2. HEMOBLASTOSES Definition abnormal proliferation of the
blood-forming tissues ( tumor of blood system) 2 large subgroups :
Leukemias - a malignant neoplasm of hematopoietic tissue
originating in and infiltrating the bone marrow Lymphomas -
regional tumors of lymphoid tissue only and affection of bone
marrow is not obligate.
3. Leukemia Leukemia generally involves the bone marrow,the
peripheral blood, and often infiltrates the spleen, liver, and
lymph nodes. normal marrow leukemic marrow
4. Etiology Etiology for leukemia is actually not clear. It is
known that leukemias are polyetiologic diseases. They develop due
to a number of mutagenic factor: 1. viruses (retrovirus HTLV-1,
HTLV-2, Eostein- Barr DNA virus. 2. ionizing radiation 3. chemical
substances 4. Hereditary factors Thus, mutation theory of leukemia
pathogenesis may be the most probable.
5. 1st stage Influence of mutagenic factor MUTATION 2nd stage
Grow and multiply Appearance of clone of leukemic cells Usually no
clinical manifestations 3rd stage Appearance of morphological
substrate in every part of bone marrow (sternum, pelvic, etc) 4th
stage Tumors progression and blastic crisis. (every new generation
of tumor cell, cellular differentiation decreases =
malignization)
6. Classification According to cellular differentiation and
clinical course : o Acute o Chronic According to cytogenesis
(cellular origin) : o Lymphoid leukemias origin lymphoid stem (B
cells and T cells) oMyeloid leukemias origin myeloid stem
7. Acute leukemias characterized by proliferation of immature
cells (blasts). If untreated, death usually occurs within 6-12
months in most patients.
8. Chronic leukemia is a proliferation of mature appearing
cells, again in the marrow, peripheral blood, and various organs.
The clinical course is relatively indolent, compared with acute
leukemia, and ranges from 2-6 years depending on the subtype of the
proliferating cell.
9. Clinical Morphological characteristics Clinic-morphological
parameters Acute Chronic (monoclonal stage) Maturity of leukaemic
cells in bone marrow (blood) Blasts (immature) *promyelocytic also
Intermediate or mature cells Leukaemic collapse (hiatus
leukaemicus) + _ Organ enlargement (leukaemic infiltration) + +++
Anaemia, thrombocytopenia +++ +/- Hemorrhagic syndrome +++ +/-
Degenerative and necrotic changes in parenchimatousorgans +++ +/-
Decreased immunity +++ +
10. Clinical Morphological Characteristics Leukemic collapse is
absent of intermediate cells in myelogram of patients in acute
leukemia Anemia due to : tumor displace normal cells decrease RBC
stem anemia, thrombocytopenia Hemorrhagic syndrome due to : tumor
displace platelets deficiency of platelets increase of vascular
permeability. leukemic infiltration of blood vessels wall (destroy)
Decrease immunity due to : T and B cells are displaced (may lead to
secondary infections)
12. A. Acute Myelogenous Leukemia the most common type of acute
leukemia in adults, 45% of all leukemias and 80-90% of acute
leukemias. Myeloblasts have nuclei with fine, delicate chromatin
and most often prominant nucleoli. The cytoplasm of myeloblasts
tends to be moderate in volume and lightly basophilic without
granules (primary azurophilic granules may be seen in myeloblasts).
Auer rods, which are angular, crystalline, and red staining, are
unique to myeloblasts but only seen in about 20% of myeloid
leukemias.
13. 1. Acute Myeloblastic Leukemia without maturation Minimal
maturation of marrow nonerythroid cells is present. Most of the
blasts are agranular. Auer rods are infrequent.
14. 2. Acute Myeloblastic Leukemia with maturation Maturation :
Auer rods are frequent (promyelocytes-myelocytes)
15. 3. Acute Promyelocytic Leukemia Maturation: the majority of
the proliferating cells are abnormal promyelocytes with numerous
primary type granules. Auer rods are frequent and often
multiple.
16. 4. Acute Myelomonocytic Leukemia Maturation:
Differentiation along both myeloid and monocytic lines. Monocytes
and promonocytes represent > 20%, but < 80% of the marrow
differential.
