Malignant disease

Published on 21/03/2015 by admin

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Last modified 22/04/2025

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Malignant disease

Cancer in children is not common.

The types of disease seen (Fig. 21.1) are very different from those in adults, where carcinomas of the lung, breast, gut and skin predominate. The age at presentation varies with the different types of disease:

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Figure 21.1 Relative frequency of different types of cancer in children in the UK.

Despite significant improvements in survival over the last four decades (Fig. 21.2), cancer is the commonest disease causing death in childhood (beyond the neonatal period). Overall, the 5-year survival of children with all forms of cancer is about 75%, most of whom can be considered cured, although cure rates vary considerably for different diagnoses. This improved life expectancy can be attributed mainly to the introduction of multi-agent chemotherapy, supportive care and specialist multidisciplinary management. However, for some children, the price of survival is long-term medical or psychosocial difficulties.

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Figure 21.2 Five-year survival rates showing the considerable improvement over the last 50 years. (ALL, acute lymphoblastic leukaemia; NHL, non-Hodgkin lymphoma.) (Sources: 1971–2000. Stiller C (Editor) Childhood Cancer in Britain – Incidence, Survival, Mortality, Oxford, 2007, Oxford University Press; and 1966–1970 & 2001–2005, National Registry of Childhood Tumours, unpublished data.)

image In children, leukaemia is the most common malignancy followed by brain tumours.

Aetiology

In most cases, the precise aetiology of childhood cancer is unclear, but it is likely to involve an interaction between environmental factors (e.g. viral infection) and host genetic susceptibility. In fact, there are very few established environmental risk factors, and although cancer occurs as a result of mutations in cellular growth controlling genes, which are usually sporadic but may be inherited, in most cases a specific gene mutation is unknown. One example of an inherited cancer is bilateral retinoblastoma, which is associated with a mutation within the RB gene located on chromosome 13. There is a wide range of syndromes associated with an increased risk of cancer in childhood, e.g. associations exist between Down syndrome and leukaemia, and neurofibromatosis and glioma. In time, the further identification of biological characteristics of specific tumour cells may also help elucidate the basic pathogenetic mechanisms behind their origin.

Investigations

Initial symptoms can be very non-specific and this can often lead to significant delays in diagnosis. Once a diagnosis of malignancy is suspected, the child should be referred to a specialist centre for further investigation.

Management

Once malignancy has been diagnosed, the parents and child need to be seen and the diagnosis explained to them in a realistic, yet positive way. Detailed investigation to define the extent of the disease (staging) is paramount to planning treatment. Children are usually treated as part of national and international collaborative studies that offer consistency in care and have contributed to improvements in outcome.

In the UK, children with cancer are initially investigated and treated in specialist centres where experienced multidisciplinary teams can provide the intensive medical and psychosocial support required. Subsequent management is often shared between the specialist centre, referral hospital and local services within the community, to provide the optimum care with the least disruption to the family.

Treatment

Treatment may involve chemotherapy, surgery or radiotherapy, alone or in combination.

Surgery

Initial surgery is frequently restricted to biopsy to establish the diagnosis, and more extensive operations are usually undertaken to remove residual tumour after chemotherapy and/or radiotherapy.

High-dose therapy with bone marrow rescue

The limitation of both chemotherapy and radiotherapy is the risk of irreversible damage to normal tissues, particularly bone marrow. Transplantation of bone marrow stem cells can be used as a strategy to intensify the treatment of patients with the administration of potentially lethal doses of chemotherapy and/or radiation. The source of the marrow stem cells may be allogeneic (from a compatible donor) or autologous (from the patient him/herself, harvested beforehand, while the marrow is uninvolved or in remission). Allogeneic transplantation is principally used in the management of high-risk or relapsed leukaemia and autologous stem cell support is used most commonly in the treatment of children with solid tumours whose prognosis is poor using conventional chemotherapy, e.g. advanced neuroblastoma.

