Diseases of White

Blood Cells

DAVID WEHBE M.D

Hemato-Onco
Balamand University
White Cell Maturation
 Leucocytes (white blood cells)
• Phagocytes
- Granulocytes
.Neutrophils
.Eosinophils
.Basophils
- Mononuclear phagocytic cells
.Monocytes
• Lymphocytes
- B cells & T cells
PB Neutrophils
PB Staff
PB Basophils
PB Eosinophils
PB Monocytes
PB Lymphocytes
 White Blood Cell Disorders
Classification :

-Disorders of cell number, Terminology:

.cytosis/philia (increase in number)
.cytopenia (decrease in number)

-Disorders of function & morphology

Normal Total Leucocytic Count

For an adult ( male or female)

Normal reference range:
4,000 – 11,000 / cmm
 Relative vs Absolute values
• Total White Blood Cell Count (TWBC)
• Differential count : gives the relative
percentage of each white blood cell.
• Absolute value : gives the actual
number of each white blood cell/cmm.
Calculation
Absolute Count = TWBC x Percent
eg: If TWBC = 6,000 /cmm
Neutrophils = 60 %
So Absolute neutrophilic count =
6,000 x 60 / 100 = 3,600 /cmm
 Categories

Disorders of white blood cells can be

classified into two broad categories:
proliferative disorders, in which there is an
expansion of leukocytes, and leukopenias,
which are defined as a deficiency of
leukocytes.
 Disorders of Cell Number
• Leucocytosis :
an increased number of leucocytes
in the peripheral blood >11,000 /cmm
• Leucopenia :
a reduced white cell count
( < 4,000 /cmm )
 Categories

• Proliferations of white cells can be reactive or

neoplastic.
• Since the major function of leukocytes is host
defense, reactive proliferation in response to an
underlying primary, often microbial, disease is
fairly common. Neoplastic disorders, although
less frequent, are much more important
clinically.
 Leukopeni
a
• The number of circulating white cells
may be markedly decreased in a variety
of disorders.
• An abnormally low white cell count
(leukopenia) usually results from
reduced numbers of neutrophils
(neutropenia, granulocytopenia).
 Leukopeni
a
• Lymphopenia is less common; in addition to
congenital immunodeficiency diseases, it is
most commonly observed in specific settings,
such as advanced HIV infection, following
therapy with glucocorticoids or cytotoxic
drugs, autoimmune disorders, malnutrition,
and certain acute viral infections.
 Pathogenesis.
• A reduction in circulating granulocytes will
occur if there is
(1)reduced or ineffective production of
neutrophils or
(2)accelerated removal of neutrophils
from the circulating blood.
 Pathogenesis.
• (1) Inadequate or ineffective granulopoiesis
is observed in the setting of:
• 1. Suppression of myeloid stem cells, as
occurs in aplastic anemia and a variety of
infiltrative marrow disorders (tumors,
granulomatous disease, etc.);
In these conditions, granulocytopenia is
accompanied by anemia and
thrombocytopenia.
 Pathogenesis.

• 2. Suppression of committed granulocytic

precursors due to exposure to certain drugs.
Drugs are responsible for most of the
significant neutropenias . Certain drugs, such
as alkylating agents and antimetabolites used
in cancer treatment, produce agranulocytosis in
a predictable, dose-related fashion.
Because such drugs cause a generalized
suppression of the bone marrow, production of
erythrocytes and platelets is also affected
 Pathogenesis.
• 3. Disease states associated with ineffective
granulopoiesis, such as megaloblastic
anemias due to vitamin B12 or folate
deficiency and myelodysplastic syndromes,
where defective precursors are susceptible to
death in the marrow.
• 4. Rare inherited conditions (such as
Kostmann syndrome) in which genetic
defects in specific genes result in impaired
granulocytic differentiation.
 Pathogenesis.

• (2) Accelerated removal or destruction of

neutrophils occurs with
• 1. Immunologically mediated injury to the
neutrophils, which may be idiopathic,
associated with a well-defined
immunologic disorder (e.g., systemic
lupus erythematosus), or produced by
exposure to drugs.
 Pathogenesis.

