Leukaemias. Lymphomas. (WHO classification) MARKÉTA HERMANOVÁ Leukaemias •Neoplastic proliferation of white blood cell precursors •Diffuse replacement of normal BM by leukaemic cells with their subsequent variable accumulation in peripheral blood (=leukaemization) •Infiltration of peripheral organs by leukaemic cells (liver, spleen, lymph nodes, meninges, gonads,….) •Consequence, particularly in acute leukaemias: bone marrow failure with anaemia, neutropenia and thrombocytopenia • Lymphomas • Neoplastic/lymphoma cells form tumor/neoplastic mass (primary nodal and/or extranodal) ◦ !Lymphomas may also present by leukaemic infiltrates and leukaemias also form solid neoplastic massess Haemato-oncological malignancies •Mutations that inhibit normal differentiation and maturation of progenitor cells, or mutations disrupting the regulation of progenitor and precursor cells by growth factors ◦ Þunregulated clonal expansion of immature hematopoietic cells → inhibition of normal hemopoiesis → release of immature blast into circulation, infiltration of peripheral organs Tumour groups of haematopoeietic and lymphoid tissue Lymphoid neoplasms/lymphomas → non-Hodgkin lymphomas (including lymphocytic leukaemias and plasma cell dyskrasias) → Hodgkin lymphomas Myeloid neoplasms -from stem cells that normally give rise to the formed blood elements (granulocytes, red cells, platelets) -3 categories → acute myeloid leukaemias → myeloproliferative disorders → myelodysplastic syndromes Histiocytic neoplasms Lymphoid neoplasms/lymphomas 6 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 8 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 Non-Hodgkin lymphomas (NHL) B-cell neoplasms precursor B-cell lymphoid neoplasms mature B-cell neoplasms T-cell neoplasms precursor T-cell lymphoid neoplasms mature T-cell neoplasms Hodgkin lymphomas (HL) Classic HL - nodular sclerosis - lymphocyte rich - mixed cellularity - lymphocyte depleted Nodular lymphocyte predominant HL Non-Hodgkin lymphomas/WHO classification I.Precursor B-Cell Lymphoid Neoplasms •B-cell acute lymphoblastic leukaemia/lymphoma (B-ALL) II.Mature B-Cell Neoplasms •B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) •B- prolymphocytic leukemia •Lymphoplasmacytic lymphhoma •Follicular lymphoma (FL) •Extranodal (MALT lymphoma)/nodal/splenic marginal zone lymphoma •Mantle cell lymphoma (MCL) •Splenic and nodal marginal zone lymphoma •Hairy cell leukaemia •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 leukaemia/lymphoma (T-ALL) IV.Peripheral T-/NK-Cell Neoplasms Mainly leukaemic: •T- cell prolymphocytic leukemia •Adult T-cell leukamia/lymphoma (HTLV1) •T-cell granular lymphocytic leukemia Mainly nodal: •Peripheral T-cell lymphoma, NOS •Angioimmunoblastic T-cell lymphoma •Anaplastic large-cell lymphoma Mainly extranodal: •NK/T-cell lymphoma, nasal type •Mycosis fungoides/Sézary syndrome •Enteropathy-type T-cell lymphoma •Panniculitis-like T-cell lymphoma •Hepatosplenic γδ T-cell lymphoma •Primary cutaneous T-cell lymphomas ……………….. Precursor B and T cell lymphoid neoplasms Acute lymphoblastic leukaemias 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, leukaemic presentation (80 %) -infiltration of bone marrow, LN, liver, spleen,… 2.Precursor-T-cell acute lymphoblastic leukemia/lymphoma -precursor T-cell (often of thymic origin) expressing TdT -Adolescent males, thymic mass/mediastinal tumour, variable splenic, hepatic, and bone marrow involvement; aggressive -B-ALL>>>T-ALL - Mature B-cells neoplasms 1.B-chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) -cell of origin: naive B-cell or postgerminal center memory B-cell (CD5+) -most frequent leukaemia in adults -infiltration of bone marrow, lymph nodes, spleen, liver -clinically indolent; transformation into high grade lymphoma – Richter´s syndrome -in lymph nodes: diffuse infiltrate of monomorphic small lymphocytes prolymphocytes and paraimmunoblasts with proliferation centres/pseudofollicles - CLL-detail Mature B-cells neoplasms 2.Mantle cell lymphoma -t(11;14); cyclinD1 locus/IgH locus -naive B-cell of mantles (CD5+, cyclinD1+(promotes G1 to S phase progression) -older males, often extranodal (lymphomatous polyposis); moderately aggressive – resistent to therapy MCL400xCÉVY MCL200xCYCLIN Immunohistochemistry: overexpression of cyclinD1 Mature B-cells neoplasms 3.Follicular lymphoma -2nd most common NHL -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 with possible transformation into high grade lymphoma (DLBCL) Spleen, follicular lymphoma Follicular lymphoma Centrocytes, centroblasts Centroblasts Nodular infiltration Loss of polarity of germinal centers 001 HE-40xIZa 008 Bcl-2 40x Follicular lymphoma Immunohistochemistry: overexpression of bcl-2 Mature B-cells neoplasms 4.Diffuse large B-cell lymphoma -most frequent lymphoma, 45 % of all NHL -cell of origin: germinal center or postgerminal center B-cell (centroblasts and immunoblasts) -de novo or progression from low grade lymphoma (CLL, FL, MZL) -variable cytogenetic alterations (bcl-6, bcl-2, MYC,…) -all ages, usually adults; 40 % extranodal; aggressive - - - Diffuse large B cell lymphoma DLBCL high2 DLBCL high imunoblasts centroblasts Mature B-cells neoplasms 5.Burkitt lymphoma African endemic (jaws) sporadic (intestinal) immunodeficiency-associated 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) → high proliferative activity -adolescents, young adults; aggressive, often association with EBV Burkitt lymphoma Burkitt - reprint Burkitt Ki 67 Ki67 Immunohistochemistry: High expression of Ki67 – marker of proliferation. HE: „starry sky“ pattern Macrophages with apoptotic bodies Mature B-cells neoplasms 6.Extranodal marginal zone lymphoma (MALT lymphomas) -postgerminal center memory B-cell -extranodal in adults with chronic inflammation (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 MALT Mature B-cells neoplasms 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. 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 -Waldenström macroglobulinemia (excess of IgM, hyperviscosity syndrome) -Indolent - - Mature B-cells neoplasms/ plasma cell dyskrasias/neoplasms 9.Plasma cell myeloma/multiple myeloma Plasmacytoma (solitary plasmocytoma of bone, extraosseous plasmocytoma) Monoclonal gammapathy of undetermined signifikance Light and heavy chain disease Primary amyloidosis -cell of origin: 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) -Myeloma: older adults; lytic lesions of bones, primary amyloidosis, renal failure (myeloma kidney due to excretion of Bence Jones proteins). -Plasmacytoma: neoplastic plasma cell masses in bone or soft tissues Multiple myeloma MYelom RTG myelom -kost Osteolytic lesions Infiltration by neoplastic plasma cells Mature T-cells neoplasms/ peripheral T- and NK-Cell Neoplasms Peripheral T-Cell Lymphoma, unspecified - wastebasket“ diagnosis - derived from mature T-cells - most patients with generalized lymphadenopathy, accompanied by eosinophilia, pruritus, fever, weight loss - worse prognosis compared with DLBCL Anaplastic Large-cell lymphoma; ALCL (ALK positive and ALK negative) - rearangements in the ALK gene (2p23) → ALK fusion proteins = tyrosinkinase activita that trigger the RAS and JAK/STAT signaling pathways - ALK+ ALCL, children and young adults, soft tissues, good prognosis - ALK- ALCL, in older adults, worse prognosis Mycosis fungoides/Sezary syndrome (leukaemic) - different manifestation of a tumour of CD4+ helper T cells that home to the skin - cutaneous lesions of MF: premycotic phase, plaques phase and tumour phase - SS: skin involvement manifested as generalized exfoliative erythroderma Enteropathy-type T-cell lymphoma - develops in some patients with coeliac disease -derived from intramucosal cytotoxic CD8+ T cells -abdominal pain, often intestinal perforation, sometimes prodrome of refractory celiac disease accompanied by ulceration (ulcerative jejunitis) -aggressive with very poor prognosis - Mature T-cells neoplasms/ peripheral T- and NK-Cell Neoplasms Mature T-cells neoplasms/ peripheral T- and NK-Cell Neoplasms Adult T-cell leukemia/lymphoma - aggressive tumour of CD4+ T cells - uniformly associated with HTLV-1 infection - Skin lesion, generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, hypercalcemia, osteolysus; aggressive Extranodal NK/T cell lymphoma, nasal and