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LEUKOCYTE NEOPLASMS Comparison of acute and chronic leukemias

Duration
WBC NEOPLASM ❖ Acute leukemias – survival is weeks to months
❖ Most are acquired genetic diseases, which means without treatment. Death due to infection and
that most patients are not born with it, they acquire bleeding
it later ❖ Chronic leukemias – survival is years without
❖ Most are not localized (except for true lymphomas); treatment
they are systemic in
nature (quickly metastatic) Predominant cell type
❖ Arises from either the Bone marrow or in the ➢ Acute – immature/blast cells
Lymphatic system predominate
❖ Most treatments are also designed to cure ■ In AML, many myeloblasts
systemically ■ In ALL, many lymphoblasts
❖ The term leukemia is more appropriately applied ➢ Chronic – maturing cells predominate
when the source of the neoplasm is the bone ■ In CML, many granulocytes
marrow. Lymphoma is applied when the source of ■ In CLL, many lymphocytes
the neoplasm is lymphoid tissue. ➢
Clinical manifestations and lab findings:
Etiology of leukocyte neoplasms ❖ Acute
● Most causes are unknown ➢ sudden onset, affects all ages
● Several known causes are: ➢ Weakness and fatigue due to anemia
○ Environmental toxins ➢ Petechiae, purpura due to low platelets
○ Certain viruses ➢ Infection due to neutropenia
○ Familial disposition ➢ Variable leukocyte count
○ Chemotherapeutic agents ❖ Chronic
➢ frequently asymptomtomatic initially; affects
Classification schemes of Leukocyte neoplasms adults
● Two major classifications: ➢ Anemia mild or absent
○ French-American-British classification ➢ Normal to slightly increased platelet count
○ WHO classification ➢ WBC count is usually high
● FAB classification was the traditional classification
but it heavily focused on morphological differences, WBC ABNORMALITIES
which may lead to misdiagnosis. They are of
common use in the classification of acute MORPHOLOGIC ABNORMALITIES OF
leukemias GRANULOCYTES
● The WHO classification, released on 2001,
attempts to standardize the classification of
Hyposegmentation
leukemia by combining morphological differences
❖ Decreased segmentation of nucleus
with genetic findings for proper diagnosis of
❖ Seen in Pelger-Huet anomaly
leukemia.
❖ Seen in Pseudo-Pelger-Huet
Classification of leukemias
● Leukemias can either be classified as:
○ Myeloid/Myelocytic- Leukemia that affects
the Myelocytic cell lines (Granulocytic,
Megakaryocytic, and Rubriblastic cell lines)
○ Lymphoid/Lymphoblastic- Leukemia that
affects the lymphoid cell lines

● They can also be classified as either: Hypersegmentation

○ Acute ❖ Neutrophils with >5 lobes
○ Chronic ❖ Seen in disorders of nuclear maturation, such as
the megaloblastic anemias

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Auer Rods
Chediak-Higashi granules
❖ Elongated, bluish-red rods composed of fused
❖ Giant, red, blue to grayish round inclusions
lysosomal granules (primary granules)
❖ Seen in lymphocytes, Neutrophils, and monocytes
❖ Seen in the cytoplasm of myeloblasts,
❖ Found in Chediak-Higashi syndrome
promyelocytes and monoblasts and in patients with
acute myelogenous leukemia

Alder-Reilly granules
Dohle bodies ❖ Large purple-black coarse cytoplasmic granules
❖ Appear as a small, light blue-gray staining area in ❖ Accumulation of degraded mucopolysaccharides
the cytoplasm of the neutrophil ❖ Found in all leukocytes
❖ Aggregates of free ribosomes of the rER ❖ Commonly found in Alder-Reilly anomaly
❖ Found in poisoning, infections, and following ❖ Mucopolysaccharidoses (Hurler’s)
chemotherapy.