• 2. Splenic sequestration, in which

excessive destruction occurs secondary
to enlargement of the spleen, usually
associated with increased destruction of
red cells and platelets as well.
• 3. Increased peripheral utilization, as
may occur in overwhelming bacterial,
fungal, or rickettsial infections.
 Morphology

Bone marrow:
• The anatomic alterations in the bone marrow
vary according to the underlying cause.

• When neutropenia is caused by excessive

destruction of mature neutrophils, the marrow
is usually hypercellular owing to the
presence of increased numbers of
granulocytic precursors.
Morphology
Bone marrow:
•Hypercellularity is also the rule in
neutropenias associated with ineffective
granulopoiesis, as occurs in megaloblastic
anemias and myelodysplastic syndromes.

•Agranulocytosis caused by agents that

suppress or destroy granulocytic precursors is
understandably associated with marrow
hypocellularity.
 Clinical Course
• The symptoms and signs of neutropenias
are related to bacterial or fungal infections.
They include malaise, chills, and fever,
followed in sequence by marked weakness
and fatigability.
• In severe agranulocytosis with virtual
absence of neutrophils, these infections can
be overwhelming and cause death within a
few days.
 Clinical Course

• A neutrophil count of less than 1000

cells per mm3 of blood is worrisome, but
most serious infections occur with counts
below 500 per mm3.
• Because infections are often fulminant,
broad-spectrum antibiotics are given
expeditiously whenever signs or
symptoms appear.
 Clinical Course

• In some instances, such as following

myelosuppressive chemotherapy,
neutropenia is treated with granulocyte
colony-stimulating factor (G-CSF), a
growth factor that stimulates the
production of granulocytes from marrow
precursors
 Reactive Proliferations of
White Cells
• Definition: Leukocytosis refers to an
increase in the number of blood
leukocytes.
• It is a common reaction to a variety of
inflammatory states and is sometimes the
first indication of neoplastic growth of
leukocytes
 Pathogenesis

• The peripheral blood leukocyte count is

influenced by several factors, including:
• 1. The size of the myeloid (for
granulocytes and monocytes) and
lymphoid (for lymphocytes) precursor and
storage cell pools in the bone marrow,
circulation, and peripheral tissues.
 Pathogenesis

• 2. The rate of release of cells from the

storage pool into the circulation
• 3. The proportion of cells that are adherent
to blood vessel walls at any time
• 4. The rate of extravasation of cells from
the blood into tissues
 Pathogenesis

• leukocyte homeostasis is maintained by

cytokines, growth factors, and adhesion
molecules through their effects on the
commitment, proliferation, differentiation,
and extravasation of leukocytes and
their progenitors.
 Pathogenesis
• In acute infection, there is a rapid increase in the
egress of mature granulocytes from the bone
marrow pool.
• The release of IL-1, TNF, and other inflammatory
cytokines stimulates bone marrow stromal cells and
T cells to produce increased amounts of colony-
stimulating factors (CSFs), which enhance the
proliferation and differentiation of committed
granulocytic progenitors and, over several days,
cause a sustained increase in neutrophil production
 Pathogenesis

• Other growth factors preferentially stimulate

other types of leukocytosis.
• For example, IL-5 causes eosinophilia by
enhancing the growth, survival, and
differentiation of eosinophils, while IL-7 plays
a central role in lymphopoiesis.
• Such factors are differentially produced in
response to various pathogenic stimuli
 Causes of Leukocytosis
Neutrophilic Acute bacterial infections, especially
leukocytosis those caused by pyogenic
organisms; sterile
inflammation(myocardial infarction,
burns)
Eosinophilic Allergic disorders such as asthma,
leukocytosis allergic skin diseases; parasitic
(eosinophilia infestations; drug reactions; certain
) malignancies (e.g., Hodgkin disease
and some non-Hodgkin lymphomas);
collagen vascular disorders and some
vasculitides; atheroembolic disease
Basophilic Rare, often indicative of a
leukocytosis myeloproliferative disease (e.g.,
(basophilia) chronic myelogenous leukemia)
Monocytosis Chronic infections (e.g., tuberculosis),
bacterial endocarditis and malaria;
collagen vascular diseases (e.g.,
systemic lupus erythematosus) and
inflammatory bowel diseases (e.g.,
ulcerative colitis)
Lymphocytosis Accompanies monocytosis in many
disorders associated with chronic
immunologic stimulation (e.g.,
tuberculosis); viral infections (e.g.,
hepatitis)
 Neutrophilia

