Hemoblastosis lecture by pathological anatomy

Medical

1. Lecture
Heamoblastoses
by Associate Professor Yulia Korneva
Department of Pathological Anatomy SZGMU n.a. I.I.
Mechnikov

5. Hemoblastoses – group of malignant
tumors from heamopoethic and lymphoid
tissue.
Hemoblastoses may be



systemic regional
(leukemias) (lymphomas)

6. Difference between leukemias and
lymphomas :
•Leukemias are the tumors, which originate in bone marrow
and gradually replace normal haemopoesis by clone of
leukemic cells, suppressing it.
• Lymphomas originate in lymphatic nodule or extralymphatic
locations (may start at any focus of lymphocytic infiltration)
•Рrogression of leukemia happen from a center to the
periphery: dissemination from bone marrow to internal
organs
•Lymphomas can metastasize in a bone marrow from
peripheral lymphoid tissue at terminal stage.

7. Leukemias

10. Leukemias – are malignant tumours,
characterized by abnormal proliferation of
immature hematopoietic cells with their
release to the peripheral blood.

15. Clinical Picture
Main syndromes include suppression of heamopoesis and organs
infiltration
1- Fever: moderate or high grade, usually irregular and starts when secondary
infection occur
2-rapidly developing marked asthenia.
3- rapidly developing severe anaemia ---> marked pallor.
4- bleeding tendency from --->----- > gums.
-------> skin
--------> orifices
--------->int. organs.
5-tender bones
6- joint pain (bleeding & infiltration)
7-Lymph nodes enlargement in --->------> more typical for A.L.L.
8-spleen & Liver enlargement. ---->more typical for A.M.L.

9-Chloromas :- more in A.M.L. (subperiosteal tumor like masses)
10-Maniphestation from C.N.S

16. ACUTE LEUKEMIAS

Results from proliferation of immature forms of
heamopoethic cells at a stage when they should not
enter the circulation.
Heterogenous group of neoplastic diseases,
characterized by proliferation of atypical elements
which originates from the stem cells of the
hematopoietic system.
Uncontrolled and progressive proliferation of these
cells lead to:-
- Replacement of normal marrow
- Invasion of peripheral blood
-Infiltration of various organs and tissues

17. aaa Name Cytogenetics
M0
minimally differentiated acute
myeloblastic leukemia
M1
acute myeloblastic leukemia,
without maturation
M2
acute myeloblastic leukemia, with
granulocytic maturation
t(8;21)(q22;q
22), t(6;9)
M3
promyelocytic, or acute
promyelocytic leukemia (APL)
t(15;17)
M4 acute myelomonocytic leukemia
inv(16)(p13q
22), del(16q)
M4eo
myelomonocytic together with
bone marrow eosinophilia
inv(16),
t(16;16)
M5
acute monoblastic leukemia (M5a)
or acute monocytic leukemia
(M5b)
del (11q),
t(9;11),
t(11;19)
M6
acute erythroid leukemias,
including erythroleukemia (M6a)
and very rare pure erythroid
leukemia (M6b)
M7 acute megakaryoblastic leukemia t(1;22)
M8 acute basophilic leukemia

18. ALL-L1: small uniform
cells
ALL-L2: large varied cells
ALL-L3: large varied cells
with vacuoles (bubble-like
features)
Each subtype is then
further classified by
determining the surface
markers of the abnormal
lymphocytes, called
immunophenotyping.
There are 2 main
immunologic types: pre-B
cell and pre-T cell. The
mature B-cell ALL (L3) is
now classified as Burkitt's
lymphoma/leukemia.
Subtyping helps determine
the prognosis and most
appropriate treatment in
treating ALL

19. Etiology:-
Unknown, some factors seem to be implicated: -
A- Environmental factors:-
•Ionizing radiation; mainly AML but ALL less important
•Chemical substances; prolonged exposure to certain
substances (benzene, phenylbutazone, chloramphenicol,
anticancer drugs, alkylating agents, natulan) ---> incidence of
leukemia mainly AML

Onset often preceded by a state of bone marrow hypoplasia,
peripheral pancytopenia
(preleukemic syndrome).