Toxic granules/vacuoles
Atypical Lymphocytes ❖ Large, purple to black azurophilic granules
❖ Atypical, or reactive, lymphocytes are lymphocytes ❖ These are primary granules
that, as a result of antigen stimulation, have ❖ They are seen during excess proliferation
become quite large ❖ Infections
❖ Causes of reactive lymphocytosis may be: ❖ Burns
➢ Cytomegalovirus ❖ Malignancy
➢ Drugs ❖ Chemical poisoning
➢ Epstein-Barr virus (infectious
mononucleosis)
➢ Syphilis
➢ toxoplasmosis
➢ viral hepatitis

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Smudge Cells and Basket Cells

❖ Smudge cells or basket cells are leukocytes that
have been damaged during preparation of the
peripheral blood smear Sѐzary cell
❖ Degenerated nuclear material ● Round lymphocytes with nucleus that is grooved or
❖ Usually occurs due to the fragility of the cell convoluted
❖ Usually seen in chronic lymphocytic leukemia (CLL) ● Seen in Sezary syndrome and Mycosis Fungoides

LE cell Flame cell

❖ Neutrophil with large purple homogenous round ● Plasma cell with red to pink cytoplasm
inclusions (with neutrophils) ● Associated with increase Immunoglobulins
❖ Seen in Lupus Erythematosus ● Found in multiple myeloma

Grape cell/Mott cell

MORPHOLOGIC ABNORMALITIES OF LYMPHOCYTES
● Plasma cell that contains small colorless vacuoles
(Russel Bodies)
Hairy Cells ● Large protein globules giving the appearance of
● Characterized by their fine, irregular pseudopods grapes
and immature nuclear features ● Seen in Multiple myeloma and reactive states of
● Seen only in hairy cell leukemia lymphocytes

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AML without maturation(M1)

MYELOPROLIFERATIVE DISORDERS
● Shows >90% marrow blasts
● <10% granulocytic
ACUTE MYELOPROLIFERATIVE DISORDERS
CD Markers:
Acute Myeloid Leukemia
○ CD13
❖ Most common family of leukemias in children ○ CD34
younger than 1 year of age, but is rare in older ○ CD117
children and adolescents. It is the most common ● May have Auer rods that may stain positively with
leukemia found in adults MPO and SBB
❖ There is unregulated proliferation of the myeloid
stem cell. It is classified using morphology and
cytochemistry (FAB) Cytogenetics (WHO) and
CD markers
❖ Platelets, RBCs, granulocytes, and monocytes may
be affected

General clinical presentation:

● Fever, malaise, weight loss, petechiae,bruises, mild AML with maturation (M2)
hepatosplenomegaly ● Associated with t(8q;21q)
● Neutropenia, anemia, thrombocytopenia, but high ● >10% promyelocytes
WBC counts (although variable) ● <50% erythroid
● Many blast cells in the Bone marrow and Blood ● >10% granulocytic
● <20% monocytic
AML, Undifferetiated/Acute Undifferentiated Leukemia ● BM still >90% blasts
(M0) ● Auer rods usually (stain positively with MPO and
● >30% blasts SBB)
● Blasts nondescript with no granules in the CD markers
cytoplasm ○ CD13
Present CD markers: ○ CD33
○ CD13
○ CD33
○ CD34
○ CD 117
● Sains negative to most cytochemical stains (even
MPO and SBB)
● Constitutes <5% of AMLs

Acute Promyelocytic Leukemia (M3)

● >30-50% promyelocytes
● Associated with t(15;17) (q22;q12)

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● Faggot cells (bundles of Auer rods) are present; ○ M5b = Seen in middle-aged adults with
heavy azurophilic granulation is observed <80% in the bone marrow (promonocytes
● Positive stains: MPO, SBB, and Specific dominate)
esterase
Clinical symptoms:
● Severe bleeding, hepatomegaly, DIC
● It accounts for 5% of the AMLs

Acute Erythroleukemia/DiGuglielmo Leukemia (M6)

● >30% marrow myeloblasts
● >50% dysplastic marrow normoblasts
● Malignant Normoblasts are PAS-positive
Acute Myelomonocytic Leukemia/Naegeli Leukemia ● Myeloblasts are SBB and MPO positive
(M4) CD MARKERS:
● >20% of the cells are monocytic in origin ○ CD45
● >30% of the cells are myeloblasts ○ CD71 (RBC)
● Auer rods usually present ○ CD13
● Positive for SBB, MPO, Specific and Nonspecific ○ CD15,
esterase ○ CD33 (Myelocytic)
CD marker: ● Vacuolization may be seen
○ CD13
○ CD33
○ CD14
● Accounts for 30% of AMLs
M4Eo:
● a variant which presents with eosinophilia

