Veah Deborah Cruzem

Justine Chlarissa Del Rosario
Arianne Mirabueno
MT0831
• a form of
hematopoiesis in
which white blood
cells (WBC,
or leukocytes) are
formed in bone
marrow located in
bones in adults and
hematopoietic
organs in the fetus.
LEUKOCYTES
∗ White blood cells
∗ Defend the body against both infectious
disease and foreign materials
∗ Five different types exist
∗ All produced and derived from Hematopoietic Stem
cell
∗ Two categories:
∗ Granulocytes & Agranulocytes
Leukocytes
∗ Presence of granules
∗ Released from the bone marrow by the
regulatory complement proteins.
∗ Includes:
∗ Neutrophils
∗ Eosinophils
∗ Basophils
Granulocytes
∗ Absence of granules
∗ Includes:
∗ Monocytes
∗ Lymphocytes
Agranulocytes
Neutrophil Maturation
Myeloblast
<1% in the normal bone marrow
15-20 µm in size
Nucleus: delicate with prominent nucleoli
Cytoplasm: contains rough endoplasmic
reticulum, a developing Golgi apparatus
initial presence of primary or azurophilic
granules
Granules color positively for
myeloperoxidase
Myeloblast
MYELOPEROXIDASE –
an enzyme that occurs in
primary granules of
promyelocytes,
myelocytes, and
neutrophils and exhibits
bactericidal, fungicidal
and viricidal properties.
o The cell is incapable of
motility, adhesion, and
phagocytosis
Promyelocyte
(Progranulocyte)
1%-5% in the bone marrow
Greater than or equal to 20 µm
Nuclear chromatin: shows slight
clumping; nucleoli began to fade
Promyelocyte
 This activates neutral
proteinases cathepsin G,
elastase, and proteinases
for killing to take place.
Neutrophilic Myelocyte
<10% of total BM cell population
Last cell capable of mitosis
Nucleus: round to oval with flattened side
near a well-developed Golgi apparatus
Nuclear chromatin: shows clumping;
nucleoli is no longer visible
 “DAWN OF
NEUTROPHILIA” – faint
blush of pink within the
cytoplasm; caused by
the granules
Neutrophilic Myelocyte
Neutrophilic Myelocyte
Some important compounds within the
secondary granules:
Thrombospondin receptor
β
2
-microglobulin
Apolactoferrin
Lysozyme
Plasminogen activators
Neutrophilic Metamyelocyte
After cessation of all active DNA synthesis
Nucleus: indented
13%-22% of BM
 Synthesis of
gelatinase
granule by the
end of stage
development
 Contain lysozyme
and acetyl
transferase
Neutrophilic Metamyelocyte
Neutrophilic Band
Nonsegmented form
40% of WBCs in BM
Absence of nuclear segments composed
of dense heterochromatin
Represents the almost mature cell
 Possesses full motility,
active adhesion properties,
and some phagocytic ability
 Membrane maturity:
changes in cytoskeleton,
changes in surface charge,
and presence of receptors
for complement (CRs),
specifically for CR1 and CR3.
 <6% of WBCs in peripheral
blood
Neutrophilic Band
Neutrophilic Band
Presence of secretory vesicle, an
important store of surface
membrane-bound receptors and
may be functional in antigen
presentation
Endocytosis
Polymorphonuclear
Neutrophil
Many-shaped nucleus
Nucleus: easily deformable; visible
segments; some appear grossly twisted
and folded
Present in the bone marrow and in the
marginating and circulating pools
50%-70% in the peripheral blood
Positive for the adhesion molecules
CD62, CD11a/CD18
 Performs phagocytosis
and pinocytosis
 Neutrophils are
attracted are attracted
to particles by several
mechanisms:
 Chemotaxis
 Complement fixation
Polymorphonuclear
Neutrophil
*First recognizable cell.
*Diameter between 14 and 18µm
*Occupied by a large oval nucleus
*Nucleus is composed of very fine non
aggregated chromatin and possesses 3 or more nucleoli.
* Cell size, 12 to 20 µm
* Contains a few, as yet undifferentiated, cytoplasmic granules
* Second largest stage in the granulocytic series
* Granules are peroxidase positive
* One to three nucleoli are also visible
* First of the maturation stages of the granulocytic leukocytes normally
found in the bone marrow
* Granules are seen in the cytoplasm
* Cell is flat and contains increasing numbers of granules as maturation
progresses.
*Appearance of a bent nucleus, cytoplasmic granules
*Absence of visible nucleoli.
Myeloblast Promyelocyte Myelocyte Metamyelocyte Matured
Eosinophils
Myeloblast Promyelocyte Myelocyte Metamyelocyte Matured
Basophils
*10-12 microns
*1-3% of circulating WBCs
*Responsible for combating
multicellular parasites and
certain infections in vertebrates
*Control mechanisms associated
with allergy and asthma.
*Acid-loving
*Nucleus with 2-3 lobes
*Stained heavily with eosin
dye used in conventional
Romanowsky stain
*Spends less than 1 week in
peripheral blood
*Actively motile
*Acid phosphatase
*Arylsulfatase
*Β-Glucuronidase
*Cathepsin
*Peroxidase
*Phospholipase
Eosinophilic
Granules Contents
*Water-soluble
*Needle-shape
*Result of eosinophil
disintegration
Charcot-Leyden
Crystal
*Irregular, s-shaped, bilobed
nuclei
*8-10 microns
*0-1% of circulating WBCs
*Obscure the cell nucleus
*Large heavily staining granules
stain with basic dyes
*contains anticoagulant heparin
*contains the vasodilator histamine
*plays a role in both parasitic
infections and allergies
*regulates the behavior of T cells
*have protein receptors on their
cell surface that bind IgE
*Mastocyte
*Rich in histamine and heparin
*Involved in wound healing and
defense against pathogens.
MAST CELLS
MONOCYTES
MONOCYTE
develop from the
same precursor as
neutrophils -
the CFU-GM.
cells that are made
in the bone marrow,
and they spread
through the body in
one to three days.
MONOCYTE
MATURATION
MONOBLAST
the earliest
precursor arising
from a committed
stem cell in the
monocytic series,
which develops
into the
promonocyte.
PROMONOCYTE
• a cell in an intermediate
stage of development
between a monoblast and
a monocyte
• Size: 12-20 microns in
diameter.
• Nucleus: The nucleus is
oval or indented and light
purple.
• Cytoplasm: The
cytoplasm is gray-blue
with fine dust like
azurophilic
MATURED MONOCYTE
incapable of mitosis and enter the circulation.
Size: 12-20 microns in diameter.
Nucleus: The nucleus is round or kidney-
shaped, but can be deeply indented or have
two or more lobes.
Cytoplasm: foamy blue gray
Function:
take longer time to get to site of infection but
arrive in larger numbers
become wandering macrophages once they
leave the capillaries
destroy microbes and clean up dead tissues
following an infection
LYMPHOCYTES
Lymphocytes
Human blood leukocytes whose site of
development is not solely the bone marrow,
but also tissues referred to as primary and
secondary lymphoid organs
Thymus and bone marrow
Spleen, Peyer’s patches, Waldeyer ring of
the tonsils and adenoids, and lymph nodes
and nodules scattered throughout the body
Hand mirror shape is a result of their
characteristic form of locomotion
DEVELOPMENT
The thymus and bone marrow give rise
to lymphocytes, foster differentiation
and are independent of antigenic
stimulation.
T cells – cells that develop under the
influence of the thymus; have a specific,
unique set of receptors and responses
B cells – derived from BM ad have a
different set of functions and capabilities
Plasma cell – end cell of B lymphocyte
maturation
B CELL
T CELL
PLASMA CELL
Lymphocyte
Maturation
Lymphoblast to Prolymphocyte
LYMPHOBLAST
 10-18 µm in size
 Nucleus: round to oval, with loose chromatin and
one or more active nucleoli.
 Cytoplasm: scanty and has basophilia
proportional to amount of RNA present
PROLYMPHOCYTE
 Slightly more clumped chromatin, lessened
nuclear prominence, change in thickness of
nuclear membrane
Lymphoblast Prolymphocyte Lymphocyte
Small lymphocyte
Most common
approx. 9 µm in size
Nucleus: round to oval; block type
chromatin pattern
Nondiving or resting
LYMPHOCYTE
LYMPHOCYTE
Medium Lymphocyte
 11-14 μm in diameter
 Contains azurophilic granules that are more
clearly discerned
 nondiving
LYMPHOCYTE
Large lymphocyte
 Rarest in PB
 15 μm
 Has a deeper shade of blue when stained
 May be part of natural killer cells
1. The first of the maturation stages of the granulocytic leukocytes
normally found in the bone marrow.
a.Myeloblast b. Promyelocyte c. Myelocyte d. Metamyelocyte
2. It is characterized by the appearance of a
bent nucleus, cytoplasmic granules, and the absence of
visible nucleoli.
a.Myeloblast b. Promyelocyte c. Myelocyte d. Metamyelocyte
3. Cells that develop under the influence of the thymus, have a
specific, unique set of receptors and responses.
a. T cells b. B cells c. Plasma cells d. Mast cells
4. Tissue equivalent of circulating basophil. Involved in allergic
inflammation and initiate localized and system anaphylaxis.
a. T cells b. B cells c. Plasma cells d. Mast cells
5. Size of matured basophil.
a. 10-12 microns b. 8-10microns c. 10-15 microns d. 6-9microns
Terminologies
 Quantitative
 Change in number
 Terminology
 Cytosis / philia
 Increase in number
 Cytopenia
 Decrease in number
LEUCOCYTES BENIGN DISORDERS
Quantitative changes (LEUKOCYTOSIS)
 Definition
Raised TWBC due to elevation of any of a single
lineage.
 Note: elevation of the minor cell populations can occur
without a rise in the total white cell count.
 Normal reference range (adult 21 years)
 4.5 -- 11.0 x 10
9
/L
LEUCOCYTES BENIGN DISORDERS
Quantitative changes (LEUKOPENIA)
 Definition
TWBC lower than the reference range for the age is
defined as leucopenia
 Leukopenia may affect one or more lineages and it is
possible to be severely neutropenic or lymphopenic
without a reduction in total white cell count.
LEUCOCYTES BENIGN DISORDERS
Quantitative changes (contd.)
 Granulocytosis
Increase in the count of all or one of the
granulocytic component
 Neutrophils
 Basophils
 Eosinophils
 Agranulocytosis
Decrease in the count of all or one granulocytic
component
Leukocytes
 Leukocytes
 Phagocytes
 Granulocytes
 Neutrophils
 Eosinophils
 Basophils
 Mononuclear
phagocytic cells
 Monocytes
 Macrophage and
denderetic cells
 Lymphocytes
 B-cells
 T-cells
N
E
B
L
M
Band
P
Neutrophils
 Count 2.5 - 7.5 x
10
9
/l
 Granular cytoplasm
 Transient stay in
blood
 Major phagocytic
role
 Bacterial killing
 3-5 lobes of nucleus
Disorders of Neutrophil
 Neutrophilia
 Infection (Bacterial)
 Inflammatory conditions
 Neoplasia
 Metabolic conditions
 Uraemia
 Haemorhage / haemolysis
 Corticosteroids
 Marrow infiltration
 Haematological
malignancies
 Chronic Myeloid Leukaemia
 Myeloproliferative disorder
CML
MM
M
N
Baso
Myeloid malignancies
Acute Myeloid Leukaemia
(AML M-3)
Chronic Myeloid Leukaemia
Disorders of Neutrophil
 Neutropenia Count <
 1.5 x 10
9
/l
 Drugs
 Chemotherapy
 Viral infection
 Inherited disorders
 Morphological abnormalities
 Pelger-Huet anomaly
 May-Hegglin anomaly
 Chediak-Higashi syndrome
Neutrophilia
 Transiently with stress and exercise by a shift of
neutrophils from the marginating pool to the
circulating pool.
