Blood and cancer

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7 Blood and cancer

Jo Ponnampalam, Nandu Thalange

Introduction

Abnormalities of the blood are found in a wide range of paediatric diseases, so examination of the cellular components and chemistry will often give helpful diagnostic information. Primary diseases of the blood, with the exception of iron deficiency anaemia, are individually quite uncommon. Their significance lies in their high morbidity (e.g. haemophilia) or severity (e.g. acute leukaemia).

Key concepts

Blood diseases generally present with evidence of failure either of the cellular components leading to anaemia, leucopenia or thrombocytopenia, or the clotting cascade with resultant easy bruising, and mucosal and soft-tissue bleeding, or bleeding into joints – haemarthrosis.

Anaemia

Iron deficiency anaemia

As shown in Case 7.1, tiredness, lethargy and listlessness are suggestive of anaemia. Pallor may be harder to detect in darker skin but may be apparent to parents, and will be clearly evident from inspection of mucous membranes. A pale blue tinge to the sclera is characteristic of iron deficiency. The findings of tachycardia with a flow murmur reflect the compensatory increase in cardiac output.

Iron deficiency is suggested by microcytic, hypochromic anaemia, but thalassaemia (see below) may also cause this picture. Iron deficiency is confirmed by the low ferritin level. Ferritin is an acute phase reactant and rises with infection or inflammation, so may be misleadingly normal in the unwell child.

Case 7.1

A boy with iron deficiency anaemia

Rajesh, a 3-year-old boy of Indian origin, presented to his GP with an acute viral infection. He was sleeping for 14 hours at night, had two naps in the daytime and had little energy for play. He ate poorly, much preferring to drink milk. His GP found that his conjunctivae were pale blue with pallor of the buccal mucosa. His heart rate was 110 beats per minute at rest, and he had a short ejection murmur at the upper left sternal edge. His GP requested a full blood count, which showed Hb 6.5 g/dL, WBC 10.5 × 10⁶/L and platelets 680 × 10⁶/L. The MCV (mean cell volume) and MCH (mean cell haemoglobin) were low and the blood film confirmed microcytosis and anisocytosis. The ferritin level was also very low, confirming iron deficiency anaemia.

Iron deficiency causes a range of effects:

• Symptoms of anaemia (see above)

• Impaired or abnormal appetite

• Mucosal abnormalities, e.g. angular cheilitis and atrophic glossitis, pruritis vulvae

• Impaired cognitive and motor development in toddlers; impaired short-term memory in older children

• Impaired neutrophil and lymphocyte function.

Iron deficiency is extremely common, affecting 15–20% of children in the UK. The commonest explanation for iron deficiency anaemia in young children is inadequate dietary intake but other causes should be considered, such as:

• Malabsorption, e.g. coeliac disease (see Chapter 12, p. 172)

• Chronic blood loss from gastroesophageal reflux (see Chapter 13, p. 164) or Meckel’s diverticulum, when ectopic gastric mucosa secretes acid, leading to ulceration and bleeding in the small bowel.

• Menstrual losses in older girls.

Iron deficiency may be prevented with adequate dietary intake in otherwise healthy children. Standard infant formulas and many weaning foods are iron-fortified. Premature infants are at higher risk and require supplementation with iron in the first months. Treatment of established iron deficiency usually requires a few weeks of oral supplementation with elemental iron.

Haemolytic anaemia

Haemolytic disease of the newborn

Case 7.2

A boy with jaundice

Oliver was noted to have early-onset jaundice within 12 hours of birth. He was promptly treated with phototherapy. Oliver’s mother was known to have blood group O, rhesus positive, excluding rhesus incompatibility, but a direct Coombs (antiglobulin) test was positive. Oliver was found to have blood group A, rhesus positive, confirming the diagnosis of ABO incompatibility.

Haemolytic disease of the newborn is a condition of rapid red cell destruction in the fetus or newborn infant caused by maternal antibodies raised against the infant’s red cells (see also Chapter 17, p. 252). Where a pregnant mother is blood group rhesus negative and the fetus rhesus positive, the leak of even a few fetal cells into the maternal circulation may be sufficient to trigger the production of IgG antibodies. These cross the placenta in the same, or more commonly in a subsequent, pregnancy to cause immune-mediated destruction of antibody-coated red cells. The same process occurs with ABO incompatibility (as shown in Case 7.2), although this usually causes milder haemolysis.

Clinical effects range from mild jaundice in the newborn period, sometimes associated with a greater drop in the physiological nadir of haemoglobin at around 10–12 weeks of age, to a severe fetal anaemia, with hydrops fetalis and fetal death.

Detection of potential rhesus haemolytic disease in ‘at-risk’ fetuses requires monitoring of maternal antibody status and fetal well-being. Treatment options include in-utero transfusion, and, if necessary, early delivery. First-line therapy in the affected newborn infant is phototherapy. If this is ineffective, exchange blood transfusion is performed in which blood is drawn from the infant and replaced with an equal volume of packed cells. Infants with haemolytic disease of the newborn require folate supplementation, and occasionally require late transfusion for correction of anaemia, typically at 6–8 weeks of age. Administration of anti-D immunoglobulin to rhesus negative women after pregnancy (including miscarriage and termination of pregnancy) reduces the risk of recurrence in subsequent pregnancies.