Acute Megakaryocytic Leukemia (M7)

● Characterized by proliferation of megakaryoblasts
and atypical megakaryocytes in the bone marrow;
blasts may have cytoplasmic blebs
● Accounts for <1% of the AMLs
● Difficult to diagnose using cytochemistry
CD MARKERS:
Acute Monocytic Leukemia/Schilling Leukemia (M5) ○ CD41
● >30% monoblasts ○ CD42
● Accounts for 5-10% of AMLs ○ CD61 positive
Nonspecific esterase positive ● Can be associated with t(1;22)
○ CD11(c)
○ CD14 positive Other myeloid neoplasms
● Can be associated with t(9;11) Myeloid Sarcoma
● Two variants: ● Extramedullary proliferation of one or more cell
○ M5a = Seen in children with >80% of lineages that disrupts tissue architecture.
monoblasts in BM Myeloid proliferations related to Down Syndrome
● Most common is leukemia of megakaryocytic
lineage

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● There is increased incidence of AML in individuals Bone marrow aspiration

with trisomy 21 ● Hypercellular and shows an increased number of
Bilineage Leukemias myeloid cells, with a slightly higher percentage of
● Contain two cell populations. One expresses immature granulocytes than is present in
myeloid antigens while the other expresses peripheral blood, and megakaryocytes are more
lymphoid antigens numerous than usual
Biphenotypic leukemias ● Myeloid-erythroid (M:E) ratio can be as high as 25:1
● Occur when myeloid and lymphoid antigens are
expressed on the same cells. Patients with this
case have poor prognosis
CHRONIC MYELOPROLIFERATIVE DISORDERS
Chronic Myeloproliferative
Leukemias
● Characterized by hypercellular bone marrow,
erythrocytosis, granulocytosis, and thrombocytosis
● Defect in the myeloid stem cell
● All may terminate into acute leukemia
● Molecular diagnostic studies are helpful in
identifying oncogenes
Chronic Myelogenous Leukemia
● Stem cell disorder affecting the granulocytic,
monocytic, erythrocytic and megakaryocytic cell
lines (but primarily, the granulocytic cell line)
● Primarily a disease of adults, occurring between the
ages of 30 and 50
● Accounts for about 20% of all the leukemias
● Common clinical findings: Weight loss,
splenomegaly, fever, night sweats,
● and malaise
● It is associated with the BCR/ABL oncogene, and
the presence of the Philadelphia chromosome due
to t(q9;q22)
Leukocyte alkaline phosphatase (LAP) stain
Exams and tests ● LAP is decreased or absent in this disorder
● CBC ● It is imperative to differentiate CML with Leukemoid
● Bone marrow aspiration reaction, since both produces a high number of
● Leukocyte alkaline phosphatase (LAP) leukocytes during CBC
● Testing for the presence of the Philadelphia Philadelphia chromosome
chromosome ● In 90% of the cases, one arm of the chromosome
CBC pair number 22 is found to be translocated to
○ WBC count: 50 – 500 x 109/L chromosome 9 (Philadelphia chromosome)
● <10% myeloblasts are present in peripheral blood, ● Occurs in the eryhroid, granulocytic, monocytic and
and there is a complete spectrum of granulocytic megakaryocytic cells
cells from the myeloblasts to the mature neutrophil ● Patients with this disorders who are negative for the
with a predominance of neutrophil and myelocytes Philadelphia chromosome usually have a poorer
● Eosinophils and basophils are increased prognosis and do not respond particularly well to
● Percentage of monocytes may also show an chemotherapy
increase ● Chronic phase can last up to 5 years; accelerated
○ Mild normochromic anemia phase (blast crisis) ultimately leads to acute
○ Platelet count is usually increased, and leukemia in most patients.
large from of the platelets may be present,
as well as the megakaryocyte fragment

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Essential Thrombocythemia ● May proceed to multiple thrombosis

