18 Oncology

Environmental factors do not appear to be clearly linked with childhood cancer. An inherited predisposition applies to a minority of tumours.

Include specific questions about:

Also be aware that childhood malignancy may present with a variety of clinical features and so special attention should be paid to the following.

New episode of wheeze (usually monophonic and fixed) may be caused by intrathoracic mass. Treatment with oral steroids, based on a presumptive diagnosis of asthma, may lead to partial response in symptoms and therefore delay the diagnosis of leukaemia or lymphoma involving mediastinal lymphadenopathy compressing the airways.

Persistent back pain should not be dismissed as innocent in children. It may reflect bone pain of bone marrow expansion (leukaemia or bone marrow metastases) or a spinal tumour.

May be:

The most common presenting features of brain tumours are:

Midline CNS tumours may result in disturbance in the hypothalamic– pituitary hormone axes and present with:

Thorough general examination including:

Specific diagnoses or concerns may be indicated by the following findings.

Malignancy accounts for a small proportion of cases of persistent lymphadenopathy in children. Possible diagnoses include acute leukaemia, non-Hodgkin’s lymphoma, Hodgkin’s disease, metastases from neuroblastoma or sarcoma.

The following features should raise suspicion of malignancy:

The following should raise suspicion of a brain tumour:

The most common reason for referral to a specialist is the identification of an abnormality on blood film.

Not all cell lines are equally affected, but the following problems occur as leukaemia or disseminated malignancy displaces normal bone marrow.

The following tests are used in diagnosis, staging, and assessment for prognosis, and as a baseline before starting treatment.

Sedation or general anaesthetic may be needed in young children when performing these procedures. The choice of imaging depends on the likely diagnosis, and may include:

These depend on the treatment being planned and may include:

This is the most common malignancy in childhood. It arises from malignant proliferation of ‘pre-B’ (common ALL) or T-cell lymphoid precursors. The cause is unknown, but in a minority it is associated with chromosomal aberrations. Possible links to patterns of childhood infection acting as a trigger have been hypothesized.

Typically with a short history (days or weeks), and with symptoms and signs reflecting pancytopenia, bone marrow expansion, and lymphadenopathy. Includes petechiae, bruising, pallor, tiredness, bone/joint pain/swelling, limp, lymphadenopathy, airway obstruction, and pleural effusion.

Overall survival is approximately 80% with current treatment. Adverse prognostic factors include:

Once considered a high-risk group, outlook is similar to that in standard risk ALL now that patients are treated with intensive chemotherapy according to strategy for B-cell non-Hodgkins lymphoma (see  p.660).

Extramedullary relapse (mainly CNS, testes) may present without bone marrow disease. Treatment is stratified according to risk factors, which include:

Long-term survival varies: 10–90% depending on risk (e.g. 90% in those with isolated extramedullary relapse more than 2yrs off treatment).

Acute myeloid leukaemia (AML) accounts for ˜5% of all childhood malignancies and <20% of all acute leukaemias. It is also known as acute non-lymphoblastic leukaemia (ANLL). AML results from malignant proliferation of myeloid cell precursors. AML can be subdivided morphologically using the French–American–British (FAB) classification system:

Cytogenetic analysis shows characteristic abnormalities:

These translocations are regarded as good prognostic indicators. Other complex karyotypes are associated with poor risk.

In AML prolonged continuation therapy is not used:

Overall survival is >60%.

All cases require BMT after intensive re-induction, usually in conjunction with ‘FLAG’ or ‘FLAG-Ida’ regimen (i.e. fludarabine, ara-C, and G-CSF support +- idarubicin).

The risk of developing acute leukaemia is increased 20–30 times, commonly either a pre-B (common) ALL or AML (especially M7). Response to chemotherapy is good and better relapse-free survival is found in those with AML. Children with Down syndrome-associated leukemia experience more complications of treatment.

