Hemoblastosis in children

Department of Pediatrics 2
The chief of department
Prof.A.Volosovets
As.Karulina J.

Hemoblastosis are tumorous diseases of

hematopoietic and lymphatic fabric.

Lymphohematopoietic cancers (i.e., acute

lymphoblastic leukemia, lymphomas) account for
approximately 40% of childhood cancers.

On the basis of structural peculiaritis of

leukaemias cells and their microscopic
peculiaritis acute leukaemia is divided by two
large groups: Acute lymphoblastic leukaemia
(ALL) and Acute myeloid leukaemia (AML).

The acute leukaemias

Acute lymphoblastic leukaemia
Acute lymphoblastic leukaemia is most common in the age
2-10 years, with a peak at 3-4 years. The incidence then
decreases with increasing age. In children it is the most
common malignant disease and accounts for 85% of
childhood leukaemia.
Acute myeloid leukaemia
Acute myeloid leukaemia accounts for 10-15% of childhood
leukaemia, but it is the commonest leukaemia of adulthood,
particularly as chronic myeloproliferative disorders and
preleukaemic conditions such as myelodysplasia usually
progress to acute myeloid leukaemia rather than acute
lymphoblastic leukaemia. The incidence increases with age.

Risk factors of leukemia in children

Factors Predisposing to Childhood Leukemia

Hereditary
Downs syndrome
Blooms syndrome
Fanconis anaemia
Ataxia telangiectasia
Kleinfelters syndrome
Osteogenesis imperfecta
Wiskott-Aldrich syndrome
Leukaemia in siblings
Chemicals
Chronic benzene exposure
Alkylating agents (chlorambucil, melphalan)
Radiation
Predisposing haematological diseases (myeloproliferative
disorders, myelodysplasia, and aplastic anaemia)
Viruses

FAB (French-American-British)
classification of acute myeloid leukaemia

M0 Acute myeloid leukaemia with minimal evidence

of myeloid differentiation
M1 Acute myeloblastic leukaemia without maturation
M2 Acute myeloblastic leukaemia with maturation
M3 Acute promyelocytic leukaemia
M4 Acute myelomonocytic leukaemia
M5 Acute monocytic/monoblastic leukaemia
M6 Acute erythroleukaemia
M7 Acute megakaryoblastic leukaemia

The cytologic appearance of the blast cells is

variable and the no completely satisfactory
morphologic classification has been devised. The
French-American-British (FAB) inclused 3
morphologic subtypes L1 to L3.
L1 - lymphoblasts are predominantly smaal, with
little cytoplasm;
L2 - cells are large and pleomorphic with increased
cytoplasm, irregular nuclear shape, and prominent
nucleoli;
L3 - cells have finely stippled and homogeneous
nuclear chromatin, prominent nucleoli, and deep
blue cytoplasm with prominent vaculation.

Common Chromosomal Abnormalities in the Acute

Leukemias of Childhood
DISEA
SE

SUBTY
PE

CHROMOSOMAL
ABNORMALITY

INFLUENCE ON PROGNOSIS

ALL

Pre-B

Trisomy 4 and 10

Favorable

t(12;21)

AML

Pre-B

t(4;11)

Unfavorable

Pre-B

t(9;22)

Unfavorable

B-cell

t(8;14)

None

General

Hyperdiploidy

Favorable

General

Hypodiploidy

Unfavorable

M1[*]

t(8;21)

Favorable

M4[*]

inv(16)

Favorable

M3[*]

t(5;17)

Favorable

General

del(7)

Unfavorable

Infant

t(4;11)

Unfavorable

Phenotypically, surface markers show that about

85% of cases of ALL are derived from progenitors
of B cells, about 15% are derived from T cells, and
about 1% are derived from B cells. A small
percentage of children diagnosed with leukemia
have a disease characterized by surface markers
of both lymphoid and myeloid derivation.
Immunophenotypes often correlate to disease
manifestations.

Chromosomal abnormalities are found in most patients

with ALL. The abnormalities, which may be related to
chromosomal number, translocations, or deletions, provide
important prognostic information. The identification of the
leukemia-specific fusion-gene sequences in archived
neonatal blood spots of some children who develop ALL at
a later date indicates the importance of in utero events in
the initiation of the malignant process, but the long lag
period before the onset of the disease in some children,
reported to be as long as 14 yr, supports the concept that
additional genetic modifications also are required for
disease expression. Specific chromosomal findings, such
as the t(9;22) translocation, which expresses BCR-ABL
fusion protein, suggest a need for additional, molecular
genetic studies.