 Infection
 Toxins: metabolic (uremia), drugs, chemicals
 Tissue destruction or necrosis: infarction, burns,
neoplasia, etc
 Hemorrhage, especially into a body cavity
 Rapid hemolysis
Neutropenia
 Aplastic anemia
 Toxins that damage marrow
 Infection Viral (Hep-B), Mycoplasma etc.
 marrow infiltration by infections or carcinomas,
Radiation therapy Chemotherapy
 Hematologic malignancies such as leukemias
 Myeloproliferative disorders
 Congenital disorders
 Increased neutrophil destruction as in
Splenomegaly, Immune destruction
Lymphocytes
 Count varies with
age
1.5 – 3.5 x10
9
/l
 The subset cells are
 B-cells
 Antibody mediated
immunity
 T-cells
 Cell mediated immunity
 NK cells
Disorders of lymphocytes
Benign disorders
 Lymphocytosis
 Viral infections
 Bacterial infections
 Protozoal infections
 Lymphopenia
 Marrow failure (drugs, irradiation)
 Infections (viral infections)
 Immune-deficiency syndromes
 Antibody deficiency
 Cell mediated immune defieciency
 Combined cell and antibody immune deficiency
Disorders of Lymphocytes
 Infectious
mononucleosis
 Epstein-Barr virus
infection
 Autoimmune
lymphoproliferative
syndrome
Disorders of Lymphocytes
Malignant disorders
 Acute lymphoblastic
(ALL) leukemia
 Chronic lymphocytic
leukemia (CLL)
 Lymphomas
 Non Hodgkin’s
lymphoma
 Hodgkin’s disease
ALL
CLL
Lymphocytosis
Normally be observed in infants and young
children.
Acute infections, including pertussis,
typhoid, and paratyphoid
Infectious mononucleosis, with "atypical"
lymphocytosis
Viral infections, including measles, mumps,
adenovirus, enterovirus, and Coxsackie virus
Toxoplasmosis
Lymphopenia
 Immunodeficiency syndromes, including
congenital (DiGeorge syndrome, etc)
and acquired (AIDS) conditions
 Corticosteroid therapy
 Neoplasia, including Hodgkin's disease,
non-Hodgkin's lymphomas, and
advanced carcinomas
 Radiation therapy
 Chemotherapy
Monocytes
 Count is 0.2-0.8 x
10
9
/l
 Functions
 Antigen presentation
 Cytokine production
 Phagocytosis
Disorders of Monocytes
 Monocytosis
 Benign
 Chronic bacterial infection
 Malignant
 Chronic Myelomonocytic Leukaemia CMML
Monocytosis
Infections: such as brucellosis,
tuberculosis and rickettsia
Myeloproliferative disorders
Hodgkin's disease
Gastrointestinal disorders, including
inflammatory bowel diseases and
sprue
Eosinophils
 Count 0.2 – 0.8 x 10
9
/l
 Bilobed nucleus
 Phagocytic activity is
low
 Modulation of
hypersensitivity and
allergic reactions
Disorders of Eosinophil
 Eosinophilia
>0.8 x 10
9
/l
 Allergic reactions
 Parasitic infections
 Malignancy
 Inflammatory conditions
 Myeloproliferative disorders
 Hypereosinophilic syndrome
Basophils
 Count 0.1 – 0.2 x 10
9
/l
 Bilobed nucleus
 Nucleus is hided
behind the granules
 Inflammatory
response
 Basophilia is seen in
Myeloproliferative
disorders (CML)
Eosinophilia
 Allergic drug reactions
 Parasitic infestations - with tissue invasion
 Extrinsic asthma
 Hay fever
 Extrinsic allergic alveolitis ("farmer's lung“)
 Chronic infections
 Hematologic malignancies: CML,
Hodgkin's disease
Eosinopenia, Monocytopenia
& Basopenia
Acute stress reactions with increased
glucocorticoid and epinephrine
secretion
Cushing's syndrome with
corticosteroid therapy
Steroid therapy
Acute inflammation
Leukemoid Reaction:
Definition
 A leukemoid reaction (LR) is a hematological disorder,
defined by a leukocyte count greater than 50,000
cells/mcL with reactive causes outside the bone marrow
 LR is characterized by a significant increase in mature
neutrophils in the peripheral blood and a differential
count showing marked left shift.
 The diagnosis of LR is based on the exclusion of chronic
myelogenous leukemia (CML) and chronic neutrophilic
leukemia (CNL).
NONMALIGNANT LEUKOCYTE
DISORDERS
 Many bands, metamyelocytes, and myelocytes are
seen
 Occasional promyelocytes and myeloblasts may
be seen.
 This condition resembles a chronic myelocytic
leukemia (CML), but can be differentiated from
CML based on the fact that in leukemoid reactions:
 There is no Philadelphia chromosome
 The condition is transient
 There is an increased leukocyte alkaline
phosphatase score (more on this later)
 Leukemoid reactions may be seen in tuberculosis,
chronic infections, malignant tumors, etc.
Leukemoid Reaction Major
Causes: Infections
 Clostridium difficile colitis
 Severe shigellosis
 Disseminated tuberculosis
 Serious bacterial infections
 Work up of LR should include cultures of blood,
sputum, and bone marrow for common bacteria and
mycobacteria. Stool cultures should not be
overlooked.
Leukemoid Reaction Major
Causes: Infections
 C. difficile colitis with an LR appears to be
associated with a much higher mortality rate (approx
50%).
Leukemoid Reaction Major
Causes: Drugs/Toxins
 Corticosteroids
 Minocycline
 Recombinant hematopoietic growth factors
 Ethylene glycol
Leukemoid Reaction Major Causes:
Malignancy
 Carcinomas (lung, oropharyngeal, gastrointestinal,
genitourinary)
 Hodgkin's lymphoma
 Melanoma
 Sarcoma
Leukemoid Reaction Major Causes:
Malignancy
 Leukemoid reactions can present simultaneously
with malignancy, late in the course of the disease, or
precede the diagnosis by as many as 4 years.
 In a study of 227 patients with carcinoma of the
lung, 33 patients (14.5%) were diagnosed with
tumor-related leukocytosis and 6 patients (2.6%)
with LR.
Leukemoid Reaction Major Causes:
Malignancy
 The mechanism of the generation of an LR in
association with a neoplasm has not been fully
elucidated.
 It is likely that various cytokines produced irregularly by
the tumor cells, including granulocyte colony-stimulating
factor (G-CSF), granulocyte-macrophage colony-
stimulating factor (GMCSF), and interleukin 6 (IL-6), may
underlie the pathogenesis of LR in such conditions.
Leukemoid Reaction versus CNL
versus CML
 CML:
 immature cells, basophilia or monocytosis
 decreased leukocyte alkaline phosphatase (LAP) score
 bcr/abl translocation.
 The differential diagnosis between LR and CNL may be
difficult or even impossible because both conditions
share:
 identical morphological features
 increased LAP score
 absence of the bcr/abl translocation.
Leukemoid Reaction versus CNL
versus CML: The Smear
 In CML, there are more immature cells, basophils,
and eosinophils.
 In LR, consist mostly of mature neutrophils. The
differential count discloses a marked left shift,
presence of myelocytes and metamyelocytes.
 In CNL, there is marked neutrophilia with no
immature cells
Leukemoid Reaction versus CNL
versus CML: The Bone Marrow
 In CML, basophilia, eosinophilia, monocytosis, or even a
minimum percentage of blasts are characteristic.
 Increased cellularity with myeloid hyperplasia is seen in
both LR and CNL.
 In LR there is marked proliferation and orderly
maturation of all normal myeloid elements with normal
morphology, without fibrosis.
Leukemoid Reaction versus CNL
versus CML: The Bone Marrow
 Similar morphological features are present in CNL
and LR, but a packed bone marrow biopsy, together
with a slight increase in reticulin fibrosis, may help
differentiate it from a reactive process.
Leukemoid Reaction versus CNL
versus CML: LAP score
 LAP is an enzyme present in the cytoplasmic
microsomes of neutrophils, bands,
metamyelocytes, and myelocytes, but not in
lymphocytes or monocytes.
 Immature neutrophils, such as those observed in
CML, have decreased LAP scores.
 Stimulated neutrophils of an LR have high LAP
scores.
Leukemoid Reaction versus CNL
versus CML: LAP score
 Leukocyte alkaline phosphatase (LAP) score is high
in infection/inflammation, polycythemia vera and
CNL.
 LAP score is low in CML.
Leukemoid Reaction versus CNL
versus CML: Cytokine Levels
 Although G-CSF, GM-CSF, and IL-6 are not
included in diagnostic criteria for CNL,
measurement of enzyme-linked immunosorbent
assay (ELISA) have been used to elucidate
cytokine-producing tumor and the development
of an LR.
 Generally CML and CNL patients have
significantly low G-CSF levels, suggesting that
neoplastic granulopoiesis can exert a
suppressor effect on G-CSF synthesis.
Leukemoid reaction
 Leukemoid reactions are characterized by blasts, promyelocytes,
myelocytes, and metamyelocytes in the peripheral blood.
 Leukemoid reactions may be secondary to benign or malignant
conditions.
 A leukoerythroblastic reaction is similar to a leukomoid
reaction with the addition of nucleated red blood cells. A
leukoerythroblastic picture indicates severe disruption of
the marrow and is common in myelofibrosis (primary or
secondary).
 In infants a leukoerythroblastic reaction suggests
severe hemolytic anemia, such as erythroblastosis
END
Prepared By:
•Savannah Lima
•Johnpaul Mojica
•Gurpreet Singh
Questions 
 1.) a hematological disorder, defined by a leukocyte count greater
than 50,000 cells/mcL with reactive causes outside the bone
marrow.
 A.neutrophilia B.eosiniophilia C.leukemoid reaction
D.neutropenia
 2.)term used for increase in neutrophils
 A.basophilia B.neutrophilia C.neutropenia D.eosinophilia
 3.)an agranulocyte with horse shoe shaped nucleus.
 A.lymphocyte B.monocyte C.segmenters D.PMN
 4.)normal value for TWBC
 A.4.5-11x10
9
B.2.5-11x10
9
C.6.5-11x10
9
D. 9.5-11x10
9
 5.)these are drugs/toxins associated with leukemoid reaction,
EXCEPT
 A.corticosteroids B.rifampin C.ethylene glycol
D.tylenol
#1 ADAO, Dyrelle
#6 CASTILLO, Gileen Grace I.
#11 DELA CRUZ, Sharmila Mae R.
MT0831
Dra. Asilo
Qualitative Non-Neoplastic WBC Disorder
∗ Recessive disorder
∗ Azurophilic granules in one or all cell types
∗ Inclusions: Lymphocyte w/ no neutrophil
abnormalities
Alder-Reilly Anomaly
∗ Dense, Large, dark lilac, azurophilic granules
(neutrophil, eosinophil, basophil, occasionally
lymphocytes and monocytes)
∗ Granules
• Larger than normal azurophilic and basophilic
granules
• Lilac with Wright-Giemsa Stain
• Metachromatic with Toluidine Blue
• Evenly distributed throughout cytoplasm
Morphology
∗ Resemble Toxic Granulation
∗ Obscure the nucleus- function normally
∗ Inclusions:
∗ more frequently seen in Bone marrow
∗ Lymphocyte inclusion: less numerous
∗ Basophilic inclusion: surrounded by clear halo & stain
metachromatically
Morphology
Normal Neutrophil
Neutrophil with Alder-Reilly
Anomaly
Alder-Reilly Anomaly with
Azurophilic Granules
Neutrophil Lymphocyte Monocyte
Toxic
Granulation
∗ Mucopolysaccharide Degradation:
∗ Hunter’s Syndrome (Mucopolysaccharidosis Type II /
MPS II)
∗ Hurler’s Syndrome (Mucopolysaccharidosis Type I/
MPS I)
∗ Maroteaux–Lamy syndrome (Mucopolysaccharidosis
Type VI/ MPS VI)
Associated Disease
Hurler’s Syndrome
Hurler’s Syndrome
∗ Aka Mucopolysaccharidosis Type II / MPS II
∗ Named after physician Charles A. Hunter
∗ X-linked recessive
∗ Deficiency or absence of the lysosomal enzyme
iduronate-2-sulfatase (I2S)
∗ Physical Appearance:
∗ Coarse facial features (gargoylism)
∗ nose with a flattened bridge, and an enlarged tongue
∗ Large head (macrocephaly)
∗ Joints of fingers, arms, and legs held in partial flexion
∗ Enlarged abdomen (due to enlarged liver and spleen)
∗ No cloudy corneas
Hunter’s Syndrome
Hunter’s Syndrome
∗ Aka Mucopolysaccharidosis Type VI/ MPS VI
∗ Name after Pierre Maroteaux and Maurice Lamy
∗ Deficiency in arylsulfatase B (ARSB)
∗ Onset before age 3
∗ No current treatment for the syndrome
∗ Physical Appearance:
∗ clouded corneas
∗ deafness
∗ thickening of the dura
Maroteaux–Lamy syndrome
Maroteaux–Lamy syndrome
∗ The following syndromes are
associated with Alder-Reilly
Anomaly EXCEPT:
a.Hunter syndrome
b.Hurler syndrome
c.Myeloperoxidase deficiency syndrome
Maroteaux-Lamy syndrome
Question #1
∗ The appearance of Alder-Reilly
Anomaly is difficult to distinguish
from:
a.Dohle bodies
b.May-Hegglin Anomaly
c.Toxic granulation
d.Chediak-Higashi syndrome
Question #2
∗ Which of the following is
associated with Alder-Reilly
inclusions?
a. membrane defect of lysosomes
b. Dohle bodies and giant platelets
c. two-lobed neutrophils
d. mucopolysaccharidosis
Questions #3
∗ The cytoplasmic abnormality of the
white blood cell of Alder-Reilly
anomaly is found in the:
a. endoplasmic reticulum
b. lysosomes
c. mitochondria
d. ribosomes
Question #4
∗ Where can Alder-Reilly inclusions
be frequently seen?
a. Peripheral blood
b. Bone marrow
c. Spleen
d. Kidney
Question #5
Chédiak-Higashi syndrome Chédiak-Higashi syndrome
Azarcon, dyna mae j.