17. 5. Acute Monocytic Leukemia Differentiatiation: Monocytic
Two subtypes: poorly differentiated form well-differentiated
form
18. 6. Acute Erythroblastic Leukemia Maturation:
erythroleukemia is rare and difficult to diagnose. More than 50% of
the nucleated marrow cells are abnormal nucleated red blood cells.
Morphology: The leukemic red cells are frequently bizarre with
extreme dysplastic features including: giant forms,
multinucleation, cytoplasmic vacuolization, cytoplasmic buds, and
megaloblastoid changes.
19. 7. Acute Megakaryocytic Leukemia blasts are often resemble
lymphoblasts, although it may be accompanied by atypical
megakaryocytes. The marrow is often fibrotic. blasts may have
granular cytoplasm and shed 'platelets blasts often clump
together
20. B. Acute Lymphoblastic Leukemia As with all acute
leukemias, acute lymphoblastic leukemia is characterized by
proliferation of blasts (lymphoblasts) in the bone marrow. Commonly
the peripheral blood and other organs are involved. Lymphoblasts
are usually small and have round to oval nuclei with coarse
chromatin which has a tendency to aggregate into masses. Nucleoli
tend to be small and inconspicuous. The cytoplasm of lymphoblasts
tends to be sparse in volume and basophilic, usually without
granules, although rarely nonspecific cytoplasmic granules can be
seen. Auer rods are never observed.
21. 1. Acute Lymphoblastic Leukemia - L1 L1 blasts are small
and homogeneous. The nuclei are round and regular with little
clefting and inconspicuous nucleoli. Cytoplasm is scanty and
usually without vacuoles.
22. 2. Acute Lymphoblastic Leukemia - L2 L2 blasts are large
and heterogeneous. The nuclei are irregular and often clefted. One
or more, usually large nucleoli are present. The volume of
cytoplasm is variable, but often abundant and may contain
vacuoles.
23. 3. Acute Lymphoblastic Leukemia - L3 Burkitts Leukemia L3
blasts are moderate-large in size and homogeneous. The nuclei are
regular and round-oval in shape. One or more prominent nucleoli are
present. The volume of cytoplasm is moderate and contains prominent
vacuoles.
24. Chronic Leukemia Myeloproliferative Disorders Chronic
Myelocytic Leukemia Polycythemia vera Myelofibrosis Essential
Thrombocythemia Lymphoid Leukemias Chronic Lymphocytic leukemia
Hairy cell leukemia Monocytoid B cell leukemia Large granular
Lymphocytosis Prolymphocytic leukemia
25. A. Chronic Myeloproliferative Disorders Chronic myelocytic
leukemia (CML), polycythemia vera (PV), myelofibrosis (MF) and
essential thrombocythemia (ET) are malignant clonal proliferations
of multipotent stem cells. While all three cell lines (myeloid,
erythroid and megakaryocytic) are involved in each disorder, each
has specific genetic abnormalities. As a result the dominant cell
differs in each allowing for the subclassification of the chronic
myeloproliferative disorders. For instance, in PV the proliferation
is predominately erythroid, yet white cell and megakaryocytic lines
are also part of the malignant proliferation.
26. 1. Chronic Myelocytic Leukemia Definition: is a malignant
tumor of multipotent stem cells with predominance of mature
granulocytes and their precursors accumulating in excess in the
marrow and blood. Clinical Course: The initial phase of CML is
stable or indolent (usually lasting 2-4 years), but is followed by
an acclerated stage (6-12 months), and finally an acute phase or
blast crisis (2-4 months) similar to acute leukemia.
27. 2. Polycythemia vera Definition: Polycythemia vera is a
malignant stem cell disorder manifest primarily as erythroid
hyperplasia and an absolute increase of the red cell mass. Myeloid
and megakaryocytic elements are part of the neoplastic
proliferation. Proposed Pathophysiology: The etiology and nature of
PV are in large part unknown. One theory is that malignant stem
cells respond to unusually low levels of erythropoietin. This
results in an increased red cell mass and suppresses erythropoietin
production, such that normal erythroid stem cells are not
stimulated at the same low erythropoietin levels. Myeloid and
megakaryocytic cells also fail to respond to regulatory
mechanisms.