Supportive care and side-effects of treatment

Cancer treatment produces frequent, predictable and often severe multisystem side-effects (Fig. 21.3). Supportive care is an important part of management and improvements in this aspect of cancer care have contributed to the increasing survival rates.

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Figure 21.3 Short-term side-effects of chemotherapy.

Infection from immunosuppression

Due to both treatment (chemotherapy or wide-field radiation) and underlying disease, children with cancer are immunocompromised and at risk of serious infection. Children with fever and neutropenia must be admitted promptly to hospital for cultures and treatment with broad-spectrum antibiotics. Some important opportunistic infections associated with therapy for cancer include Pneumocystis jiroveci (carinii) pneumonia (especially in children with leukaemia), disseminated fungal infection (e.g. aspergillosis and candidiasis) and coagulase-negative staphylococcal infections of central venous catheters.

Most common viral infections are no worse in children with cancer than in other children, but measles and varicella zoster (chickenpox) may have atypical presentation and can be life-threatening. If non-immune, immunocompromised children are at risk from contact with measles or varicella, some protection can be afforded by prompt administration of immunoglobulin or zoster immune globulin. Aciclovir is used to treat established varicella infection, but no treatment is available for measles. During chemotherapy and from 6 months to a year subsequently, the use of live vaccines is contraindicated due to depressed immunity. After this period, re-immunisation against common childhood infections is recommended.

Other supportive care issues

Fertility preservation

Some patients may be at risk of infertility as a result of their cancer treatment. Appropriate fertility preservation techniques may involve surgically moving a testis or ovary out of the radiotherapy field; sperm banking (which should be offered to boys mature enough to achieve this); and consideration of newer techniques such as cryopreservation of ovarian cortical tissue, although the long-term efficacy of this is still uncertain.

Psychosocial support

The diagnosis of a potentially fatal illness has an enormous and long-lasting impact on the whole family. They need the opportunity to discuss the implications of the diagnosis and its treatment and their anxiety, fear, guilt and sadness. Most will benefit from the counselling and practical support provided by health professionals. Help with practical issues, including transport, finances, accommodation and care of siblings, is an early priority. The provision of detailed written material for parents will help them understand their child’s disease and treatment. The children themselves, and their siblings, need an age-appropriate explanation of the disease. Once treatment is established and the disease appears to be under control, families should be encouraged to return to as normal a lifestyle as possible. Early return to school is important and children with cancer should not be allowed to under-achieve the expectations previously held for them. It is easy to underestimate the severe stress that persists within families in relation to the uncertainty of the long-term outcome. This often manifests itself as marital problems in parents and behavioural difficulties in both the child and siblings.

Summary

Malignant disease in children

Leukaemia

Acute lymphoblastic leukaemia (ALL) accounts for 80% of leukaemia in children. Most of the remainder is acute myeloid/acute non-lymphocytic leukaemia (AML/ANLL). Chronic myeloid leukaemia and other myeloproliferative disorders are rare.

Clinical presentation

Presentation of acute lymphoblastic leukaemia peaks at 2–5 years. Clinical symptoms and signs result from disseminated disease and systemic ill-health from infiltration of the bone marrow or other organs with leukaemic blast cells (Fig. 21.5). In most children, leukaemia presents insidiously over several weeks (see Case History 21.1) but in some children the illness presents and progresses very rapidly.

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Figure 21.5 Signs and symptoms of acute leukaemia.

Case History

21.1 Disseminated disease, e.g. bone marrow infiltration, causing systemic ill-health

A 4-year-old girl was generally unwell, lethargic, looking pale and occasionally febrile over a period of 9 weeks. Two courses of antibiotics for recurrent sore throat failed to result in any benefit. Her parents returned to their general practitioner when she developed a rash. Examination showed pallor, petechiae, modest generalised lymphadenopathy and mild hepatosplenomegaly. A full blood count showed:

Blast cells were seen on the peripheral blood film. Cerebrospinal fluid (CSF) examination was normal. Bone marrow examination confirmed acute lymphoblastic leukaemia (Fig. 21.6).