20. B-Genetic:-
May act by facilitating environmental factors.
C- Viruses:-
Based on experiments with laboratory animal, has
never proved humans. Typical products of viruses have
been identified in some adult patients.
HTLV (human T cell lymphotrophic virus) in T cell
ALL and hairy cell leukemia.
D- Immunological Factors: -
Patient with acquired or congenital immune
deficiency syndrome or subjected to prolonged
immunosuppressive treatment has ↑ incidence of
leukemia.

21. Differential Diagnosis :
D.D. between various forms of acute leukemia
is mainly on cytomorphologic, cytochemical criteria
rather than on clinical data, which are often analysed all
together.
age: may occur at any age but in general:
-A.L.L --- > the peak incidence in 1st 6 years of life.
Uncommon after age of 20
-A.M.L.--- >more commonly at slightly older age
groups centering around the teen-age or adolescent
period

25. Blood Picture :-
Acute Lymphoblastic Leukemia: * W.B.cs ---> ( ) 10,000 --
- 100,000 Or more but 40% are leukopenic
- Lymphocytes are likely to be the predominant cells.
- The diagnosis is established by detecting lymphoblastes in the
peripheral smear.
(N.B. Lymphoblastes : large cells with clear cytoplasm,
prominant nucleus, definite nucleole.
Diff. From myeloblasts :- absent specific granules in cytoplasm,
-ve peroxidase stain
-PAS +ve - Sudan Black -ve or weekly +ve
* platelets : usually < 100.000
may be completely absent.
* R.B.Cs ---> severe form of normocytic normochromic anemia
occurs early.

27. Blood Picture :-
Acute Myeloblastic Leukemia

- W.B.Cs. count as A.L.L.
- Leukopenia is as likely to occur as A.L.L
- The cells are peroxidase +ve, PAS –ve, Sudan black +ve ,
acid phosphatase +ve
- In 10 - 20% :Auer bodies are present rod like structures.
in cytoplasm of------------> myeloblast

Anemia and thrombocytopenia!

39. Myeloproliferative
disorders
Dr. Tzoran

41. Pathogenesis
•Disease of adult
•Peak incidence in 7
th
decade
•6-9/100,000

•Dysregulated proliferation
•No specific genetic abnormality
•CML (Ph chromosome t(9;22) BCR/ABL)
•Growth-factor independent proliferation
•PV, hypersensitiviy to IGF-1

•Bone marrow fibrosis in all MPD
•Fibrosis is secondary phenomena
•Fibroblasts are not from malignant clone
•TGF-β & Platelet like growth factor

42. Types of myeloproliferative diseases
•1. Chronic myeloid leukemia – was already discussed
•2. Polycythemia Vera
•3. Essential thrombocythemia
•4. Primary myelofibrosis

43. Polycythaemia vera
(Polycythaemia rubra vera)
•Polycythaemia vera is a clonal stem cell disorder
characterized by increased red cell production

•Abnormal clones behave autonomous
•Same abnormal stem cell give rise to granulocytes and platelets
•Rarely transforms into acute leukemia

44. Polycythaemia vera
(Polycythaemia rubra vera)
•Clinical features
•Age
•55-60 years
•May occur in young adults and rare in childhood
•Majority patients present due to vascular complications
•Thrombosis (including portal and splenic vein)
•DVT
•Hypertension
•Headache, poor vision and dizziness
•Skin complications (pruritus, erythromelalgia)
•Haemorrhage (GIT) due to platelet defect

45. Polycythaemia vera
(Polycythaemia rubra vera)
•Hepato-splenomegaly

•Erythromelalgia

•Increased skin temp
•Burning sensation
•Redness
Liver
40%
Spleen
70%
Erythromelalgia

