Incidence and distribution of childhood cancers

Approximately 1 in 600 children will be diagnosed with cancer before the age of 15 years, and the incidence has slowly increased since the 1970s. The distribution of cancer types in children aged 0–14 years is shown in Table 16.3.1. The incidence varies by sex and ethnic origin, and the types of tumour also vary by age.

Table 16.3.1 Frequency of malignancy in childhood

Malignant disease	Frequency (%)
Leukaemia	35
Primary central nervous system tumours	20
Lymphoma: non-Hodgkin and Hodgkin	10
Wilms’ tumour	6–8
Neuroblastoma	6–8
Rhabdomyosarcoma, soft tissue sarcoma	5
Sarcoma of bone: Ewing and osteosarcoma	4
Histiocytosis	5
Teratoma	2
Retinoblastoma	1
Hepatic	1
Other	5

Acute leukaemia – acute lymphoblastic (ALL) or acute myeloblastic leukaemia (AML) – accounts for just over one-third of all childhood cancers. Primary brain or central nervous system (CNS) tumours account for another third and are the most common solid cancer tumours. Lymphomas (non-Hodgkin lymphoma and Hodgkin disease) make up 10% of all childhood malignancies. The most common abdominal tumours are neuroblastoma and Wilms’ tumours, accounting for 6–8% of childhood cancers respectively. Bone tumours (e.g. Ewing sarcoma and osteosarcoma) and soft tissue sarcomas (e.g. rhabdomyosarcoma) account for a small proportion of childhood cancers. In adolescent patients, melanoma, bone sarcomas, thyroid cancers and germ cell tumours are more common.

Aetiology of childhood cancer

When confronted with a diagnosis of childhood cancer, parents often ask: ‘Why did this happen to my child?’ or ‘Did this happen because of something I have done or passed on to my child?’ With the exception of several known predisposing genetic syndromes (Table 16.3.2), the proportion of paediatric cancers that have a clearly hereditary component is very small. Similarly, despite extensive epidemiological studies, few environmental agents have been linked consistently with childhood malignancy.

Table 16.3.2 Inherited/genetic syndromes associated with increased risk of childhood malignancy

Cancer	Associated syndrome
Leukaemia	Trisomy 21, Bloom syndrome, Fanconi anaemia, ataxia telangiectasia, neurofibromatosis, Kostmann syndrome, Klinefelter syndrome, Li–Fraumeni syndrome, Diamond–Blackfan anaemia, Noonan syndrome
Central nervous system tumours	Neurofibromatosis, tuberous sclerosis, Li–Fraumeni syndrome, von Hippel–Lindau syndrome
Lymphoma	Immunodeficiency disorders
Wilms’ tumour	Denys–Drash syndrome, Beckwith–Weidermann syndrome, WAGR syndrome
Rhabdomyosarcoma	Li–Fraumeni syndrome

WAGR, Wilms’ tumour, aniridia, genitourinary anomalies and mental retardation.

It is hypothesized that cancer initiation results from a series of genetic mutations resulting in the inability of a cell to respond normally to intracellular and/or extracellular signals that control cell proliferation, differentiation or death (apoptosis). Examples include mutations involving tumour suppressor genes (e.g. RB1, p53 or WT1) or activation of cellular proto-oncogenes (e.g. myc or abl). The number of required genetic alterations may differ depending on the type of malignancy from as few as one to a complex cascade arising directly or indirectly from inherited gene mutations, environmental, chemical or radiation-induced DNA damage or random errors in DNA synthesis.

Approach to management of a patient with suspected malignancy

Treatment types and duration vary for individual children and adolescents depending on the age at diagnosis, type of cancer, stage and specific biological differences of the tumour. Prompt referral to a paediatric oncology centre for diagnostic work-up and management is critical for all children and adolescents with a suspected malignancy. A centralized multidisciplinary team approach, utilizing skills of specialist medical, nursing and allied health practitioners is the ‘gold standard’ in delivery of excellence in care to children with cancer. A number of steps are involved before a child can start treatment:

• Diagnosis will be made by a combination of diagnostic tests, radiological imaging and biopsies that varies dependent on the cancer type. Examples of these will be shown later as we discuss specific tumour groups.