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Figure 21.6 Leukaemic blast cells on a bone marrow smear.

Diagnosis: Acute lymphoblastic leukaemia.

Management of acute lymphoblastic leukaemia

A number of factors contribute to prognosis in ALL and dictate the intensity of therapy (Table 21.1).

Table 21.1

Prognostic factors in acute lymphatic leukaemia

Prognostic factor High-risk features
Age <1 year or >10 years
Tumour load (measured by the white cell count, WBC) >50 × 109/L
Cytogenetic/molecular genetic abnormalities in tumour cells e.g. MLL rearrangement, t(4;11), hypodiploidy (<44 chromosomes)
Speed of response to initial chemotherapy Persistence of leukaemic blasts in the bone marrow
Minimal residual disease assessment (MRD) (submicroscopic levels of leukaemia detected by PCR) High

A typical treatment schema is shown in Figure 21.7.

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Figure 21.7 Treatment schema for standard-risk acute lymphoblastic leukaemia.

Brain tumours

In contrast to adults, brain tumours in children are almost always primary and 60% are infratentorial. They are the most common solid tumour in children and are the leading cause of childhood cancer deaths in the UK. The types of brain tumour are:

Lymphomas

Lymphomas are malignancies of the cells of the immune system and can be divided into Hodgkin and non-Hodgkin lymphoma (NHL). NHL is more common in childhood, while Hodgkin lymphoma is seen more frequently in adolescence.

Hodgkin lymphoma

Clinical features

Classically presents with painless lymphadenopathy, most frequently in the neck. Lymph nodes are much larger and firmer than the benign lymphadenopathy commonly seen in young children. The lymph nodes may cause airways obstruction (see Case History 21.2). The clinical history is often long (several months) and systemic symptoms (sweating, pruritus, weight loss and fever – the so-called ‘B’ symptoms) are uncommon, even in more advanced disease.

Non-Hodgkin lymphoma

T-cell malignancies may present as acute lymphoblastic leukaemia or non-Hodgkin lymphoma, with both being characterised by a mediastinal mass with varying degrees of bone marrow infiltration. The mediastinal mass may cause superior vena caval obstruction. B-cell malignancies present more commonly as non-Hodgkin lymphoma, with localised lymph node disease usually in the head and neck or abdomen. Abdominal disease presents with pain from intestinal obstruction, a palpable mass or even intussusception in cases with involvement of the ileum.

Management

Multi-agent chemotherapy. The majority of patients now do well and survival rates of over 80% are expected for both T- and B-cell disease.

Case History

21.2 Pressure from a mass on local structures or tissue, e.g. airway obstruction secondary to enlarged lymph nodes

A 14-year-old girl complained of a cough for 2 weeks which was non-productive and worse at night. She had seen her general practitioner and her chest was clear. She returned 2 weeks later, as she had noticed a swelling in her neck. On examination, she had a large anterior cervical lymph node which was non-tender. On referral to hospital, she had a chest X-ray, which showed a large mediastinal mass (Fig. 21.10).

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Figure 21.10 Chest X-ray showing a large mediastinal mass.

Neuroblastoma

Neuroblastoma and related tumours arise from neural crest tissue in the adrenal medulla and sympathetic nervous system. It is a biologically unusual tumour in that spontaneous regression sometimes occurs in very young infants. There is a spectrum of disease from the benign (ganglioneuroma) to the highly malignant (neuroblastoma). Neuroblastoma is most common before the age of 5 years.

Clinical features

At presentation (Box 21.1), most children have an abdominal mass, but the primary tumour can lie anywhere along the sympathetic chain from the neck to the pelvis. Classically, the abdominal primary is of adrenal origin, but at presentation the tumour mass is often large and complex, crossing the midline and enveloping major blood vessels and lymph nodes. Paravertebral tumours may invade through the adjacent intervertebral foramen and cause spinal cord compression. Over the age of 2 years, clinical symptoms are mostly from metastatic disease, particularly bone pain, bone marrow suppression causing weight loss and malaise (see Case History 21.3).

