •Leukemia (hemoblastosis) •Diffuse replacement of normal BM by leukemic cells with their subsequent variable accumulation in peripheral blood (=leukemization) •Infiltration of peripheral organs (liver, spleen, lymph nodes, meninges, gonads,….) n n •Lymphoma (hemoblastoma) •Neoplastic/lymphoma cells form tumor/neoplastic mass (nodal and/or extranodal) n !Lymphomas may also present by leukemic infiltrates and leukemias also form solid neoplastic massess Hematooncology •Mutations that inhibit normal differentiation and maturation of progenitor cells, or mutations disrupting the regulation of progenitor and precursor cells by growth factors n Þunregulated clonal expansion of immature hematopoietic cells → inhibition of normal hemopoiesis → release of immature blast into circulation, infiltration of peripheral organs n Hematooncology nMyeloid neoplasms -from stem cells that normally give rise to the formed blood elements (granulocytes, red cells, platelets) -3 categories n → acute myelogenous leukemias n → myeloproliferative disorders n → myelodysplastic syndromes n n Lymphoid neoplasms/lymphomas n→ non-Hodgkin lymphomas n(incl. lymphocytic leukemias and plasma cell dyskrasias) n→ Hodgkin lymphomas n n Histiocytic neoplasms n 5 LYMPHOID NEOPLASMS (B-cell) – cells of origin f8-02_b.jpg kopie LYMPHOID NEOPLASMS (B-cell) – immunophenotype of cells of origin f8-02_b.jpg TdT TdT CD79a TdT CD79a CD20 CD79a CD20 CD79aCD138 CD79aCD138 CD79a CD20 CD79a CD20 CD79a CD20 CD10/Bcl6 kopie f8-04_c.jpg 7 T LYMPHOID NEOPLASMS – CELLS OF ORIGIN TdTCD7 TdT CD7 CD2/CD5 CD3cy CD7 CD2/CD5 CD3mem CD7 CD2/CD5 CD3mem CD4 CD7 CD2/CD5 CD3mem CD8 CD7 CD2/CD5 CD3mem CD4 CD10/bcl6 CD57 CD7/CD2 CD3cy CD56 TdT CD7 CD2/CD5 CD1a CD3cy-mem CD3mem kopie WHO classification of lymphomas nB-cell neoplasms 1.precursor B-cell neoplasms 2.peripheral B-cell neoplasms n nT-cell neoplasms 1.precursor T-cell neoplasms 2.peripheral T-cell neoplasms n nHodgkin lymphomas 1.Classical subtypes 2.Lymphocyte predominance Non-Hodgkin lymphomas/WHO classification I.Precursor B-Cell Neoplasms •B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) II.Peripheral B-Cell Neoplasms •B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) •B- prolymphocytic leukemia •Lymphoplasmacytic lymphhoma •Follicular lymphoma (FL) •Extranodal marginal zone lymphoma (MALT lymphoma) •Mantle cell lymphoma (MCL) •Splenic and nodal marginal zone lymphoma •Hairy cell leukemia •Plasmacytoma/plasma cell myeloma •Diffuse large B-cell lymphoma (DLBCL) •Burkitt lymphoma Non-Hodgkin lymphomas/WHO classification III.Precursor T-Cell neoplasms. •T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) IV.Peripheral T-/NK-Cell Neoplasms •T- cell prolymphocytic leukemia •Mycosis fungoides/Sézary syndrome •Peripheral T-cell lymphoma, NOS •Angioimmunoblastic T-cell lymphoma •Anaplastic large-cell lymphoma •Enteropathy-type T-cell lymphoma •Panniculitis-like T-cell lymphoma •Hepatosplenic γδ T-cell lymphoma •NK/T-cell lymphoma, nasal type •NK-cell leukemia •Adult T-cell leukamia/lymphoma (HTLV1) Neoplasms of immature B and T cells (precursor B and T cell neoplasms) 1.Precursor -B-cell acute lymphoblastic leukemia/lymphoma -bone marrow precursor B-cell expressing TdT and lacking surface Ig -children (peak at age 4), highly aggressive/chemosensitive, leukemic presentation (80 %) -infiltration of bone marrow, LN, liver, spleen,… -diverse chromosomal translocation (t(12;21) n 2.Precursor-T-cell acute lymphoblastic leukemia/lymphoma -precursor T-cell (often of thymic origin) expressing TdT -diverse chromosomal translocations (TCR loci) -Adolescent males, thymic mass, variable splenic, hepatic, and bone marrow involvement; aggressive -B-ALL>>>T-ALL - Neoplasms of mature B-cells (peripheral B cells neoplasms) 1.B-chronic lymphocytic leukemia/small lymphocytic lymphoma -naive B-cell or postgerminal center memory B-cell (CD5+) -trisomy 12, deletions 11q, 13q, 17p -adults; bone marrow, lymph nodes, spleen, liver; indolent; transformation into high grade lymphoma – Richter´s syndrome 2.Mantle cell lymphoma n- naive B-cell of mantles (CD5+, cyclinD1+(promotesG1 to S phase progression) -t(11;14); cyclinD1 locus/IgH locus -older males, often extranodal (lymphomatous polyposis); moderately aggressive – resistent to therapy 3.Follicular lymphoma -germinal center B-cell (CD10+, bcl-2+, bcl-6+): centrocytes; centroblasts and immunoblasts -t(14;18); bcl-2/IgH (bcl-2 (inhibitor of apoptosis) overexpression – promotion of the survival of follicular lymphoma cells -adults; primary nodal, later disseminated; indolent - n Spleen, follicular lymphoma Follicular lymphoma Centrocytes, centroblasts Centroblasts Nodular infiltration Loss of polarity of germinal centers 4.Diffuse large B-cell lymphoma -germinal center or postgerminal center B-cell (centroblasts and immunoblasts) -diverse chromosomal translocations (bcl-6 rearrangement) -all ages, usually adults; 40 % extranodal; aggressive 5.Burkitt lymphoma n (African endemic (jaws); sporadic (intestinal); HIV+ related) -germinal center B-cell (CD10+)?; „starry sky“ pattern; high mitotic rate, high apoptotic rate -t(8;14) (c-myc/IgH), t(2;8) (c-myc/kappa light chains), t(8;22) (c-myc/lambda light chains) -adolescents, young adults; aggressive, often association with EBV 6.Extranodal marginal zone lymphoma (MALT lymphomas) -postgerminal center memory B-cell -extranodal in adults with chronic infalmmation (Helicobacter pylori gastritis, Sjogren´s syndrome, chronic lymphocytic autoimmune thyreoiditis,…); indolent, possible transformation into high grade lymphoma -+ nodal marginal zone B-cell lymphoma; + splenic marginal zone B-cell lymphoma - - - n Diffuse large B cell lymphoma DLBCL high2 DLBCL high imunoblasts centroblasts Burkitt lymphoma Burkitt - reprint Burkitt Ki 67 Ki67 7.Hairy cell leukemia -postgerminal center memory B-cell (no known the physiological equivalent; hairlike projections) -no specific chromosomal abnormality -older males; pancytopenia, infections, bone marrow, liver and spleen infiltration, no lymph nodes involvement; indolent 8.Multiple (plasma cell) myeloma/plasmacytoma -plasma cell derived from a postgerminal center B-cell; neoplastic cell synthesizes and secretes a single homogeneous immunoglobulin or its fragments (monoclonal neoplastic proliferation of plasma cells) -diverse reaarangements involving IgH; -Myeloma: older adults; lytic lesions of bones, primary amyloidosis, renal failure. -Plasmacytoma: neoplastic plasma cell masses in bone or soft tissues -+ monoclonal gammapathy of undetermined significance; + heavy chain disease; +extraosseal plasmacytoma; +primary or immunocyte-associated amyloidosis 9.Lymphoplasmacytic lymphoma -peripheral CD5- post-germinal center memory B-cell with activated plasma cell differentiation program ; neoplastic cells with PAS+ inclusions containing Ig (cytoplasmic Russell bodies and nuclear Dutcher bodies) -lymph nodes, bone marrow and spleen involvement -Waldenstrom