Definition :
Increase in the number of neutophils
and/or its precursors > 7,000/cmm
 Causes of Neutrophilia
• Infections (pyogenic bacteria)
• Inflammations produced by :
Toxins,infectious agents,neoplasms
or burns .
• Following haemorrhage.
Reactive changes :
Left shift , toxic granulation , high LAP score.
 Causes of Neutrophilia (cont.)
• Chronic granulocytic leukaemia
• Other myeloproliferative disorders
Diagnosis :
Low LAP score .
Philadelphia chromosome .
PB Neutrophilia
Left Shift
Left Shift
 Eosinophilia
• Definition :
An increase in the total number of
eosinophils in the peripheral blood
more than 400/cmm .
If eosinophilic count is > 600/cmm
further investigations are required.
 Causes of Eosinophilia
• Allergy
Atopic ,drug sensitivity & pulmonary
eosinophilia .
• Infections
Parasites ,recovery from infection
• Malignancy
Hodgkin’s disease , NHL & MPD
• Skin disorder
• Drugs
• GIT disorders
• Hypereosinophilic syndrome
Eosinophilia
 Basophilia
• Definition
Increased basophils in the peripheral
blood > 100/cmm
- Most commonly associated with:
.Hypersensitivity reactions to drugs or food
.Inflammatory conditions e.g RA,ulcerative
colitis.
.Chronic myeloid leukaemia & MPD
Basophilia
 Lymphocytosis

• Definition :
An increase above normal in the number
of circulating lymphocytes ( > 4,000/cmm)
 Causes of Lymphocytosis
• Acute infections: Infectious mononucleosis,
acute infectious lymphocytosis,mumps,
rubella,pertussis .
• Chronic infections: tuberculosis,syphilis,
brucellosis,infectious hepatitis .
• Thyrotoxicosis (usually only relative)
• Chronic lymphocytic leukaemia
Lymphocytosis
 Infectious Mononucleosis
• Caused by Epstein-Barr Virus (EBV)
• Blood picture shows leucocytosis with
absolute lymphocytosis and increased
number of atypical lymphocytes .
• Diagnosis :
- Monospot test .
- EBV serology .
Infectious Mononucleosis
 Monocytosis
• Definition :
A monocytosis is present when the
peripheral monocyte numbers rise
above 800/cmm .
 Causes of Monocytosis
• Chronic bacterial infections :
tuberculosis,bacterial endocarditis,
brucellosis.
• Other infections :malaria,Kala-azar,
trypanosomiasis,typhus……..
• Hodgkin’s disease .
• Monocytic & myelomonocytic leukaemia
Monocytosis
 Pathogenesis
• In most instances, it is not difficult to
distinguish reactive leukocytosis from
leukocytosis caused by flooding of the
peripheral blood by neoplastic white blood
cells (leukemia).
• Uncertainties may arise in two settings:
• 1. Particularly in children, acute viral infections
can produce the appearance of activated
lymphocytes in the peripheral blood and
marrow that resemble neoplastic lymphoid
cells.
 Pathogenesis

• 2. At other times, particularly in

inflammatory states and severe chronic
infections, many immature granulocytes
appear in the blood, simulating a picture of
myelogenous leukemia (leukemoid
reaction).
• Special laboratory studies (Flow Cytometry)
are helpful in distinguishing reactive and
neoplastic leukocytoses.
 Neoplastic Proliferations of
White Cells