Haemolytic disorders of childhood

Haemolytic anaemias are characterized by shortened red cell lifespan, with a compensatory increase in erythropoiesis, increased synthesis of bilirubin, and anaemia. Presentation may occur at birth with early-onset or severe neonatal jaundice, with inter-current infection provoking haemolysis or aplastic crisis, with symptoms of anaemia, with specific complications such as dactylitis in sickle-cell anaemia (see below), or by chance, following routine investigations (see Case 7.3).

Haemolytic anaemias may arise from:

• Structural membrane abnormalities of the red cell, e.g. hereditary spherocytosis

• Abnormalities of haemoglobin, e.g. thalassaemia, sickle-cell anaemia

• Metabolic abnormalities of the red cell, e.g. glucose-6-phosphate dehydrogenase (G6PD) deficiency or pyruvate kinase deficiency

• Hypersplenism and immune-mediated haemolysis.

General principles of treatment of haemolytic anaemias

• Folic acid requirements are increased due to high red cell turnover, and supplementation is usually required to optimize erythropoiesis

• Chronic anaemia is usually well-tolerated and transfusion is done as infrequently as symptoms allow

• Transfusion may be required for acute haemolytic crises. These occur secondary to inter-current infection, notably with parvovirus which causes a temporary depression of erythropoiesis – aplastic crisis. In G6PD deficiency (an X-linked condition, therefore very rare in girls) a variety of oxidant drugs will provoke acute haemolysis

• Blood transfusions ultimately may lead to iron overload, particularly in thalassaemia, requiring use of iron chelation therapy with desferrioxamine administered by overnight subcutaneous infusion 5–6 days per week. Newer oral agents, deferiprone (DFP) and deferasirox (DFX), approved for use in 2006, are available. DFP is less effective than DFO in treating liver disease, and so is usually used in combination with DFO. DFX is as effective as DFO, but long-term efficacy and safety is not yet established, and use is not recommended in patients with cardiac involvement. All chelation agents have significant side-effects, notably agranulocytosis with DFP.

• Symptomatic pigment gallstones require cholecystectomy

• Bone marrow transplantation may be appropriate for thalassaemia and severe sickle-cell disease

Hyposplenism secondary to progressive splenic infarction in sickle-cell disease, or following splenectomy, is treated with prophylactic phenoxymethylpenicillin (‘penicillin V’) and pneumococcal immunization due to the risk of overwhelming pneumococcal infection.

Case 7.3

A boy with severe haemolysis

Craig was admitted to hospital at the age of 4 years with severe gastroenteritis. He was noted to have pallor, splenomegaly and mild jaundice. A urine dipstick was positive for urobilinogen and haemoglobin, but negative for bilirubin, suggesting haemolysis. His blood count showed anaemia (Hb 4.7 g/dL), with spherocytes and red cell fragments on his blood film. A Coombs test was negative, excluding autoimmune haemolysis. Examination of parental blood specimens showed that his father also had mild anaemia with spherocytes, suggesting the diagnosis of hereditary spherocytosis.

Hereditary spherocytosis

Thalassaemia

Thalassaemia is the commonest single-gene disorder worldwide. A gene deletion results in reduced synthesis of either alpha- or beta-globin chains, producing alpha- or beta-thalassaemia, respectively.

Normal individuals have four alpha-globin and two beta-globin genes. Alpha- and beta-globin chains combine to form α₂β₂ tetramers. Loss of a single alpha gene is asymptomatic, but loss of impairment of two or three alpha-globin genes results in alpha-thalassaemia trait and haemoglobin H disease respectively, characterized by hypochromic microcytic anaemia. Haemoglobin H is a β₄ tetramer which results from inadequate alpha-globin synthesis. If all four alpha chains are affected, no normal haemoglobin is made, resulting in fetal death from hydrops fetalis.

There is considerable variation in ethnic distribution of the different abnormal genes, with the Mediterranean, Middle East, Indian subcontinent and South-East Asia most affected.

Clinical features result from increased erythropoiesis occurring in the bone marrow and in extramedullary sites such as the liver. This process is driven by erythropoietin produced in response to relative tissue hypoxia.

The hallmark of thalassaemia major is hypochromic, microcytic anaemia, which may be severe, with associated hypersplenism due to increased red cell destruction (see Figure 7.1). Beta-thalassaemia also produces skeletal abnormalities, most notably frontal bossing, due to hyperplasic marrow, and growth failure.

Figure 7.1 Blood film of patient with thalassaemia showing characteristic findings of hypochromic, microcytic anaemia with target cells and faint basophilic stippling.

Sickle-cell disease

Sickle-cell anaemia results from a glutamate to valine substitution in position 6 of the beta-globin gene. When present in the homozygous form this renders the red cell prone to sickling. Common triggers are hypoxia, dehydration and fever, and the result is less compliant sickle-shaped red cells which occlude small vessels causing tissue ischaemia and end-organ damage. The sickle cells are rapidly removed from the circulation causing anaemia and hypersplenism (as shown in Case 7.4). Ultimately, hyposplenism results from recurrent splenic infarction. Hydroxycarbamide (see below) may help preserve splenic function, thereby reducing infection risk.