CLINICAL MANIFESTATIONS:
Common symptoms and signs at presentation
result from bone marrow failure or, less commonly,
organ infiltration.
1. Anaemia can result in pallor, lethargy, and
dyspnoea.
2. Neutropenia results in predominantly bacterial
infections of the mouth, throat, skin, chest or
perianal region.
3. Thrombocytopenia may present as spontaneous
bruising, menorrhagia, bleeding from
venepuncture sites, gingival bleeding, or prolonged
nose bleeds.

4. bone pain
5. superficial lymphadenopathy
6. abdominal distension due to abdominal
lymphadenopathy and hepatosplenomegaly
7. respiratory embarrassment due to a large
mediastinal mass
8. testicular enlargement
9. meningeal syndrome
10. gum hypertrophy and skin infiltration

Abnormalities of the hematopoietic system manifest as

pallor, which indicates anemia; bleeding from orifices,
petechiae, purpura, and ecchymosis, which indicate
thrombocytopenia or disseminated intravascular
coagulation; cellulitis or other evidence of infection,
which indicates leukopenia; skin nodules, which indicate
leukocytosis; and other abnormalities of the formed
elements of the blood. Abnormalities of the lymphatic
system include lymphadenopathy, superior vena cava
syndrome, or respiratory distress when the patient is in a
supine position, suggesting an upper anterior
mediastinal mass or thymic enlargement.

DIAGNOSIS
Full blood count usually but not invariably shows reduced
haemoglobin concentration and platelet count. The white cell
count can vary from 1,0109/l to 200109/l, and the differential
white cell count is often abnormal, with neutropenia and the
presence of blast cells. The anaemia is a normochromic,
normocytic anaemia, and the thrombocytopenia may be severe
(platelet count 10109/l).
Coagulation screening may yield abnormal results,
particularly in promyelocytic leukaemia (acute myeloid
leukaemia M3) when granules from the leukaemic blasts can
have procoagulant activity and trigger a consumptive
coagulopathy.
Biochemical screening is particularly important if the
leucocyte count is very high, when there may be evidence of
renal impairment and hyperuricaemia.

Chest radiography is mandatory to exclude the presence of a

mediastinal mass, which is present in up to 70% of patients with T
cell acute lymphoblastic leukaemia. In childhood acute
lymphoblastic leukaemia lytic bone lesions may also be seen.
Bone marrow aspiration with or without trephination is
essential to confirm acute leukaemia. The marrow is usually
hypercellular, with a predominance of immature (blast) cells.
Immunophenotyping of the antigens present on blasts isolated
from the bone marrow or peripheral blood is the most reliable
method of determining whether the leukaemia is lymphoid or
myeloid, and cytochemistry helps to confirm myeloid or
monocytic origin.

Cytogenetics and molecular studies often detect abnormalities

within the leukaemic clone that can have diagnostic or
prognostic valuefor example, the Philadelphia chromosome,
which is the product of a translocation between chromosomes
9 and 22, the presence of which confers a very poor prognosis
in cases of acute lymphoblastic leukaemia.
Atraumatic lumbar puncture with cerebrospinal fluid cytospin
is an important initial staging investigation in ALL or AML with
neurological symptoms to detect leukaemic cells in the
cerebrospinal fluid, indicating involvement of the central
nervous system.

Differential diagnosis of acute leukaemia

If lymphadenopathy: infections such as infectious
mononucleosis or lymphoma
If hepatosplenomegaly: myeloproliferative or
lymphoproliferative disorder, myelodysplasia, metabolic,
storage or autoimmune disorders (rarely, tropical disease, eg
visceral leishmaniasis)
If no peripheral leukaemic blasts but pancytopenia: aplastic
anaemia or infiltrated bone marrow involvement from
nonhaemopoietic small round cell tumour
Myelodysplasia
Lymphoblastic lymphoma: lymphomatous presentation with 25%
of blasts in the marrow (distinction may be arbitrary as treatment
may be the same)

Current chemotherapeutic regimens for treating children

with AML follow five treatment principles:
1. Aggressive induction therapy improves induction success
rates as well as long-term survival.
2. Consolidation or intensification therapy after remission is
achieved is important for long-term disease-free survival.
3. Maintenance therapy may give results comparable with
the use of consolidation or intensification therapy, but it does
not have a role in patients receiving aggressive postremission
therapy.
4. The type of treatment or prophylaxis for CNS leukemia
does not appear important in influencing long-term survival.
5. Targeted treatment of other extramedullary disease appears
not to affect long-term survival.