Zipagan, valerie
mt0831
Chédiak-Higashi syndrome Chédiak-Higashi syndrome
Eponym Eponym
Alexander Moisés Chédiak
--- Cuban physician and serologist
Otokata Higashi
--- Japanese pediatrician
Chédiak-Higashi syndrome Chédiak-Higashi syndrome
Background Background
Beguez Cesar in 1943
Steinbrinck in 1948
Chédiak in 1952
Higashi in 1954
rare childhood autosomal
recessive disorder
Chédiak-Higashi syndrome Chédiak-Higashi syndrome
Background Background
hypopigmentation of the
skin, eyes, and hair; prolonged
bleeding times; easy bruisability;
recurrent infections; abnormal
natural killer cell function; and
peripheral neuropathy
Morbidity results from patients
succumbing to frequent bacterial
infections or to an accelerated-
phase lymphoproliferation into
the major organs of the body
Chédiak-Higashi syndrome Chédiak-Higashi syndrome
Cause Cause
mutations in the LYST gene
What is the official name
of the LYST gene?
The official name of this gene is
“lysosomal trafficking regulator.”
LYST is the gene's official symbol.
What is the normal function
of the LYST gene?
provides instructions for making a
protein known as the lysosomal
trafficking regulator
determine the size of lysosomes
and regulate their movement within cells.
Chédiak-Higashi syndrome Chédiak-Higashi syndrome
Pathophysiology Pathophysiology
How are changes in the LYST gene
related to health conditions?
At least 30 mutations
in the LYST gene
Childhood form
abnormally short, nonfunctional version
of the lysosomal trafficking regulator protein
Adult version
usually change a single protein building block (amino acid) in
the protein
Chédiak-Higashi syndrome Chédiak-Higashi syndrome
Pathophysiology Pathophysiology
abnormally large lysosomes and
related structures in cells
throughout the body= interfere
with normal cell functions
cellular structures called melanosomes
(which are related to lysosomes) are
abnormally large= melanin is trapped
within the giant melanosomes
lysosome-like structures inside blood cells
called platelets= abnormal bruising
and bleeding
abnormal lysosomes in nerve cells= neurological
problems associated with this disease
Chédiak-Higashi syndrome Chédiak-Higashi syndrome
Pathophysiology Pathophysiology
Where is the LYST gene located?
Cytogenetic Location: 1q42.1-q42.2
Molecular Location on chromosome 1: base pairs
235,824,342 to 236,030,219
The LYST gene is located on the long (q) arm
of chromosome 1 between positions 42.1 and 42.2.
More precisely, the LYST gene is located from base
pair 235,824,342 to base pair 236,030,219 on
chromosome 1.
SYMPTOMS: SYMPTOMS:
Children with this condition may have:
 Albinism
 Increased infections in the lungs, skin, and mucous
membranes
 Nystagmus
 Accelerated phase - (EBV)
◦ fever, episodes of abnormal bleeding, overwhelming
infections, and organ failure.
Common:
 Infections – (mucous membranes, skin,respiratory
tract)
 Neuropathy
OTHER SYMPTOMS: OTHER SYMPTOMS:
 Decreased vision
 Mental retardation
 Muscle weakness
 Peripheral neuropathy
 Nosebleeds or easy bruising
 Numbness
 Tremor
 Uncontrolled bowel movements
 Seizures
 Photophobia
 ataxia
DIAGNOSIS/EXAM/TEST: DIAGNOSIS/EXAM/TEST:
 Physical exam
 Biopsy of skin, muscle, and nerves - granules
 Bone marrow smears - giant inclusion bodies white
blood cells (leukocyte
precursor ).
 Prenatal testing
 EEG - seizures
 Brain MRI or CT scan – small brain (atrophy)
 EMG or nerve conduction velocity testing – delayed
nerve signaling
 Peripheral blood smear - neutropenia and
hypergammaglobulinemia.
 Fluorescence cytometric analysis - analysis of cellular
granularity and surface
molecules
TREATMENT: TREATMENT:
 no specific treatment
 Bone marrow transplants
 Antibiotics- infections
 Antiviral drugs - terminal phase of the
disease
◦ Acyclovir
◦ Cyclophosphamide
◦ prednisone
 Vitamin C therapy - improved immune
function and clotting in some patients.
MORTALITY/MORBIDITY: MORTALITY/MORBIDITY:
 Death - first decade result of infection, bleeding,
or development of the accelerated lymphoma
like phase
 The second and third decades – survival
reported
RACE:
 Affects all races
 Al-Khenaizan - underreported in persons of darker-
skinned races.
AGE:
Usually appear soon after birth or in children younger
than 5 years.
PHOTOS
PHOTOS
Questions: Questions:
 What do you call the phase where there is a lymphoma like
syndrome?
a. slow phase c. latent phase
b. primary phase d. accelerated phase
 What is the diagnostic hallmark of Chediak-Higashi
syndrome?
a. Small inclusion bodies c. Medium inclusion bodies
b. Giant inclusion bodies d. Darkly pigmented
inclusion
 What is the medical term for jerky eye movement?
a. Hyperhidrosis c. Nystagmus
b. seizures d. Ataxia
 What is the official name of the gene affected in patients
with Chediak-Higashi syndrome?
a. Lysosome transport regulator
b. Lysosomal trafficking regulator
c. Lysosyme transcriptase regulator
d. Lysosomal transferase regulator
 What disease form of the Chediak-Higashi syndrome is
very fatal?
a. childhood form c. pregnant form
b. teenage form d. Late adulthood form
Prepared by: Valerie S. Zipagan
May Hegglin Anomaly
Chua, Cristina
Dela Pena, Andrew Vittorio
Guia, Alexa
May-Hegglin anomaly (MHA)
oAlso known as Dohle leukocyte
inclusions with giant platelets and
macrothrombocytopenia with
leukocyte inclusions
oIt is a rare genetic disorder of the blood
platelets that causes them to be
abnormally large.
oThe anomaly also causes abnormalities
in the  white blood cells known
as leukocytes.
Background
oIn 1909, Richard May described the
presence of leukocyte inclusions and
large platelets in an asymptomatic
young woman.
oIn 1945, Robert Hegglin described a
man and his 2 sons who were healthy
but had a triad consisting of
thrombocytopenia, giant platelets,
and leukocyte inclusions (see picture
on next slide)
Background
Blood smear (original
magnification X2000) in a
patient with May-Hegglin
anomaly (MHA)
demonstrates a
characteristic giant
platelet with poorly
defined granulation. A
normal-sized platelet is
also present. The trilobed
neutrophil contains a
large, well-defined,
basophilic, peripherally
placed cytoplasmic
inclusion body (resembling
a Döhle body). Used with
permission from Little,
Brown
Background
o His diagnostic triad was later given the
eponym May-Hegglin anomaly (MHA).
o May-Hegglin anomaly
- is an autosomal dominant disorder
characterized by various degrees of
thrombocytopenia that may be associated
with:
 purpura and bleeding
 giant platelets containing few granules
 and large (2-5 µm), well-defined, basophilic,
cytoplasmic inclusion bodies in granulocytes
that resemble Döhle bodies.
Background
oMay-Hegglin anomaly
- is one of a family of
macrothrombocytopenias
characterized by mutations in
the MYH9 gene.
oThe other members of this family
include:
- Sebastian syndrome
- Epstein syndrome
- Fechtner syndrome
Pathophysiology
oPatients have a mutation of
the MYH9 gene present in
chromosomal region 22q12-13.
oThe mutation results in disordered
production of nonmuscle myosin
heavy-chain type IIA, which leads to
invariable macrothrombocytopenia
secondary to defective
megakaryocyte maturation
Pathophysiology
o Platelet function in patients with May-Hegglin
anomaly has been reported as normal.
o However, in one study, epinephrine response
was described as abnormal in 8 of 15 patients
o Leukocyte Döhle inclusion bodies are
visualized on standard Wright stain and
appear bright blue and spindle shaped
o Ultrastructural studies reveal that these
bodies consist of clusters of ribosomes
oriented along parallel myosin heavy-chain
filaments 7–10 nm in diameter
o Neutrophil function is considered to be
normal, and patients have no increased
susceptibility to infections.
Signs and Symptoms
o Asymptomatic
o Minor hemorrhages
o Mild leukopenia
o Mild reduction in level of blood platelets
o Skin hemorrhage
o Nosebleed
o Excessive oral bleeding during dental
procedures
o Headache
o Muscle weakness on one side of body
Signs and Symptoms
o Intracranial bleeding
o Large blood platelets
o Mild reduction of level of blood
platelets
o Prolonged bleeding time
o Bleeding inside the brain
o Excessive menstrual bleeding
o Easy bruising
o Gums that bleed easily
o Excessive bleeding after operations
oActive bleeding from the mucosal
surfaces may be observed.
oThe most common sites of bleeding
include the mouth and nose.
oProlonged and excessive bleeding
and oozing associated with
lacerations and sutures may also be
observed.
Skin Hemorrhage
Nosebleed
Intracranial hemorrhage
Bleeding inside the brain
Causes
oMutation of MYH9 gene
oMalignant hypertension
oThrombotic thrombocytopenic
purpura
oSchulman-Upshaw syndrome
Lab Diagnosis
Platelet Count and Morphology
o Degree of thrombocytopenia varies
o Platelet count is usually 40-80 X 10
9
/L
(Normal Value 150-450 X 10
9
/L)
o Characterized by macrothrombocyte
- Platelets are enlarged 15-20 µm in diameter
(Normal size 1-4 µm)
o Mean platelet volume 30 fL
(Normal Value 6.8-10.2 fL)
Clinical Features of MYH9 -Related
Thrombocytopenias
Condition
Macrothromb
ocytopenia
Granulocyte
inclusions
Nephritis and
Deafness
Cataracts
MHA Yes Linear Döhle No No
Epstein
syndrome
Yes Absent or
faint
Yes No
Fechtner
syndrome
Yes Spherical
granules
Yes Yes
Sebastian
syndrome
Yes Spherical
granules
No No
Wright Stain
Döhle bodies
1.Neutrophils (most commonly seen)
2.monocytes
3.eosinophils
4.basophils
Döhle bodies and Macrothrombocyte
Döhle bodies and Macrothrombocyte
Döhle bodies (Eosinophil)
Electron Microscopy
oIncreased amount of disorganized
microtubule
Immunocytochemistry
oDetectection of
NMMHCIIA complexes within the
leukocytes
- Confirmatory test
Treatment
o Specific treatment is not required
o In rare patients with severe bleeding,
platelet transfusion may be required
Complication
- bleeding risk is increased by taking
drugs that decrease platelet
function
e.g. Aspirin and NSAIDs
Questions:
1. Mutation of what gene will result to
MHA?
a. MYJ9 b. MZH9
c. MYH9 d. MXH9
2. Other name for MHA?
a. Dohle leukocyte inclusions with small platelets
b. Dohle leukocyte inclusions with giant leukocytes
c. Dohle leukocyte inclusions with giant rbc
d. Dohle leukocyte bodies with giant platelets
3. What are the 2 most common site of
bleeding in MHA?
a. mouth and nose b. mouth and skin
c. nose and skin d. skin and brain
4. What inclusion bodies is commonly seen in
MHA?
a. Heinz bodies b. Döhle bodies
c. Cabot ring d. Siderotic granules
5. What platelet morphology
characterized MHA?
a.Microthrombocytes
b.Macrothrombocytes
c.Microleukocytes
d.Macroleukocytes
PELGER-HUET
PELGER-HUET
ANOMALY
ANOMALY
Mangon, Kimberly Christine L.
