After reading this chapter you should be able to assess, diagnose and manage:
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leukaemias and lymphoproliferative disorders
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solid tumours
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understand the associations of specific syndromes with propensity to malignancy
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oncological emergencies
and understand:
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side effects of treatment for malignancy
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risks and benefits of ionising radiation in patient care
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role of bone marrow transplantation and immunosuppressive therapy
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services involved in providing shared care
Although malignant disease in children and young people is relatively uncommon, it remains the major cause of death in the UK of those between 1 and 15 years of age. Like many illnesses, the impact of diagnosis and treatment on the child and family is significant and can have long-term implications for the individual concerned. In the UK, all children with suspected malignant disease are referred to one of 19 Primary Treatment Centres where diagnostic and staging investigations are undertaken, treatment options considered by the multidisciplinary team meeting (MDT) and proposed management discussed with patient and families.
Treatment protocols are complex and evolve over time as further understanding of their efficacy becomes clearer. The AKP exam does not require a detailed knowledge of the chemotherapy or radiotherapy regimens used although a broad understanding of the modalities used and an awareness of some of the common side effects of the drugs and radiotherapy are important.
Leukaemia
Acute lymphoblastic leukaemia (ALL) is much more common than acute myeloid leukaemia (AML) in the paediatric age range and both are seen more frequently than chronic myeloid leukaemia (CML). All can present at any age from infants to teenagers.
ALL and non-Hodgkin Lymphoma (NHL) are overlapping diseases with the distinction based on the major site involved and the cell of origin. A finding of ‘extensive bone marrow involvement with lymph node extension’ would indicate a diagnosis of leukaemia whilst ‘significant lymph node involvement with some marrow disease’ would be defined as a lymphoma.
Clinical presentation
Children and young people present with consequences of bone marrow failure—anaemia, white cell abnormalities—initially leucopenia and then leucocytosis—and thrombocytopenia. This leads to:
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pallor
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lethargy
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recurrent infections
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easy bruising and bleeding
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progressive lymphadenopathy
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bone pain
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headache, vomiting—if CNS involvement
On examination, children may demonstrate signs indicative of pancytopenia with pallor, bruising and signs of infection whilst widespread lymphadenopathy is common. A slightly enlarged liver and spleen may be palpable although those with chronic leukaemia may have a markedly enlarged spleen. Those with CNS disease may have papilloedema and boys can have enlarged and firm testicles indicative of disease infiltration.
Alternative diagnoses
Aplastic anaemia
The underlying pathological process in aplastic anaemia is one of reduced cell division in all three cell lines leading to erythropenia, leukopenia and thrombocytopenia. In leukaemia the process is that of proliferation of immature white cells (blast) which then crowd out the other normal progenitor cells. A bone marrow aspirate is necessary to clarify this distinction ( Table 22.1 ).
| RCPCH normal range | Leukaemia—patient 1 | Leukaemia—patient 2 | Aplastic anaemia | |
|---|---|---|---|---|
| Haemoglobin | 110–140 g/l | 67 | 67 | 67 |
| WCC | 5.0–12.0 x 10 9 /l | 13 | 220 | 0.3 |
| Platelets | 150–450 x 10⁹/l | 34 | 34 | 21 |
| Reticulocytes | 50–150 x 10⁹/l | 120 | 120 | 5 |
| Urate | 0.15–0.35 mmol/l | 0.21 | 0.65 | 0.08 |
Some conditions will lead to changes in appearance or number of the white cells in the peripheral circulation and so mimic the presentation of acute leukaemia, but more detailed investigations will clarify the diagnosis. These would include:
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infectious mononucleosis
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parvovirus B19 infection
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HIV
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pertussis
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autoimmune conditions
Investigations
An initial full blood count will usually raise suspicions of leukaemia with anaemia and thrombocytopenia present to varying degrees. The white cell count may be low or normal in the early stages of disease as the immature blast cells are confined to the bone marrow. Further proliferation of the malignant clone leads to the immature blast cells passing into the circulation and leading to a progressive elevation of the count.
Samples of the malignant cells are obtained by bone marrow aspirate and will identify sheets of blast cells. Further clarification as to the specific cell line (T-cell, B-cell, myeloid or other) involved will come from immunochemistry on the malignant cells.