macroglobulinemia (excess of IgM, hyperviscosity syndrome) -Indolent - - Multiple myeloma MYelom RTG myelom -kost Osteolytic lesions Infiltration by neoplastic plasma cells Neoplasms of mature B-cells B-CLL HCL MM MALT MALT Neoplasms of mature T-cells (peripheral T cells neoplasms) 1.Adult T-cell leukemia/lymphoma -helper T-cell (CD25+; IL-2 receptor) -HTLV-1 provirus in neoplastic cells -lymph nodes, bone marrow, hypercalcemia, osteolysus; aggressive 2.Anaplastic large cell lymphoma T or null cell -cytotoxic T cell -rearangements of ALK -children, young adults, lymph nodes, soft tissues, skin; aggressive n3. Extranodal NK/T cell lymphoma, nasal and nasal typ n- NK cells, cytotoxic T cells (before WHO classification: angiocentric lymphoma) -nasal (lethal midline granuloma), lung (lymphomatoid granulomatosis), CNS, skin -aggressive, accompanied with hemophagocytic syndrome 4.Enteropathy-type-T-cell lymphoma -IEL (intraepithelial T cell; CD3+, CD4-, CD8+/-) -clonal reaarangement of TCR -often associated with CS (ulcerative jejunitis, therapy refractory sprue) -aggressive n n n5. Peripheral T-cell lymphoma (unspecified) n6. Mycosis fungoides/Sezary syndrome (leukemic) - helper cells - no specific chromosomal abnormality - skin involvement (patches, plaques, nodules n or generalized erythema) n7. T-chronic prolymphocytic leukemia - splenomegaly, leukemia - More aggressive than B-CLL n8. T-cell granular lymphocytic leukemia - CD8+ T cells or CD56+ NK cells (Asia, EBV) - splenomegaly, neutropenia, associated with autoimmune diseases – n reumatoid arthritis - indolent (CD8+); aggressive (CD56+) - n+ angioimmunoblastic T-cell lymphoma, panniculitis-like T-cell lymphoma, hepatosplenic γδ T-cell lymphoma n - n n Differences between HL and NHL Hodgkin lymphoma Non-Hodgkin Lymphoma Usually localized to a single axial group of LN (cervical, mediastinal, para-aortic) Involvement of multiple peripheral LN Contiguous spreading Non-contiguous spreading Mesenteric LN and Waldeyer ring rarely involved …… commonly involved Extranodal rare Extranodal common Diagnostic (neoplastic) cells admixed with reactive non-malignant inflammatory cells Neoplastic/lymphoma cells dominate B-cell origin B- or T-cell origin Hodgkin lymphoma nneoplastic cells (diagnostic cells) – minor fraction (germinal or post-germinal B-cells) nreactive lymphocytes, macrophages, granulocytes – major fraction of tumor mass n n nClassical HL: nNodular sclerosis nLymphocyte-rich nMixed cellularity nLymphocyte depletion n n+ Lymphocyte predominance/nodular n(diagnostic cells – the L&H (pop corn) cells- B phenotype) Hodgkin lymphoma nClinical picture nPainless enlargement of lymph nodes (cervical, mediastinal, para-aortic: often localized to single axial group with spread by contiguity); mesenteric nodes and Waldeyer ring rarely involved, extranodal involvement uncommon nYoung patients nNight sweats, weight loss n nNeoplastic cells in classical HL nDiagnostic Reed-Sternberg and Hodgkin cells (multiple or single nucleus) nLacunar cells n n n n n n Diagnostic cells – HL, classical NSHD-RS cell MCHD-Hodgkin cell NSHD-lacunar cell NSHD - Sternberg cell Lacunar cells R-S cell S-cell H-cell Myeloid neoplasms nNeoplasms originated from hematopoietic progenitor/stem cells capable of giving rise to differentiated cells of myeloid series nCells of the myeloid series n (erythrocytes, granulocytes, monocytes, platelets) nPrimary involvement of bone marrow n (secondary spleen, liver and lymph nodes) n3 