Santos, Czarinnah F.
Vergara, Verlyn C.
• PHA is a benign dominantly inherited
defect of terminal neutrophil differentiation
secondary to mutations in the lamin B
receptor (LBR) gene.
• Pelger, a Dutch hematologist, described
leukocytes with dumbbell-shaped bilobed
nuclei, a reduced number of nuclear
segments, and coarse clumping of the
nuclear chromatin.
• Huet, a pediatrician, identified it as an
inherited disorder.
• Genome-wide analysis of individuals from
the Gelenau region of Germany was used
to identify the affected gene in humans
as LBR gene, located on subband 1q42.1
• Heterozygotes have neutrophils with a
predominance of bilobed dumbbell-
shaped nuclei, which are also described
as pince-nez (ie, looking like pinched-
nose spectacles)
• LBR also interacts with HP-1
heterochromatin proteins
• LBR abnormalities do not affect
neutrophil function
• Distinguishing this autosomal dominant
disorder from acquired or
pseudo–Pelger-Huët anomaly is
important
• Homozygous individuals are rare
• In Homozygous individuals:
–Neutrophils contain a single, round,
eccentric nuclei with clumped chromatin
and little or no nuclear segmentation
–Basophils, eosinophils, and
megakaryocytes also show dense
nuclear chromatin and rounded nuclear
lobes
• Unique physical findings are not
observed in heterozygous
individuals with Pelger-Huët
anomaly
• Homozygous individuals
inconsistently have skeletal
anomalies such as postaxial
polydactyly, short metacarpals,
short upper limbs, short stature,
or hyperkyphosis.
MORTALITY/MORBIDITY
• Neutrophilic function is normal
• HETEROZYGOUS:
– are in good health
– natural resistance to infection is unimpaired
• HOMOZYGOUS:
– Skeletal anomalies
– Developmental delay
– Seizures
• From Switzerland,
Germany, or Holland
• In ALL ethnic groups
- Whites, Blacks and Asians
• Male-to-female ratio is 1:1
• May also be in individuals of all ages
• Distinguished from:
Acquired or pseudo–Pelger-Huët
anomaly
• observed in individuals with myeloid
leukemia, myelodysplasia, and bi-
lineage acute lymphocytic leukemia
Acquired or pseudo–Pelger-Huët
anomaly
–in the course of acute or chronic
myelogenous leukemia and in
myelodysplastic syndromes
–cells tend to appear late in the disease
–morphologic changes have been
described in myxedema
• MYXEDEMA
– Panhypopituitarism
– Vitamin B-12 and folate deficiency
– Multiple myeloma
– Enteroviral infections
– Malaria
– Muscular dystrophy
– Drug sensitivity
In Acquired or pseudo–PHA:
– Fewer bilobed cells
– Higher percentage of normal trilobed
neutrophils
– Presence of leukemic and immature cells
*predicative of the clinical onset of
myelodysplastic disorders and
malignant conditions.
• Heterozygous PBS
– neutrophils are bilobed, spectacle-shaped nuclei -
> pince-nez
– Cells with twin, joined, and plump nuclei
resembling dumbbells are predominant
– A thin bridge joins the two lobes
– 69-93% of the neutrophils show nuclear
segmentation that is arrested at the bilobe level
– neutrophils that possess a nonlobulated oblong
or peanut-shaped nucleus is often present
– >10% of cells contain 3 lobes; 4 lobes are rare
• Homozygous PBS
– neutrophils with a single, round, eccentric
nucleus (clumped chromatin and little or no
nuclear segmentation)
– most neutrophils are round or oval
– basophils, eosinophils, and megakaryocytes
show dense nuclear chromatin and rounded
nuclear lobes
– bone marrow: normal morphologic features in
the myeloid precursors to the myelocyte stage
• Electron microscopy: persistence of
nucleoli in the mature neutrophils with a
single oval nucleus -> altered and
retarded nuclear maturation of the
myeloid precursors
• No treatment is needed
• have good health
• natural resistance to infection is
unimpaired
-
END
Questions:
• What is the treatment for Pelger-Huët anomaly?
a. Corticosteroids b. Splenectomy c. Platelet transfusion
d. none
• Describe the nucleus of the neutrophil in heterozygous Pelger-Huët
anomaly.
a. spectacle-shape b. Single c. Eccentric d. bilobed, oval
• What is the gene affected in Pelger-Huët anomaly?
a. DAF b. LBR c. MYH9 d. PIGA
• Heterozygotes have neutrophils with a predominance of bilobed
dumbbell-shaped nuclei which are also described as what?
a. Pince-nez b. Rosette c. Oval d. Irregular
• The following are findings in homozygous Pelger-Huet EXCEPT:
a. postaxial polydactyly b. short stature c.
Hyperkyphosis d. resistance to infection
ANSWERS
• D
• A
• B
• A
• D
Dohle Bodies
• first described by H. Dohle in 1911 in
patients with scarlet fever
• remnants of free ribosomes or rough-
surfaced endoplasmic reticulum
Morphology
• small, oval inclusions in the peripheral
cytoplasm of polymorphonuclear
neutrophils
• stain pale blue with Wright stain
Dohle Bodies
• are considered normal if they are
present only in small numbers
• If there are many neutrophils in
the bloodstream containing Döhle
bodies, these can be referred to
as toxic neutrophil.
Dohle Bodies
• They are found in:
– Infective and inflammatory states
– severe burns
– Tuberculosis
– post chemotherapy
– pregnancy
Dohle Bodies
• More abundant in cats and
horses
Vacuoles
• Vacuoles are vacuoles
• vacuoles appear as holes in the
cytoplasm and are frequently
found in association with toxic
granulation.
• They are form by the ingestion
and degradation of bacteria and
are unevenly distributed.

Vacuoles
• The occasional tiny single
"vacuole" present in the
cytoplasm of one or two
lymphocytes is always NOT
significant.
• On the other hand, they are
Clinically significant when
associated with toxic
granulation, degranulation or
Dohle bodies
Vacuoles
• Found in
– Infection and Toxic effect of
ethanol.
– They are also found in Jordan's
anomaly
WHITE BLOOD
CELL
INCLUSION
BODIES
By: Elizes, Nicole Joy B.
Toxic granulation
Refers to changes in granulocyte cells
seen on examination of the
peripheral blood film of patients with
inflammatory conditions.
Toxic granulations are abnormally large,
dark coarse granules found in
granulocytes, particularly neutrophils.
Toxic Granulation
• Morphology:
Increased granulation. Granulation is
more basophilic and larger than
normal.
• Found in:
- Severe bacterial infection
- Normal pregnancy
- G-CSF and GM-CSF Therapy
- Patients with sepsis
Drumstick
 Represent the inactive X chromosome
of the female. The presence and
frequency of drumstick is related to
the number of X chromosome.
 They do not occur in normal males, in
individuals with the testicular
feminization syndrome who are
phenotypically female but genetically
(XY) male, or in Turner’s syndrome
(XO) females.
Drumstick
Morphology:
Drumstick shaped nuclear
appendage. ± 1.5 µm in diameter and
attached to the nucleus by a filament.
Found in:
- Neutrophils of females
- Males with Klinefelter syndrome
Sessile Nodule
• Morphology:
Inactive X chromosome found as
nodule on neutrophils of females.
• Found in:
- Neutrophils of females
Detached nuclear
fragments
• Morphology:
Detached nuclear material in cytoplasm.
• Found in:
- Dysplastic granulopoiesis due to HIV
infection
- Patients on anti cancer chemotherapy
- Administraion of drug interfering with
DNA synthesis, including chlorambucil,
mycophenolate, mofetil and tacrolimus
Actin Inclusion
• Found in:
- Congenital abnormality associated
with anemia and grey skin
Large Granular Lymphocyte
• Morphology:
Small eosinophilic granules in the
cytoplasm of large lymphocytes
• Found in:
Natural killer cells
Lymphokine activated T cells
Mott Cells
• Morphology:
Plasmacytoid lymphocyte with globular
inclusions composed of immunoglobulin.
• Found in:
Reactive changes in peripheral blood
Auer Rods
• Morphology:
Small azurophil rods in the cytoplasm of
myeloblasts and promyelocytes.
• Needle-shaped, pink-staining inclusion in the
cytoplasm
• These inclusions contain enzymes such as acid
phosphatase, peroxidase, and esterase and may
represent abnormal derivatives of cytoplasmic
granules.
Found in:
Acute myeloblastic leukemia
Myelodysplastic syndromes
• The End..
Questions
• 1. These are plasmacytoid lymphocyte with
globular inclusions composed of
immunoglobulin.
• A. large Granular lymphocyte
• B. Auer Rod
• C. Mott Cells
• D. None
• 2. What disease can be found in Large
granular lymphocyte?
• A. Natural killer cells
• B. Lymphokine activated T cells
• C. Both
• D. None
• 3. A needle-shaped, pink-staining inclusion in
the cytoplasm of myeloblasts and
promyelocytes containing azurophil rods.
• A. Auer Rods
• B. Mott Cell
• C. Large Granular Lymphocyte
• D. None
• 4. What disease can be found in mott cell?
• A. chronic LGL lymphocytosis
• B. Reactive changes in peripheral blood
• C. aggressive LGL leukemia
• D. None
• 5. These inclusions contain enzymes that
may represent abnormal derivatives of
cytoplasmic granules.
• A. Acid Phosphatase
• B. Peroxidase
• C. Esterase
• D. All the above
QUESTIONS
QUESTIONS:
1. In what condition/s can you find toxic
granulation?
A. Severe bacterial infection
B. Patients with sepsis
C. HIV
D. Both a and b
E. Both b and c
QUESTIONS:
2. It refers to changes in granulocyte cells
seen on examination of the
peripheral blood film of patients with
inflammatory conditions?
A. Infection
B. Sepsis
C. Toxic granulation
D. None of the above
QUESTIONS:
3. Which of the following findings in
the cytoplasm of granulocytes is
suggestive of an inflammatory process ?
A. Toxic granulation
B. Dohle bodies
C. Cytosolic vacuolation
D. All of the above
QUESTIONS:
4. In what particular white blood cell can
you find toxic granulations?
A. Eosinophil
B. Basophil
C. Lymphocyte
D. Neutrophil
QUESTIONS:
5. Which of the following inclusion bodies
are found in neutrophils of female?
A. Drumstick
B. Detached nuclear fragments
C. Sessile nodule
D. Both a and b
E. Both a and c
Questions
• Give at least 3 condition where you
can find your Dohle bodies
• This is a familial disorder in which
vacuoles are present in the cytoplasm
of granulocytes, lymphocytes, and
monocytes.
• In relation to the formation of
vacuoles, this is often seen with
prolonged exposure to drugs such as
antimicrobial agents and alcohol or
radiation.
CHRONIC MYELOCYTIC CHRONIC MYELOCYTIC
LEUKEMIA(CML) LEUKEMIA(CML)
Maglanque, Carolina G.
#18
CHRONIC MYELOCYTIC LEUKEMIA (CML) CHRONIC MYELOCYTIC LEUKEMIA (CML)
•Chronic Granulocytic Leukemia (CGL).
•Form of leukemia characterized by the increased
and unregulated growth of predominantly myeloid
cells in the bone marrow and blood.
•Resistance to apoptosis, abnormal signaling and
adhesion.
•9;22 chromosomal translocation(Philadelphia
chromosome)
•Peak age of 30-50.
