Modified by

Mohamed Kamal, MD, DipRCPath

Introduction
B blast T blast NK blast?
 Acute leukemias
Defined as proliferation of immature white blood
cells > 20% of the cells of the bone marrow or
peripheral blood.
 Chronic leukemias
Cells having the capacity to differentiate
 Acute Chronic

Onset rapid gradual

Agressiveness Very agressive less aggressive

Differentiation Undifferentiated more mature cells

with many blasts
Cell of origin Lymphoid

Acute lymphobastic Chronic lymphocytic

Myeloid
Acute myeloid Chronic myeloid
Hematologic cancers are currently responsible for
approximately 9.5 % of newly diagnosed cancers
 Adult

Adult, children

Children, adult
Adult

American Cancer society

Deaths due to leukemias per million persons in 2012

0-7 8-13 14-22 23-29 30-34 35-39 40-46 47-64 65-85 86-132
 Leukemic blood film

Normal blood film

 Definition
• Disease characterized by an abnormal increase in the number of red /white
blood cells / platelets, in blood- forming tissues such as the bone marrow,
spleen, lymph nodes and often in the blood
• preventing the normal manufacture of red and white
blood cells and platelets, resulting in
– anemia
– increased susceptibility to infection
– impaired blood clotting
– enlargement of the lymph nodes, spleen and liver
• German Leukämie (1848), invented by Virchow
– Greek leukos "clear, white"
– + haima "blood"
Acute lymphoblastic
Leukemia/ lymphoma
 B-cell maturation

Pan,B cell marker CD19/ CD79a

HLA DR

Acute lymphoblastic leukemia/lymphoma

Antigenic stimulation
Tdt: Terminal deoxynucleotidyl transferase
T-cell maturation
CD3
 AETIOLOGY

• Radiation exposure
• Chemical exposure
• Inherited syndromes
• Viral infections
• Race and Gender
• Others risk factors
 AETIOLOGY (CONT.)

• Radiation Exposure
– Japanese survivors of the atomic bomb in World War II had an increased risk of
acute leukemia six to eight years after exposure.
– Studies in the 1950s showed that fetuses exposed to radiation, as X-rays, within the
first months of development present an increased risk for ALL, however, more recent
studies have failed to replicate these outcomes.
– Nevertheless, it’s still not recommended for pregnant women to undergo X-ray imaging.

• Chemical Exposures
– prolonged exposure to chemicals like hair dyes, benzene, and chemotherapeutic drugs
show a strong link to the development of ALL.
 AETIOLOGY (CONT.)

• Inherited Syndromes
– some inherited syndromes exist with genetic changes that raise
the risk of ALL:
• Down syndrome
• Klinefelter’s syndrome
• Fanconi’s anemia
• ataxia-telangiectasia
• Neurofibromatosis

– People who have relatives with ALL are also at an increased risk for
the disease.
 AETIOLOGY (CONT.)

• Viral Infections
– Infection with human T-cell leukemia virus-1 (HTLV-1) can cause a rare
type of T ALL in Asia

– Epstein-Barr virus
• Hematologic malignancies
– B ALL
– Burkitt lymphoma
– Classic Hodgkin disease
• Non hematologic malignancies
 AETIOLOGY (CONT.)

• Race and Gender

– African-Americans are at higher risk for ALL than Caucasians
– men have a higher risk than women.
– The reasons for these differences in risk aren’t well
understood.

• Other Risk Factors

– cigarette smoking
– long exposure to diesel fuel
– gasoline
– pesticides
– electromagnetic fields
 Normal blood Normal Bone marrow

Blood Lymphoblastic lymphoma/ leukemia Bone marrow lymphoblastic

lymphoma/leukemia
 Normal LN
Lymphoblastic
lymphoma/leukemia

• Effaced nodal
architecture
Lymphoblastic lymphoma
• Intermediate sized
blasts with scant
cytoplasm and round
nuclei

