General Aspects of ChildhoodLeukemia 1

General Aspects of Childhood Leukemia

Paul Imbach

Definition

and General Characteristics – 6 Incidence – 6

Etiology and Predisposing Factors – 6 Genetics – 6

Ionizing Radiation – 7 Chemicals and Drugs – 7 Infection – 7

Immunodeficiency – 8 Socioeconomic Situation – 8 Pathogenesis – 8

Molecular Pathogenesis – 9

Minimal Residual Disease – 9

Definition and General Characteristics

 Uncontrolled proliferation of immature white blood cells with a different immuno- logical subtype which is lethal within 1–6 months without treatment

 The disorder starts in the bone marrow, where normal blood cells are replaced by leukemic cells

 Morphological, immunological, cytogenetic, biochemical, and molecular genetic factors characterize the subtypes with various responses to treatment

Incidence

 Thirty-three percent of all cancers in children are leukemias

 Annually 45 of each million children less than 16 years of age are newly diagnosed as having leukemia

 Incidence peak at 2–5 years

 Occurrence in all age groups during childhood, grouped by type of leukemia:

– 75% acute lymphoblastic leukemia – 20% acute myelogenous leukemia

– 5% undifferentiated acute leukemia and chronic myelogenous leukemia

Etiology and Predisposing Factors

 The cause of human leukemia is unknown

 Predisposing factors in the pathogenesis of leukemia and other malignant disor- ders in childhood are described in the section Pathogenesis

 There is a 2–4 times higher incidence of leukemia in siblings than in children in the general population aged 0–15 years (1:720–1,000)

 In a monocytic twin there is an increased risk of leukemia within months after the co-twin develops leukemia

Genetics

 Higher risk in the following congenital disorders:

– Trisomy 21 (14 times higher) – Other trisomies

6 Chapter 1 - General Aspects of Childhood Leukemia

Abbreviations

 ALL: acute lymphoblastic leukemia (Chap 2)

 AML: acute myelogenous leukemia (Chap 3)

 CML: chronic myelogenous leukemia (Chap 4)

– Turner syndrome – Klinefelter syndrome – Monosomy 7

– Neurofibromatosis type 1 (von Recklinghausen disease) – Fanconi anemia (high fragility of chromosomes) – Bloom syndrome

– Kostmann syndrome

– Shwachman–Diamond syndrome (dysfunction of bone marrow and exocrine pancreatic insufficiency)

– Poland syndrome (absence of pectoralis major muscle and variable ipsilateral upper-extremity defects)

– Rubinstein–Taybi syndrome – Congenital agammaglobulinemia

– Ataxia-telangiectasia (highly fragile chromosomes) – Wiskott–Aldrich syndrome

Ionizing Radiation

Atomic bomb survivors (from Hiroshima and Nagasaki) developed leukemia with an incidence of 1:60 within a radius of 1,000 m of the epicenter occurring after 1–

2 years (peak incidence after 4–8 years). There was a predominance of ALL in child- ren and of AML in adults, which may reflect the different pathogenesis in the vari- ous age groups.

Chemicals and Drugs

 Benzene (related to AML)

 Chloramphenicol (usually related to ALL)

 Chemical warfare agent, i.e. nitrogen-Lost (related to AML)

 Cytotoxic agents; e.g. correlation between alkylating agents and Hodgkin disease and other malignancies – especially after irradiation there is a higher incidence of leukemia, ovarian carcinoma, and other solid tumors

Infection

 Correlation between viruses and development of leukemia has been observed, es- pecially after RNA virus infection in mice, cats, chicken, and cows

 Human T-cell leukemia virus (HTLV) has been demonstrated in adults to be linked to T-cell lymphoma in some geographical areas

 Association between Epstein–Barr virus (EBV) and occurrence of Burkitt lymphoma

 Human immunodeficiency virus (HIV): HIV infection and/or immunodeficiency causes a higher incidence of malignancy

 In humans vertical or horizontal transmission of human leukemia has not been

demonstrated except in rare cases of a mother with leukemia to her newborn or in

identical twins with prenatal leukemia

Immunodeficiency

There is correlation between immunodeficiency and development of leukemias (i.e.

congenital hypogammaglobulinemia, Wiskott-Aldrich syndrome, HIV infection) Socioeconomic Situation

 Higher incidence of neoplasia in higher socioeconomic groups

 Similar frequencies in urban and nonurban areas: no correlation between different nutritional conditions

Pathogenesis

The etiology and/or predisposition (see above) indicates a correlation between leukemogenesis and different risk factors:

 Higher instability/fragility of chromosomes

 Deficiency of the immune response cascade

 Certain exposures (ionizing radiation, chemicals, viruses)

The leukemic cell is pathophysiologically characterized by a certain degree of differentiation during hematopoiesis (see Fig. 1.1.)

Fig. 1.1 Differentiation during hematopoiesis

8 Chapter 1 - General Aspects of Childhood Leukemia

Molecular Pathogenesis

 Cytogenetic alterations of genes coding for immunoglobulin and T-lymphocyte re- ceptors, or various transcription factors:

– Chromosomal deletions, mutations or chemical alterations (i.e. methylation) of DNA may lead to inactivation of the tumor suppressor gene (i.e. p53) or activa- tion of the oncogene

– Molecular products may disturb normal apoptosis (programmed cell death) mechanisms, such as the Bcl-2 pathway

Minimal Residual Disease

Molecular detection techniques (polymerase chain reaction PCR; fluorescence-ac-

tivated cell sorting FACS) detect leukemic cells with chromosomal alterations, clonal

antigen receptors, or immunoglobulin rearrangements at the level of 1 leukemic cell

to 10

–10

normal cells. An early disappearance of minimal residual disease during

treatment seems to be correlated with a good prognosis