46. Polycythaemia vera
(Polycythaemia rubra vera)
•Laboratory features and
morphology
•Hb, PCV (HCT), and Red
cell mass increased
•Increased neutrophils and
platelets
•Plasma urate high
•Circulation erythroid
precursors
•Hypercellular bone marrow
•Low serum erythropoietin
Bone marrow in PV

47. Myelofibrosis
Chronic idiopathic myelofibrosis
•Progressive fibrosis of the marrow &
increase connective tissue element
•Extramedullary erythropoesis is typical
•Insidious onset in older people
•Splenomegaly- massive
•Hypermetabolic symptoms
• Loss of weight, fever and night
sweats Myelofibrosis
Chronic idiopathic myelofibrosisc
•Bleeding problems
•Bone pain
•Gout
•Can transform to acute leukaemia in 10-
20% of cases

48. Myelofibrosis
Chronic idiopathic myelofibrosis
•Anaemia (bad prognosis)
•High WBC at presentation
•Later leucopenia and
thrombocytopenia
•Bone marrow aspiration- Failed
due to fibrosis
•Trephine biopsy- fibrotic
hypercellular marrow

49. Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis
•Clonal myeloproliferative disease of megakaryocytic lineage
•Sustained thrombocytosis
•Increase megakaryocytes
•Thrombotic or/and haemorrhage episodes

•Positive criteria
•Platelet count >600 x 10
9
/L
•Bone marrow biopsy; large and increased megakaryocytes.

50. Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis
•Clinical features

•Haemorrhage
•Microvascular occlusion
•TIA, gangrene
•Splenic or hepatic vein
thrombosis
•Hepatosplenomegaly

51. Lymphomas

52. Lymphomas - neoplasms of lymphoid
origin (lymph nodes or extra nodal lymphatic
tissues), typically causing lymphadenopathy

•lymphomas as clonal expansions of cells (B or T
lymphocytes or NK cells) at certain developmental stages
•Hodgkin Lymphoma – relatively uniform in histology,
clinical presentation and course of the disease. Hodgkin's
disease was named after the doctor who first recognized it
in 1832 - Thomas Hodgkin. It is now called Hodgkin's
lymphoma.

•Non Hodgkin Lymphoma – a large and heterogeneous
category with various cell origin, histology, clinical course.
Comprises most of lymphomas

53. Hodgkin Lymphoma
•Hodgkin’s disease is one of two
common types of cancers of the
lymphatic system. Non-Hodgkin’s
lymphoma, the other type, is far more
common. Hodgkin’s disease is named
after the British physician Thomas
Hodgkin, who first described the
disease in 1832 and noted
characteristics that distinguish it from
other lymphomas.
•Advances in diagnosis, staging and
treatment of Hodgkin’s disease have
helped to make this once uniformly
fatal disease highly treatable with the
potential for full recovery.
Sir Thomas Hodgkin (1798-1866)

54. WHO/REAL Classification of Lymphoid Neoplasms
B-Cell Neoplasms
Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma
(precursor B-acute lymphoblastic leukemia)
Mature (peripheral) B-neoplasms
B-cell chronic lymphocytic leukemia / small lymphocytic
lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
‡

Splenic marginal zone B-cell lymphoma
(+ villous lymphocytes)*
Hairy cell leukemia
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B-cell lymphoma of MALT type
Nodal marginal zone B-cell lymphoma
(+ monocytoid B cells)*
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal large B-cell lymphoma
Primary effusion lymphoma
†
Burkitt’s lymphoma/Burkitt cell leukemia
§
T and NK-Cell Neoplasms
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma
(precursor T-acute lymphoblastic leukemia

‡
Formerly known as lymphoplasmacytoid lymphoma or immunocytoma
II
Entities formally grouped under the heading large granular lymphocyte
leukemia of T- and NK-cell types
* Provisional entities in the REAL classification


Mature (peripheral) T neoplasms
T-cell chronic lymphocytic leukemia / small
lymphocytic lymphoma
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemia
II