28. 3. Primary Myelofibrosis Definition: Primary myelofibrosis
is a hematopoietic stem cell malignancy of red, white and
megakaryocytic cells - a panmyelosis.Marrow fibrosis with either
increased or decreased cellularity is a constant feature of this
disorder. The fibrosis is secondary probably due to the production
of PDGF (platelet derived growth factor) by malignant
megakaryocytes. PDGF is a known mitogenic stimulus of
fibroblasts.
29. 4. Essential Thrombocythemia Definition: Essential
thrombocythemia (ET) is also a hematopoietic stem cell neoplasm the
etiology and pathogenesis of which is unknown.
30. B. Chronic Lymphoid Leukemia The chronic malignant
lymphoproliferative tumor originate in the bone marrow and slowly
progress to involve the peripheral blood, lymph nodes, spleen, and
liver. The proliferating cellular elements appears morphologically
mature, and may be of B, T, or natural killer (NK) origin.
31. 1. Chronic Lymphocytic Leukemia Definition: CLL is a
proliferation of mature appearing, but functionally incompetent
lymphocytes, in the marrow, peripheral blood, and various organs.
The most characteristic feature of CLL is a peripheral blood
absolute lymphocytosis (>5.0 x109/L, but usually >15.0 x109/L
and sometimes > 100.0 x109/L). Clinical Features:
Lymphadenopathy and splenomegaly are common especially late in the
disease because small lymphocytes accumulate in the marrow, spleen,
lymph nodes and liver. Hypogammaglobulinemia is also common late in
the disease course with an associated increased susceptibility to
infection. Ten percent of patients have an IgM monoclonal
gammopathy. Anemia and thrombocytosis may indicate marrow
replacement or autoimmune destruction.
32. Morphology: CLL tumorous elements are generally smaller
than normal and appear to be more fragile resulting in
characteristic "smudge" cells. The smudge cell nuclei are smashed
against the glass slide.
33. Gross good leukemic infiltration chronic lymphocytic
leukemia
34. 2. Chronic Prolymphocytic Leukemia Morphology:
Prolymphocytic leukemia can be thought of as a morphologic variant
of chronic lymphocytic leukemia. The predominate cell is a
prolymphocyte, larger than the lymphocytes of CLL (10-15m), This
cell resembles activated lymphocytes with fine almost blastic
chromatin, a single large nucleolus, and pale blue cytoplasm.
Clinical Features: The peripheral WBC count is high (usually
>100.0 x10 /L). Splenomegaly is common, but lymphadenopathy
unusual. Patients with prolymphocytic leukemia tend to be older (70
years) than patients with CLL (64 years) and have an aggressive
clinical course. The median survival of prolymphocytic leukemia is
3 years versus the 8 years of CLL.
35. 3. Hairy Cell Leukemia Definition: Hairy cell leukemia
(HCL) is a low grade B cell leukemia of moderately large
mononuclear cells having distinctive "hairy" cytoplasmic
projections. Morphology: The abundant cytoplasm creates a "fried
egg" appearance to each cell in tissue sections producing a
characteristic "honeycomb" appearance on biopsy of bone
marrow.
36. Signs and Symptoms Acute leukemia frequently presents with
weakness, fatigue, fever, pallor, shortness of breath, weight loss,
bone pain, night sweats and recurrent infections. The symptoms are
often like the flu. Bruising, nosebleeds, unusally heavy menstrual
periods, and swollen gums are commonly encountered in leukemia.
Physical examination and laboratory studies may reveal anemia,
splenomegaly, hepatomegaly and lymphadenopathy. The chronic
leukemias are often asymptomatic, but may present with relatively
nonspecific and mild symptoms and signs. At later stages the signs
and symptoms may be more like those of acute leukemia.
