16.3 Cancers
Over the past 30 years we have seen dramatic improvements in the treatment and survival of childhood cancer. Survival rates have climbed from below 30% to more than 80%. This improvement is largely due to the use of clinical cancer trials conducted through collaborative national and international childhood cancer study groups and underpins the need for a continued cohesive approach to the treatment of rare diseases. Despite these remarkable improvements, 20–25% of children diagnosed with cancer are not cured with current therapies and many cured patients will be left with long-term complications of therapy. This clearly dictates the need for ongoing research to improve survival outcomes.
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:
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:
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
Presentation
The clinical presentation of ALL can be quite variable, but most children will present with a 3–4-week prodrome that may include pallor, increased bruising or bleeding, lethargy, anorexia, recurrent infection or fevers, anorexia, bone pain or reluctance to walk.
Common physical examination findings include pallor (80%), petechiae (50%), lymphadenopathy (35%), hepatomegaly or splenomegaly (50–60%). Rarely, skin infiltration (chloroma) and testicular infiltration (usually presenting as a painless swelling) are seen.
T-cell leukaemia, more common in older boys, presents with a mediastinal mass in 50% of cases. This can result in life-threatening airway compromise and obstruction of the superior vena cava. Some 30% of patients with T-cell ALL present with a leukocyte count greater than 100 × 109/L, and there is a higher incidence of CNS disease.
Investigations
The peripheral blood film can be normal but will usually demonstrate the presence of leukaemic blasts with or without anaemia and thrombocytopenia. The white blood cell count (WCC) is frequently raised at diagnosis (leukocytosis), with a presenting WCC below 10 × 109/L in 25%, 10–50 x 109/l in 50% and above 50 x 109/l in 25% of patients. A bone marrow aspirate and biopsy (trephine) are the ‘gold standard’ diagnostic tests and will show replacement of normal haematopoiesis by leukaemic cells (Fig. 16.3.1).
A lumbar puncture is also done during the staging work-up; approximately 5–10% of patients show leukaemic spread to the CSF.
Classification and prognostic factors
Specific chromosomal translocations can also be identified, for example t(8;14) in B-cell ALL and the unfavourable t(9;22) or the BCR-abl gene (Philadelphia chromosome) identified in CML and 5% of paediatric patients with ALL.
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: | |
| No central nervous system or testicular disease | ||
| 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 |
MRD, minimal residual disease; WCC, white blood cell count.
Treatment
Current combination chemotherapy protocols for ALL result in cure of 80% of patients. Much of the required therapy can be given on an outpatient basis. Treatment consists of phases of therapy including induction, consolidation, CNS-directed therapy, re-induction, and continuation or maintenance therapy.
By the end of the first month of therapy (induction) with 3–4-drug combination chemotherapy (vincristine, asparaginase, prednisone, daunorubicin), remission will be achieved in more than 95% of patients. Further combination therapy is required to prevent relapse. The optimal total duration of therapy varies in clinical trials between 2 and 3 years.
CNS-targeted therapy using high-dose intravenous and intrathecal methotrexate has allowed cranial irradiation to be avoided except in patients with overt CNS disease or high-risk disease requiring a bone marrow transplant. This has reduced, but not eliminated, potential long-term cognitive, endocrine and growth complications.
Sally was a 3-year-old girl who presented with a 2–3-week history of intermittent fever, lethargy and poor appetite. Reluctance to walk and increased bruising were also noted for 1–2 days prior to presentation. Examination confirmed a pale child with truncal petechiae, limb bruising, cervical lymphadenopathy, splenomegaly and hepatomegaly. What was the differential diagnosis?
The presence of fever suggested infection, pallor suggested anaemia, and petechiae and bruising suggested thrombocytopenia. A blood count would confirm this. Lymphadenopathy and hepatosplenomegaly were consistent with infection (e.g. infectious mononucleosis, cytomegalovirus) or leukaemic infiltration. Reluctance to walk, fever and mild anaemia may be consistent with a primary joint problem such as juvenile rheumatoid arthritis or osteomyelitis. A blood count and film were warranted and a bone marrow aspirate was needed to confirm the diagnosis of acute leukaemia. Other paediatric malignancies that may present with bone marrow involvement should be considered, including lymphoma, neuroblastoma, rhabdomyosarcoma and Ewing sarcoma.
Acute myeloid leukaemia
AML is a cancer of the myeloid white blood cells, which are produced in the bone marrow. AML accounts for 20% of acute leukaemia.
Differential diagnosis
Like ALL, the differential diagnosis can include infection, juvenile rheumatoid arthritis, idiopathic thrombocytic purpura, aplastic anaemia and osteomyelitis.
Presentation
Presenting symptoms and signs are similar to those of ALL, and can include pallor, bleeding, fever, anorexia, malaise and bone pain. Certain subtypes of AML have more distinctive presenting clinical features. Acute promyelocytic leukaemia (APML) can present with serious haemorrhage or disseminated intravascular coagulation (DIC), whereas acute monoblastic or myelomonoblastic leukaemia may present with skin infiltration (chloroma) or gum hypertrophy. CNS leukaemia is diagnosed in 5–15% of patients.
Classification and prognostic factors
As well as bone marrow aspirate and trephines, it is important to exclude testicular disease in boys and CNS disease, as these are both sanctuary sites of disease.
In AML, characteristic morphological features include the presence of Auer rods as well as positive staining for myeloperoxidase and monocyte-associated esterases (Fig. 16.3.2). Classification into one of eight morphological subclasses using the French–American–British (FAB) system is possible.
Fig. 16.3.4 Dual-colour fluorescence in situ hybridization with probes PML (15q22) and RARA (17q12), demonstrating the presence of a PML–RARA fusion resulting from the 15:17 translocation arrows in acute promyelocytic leukaemia.
Fig. 16.3.5 Brain magnetic resonance image confirming the presence of a bilateral optic tumour with no evidence of raised intracranial pressure.
In addition to morphology and immunophenotype, genetic features of leukaemic cells can provide diagnostic and prognostic information. In AML, characteristic translocations are seen within FAB morphological subgroups; for example, M3 or APML is identified by the translocation t(15;17), and t(8;21) is a favourable cytogenetic abnormality seen in FAB M1 and M2.
Treatment
In contrast to ALL, therapy for AML is of shorter duration but more intensive, often requiring frequent hospital admissions with aggressive supportive care, including blood products and antimicrobials during lengthy periods of marrow suppression.
Overall, the outlook for patients with AML is less optimistic, with survival rates reported of 50–75%.
Monica is an 8-year-old girl who presented with a 1-week history of lethargy, poor appetite, recurrent epistaxis and gum bleeding when brushing her teeth. Examination revealed anaemia, gum hypertrophy, bruising on the lower limbs and trunk, hepatosplenomegaly and inguinal lymphadenopathy.
A full blood count confirmed anaemia and thrombocytopenia with a haemoglobin level of 8.2 g/L and platelets 12 × 109/L, and a white cell count of 1.6 × 109/L with circulating blast cells. Her coagulation profile was prolonged, consistent with mild disseminated intravascular coagulation.
Bone marrow aspirate confirmed the diagnosis of acute promyelocytic leukaemia (Fig. 16.3.3), and this was confirmed by immunophenotyping and cytogenetics (Fig. 16.3.4). Lumbar puncture was performed to exclude CNS spread.
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