Epidemiology Epidemiology
º Exposure to ionizing radiation
Example:
-People exposed to the atomic
bombings of Hiroshima
• Philadelphia chromosome
Philadelphia chromosome Philadelphia chromosome
Signs and Symptoms Signs and Symptoms
º Enlarged spleen
º Malaise, low-grade fever
º Gout
º Increase susceptibility to infection
º Anemia
º Thrombocytopenia with easy bruising
º Night sweats
Diagnosis Diagnosis
*Complete Blood Count
Peripheral Blood
º Increase granulocytes of all types
º Normal or decrease erythrocytes
º Normal reticulocytes
º Presence of nucleated RBCs
º Normal or increase platelets
º LAP is decrease(<13)
Diagnosis Diagnosis
B. Bone marrow aspiration and biopsy
Bone Marrow in CML Bone Marrow in CML
Bone Marrow in CML Bone Marrow in CML
Diagnosis Diagnosis
C. Fluorescent In Situ
Hybridization(FISH)
º Philadelphia chromosome
- BCR/ABL fusion gene
-TRITC (red) for BCR on ch 22, FITC (green) for
ABL on ch 9
-If the BCR/ABL fusion gene is present, a
YELLOW YELLOW fusion signal will appear
Classification Classification
¯Chronic phase
- few blast in the blood and bone
marrow.
- 3-4 years(without therapy)
Classification Classification
´Accelerated phase
- more blast in the blood and bone
marrow; fewer normal cells.
-fatal within months
WHO criteria:
º 10–19% myeloblasts in the blood or bone marrow
º >20% basophils in the blood or bone marrow
º Platelets count <100,000, unrelated to therapy
º Platelet count >1,000,000, unresponsive to therapy
º Cytogenetic evolution with new abnormalities in addition to
the Philadelphia chromosome
º Increasing splenomegaly or white blood cell count,
unresponsive to therapy
Classification Classification
IBlast crisis
- terminal phase and clinically behaves
like an acute leukemia.
- more than 30% of the cells in the
blood or bone marrow are blast cells.
- fatal within weeks.
Criteria:
º >20% myeloblasts or lymphoblasts in the blood or bone
marrow
º Large clusters of blasts in the bone marrow on biopsy
º Development of a chloroma (solid focus of leukemia outside
the bone marrow)
Treatment Treatment
¯ Targeted therapy
- tyrosine kinase inhibitors
 Imatinib mesylate (Gleevac or Glivec)
- first line therapy
 Dasatinib ( Spyrcel)
-TK inhibitor that blocks several oncogenic
proteins
 Nilotinib ( Tasigna)
-bind more tightly than imatinib to the Bcr-Abl
abnormal fusion
 Omacetaxine
-administered subcutaneously .
 Ponatinib
-oral drug
Treatment Treatment
´Chemotherapy
- stops the growth of the cell
 Hydroxyurea ( Hydrea)
IStem cell transplant
- for patient who developed T315I
mutation
Treatment Treatment
¯Surgery
 Splenectomy
±Biologic therapy/ Immunotherapy
- uses the patient’s system to fight
cancer.
Prognosis Prognosis
Depends on the following:
º The patient’s age.
º The phase of CML.
º The amount of blasts in the blood or
bone marrow.
º The size of the spleen at diagnosis.
º The patient’s general health.
Lowest risk group: 98 months
Middle group: 65 months
Highest risk group: 42 months
Questions:
Questions: Questions:
¯ Philadelphia chromosome is characterized
by which translocation?
A. 19;22 B. 9;22 C. 9;12
D.19;12
´ In CBC, what is the common findings for
granulocytes?
A. Increase B. Decrease C.
Normal D. Absent
I Level of Leukocyte alkaline phosphatase in
CML.
A. Increase B. Decrease C. Normal
¯ Classsified as terminal phase in CML.
* Chronic B. Accelerated C. Blastic D.
Refractory
¯ Stage of CML which is fatal within months.
A. Chronic B. Accelerated C. Blastic D.
Refractory
Prepared by :
Alejandro, Louie Carmela Kim
Putong, Ma. Fatima B.
Mendoza, Maria Lady Lyn
ACUTE LEUKEMIA ACUTE LEUKEMIA
 Is a result of malignant transformation of a stem cell leading to
unregulated proliferation and arrest in maturation at the
primitive blast stage.
 Acute leukemia is a form of cancer that affects the white blood
cells. It can present in many forms such as Acute Lymphocytic
Leukemia (ALL), which is very common in children,
especially 2-5 years of age; and Acute Myelogenic Leukemia
(AML).
 See video
ACUTE LEUKEMIA SUMMARY
Age : all ages (young and old)
Clinical onset : sudden
Course (untreated) : 6 months or less
Leukemic cells : immature >30% blasts
Anemia : prominent
Thrombocytopenia : prominent
WBC count : variable
Lymphadenopathy : mild
Splenomegaly : mild
 Symptoms
 low fever, anemia, pale skin, general ill feeling, easily bruised skin, and/or frequent nose bleeds
or bleeding gums.
 abdominal pain with an enlarged spleen, and infections with sores in the mouth.
Causes
 unknown, but risk of contracting the disease increases with a family history, Down Syndrome,
or other congenital disorders, identical twins, or exposure to toxic chemicals.
Diagnosis
 The first indication of a problem is typically an observation of the
aforementioned symptoms.
 A physical exam with studies of the blood, bone marrow, or cerebral spinal
fluid should follow to confirm the diagnosis.
 In some cases certain x-rays or CT scans may also be used to confirm the
diagnosis.
Treatment
 blood or platelet transfusions, anticancer medication and radiation treatments.
 A bone marrow transplant may be necessary in some cases. A physician may
also prescribe cortisone drugs and pain relievers (except aspirin) to help a
patient deal with symptoms.
Laboratory diagnosis: Laboratory diagnosis:
 Increased number of immature cells in the bone marrow including blast,
promeolocytes , promonocytes
 The term used to described the coexistence of immature and mature cell forms
is “hiatus leucaemicus”
 Identification of the cell lineage of the leukemic cells.
Peripheral blood: Peripheral blood:
 Anemia- normocytic,normochromic
 Decreased platelets
 Variable WBC count
 Classification of the degree of peripheral
involvement:
 Leukemic- increased WBC due to blast
 Subleukemic- blast without increased WBC
 Aleukemic- decreased WBC with no blast.
Acute Lymphoblastic leukemia Acute Lymphoblastic leukemia
 Is primarily a disease of childhood (2 and 10
years) and rare in adult
 is a form of leukemia, or cancer of the white
blood cells characterized by excess lymphoblast
 Malignant, immature white blood cells
continuously multiply and are overproduced in
the bone marrow
 causes damage and death by crowding out
normal cells in the bone marrow, and by
spreading to other organs
Signs and symphtoms Signs and symphtoms
 fatigue,
 pallor,
 fever,
 weight loss,
 irritability,
 anorexia,
 infection,
 bleeding,
 and bone pain
Types of ALL Most common cell
L1 children
• small with fine or
clumped
homogenous nuclear
chromatin
• absent or indistinct
nucleoli
L2 adult
• large and
heterogenous with
variable nuclear
chromatin and
prominent nucleoli
• nucleus is irregular
L3 is a very rare
form of ALL
• is large, with fine,
homogenous nuclear
chromatin containing
prominent nucleoli
• nucleus is regular
oval to round
 Age , WBC count and cell type(most
imp.)
 Chromosomal translocation- the
strongest predictor of adverse treatment
outcome for children and adult
 Philadelphia chromosome(t(9;22))-is an
indicator of adverse effects
 (t(9;21))-marker in childhood with ALL
patient
 Early pre-B cell(most common
presence of surface immunoglobulin)
 Mature pre-B cell( presence of
cytoplasmic immunoglobulin)
 B cell
 T cell
Diagnosis Diagnosis
 complete blood count
 blood smears
 bone marrow biopsy
TREATMENT TREATMENT
 Methotrexate
 Chemotherapy
 radiation therapy
Questions Questions
 How can you differentiate the
immature pre-B cell from mature pre-
B cell?
a)Presence of surface immunoglobulin
b)Presence of cytoplasmic
immunoglobulin
c)Both
d)Neither
 How can you differentiate the mature
pre-B cell from immature pre-B cell?
a)Presence of surface immunoglobulin
b)Presence of cytoplasmic
immunoglobulin
c)Both
d)Neither
 What is the most common treatment
for ALL?
a)Chemotherapy
b)Radiotherapy
c)Methotrexate
d)Aspirin
 What is the strongest predictor of
adverse treatment outcome for
children and adult?
a)Philadelphia chromosome
b)(t(9;21))
c)Chromosomal translocation
d)A and b
e)A and c
ACUTE MYELOID
ACUTE MYELOID
LEUKEMIA
LEUKEMIA
(AML)
(AML)
Prepared by : Putong, Ma Fatima B. Prepared by : Putong, Ma Fatima B.
MT0831 MT0831
Acute myeloid leukemia
• Acute myeloid leukemia (AML) is one of four types of
leukemia.
• The most common family of leukemia in children younger
than 1 year of age. It is rare in older children and
adolescents, but a second incidence peak occurs at 40 years
of age.
• AML is cancer of the blood-forming tissue (bone marrow).
• Normal bone marrow produces red cells, white cells, and
platelets.
• AML causes bone marrow to produce too many immature
white blood cells (blast cells).
• See Video
Acute Myeloid Leukemia
See Video
Acute myeloid leukemia
• Suppresses normal blood cell production.
– Anemia, leucopenia, thrombocytopenia
– Acute in which the onset is usually rapid, the
disease is very aggressive, and the cells involved
are usually poorly differentiated with many blasts.
• characterized by clonal proliferation of
myeloid precursor cells with reduced capacity
to differentiate into more mature cellular
elements.
• results in accumulation of leukemic forms in
bone marrow, peripheral blood, and other
tissues.
ACUTE MYELOID
LEUKEMIA
--the myeloblast is a
large blast with a
moderate amount of
cytoplasm, fine lacey
chromatin, and
prominent nucleoli;
10-40% of
myeloblasts contain
Auer rods
Myeloblasts with Auer Rod
Classification of Acute Myeloid Leukemias
AML with
Recurrent
Abnormal
Karyotypes
AML with
Dysplasia
AML as a result
of previous
therapy-related
Myelodysplasias
AML not
otherwise
Categorized
Acute Leukemia
of Ambigiuos
Lineage
•AML with
t(8;21)
(q22;q22)
•AML with inv
(16) 9p13q22)
or t(16;16)
(p13;q22)
•AML with
t(15;17)
(q22;q12) (APL)
•AML with
11q23
•AML occurring
after a diagnosis
of a
myeloproliferative
or
myelodysplastic
disease
•AML with
history of
alkylating
agent exposure
•AML with
topoisomerase
exposure
•AML with
other
exposures
such as
radiation
•AML with minimally
differentiated
•AML without
maturation
•Acute
myelomonocytic
leukemia
•Acute
monobalstic/monocyt
ic leukemia
•Acute erythroid
leukemia
•Acute
Megakaryocytic
Leukemia
•Acute Basophilic
Leukemia
•Acute
bilineage
leukemia
•Acute
biphenotypic
leukemia
FAB Classification (Summary)
M0: minimally differentiated
M1: without maturation
M2: with maturation.
M3: promyelocytic
M4: myelomonocytic
M5: monoblastic
M6: erythroleukemia
M7: megakaryoblastic
ACUTE MYELOID LEUKEMIA(M0)
M0
•Minimally differentiated
Auer Rods (absent)
•No cell maturation
•Negative in :
Myeloperoxidase
Sudan Black B
ACUTE MYELOID LEUKEMIA(M1)
M1
•“Myeloblastic without maturation”
•The bone marrow shows ≥ 90% blasts and < 10% promyelocytes
•The disease occurs in older adults
•Blasts same with M0
•Auer rods (usually Positive) for MYELOPEROXIDASE or
SUDAN BLACK B dye.
•No specific recurrent chromosome abnormalities
MYELOBALSTIC WITH MATURATION
M2
•“Myeloblastic with maturation”
•The bone marrow shows 30-89% blasts and > 10%
promyelocytes;
•Auer rods and other aspects are present
•Monocytic line –increased
•It has a less favorable prognosis
ACUTE PROMYELOCUTIC LEUKEMIA (M3)
M3
•“Hyper granular Promyelocytic”
•This form of AML has a bone marrow with >30% blasts
•Is more virulent than other forms
•Occurs with a medium age of 39
•WBC count – decreased (low)
•Treatment causes a release of the granules and may send the patient into
disseminated intravascular coagulation and subsequent bleeding
M3m – Hypogranular Promyelocytic
ACUTE MYELOMONOCYTIC LEUKEMIA (M4)
M4
•“Acute Myelomonoblastic Leukemia”
•Both myeloblasts and monoblasts are seen in the bone
marrow and peripheral blood
•Infiltration of extramedullary sites is more common
than with the pure granulocytic variants
•WBC –elevated
•Monocytic cells constitute atleast 20% of all marrow
cells.