37. Causes of death Hemorrhagic syndrome Brain infusion Profuse
GIT bleeding Secondary infections Pneumonia etc. Progression of
tumor Paraneoplastic syndrome Cytostatic disease Cytostatic drugs
affect healthy cells too. Acute renal failure Severe brain edemas
Respiratory distress
38. close-up gut hemorrhages due to shock case of leukemia
39. Brain: Hemorrhages Due To Acute Myelogenous Leukemia
Infiltrate
40. Lymphomas Malignant lymphomas (ML) are cohesive malignant
proliferations of tumorous arising in lymph nodes and in lymphoid
tissue of various organs (extranodal). Malignant lymphomas may also
be thought of as neoplasms of the immune system. Rarely, the term
lymphoma is used to refer to a malignant proliferation of true
histiocytic cells, but more on that later.
41. Classification According to cell type : B cellular origin
B-cells precursor most often 65% cases of all T cellular and NK
origin T cell and NK Histiocytic lymphoma rare According to the
architectural (growth) pattern Hodgkins lymphomas Non-Hodgkins
lymphomas
42. In lymphoma, normal lymph node architecture is distorted or
effaced by the proliferating malignant lymphoid cells
43. The effacement of nodal architecture may be either diffuse
or follicular. The follicular pattern may evolve into a diffuse
pattern.
44. In this illustration we see a proliferation of small
lymphocytes in a diffuse pattern or malignant lymphoma, small
lymphocytic.
45. Here we see a follicular pattern of growth with follicular
structures growing beyond the capsule. Looking inside one of the
follicles you see a predominance of one cell type-in this case
small cleaved lymphocytes. Thus, you can make a diagnosis of
malignant lymphoma, follicular, small cleaved cell
46. This example of Reactive lymphoid hyperplasia is
characterized by hyperplasia of follicular (germinal) centers. Most
important is the mixture of large and small lymphocytes; plasma
cells (green) and "tingible body" macrophages (blue) in the
reactive germinal center.
47. Hodgkins and Non-Hodgkins there were two large categories
of lymphoma: the Hodgkin's and the Non-Hodgkin's lymphomas. These
two types of lymphoma are distinguished by differing morphologic
and clinical features. Hodgkin's lymphomas are characterized by the
presence of giant mononucleate Hodgking cells, bilobed or
multinucleate Reed-Sternberg cells in a reactive appearing cellular
background. In contrast, the non-Hodgkin's lymphomas generally
consist of a uniform proliferation of cells.
48. The major clinical manifestation of malignant lymphoma is
painless lymph node enlargement. Such nodes are usually firm or
rubbery, often multiple and fixed in place. Systemic symptoms
include fever, malaise, night-sweats, weight loss, and pruritis. As
lymphoma progresses, spread may occur to spleen, liver, bone
marrow, and other organs. Common primary sites of lymphoma include
cervical, supraclavicular, mediastinal, axillary, periaortic, and
inguinal lymph nodes. Common extranodal sites of lymphoma include
the gastrointestinal tract, CNS, skin, spleen, bone marrow,
pharyngeal tissues, salivary glands, thymus, and lung among
others.
49. The physical presence of disease and the presence or
absence of symptoms are the measures for the respective pathologic
and clinical staging of lymphoma.
50. Hodgkins Lymphoma is a neoplastic proliferation of lymphoid
cells predominantly involving lymphoid tissues. The malignant cell
are the Hodgkin and Reed- Sternberg cells. The Reed-Sternberg cell
is a lymphoid cell and in most cases, is a B cell, and clonal. R-S
cells are very large with abundant pale cytoplasm and two -four
oval lobulated nuclei containing large nucleoli.
51. Hodgkin lymphoma is separated from non- Hodgkin lymphoma
not only by a unique histologic appearance, but also because the
systemic manifestations (such as fever) and the clinical
presentation are distinctive. Hodgkin lymphoma generally presents
as regional enlargement of a single group of peripheral lymph
nodes, as opposed to non- Hodgkin lymphoma in which nodal
involvement is more widely disseminated.
52. Hodgkin lymphoma is rarely extranodal whereas extranodal
involvement is frequent in non- Hodgkin lymphomas. At presentation,
bone marrow involvement by HD is highly unusual (< 5%). When
Hodgkin lymphoma involves the spleen or liver it generally presents
as a mass lesion rather than as diffuse involvement.
