1. Leukocytes /mm3 Differential count: neutrophils %, 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

2. 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

3. 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)

4. 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)

5. Myelodysplastic syndrome
Clinical symptoms and complications ???

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

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

8. 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

9. Chronic myeloproliferative diseases

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

11. 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

12. 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)

13. 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 / mm3

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

15. 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, % lymphoblastic

16. Chronic myeloid leukaemia

17. Chronic myeloid leukaemia
uric acid deposition

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

19. 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

20. 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)

21. Polycythemia vera. Plethora.

22. Polycythemia vera. Plethora.

23. distension of retinal vessels
Polycythemia vera
distension of retinal vessels

24. Polycythemia vera
Gout - right great toe

25. Gouty tophi

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

27. Essential thrombocythaemia
the least common CMPD
PLT exceed /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

28. Essential thrombocythaemia
haemorrhages

29. Essential thrombocythaemia
thrombosis, gangrene

30. Chronic idiopathic myelofibrosis
Myelofibrosis with myeloid metaplasia
Agnogenic myeloid metaplasia

31. 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

32. 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.

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

34. 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

35. Acute leukaemia

36. 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

37. 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

38. 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

39. 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

40. 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

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

42. 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

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

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

45. 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

46. 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/