Cancer in Children: Clinical Management, 5th Edition

Chapter 26. Rare tumours

David A. Walker

Introduction

Cancer is a ‘moderate-risk’ disease of childhood (age 0–14 years), affecting one in 650 children. The tumours included in this chapter are those which are rare among the generality of childhood tumours. They are not rare variants of the common childhood tumour categories and they have been reported to have the capacity to invade and metastasize.

This diverse group of rare tumours is collected together to enhance access to agespecific information on diagnosis, treatment, and outcome. There are often insufficient recent data available to reach a consensus on the best treatment. This lack of information is disabling for the oncologist and a source of anxiety for the child and family when no one seems to be familiar with the condition and its treatment. Many of the tumours are more common in adulthood, and the recommended treatment plans have evolved from adult practice which, if followed without modification, may cause unacceptable morbidity in a developing child.

National groups are focusing on these rare tumours through national tumour registration, development of clinical guidelines, and promotion of a network of clinicians with a special interest. These developments will increasingly provide opportunities for the development and evaluation of new treatment approaches and promote relevant research.

The epithelial cancers (carcinomas) are the single largest group, accounting for 2–3 per cent of all childhood malignant disease in Western populations. For most sites, incidence increases with age throughout childhood and well into adult life. Presumably the childhood cases represent the very beginning of the age–incidence curve, although it is noteworthy that the most common carcinomas of adulthood, those of lung and breast, are exceptionally rare in childhood in all regions of the world. Exceptions to this age–incidence pattern are adrenal carcinoma and nasopharyngeal carcinoma, where there is a bimodal age distribution.

Sex incidence and 5-year survival rates of selected rare malignant tumours are given in Tables 26.1 and 26.2.

Head and neck

Nasopharyngeal carcinoma

Nasopharyngeal carcinomas (NPCs) are the most common epithelial tumour in childhood, accounting for 30 per cent of the nasopharyngeal malignancies in this age group.

Incidence

There is considerable variation in international incidence in childhood. In predominantly White populations, the incidence in childhood is usually no more than 0.4 per million, whereas in the US Black population it is about one per million. In Chinese populations, rates in children are 0.8 per million. The highest incidence is apparently in North Africa; reliable incidence rates are not available, but nasopharyngeal carcinoma could well account for 10 per cent of childhood cancer. There is a bimodal age distribution with an early peak in adolescence and young adulthood in European and American Caucasians but not in Southeast Asians or North Africans. It is more common in males, although this male preponderance is less marked in the younger age groups.

Table 26.1. Sex incidence and 5-year survival rate: selected rare malignant tumours from National Registry of Childhood Tumours, UK, 1981–1995

ICD-10 code

Site

Male

Female

5-year survival rate (%)

COO-06

Mouth

5

7

92

C07-08

Salivary glands

17

18

94

C11

Nasopharynx

32

13

54

C1 5-21,26

Gastrointestinal

12

6

33

CIS-21,26

Malignant carcinoid, gut

3

1

(75)

C25

Pancreas

1

2

(33)

C34

Bronchus, lung

2

1

(33)

C34

Malignant carcinoid, lung

2

0

(100)

C37

Thymus

8

1

(0)

C44

Skin

40

52

99

C56

Ovary

0

19

62

C62

Testis

1

0

(0)

CM

Kidney

13

9

68

C67

Bladder

5

2

100

C73

Thyroid

28

56

98

C74

Adrenal

3

24

38

Table 26.2. Sex incidence and 5-year survival rate: selected rare malignant tumours from National Registry of Childhood Tumours, UK, 1981–1995

ICD-10 classification

Site

Male

Female

5-year survival rate (%)

8720–8780/3

Malignant melanoma

88

110

90

Skin

78

104

93

Eye

6

4

(80)

Central nervous system

4

2

(17)

8971/3

Pancreatoblastoma

3

2

(20)

8972/3

Pulmonary blastoma

0

1

9050–9053/3

Malignant mesothelioma

0

2

(50)