● Characterized by excessive proliferation of cells of Exams and tests
the megakaryocytic lineage ● CBC
● platelet count usually to levels greater than 1 ● Bone marrow biopsy
million/µL CBC
● Platelets appear large and morphologically ● Disease is characterized by an absolute increase in
abnormal the red blood cells, white blood cells and platelets
● Platelets are functionally abnormal ● Red blood cell count (7-10 x 1012/L) hemoglobin
● It must be differentiated from reactive (>20g/dL), hematocrit
thrombocytosis or Polycythemia vera ● (>60%). White blood cell count and platelet count
are increased
● Peripheral blood smear shows normocytic
normochromic red blood cells, moderate
anisocytosis, and slight polychromatophilia
● Reticulocyte count generally shows slight elevation,
although not usually over 4%
○ ESR is usually decreased
○ LAP is usually increased, which aids in the
distinguishing polycythemia vera from other
types of erythrocytosis
Bone marrow biopsy
● Hypercellular showing an overall increase in the
● Common consequences of ET are Vascular
granulocytic, erythroid, and megakaryocytic cells
occlusion (a lot of thrombus in here!) and
● Distribution, morphology and maturation of the
hemorrhage (due to defective platelets)
marrow cells are normal
● Mutation in the JAK2 V617F gene (present in
● Bone marrow iron stores are decreased or absent
50-60% cases)
from unknown blood losses and excessive
Polycythemia Vera
erythropoiesis
● Chronic myeloproliferatve disease of unknown ● Treatment of PCV = Therapeutic Phlebotomy,
origin that is found in patients over 60 years of age splenectomy, chemotherapy
● Malignant hyperplasia of the multipotential myeloid ● Life expectancy:
stem cells causes an increase in all cell lines; RBCs ○ 20 years after diagnosis
are the most affected. There is also ineffective Remember! It must be differentiated with other forms of
erythropoiesis polycythemia, such as:
● High blood viscosity can cause high blood
● Secondary Polycythemia
pressure, stroke, and heart attack
○ increased EPO (smoking, emphysema,
● Mutations in the JAK2 gene produces polycythemia
high altitude)
vera
● Relative (Pseduo-) polycythemia
○ Decreased plasma volume with a normal
RBC mass caused by dehydration
(diarrhea, diuretics, burns)
○ Normal EPO, increased Hgb and HCT
Chronic Idiopathic Myelofibrosis
● Primary myelofibrosis or agnogenic myeloid
metaplasia
● Characterized by fibrosis and granulocytic
hyperplasia of the bone marrow, with granulocytic
Common clinical findings: and megakaryocytic proliferation in the liver and
● Splenomegaly spleen
● Skin Plethora ● It is generally found in the middle aged or elderly
● Conjunctival plethora people
● Engorged vessels in the optic vessels
● May proceed to MI

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Common clinical symptoms:

● Bleeding due to abnormal platelets, extramedullary
hematopoiesis causes hepatosplenomegaly
● Other symptoms include:
○ night sweats
○ low-grade fever
○ weight loss
○ anorexia.
● Patients often complain of left upper quadrant
discomfort due to the enlarged spleen and liver
Exam and tests
● CBC
● Leukocyte alkaline phosphatase (LAP) stain
● Bone marrow biopsy
CBC
● Normocytic normochromic anemia
● Stained blood smear characteristically shows
teardrop-shaped red cells
● Presence of nucleated red cells
● Polychromatophilia is present, and the reticulocyte
count is increased
● White blood cell count is variable but is increased in
the majority of patients
● Immature granulocytes are generally present on the
stained blood smear and the number of basophils is
often increased
● Dwarf megakaryocytes or small megakaryoblasts
are present in small numbers in peripheral blood
● Platelet count is increased in about 50% of the
cases at diagnosis but decreases below normal as
the disease progresses
Leukocyte alkaline phosphatase (LAP) stain
● LAP is increased in the majority of cases but may
be normal or decrease
● Bone marrow biopsy
● BM is usually hypocellular and the collagen content
is increased
● However, in the early stages of the disease, the
marrow may be hypercellular and contain an
increased number of megakaryocytes, some of
which are abnormal
● Marrow generally becomes fibrotic with the
abundance of reticulin fibers

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