Case 7.4

A boy with sickle-cell crisis

John, aged 4 years, and his family were refugees from Sierra Leone. He was admitted to hospital with severe abdominal pain. On examination he was jaundiced with pallor and tachycardia, and he had severe upper abdominal tenderness, despite morphine analgesia, with what appeared to be a massively enlarged spleen. An urgent blood count and film showed sickle cells with severe anaemia (Hb 3.8 g/dL) and thrombocytopenia. A diagnosis of splenic sequestration crisis, secondary to sickle-cell anaemia, was made. He was treated with oxygen, analgesia, intravenous fluids, broad-spectrum antibiotics and repeated transfusions, and eventually made a full recovery. Homozygous sickle-cell anaemia was later confirmed. He was treated with regular folic acid and penicillin and periodic blood transfusion for symptomatic anaemia.

There are a number of clinical problems particular to sickle-cell disease:

Hydroxycarbamide is now established as an effective treatment for sickle-cell disease. It is a ribonucleoside reductase inhibitor which inhibits cell division, and is widely used for the adult conditions chronic myeloid leukaemia and polycythaemia rubra vera. Randomized trials have shown that it is effective in reducing painful crises, dactylitis, episodes of sickle chest, and transfusion requirements, with an overall survival benefit. It has several actions:

• Increasing fetal haemoglobin

• Reducing rate of sickling

• Decreasing leucocytes, thereby reducing marginating neutrophils, which adhere to vascular endothelium and are implicated in painful crises and sickle chest.

Use of hydroxycarbamide in trials was associated with a 60% reduction in hospital admissions. Its use is indicated in patients with more than three admissions per year with painful crises, over the last 2 years, two or more episodes of sickle chest, or severe impairment in normal life due to pain. However, in May 2011 the outcome of a randomized control trial of hydroxycarbamide in children aged 9–18 months, treated for 2 years, showed very significantly improved outcomes compared with placebo, suggesting that it may have a wider role in the treatment of children.

Hydroxyurea is potentially leukaemogenic, and has significant toxicity. The most significant side-effect is myelosuppression. Skin rashes, nail discoloration, nausea/vomiting and diarrhoea may also occur. Frequent blood tests for monitoring purposes are required whilst on treatment.

Bruising and bleeding

Idiopathic thrombocytopenic purpura

Case 7.5

A girl with easy bruising

Kara, a 4-year-old girl, developed an upper respiratory tract infection with fever from which she recovered within a few days. One week later she developed large bruises over her shins, knees and elbows, and smaller bruises over her thighs, buttocks and trunk. A single episode of epistaxis (bleeding nose) took 20 minutes to staunch. She appeared well apart from the bruising, and evidence of her recent nose bleed. She had no lymphadenopathy, fever or hepatosplenomegaly. Her blood tests showed Hb 13.5 g/dL, WBC 10 × 10⁶/L with a normal differential white cell count and no blasts, but her platelet count was only 13 × 10⁶/L. Clotting studies were normal.

The acute-onset, easy bruising in Case 7.5 suggests thrombocytopenia, which was confirmed. The most likely cause is idiopathic thrombocytopenic purpura (ITP). If there is severe bleeding, platelets may be given. Most cases of acute ITP resolve spontaneously over days or a few weeks. Treatment with steroids or intravenous immunoglobulin will accelerate the rate of recovery in most cases. Treatment is considered in children with a platelet count below 30 × 10¹²/L with significant bleeding, depending on severity. Steroids can disguise aleukaemic leukaemia, which may present with isolated thrombocytopenia, and bone marrow examination is recommended before starting steroids. Treatment may incur significant side-effects and will not reduce the risk of developing chronic ITP, which occurs in 10–30% of cases and most cases can safely be managed conservatively.

Haemophilia

The two main forms are haemophilia A (80–85% of cases) and haemophilia B. Both are inherited conditions with X-linked recessive inheritance and consequently boys are affected, with deficient production of clotting factors and an increased tendency to haemorrhage, either spontaneously or after trauma. In haemophilia A, factor VIII is affected (as in Case 7.6) and in haemophilia B, factor IX levels are reduced; both are involved in the conversion of fibrinogen to fibrin in the clotting cascade.

Case 7.6

A boy with a large haematoma

James, who was 3 years old and a known haemophiliac, presented with a large haematoma of his left thigh, after a fall. James had previously had an implantable venous access device (Portacath™) sited because of severe needle phobia, coupled with the need for frequent intravenous access. He received regular recombinant factor VIII to maintain levels at around 30% of normal. In view of the muscle haemorrhage, he received additional factor VIII to elevate his levels to 70% of normal and regular physiotherapy to maintain mobility.

Clinical manifestations may begin in early infancy or even in utero with intracranial haemorrhage or cephalohaematoma. Later, once the child begins to walk, haemarthroses or soft-tissue bleeds are more common and simple cuts and surgical wounds may bleed profusely. Head injuries carry an increased risk of intracranial haemorrhage. The severity is proportional to the factor concentration in the blood, with the most severely affected having levels <1% of normal values. The activated partial thromboplastin time (APTT) is prolonged.

Recombinant human factor VIII and IX is now available for intravenous injection either to treat an acute event or as regular replacement in severe cases. After intracranial haemorrhage – or, if surgery is necessary – factor VIII levels are restored to the normal range. In individuals with mild or moderate disease, factor levels can be temporarily boosted with intravenous DDAVP (desmopressin). Anti-fibrinolytics, such as tranexamic acid, are useful adjunctive therapy. Drugs with anti-platelet activity, such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), must be avoided.

von Willebrand disease

The commonest inherited bleeding disorder, von Willebrand disease is caused by a relative lack of von Willebrand factor, which acts both as a carrier for factor VIII and to promote adherence of platelets to damaged endothelium. Milder forms are inherited as an autosomal dominant trait, the more severe as autosomal recessive. Clinical features include mucocutaneous bleeding and prolonged haemorrhage after surgery and trauma. There may be mild thrombocytopenia but more usually platelets are normal. APTT and bleeding times are usually prolonged, levels of von Willebrand factor and von Willebrand antigen are reduced and the ristocetin cofactor assay is abnormal.