Classically associated with Philadelphia chromosome +ve disease (t(9;22) translocation). It is rare. It has a chronic phase with non-specific symptoms (fever, night sweats, and hepatosplenomegaly). During this phase the only cure is BMT. Some benefit from A-interferon therapy. The chronic phase progresses to a blast phase that is similar to acute leukaemia. BMT is required. Prognosis is worse if BMT delayed until blast crisis.

Classified with the myelodysplasias, it is also known as juvenile CML.

There are two distinct disease entities that differ in regard to natural history, presentation, and management. Both are more common in boys than girls.

The annual incidence of NHL is 10 per million. The majority are high-grade tumours that are divided into categories, using histology, immunophenotype, and cytogenetics (see Box 18.1).

Lymphoblastic (T cell, pre-B cell) lymphoma is treated like ALL. Mature B cell disease is treated with short series of dose-intensive courses of chemotherapy. Risk of tumour lysis (  p.684) is high.

Survival is >70% (>90% in those with localized disease).

The incidence of Hodgkin’s Lymphoma (HL), or Hodgkin’s Disease, is very low before age 5yrs and rises with age. It is more common in patients with previous EBV infection. The histology shows Reed–Sternberg cells in an apparently reactive lymph node infiltrate.

Progressive, painless lymph node enlargement, the most common sites being cervical (80%) and mediastinal (60%). Dissemination to extranodal sites is less common, lungs and bone marrow being most frequently involved. Fever, night sweats, weight loss (>10%) constitute ‘B’ symptoms and are common in advanced stages.

HL is divided into two subtypes, which are then further subdivided by histology. Classical HL includes nodular sclerosing (most common), mixed cellularity, and lymphocyte-depleted histology. Nodular lymphocyte–predominant HL is the other subtype, characterized by its distinctive histology and favorable prognosis.

National practices differ, influenced by the balance between cure and adverse long-term effects. Low stage disease may be cured with involved field radiotherapy alone, but chemotherapy with low dose involved field radiotherapy for selected cases is now more commonly employed. Chemotherapy usually includes alkylating agents, vinca alkaloids, anthracyclines and steroids, and the addition of radiotherapy is considered essential at least for bulky mediastinal or stage IV disease. Reductions and augmentations of these therapies is being explored in the context of clinical trials and the role of PET scanning is likely to play an increasing role in monitoring of disease and determination of therapy.

5-yr survival >90% (stage IV, 70%; stage I, 97%).

Cure is still possible with second line therapy, including autologous stem cell transplant.

Brain tumours are the most common solid tumours, accounting for 25% of all childhood malignancies (see Box 18.2 for classification).

This requires prompt treatment:

See  pp.531, 946.

Treatment includes excision and craniospinal radiotherapy. Additional chemotherapy carries a survival advantage, allowing reduction in drug dose and/or field of radiotherapy, particularly in younger patients. Chemotherapy regimens include alkylating agents (e.g., Lomustine (CCNU), cyclophosphamide), platinum drugs (cisplatin, carboplatin), and vincristine. These are usually given after radiotherapy.

A malignant embryonal tumour derived from neural crest tissue with a wide spectrum of behaviour. It represents 7% of all childhood malignancies. Median age of presentation at 2yrs. Sites of involvement include:

May be locally invasive; surrounds, rather than displaces vessels and other structures. Distant metastases to bone, bone marrow, liver, CNS, lungs, and skin (especially infants).

Non-specific and variable. Depends on site, spread, and metabolic effects:

Disseminated neuroblastoma only cured in 20–30%, despite intensive treatment. Survival in low risk cases (low stage, infants) is >90%.

Options include further surgery, chemotherapy, and/or radiotherapy, depending on p treatment. After previous high dose chemotherapy and stem cell transplant, cure is unrealistic. Treatment aimed at palliation.

Disseminated disease restricted to bone marrow, liver, and skin. Characteristically resolves spontaneously. Chemotherapy is only for life-threatening symptoms. Resection (complete or partial) is usually sufficient for localized disease.