Principles of therapy

Most children with ALL are treated on clinical trials conducted by

national or international cooperative groups. In general, the initial
therapy is designed to eradicate the leukemic cells from the bone
marrow; this is known as remission induction. During this phase,
therapy usually is given for 4 wk and consists of vincristine weekly,
a corticosteroid such as dexamethasone or prednisone, and either
repeated doses of native L-asparaginase or a single dose of a
long-acting, pegylated asparaginase preparation. Intrathecal
cytarabine or methotrexate, or both, also may be given. Patients
at higher risk also receive daunomycin at weekly intervals. With
this approach, 98% of patients are in remission, as defined by
<5% blasts in the marrow and a return of neutrophil and platelet
counts to near-normal levels after 45 wk of treatment. Intrathecal
chemotherapy is usually given at the start of treatment and once
more during induction.

The second phase of treatment focuses on CNS

therapy in an effort to prevent later CNS relapses.
Intrathecal chemotherapy is given repeatedly by lumbar
puncture in conjunction with intensive systemic
chemotherapy. The likelihood of later CNS relapse is
thereby reduced to <5%. A small proportion of patients
with features that predict a high risk of CNS relapse may
receive irradiation to the brain and spinal cord. This
includes those patients who, at the time of diagnosis,
have lymphoblasts in the CSF and either an elevated
CSF leukocyte count or physical signs of CNS leukemia,
such as cranial nerve palsy.

After remission has been induced, many regimens provide 1428

wk of multiagent therapy, with the drugs and schedules used
varying depending on the risk group of the patient. Finally, patients
are given daily mercaptopurine and weekly methotrexate, usually
with intermittent doses of vincristine and a corticosteroid. This
period, known as the maintenance phase of therapy, lasts for 2
3 yr, depending on the protocol used. Many patients benefit from
administration of a delayed intensive phase of treatment (delayed
intensification), approximately 57 mo after the beginning of
therapy, and after a relatively nontoxic phase of treatment (interim
maintenance) to allow recovery from the initial intensive therapy. A
small number of patients with particularly poor prognostic
features, principally those with the t(9;22) translocation known as
the Philadelphia chromosome, may undergo bone marrow
transplantation during the first remission. In ALL, this chromosome
is similar but not identical to the Philadelphia chromosome of
chronic myelogenous leukemia (CML).

Lymphoma is the third most common cancer among

children, with an annual incidence of 15 per million
children 14 yr of age. The two broad categories of
lymphoma, Hodgkin disease (HD) and non-Hodgkin
lymphoma (NHL).
Female predominance is found among young children,
with a ratio of 4 : 1 for children 37 yr of age, 3 : 1 for
children 79 yr of age, and 1.3 : 1 for children >10 yr of
age. Clustering of cases in families or races may
suggest a genetic predisposition to the disease or a
common exposure to an etiologic agent.

Several studies suggest that infectious agents may be involved,

such as human herpesvirus 6, cytomegalovirus, and EpsteinBarr virus (EBV). The role of EBV is supported by prospective
serologic studies. The large proportion of patients with HD who
have high EBV antibody titers suggests that enhanced activation
of EBV may precede the development of HD, a possibility that
also is supported by in situ hybridization evidence of the EBV
genomes in Reed-Sternberg cells. EBV antigens have been
demonstrated in HD tissues, although EBV status is not
prognostic of outcome. HD may represent a common result of
multiple pathologic processes that include viral infection and
exposure of a genetically susceptible host to a sensitizing agent.
Pre-existing immunodeficiency, either congenital, such as
ataxia-telangiectasia, or acquired, such as HIV infection,
increases the risk of HD.