Treatment with DDAVP boosts von Willebrand factor and factor VIII levels up to eight-fold. If ineffective, intermediate-purity factor VIII, and, in future, recombinant von Willebrand factor may be used.

Bone marrow failure

Bone marrow failure arises from disease affecting or replacing the bone marrow. All causes of bone marrow failure are rare. Marrow infiltration from acute leukaemia is the commonest cause. Aplastic anaemia presents in a similar way.

Aplastic anaemia

Aplastic anaemia results from reduced numbers of all haematopoietic cells – erythroblasts, myeloblasts and megakaryocytes – resulting in pancytopenia (as shown in Case 7.7). The majority of cases (50–75%) are idiopathic, but it may be congenital – Fanconi anaemia, or acquired following viral infection or toxin exposure.

The principal manifestations are symptomatic anaemia, infections secondary to leucopenia and bleeding secondary to thrombocytopenia. Treatment is with:

• Supportive therapy

• CMV (cytomegalovirus) negative, leuco-depleted, irradiated blood transfusions

• Prophylactic antifungal and antibiotic therapy

• Aggressive treatment of intercurrent infection

• Use of haematopoietic growth factors, e.g. G-CSF (granulocyte colony-stimulating factor), erythropoietin

• Immunosuppressive drugs, e.g. ciclosporin, anti-thymocyte globulin

• Bone marrow transplantation.

Case 7.7

A girl with pallor and easy bruising

Joanna presented at 14 years of age with very severe oral candidiasis, lethargy and malaise. On examination she was strikingly pale, and had a number of bruises, but no history of trauma. An urgent blood count showed pancytopenia (Hb 5.9 g/dL, WBC 1.1 × 10⁶/L, platelets 6 × 10¹²/L). Bone marrow aspirate showed hypocellularity. A diagnosis of severe aplastic anaemia was made. Joanna was initially treated with broad-spectrum antibiotics and amphotericin with initial clinical improvement but her cell counts did not recover with growth factor support and immunosuppressive therapy. Joanna was listed for urgent bone marrow transplant but died of overwhelming Gram-negative infection 3 weeks later.

Aplastic anaemia is severe, and without bone marrow transplantation (BMT) the 12-month survival is under 10%. With BMT, survival is 70–90%.

Malignant disease

Childhood cancer is rare, affecting approximately 12–14 per 100 000 children each year. Nevertheless, it accounts for 20% of deaths in childhood between 1 and 14 years of age. Childhood cancer is 15–20% more common in boys. Major improvements in cytotoxic chemotherapy regimes and supportive care with antibiotics, blood products and nutrition have dramatically improved survival. More than 75% of children now survive at least 5 years after diagnosis. In 1971, fewer than 100 adult survivors of childhood cancer over 30 years of age were known in England and Wales. By 2000, this figure had risen to over 7000. However, these figures disguise major variation in outcome; for example, stage IV neuroblastoma carries a 5-year survival of only 25% whereas isolated retinoblastoma has almost a 100% cure rate.

Leukaemia accounts for around 30% of cancers, lymphoma a further 10% and central nervous system (CNS) tumours 25%. Embryonal tumours (neuroblastoma, Wilms’ tumour, hepatoblastoma and retinoblastoma) account for 15%. The remaining 20% are made up of a wide variety of neoplasms with widely differing characteristics.

Risk factors

For the great majority of childhood cancers, there are no identifiable risk factors.

• Radiation. Radiation is a recognized cause of cancer, and children are more susceptible to the effects of radiation than are adults. Most evidence comes from high-dose, relatively short-term radiation such as following nuclear accidents or radiotherapy. The tumour most strongly associated with radiation exposure is papillary thyroid cancer. Risk can be reduced in the aftermath of exposure by taking potassium iodide. There is a lack of knowledge about the long-term risks of low-dose exposure, such as domestic radon, over prolonged periods.

• Genetic factors. Genetic factors may increase the likelihood of cancer through a range of mechanisms.

• Abnormal chromosomal complement, e.g. Down syndrome (leukaemia), or Turner’s syndrome (Wilms’ tumour)

• Specific gene defects, e.g. mutations in Rb gene predispose to retinoblastoma

• Defects of tumour suppressor genes, e.g. p53 mutations in Li-Fraumeni syndrome predispose to a wide range of cancers

• Syndromes with abnormal somatic growth such as neurofibromatosis or Beckwith’s syndrome

• Defects of DNA repair, e.g. ataxia telangiectasia.

• Infection. Infection may be a major trigger factor for some forms of cancer, e.g. hepatitis B and hepatocellular carcinoma, AIDS and non-Hodgkin’s lymphoma. Epstein–Barr virus has also been implicated in non-Hodgkin’s lymphoma, particularly Burkitt’s lymphoma.

• Environmental factors. Chemical and drug exposure may be implicated in the development of particular cancers, e.g. antenatal exposure to the barbiturate sodium pentothal (thiopental sodium) has been linked to brain and spinal cord tumours, and there is limited evidence suggesting a link between pesticide exposure and soft-tissue sarcomas.