• fine chromatin, indistinct

nucleoli

• frequent mitosis

• "starry sky" appearance

 Lymphoblastic Leukemia/ lymphoma

T-LBL B-LBL
Epidemiology 90% 10%

Adolescent children

Male Male?
Clinical Mediastinal mass, Skin, gonads, lymph
presentation CNS, pleural nodes, bone, soft
effusion, skin, tissue
gonads, lymph nodes,
liver, spleen
Cell of origin Precursor T blast Precursor B blast

IHC TdT+ pan T cell Tdt+ pan B cell

markers+ markers+
Lymphoblastic lymphoma Tdt

B ALL CD19/CD79a T ALL CD3

 Prognostic factors for ALL

• Age at diagnosis
− Children: between 1 and 9 tend to have better cure rates
− adult: < 50 better outcome
• Initial white blood cell (WBC) count
− greater than 30,000 cells/ cubic millimeter at diagnosed are at higher risk and
need more intensive treatment.
• ALL subtype
− T worse than B
• Gender
− Girls with ALL may have a slightly higher chance of being cured than boys, but as
treatments have improved in recent years, this difference has shrunk.
• Response to initial treatment
• Translocations
 ALL subtypes, WHO 2017
B-lymphoblastic leukemia/lymphoma
B-lymphoblastic leukemia/lymphoma, NOS
B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1 poor prognosis
• Precursor B-cell ALL
B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged poor prognosis
• Precursor T-cell ALL
B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1 very favourable
• Burkitt-type ALL
prognosis
• Philadelphia
B-lymphoblastic chromosomewith
leukemia/lymphoma positive (BCR-ABL
hyperdiploidy fusion) ALL
very favourable (see below)
prognosis
B-lymphoblastic leukemia/lymphoma with hypodiploidy worst prognosis
B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH rare disease ?
B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1 poor prognosis
Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like poor prognosis
Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21 poor prognosis
T-lymphoblastic leukemia/lymphoma poor
Provisional entity: Early T-cell precursor lymphoblastic leukemia very poor
Provisional entity: Natural killer cell lymphoblastic leukemia/lymphoma
WHO Classification of Haematolymphoid Tumours, 5th edition: B-cell lymphoid
proliferations and lymphomas WHO-HAEM5
 Translocations of B-ALL
• Unfavorable
– t(9;22) (Philadelphia chromosome)
– hypodiploid < 44 chromosomes
– t (4:11)

• Favorable
– hyperdiploid chromosomes > 50 chromosomes
– t(12,21)
 T-ALL
• adult ALL
– Myeloid cells associated genes mutations

• typical T-ALL
– mutations in NOTCH1 or CDKN1/2
ALL adverse prognostic factors

• Sex: male
• Age < 1 years or > 10 years
• Initial WBC count > 50.000 mm3
• Presence of CNS involvement
• Cytogenetic abnormalities: hypodipoid, t(9:22), ----
• Pro B ALL, early T ALL, mature T ALL
• Slow response to initial thearpy
 Acute myeloid leukemia
AML

≥ 20% blasts in peripheral blood or bone marrow

B blast T blast NK blast?
 Acute myeloid leukemia

• De novo: mutations in specific genes

• Secondary AML following acquisition of additional

mutations
− atypical CML

− chronic myeloid leukaemia

− essential thrombocythaemia
− idiopathic myelofibrosis
− polycythaemia vera
− Chronic myelomonocytic leukemia
− systemic mastocytosis
 AML WHO 2017/ prognosis (1)
• AML with recurrent genetic abnormalities

– AML with t(8; 21); favorable

– AML with translocation or inversion in chromosome 16;
favorable
– AML with t(9; 11); intermediate
– APL (M3) with t(15; 17); favorable
– AML with t(6; 9); poor
– AML with a translocation or inversion in chromosome 3;
aggressive, short survival
– AML (megakaryoblastic) with t(1; 22); higher risk than
without translocation
– AML with BCR-ABL1; aggressive
higher prevalence in pediatric than in adult cases
 AML WHO 2017: prognosis (2)
• AML with genes mutations
– AML with mutated NPM1; intermediate
– AML with biallelic mutations of CEPBA;
favorable
– AML with mutated RUNX1; poor
– AML with BCR-ABL1; prognosis?