53. Hodgkin's Lymphoma - Spleen 8 y/o man with
hepatosplenomegaly. Splenectomy specimen showed scattered
gray-white nodules metastases (waxy spleen)
54. Hodgkin's Lymphoma - Spleen show a single or a few large
nodules
55. Histological Inspection 2 groups of cells : Non specific
(non tumorous) cellular elements Monocytes Lymphocytes Plasma cells
Eosinophils Basophils etc. Specific tumorous cells
Reed-Berezovsky-Sternberg cells Hodgkins cells
56. Classic Reed-Sternberg cells are large (15-45 m) with
abundant pale cytoplasm and two or more oval lobulated nuclei
containing prominent "owl-eye" eosinophilic (H&E)
nucleoli.
57. In some R-S cell variants the cytoplasm shrinks during
formalin fixation and processing of tissue, leaving an empty space
around the nucleus. Such R-S variants are known as "lacunar
cells".
58. Another R-S variant is the "L&H" or "popcorn" cell with
a fluffy, lobulated nucleus having fine chromatin and small
nucleoli.
59. Other common R-S variants are mononuclear Hodgkin cells and
"mummified" cells.
60. Clinical-morphological variants (according to histology):
Lymphoid (with prevalence of lymphoid tissue) Prevalence of
lymphoid tissue [nonspecific > specific (isolated elements)]
Nodular sclerosis variant isolated specific cells prevalence non
specific cells Mixed cell variant [nonspecific = specific] Variant
with emanciation of lymphoid tissue [nonspecific <
specific]
62. 1. Nodular Lymphocyte Predominant Hodgkin Lymphoma often
vaguely nodular. There is recent immunologic evidence indicating
that the nodular form of LP Hodgkin lymphoma is of B cell origin
and thus distinct from other forms of Hodgkin lymphoma.
63. 2. Nodular Sclerosis Classical Hodgkin Lymphoma "Lacunar"
R-S variants and sclerosing bands of collagenous fibrosis forming a
nodular pattern are characteristic features. The fibrosis thickens
the capsule and divides the proliferating process into "nodules" or
islands
64. Nodular Sclerosis Classical Hodgkin Lymphoma The lymph node
is massively enlarged and has a nodular appearance due to bands of
fibrosis
65. Nodular Sclerosis Classical Hodgkin Lymphoma In more
advanced cases of Hodgkins Lymphoma, several lymph nodes from the
same group may become matted together, as seen in this group of
mediastinal lymph nodes. Note the anthracotic pigment in some lymph
nodes.
66. 3. Mixed Celularity Classical Hodgkin Lymphoma Mixed
cellularity Hodgkin Lymphoma has numerous R-S cells in a mixed
inflammatory background that obliterates the normal architecture.
Plasma cells and eosinophils are frequent. Only small amounts of
fibrosis and occasional necrosis may be present.
67. 4. Lymphocyte Rich Classical Hodgkin Lymphoma Classic R-S
cells are rare and difficult to find, but mononuclear "L&H"
Hodgkin cells with "popcorn" shaped nuclei and inconspicuous
nucleoli are present against a background of small lymphocytes.
HD,LP may be diffuse (shown here) or vaguely nodular.
68. 5. Lymphocyte Depleted Classical Hodgkin Lymphoma
characterized by many Reed-Sternberg cells and variants (small
lymphocytes are virtually absent) or by extensive fibrosis. There
are two subtypes, a sarcomatous subtype with numerous bizarre
Reed-Sternberg cells and a "diffuse fibrosis" variant, with
extensive fibrosis and rare Reed- Sternberg cells.
69. In the sarcomatous variant sheets of bizarre anaplastic
Reed-Sternberg-like variants are seen.
70. In the diffuse fibrosis variant there is a disorderly
diffuse fibrosis, rare lymphocytes, and often few, but easily
identifiable Reed-Sternberg cells in a hypocellular
background.
71. Non-Hodgkin Lymphoma The non-Hodgkin lymphomas are
neoplasms of the immune system arising almost anywhere in the body,
but most frequently (80%) developing in lymph nodes. The pathology
of a lymphoma depends on: the cell lineage on the degree of cell
differentiation on the location of the cell of origin (humoral
factors, i.e. growth factors). The diagnosis of non-Hodgkin
lymphoma is based on partial or complete obliteration of the lymph
node by a usually monomorphous lymphoid cell type the pattern of
growth.