The Reed-Sternberg cell is a large cell (1545 mm in

diameter) with multiple or multilobulated nuclei. This cell
type is considered the hallmark of HD, although similar
cells are seen in infectious mononucleosis and other
conditions. The Reed-Sternberg cell is clonal in origin
and arises from the germinal center B cells. HD is
characterized by a variable number of Reed-Sternberg
cells surrounded by an inflammatory infiltrate of
lymphocytes, plasma cells, and eosinophils in different
proportions, depending on the HD histologic subtype.

Classification Systems for Hodgkin Disease

I. RYE CLASSIFICATION defines four major
histologic subtypes:
Lymphocyte predominance
Mixed cellularity
Nodular sclerosis
Lymphocyte depletion

II. NEW WHO/REAL CLASSIFICATION (The Revised

European-American Classification of Lymphoid
Neoplasms (REAL) classification system)

Nodular lymphocyte predominance

Classical Hodgkin lymphoma
Lymphocyte rich
Mixed cellularity
Nodular sclerosis
Lymphocyte depletion
Anaplastic large cell lymphoma Hodgkin-like

Ann Arbor Staging Classification for Hodgkin

Disease
Stage I

Involvement of a single lymph node region or a single extralymphatic

organ or site

Ann Arbor Staging System for Hodgkins Disease

Stage II

Involvement of two or more lymphoid regions on the same side of organ

the diaphragm; or localized involvement of an extralymphatic organ or
site and of one or more lymph node regions on the same side of the
diaphragm

Stage III

Involvement of node regions on both sides of the diaphragm, which may

be accompanied by localized involvement of an extralymphatic organ or
site or by splenic involvement

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic

organ or tissues, with or without associated lymph node enlargement

CLINICAL MANIFESTATIONS:
1. Painless, non-tender, firm, rubbery, cervical or supraclavicular
lymphadenopathy.
2. Affected lymph nodes are firmer than inflammatory nodes. Most
patients present with some degree of mediastinal involvement.
3. Clinically detectable hepatosplenomegaly rarely is encountered.
4. Symptoms and signs of airway obstruction (dyspnea, hypoxia,
cough), pleural or pericardial effusion, hepatocellular dysfunction,
or bone marrow infiltration (anemia, neutropenia, or
thrombocytopenia).
5. Systemic symptoms are unexplained fever >39C, weight loss
>10% total body weight over 3 mo, or drenching night sweats.

DIAGNOSIS
Evaluation includes history, physical examination, and
imaging studies, including chest radiograph; CT scans of
the chest, abdomen and pelvis; gallium scan; and
positron emission tomography (PET) scan.
Laboratory studies include a complete blood cell count
(CBC) to identify abnormalities that might suggest
marrow involvement, erythrocyte sedimentation rate
(ESR), and serum copper and serum ferritin levels, liver
function tests

TREATMENT
Chemotherapy and radiation therapy are effective in the
treatment of HD. Current treatment of HD in pediatric
patients involves the use of combined chemotherapy
with or without low-dose involved field radiation therapy.
Treatment is determined largely by disease stage, age at
diagnosis, presence or absence of B symptoms, and the
presence of hilar lymphadenopathy or bulky nodal
disease. Radiation therapy alone, at standard doses of
3,5004,000 cGy, initially was used and resulted in
prolonged remission and cure rates of 4095% in
patients with surgically low-staged HD.

Chemotherapy Regimens Commonly Used for Children and

Young Adults With Hodgkin Disease
CHEMOTHERAPY
REGIMENS

CORRESPONDING AGENTS

ABVD

Doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine

ABVE (DBVE)

Doxorubicin (Adriamycin), bleomycin, vincristine, etoposide

VAMP

Vincristine, doxorubicin (Adriamycin), methotrexate, prednisone

OPPA COPP
(females)

Vincristine (Oncovin), prednisone, procarbazine, doxorubicin (Adriamycin),

cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine

OEPA COPP (males)

Vincristine (Oncovin), etoposide, prednisone, doxorubicin (Adriamycin),

cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine

COPP/ABV

Cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine,

doxorubicin (Adriamycin), bleomycin, vinblastine

BEACOPP (advanced
stage)

Bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide,

vincristine (Oncovin), prednisone, procarbazine

COPP

Cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine

CHOP

Cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin),

prednisone

ABVE-PC (DBVE-PC)

Doxorubicin (Adriamycin), bleomycin, vincristine, etoposide, prednisone,

cyclophosphamide