• Malignant proliferative diseases constitute

the most important disorders of white cells.
• These diseases can be classified into
several categories:
• 1. Lymphoid neoplasms
• 2. Myeloid neoplasms
• 3. histiocytoses
 Categories
• Myeloid neoplasms arise from hematopoietic stem
cells that give rise to cells of the myeloid (i.e.,
erythroid, granulocytic, and/or thrombocytic) lineage.
Three categories of myeloid neoplasia are recognized:
1. acute myelogenous leukemias, in which
immature progenitor cells accumulate in the bone
2. marrow;
myelodysplastic syndromes, which are
associated with ineffective hematopoiesis and
resultant peripheral blood cytopenias;
3. chronic myeloproliferative disorders, in which
increased production of one or more terminally
differentiated myeloid elements usually leads to
elevated peripheral blood counts.
 Categories
• Lymphoid neoplasms encompass a
diverse group of entities. In many but not
all instances, the phenotype of the
neoplastic cell closely resembles that of a
particular stage of normal lymphocyte
differentiation, a feature that is used in the
diagnosis and classification of these
disorders.
 Categories

• The histiocytoses are uncommon proliferative

lesions of macrophages and dendritic cells.
• "histiocyte" is often applied to cells of macrophage
or dendritic-cell lineage.
• A special category of immature dendritic cells
referred to as Langerhans cells gives rise to a
spectrum of neoplastic disorders, some of which
behave as disseminated malignant tumors, and
others as localized benign proliferations. This
group is called Langerhans cell histiocytoses.
 Etiology and pathogenesis
1. Chromosomal translocations and
oncogenes. Non random chromosomal
abnormalities, most commonly
translocations, are present in the majority
of white cell neoplasms. Many specific
rearrangements are associated with
particular neoplasms, suggesting a
critical role in their genesis.
 Etiology and pathogenesis
• Chromosomal translocations frequently
occur in myeloid neoplasms
 Etiology and pathogenesis
• 2. Inherited genetic factors：individuals
with genetic diseases that promote
genomic instability.
• telangiectasia, are at increased risk for
development of acute leukemia. In
addition, both Down syndrome (trisomy 21)
and neurofibromatosis type I are
associated with an increased incidence of
childhood leukemia.
 Etiology and pathogenesis
3. Viruses.
Three viruses-human T-cell leukemia
virus-1 (HTLV-1), Epstein-Barr virus (EBV),
and Kaposi sarcoma herpesvirus/human
herpesvirus-8 (KSHV/HHV-8) have been
implicated as causative agents.
 Etiology and pathogenesis
• HTLV-1 has been associated only with adult T-
cell leukemia/lymphoma.
• EBV genomes are found in the tumor cells of a
subset of Burkitt lymphoma, 30% to 40% of
cases of Hodgkin lymphoma, many B-cell
lymphomas occurring in the setting of T-cell
immunodeficiency, and rare natural killer cell
lymphomas.
• KSHV is uniquely associated with an unusual
type of B-cell lymphoma that presents as a
malignant effusion, often in the pleural cavity.
 Etiology and pathogenesis

• 4. Environmental agents.

• The most clear-cut associations are

those of Helicobacter pylori infection with
gastric B-cell lymphoma and gluten-
sensitive enteropathy with intestinal T-cell
lymphoma.
 Etiology and pathogenesis

• 5. Iatrogenic factors.
• Radiotherapy and certain forms of
chemotherapy used to treat cancer
increase the risk of subsequent myeloid
and lymphoid neoplasms.
• This association is believed to stem
from mutagenic effects of ionizing
radiation and chemotherapeutic drugs
on hematolymphoid progenitor cells.
 Myeloid neoplasm
• The common feature that unites this
heterogeneous group of neoplasms is an
origin from hematopoietic progenitor
cells capable of giving rise to terminally
differentiated cells of the myeloid series
(erythrocytes, granulocytes, monocytes,
and platelets).
 categories
• Acute myelogenous leukemias,
characterized by the accumulation of immature
myeloid forms in the bone marrow and the
suppression of normal hematopoiesis
• Myelodysplastic syndromes, associated with
ineffective hematopoiesis and associated
cytopenias
• Chronic myeloproliferative disorders, usually
associated with an increased production of
terminally differentiated myeloid cells
 Acute myelogenous leukemias
• Acute myelogenous leukemias affect
primarily adults, peaking in incidence
between the ages of 15 and 39 years, but
are also observed in older adults and
children.
• AML is quite heterogeneous, reflecting the
complexities of myeloid cell differentiation
 Pathophysiology
• Most AMLs are associated with acquired
genetic alterations that inhibit terminal myeloid
differentiation. As a result, normal marrow
elements are replaced by relatively
undifferentiated blasts exhibiting one or more
types of early myeloid differentiation.
• The replication rate of these blasts is actually
lower than that of normal myeloid progenitors,
highlighting the pathogenic importance of
blocked maturation and increased survival.
 Pathophysiology
• In all AMLs, the accumulation of proliferating
neoplastic myeloid precursor cells in the
marrow suppresses remaining normal
hematopoietic progenitor cells by physical
replacement as well as by other unknown
mechanisms.
• The failure of normal hematopoiesis results in
anemia, neutropenia, and thrombocytopenia,
which cause most of the major clinical
complications of AML.
 Pathophysiology