Symptoms and signs

Symptoms and signs are non-specific and often relatively subtle in the early stages. Constitutional symptoms such as malaise, fever, pruritus and anorexia are common. Unfortunately many diseases are already advanced when first detected. Typical presentations include:

• Visible or palpable mass. The most obvious presentation of cancer is with a visible enlarging mass, such as a neck, soft-tissue or scrotal swelling, or incidentally recognized abdominal mass.

• Headaches and neurological symptoms and signs. Brain and spinal cord tumours produce elevated intracranial pressure and neurological symptoms or signs depending on their location and speed of growth. Epilepsy is an uncommon manifestation.

• Local effects. Osteosarcomas lead to pain and disability at the site of the tumour. Retinoblastoma causes visual loss. Wilms’ tumour may produce haematuria.

• Distant tumour effects. ‘Dancing-eyes syndrome’ is a characteristic neurological syndrome arising from neuroblastoma. The mechanism is unknown. Tumours may also produce distant effects by impairing endocrine function or by secreting hormones. For example, hypothalamic tumours such as craniopharyngiomas will result in panhypopituitarism with failure of growth and puberty, hypothyroidism, diabetes insipidus and adrenal insufficiency (see Chapter 12). Pituitary tumours, phaechromocytomas and neuroblastomas may all secrete hormones causing distant effects. The most common functional pituitary tumour is a prolactinoma, which produces breast enlargement and galactorrhoea. Catecholamines from neuroblastomas or phaeochromocytomas may produce labile hypertension. These catecholamines may be detected in urine and are useful as tumour markers for diagnosis and monitoring.

• Bone marrow failure (see above). Bone marrow failure is seen most commonly with leukaemia, and results in anaemia with pallor, thrombocytopenia causing easy bruising and bleeding, or leucopenia resulting in severe infection. Bone marrow metastases, most commonly seen in neuroblastoma, may produce a similar picture. Bone pain is common.

Surveillance

Some children have an increased risk of developing cancer. For example children with Beckwith syndrome have a greater risk of developing Wilms’ tumours of the kidney. Regular ultrasound scans to detect such tumours are necessary. Early detection facilitates treatment at an earlier stage. Children who have recovered from cancer are at risk of relapse and second malignancy and undergo regular surveillance.

Diagnosis and staging

Diagnosis, classification and grading of malignant disease require a range of investigations, including a tissue sample (bone marrow aspirate or tissue biopsy) for confirmation of the primary disease, and quantification of local and distant tumour spread by use of ultrasound, CT and MRI or nuclear medicine scans. Histology and molecular genetic studies shed further light on the disease, and frequently determine the approach to treatment.

Having established a diagnosis, and determined the extent of disease, treatment options may then be considered. Treatment has to take account of the effect on the child, e.g. cranial radiotherapy in infants and very young children (<6 years) has very severe effects on brain development and is not recommended.

Treatment

Treatment of childhood malignancy is a complex area, but the principal elements of management are:

• Chemotherapy

• Radiotherapy

• Surgery

• Supportive and palliative care

• Surveillance for recurrence or further malignancy

• Surveillance for ‘late effects’.

Presentations of principal childhood malignancies

Leukaemia

Around 2–4/100 000 children per year develop acute leukaemia and over 80% of those have acute lymphoblastic leukaemia (ALL) (as in Case 7.8), most of the rest having acute myeloid leukaemia (AML). The peak incidence is between 2 and 5 years, and although there is an increased incidence in children with chromosomal disorders, e.g. Down syndrome, or with immunodeficiency, this condition mostly occurs in previously well children.

Common clinical features are lethargy, pallor, easy bruising, bone pain and swelling of lymph glands, liver and spleen. Some children may develop infection due to neutropenia. Although primarily a bone marrow disease, the CNS (cranial nerve palsies or meningism), the testes (swelling, usually painless) and mediastinum (lymphadenopathy causing breathlessness) may all be involved at presentation.

There is usually leucocytosis due to blast cells (although normal leucocyte numbers may be reduced), anaemia and thrombocytopenia. Renal and hepatic function are sometimes affected. A secondary coagulopathy, or even disseminated intravascular coagulation, may be present. A lumbar puncture is required as the finding of blast cells in the cerebrospinal fluid is of grave prognostic significance and requires intensive CNS-directed treatment.

Case 7.8

A boy with bone marrow failure

Edward presented to his GP with pallor and numerous bruises. A blood count showed severe anaemia (Hb 5.0 g/dL), thrombocytopenia and numerous blast cells (WBC 145 × 10⁶/L) indicating leukaemia. He was urgently referred to hospital by which time immunophenotyping had confirmed ALL. On examination, he was miserable, with marked hepatosplenomegaly and some mild neck stiffness. He was commenced on broad-spectrum antibiotics and referred urgently to a specialist paediatric oncology unit where he underwent bone marrow aspirate and lumbar puncture. These confirmed total involvement of bone marrow with blasts, which were also present in cerebrospinal fluid, indicating meningeal involvement. Edward subsequently underwent intensive chemotherapy for a period of 3 years.