9310/3

Malignant ameloblastoma

1

0

(100)

9370/3

Chordoma

4

5

(78)

9590/3

Malignant granular cell tumour

1

2

100

Aetiology

There is evidence for family clustering and an association with specific HLA types. A possible causative role of dietary carcinogen intake has been raised but not proven. Rare cases of NPC complicating invasive juvenile laryngeal papillomatosis have been reported, especially after the use of radiation therapy. An association with the Epstein–Barr virus (EBV) has been clearly established by sero-epidemiologic surveys. Indeed, in Southern China population screening for NPC is performed using EBV serology. The EBV antibody level is used to quantify tumour burden, response to treatment, and screening for relapse. EBV DNA has been shown to be present in premalignant carcinoma in situ lesions as well as in active tumour. It has been shown to be clonal and arise from a single EBV-infected cell. The precise role of EBV in oncogenesis remains unclear. Its ubiquitous distribution in populations coupled with wide variations in tumour incidence suggests that genetic and environmental factors interact.

Pathology

The tumours are most commonly undifferentiated carcinomas (WHO type 3) or nonkeratinizing carcinomas (WHO type 2). WHO type 2 and 3 NPCs are accompanied by an inflammatory infiltrate of lymphocytes, eosinophils, and plasma cells, which explains the earlier name of lymphoepithelioma. The tumours usually arise in the fossa of Rosenmüller and spread locally to the rest of the pharynx and the base of skull. They metastasize preferentially to cervical lymph nodes, bone, mediastinum, lung, and liver.

Clinical presentation

The most common clinical presentation is with cervical lymphadenopathy (80 per cent); the primary tumour in the nasopharynx is often clinically undetectable. Symptoms related to the primary tumour result from involvement of local structures and include hearing loss, local mass, nasal obstruction, otitis media, epistaxis, cranial nerve palsies, and headache. Disseminated tumour may produce symptoms related to the site of metastasis (<10 per cent). Rarely, a paraneoplastic syndrome in patients with disseminated disease may occur with osteoarthropathy, clubbing, and bone or joint pain. Delays in diagnosis are frequent.

Tumour staging

Tumour evaluation should be directed at the delineation of the extent of the primary tumour, local lymph node involvement, and a search for distant metastases. Nasolaryngoscopy may not reveal a primary tumour, but blind biopsies may be taken. Imaging of the base of skull with plain radiography, CT, or MRI scans (Fig. 26.1) permits definition of tumour size, site, and lymph node involvement as well as local bony or central nervous system invasion which can be confirmed by examination of the cerebrospinal fluid. Evidence of metastatic disease should be sought with radionuclide bone scanning, chest CT, and abdominal ultrasound or MRI. Positron emission tomography may image symptomatic tumour deposits which are not otherwise detectable. Raised serum-IgA antibody to the viral capsid antigen may be of prognostic value and has been used as a tumour marker. The staging system in the 5th edition of the American Joint Cancer Committee (AJCC) is currently used (Table 26.3).

Surgery

The curative role of surgical treatment is limited by the high incidence of early spread of the primary tumour at diagnosis. Surgical efforts are generally limited to biopsy and the treatment of otitis media prior to local radiotherapy. Therefore successful treatment of this tumour depends on the use of radiotherapy and chemotherapy.

Fig. 26.1 CT scans showing (a) axial and (b) sagittal images of a nasopharyngeal carcinoma invading the skull base.