• Therapeutically, the aim is to clear the bone

marrow of the leukemic clone, thus permitting
resumption of normal hematopoiesis. This
can be accomplished by treatment with
cytotoxic drugs or, in the specific case of
acute promyelocytic leukemia, by overcoming
the block in differentiation with pharmacologic
doses of retinoic acid.
Chromosomal Abnormalities

• Particular chromosomal abnormalities

correlate with the clinical setting in
which the tumor occurs. AML arising de
novo in patients with no risk factors are
often associated with balanced
chromosomal translocations,
particularly t(8;21), inv(16), and
t(15;17).
 Chromosomal Abnormalities

• In contrast, AMLs following

myelodysplastic syndromes or exposure
to DNA-damaging agents (such as
chemotherapy or radiation therapy) are
commonly associated with deletions or
monosomies involving chromosomes 5
and 7 and usually lack chromosomal
translocations.
 Classification
• In the most widely used system in current use, the
revised FAB, AML is divided into eight (M0 to M7)
categories.
• This scheme takes into account both the degree
of maturation (M0 to M3) and the lineage of the
leukemic blasts (M4 to M7).
• Histochemical stains for peroxidase, specific
esterase, and nonspecific esterase, and
immunostains for myeloid specific antigens play
important roles in defining the type of myeloid
differentiation that blasts exhibit.
 French-American-British (FAB) Classification of AML
FAB Approximate % of
subtype Name adult patients Prognosis
M0 Undifferentiated acute 5% Worse
myeloblastic leukemia
M1 Acute myeloblastic 15% Average
leukemia with minimal
maturation
M2 Acute myeloblastic 25% Better
leukemia with maturation
M3 Acute promyelocytic 10% Best
leukemia
M4 Acute myelomonocytic 20% Average
leukemia
M4 eos Acute myelomonocytic 5% Better
leukemia with eosinophilia
M5 Monocytic leukemia 10% Average
M6 Acute erythroid leukemia 5% Worse
M7 Acute megakaryoblastic 5% Worse
leukemia
Morphology

• The diagnosis of AML is based on

finding that myeloid blasts make up
more than 20% of the cells in the
marrow
Diffuse replacement of normal haematopoiesis
in bone marrow by leukemic cells
Morphology

Myeloblasts have :
• delicate nuclear chromatin.
• two to four nucleoli.
• and more voluminous cytoplasm than
Lymphoblasts.
• The cytoplasm often contains fine,
azurophilic ,peroxidase-positive granules.
Morphology

• Distinctive red-staining peroxidase-

positive structures called Auer rods,
which represent abnormal azurophilic
granules, are present in many cases and
are particularly numerous in acute
promyelocytic leukemia.
• The presence of Auer rods is taken to be
definitive evidence of myeloid
differentiation.
Morphology
• Monoblasts often have folded or
lobulated nuclei, lack Auer rods, and are
peroxidase negative and nonspecific
esterase positive.
• In some AMLs, blasts exhibit
megakaryocytic differentiation, which is
often accompanied by marrow fibrosis
caused by the release of fibrogenic
cytokines.
• Rarely, the blasts of AML show evidence
of erythroid differentiation (erythroblasts)..
Morphology
• The number of leukemic cells in the
peripheral blood is highly variable. Blast
counts can be more than 100,000 cells
per microliter but are under 10,000 cells
per microliter in about 50% of the patients.
• Occasionally, the peripheral smear
might not contain any blasts
(aleukemic leukemia). For this reason,
bone marrow examination is essential to
exclude acute leukemia in pancytopenic
patients.
 Acute
myelogenous
leukemia
(FAB M1
subtype).