Cytogenetics of the leukaemia cells is also undertaken as specific translocations and deletions have been identified which have prognostic implications. Cerebrospinal fluid from a lumbar puncture is examined for the presence of blasts and, if present, indicates CNS disease.
Treatment and management
Intensive chemotherapy is given following the current national trial protocol. For children with ALL, the treatment sequence involves blocks of chemotherapy over the initial months and then maintenance therapy over the following years. Children with AML have blocks of very intensive chemotherapy over a 6- to 8-month period and are rendered profoundly immunosuppressed over this time.
The direct administration of chemotherapy into the intrathecal space is via a lumbar puncture and, in paediatric practice, this usually occurs under anaesthesia. Clinical errors have occurred whereby an inappropriate chemotherapy agent—usually vincristine—was injected rather than the required intrathecal agent. Death of the patient is the usual outcome of this error.
Following a national review, the current UK practice only allows those who have been specifically trained and whose names appear on the hospital Trust register be involved in any aspect of intrathecal treatment—prescription, transporting or administration.
Clinicians who are not on their Trust register must decline if asked to prescribe, check or administer intrathecal chemotherapy.
Important sequelae
The 5-year survival for good risk acute lymphoblastic leukaemia (female, between 2–10 years, white count under 50 at presentation, no CNS disease and no adverse cytogenetics) is 93%. For AML it is around 70%.
Lymphoproliferative disorders
Non-Hodgkin Lymphoma (NHL)
Clinical presentation
The site of the initial disease in NHL will dictate the presenting features. Children with massive lymphadenopathy in the chest invariably have T-cell (thymic modulated) NHL and will present with:
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dyspnoea (orthostatic in extreme situations)
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pleural effusion
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collapse
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generalised pallor
Those with abdominal disease will usually have B-cell NHL and will have:
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anorexia
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diarrhoea
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abdominal distention
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ascites
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jaundice (if massive liver involvement)
Peripheral lymphadenopathy—cervical, axillary or inguinal—may be the first sign of malignancy.
Alternative diagnoses
Other causes of lymphadenopathy would need to be considered and would include:
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malignant diseases (soft tissue sarcomas, thyroid carcinoma)
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infections (Epstein-Barr, Mycobacterium, cat-scratch disease, toxoplasmosis)
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autoimmune conditions (Kawasaki disease, systemic lupus erythematosus)
Associations
Many conditions associated with immunodeficiency lead to an increased risk of developing non-Hodgkin lymphoma and include:
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congenital immunodeficiencies
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Wiskott-Aldrich syndrome
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ataxia telangiectasia
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X-linked lymphoproliferative syndrome
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acquired immunodeficiencies
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HIV
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immunosuppressive treatments following solid organ transplants
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Investigations
A CXR will be requested for those with respiratory symptoms and shows a mediastinal mass ( Figure 22.1 ). Imaging with CT ( Figure 22.2 and Figure 22.3 ) and MRI is necessary but the exact modality will depend on site of the primary disease. These images will determine the extent of disease and will allow assessment of future response to treatment. Tissue diagnosis is essential for diagnosis and will include histological examination, cytogenetics and immunochemistry which will determine the cell lineage. Lactate dehydrogenase (LDH) is not pathognomonic of lymphoma and can be raised due to any condition which increases white cell activity. Patients are at risk of tumour lysis syndrome and biochemical assessment is necessary before treatment commences and monitored closely through the early stages of chemotherapy.
Treatment and management
Complex protocols are used and the regimens are usually started in the designated UK specialist units before care is transferred to local shared care centres where possible.
Potential complications
Patients with rapidly progressive thoracic disease may develop superior vena caval (SVC) obstruction and airway occlusion (see below). Critical airway compromise may be evident from an inability of the patient to lie flat due to marked dyspnoea. These patients need rapid assessment by a senior anaesthetist and close monitoring in an intensive care setting. Initiation of treatment is required urgently to counter the evolving cardiovascular and respiratory compromise and the tumours usually have rapid response to treatment, shrinking over 24 to 48 hours. Those with abdominal disease can develop rapidly progressive distension from ascites along with peripheral oedema.