Table 26.3. American Joint Cancer Committee (AJCC) staging system for nasopharyngeal carcinoma (5th edition)

T1

Tumour confined to the nasopharynx

T2

Tumour extends to the soft tissue of oropharynx and/or nasal fossa

T2a

Without parapharyngeal extension

T2b

With parapharyngeal extension

T3

Tumour invades bony structures and/or paranasal sinuses

T4

Tumour with intracranial extension and/or involvement of cranial nerves, infratemporal fossa,
hypopharynx, or orbit

NO

No regional lymph node metastasis

N1

Unilateral metastasis in lymph node(s) measuring 6 cm in greatest dimension above the
supraclavicular fossa

N2

Bilateral metastasis in lymph node(s) measuring 6 cm in greatest dimension above the
suprclavicular fossa

N3

Metastasis in lymph node(s)

N3a

>6 cm in greatest dimension

N3b

Extension to the supraclavicular fossa

MO

No distant metastasis

M1

Distant metastasis

Stage I

     T1

NO

MO

Stage HA

     T2a

NO

MO

Stage IIB

     T1

N1

MO

     T2a

N1

MO

     T2b

NO-1

MO

Stage III

     T1

N2

MO

     T2

N2

MO

     T3

NO-2

MO

Stage IVA

     T4

NO-2

MO

Stage IVB

     Any T

N3

MO

Stage IVC

     Any T

Any N

M1

Chemotherapy

In principle, the high incidence of metastatic relapse favours aggressive systemic therapy early in treatment. The role of chemotherapy in this tumour is now established in children as a result of a number of prospective but non-randomized reports of the use of adjuvant chemotherapy. A recently published randomized study has shown that chemotherapy with 5-fluorouracil, cisplatin, and radiotherapy is superior to radiotherapy alone in adults with advanced disease. Tumour shrinkage with initial chemotherapy has been well documented. Tumours that do not respond to combined chemotherapy and radiotherapy do poorly with other treatments. The recent report of exceptional survival rates using adjuvant interferon also raises the possibility that biologic modifiers may have a role to play in tumour control. The GPOH reported results of multimodality treatment using pre-radiation chemotherapy (methotrexate, 5-fluorouracil, and cisplatin) and radiotherapy to the primary tumour bed (54.9 Gy) and whole neck (45 Gy). Subsequently, all patients were treated with adjuvant interferon-b (105 U/kg, three times a week for 6 months) with a high response rate (91 per cent) and sustained remission.

Radiation

Irradiation of the nasopharynx requires careful planning to encompass the whole tumour volume with adequate margins yet exclude adjacent involved structures. Doses >50Gy have not been shown to be more effective in younger age groups, and so most therapists have avoided the 70-Gy doses advised in the adult population. Irradiation has been used to treat metastatic tumour recurrence with good effect.

Prognosis

The CCSG study from the early 1980s using radiotherapy alone (35–80 Gy) reports overall and relapse-free survival of 51 per cent and 36 per cent, respectively, at 5 years, and 45 per cent and 33 per cent, respectively, at 10 years. Tumour staging predicts outcome; 5-year overall survival for T1–2 and T3–4 tumours are 63–90 per cent and 22–75 per cent, respectively. Survival rates in children and young people (aged <30 years) were better than those in adult patients.

Late effects

In view of the substantial number of survivors, careful consideration must be given to the late effects of therapy. Cervical and temporomandibular joint fibrosis are well-recognized complications which are more common in patients treated with higher doses. Irradiation of the thyroid gland, inner ear, and hypothalamus requires careful monitoring of hearing, growth, and endocrine functions.

Thyroid cancer

Thyroid cancer (TC) has an incidence of 0.2–1.5 per million per year and is considerably more common in girls than boys. Five to ten per cent of all TC occurs in childhood and adolescence.

Pathology

The majority of tumours in the young age group are of the highly differentiated papillary type or the less differentiated follicular and mixed types. Anaplastic tumours are exceptional. Medullary thyroid carcinoma (MTC) accounts for up to 20 per cent of all TCs in childhood, the majority of which are associated with the multiple endocrine neoplasia (MEN) syndrome type 2 in which a high proportion are multifocal and bilateral. TC metastasizes to local lymph nodes, lung, and bone.

Aetiology

Aetiologic factors implicated include a history of exposure to environmental or therapeutic irradiation, genetic predisposition (familial adenomatous polyposis, Cowden's disease) and dietary iodide intake or changes in endocrine status.

