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 A. myeloid

from the hematopoietic stem cells giving rise to cells of myeloid lineage thrombocytic, granulocytic, erythroid

Acute myelogenous (myeloid) leukaemias Myelodysplastic syndromes Chronic myeloproliferative neoplasms

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. histiocytoses – proliferative lesions of histiocytes

Langerhans histiocytosis

Bone marrow(BM)

hypercellular

Dysplastic

Ineffective – bone marrow failure

Peripheral blood (PB)

Blood cells: few and pathological

(size, shape, function)

Myelodysplastic syndrome

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 +-)

Myelodysplastic syndrome

purpura

Myelodysplastic syndrome

• primary – de novo - old people – over 60

• secondary – therapy related – toxic exposure - worse prognosis

Myelodysplastic syndromeSubcategories

• 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

Sideroblastic anaemia (Perl´s stain)collars of iron granules around the nucleus

(Chronic) myeloproliferative

neoplasms

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, hepatomegalysequestration of excess blood cells, extramedullary hematopoiesis, leukaemic infiltration

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 myeloproliferative diseases

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.

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 myelogenous leukaemia (CML)

Chronic myeloid leukaemia

Chronic myeloid leukaemia

uric acid deposition

Polycythaemia vera

• increased proliferation of all three series

• most striking: red cells

• hypercellular BM

• PB: HTC 60%, Hb over 180g/l

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.

Polycythemia veradistension of retinal vessels

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 • abnormal neoplastic megakaryocytes release

fibrogenic factors – PDGF and TGFastimulate 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 courseuntreated: death in weeks, monthsProblems – symptoms result from:A. failure of normal hematopoiesis –

anemia, neutropenia, thrombocytopeniaB. infiltration of organs by neoplastic cells

• 1. Myeloid (adults)• 2. Lymphoblastic (young; B or T)

further subdivision:genetics, morphology, immunophenotype

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

• 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

Acute myeloid leukaemia

Acute myeloblastic leukaemia: Staphylococcus aureus lesions

Acute myeloblastic leukaemiamixed infectionStreptococci, Candidaprevious chemotherapyand neutropenia

AML, M5leukaemic infiltrationof the gumsexpansion andthickeningpartial coverings of the teeth

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 sarcomaLocalization

1. Bones – subperiosteal

(skull, paranasal sinuses, sternum, ribs, vertebrae, pelvis)

2. Lymph nodes

3. Skin

Myeloid sarcoma - poorly differentiated

…a high index of suspicion...Stains: CHAE, MPO, lysozyme; CD15,

CD68, CD117, CD43 (CD43 only!)

Differential diagnosis1. Lymphoblastoma2. Burkitt lymphoma3. Large cell lymphoma4. Small round cell tumours

(neurobl., Ewing/PNET, medullobl.)

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 neoplasmsB-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/

Precursor T cell neoplasms

• T-ALL– less common than B-ALL

• T-ALL, T-LBL - adolescent male

• clinically: similarities with B-ALL;

• all acute leukemias share some clinical similarities

• But difference: AML adults, ALL: children

• T-LBL - rapidly growing mass in mediastinum