ACUTE MONOCYTIC LEUKEMIA (M5)
M5
• “Acute Monoblastic Leukemia”
• >80% of the nonerythroid cells in the bone marrow are
monocytic
•There is extensive infiltration of the gums, CNS, lymph nodes
and extramedullary sites
•This form is further divided into
•M5A - Poorly differentiated (>80% monoblasts)
•M5B - Well differentiated (<80% monoblasts)
ERYTHROLEUKEMIA (M6)
M6
•“Erythroleukemia”
•Di Guglielmo’s Syndrome
•This is rare and is characterized by a bone marrow having a predominance of
erythroblasts
•It has 3 sequentially morphologically defined phases;
•Preponderance of abnormal erythroblasts
•Erythroleukemia – there is an increase in both erythroblasts and myeloblasts
•Myeloblastic leukemia – M1, M2, or M4
•Anemia is common
ACUTE MEGAKARYOBASTIC LEUKEMIA (M7)
M7
Signs and Symptoms
• • Anemia Anemiaweakness and easy fatigue
• • Neutropenia Neutropeniainfections
• • Thrombocytopenia Thrombocytopeniagingival bleeding, ecchymoses, epistaxis, menorrhagia
These three give rise to clinical findings :
• Pallor
• Fatigue
• Shortness of breath on exertion
• Easy bruising
• Petechiae
• Bleeding in the nose or from the gums
• Prolonged bleeding from minor cuts
• Recurrent minor infections or poor healing of minor cuts
• Loss of appetite or weight loss
• Mild fever
Treatments for AML
There are four general types of therapy
 Chemotherapy
Phase One – Remission induction therapy
Phase Two – Remission continuation therapy
 Bone marrow transplant
 Radiotherapy
 Immunotherapy
Prognosis for AML
• Survival rates greatly improved over past 25 years.
• Remission rates inversely related to age.
• Dependent upon several factors.
– Age
– White blood cell count
– Presence of translocations in bone marrow
QUESTIONS
1. What FAB classification where monocytic
line increases?
a. M2
b. M3
c. M4
d. M1
• 2. What FAB classification is associated w/
t(16;16) or inv(16)(p13q22)?
a.M4
b.M3
c.M2
d.M1
3.What do you call the large blast with a
moderate amount of cytoplasm, fine lacey
chromatin, and prominent nucleoli which
contains 10-40% Auer rods in AML?
a. Promyeloblast
b. Myeloblast
c. Promonoblast
d. Prokaryoblast
4.What form of AML has a bone marrow with
>30% blasts and it is more virulent than other
forms?
a. M3
b. M4
c. M5
d. M2
5. What form of AML wherein infiltration of
extra medullary sites is more common than with
the pure granulocytic variants?
a.M4
b.M3
c.M5
d.M2
Chronic Lymphocytic
Leukemia
CLL/ Chronic Lymphoid Leukemia
# 24
Ong, Tanya
Yuin
MT0831
Dr. Asilo
Understanding CLL
• Chronic lymphocytic leukemia (CLL) is one of the four
main types of leukemia.
• Common in people 60 years and older.
• Children do not get CLL.
• CLL is the most common type of leukemia in North
America and Europe.
• It is characterized by accumulation of small lymphoid
cells in the peripheral blood, bone marrow, & lymphoid
organs.
• They are derived from recirculating CD 5+, IgM+, IgD+
B cells which are normally present in the peripheral
blood
• CLL has a peripheral blood
(lymphocytosis > 10 x 10⁹/ L)
• CLL starts with a change (mutation) to the
DNA of a single cell called a lymphocyte.
• The change occurs in a B lymphocyte but other
cells transforming from normal to leukemic
may have features of a T lymphocyte or a NK
cell.
• Over time, the CLL cells multiply and replace
normal lymphocytes in the marrow and lymph
nodes.
• Presence of “Smudge Cells” or bare nuclei can
be frequently found.
Common
Target
Cell of
CLL
Other
target cells
Healthy Normal
Lymphocytes
Chronic Lymphocytic
Leukemia Cells
Symptoms and Signs
• CLL signs and symptoms usually develop
slowly.
• No known cause of CLL.
• Some people with CLL do not even have any
symptoms.
• Many of the signs and symptoms of CLL are
more likely to be caused by other illnesses.
• Specific blood tests and bone marrow tests
are needed to make a diagnosis.
Some signs and symptoms of
CLL include :
• Tiring more easily. People may
have less energy due to fewer
healthy red cells and more CLL
cells.
• Shortness of breath during
normal activities. This is due to
fewer healthy red cells and
more CLL cells.
• Swollen lymph nodes or spleen.
High numbers of CLL cells can
gather in the lymph nodes or
spleen as the number of
CLL cells grows.
• Infections. People with a very high number
of CLL cells building up in the marrow may
have repeated infections of the skin or
other parts of the body.
• Weight Loss. Some people with CLL lose
weight because they eat less and/or
because they are using more energy.
*Some patients may also have other
symptoms, such as aches, fever
or night sweats.
Prognosis
• Late stage patients usually have a more progressive
disease.
• Significant subset of early stage eventually progress by
--refractory to treatment
--infectious Complications
--autoimmune complications
• Stage Definition
0 Absolute lymphocytosis >15 x 10
9
/L.
1 Stage 0 + enlarged lymph nodes.
11 Stage 0 + liver or/and spleen ↑ ±
adenopathy.
111 Stage 0 + anemia ±organomegally or
adenopathy.
1V Stage 0 + thrombocytopenia ±
organomegally or
adenopathy.
Notes to consider:
• Average survival of the patient is 5 years but may
take an aggressive course with only 1-2 years of
survival.
• CLL is a Highly Variable disorder.
• Not associated with radiation/ exposure to
occupational hazard.
• Has the strongest tendency for familial incidence.
• May results to altered humoral immunity resulting
from suppression of all classes of
immunoglobulins, leading to
hypogammaglobulinemia.
• May develop autoimmune disorders and produce
autoantibodies to neutrophils, platelets, or RBCs
(AIHA)
READY?? READY??
? ?
Question # 1
1.) What do you call a “ Bare Nuclei” ?
A. Smudge Cells B. Vacuoles C. Pelger-Huet Cells D.
Dohle Bodies
Question # 2
2.) What is the average survival of a
patient with CLL?
A. 10 years B. 15 years C. 5 years D.
2 years
Question # 3
3.) The most common target cell of the
Chronic Lymphocytic Leukemia.
A. T-Cell B. B-Cell C. Natural
Killer Cell
D. Lymphocyte Progenitor Cells
Question # 4
4.) Where is CLL most commonly
found?
A. Africa B. Southeast Asia C. North America
D. India
Question # 5
5.) Which of the following is not a Sign
& Symptoms of a CLL?
A. Anorexia B. Night
Sweat
C. Swollen Lymph Nodes D. Fever
Hodgkin’s Disease
Balasta, Darwin
Basa, Aaronn
Giorla, Jake
∗ Hodgkin's lymphoma is a malignant disorder
characterized by painless, progressive enlargement of
lymphoid tissue, usually first evident in cervical lymph
nodes. Characterized by splenomegaly and the
presence of Reed-Sternberg cells in lymphoid tissue.
∗ The nomenclature of HL, formerly called Hodgkin's
disease, is little changed from that of the Rye
conference.
∗ The hallmark of HL is the Hodgkin Reed–Sternberg
(HRS vs. RS) cell.
∗ Accurate diagnosis and staging are critically important
for successful treatment.
∗ Clinical staging provides strong predictor of prognosis
and selection of a specific treatment regimen
Hodgkin's Lymphoma
∗ treatment of Hodgkin's disease is based on solid
principles of radiobiology and chemotherapy that
serve as a model for all other treatment regimens
(treatment has become very successful).
∗ untreated, 90% of patients with Hodgkin's disease die
within 2-3 years. 80% or more are now curable with
modern therapy.
∗ one of the best examples of a malignancy that can be
cured if diagnosed and managed well
∗ Its cause remains unknown.
∗ Hodgkin's disease usually presents as an
enlargement of the lymphoid organs,
frequently accompanied by systemic symptoms
such as
∗ fever
∗ weight loss
∗ Fatigue
∗ unique in several respects.
∗ Unlike the non-Hodgkin's lymphomas, the
tumor masses
∗ largely comprise normal reactive T cells
∗ usually CD4 predominant, not a clone of
malignant lymphocytes.
DIAGNOSIS &
CLASSIFICATION
∗ Reed-Sternberg cell - which is a large
binucleated, multinucleated or mononuclear
(Hodgkin) cell with each nucleus bearing a very
large inclusion-like nucleolus
∗ closely resembles a macrophage-like cell than a
lymphocyte.
∗ Immunophenotyping studies : monoclonal B cells
derived from germinal center cells
∗ These neoplastic cells appear in an
immunoproliferative background containing
variable numbers of lymphocytes, histiocytes,
eosinophils and plasma cells
∗ Relative number may vary from very high to very
low, but always make up < 2% of the apparent
tumor load.
∗ difficult to study because they are present in small
numbers and are difficult to separate from the
surrounding infiltrate of reactive cells.
∗ mechanism and their precise role in the malignant
process remain obscure
REED-STERNBERG CELLS &
LYMPHOCYTIC/HISTIOCYTIC
CELLS
Reed-Sternberg cell in a marrow smear
(Wright's stain), showing the mirror nuclei
with prominent nucleoli.
Lymph node section from a patient with
Hodgkin's disease, showing a classic Reed-
Sternberg cell
- Lymphocyte-Predominant Hodgkin Lymphoma
- Classical Hodgkin Lymphoma
Type of Hodgkin’s Disease
Lymphocyte-Predominant Hodgkin
Lymphoma
Is the least common form of HD and accounts for fewer
than 1% of all HD cases. The disease affects more
men than women, and it tends to occur in individuals
who are older, HIV-positive, or residents of non-
industrialized nations. The disease usually arises in the
lymph nodes of the abdomen and pelvis (hip region),
while sparing the nodes of the neck and underarms.
LDHD is an aggressive form of HD, and most patients
are diagnosed with advanced-stage disease.
Divided into two subtypes:
- Nodular Lymphocyte-Predominant Hodgkin lymphoma
- Diffuse lymphocyte-Predominant Hodgkin Lymphoma
Nodular Lymphocyte- Predominant Hodgkin
lymphoma
∗ Nodular lymphocyte predominant Hodgkin's disease
(nLPHD) accounts for about 5% of all HD cases. It is three
times more common in men than in women, and it primarily
affects young adults in their third through fifth decades of life.
Most patients (75%) are diagnosed at an early stage (e.g.,
Stage 1), and a majority (by some reports up to 90%) respond to
therapy with a complete response. The peripheral lymph nodes
(underarm, neck, ear, and groin nodes) are frequently involved,
whereas the deep, intrathoracic (within the trunk) nodes are
spared.
∗ Classic Reed-Sternberg cells are not seen or are very
uncommon in patients' tissue samples. Instead, large, circular
meshworks of cells take over the lymph nodes. These nodules
contain unusual lymphocytes and histiocytes known as "L & H
cells" or "popcorn cells," as well as B-cells and scattered T-cells.
The T-cells may be distributed in a nodular (knot-like)
arrangement within the tissues.
∗ L & H (Popcorn) cells
∗ In its early stages, LPHD is characterized by
lymphocytes that are mostly B-cells; however,
in LPHD's later stages, T-cells may surpass B-
cells in number. LPDH has a slow clinical
course. Late relapses are common, but they
usually do not affect survival; survival is
favorable even among patients with recurrent
disease. Patients with this diagnosis are more
likely than other HD patients to develop non-
Hodgkin's lymphomas (NHLs), typically large
cell lymphoma of B-cell type.
Diffuse Lymphocyte-Predominant
Hodgkin Lymphoma
∗ is an extremely rare form of Hodgkin's
disease. It not as well defined as nLPHD.
In dLPHD, there are no circular meshworks
of cells, and B-cells are missing. Instead,
the lymphatic tissue is dominated by
spread out arranged T-cells.