Important sequelae
The 5-year survival figures for children with NHL will vary depending on the histological diagnosis. Those with T-cell disease can expect 70% overall response, those with B-cell disease have 90%. Long-term effects are well recognised and will be the result of the chemotherapeutic agents used and the general impact of treatment such as time out of education and impact on family life.
Hodgkin Lymphoma (HL)
Clinical presentation
Hodgkin lymphoma usually presents in teenagers and young adults but has been identified in young children. Patients will present with painless, persistent lymphadenopathy, usually in the cervical or axillary areas, but a large mediastinal mass may produce respiratory symptoms. ‘B symptoms’ have been identified and their presence leads to more intensive treatment protocols.
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fever (greater than 38 o C)
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weight loss (greater than 10% body weight)
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drenching night sweats
Investigations
A tissue biopsy is needed to confirm diagnosis and exclude other causes of lymphadenopathy. Immunohistochemistry will identify characteristic surface antigens seen in HL.
Imaging has a major role in staging and will include a CT scan (cervical, mediastinal, abdominal and pelvic areas) and positron emission tomography (PET) scan ( Figure 22.4 ). The PET scan will identify sites of active disease in lymph nodes and organs and will be used to monitor treatment response.
Extensive disease is seen in submandibular, cervical, axillary, para-aortic and pelvic lymph nodes. Massive splenomegaly is evident as is liver and bone marrow involvement.
Treatment and management
Although there are differences in the details of management between international protocols, they all use a combination of treatment modalities with systemic chemotherapy and radiotherapy to affected sites. Some patients, however, can omit radiotherapy if they have a sufficiently good response to initial chemotherapy.
Long-term prognosis is dependent upon stage of disease at presentation but is generally very encouraging. Patients with Stage 1 (localised) disease have a UK 5-year survival of over 90% whilst the figure for those with Stage 4 (widely disseminated) disease is around 80%.
Important sequelae
Patients treated for HL during childhood or teenage years are at risk of significant long-term problems. Treatment protocols include an anthracycline which can induce a cardiomyopathy, but current protocols have reduced doses of this agent and therefore minimise this effect.
Radiotherapy to various sites may lead to tissue hypoplasia and an increased risk of malignancy within the radiation field. Further details are presented in the section on radiotherapy.
Central nervous system tumours
Clinical presentation
The presenting symptoms will depend upon the age of the child and the exact site of the lesion, but the most common ones are due to a raised intracranial pressure or from mass effect. They include:
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headaches (often worst when waking up)
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vomiting (usually relieves the headache)
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visual disturbance
Specific neurological signs may indicate the site of the lesion such as those in the posterior fossa (brain stem, fourth ventricle and cerebellum) inducing ataxia.
Very young children with central tumours may have regression of developmental milestones whilst lesions in the cerebral cortex can lead to seizures. Those with hypothalamic or midline lesions can present with endocrinopathies including:
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isolated growth hormone deficiency
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multiple-pituitary hormone deficiency including diabetes insipidus
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growth hormone excess
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gonadotrophin dependent sexual precocity
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pathological pubertal delay
Severe hydrocephalus presents with bradycardia, bradypnea and systolic hypertension, and death can occur from herniation of brain stem if not identified and treated promptly.
The HeadSmart campaign provides age-appropriate cards and online information aimed at increasing awareness of parents and healthcare professionals to the signs and symptoms.
Associations
Syndromes with a higher incidence of CNS malignancy include:
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neurofibromatosis type 1 (NF-1)—gliomas, particularly of optic pathway
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neurofibromatosis type 2 (NF-2)—Schwannomas particularly of auditory nerves
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tuberous sclerosis—develop SEGA (subependymal giant cell tumours).
Investigations
The patient with a suspected CNS tumour may present in extremis and would therefore need an urgent CT scan. This would allow the clinical team to assess the need for neurosurgical intervention to reduce a raised, and potentially critical, intracranial pressure.
MRI scans of the brain and the spine are then required in all patients to delineate the location and extent of the tumour ( Figure 22.5 ). MR spectroscopy can be used to detect chemical composition in some lesions and thereby suggest the tumour type. Histological examination of tissue removed by surgical excision or biopsy is, however, required for diagnosis.