categories: 1.Acute myelogenous leukemias 2.Myelodysplastic syndromes 3.Chronic myeloproliferative disorders n Acute myelogenous leukemia (AML) nPeak incidence 15-39 years nReplacement of normal bone marrow elements by undifferentiated elements (myeloid blasts) nHiatus leukemicus nImmature blasts released into peripheral blood nLeukemic infiltrates in bone marrow, liver, spleen, lymph nodes…. ÞClinical signs of bone marrow failure n → anemia (fatigue, palor) → trombocytopenia (abnormal bleeding) n → leukopenia (infections - fever) nGenerally poor prognosis (60 % remision; 15-30 % disease free for 5 years) n AML classification nFAB classification 1.M0 AML minimally differentiated 2.M1 AML without differentiation 3.M2 AML with maturation 4.M3 acute promyelocytic leukemia 5.M4 acute myelomonocytic leukemia 6.M5 acute monocytic leukemia 7.M6 acute erythroleukemia 8.M7 acute megakaryocytic leukemia n nWHO classification 1.AML with recurrent chromosomal rearrangements/with genetic aberrations n- t(8;21) – favorable prognosis; inv16 - favorable; t(15;17) - intermediate; t(11q23v) – poor 2.AML with multilineage dysplasias/with MDS-like features n- with prior myelodysplastic syndrome (very poor prognosis) -without prior myelodysplastic syndrome (poor prognosis) 3.AML, therapy related (alkylated agents related; epipodophyllotoxin related) – very poor prognosis 4.AML, not otherwise specified (M0-M7), intermediate prognosis n Myelodysplastic syndromes (MDS) n Clonal stem/progenitor cell disorder characterized by maturation defects (=ineffective maturation of myeloid progenitors) associated with ineffective hematopoiesis and an increased risk of development of AML. n nidiopathic ntherapy-related n •Bone marrow: hypercellular or normo-cellular •Peripheral blood: cytopenia of one or more cell lines •Risk of transformation into AML n(abnormal stem cell clone genetically unstable→additional mutations→AML Chronic myeloproliferative disorders nChronic myelogenous leukemia n nPolycythemia vera n nEssential thrombocytosis n nPrimary myelofibrosis n Chronic myelogenous leukemia nadults, peak incidence in 4th and 5th decade n ncell of origin: pluripotent stem cell n nacquired genetic abnormality: t(9;22); BCR-ABL fusion gene: fusion protein with tyrosinkinase activity; Philadelphia chromosome n nclinical picture: anemia, hypermetabolism due to increased cell turnover: fatigability, weakness, weight loss, anorexia…..slow progression-accelerated phase-blastic crisis (AML-like) n npoor prognosis; therapy: transplantation of bone marrow, imatinib mesylate (inhibitor of the BCR-ABL tyrosine kinase) Chronic myelogenous leukemia •Elevated leukocyte count (>100,000 cells μ/l) n •Hypercellular bone marrow n (hyperplasia of granulocytic and megakaryocytic precursors) n •Circulating cells: predominantly neutrofils, metamyelocytes and myelocytes, myeloblasts <5 % • •Extreme hepatosplenomegaly, spleen up to 20 kg • •Extramedullary hematopoiesis n Polycythemia vera nmultipotent myeloid stem cell n nincreased marrow production of erythroid, granulocytic and megakaryocytic elements n nsymptoms related to the increased red cell mass and hematocrit: plethora, cyanosis owing stangnation and deoxygenation, headache, dizziness, hypertension, GIT symptoms, hyperuricemia due to increased cell turnover, increased risk of major bleeding and thrombosis n ntransition into myelofibrosis n ndevelopment of AML (treatment related – alkylating drugs) n Thank you for your attention.