Classical Hodgkin Lymphoma
∗ Comprises a group of heterogenous germinal center
cell disorders
∗ Reed-Sternberg cells, large lymphoid cell with a
bilobed nucleus or two nuclei with prominent
eosinophilic nucleoli and abundant cytoplasm, are
the diagnostic neoplastic cells
∗ Can be divided into four subtypes depending on the
architectural features, composition of the reactive
background, and relative proportion of neoplastic
cells:
- Nodular Sclerosis Hodgkin’s disease
- Mixed Cellularity Hodgkin’s disease
- Lymphocyte Rich Hodgkin’s disease
- Lymphocyte Depleted Hodgkin’s disease
Classical Hodgkin
Subtype
Diagnostic Feature
Nodular Sclerosis
Broad collagen bands with thickening
of the nodal capsule and lacunar cells
Mixed Cellularity
Reed-Sternberg cells are scattered
among the diffuse background
proliferation of small lymphocytes,
histiocytes, eosinophils, neutrophils
and plasma cells
Lymphocyte Rich
Background cellularity is less
heterogenous
Lymphocyte Depleted
Scarcity of cells of reactive
background, and neoplastic Reed-
Sternberg cells
Nodular Sclerosis Hodgkin Lymphoma
Mixed Cellularity Classical Hodgkin Lymphoma
Lymphocyte Rich Hodgkin Disease
Lymphocyte Depleted Hodgkin Lymphoma
∗ most common presentation of a Hodgkin's disease patient
is the appearance superficial lymph node or group of
nodes in a young adult.
∗ first appearance in a single node group a healthy
individual make it difficult to distinguish from the
lymphadenopathy associated with an infectious process.
∗ Hodgkin's nodes can on occasion wax and wane in the
same way as those associated with an infectious process.
∗ The diagnosis is obviously easier when the mass is large,
presents in more than one area, and is associated with
systemic symptoms (B symptoms) such as:
∗ night sweats, fever, weight loss, pruritus, or fatigue.
CLINICAL FEATURES
∗ most common areas of involvement in young patients :
∗ cervical, axillary, and mediastinal nodes
∗ incidence of Hodgkin's disease has been linked to
several factors, including
∗ environment, social status, infectious agents, and genetic
propensity.
∗ slightly more common in men, occurred as clustered
cases in families, communities, and schools.
∗ Patients who have had infectious mononucleosis or
have a positive test for prior EBV infection have a
threefold increased risk for developing the disease.
∗ Accurate staging is extremely important
∗ natural history of the disease suggests that it arises in a single site
and then spreads
∗ primary objective of staging is to determine the current location of all
the disease in the patient in order to plan a treatment that will
address each of the involved areas and all contiguous sites of
possible spread.
STAGING
Staging System for Hodgkin’s Disease
Stage Description Example
I Involvement of a single lymphoid region or a single
nonlymphoid site (I
E
)
Nodes on one side of the neck only
II Involvement of two or more regions on the same
side of the diaphragm
Nodes in the neck and chest
III Involvement of two or more regions on both sides
of the diaphragm
Nodes in the neck and retroperitoneum or
the spleen
IV Spread of disease from lymphoid sites to
nonlymphoid organs, involvement of more than one
nonlymphoid organ
Nodes in the chest and infiltration of the
marrow and lung
B Each stage is further modified as B by the
presence of fever, weight loss, or night sweats
Nodes in the retroperitoneum and groin with
fever and night sweats (IIB)
History & Physical Examination
∗The history should document the timing
and characteristics of the onset of the
disease and the presence of systemic (B)
symptoms
∗physical examination, all portions of the
lymphoid organs should be carefully
examined
∗Special attention should be paid
∗ the oral pharynx (Waldeyer's ring), the
popliteal and epitrochlear regions, the
subclavicular regions, common axillary,
anterior and posterior cervical, and
inguinal regions.
Biopsy
∗biopsy of the principal tumor mass or
accessible enlarged node should be done,
and the results reviewed with an
experienced hematopathologist.
Radiologic Studies
∗routine chest x-ray will reveal patients with bulky mediastinal disease
∗computed tomography (CT) scan accurately detect lymph node involvement of
the mediastinum and abdominal nodes
∗bipedal lymphangiography can be performed to evaluate retroperitoneal nodes
of the lower abdomen.
∗magnetic resonance image (MRI)
Laboratory Studies
∗laboratory evaluation of the Hodgkin's disease patient should include a
∗ complete blood count, tests of renal and liver function(ALP, LDH), serum calcium,
and bilateral iliac crest marrow aspirates and biopsies.
∗studies of iron supply if anemia is present
∗Abnormalities of the granulocyte and lymphocyte counts.
∗guided needle biopsy of the lesion or laparoscopic liver biopsy if abnormal
liver chemistries or a suspicious lesion on CT
Therapy
∗both radiotherapy and chemotherapy can cure Hodgkin's disease
THANKS!! ^_^
NAVAL, RICA NELL A.
#23
DE LEON, LYSANDER LINUS D.
# 9
MULTIPLE
MYELOMA
MULTIPLE MYELOMA is….
*neoplastic proliferation of plasma cells, primarily
occurring in the bone marrow
*plasma cell cancer characterized by
monoclonal gammopathy and multifocal
destructive bone lesions throughout the skeleton
* also called plasma cell myeloma or Kahler's
disease
INCIDENCE
 rare under age 40
 50-75 yrs. (peak of incidence.)
 mean age at the time of diagnosis is 62 years
 equal sex distribution
 second most prevalent blood cancer (10%)
after non-Hodgkin's lymphoma.
 1% of all cancers and 2% of all cancer deaths
PATHOGENESIS
 Chromosomal and gene damages  loss of
control on antibody production
 Clonal proliferation of malignant plasma cells –
BONE MARROW
 May synthesize complete Ig or an L-chain subunit
-IgG --- 50% of patients
-IgA --- 25%
 Decreased ability to synthesize normal Ig against
specific ags
 Chromosome 13,14 abnormalities --- 50%
patients
SYMPTOMS
 Bone pain -- most common symptom
 Infection – most common cause of death
 Neurologic symptoms
 Renal failure – 50% of cases
 Anemia (NC,NC)
 Bleeding
Conditions associated with M
proteins
 Stable production
 Monoclonal gammopathy of undetermined significance
 Smouldering multiple myeloma
 Progressive production
 Multiple myeloma (IgG, IgA, free light chains, IgD, IgE)
 Plasma cell leukaemia; Solitary plasmacytoma of bone
 Extramedullary plasmacytoma
 Waldenström's macroglobulinaemia (IgM)
 Chronic lymphocytic leukaemia; Malignant lymphoma
 Primary amyloidosis Heavy chain disease
 Non neoplastic conditions: Cirrhosis,Sarcoid,Ca
Colon/Breast
Multiple Myeloma
LABORATORY FINDINGS
Peripheral Blood Smear
-normochromic, normocytic anemia
-normoblasts may be present
-leukocyte count is slightly decreased, normal, or slightly
increased
-platelet count is usually normal, but may be decreased
Most striking feature: marked degree of rouleau formation
Peripheral Blood Smear
LABORATORY FINDINGS
Bone marrow
-presence of plasma cells or myeloma cells (less than 1% to over 90%)
Serum protein electrophoresis
-shows an M-spot (homogeneous band in the gamma- or beta-region)
-hypogammaglobulinemia (when only light chains are produced by the
neoplastic plasma cells)
Immunoelectrophoresis
-shows that monoclonal protein is:
*IgG in over half the cases
*IgA in about one-fifth
*IgD in less than 1%
*IgE very rarely
Bone Marrow Aspirate (Normal)
Bone Marrow Aspirate (MM)
Bone Marrow Aspirate (MM)
LABORATORY FINDINGS
-5% of myeloma proteins are cryoglobulins
(proteins that precipitate from cooled serum and
redissolve on warming)
-Bence Jones protein
-Myeloma kidney—due to excretion of light chains
-Amyloidosis (10-15% of cases) -- may be a factor
in the renal failure.
LABORATORY FINDINGS
 Other Findings:
-serum monoclonal immunoglobulin
-radiologic evidence of lytic bone lesions
(osteoclastic activity, hypercalcemia and
neurologic changes)
-Serum globulin is usually increased
-elevated ESR
Laboratory Diagnosis
Helpful Mnemonics:
•[C] Calcium elevation in the blood S.
Calcium >10.5 mg/l or upper limit of
normal{8.6-10 mg/l}
•[R] Renal insufficiency S. Creatinine > 2
mg/dl{0.6-1.3 mg/dl}
•[A] Anemia Hemoglobin < 10 g/dl or 2 g <
normal{12-18g/dl}
•[B] Lytic bone lesions or osteoporosis
Lytic lesions(Punched out lesions) on X
Ray.
Vertebral collapse secondary to
osteoporosis/pathological fracture
1.Normal Plasma 2.Polyclonal Hyperglobulinemia
3.Monoclonal Spike4.Bence Jones proteins in urine
Bence Jones Protein
MULTIPLE MYELOMA
DIAGNOSTIC CRITERIA: ALL 3 REQUIRED
1.Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy-
proven plasmacytoma
2.Monoclonal protein present in the serum and/or urine*
3.Myeloma-related organ dysfunction (1 or more)
• [C] Calcium elevation
• [R] Renal insufficiency
• [A] Anemia Hemoglobin
• [B] Bone lesions or osteoporosis
*Non-secretory Multiple myeloma
Differential Diagnosis
MGUS
Asymptomatic
Multiple Myeloma
Symptomatic Multiple
Myeloma
Serum M protein <30 g/L Serum M protein >30 g/L
M protein in the serum
or urine
Clonal † bone marrow
plasmacytosis <10%
Clonal bone marrow
plasmacytosis >10%
Clonal bone marrow
plasmacytosis or
plasmacytoma
No other B cell
lymphoproliferative
disorder
No related organ and
tissue impairment
Related organ and
tissue impairment
No related organ and
tissue impairment
STAGING
 International Staging System
 Durie-Salmon staging system
STAGING
International Staging System
 Stage I: β
2
-microglobulin (β2M) < 3.5 mg/L,
albumin >= 3.5 g/dL
 Stage II: β2M < 3.5 mg/L and albumin <
3.5 mg/dL; or β2M 3.5 mg/L - 5.5 mg/L
irrespective of the serum albumin
 Stage III: β2M >= 5.5 mg/L
STAGING
Durie-Salmon staging system
 Stage I: all of
 Hb > 10g/dL
 normal calcium
 Skeletal survey: normal or single plasmacytoma or
osteoporosis
 Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA
 Urinary light chain excretion < 4 g/24h
 Stage II: fulfilling the criteria of neither I nor III
 Stage III: one or more of
 Hb < 8.5g/dL
 high calcium > 12 mg/dL
 Skeletal survey: Three or more lytic bone lesions
 Serum paraprotein > 7g/dL if IgG, > 5 g/dL if IgA
 Urinary light chain excretion > 12g/24h
 Stages I, II, and III of the Durie-Salmon staging
system can be divided into A or B depending on
serum creatinine:
A: serum creatinine < 2 mg/dL (< 177 umol/L)
B: serum creatinine > 2 mg/dL (> 177 umol/L)
PROGNOSIS
 62 months for stage 1 disease
 45 months for stage 2 disease
 29 months for stage 3 disease.
 Chromosome 13 abnormalities – POOR
PROGNOSIS
TREATMENT
 Initial therapy
- depends on the patient’s age
- high-dose chemotherapy with hematopoietic
stem-cell transplantation: patients under the age of
65
- Autologous stem cell transplantation: the
transplantation of a patient’s own stem cells after
chemotherapy (most common type of stem cell
transplantation for multiple myeloma)
- Allogeneic stem cell transplantation --
transplantation of a healthy person’s stem cells into
the affected patient (available to a small percentage
of patient)
- Patients over age 65 -- chemotherapy with
melphalan and prednisone
Thank you for listening 
QUESTIONS
QUESTIONS
1. All of the following are symptoms associated
with multiple myeloma EXCEPT…
a. Weakness, Fatigue
b. Spinal cord compression
c. Normocytic, hypochromic anemia
d. Hypercalcemia
QUESTIONS
2. Abnormalities with which chromosome is
associated with multiple myeloma with POOR
PROGNOSIS?
a. Chormosome 15
b. Chromosome 20
c. Chromosome 13
d. Chromosome 8
QUESTIONS
3. Which of the following statements is TRUE
about multiple myeloma?
a. MM is a neoplastic proliferation of plasma
cells, primarily occurring in the bone marrow
b. plasma cell cancer characterized by
monoclonal gammopathy and multifocal
destructive bone lesions throughout the skeleton
c. Either
d. Neither
QUESTIONS
4. Peak of incidence for multiple myeloma occurs
between
a. 0-10 years old
b. 20-30 years old
c. 50-75 years old
d. 35-40 years old
QUESTIONS
5. Another term for Multiple Myeloma is…
a. plasma cell myeloma
b. Kahler’s disease
c. either
d. neither
Questions
1.) Cause of recurrent infection of a patient with
multiple myeloma
a.) neutropenia
b.) Waldenström's macroglobulinaemia
c.) renal impairment
d.) M protein
Questions
2.) Which of the following is true in the diagnosis
of Multiple Myeloma
a.) Serum M protein >30 g/L
b.) No related organ and tissue impairment
c.) Serum M protein <30 g/L
d.) Calcium elevation in the blood
Questions
3.) What causes hypercalcemia in a patient with
multiple myeloma?
a.) neutropenia
b.) renal impairment
c.) OFA secretion of Myeloma cells
d.) none of the above
Questions
3.) Laboratory procedures done in the diagnosis of
multiple myeloma:
a.) Blood chemistry: calcium determination
b.) Imaging tests
c.) both
d.) neither
Questions
4.) True or false: Multiple myeloma could be ruled
out if there is an absence of M proteins in the
patients serum, even if the common symptoms are
present.