Box 21.1   Presentation of neuroblastoma

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Case History

21.3 Neuroblastoma

Jack, a 3-year-old boy, was taken to his general practitioner by his mother because he was not eating as well as usual and had a distended abdomen. Recently, he appeared reluctant to walk and sometimes cried when he was picked up. His grandmother thought he had lost weight. On examination, the general practitioner confirmed that he seemed generally miserable and pale. He was concerned to note a large abdominal mass. Urgent referral to his local hospital was made and, on arrival, he was also noted to be hypertensive.

Differential diagnosis and specific investigations

An initial ultrasound examination confirmed the abdominal mass and an MRI scan characterised a very large upper abdominal mass in complex relationship with the left kidney and the major vessels but extending towards the midline, suggestive of neuroblastoma (Fig. 21.11). Subsequent investigations confirmed bone marrow infiltration by tumour cells and a positive MIBG scan showing uptake at the primary and distant sites consistent with metastatic disease (Fig 21.12).

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Figure 21.11 Transverse MRI image showing a large left-sided primary neuroblastoma arising from the adrenal region and distorting coeliac and mesenteric blood vessels.
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Figure 21.12 The MIBG scan ‘maps’ metastatic tumour marrow. This image shows the lower half of the abdomen, pelvis and legs. The dark areas are evidence of high isotope uptake and the pattern is consistent with widespread metastatic disease. (Normal uptake from excretion of isotope into urine in the bladder has been blocked in this exposure.)

Diagnosis: Metastatic neuroblastoma.

Investigations

Characteristic clinical and radiological features with raised urinary catecholamine levels suggest neuroblastoma. Confirmatory biopsy is usually obtained and evidence of metastatic disease detected with bone marrow sampling, MIBG (metaiodobenzyl-guanidine) scan (as in Fig. 21.12) with or without a bone scan.

Age and stage of disease at diagnosis are the major factors which influence prognosis. Unfortunately, the majority of children over 1 year present with advanced disease and have a poor prognosis. Increasingly, information about the biological characteristics of neuroblastoma is being used to guide therapy and prognosis. Overexpression of the N-myc oncogene, evidence of deletion of material on chromosome 1 (del 1p) and gain of genetic material on chromosome 17q in tumour cells are all associated with a poorer prognosis.

Investigations

Ultrasound and/or CT/MRI (Fig. 21.13) is usually characteristic, showing an intrinsic renal mass distorting the normal structure. Staging is to assess for distant metastases (usually in the lung), initial tumour resectability and function of the contralateral kidney.

Wilms tumour

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Figure 21.13 Large Wilms tumour arising within the left kidney, showing characteristic cystic and solid tissue densities.

Soft tissue sarcomas

Rhabdomyosarcoma is the most common form of soft tissue sarcoma in childhood. The tumour is thought to originate from primitive mesenchymal tissue and there are a wide variety of primary sites, resulting in varying presentations and prognosis.

Bone tumours

Malignant bone tumours are uncommon before puberty. Osteogenic sarcoma is more common than Ewing sarcoma, but Ewing sarcoma is seen more often in younger children. Both have a male predominance.

Management

In both tumours, treatment involves the use of combination chemotherapy given before surgery. Whenever possible, amputation is avoided by using en bloc resection of tumours with endoprosthetic resection (Fig. 21.15d). In Ewing sarcoma, radiotherapy is also used in the management of local disease, especially when surgical resection is impossible or incomplete, e.g. in the pelvis or axial skeleton.

Retinoblastoma

Retinoblastoma is a malignant tumour of retinal cells and, although rare, it accounts for about 5% of severe visual impairment in children. It may affect one or both eyes. All bilateral tumours are hereditary, as are about 20% of unilateral cases. The retinoblastoma susceptibility gene is on chromosome 13, and the pattern of inheritance is dominant, but with incomplete penetrance. Most cases present within the first 3 years of life. Children from families with the hereditary form of the disease should be screened regularly from birth.