• AML with myelodysplasia-related

changes

• Therapy related myeloid neoplasms

(chemo/ radiotherapy)
 AML WHO 2017 (3)
• AML not otherwise specified (cases of AML that don’t
fall into one of the above groups, and is similar to the
FAB)
– AML with minimal differentiation (M0)
– AML without maturation (M1)
– AML with maturation (M2)
– Acute myelomonocytic leukemia (M4)
– Acute monoblastic and monocytic leukemia (M5)
– Acute pure erythroid leukemia (M6)
– Acute megakaryoblastic leukemia (M7)
– Acute basophilic leukemia
– Acute panmyelosis with fibrosis
• Myeloid sarcoma (granulocytic sarcoma or chloroma)
• Myeloid proliferations related to Down syndrome
WHO Classification of
Haematolymphoid Tumours,
5th edition: WHO-HAEM5
Non
granular
cytoplasm CD13

Myeloperoxidase
Prominent nucleolus

Granular

Cytoplasm
 Myeloid +
monocytic
Granular markers

Cytoplasm

Monocytic
markers

Erythroid
markers

Platelet
markers
 Prognosis in AML
• GOOD PROGNOSIS
– Age <40
– M2, M3 and M4
– Blasts with Auer rods
– Total WBC <25.000/cm3
– Translocations and inversions
abnormal fusion of the
– Absence of preceeding myelofibrosis primary granules.
– patient with Down’s syndrome (azurophilic)
– BAD PROGNOSISAge <2 and >55
– – M0, M6, M7
– Total WBC >100.000/cm3
– Deletions
– Leukemias preceeded by myelofibrosis
 ALL AML

Age Usually children usually adult

Lymphadenopathy Usually present Usually absent

Hepatosplenomegaly Mild Mild

Skin inolvement Present Present M4/M5

Gum hypertrophy Absent Present

CNS involvement Present Present

Granulocytic sarcoma Absent Present in some

cases
Mediastinal mass Present in TALL Absent

Associated with DIC Absent Present in M3

Prognosis Good bad

DIC: disseminated intravascular coagulopathy

Acute leukemias of ambiguous lineage
− Acute undiferentiated leukemias

− Mixed leukemias that have both lymphocytic and

myeloid features.
⚫ Mixed phenotype acute leukemia B/myeloid
⚫ Mixed phenotype acute leukemia T/myeloid
⚫ Mixed phenotype acute leukemia NOS
⚫ Mixed phenotype acute leukemia with t(9/22); BCR-
ABL1
⚫ Mixed-phenotype acute leukaemia with t(v;11q23.3);
KMT2A-rearranged
 Novel AML targets and therapies.

Julian R Davis et al. J Investig Med 2018;66:1088-1095

Copyright © American Federation for Medical Research. All rights reserved.

Chronic lymphocytic leukemia / Small
lymphocytic lymphoma (CLL/SLL)

Cell of origin: mature B cell

 CLL/ SLL
Definition WHO 2017

Presence of monoclonal B-lymphocytes co-expressing

CD19, CD5 and CD23, with weak or no expression of
CD20, CD79b, FMC7 and surface immunoglobulin.
The monoclonal B cells must represent the majority of
leucocytes with an absolute lymphocyte count > 5 ×
109cells/L, which has persisted for at least 1 month

SLL requires the presence of

lymphadenopathy and/or
splenomegaly.
 Aetiology
• Unknown, but

• Environmental factors
– exposure to insecticides
– little evidence indicates that ionizing radiation can increase the
risk of CLL
– scant evidence that viral infections are risk factors
– increased incidence in farmers, rubber manufacturing
workers and tire repair workers

• Hereditary factors/ familial association

– 9% of patients have a relative with CLL
– first-degree relatives of patients with CLL have an 8.5-
fold increased risk
– concordance of CLL is higher among monozygotic twins than among
dizygotic twins
 Clinical presentation
• Most common form of leukemia
• Patients with leukemic involvement : chronic lymphocytic
leukemia
• Patients with primarily nodal or splenic involvement:
small lymphocytic lymphoma
• mean age of 65
• male predominance (2:1 M:F).
• presentation
− Many patients are asymptomatic at first presentation, with
lymphocytosis noted incidentally
− others may present with anemia, thrombocytopenia
− Others with organ involvement
Small lymphocytic lymphoma/ Chronic lymphocytic leukemia