• Staging investigations are then needed to document whether the cancer has spread. These tests give important information about survival and allow clinicians to decide on the most suitable clinical trial.

• Toxicity assessment such as echocardiography, glomerular filtration rate and audiology are regularly carried out to ensure that treatment does not affect normal structures such as the heart, kidneys and hearing.

• Treatment usually involves combinations of four common treatment options, although scientists are researching new novel treatments that may improve survival:

• Chemotherapy with drugs that kill rapidly dividing cancer cells. Unfortunately, these drugs cause side-effects by affecting normal cells such as bone marrow or hair follicles. Depending on the chemotherapy agent, the drug may be given intravenously, orally, intramuscularly or intrathecally (into the cerebrospinal fluid, CSF).

• Surgery – some tumours can be removed by a surgical procedure at diagnosis; others are removed after chemotherapy to make the tumour smaller or easier to remove.

• Radiotherapy is the medical use of ionizing radiation as a cancer treatment or part of treatment to control cancer cells. Some tumours are very radiosensitive (e.g. lymphomas), whereas others, such as osteosarcomas, are not radiosensitive.

• Bone marrow transplant treats diseased bone marrow by ablating the marrow with a combination of chemotherapy and/or radiotherapy, coupled by replacement with a stem cell infusion (of bone marrow, peripheral stem cells or cord blood).

Acute leukaemia

Leukaemia is the abnormal proliferation of lymphoblasts (ALL) or myeloblasts (AML) in the bone marrow. ALL accounts for 80% of all childhood leukaemia, with AML accounting for the majority of the remainder. In ALL, presentation peaks at age 2–5 years, whereas there is no peak in AML. Chronic leukaemia, including chronic myeloid leukaemia (CML) and juvenile myelomonocytic leukaemia (JMML), is rare, accounting for fewer than 5% of cases.

The cause of leukaemia is unknown, but the theory is that a abnormal stem cell develops capable of indefinite renewal. These cells occupy the marrow space, leading to reduced numbers of normal haematopoietic cells, resulting ultimately in pancytopenia. Secondary involvement of the reticuloendothelial system (leading to lymphadenopathy and hepatosplenomegaly), bone, joints and, rarely, CNS, testes and skin can occur.

A two-step pathogenesis for ALL (Greaves’ hypothesis) has been suggested, with the initial event, occurring during fetal life, driving clonal expansion and a second trigger occurring during childhood, possibly resulting from viral stimuli of cellular proliferation. This theory stems from evidence that a significant proportion of children presenting with ALL have molecular evidence of leukaemic clones identified retrospectively at birth on newborn screening cards.

Leukaemia can be further classified into distinct categories:

• precursor B-cell ALL (early pre-B, pre-B, transitional pre-B): 80–85%

• mature B-cell ALL: 2–3%

• T-cell ALL: 10–15%.

Classification is on the basis of:

• Morphological characteristics – appearance of the blood film, bone marrow aspirate and bone marrow trephine under the microscope

• Cytogenetics – the study of tumour chromosomal material using techniques such as florescence in situ hybridization (FISH) and comparative genomic hybridization (CGH)

• Immunophenotyping – a technique used to identify surface markers and antigens on leukaemia and lymphoma cells to aid diagnosis and classification.

Acute lymphoblastic leukaemia

Table 16.3.3 shows prognostic risk factors for ALL. Clinical features such as age and WCC at diagnosis are becoming less significant as protocols stratify treatment based on the response to treatment; for example, reduction of initial blast count following steroid therapy is an important prognostic factor, as is detection of minimal residual disease (MRD) by molecular methods after chemotherapy.

Table 16.3.3 Risk group classification for acute lymphoblastic leukaemia

Risk group	Clinical features	Molecular/genetic features
Low risk	Age 2–10 years, WCC < 50 × 10⁹/l	DNA index > 1.16
	Not T-cell phenotype	Absence of: t(9;22) BCR–abl t(4;11) MLL/AF₄ t(1;19) MLL rearrangement
	No central nervous system or testicular disease
	Rapid response to induction therapy
	Rapid response to induction therapy	t(12;21) TEL/AML1
High risk and very high risk	Induction failure	t(9;22), t(4;11)
	Age < 12 months	MLL rearrangements
	Poor prednisone response
	High MRD levels