Questions
5.) What causes Lytic bone lesions in a patient
with multiple myeloma?
a.) Osteoblasts
b.) Osteocytes
c.) Bone Macrophages
d.) neither
NON- HODGKIN’S LYMPHOMA
Non-Hodgkin’s Lymphomas
 non-Hodgkin's lymphomas (NHLs) are a
heterogeneous group of disorders characterized by
malignant proliferation of B or T lymphocytes. From
a clinical standpoint, lymphomas generally present
as SOLID TUMORS of the lymphoid system
 type of cancer that originates in a subset of white
blood cells called lymphocytes.
 lymph nodes
 Spleen tonsils, thymus
 Lymphatic tissue
Hodgkin's vs. non-Hodgkin's lymphoma:
What's the difference?
Hodgkin’s
Lymphoma
Non Hodgkin’s
lymphoma
-Less common -more common
- Reed-Sternberg cell -no Reed-Sternberg
cell
-Young people (20-30)
Older people (55 and
up)
-risk increases with age
(60’s)
Reed-Sternberg cell
Simplified schema of
Hematopoetic Cancers

Myeloid
Lymphoid
Acute and chronic
Myeloid
‘Leukemias’
Lymphomas
Hodgkins (30%)
Non Hodgkins
(70%)
WBC
RBC
Platelets
B Cells
T cells
NHL: Epidemiology
 85% are B cell type and 15% are T cell
type
 5
th
most frequently diagnosed cancer
overall for both males and females
 males > females
 incidence
 NHL increasing over time
 Hodgkin lymphoma stable
Mechanisms of lymphomagenesis
 Genetic alterations
 Infection
 Antigen stimulation
 Immunosuppression
NHL : Etiology
 cause of NHL is unknown but substantial
evidence suggests:
 viral cause (human T-cell leukemia-
lymphoma virus, Epstein-Barr virus,
hepatitis C virus, HIV)
 Helicobacter pylori infection mucosa-
associated lymphoid tissue (MALT
lymphoma)
 immunosuppression, AIDS, primary
immune disorders
Risk factors for NHL
 immunosuppression or
immunodeficiency
 connective tissue disease
 family history of lymphoma
 infectious agents
 ionizing radiation
NHL:Pathophysiology
 Most (80 to 85%) NHLs arise from B
cells; the remainder arise from T cells or
natural killer cells
Classification
 Rappaport classification
 Lukes-Collins classification
 International Working Formulation
 based almost entirely on morphologic criteria
 Revised European American Classification
(REAL)
 WHO classification, 2000 (most recent)
NHL: WHO Classification
B-cell neoplasms T- and NK-cell neoplasms
Precursor B-cell neoplasm Precursor T-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma
(precursor B-cell acute lymphoblastic leukemia)
Precursor T-lymphoblastic lymphoma/leukemia
(precursor T- cell acute lymphoblastic leukemia)
Mature (peripheral) B-cell neoplasms Mature (peripheral) T-cell neoplasms
B-cell chronic lymphocytic leukemia/small
lymphocytic lymphoma
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemia
B-cell prolymphocytic leukemia Aggressive NK-cell leukemia
Lymphoplasmacytic lymphoma Adult T-cell lymphoma/leukemia
Splenic marginal zone B-cell lymphoma (with
or w/o villous lymphocytes)
(human T-cell lymphotropic virus type I positive)
Extranodal NK/T-cell lymphoma, nasal type
Hairy cell leukemia Enteropathy type T-cell lymphoma
Plasma cell myeloma/plasmacytoma Hepatosplenic gammadelta T-cell lymphoma
Extranodal marginal zone B-cell lymphoma of
mucosa- associated lymphoid tissue type
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides/Sezary syndrome
Nodal marginal zone B-cell lymphoma (with or
w/o monocytoid B cells)
Anaplastic large cell lymphoma, T/null-cell,
primary cutaneous type
Follicular lymphoma Peripheral T-cell lymphoma, not otherwise
Mantle cell lymphoma
Diffuse large B-cell lymphoma
characterized
Angioimmunoblastic T-cell lymphoma
Mediastinal large B-cell lymphoma
Primary effusion lymphoma
Anaplastic large cell lymphoma, T/null-cell,
primary systemic type
Burkitt's lymphoma/Burkitt's cell leukemia
WORKING FORMULATION
 Clinically very useful and practical
 Divides lymphomas into :
1. Low grade
2. Intermediate grade and
3. High grade NHL
based on aggressiveness
 Based on morphology (Architecture
and Cell size)
 Low grade /Indolent NHL
Are INCURABLE
 Intermediate /High Grade
Are more “Aggressive” but potentially
CURABLE!
NHL: Diagnosis
 immunophenotyping (flow cytometry) and
cytogenetics
 Bone Marrow Biopsy
 CT scan of chest, abdomen and pelvis
 Lumbar Puncture if
CNS symptoms or aggressive
lymphoma with bone marrow
involvement
 peripheral blood
Diagnosis of NHL
 Biopsy of lymph node is preferred to
show nodal architecture (follicular region
vs. diffuse).
 Flow cytometry:
 CD 19, CD20 for B cell lymphomas
 CD 3, CD 4, CD8 for T cell lymphomas
NHL:Clinical manifestations
 Variable
 severity: asymptomatic to extremely ill
 time course: evolution over weeks, months, or
years
 Systemic manifestations
 fever, night sweats, weight loss, anorexia,
pruritis
 Local manifestations
 lymphadenopathy, splenomegaly most common
 any tissue potentially can be
infiltrated
NHL: Staging Ann Arbor Staging
System
 I :indicates that the cancer is located in a single
region, usually one lymph node and the
surrounding area
 II :indicates that the cancer is located in two
separate regions, an affected lymph node or
organ and a second affected area, and that both
affected areas are confined to one side of the
diaphragm - that is, both are above the
diaphragm, or both are below the diaphragm.
 III: Involvement above and below diaphragm
 IV: Diffuse or disseminated involvement of 1 or
more extralymphatic tissues or organs
 (A= Absence of systemic symptoms, B= Presence
of B symptoms)
Staging of lymphoma
Stage I Stage II Stage III Stage IV
NHL: Ann Arbor Staging System
 Suffix ‘A’ means absence of B symptoms
 Suffix ‘B’ means presence of B symptoms
 Suffix ‘E’ means extra nodal (not in
the lymph nodes) disease
 Suffix ‘S’ means splenic involvement
 Suffix ‘X’ means bulky disease argest
deposit is >10 cm large
 For example: Stage IIIB-S means disease
above and below the diaphragm, with B
symptoms and Splenic involvement
NHL: Two most common
subtypes
 Diffuse Large Cell
Lymphoma 39%
 Follicular Lymphoma
21%
Follicular lymphoma
 most common type of “indolent” lymphoma
 lymphoma of follicle center B-cells (centrocytes and
centroblasts),
 usually widespread at presentation
 often asymptomatic
 not curable
 cell of origin: germinal center B-cell
 Prefer treatment if asymptomatic (“watch-and-wait”)
 several chemotherapy options if symptomatic
 median survival: years
 although considered “indolent”, morbidity and mortality
can be considerable
 transformation to aggressive lymphoma can occur
NHL :
Diffuse large cell Lymphoma
 Commonest subtype
 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%
Treatment: Diffuse large cell
Lymphoma
 Limited stage (I or II) Non bulky:
Combination of abbreviated chemotherapy (3-
4 cycles of CHOP) and radiation
 Advanced Stage (III or IV) or bulky disease:
Full 6-8 cycles of chemoRx with additional
XRT to bulky areas
 Rituximab
 Chemotherapy regimen is CHOP:
Cyclophosphamide, Hydroxydoxorubicin,
Oncovin and Prednisone)
Other Important
Non Hodgkins Lymphomas
 Mantle Cell Lymphoma: due to CD5 positive
antigen-naive pregerminal center B-cell within the mantle
zone that surrounds normal germinal center follicles
 comprising about 6% of NHL cases
 subtype of B-cell lymphoma essentially is an
abnormal break and subsequent translocation in
a gene that causes the cells to divide too early
before becoming capable of helping to fight
diseases
 do not die as they should
 therefore accumulate in the lymphoid system
Burkitt’s Lymphoma
 African variety: jaw tumor, strongly linked
to Epstein-Barr Virus infection.
 Most rapidly growing human tumor.
 associated with a chromosomal
translocation of thec-myc gene. This
gene is found at 8q24.
Classification:Burkitt’s Lymphoma
 endemic variant occurs in equatorial
Africa. It is the most common malignancy
of children in this area
 involves the jaw or other facial bone,
distal ileum, cecum, ovaries, kidney or
the breast.
 Sporadic type of Burkitt lymphoma -(also
known as "non-African") is another form
of non-Hodgkin lymphoma found outside
of Africa.
 jaw is less commonly involved
 Immunodeficiency-associated Burkitt
lymphoma is usually associated
with HIV infection

or occurs in the setting
of post-transplant patients who are taking
immunosuppressive drugs. Burkitt
lymphoma can be one of the diseases
associated with the initial manifestation
of AIDS.
Microscopic exam
 tumor consists of population of medium
size lymphoid cells with high proliferative
activity and apoptotic activity. The "starry
sky" appearance
 Gastric MALT Lymphoma: form
of lymphoma involving the mucosa-
associated lymphoid tissue (MALT),
frequently of the stomach, but virtually
any mucosal site can be afflicte
 associated with chronic inflammation as a
result of the presence of Helicobacter pylori
 treatment with antibiotic eradication of H.
pylori
 Small Lymphocytic lymphoma and
Chronic Lymphocytic Leukemia: is a
type of non-Hodgkin lymphoma
characterized by an excess of white
blood cells in the lymph nodes.
When cancer cells are found in the blood
and bone marrow the disease is called
chronic lymphocytic leukemia (CLL).
 is very indolent but relentless, with
median survivals of almost a decade.
 predominantly in older individuals.
Mycosis Fungoides
 Malignancy of helper T cells.
 Affinity for skin.
 Can be treated with electron beam
radiation, ultraviolet light, or topical
alkylating
Summary
NON HODGKINS LYMPHOMA
 Extremely heterogenous group of
disease
 WHO classification is probably going to
stay
 Indolent NHL : Slow growing but
incurable
 Aggressive NHL: Faster growing
but/therefore potentially curable
 Follicular NHL: Commonest indolent
type
 DLCL: Commonest aggressive type
THANKYOUU… 
questions
Which type of lymphoma has no
Reed-Sternberg Cell upon
microscopic examination?
a.Hodgkin’s lymphoma
b.Non- Hodgkin’s lymphoma
2.Which type of lymphoma occurs at a
higher percentage than the other?
a.Hodgkin’s lymphoma
b.Non- Hodgkin’s lymphoma
3. Which cell type comprises more than
80 % in NHL?
a. B cell
b. T cell
4. Most common type of “indolent”
lymphoma
a. Diffuse large cell Lymphoma
b. Follicular lymphoma
c. Mantle Cell Lymphoma
d. None of the above
5. Most common type of “aggressive”
lymphoma
a. Diffuse large cell Lymphoma
b. Follicular lymphoma
c. Mantle Cell Lymphoma
d. None of the above

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