nasal typ - Aggressive tumour, usually derived from NK cells - Strongly associated with EBV infection -Most frequently presentation as a destructive nasopharyngeal mass („lethal midline granuloma“) Large granular lymphocytic leukemia - Tumour of cytotoxic T cells or NK cells -Associated with mutations in the transcription factor STAT3 and with autoimmune phenomena and cytopenias -T-cell origin – indokent clinical course, NK-cell tumours more aggressive 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 neoplastic cells (diagnostic cells) – minor fraction (germinal or post-germinal B-cells) reactive lymphocytes, macrophages, granulocytes – major fraction of tumor mass Classical HL: Nodular sclerosis Lymphocyte-rich Mixed cellularity Lymphocyte depletion + Lymphocyte predominance/nodular (diagnostic cells – the L&H (pop corn) cells- B phenotype) Hodgkin lymphoma Clinical picture Painless 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 Young patients Night sweats, weight loss Neoplastic cells in classical HL Diagnostic Reed-Sternberg and Hodgkin cells (multiple or single nucleus) Lacunar cells 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 Neoplasms originated from hematopoietic progenitor/stem cells capable of giving rise to differentiated cells of myeloid series Cells of the myeloid series (erythrocytes, granulocytes, monocytes, platelets) Primary involvement of bone marrow (secondary spleen, liver and lymph nodes) 3 categories: 1.Acute myeloid leukaemias 2.Myelodysplastic syndromes 3.Chronic myeloproliferative disorders Acute myeloid leukeamia (AML) Associated with diverse aquired mutations that lead to abnormal expression of transcription factors, which interfere with myeloid differentiation; often assoc. with mutations in genes encoding GFR signaling pathways components or regulators of the epigenome Replacement of normal bone marrow elements by immature myeloid blasts Hiatus leukemicus Immature myeloid lineage blasts released into peripheral blood Leukaemic infiltrates in bone marrow, liver, spleen, lymph nodes…. ÞClinical signs of bone marrow failure ◦ → anemia (fatigue, palor) → trombocytopenia (abnormal bleeding) ◦ → granulocytopenia (bacterial infections - fever) Peak incidence 15-39 years Generally poor prognosis (60 % remision; 15-30 % disease free for 5 years) •WHO classification* •I. AML WITH RECURRENT GENETIC ABNORMALITIES •AML WITH BALANCED TRANSLOCATIONS/INVERSIONS ◦AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 ◦AML with inv(16)(p13;1q22) or t(16<16)(P13.1;q23); CBFB-MYH11 ◦Acute promyelocytic leukaemia with PML-RARA ◦AML with t(9;11)(p21.3.;q23.3); KMT2A-MLLT3 ◦AML with t(6;9)(p23;q34.1); DEK-NUP214 ◦AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM ◦AML (megakaryoblastic) with t(1;22)(q13.3;q13.1); RB?15-MKL1 ◦AML with BCR-ABL1 •AML WITH GENE MUTATIONS ◦AML with mutated NPM1 ◦AML with biallelic mutation of CEBPA ◦AML with mutated RUNX1 •II. AML WITH MDS-RELATED CHANGES ◦ Acute myeloid leukaemie (AML) *just informative, no active knowledge requidred •III. THERAPY-RELATED MYELOID NEOPLASMS •IV. AML, NOT OTHERWISE SPECIFIED** ◦AML with minimal differentiation ◦AML without maturation ◦AML with maturation; ◦Acute myelomonocytic leukaemia ◦Acute monoblastic and monocytic leukaemia ◦Pure erythroid leukaemia ◦Acute megakaryoblastic leukaemia ◦Acute basophilic leukaemia ◦Acute panmyelosis with myelofibrosis •V. MYELOID SARCOMA •VI. MYELOID PROLIFERATIONS ASSOCIATED WITH DOWN SYNDROME ◦Transient abnormal myelopoiesis associated with Down syndrome ◦Myeloid leukaemia associated with Down syndrome ◦ Acute myeloid leukaemia (AML) **corresponding with previous FAB classification (M0-M7) French-American-British (FAB) AML classification* 1.M0 AML with minimal differentiation 2.M1 AML without maturation 3.M2 AML with maturation 4.M3 acute promyelocytic leukemia 5.M4 acute myelomonocytic leukemia 6.M5 acute monoblastic and monocytic leukemia 7.M6 pure erythroid leukaemia 8.M7 acute megakaryoblastic leukaemia Myelodysplastic syndromes (MDS) 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. de novo or following genotoxic exposures; frequently harbor mutations in splicing