Aggressive NK leukemia
Adult T-cell lymphoma/leukemia (HTLV-1+)
Extranodal NK/T-cell lymphoma, nasal type
#

Enteropathy-like T-cell lymphoma**
Hepatosplenic γδ T-cell lymphoma*
Subcutaneous panniculitis-like T-cell lymphoma*
Mycosis fungoides/Sézary syndrome
Anaplastic large cell lymphoma, T/null cell,
primary cutaneous type
Peripheral T-cell lymphoma, not otherwise characterized
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, T/null cell,
primary systemic type
Hodgkin’s Lymphoma (Hodgkin’s Disease)
Nodular lymphocyte predominance Hodgkin’s lymphoma
Classic Hodgkin’s lymphoma
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
Lymphocyte-rich classic Hodgkin’s lymphoma
Mixed cellularity Hodgkin’s lymphoma

Lymphocyte depletion Hodgkin’s lymphoma

†
Not described in REAL classification
§
Includes the so-called Burkitt-like lymphomas
** Formerly known as intestinal T-cell lymphoma
#
Formerly know as angiocentric lymphoma

55. Pathogenesis of lymphomas
•Genetic alterations - lack of apoptosis (bcl-2),
proliferation (c-myc)
•Infection – viral (EBV, HCV, HTLV-1), bacterial –
H. Pylori
•Environmental factors – chemicals, diet
•Immunosuppression – AIDS, post transplant (solid
organs, BMT)
•Chronic antigen stimulation - autoimmunity
•Family history – 3.3 times increase risk

56. Epidemiology of lymphomas
•5
th
most frequently diagnosed cancer, ±4% of all
cancers and cancer deaths in USA
•males > females
•whites > other races
•incidence
•NHL increasing over time
•Hodgkin lymphoma stable

57. Clinical manifestations
•Variable
•severity: asymptomatic to extremely ill
•time course: evolution over weeks, months, or years
•Systemic manifestations
•Weakness, fever, night sweats, weight loss, anorexia, pruritus
•Local manifestations
•lymphadenopathy, splenomegaly - most common
•any tissue potentially can be infiltrated

58. Other complications of lymphoma
•bone marrow failure (infiltration)
•CNS infiltration
•immune hemolysis or thrombocytopenia
•compression of structures (eg spinal cord, ureters) by
bulky disease
•pleural/pericardial effusions, ascites

59. Stage I Stage II Stage III Stage IV
Staging of lymphoma – Ann Arbor system
A: absence of B symptoms
B: fever, night sweats, weight loss

60. Three types of lymphoma worth
knowing about
•Follicular lymphoma
•Diffuse large B-cell lymphoma
•Hodgkin lymphoma

61. Follicular lymphoma
•most common type of “indolent” lymphoma in the
Western world
•usually widespread at presentation
•often asymptomatic
•not curable (some exceptions)
•associated with BCL-2 gene rearrangement [t(14;18)]
•cell of origin: germinal center B-cell

62. Follicular lymphoma
•defer treatment if asymptomatic (“watch-and-wait”)
•median survival: years
•although considered “indolent”, morbidity and
mortality can be considerable
•transformation to aggressive lymphoma can occur

63. Diffuse large B-cell lymphoma
•most common type of “aggressive” lymphoma
•usually symptomatic
•extranodal involvement is common
•cell of origin: germinal center B-cell
•treatment should be offered
•curable in ~ 40%

64. Hodgkin lymphoma
•cell of origin: germinal centre B-cell
•Reed-Sternberg cells (or RS variants) in the affected
tissues
•most cells in affected lymph node are polyclonal
reactive lymphoid cells, not neoplastic cells