Nearly all children in the UK are managed as part of a clinical trial. The latest clinical trial, UKALL 2011, commenced in April 2012. UKALL 2003, its predecessor, introduced assessment of minimal residual disease, which is now accepted as standard therapy. Management requires exemplary supportive care with antibiotics, transfusion of red cells or platelets and avoidance of tumour lysis syndrome (acute renal failure secondary to large elevation of uric acid following initiation of therapy) with copious fluids and allopurinol (an inhibitor of uric acid synthesis). Multi-agent cytotoxic chemotherapy is required involving four main phases: an induction phase to bring the disease into remission, a maintenance phase lasting up to 3 years, intensification blocks of more aggressive treatment, and a phase of treatment directed specifically at protecting the CNS. Over 90% of children with ALL are now cured but relapse in the bone marrow, CNS or testes remains a risk for several years after treatment finishes. Relapse requires further multi-agent chemotherapy, usually with craniospinal radiotherapy, and in some cases bone marrow transplantation.

Innocent cervical lymphadenopathy

Case 7.9

A boy with cervical lymphadenopathy

Adam, aged 4 years, was referred with several hard, pea-sized lymph glands that had persisted for several months, after an episode of tonsillitis. He was otherwise well, and was on the 75th centile for height and weight. On examination, the glands were very hard and mobile – typical of innocent ‘lead shot’ glands. Adam’s parents were reassured as to the innocent nature of the lymphadenopathy, and were advised that the glands would gradually involute over several months.

Cervical lymphadenopathy is universal in children. Prevalence studies indicate that up to 45% of otherwise healthy children have cervical lymphadenopathy at any one time. Usually (as in Case 7.9) the lymphadenopathy is bilateral, generalized and transient, in association with an infection, typically of the upper respiratory tract, and predominantly involving glands in the anterior triangle (see Figure 7.2 for an anatomical description of cervical lymph nodes). Unilateral lymphadenopathy signifies staphylococcal or streptococcal infection in 40–80% of cases. Subacute and chronic lymphadenitis occurs with cat scratch disease, toxoplasmosis and occasionally atypical mycobacteria. Persistent enlargement of glands in the supraclavicular region is much more commonly associated with malignancy. Malignant disease or mycobacterial infection is more likely if there are associated constitutional symptoms such as fever, night sweats, malaise and weight loss.

Figure 7.2 Anatomical landmarks of the neck.

No investigation is necessary in the great majority of children, but where necessary, a blood count, ESR (erythrocyte sedimentation rate), serology for Epstein–Barr virus, toxoplasmosis and cytomegalovirus (causes of glandular fever), and Bartonella henselae (the cause of cat scratch disease), will exclude serious disease and may establish the cause. Fine-needle biopsy under ultrasound guidance, or excision biopsy of an affected gland, is rarely necessary. All biopsy material should be sent for histology and mycobacterial and fungal cultures.

Cervical lymphadenopathy secondary to malignancy is characteristically progressive, firm and frequently associated with constitutional symptoms. In the young child, neuroblastoma and leukaemia are the commonest causes, but in the older child and adolescent, Hodgkin’s disease and non-Hodgkin’s lymphoma are more common (Case 7.10).

Case 7.10

A boy with cervical lymphadenopathy

Peter, aged 14 years, presented with a progressively enlarging lymph gland in the supraclavicular region. He had drenching night sweats. The gland was painless, very firm, and the size of a chestnut when he was first seen by his doctor, but enlarged progressively over the next 3 weeks. A blood count and ESR showed a mild hypochromic, microcytic anaemia with an elevated ESR (106 mm/h). Lymphoma was strongly suspected, and a chest X-ray showed marked mediastinal lymphadenopathy. Peter underwent excision biopsy which confirmed non-Hodgkin’s lymphoma.

Lymphoma

• Hodgkin’s lymphoma. Hodgkin’s lymphoma is distinguished clinically by the contiguous spread of disease from one lymph node group to the next, and pathologically by a unique histological feature, the Reed–Sternberg cell, an atypical histiocyte. About 50% of cases are triggered by Epstein-Barr virus infection, and probably represents an abnormal immune response in a genetically susceptible individual.

Firm painless swelling of lymph nodes is the commonest presentation, particularly in the cervical region. Where the primary site is retroperitoneal or mediastinal other symptoms are more common, including cough, shortness of breath, fever, weight loss, sweating and pruritus.

Chest X-ray and abdominal and pelvic CT scans are combined with a bone marrow aspirate and biopsy to stage disease extent. If available, positron emission tomography CT (PET-CT) scanning offers superior detection of affected tissues, and is valuable for monitoring treatment response. MRI scanning may be used for suspected brain or spinal cord involvement. Excision biopsy allows tissue diagnosis. Treatment requires a combination of chemo- and radiotherapy. Refractory or relapsed lymphoma is treated with aggressive chemotherapy and salvage bone marrow or stem cell transplantation.

• Non-Hodgkin’s lymphoma. Non-Hodgkin’s lymphoma (NHL) arises from B- or T-cell lines, including primitive precursors. T-cell lymphoma is uncommon. Although arising in lymphoid tissue, extra-nodal spread is common. Thirty-five subtypes of non-Hodgkin’s lymphoma are recognized. Some cases are triggered by Epsten-Barr virus, notably Burkitt’s lymphoma. Human T-cell leukaemia/lymphoma virus type 1 (HTLV-1) is predominantly seen in patients of Japanese or Afro-Caribbean origin. Helicobacter pylori infection of the stomach may cause mucosa-associated lymphoid tissue (MALT) lymphoma. Antibiotics are curative in 70-80%.

Features vary with the primary site. Bone pain, skin lesions and testicular swelling mark more widespread disease. Bone marrow involvement may be substantial, particularly in T-cell disease, overlapping with T-cell leukaemia.