This is an embryonal tumour of the kidney representing 6–7% of all childhood malignancies. Up to 75% present at <4yrs of age (90% <7yrs). Most causes are sporadic, but 1% have an affected family member. Wilms’tumour may be associated with the following conditions.

Mutations of the WT1 tumour suppressor gene on chromosome 11p13 detected in Wilms’ tumours; abnormalities of 11p15 are also implicated, associated with BWS.

Mostly as a visible or palpable abdominal mass. Usually painless. Haematuria and hypertension may also be seen.

Bilateral cases are unusual and more often associated with genetic predisposition. Extrarenal Wilms’ tumours are very rare. Metastases occur in 10% of cases, most commonly to the lung.

Overall survival ranges from 770% for stage IV disease to >95% for stage I.

Multiple foci of premalignant tissue, also known as nephrogenic rests, characterize this condition. They may be observed on renal US and CT scan. The condition is associated with Wilms’ tumour, but may exist without tumour formation (seen on 1% of routine post-mortem examinations). Close monitoring is required due to risk of subsequent tumour formation.

Occurs in infants and is treated with surgery; chemotherapy is only indicated for incompletely excised cases.

A bone metastasizing renal tumour of childhood. It is more aggressive than Wilms’ tumour and accounts for about 6% of cases.

Rare (<2% renal tumours) and occurs mainly in infants. It is associated with posterior fossa CNS tumours and has an unfavourable outcome.

These tumours are rare in childhood (5% of all paediatric malignancies).

Localized pain and swelling, pathological fracture, and rarely erythema. Most affect the long bones around the knee (67%) and humerus. The metaphysis is a more common site than mid-shaft. Delay in diagnosis is common.

Chemotherapy, followed by surgery and then further chemotherapy. The aim is to perform limb-preserving surgery whenever possible.

Adverse outlook is associated with:

Most recurrences are isolated pulmonary metastases. Surgical resection can result in long-term survival in 20–30% of patients. The role of chemotherapy for recurrent OS is uncertain. The role of radiotherapy is limited to palliation.

ES usually occurs in bone, but may also occur in soft tissues. ES and peripheral PNETs share a common immunophenotype (CD99 or MIC2) and cytogenetic profile (t(11;22) in 85% and t(21;22) in 5–10%). Both tumour categories belong to the Ewing’s family of tumours. (Note: Peripheral PNET should not be confused with CNS PNET tumours.)

Localized pain and swelling, and sometimes pathological fracture. The diaphysis of long bones is more commonly affected than metaphysis. The axial skeleton is involved more often than in OS with pelvis the most common site. Metastases to lungs and bone are more common at diagnosis than in OS.

Chemotherapy, followed by surgery and then further chemotherapy. For extremity sites, limb-preserving surgery is the aim whenever possible. Radiotherapy is an effective adjunct, and an alternative to surgery, particularly at axial sites.

Adverse outlook associated with:

Bony metastases confer a particularly grave prognosis with <20% long-term survivors.

Salvage therapy is rarely successful, and will depend on treatment previously received. Second-line chemotherapy may include combinations involving Etoposide, carboplatin, cyclophosphamide, topotecan and ironotecan. Surgery and radiotherapy may also have a role in treatment.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. It accounts for 6% of all childhood malignancies (commonly aged <10yrs). The majority of cases are sporadic. Most are either embryonal or alveolar (more aggressive) subtypes. Botryoid (good prognosis) and spindle cell types are also recognized. A small number of cases are associated with Li–Fraumeni syndrome.

Mass, pain and obstruction of:

Lymph node involvement is common. Distant metastases are rare.

Ranges from <10% survival for bony metastatic disease to >90% for excised paratesticular tumours. Favourable features are:

Imaging of primary tumour site by US or MRI and CXRs to screen for pulmonary metastatic recurrence.