65. Hodgkin's Disease –
Reed Stenberg Cell
•Presence of typical Reed-Sternberg
cell and reactive component are
mandatory for diagnosis of
Hodgkin's lymphoma.
Characteristics of typical Reed-
Sternberg cell : size between 20 - 50
microns; abundant, amphofilic,
finely granular/homogenous
cytoplasm; two mirror-image nuclei
("owl eyes") each with an
eosinophilic nucleolus and a thick
nuclear membrane (chromatin is
distributed on the inner surface of
the nuclear membrane, generating a
halo image around the nucleolus).
Reed-Sternberg cell has a B-cell
origin. (H&E, ob.x40)

66. Reed-Sternberg cell

67. RS cell and variants
popcorn cell lacunar cell classic RS cell
(mixed cellularity) (nodular sclerosis)
(lymphocyte
predominance)

68. The Scream, 1893
Edvard Munch
Reed-Sternberg cell

69. Hodgkin lymphoma
Histological subtypes
•Nodular lymphocyte predominance Hodgkin lymphoma
•Classical Hodgkin lymphoma
•nodular sclerosis (most common subtype)
•mixed cellularity
•lymphocyte-rich
•lymphocyte depleted

70. Associated (etiological?) factors
•EBV infection
•smaller family size
•higher socio-economic status
•Caucasian > non-Caucasian
•possible genetic predisposition
•other: HIV? occupation? herbicides?

71. Clinical manifestations:
•lymphadenopathy, mostly mediastinal
•contiguous spread
•extra nodal sites relatively uncommon except in
advanced disease
•“B” symptoms: fever, night sweats, and unintentional
weight loss
•very rare causes obstruction, like superior vena cava
syndrome

72. Hodgkin lymphoma

73. Hodgkin lymphoma

74. Hodgkin disease
•Massive involvement of
paratracheal, hilar and
subcarinal lymph nodes
as well as two vertebral
bodies.

75. Hodgkin Lymphoma

•This is a liver that is involved with Hodgkin's disease. The staging of Hodgkin's disease
is very important in determining therapy. Thus, it is important to determine whether
the patient has only a single lymph node region involved, multiple node regions, or
extranodal involvement. This picture could probably suffice for non-Hodgkin's
lymphomatous hepatic disease as well.

76. Myelodysplastic
Syndromes
Dr. Fineman

77. MDS
•• Clonal stem cell disorders
•• Maturation defects
•• Ineffective hematopoiesis
•• Blood cytopenias
•• Risk of transformation to AML

78. FEATURES USED TO DEFINE
MDS

•• Blood cytopenias
•• Ineffective hematopoiesis
•• Dyserythropoiesis
•• Dysgranulopoiesis
•• Dysmegakaryopoiesis
•• Increased myeloblasts

79. FAB CLASSIFICATION OF MDS

•• Refractory Anemia
•• Refractory Anemia with Ringed Sideroblasts
•• Refractory Anemia with Excess Blasts (RAEB)
•• Refractory Anemia with Excess Blasts in
Transformation (RAEB-T)
•• Chronic Myelomonocytic Leukemia (CMML)

80. Multiple Myeloma

81. Multiple Myeloma
Definition:
B-cell malignancy characterised by
abnormal proliferation of plasma cells able
to produce a monoclonal immunoglobulin
( M protein )
Incidence:
3 - 9 cases per 100000 population / year
more frequent in elderly
modest male predominance

82. Multiple Myeloma = M-CRAB
•Monoclonal protein
•Calcium
•Renal failure
•Anemia
•Bone pain with lytic lesions

83. Multiple Myeloma
Clinical manifestations are related to malignant
behaviour of plasma cells and abnormalities produced
by M protein

plasma cell proliferation:
multiple osteolytic bone lesions
hypercalcemia
bone marrow suppression ( pancytopenia )

monoclonal M protein
decreased level of normal immunoglobulins
hyper viscosity, RENAL FAILURE, amyloidosis

84. Multiple Myeloma
Clinical symptoms:

•bone pain, pathologic fractures
•weakness and fatigue
•serious infection
•renal failure
•bleeding diathesis (hyper viscosity)

86. Thank you for attention!