Leukocytes 4-10 000/mm3 Differential count: neutrophils 60- 70%, eosinophils 2-4% basophils - up to 1% ly: 20 – 30%, mono 3-8% ↓ Leukopenias most often: neutropenia lymphopenia: less common – congenital ID diseases, corticosteroid therapy ↑ Proliferations : reactive – infections, other conditions neoplastic

NEOPLASTIC PROLIFERATIONS OF WHITE CELLS myeloid from the hematopoietic stem cells giving rise to cells of myeloid lineage thrombocytic, granulocytic, erythroid Acute myelogenous (myeloid) leukaemias Myelodysplastic syndromes Chronic myeloproliferative disorders B. lymphoid - tumors of lymphocytes, lymphomas and leukaemia Hodgkin lymphoma versus non-Hodgkin lymphomas; B- versus T- cell lymphomas precursor cells (B or T or NK) – lymphoblastic versus mature cells – B or T (or NK) C. histiocytic – proliferative lesions of histiocytes Langerhans histiocytosis

Myelodysplastic syndrome Bone marrow(BM) Hyper /normocellular Dysplastic – architecture, cytology Ineffective – bone marrow failure Peripheral blood (PB) - pancytopenia Blood cells: few and pathological (size, shape, function)

Myelodysplastic syndrome clonal disorders of stem cells defects of maturation in the BM - ineffective hematopoiesis (progressive failure of BM function) cells in the PB : decreased numbers – pancytopenia + defective in function, pathological shapes BM: hypercellular, but dysplastic: pathological forms, architecture blasts may be increased (but less than 20%, threshold AML versus MDS)

Myelodysplastic syndrome Clinical symptoms and complications ???

Myelodysplastic syndrome Clinical symptoms and complications Anemia Thrombocytopenia - bleeding Leukopenia – infection (Splenomegaly +-) Asymptomatic – one half

Myelodysplastic syndrome primary – de novo - old people – over 60 secondary – therapy related – toxic exposure - worse prognosis, more prone to AML

Myelodysplastic syndrome Subcategories Refractory anemia –– unilineage dysplasia RA with ringed sideroblasts – the nucleus encircled by siderotic granules RA with multilineage dysplasia RA with excess blasts –more than 5%, less than 20% MDS unclassifiable MDS assoc. with isolated del. (5q) chromosome

Chronic myeloproliferative diseases

Chronic myeloproliferative diseases Clonal disorders Adults 1. Chronic myeloid leukemia 2. Polycythemia vera 3. Essential thrombocytemia 4. Chronic osteomyelofibrosis

Chronic myeloproliferative diseases Common principles: 1. Bone marrow: stem cell genetic abnormalities, neoplastic proliferation of one or more (all) BM myeloid series (red, white, megakaryocytes) disorder of an individual series more pronounced in each of the categories 2. Peripheral blood: increased numbers of cells; relatively normal maturation 3. Splenomegaly, hepatomegaly sequestration of excess blood cells, extramedullary hematopoiesis, leukaemic infiltration

Chronic myeloproliferative diseases common features phases of the disease in time: 1. onset insidious proliferative phase, 2. progression - spent phase - osteomyelofibrosis - blast phase all can (do not have to) progress to AL; CML does it invariably)

Chronic myelogenous leukaemia (CML) t(9; 22) – Philadelphia chromosome, bcr-abl gene pluripotent stem cell defect abnormal fusion protein - increased tyrosine kinase activity most striking : proliferation of G increased cellularity maturation retained (no hiatus leukaemicus) hematopoiesis also extramedullary splenomegaly (hepatomegaly) PB: leukocytosis – exceeds even 100 000/ mm3

CML PB: no hiatus leukaemicus; mature neutrophils, some metamyelocytes, and a myelocyte.

Chronic myelogenous leukaemia (CML) Phases 1. chronic – aver. 3 ys 2. accelerated – gradual failure of response to treatment, increasing anemia and thrombocytopenia, basophilia 3. blast crisis –after accelerated phase or without the acceler. phase Blast crisis = acute leukaemia - 70% myeloid, 30% lymphoblastic

Chronic myeloid leukaemia

Chronic myeloid leukaemia uric acid deposition

JAK2 mutation In one half of Polycythemia vera Essential thrombocythemia Chronic myelofibrosis

Polycythaemia vera morbus Vaquez increased proliferation of all three series most striking: red cells hypercellular BM PB: HTC 60%, Hb over 180g/l For the diagnosis: exclude secondary polycythemia

Polycythaemia vera increased RC mass - symptoms: hypervolemia, blood stasis (mostly venous), cyanosis – stagnation and deoxygenation of blood hypertension, thromboses, bleeding – abnormal blood flow, abnormalities of PLT granulopoiesis may be elevated plt elevated + functional abnormalities SPENT PHASE: myelofibrosis (20%/10 ys)

Polycythemia vera. Plethora.