A cervical lymphoma presents with painless neck swelling, as in Case 7.10. Mediastinal involvement leads to general malaise, shortness of breath and signs of pleural effusions or superior vena caval obstruction. Abdominal lymphoma causes nausea and vomiting, bowel disturbance including obstruction, pain, weight loss, melaena, ascites and fever.

Treatment is with a multi-agent cytotoxic chemotherapy regime similar to that for acute leukaemia.

Brain tumours

Case 7.11

A boy with elevated intracranial pressure and ataxia

Aaron, aged 6 years, started to awaken with headaches. He was very miserable and frequently vomited. His symptoms worsened, prompting referral to hospital. He was noted to be mildly ataxic. Fundus examination proved impossible, but in view of the history, he underwent an urgent CT scan. This showed a cerebellar tumour with hydrocephalus. Biopsy showed a juvenile pilocytic astrocytoma. He underwent surgical debulking and post-operative cranial irradiation.

Children usually present with symptoms of rising intracranial pressure, particularly headache and vomiting. Features in the history that should elicit concern are a short history of headaches, with progressive symptoms, particularly if associated with functional impairment such as difficulty walking, unsteadiness, etc. (see also Chapter 14, p. 187).

As Case 7.11 shows, manifestations of cerebral tumours are primarily related to anatomical site and pressure effects – tumours may obstruct CSF (cerebrospinal fluid) flow leading to hydrocephalus (see Chapter 14, p. 187). This may lead to a rapid rise in intracranial pressure.

Other presentations of brain tumours include:

• Focal neurological signs such as hemiplegia or cranial nerve palsies

• Rapidly rising head circumference in an infant

• Ataxia due to cerebellar dysfunction

• Seizures (rarely)

• Neck stiffness (posterior fossa tumours)

• Temporal visual field loss (lesions affecting the optic nerves or chiasm, e.g. hypothalamic tumours)

• Papilloedema

• Percussion of the skull may reveal a ‘cracked-pot’ percussion note, typical of hydrocephalus.

Investigation of a suspected brain tumour is with a brain scan. An MRI scan is preferable, but often a CT scan can be done much more quickly. Tissue diagnosis of the tumour is usually indicated, although the risks of surgery may preclude a biopsy, particularly for brain stem tumours. Tumour markers such as alpha-fetoprotein and human chorionic gonadotrophin may be elevated with germ cell tumours.

The therapeutic approach is determined by the site and extent of the tumour and its histological character. A small well-circumscribed astrocytoma in a peripheral cortical location may be entirely resected surgically with low recurrence risk. A glioma in the brain stem however cannot be resected without devastating damage and therefore treatment depends on radiotherapy. Adjunctive chemotherapy may improve survival rates if the histology is favourable.

Prognosis is extremely variable. Learning difficulties, residual weakness, cerebral palsy and epilepsy are all common sequelae.

Glioma

Gliomas arise from astrocytes and account for 50% of all childhood brain tumours. They range from benign, low-grade tumours, typically in the cerebellum or optic nerves, sometimes associated with neurofibromatosis, to aggressive high-grade tumours in the brain stem or cerebrum. Surgery is contraindicated in brain stem gliomas. Chemotherapy and radiotherapy may be employed, but often have only limited success. Slow-growing peripheral gliomas with clear resection margins have a 5-year survival rate in excess of 90%, compared with less than 5% for an aggressive anaplastic brain stem glioma. Use of newer agents, such as the alkylating agent temozolomide, or drugs targeting specific receptors such as vascular endothelial growth factor (e.g. bevacizumab) or epidermal growth factor (e.g. erlotinib), has improved prognosis somewhat for supratentorial gliomas, but the overall picture remains bleak for brain stem gliomas.

Medulloblastoma

Thirty per cent of brain tumours are due to embryonal primitive neuro-ectodermal tumours (PNETs), which, in the cerebellum, are referred to as medulloblastomas. Medulloblastomas account for 90% of all PNETs. For a case history of medulloblastoma, see Chapter 14, Case 14.2, p. 187. PNETs are malignant with a propensity to metastasize within the brain and spinal cord. Treatment of medulloblastoma entails surgery, followed in children over 4 years by craniospinal radiotherapy.

Craniopharyngioma

Case 7.12

A girl with growth failure

Sunila, aged 7 years, was seen with a 2-year history of growth failure. Her mum had also noticed that she did not seem to see as well on the left side, and would occasionally bump into things. She was found to have bilateral optic atrophy with visual field loss, which was worse on the left side. She underwent an urgent CT scan which showed moderate hydrocephalus and a large midline tumour with calcification, indicating a craniopharyngioma. She underwent subtotal resection with radiotherapy. Subsequently, Sunila developed panhypopituitarism, epilepsy and significant learning difficulties, and was registered blind.

Craniopharyngioma, an embryonal tumour, arises in the suprasellar region, and is a benign tumour, but with a high rate of local recurrence. As in Case 7.12, progressive growth failure, often going back a number of years, is the earliest sign. The tumour contains solid and cystic elements, often with calcification, readily seen on CT scan. Treatment is with surgery and post-operative radiotherapy. Proximity to the pituitary gland and optic chiasm commonly leads to panhypopituitarism and/or blindness.

Neuroblastoma

Neuroblastoma (as in Case 7.13) is a tumour of neural crest cells and arises from the adrenal glands or sympathetic nerve root ganglia. The tumour secretes catecholamines, whose metabolites, vanillylmandelic acid and homovanillic acid, may be measured in urine.