Germ cell tumours (GCTs) comprise a heterogeneous group of neoplasms, often with mixed histology. They arise from primordial germ cells in gonads or, following aberrant germ cell migration, in midline extragonadal sites, including sacrococcygeal, mediastinal, or CNS sites. GCTs are rare occurring in 3–5 per million children <15yrs of age, with peak incidence seen in children aged <3yrs. 10% of girls with ovarian GCTs are found to have an underlying intersex state.

The nomenclature of GCTs is complicated.

Site-dependent. Testicular masses are usually painless. Ovarian tumours present as either painful or painless abdominal mass. Metastases are rarely present at diagnosis (lungs, the commonest site, bone, and bone marrow).

Note: Testicular tumours should be removed via an inguinal approach. Sacrococcygeal teratomas should be removed together with the coccyx to reduce risk of malignant relapse. Chemotherapy is reserved for intermediate and high risk disease.

Survival >90% for malignant extracranial GCTs.

Long-term survival for HBL is >70%, even in presence of lung metastases. Survival for HCC is significantly lower.

Up to 5% of malignancies in childhood are very rare. They include:

Risk factors include:

Most cases arise on healthy skin and may be related to sun exposure. Surgery is the mainstay of treatment. Survival around 90% for local disease; 25% for metastatic disease.

Tumours in the adrenal medulla and sympathetic ganglia are usually sporadic, but may be associated with von Hippel–Lindau disease and multiple endocrine neoplasia types 2a and 2b (see  p.440). They present with endocrine manifestations, (e.g. hypertension, excessive sweating) or a mass. Less than 10% of phaeochromocytomas are malignant.

Plasma and urine catecholamine levels are usually raised.

Surgery after α-adrenergic antagonists to control sympathetic symptoms.

The commonest epithelial cancer in children. It is found in teenagers and associated with antibodies to EBV:

These carcinomas are rare.

Langerhans cell histiocytosis (LCH) is a disorder of unknown cause with a wide range of presentations. It is not a malignant condition, but may behave like one in its severest forms. Usually managed by paediatric oncologists.

Langerhans cells are normally found in skin, lymph nodes, and airways. LCH results from monoclonal proliferation and accumulation of histiocytes, with the characteristics of Langerhans cells, in skin, bone, pituitary, CNS, lungs, intestines, spleen, or bone marrow. It may manifest as single- or multisystem disease. Single-system disease is usually confined to bone, occasionally to skin, and seen more in older children. The natural history varies from spontaneous resolution to repeated recurrence, or death.

Note: LCH was previously known as ‘histiocytosis X’, which was subdivided into eosinophilic granuloma, Letterer–Siwe disease, and Hand–Schüller–Christian disease

Approximately 1 in 200,000 children affected each year.

Presentation Depends on site of disease, but may include:

Biopsy with confirmation of Birbeck granules (or positivite CD1a or S100 immunohistochemistry). Diagnosis can be made without biopsy in the presence of characteristic pituitary/hypothalamic abnormality, where biopsy considered too hazardous, or of lytic bone lesions with clinical features suggesting spontaneous resolution.

Suspected LCH should be fully staged to identify possible multisystem disease. Investigations should include skeletal survey, abdominal ultrasound, early morning urine for osmolality, FBC and film, coagulation studies, and liver enzymes.

>80% survive long-term without significant sequelae. Survivors `of multisystem or CNS disease may have lasting disabilities.

A rare condition that may be p (familial haemophagocytic/erythrophagocytic lymphohistiocytosis, FHL or FEL) or s to infection (sHLH). Characterized by accumulation of phagocytic mononuclear cells, rather than dendritic or antigen-presenting cells as seen in LCH.

Recovery may be spontaneous in sHLH with resolution of infection, but FHL is fatal without treatment. Steroids, etoposide, IT methotrexate may stabilize the disease. Allogeneic BMT is required for cure. Overall survival is ˜50%.