Polycythemia vera. Plethora.

distension of retinal vessels Polycythemia vera distension of retinal vessels

Polycythemia vera Gout - right great toe

Gouty tophi

Polycythemia vera, spent phase, advanced marrow myelofibrosis. Massive splenomegaly (3020 gm; normal: 150 to 200 gm) largely owing to extramedullary hematopoiesis

Essential thrombocythaemia the least common CMPD PLT exceed 600 000 /mm3 BM: increased cellularity, megakaryocytes: abnormal, often large PB: PLT: often large Symptoms: thrombosis and hemorrhage – abnormalities of quantity and quality of PLT rel. indolent Giant platelets

Essential thrombocythaemia haemorrhages

Essential thrombocythaemia thrombosis, gangrene

Chronic idiopathic myelofibrosis Myelofibrosis with myeloid metaplasia Agnogenic myeloid metaplasia

Chronic idiopathic myelofibrosis abnormal neoplastic megakaryocytes release fibrogenic factors – PDGF and TGFa stimulate fibroblasts to proliferation early: BM hypercellular, minimal fibrosis progression: BM hypocellular, fibrotic; osteosclerosis obliteration of BM space: extramedullary hematopoiesis - spleen; later: liver PB: leukoerythroblastic=erytroid and granulocytic precursors 20% - progression to AML

Primary myelofibrosis (peripheral blood smear). Two nucleated erythroid precursors and several teardrop-shaped red cells (dacryocytes). Immature myeloid cells present in other fields. An identical picture - in other diseases producing marrow distortion and fibrosis.

Leukaemia Acute – myeloid; lymphoblastic - B, T Chronic – myeloid, lymphocytic – B, T

Acute leukaemia (AL) Common: acute course untreated: death in weeks, months Problems – symptoms result from: A. failure of normal hematopoiesis – anemia, neutropenia, thrombocytopenia B. infiltration of organs by neoplastic cells 1. Myeloid (adults) 2. Lymphoblastic (young; B or T) further subdivision: genetics, morphology, immunophenotype

Acute leukaemia

Acute myeloid leukaemia Categories: AML with recurrent gen. abnormalities –balanced translocations, often complete remission, favourable prognosis (fusion gene - chimeric protein); t(15;17) – AML M3 – promyelocytic – treatment with transretinoic acid; t(8; 21) or inversion of chromosome 16 AML therapy related AML with multilineage dysplasia AML – NOS- minim.differentiated Without maturation With maturation

Acute myeloid leukaemia FAB classification = French – American – British M0 – without maturation – myeloblastic M1 – without maturation M2 – with maturation M3 – promyelocytic – now categorised rather according to the genetics – t(15; 17) M4 – myelomonocytic M5 – a – monoblastic, b- monocytic M6 – erythroid M7 – megakaryoblastic

Myeloid sarcoma Tumour mass of immature myeloid cells Extramedullary (bone) Association - before or concurrently: 1. AML (or as a relapse) 2. Chronic myelogenous leukaemia other myeloproliferative disorders 3. MDS Extramedullary myeloid tumour, granulocytic sarcoma, chloroma

Myeloid sarcoma Localization 1. Bones – subperiosteal (skull, paranasal sinuses, sternum, ribs, vertebrae, pelvis) 2. Lymph nodes Skin Histological types A. Granulocytic B. Monoblastic C. Trilineage haematopoiesis

Myeloid sarcoma - poorly differentiated …a high index of suspicion... Stains: CHAE, MPO, lysozyme; CD15, CD68, CD117, CD43 (CD43 only!) Differential diagnosis 1. Lymphoblastoma 2. Burkitt lymphoma 3. Large cell lymphoma 4. Small round cell tumours (neurobl., Ewing/PNET, medullobl.) Lymphoblastoma

Myeloid sarcoma Prognosis If + MPD, MDS = as a blast transformation If + AML – as this AML If isolated: curative radiotherapy prolonged survival

Precursor (lymphoblastic)B-cell neoplasms B-acute lymphoblastic leukaemia/ lymphoblastic lymphoma 1. Leukaemia (more common): involves the bone marrow and PB 2. occasionally solid primary nodal or extranodal mass /B-lymphopblastic lymphoma/ without PB and BM involevement - leukaemization possible. biologic unity of B-ALL and B-LBL, division arbitrary

Precursor (lymphoblastic)B-cell neoplasms Small to medium sized cells scant cytoplasm, dispersed chromatin, and inconspicuous nucleoli

Acute lymphoblastic leukemia/lymphoma. Lymphoblasts: condensed nuclear chromatin, small nucleoli, and scant agranular cytoplasm

Lymphoblastic leukaemia More common B B-ALL – children, but also adults; relatively frequent, good prognosis Children: 95% complete remission, 80% cured /adults worse/ Lymphoblastoma (LBL) More common: T B-LBL – rare T-LBL- rapidly growing mass in mediastinum, adolescent male

Acute B-cell lymphoblastic leukaemia B-ALL – children, but also adults; relatively frequent B-LBL - much less common - skin, bone, soft tissues, LN Symptoms: BM failure Enlarged LN, liver, spleen Antigenic profile:TdT, CD10 (CALLA) various degree of differentiation, B-antigens (CD79a, CD20) Genetic abnormalities– prognostically important Good: hyperdiploidy; t (12, 21) Poor: t(9, 22), hypodiploidy In general: a good prognosis leukaemia Children: 95% complete remission, 80% cured /adults worse/