Rare tumours

Liver tumours

Primary malignant liver tumours are mostly hepatoblastoma (65%) or hepatocellular carcinoma (25%). Presentation is usually with abdominal distension or with a mass. Pain and jaundice are rare. Elevated serum α-fetoprotein (αFP) is detected in nearly all cases of hepatoblastoma and in some cases of hepatocellular carcinoma. Management includes chemotherapy, surgery and, in inoperable cases, liver transplantation is required. The majority of children with hepatoblastoma can now be cured, but the prognosis for children with hepatocellular carcinoma is less satisfactory.

Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare disorder characterised by an abnormal proliferation of histiocytes. It is no longer believed to be a truly malignant condition and is classified as a disorder of dendritic (antigen presenting) cells. However, its sometimes aggressive behaviour and its response to chemotherapy place it within the practice of oncologists. Clinically, its manifestations include:

• Bone lesions – present at any age with pain, swelling or even fracture. X-ray reveals a characteristic lytic lesion with a well-defined border, often involving the skull (Fig. 21.17).

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Figure 21.17 Lytic bone lesions on a skull X-ray in Langerhans cell histiocytosis.

• Diabetes insipidus – may be associated with skull disease with proptosis and hypothalamic infiltration

• Systemic LCH – the most aggressive form which tends to present in infancy with a seborrhoeic rash (Fig. 21.18) and soft tissue involvement of the gums, ears, lungs, liver, spleen, lymph nodes and bone marrow. This form of LCH is usually progressive and requires chemotherapy, although spontaneous regression may occur.

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Figure 21.18 Rash in systemic Langerhans cell histiocytosis. It is often mistaken for seborrhoeic dermatitis or eczema.

The prognosis is variable, but most patients are cured.

Long-term survivors

Improved survival rates means an ever-increasing population of adult survivors of childhood cancer. Over half have at least one residual problem as a consequence of either the disease or its treatment (Table 21.2).

Table 21.2

Some problems that may occur following cure of childhood cancer

Problem Cause
Specific organ dysfunction Nephrectomy for Wilms tumour
Toxicity from chemotherapy, e.g. renal from cisplatin or ifosfamide, cardiac from doxorubicin or mediastinal radiotherapy
Growth/endocrine problems Growth hormone deficiency from pituitary irradiation
Bone growth retardation at sites of irradiation
Infertility Gonadal irradiation
Alkylating agent chemotherapy (cyclophosphamide, ifosfamide)
Neuropsychological problems Cranial irradiation (particularly at age <5 years)
Brain surgery
Second malignancy Irradiation
Alkylating agent chemotherapy
Social/educational disadvantage Chronic ill health
Absence from school

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All survivors need regular long-term follow-up to provide appropriate treatment or advice. This need for specialist multidisciplinary follow-up continues into adulthood, and its provision presents a challenge within adult healthcare services. Until recently, the majority of survivors have remained under the care of paediatric oncologists, although specialist adult clinics are being established. Some survivors will require specific counselling for problems such as poor or asymmetric growth, infertility and sexual dysfunction, and advances in the use of adult growth hormone. Assisted conception techniques have enhanced the lives of many patients. The risk of second cancer is small, but nevertheless survivors are at increased risk and this may rise with increasing survival rates. When new treatment protocols for childhood cancers are developed, there is a need to reduce, whenever possible, the toxicity of treatment to spare the children adverse short- and long-term effects.

Palliative care

When a child relapses, further treatment may be considered. A reasonable number can still be cured and others may have a further significant remission with good-quality life. However, for some children, a time comes when death is inevitable and the staff and family must make the decision to concentrate on palliative care.

Most parents prefer to care for their terminally ill child at home, but will need practical help and emotional support. Pain control and symptom relief are a serious source of anxiety for parents, but they can often be achieved successfully at home. Health professionals with experience in palliative care for children work together with the family and local healthcare workers. After the child’s death, families should be offered continuing contact with an appropriate member of the team who looked after their child, and be given support through their bereavement.

image With adequate support from health professionals, palliative care for children can usually be provided at home.

Summary

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