May be given as adjuvant treatment (following surgery), or neoadjuvant treatment (before surgery). Combinations of drugs used to increase efficacy, reduce development of resistance, and limit single organ toxicity. Maximizing dose intensity (treatment frequency) increases efficacy.

Antimetabolites Structural analogues of chemicals found in the intermediate steps in the synthesis of nucleic acids and proteins. They include:

Side-effects include renal toxicity (MTX), myelosuppression, hepatotoxicity, and mucositis.

Anti-tumour antibiotics Originally isolated from bacteria and fungi, they have antibiotic and anti-tumour activity. They include the following:

Epipodophyllotoxins semi-synthetic analogues of podophyllotoxin. They stabilize normally transient DNA–protein complexes by inhibition of topoisomerase I or II:

Vinca alkaloids Bind to tubulin, interfering with mitotic spindle:

Covalent binding to DNA, to prevent replication and transcription:

Side-effects—myelosuppression, alopecia, mucositis, tubular nephropathy (ifos), bladder toxicity (cyclo), encephalopathy (ifos), late effects on fertility, s leukaemia (CCNU).

Permanent cross-linking of DNA and inhibition of DNA synthesis. Cisplatin, carboplatin. Used in sarcoma, neuroblastoma, CNS tumours.

Side-effects—high emetogenicity, nephrotoxicity, ototoxicity, neurotoxicity (mainly cisplatin), myelotoxicity (carboplatin).

Chemotherapy should only be given by individuals fully trained in the avoidance and management of the complications, working in centres fully equipped and accredited to support chemotherapy.

Usually calculated according to surface area. Intravenous fluid to prevent tumour lysis syndrome (see  p.684) is required with certain drugs (e.g. ifosfamide, cisplatin, methotrexate). Mesna is given with cyclophosphamide and ifosfamide to protect from bladder inflammation.

The type and level of monitoring depend on agents used. This may include peripheral blood cell counts, GFR measurement, echocardiogram before and between courses of chemotherapy.

This involves the delivery of myeloablative doses of chemotherapy and/or radiotherapy, followed by rescue with haemopoietic stem cells. The latter may be autologous (from patient) or allogeneic (from sibling, unrelated donor, or haplo-identical from parent). Indications for use in treatment of childhood malignancy:

Stem cells are harvested from bone marrow or peripheral blood by leucopheresis following ‘mobilization’ with granulocyte colony stimulating factor (G-CSF).

Conventional BMT is used for allografts. Peripheral blood stem cell transplants (PBSCT) are favoured for autografts. This offers advantages including less risk of tumour contamination, more rapid engraftment, less severe infections, avoidance of anaesthetic. Conditioning for BMT involves myeloablative radiotherapy or chemotherapy. The aim is to achieve a state of complete remission prior to conditioning. Monoclonal antibodies are used to suppress immune function of donor T-lymphocytes against recipient.

Allografts carry greater risk, with approximately 10% procedure-related mortality. Morbidity and mortality from stem cell transplant are due to:

GVHD is a particular risk. It may affect any organ system but commonly skin, liver and the gastro-intestinal system. Ciclosporin A or tacrolimus are given as prophylaxis and steroids, monoclonal antibodies and other immunosuppressants may be employed in treatment.

In the use of ionizing radiation to kill cancer cells, dose and fractionation (number of treatments to deliver a total dose) vary according to the nature of the tumour and tolerance of the tissue.

Strategies to increase therapeutic success include:

Surgical interventions for solid tumours include the following.

All paediatric oncology treatment centres should have clear local guidelines for supportive management, which should be referred to for details. This section should not be regarded as a substitute for such guidelines. Fever should be treated as an emergency. Immunocompromised children may succumb to overwhelming sepsis within hours. Greatest risk is associated with the nadir white cell count (typically at around 10 days) for most regimens. In the absence of neutropenia, central venous line infection should be considered, particularly if there are symptoms (e.g. rigors) associated with line flushing.