Peripheral blood Lymph node

Immunohistochemistry Usually diffuse pattern of growth

of small lymphocytes

CD20 CD5
CD23
 Chronic lymphocytic leukemia

Bone marrow biopsy: diffuse infiltration by small to medium size

lymphocytes

B cell markers : CD20+, CD79+ CD5+, CD23+

 Prognostic factors of SLL/CLL
Favorable Unfavorable

FISH / Deletion in the long arm of Deletion in the short arm of

cytogenetic chromosome 13 [del(13q)] chromosome 17 [del(17p)] or
as a sole abnormality the long arm of chromosome 11
[del(11q)]

TP53 Wild-type Mutated

IgV H >2% mutation ≤2% mutation

Karyotype Complex, ≥3 unrelated

chromosome abnormalities in >
one cell

FISH: fluorescent in situ hybridization

Chronic myeloid leukemia
 Chronic myeloid leukemia

• CML is a clonal chronic myeloproliferative disorder resulting in

absolute increase in cells of the granulocytic lineage including
neutrophils, eosinophils, and basophils.

• It affect the pluripotent stem cell that undergoes malignant

transformation, leading to a striking overproduction of immature
granulocytes, sometimes megakaryocytes and RBCs

.
 Chronic myeloid leukemia

• CML is a clonal chronic myeloproliferative disorder resulting affecting the

pluripotential hematopeitic stem cell in absolute increase in cells of the
granulocytic lineage including neutrophils, eosinophils, and basophils.

• Pathogenesis:
− balanced reciprocal translocation t(9;22) (q34q11)
present in hematopoeitic stem cell
− present in > 90%
− Abelson tyrosine kinase 1 gene involved in cell growth and proliferation
and break cluster region translocations generate an oncoprotein
BCR-ABL1 excessive proliferation and reduced apoptosis.
 tyrosine kinase

reciprocal translocation t(9;22) in which a piece of chromosome 9 containing the

oncogene c-abl is translocated to chromosome 22 and fused to the gene BCR

"always on" or continuously activated leading to unregulated cell division

Bone marrow film at 400X magnification demonstrates clear dominance of
granulopoiesis. The number of eosinophils and megakaryocytes is increased
Bone marrow biopsy
 Chronic myeloid leukemia,3 phases
Chronic phase Accelerated phase Blast phase
Blood and marrow blasts: increasing blood basophils Accumulation of blasts in
< 10% increasing blood + marrow extramedullary sites (bone, CNS,
blasts: > 10-19% lymph nodes, skin)
blasts in blood or marrow: ≥ 20%

Asymptomatic Fever
Fatigue, weight loss Fatigue, bone pain
Abdominal pain Progressive splenomegaly
splenomegaly Myeloid sarcoma

Months to years 6- 9 Months 3- 6 Months

 Poor-prognosis characteristics
Clinical and laboratory factors
• Older age
• Symptomatic presentation
• Poor performance status
• African American descent
• Hepatomegaly
• Splenomegaly
• Negative Ph chromosome or BCR/ABL
• Anemia
• Thrombocytopenia
• Thrombocytosis
• Decreased megakaryocytes
• Basophilia
• Myelofibrosis (increased reticulin or collagen)
 Diagnosis of Leukemias

• Complete blood count

• Bone marrow aspirate and biopsy
• Lymph node biopsy
• Flow cytometry
• Cytogenetics
• Imaging tests
− Computed tomography (scan CT)

− Magnetic resonance imaging (MRI)

− Positron emission tomography (PET scan)
• Molecular tests
Reactive leucocytosis that simulate leukemias are termed
leukemoid reaction, and have the following characteristics:
 Common mutations in de novo and secondary AML. A number of clonal blood disorders with
a myeloid phenotype are represented.

Carolyn S. Grove, and George S. Vassiliou Dis. Model.

Mech. 2014;7:941-951

© 2014. Published by The Company of Biologists Ltd