72. The two most often encountered patterns of growth are
follicular (sometimes referred to as nodular) in which the lymphoma
mimics follicular center structures and diffuse in which the
lymphoid cells proliferate in an apparently unorganized
fashion.
73. Non-Hodgkins Lymphomas Low-Grade Small Lymphocytic Lymphoma
Follicular Small Cleaved Cell Follicular Mixed Cell Type
Intermediate-Grade Follicular Predominantly Large Cell Lymphoma
Diffuse Small Cleaved Cell Lymphoma Diffuse Mixed Small and Large
Cell Lymphoma Diffuse Large Cell Lymphoma High-Grade Large Cell
Immunoblastic Lymphoma Lymphoblastic Lymphoma Small Noncleaved Cell
Lymphoma
74. 1. Small Lymphocytic Lymphoma is always diffuse The
malignant cells are uniform small lymphocytes with scant cytoplasm.
The nuclei are round with clumped chromatin. Mitoses are rare.
75. Occasionally, these cells have plasmacytoid or
lymphoplasmacytic features nearly always involves the bone marrow
and commonly involves the peripheral blood. Cells of Small
Lymphocytic Lymphoma with plasmacytoid /plasma cells
76. 2. Follicular small cleaved cell is a proliferation of
predominantly of small cleaved lymphocytes The growth pattern is
follicular and the cells are always of B phenotype
77. The cells of ML, F,SCC are slightly larger than normal
small lymphocytes and have an irregular clefted nucleus. The
chromatin is clumped and nucleoli are indistinct. Cytoplasm is
scant. A few large lymphocytes may be present Involvement of bone
marrow is relatively common
78. 3. Follicular Mixed Cell Type includes those cases in which
there is no clear preponderance of small or large cells These show
a follicular pattern of growth and are of B cell origin Follicular
mixed frequently evolves to ML,large cell.
79. 4. Follicular Predominantly Large Cell Lymphoma lymphomas
in which the majority of cells within the neoplastic follicles are
large cleaved or noncleaved lymphocytes.
80. 5. Diffuse Small Cleaved Cell Lymphoma arises in the mantle
zone of secondary follicles. Small lymphocytes are arranged in a
diffuse or vaguely nodular pattern may have wide mantle zones
around small atrophic follicular centers.
81. 6. Diffuse Mixed Small and Large Cell Lymphoma consists of
both small and large-sized malignant lymphocytes. Immunologically,
these are a heterogeneous group. Many T cell lymphomas as shown
below are morphologically represented in this group
82. 7. Diffuse Large Cell Lymphoma represents the morphologic
expression of transformed lymphocytes. Most are of B-cell origin
(60-80%), with some of T-cell origin (10- 20%). Large cell
lymphomas are often localized and frequently form rapidly enlarging
destructive masses.
83. Diffuse Large B-cell Lymphoma The specimen shows several
enlarged cervical lymph nodes that were removed from a 45 year-old
male. The cut-surface has a homogenous, fleshy appearance
84. 8. Large Cell Immunoblastic Lymphoma is a difuse ML with
prominent plasmacytoid cell differentiation, (an eccentric nucleus
with conspicuous central nucleoli and abundant basophilic cytoplasm
and visible paranuclear "hof") are termed immunoblastic
(B-immunoblasts).
85. 9. Lymphoblastic Lymphoma diffusely effaces the node
architecture. Mitotic figures are numerous. Most to be of T cell
origin. The neoplastic cells are mono-morphous moderate sized cells
with scanty cytoplasm and round or sometimes highly convoluted
nuclei.
86. 10. Small Noncleaved Cell Lymphoma Burkitt's lymphoma a
proliferation of highly uniform cells with round to oval nuclei
containing two or more prominent nucleoli. The chromatin is more
clumped than in lymphoblastic lymphoma. Moderate amounts of
basophilic cytoplasm are present which may contain clear lipid
vacuoles. Mitoses are numerous and a "starry-sky" pattern is often
present. The "stars" are macrophages