Fever (temperature >38°C) with neutrophil count <1.0 × 10⁹/L, leading to increased risk of bacterial infections. Complicates chemotherapy, spinal radiotherapy, bone marrow disease.

Include inspection of the skin, mouth, IV line sites, surgical sites, and the perianal area.

This involves lysis of malignant cells on starting chemotherapy, releasing intracellular contents, exceeding renal excretory capacity and physiological buffering mechanisms. Abnormalities include:

Mainly seen in ALL, NHL (especially B cell), occasionally AML, rarely solid tumours (e.g. germ cell, neuroblastoma). May occur spontaneously or be precipitated by single dose of steroids or chemotherapy. Risk is increased with high white count, bulky disease, pre-existing renal impairment or infiltration.

Key is prevention and monitoring.

Rarely complicates malignancy (usually disseminated), e.g. rhabdomyosarcoma. Manage with hyperhydration (normal saline) and frusemide; bisphosphonates more effective than steroids or calcitonin.

Due to chemotherapy or antibiotics.

Particular care needed when any of these drugs used in combination.

Possible causes in the oncology patient include the following.

Blood products should be leucodepleted to reduce viral transmission and incidence of reactions. The latter are treated with antihistamine and/or steroid. Irradiated products should be used to prevent transfusion associated GVHD around the time of stem cell harvesting, following transplant, during treatment with fludarabine, and for patients with Hodgkin’s disease.

Chemotherapy varies in its emetogenicity: oral antimetabolites and vincristine require no prophylaxis; cisplatin and ifosfamide require multiple agents. Aim to prevent severe symptoms.

Good nutritional status is essential for recovery, but is compromised by the presence of malignancy, direct effects of treatment, and mucositis and infection:

Emergency treatment needed for acute complication of tumours, e.g.:

See  p.653. ⚠ Neurosurgical emergency. High dose dexamethasone pre-operatively.

Follow-up after completion of treatment is focused on disease recurrence and long-term adverse effects of cancer and its treatment.

This involves clinical review, combined with imaging or laboratory testing to pick up pre-symptomatic recurrence, which may be amenable to further attempts at curative treatment. For example:

This is a growing discipline, since there is now a childhood cancer survivor for every 900 adults. Monitoring is focused on the following.

May occur months or years after treatment has been completed. Sequelae usually progressive and irreversible, and will depend on sites, dose, mode of treatment, and age of patient at time of treatment.

Gonads: infertility/hypogonadism.

Risk of 4–6% of occurrence within radiotherapy field. Common second malignancies include solid tumours occurring in the field of radiotherapy, as well as non-melanoma skin cancers. Epithelial tumours predominate.

Sequelae depend on age at the time of exposure, drugs and doses (see  p.678). Well recognized long-term toxicities include:

It is understood that the long-term effects of treatment go beyond the purely physical consequences of treatment and this is an evolving area of clinical research. Cancer survivors (and their family members) are at increased risk of impaired psychosocial wellbeing. Risk is not clearly associated with a specific cancer type or treatment and is likely to be multi-factorial in origin. Survivors are also at increased risk for needing special education and, as they enter adulthood, unemployment or underemployment.

Around 30% of children with cancer will die, mostly from progressive disease. Death from complications of treatment is more likely to be swift, with limited opportunity for preparation. Palliative care is the active total care of patients whose disease is no longer curable. It needs to embrace physical, emotional, social, and spiritual needs of children and their families. Chemotherapy, radiotherapy, and surgery may still be used for palliation and control of symptoms.

It is extremely important to be honest with an open approach, avoiding false hope. What to tell the child is always difficult; many families tend to be over-protective. This risks loss of their child’s trust when the truth can no longer be hidden.

There are few paediatricians specializing in palliative care:

Anticipated symptoms will depend on the diagnosis. Symptom control measures may be pharmacological or non-pharmacological. Aim to correct the underlying cause, e.g. constipation, infection. Good communication and consideration of psychosocial and spiritual factors will contribute to good control.