factors, epigenetic regulators, and transcription factors Primary/idiopathic (six categories based on morphological and cytogenetic features in the WHO classification) Secondary/therapy-related Predominantly in older adults Clinically: weakness, infections, hemorrhages due to pancytopenia Treatment: allogeneic HSC transplantation (in younger patients), supportive treatment with ATB and blood products transfusion, thalidomide-like drugs and DNA methylation inhibitors in some patients •Bone marrow: hypercellular or normocellular or (hypocellular) -Dysplastic differentiation of erythroid, granulocytic, monocytic and megakaryocytic lineages to various degree •Peripheral blood: cytopenia of one or more cell lines •Risk of transformation into AML (abnormal stem cell clone genetically unstable→additional mutations→AML Chronic myeloproliferative disorders - presence of mutated constitutively activated tyrosine kinases or other aberrations in signaling pathways that lead to growth factors independence Chronic myeloid leukaemia, BCR-ABL1-positive Polycythaemia vera Essential thrombocythaemia Primary myelofibrosis Chronic neutrophilic leukaemia Chronic eosinophilic leukaemia Myeloid leukaemia, unclassifiable Chronic myeloid leukaemia (CML) presence of aquired genetic abnormality: t(9;22); BCR-ABL fusion gene: fusion protein with tyrosinkinase activity; Philadelphia chromosome; BCR-ABL preferentially drives the proliferation of granulocytic and megakaryocytic progenitors, abnormal release of immature granulocytes from the marrow into blood adults, peak incidence in 5th and 6th decade Clinical features: - anemia, hypermetabolism due to increased cell turnover: fatigability, weakness, weight loss, anorexia - slow progression-accelerated phase-blast crisis (AML-like) Therapy: - transplantation of bone marrow - imatinib mesylate (inhibitor of the BCR-ABL tyrosine kinase) Chronic myeloid leukaemia (CML) •Elevated leukocyte count (>100,000 cells μ/l) •Hypercellular bone marrow (hyperplasia of granulocytic and megakaryocytic precursors) •Circulating cells: predominantly neutrofils, metamyelocytes and myelocytes, myeloblasts <5 % • •Extreme hepatosplenomegaly, spleen up to 20 kg • •Extramedullary hematopoiesis Polycythemia vera § the transformed progenitor cells have markedly decreased requirements for erythropoietin and other hematopoietic growth factors due to activating mutations in the tyrosine kinase JAK2 § § increased marrow production of red cells, granulocytes and platelets (panmyelosis) § § symptoms 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, abnormal blood flow and platelet function lead to increased risk of major bleeding and thrombosis § § transition into myelofibrosis, accompanied by increased extramedullary haematopoiesis § § transformation to AML in 2 % of patients Histiocytic and dendritic cell neoplasms Langerhans cell histiocytosis (histiocytosis X) Immunophenotype: CD1a+, langerin+, S100+; ultrastructurally cytoplasmic tennis–racket shape Birbeck granules) - monoostotic (solitary osteolytic lesion (eosinophilic granuloma), involvement of adjacent soft tissues) - polyostotic (multifocal osteolytic lesion (Hand-Schüller-Christian d.), involvement of adjacent soft tissues) - disseminated and multisystem (Letterer-Siwe disease; skin, bones, liver, spleen and bone marrow affected) Pulmonary Langerhans cell histiocytosis – special category, in smokers, reactive?, neoplastic? (BRAF mutated in some lesions) -derived from mononuclear phagocytes (macrophages and dendritic cells (antigen presenting cells) or histiocytes -rare tumours, <1% of tumours presenting in lymph nodes and soft tissues Histiocytic and dendritic cell neoplasms Langerhans cell sarcoma (high grade malignancy, skin and soft tissue involvement, multisystem) Histiocytic sarcoma Dendritic cell sarcomas (follicular DCS, interdigitating DCS, other rare forms….) Erdheim Chester disease - rare clonal systemic proliferation of histiocytes, with foamy component and containg giant Touton cells - involvement of different organs (bones, retroperitoneum, CNS,……), multisystem disease and CNS involvement with worse prognosis Thank you for your attention.