Case 7.13

A boy with ‘panda eyes’

Sachin, aged 14 months, was referred urgently by his GP, with unexplained black eyes and failure-to-thrive. On examination he had a squint with periorbital ecchymosis. He was wasted and miserable, and his parents reported recent weight loss. He was initially investigated with a skeletal survey to look for evidence of non-accidental injury, and this showed apparent metastatic deposits in his ribs, pelvis and right femur. A cranial MRI scan also showed periorbital metastatic deposits. Urinary catecholamine metabolites were elevated and abdominal ultrasound showed a large retroperitoneal mass arising from the sympathetic chain. Biopsy confirmed neuroblastoma. In view of his metastatic disease, he had stage IV disease and was treated with intensive chemotherapy and subsequently surgery, followed by further cycles of chemotherapy.

With an incidence of around 1:100 000, neuroblastoma accounts for approximately 8% of all childhood tumours. It may present with an abdominal mass, nausea, vomiting or diarrhoea with failure to thrive, and signs of metastatic disease such as bone pain or proptosis. Fever and weight loss are common. Around two-thirds of primary tumours are abdominal.

Imaging with ultrasound and CT or MRI and bone marrow aspiration and biopsy determine the extent of tumour spread. The majority of children will undergo an MIBG (meta-iodobenzylguanidine) scan to permit accurate staging of the tumour. A biopsy is required to establish the histology and cytogenetics of the disease, notably the degree of amplification of the oncogene MYC-N, with more copies signifying a worse prognosis, and indicating the need for more aggressive chemotherapy. Histologically, neuroblastoma is a small round cell tumour, similar to lymphomas and Ewing’s sarcoma. Staging is conventional on a I to IV scale according to disease extent. Uniquely, neuroblastoma has a stage IV ‘special’, which involves a localized primary with dissemination specifically to skin, liver and bone marrow in an infant. This widespread form of the disease often undergoes remission either spontaneously or with minimal chemotherapy and therefore has an excellent prognosis.

After initial chemotherapy, the primary tumour is resected where possible, after which the more advanced stages will require further multi-agent cytotoxic chemotherapy, sometimes combined with stem-cell rescue therapy. Currently, clinical trials are underway testing the effectiveness of chimeric monoclonal antibodies against the ganglioside GD2, with promising early results, including patients who have relapsed post-bone marrow transplant.

Wilms’ tumour

The differential diagnosis of an abdominal mass includes Wilms’ tumour (Case 7.14), neuroblastoma, hepatoblastoma and non-Hodgkin’s lymphoma.

Wilms’ tumour is an embryonal renal tumour with an incidence of approximately 8 per million. It accounts for about 6% of childhood tumours. Patients with abnormalities of chromosome 11 have an increased risk of Wilms’ tumour, as well as other abnormalities, including hemihypertrophy, aniridia, genitourinary abnormalities and learning difficulties, most notably Beckwith syndrome. Familial Wilms’ tumour accounts for around 2% of all cases.

Case 7.14

A boy with a mass

Toby, aged 6 years, was referred by his GP subsequent to the discovery of an abdominal mass after presenting with pallor and anorexia. On examination the mass was very firm, and occupied the entire right flank up to the midline. Urinalysis showed blood 2+. An urgent ultrasound showed a large tumour arising from the right kidney. Urine was sent for catecholamine metabolites, but was negative. A biopsy confirmed Wilms’ tumour (nephroblastoma). Staging of the tumour showed local invasion, but the tumour was apparently confined to the abdomen without distant metastases (stage III). Histology was unfavourable, so Toby underwent chemotherapy followed by surgery and radiotherapy.

The majority of patients with Wilms’ tumour do well, with survival rates over 60%.

Osteosarcoma and Ewing’s sarcoma

Case 7.15

A girl with a painful limp

Kirsten, aged 12 years, was referred with a very painful limp affecting her right leg, making it increasingly difficult for her to weight bear, and disturbing her at night. The pain had initially been attributed to a sporting injury, but was failing to improve. X-ray showed evidence of new bone formation and lytic lesions with a classic ‘sunburst appearance’ in the lower femur, characteristic of osteosarcoma. Kirsten underwent staging scans, including a chest CT scan and a radionuclide bone scan, to look for evidence of metastatic disease. She underwent aggressive chemotherapy followed by limb-sparing surgery.

Bone tumours may be primary or secondary. Secondary bony metastases are commonly seen with neuroblastoma.

The majority of osteosarcomas occur in adolescents and young adults, presenting with limb pain, swelling or limp (Case 7.15). The metaphyses of long bones are most commonly affected and metastases may occur in the lung. Disease is confirmed radiologically with X-ray, bone scan and CT scan of the chest. After preliminary chemotherapy, surgical resection is attempted, with limb preservation where possible. Further chemotherapy is usually required.

Primary Ewing’s sarcoma may affect bone or soft tissue, causing pain, swelling and systemic upset such as fever and weight loss. Metastases occur in lungs, bone, bone marrow and lymph nodes. Radiological staging with PET-CT or MRI is required with bone marrow aspiration and biopsy. Tissue biopsy is required for histological confirmation. Treatment is with multi-agent chemotherapy and surgical excision of residual primary disease. In more advanced disease, high-dose marrow ablative chemotherapy is combined with autologous bone marrow rescue. With modern treatment, 5-year survival is now 50-75%, with better survival in younger patients (<15 years).