• Myeloblasts have delicate nuclear chromatin,

prominent nucleoli, and fine azurophilic
granules in the cytoplasm
 Acute
promyelocytic
leukemia
(FAB M3
subtype).

• Bone marrow aspirate shows neoplastic promyelocytes with

abnormally coarse and numerous azurophilic granules. Other
characteristic findings include the presence of several cells
with bilobed nuclei and a cell in the center of the field that
contains multiple needlelike Auer rods
 Acute
monocytic
leukemia
(FAB M5b
subtype).

• Peripheral smear shows one monoblast and

five promonocytes with folded nuclear
membranes
 Clinical Features
• Most patients present within weeks or a
few months of the onset of symptoms
related to anemia, neutropenia, and
thromobocytopenia, most notably fatigue,
fever, and spontaneous mucosal and
cutaneous bleeding.
•
 Clinical Features
• Often, the bleeding diathesis caused by
thrombocytopenia is the most striking clinical
feature. Cutaneous petechiae and
ecchymoses, serosal hemorrhages into the
linings of the body cavities and viscera, and
mucosal hemorrhages into the gingivae and
urinary tract are common. Procoagulants
and fibrinolytic factors released by leukemic
cells, especially in acute promyelocytic
leukemia (M3), exacerbate the bleeding
diathesis.
Cutaneous petechiae and ecchymoses
 Clinical Features

• Infections are frequent, particularly in the

oral cavity, skin, lungs, kidneys, urinary
bladder, and colon, and are often caused by
opportunists such as fungi, Pseudomonas,
and commensals.
 Clinical Features
• Signs and symptoms related to infiltration of
tissues are usually less striking in AML.
• Mild lymphadenopathy and organomegaly
can occur. In tumors with monocytic
differentiation (M4 and M5), infiltration of the
skin (leukemia cutis) and the gingiva can be
observed, likely reflecting the normal
tendency of non-neoplastic monocytes to
extravasate into tissues
 Clinical Features
• Central nervous system spread is less
 common than in ALL but still seen.
• Quite uncommonly, patients present with
localized masses composed of myeloblasts in the
absence of marrow or peripheral blood
involvement. These tumors, known variously as
myeloblastomas, granulocytic sarcomas, or
chloromas, inevitably progress to systemic AML
over a period of up to several years.
 Prognosis
• AML is a difficult disease to treat.
• Approximately 60% of the patients achieve
complete remission with chemotherapy,
but only 15% to 30% remain free from
disease for 5 years.
• AMLs associated with t(8;21) or inv(16)
have a relatively good prognosis with
conventional chemotherapy.
 Prognosis
• In contrast, the prognosis is dismal for
patients with AML with prior
myelodysplastic syndrome or following
genotoxic therapy, possibly because of
damage to normal hematopoietic stem
cells. These "high-risk" forms of AML, as
well as relapsed AML of all types, are
increasingly being treated with allogeneic
bone marrow transplantation.
 NONMALIGNANT LEUKOCYTE
DISORDERS
– Congenital qualitative or quantitative disorders

–may affect both T and B cells or only one cell type.

Most will severely compromise the immune system
• Severe combined immunodeficiency system (SCIDS)
– This is a heterogenous group of disorders in which both B
and T cells are profoundly deficient
– In some cases there is no rearrangement of the B cell and
T cell receptor genes to produce immunocompetent cells
– A bone marrow transplant or gene therapy are the only
effective treatments
 NONMALIGNANT LEUKOCYTE
DISORDERS
• Wiskott-Aldrich Syndrome
– Is a sex-linked progressive disorder characterized by
» Eczema
» Thrombocytopenia
» Immunodeficiency due to progressive decrease in T cell
immunity
» There is also an intrinsic B lymphocyte abnormality
resulting in an inability to respond to polysaccharide
antigens
» Most children die before the age of 10 from bleeding and
infections
» Treatment is a bone marrow transplant
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