Radiation

Ionizing irradiation is strongly implicated in the oncogenesis of TC. Evidence for this comes from clinical reports describing excess risk of TC in those who had previously received therapeutic irradiation. This risk is enhanced in patients with neuroblastoma who had received treatment with meta-iodobenzylguanidine (MIBG). The impact of environmental irradiation has been intensively studied since atmospheric testing of nuclear weapons after the Second World War and more recently after the radiation leak at Chernobyl. Incidence rates after the accident were raised by up to 10-fold in heavily contaminated areas and are thought to be related to exposure to radioactive iodine. Younger children, some of whom were irradiated in utero, were more vulnerable than adolescents. The tumours have been reported as being more aggressive in their clinical behaviour.

ret proto-oncogene mutations

Oncogenic rearrangements of the ret tyrosine kinase receptor have been characterized in patients with both differentiated papillary TC and MTC. Specific somatic rearrangements (retPTC1ret–PTC2, and ret–PTC3) have been identified; all are formed by the fusion of the truncated tyrosine kinase domain of ret to the amino terminus of different gene fragments. Their frequency varies according to geographic area, with the highest being in Italy (33–35 per cent) and the lowest in Saudia Arabia (2.5 per cent) and Japan (0–9 per cent). ret-PTC1 mutation is most common in sporadic cases, whilst ret/PTC3 is most common in radiationinduced cases in both adults and children. These mutated receptors are now being targeted for new therapies.

Medullary thyroid cancer

MEN type 2 syndromes are associated with MTC development. Previously MEN risk was estimated by the pentagastrin stimulation test in which enhanced calcitonin secretion indicated the existence of the MEN syndrome. Germ-line point mutations of the ret proto-oncogene have identified these genes as being causative in MTC. Screening for these mutations in at-risk individuals permits their identification without the use of the pentagastrin stimulation test.

Clinical presentation

Clinical presentation is commonly with thyroid swelling in a euthyroid patient or during surveillance of patients previously irradiated or individuals from kindreds with familial predisposition to TC. The use of family photographs to time the onset of the swelling may be a valuable clue to the differential diagnosis. There may be associated symptoms including hoarseness, dysphagia, dyspnoea, haemoptysis, recurrent laryngeal nerve palsy, or thyrotoxicosis.

Investigation

Scanning of the thyroid with [123I] sodium iodide will differentiate between multinodular goitre and hot and cold nodules. The majority of hot nodules are benign. Cold nodules require further imaging with ultrasound to exclude cysts.

Diagnosis

Fine-needle aspiration biopsy is not recommended in children, in contrast with adult practice. Measurement of serum thyroglobulin (TG) after thyroid-stimulating hormone (TSH) suppression and serum calcitonin will help differentiate between MTCs and TCs. TG is a useful tumour marker. Distant metastases can be demonstrated by 131I uptake studies after resection of the primary tumour and blockade of iodine uptake by the thyroid remnant. Conventional imaging with radiography and CT/MRI scans will demonstrate local spread to the mediastinum and lung.

Surgery

In the papillary/follicular tumours, conservative resection of the primary is recommended with resection restricted to lobectomy and ishiectomy in solitary nodules. Radical neck dissection, with its attendant risks, is generally avoided in children with differentiated tumours. Total thyroidectomy is recommended for MTC in view of the high incidence of multifocal tumours, in individuals affected by MEN type 2A as a prophylactic procedure before the age of 5 years, and in those with MEN type 2B in the first year of life. Complete thyroidectomy is also advocated in patients exposed to significant environmental radiation in order to remove all residual potentially tumour-bearing tissue and in those with papillary tumours occurring at age <10 years because of the reputation of enhanced aggressiveness.

Radiotherapy

Adjuvant therapy with

131I after thyroid ablation is used for treatment of metastatic deposits. Shrinkage of secondary tumours with 131I therapy is easily demonstrated, and repeated doses can be used. Its role in patients without metastases is unknown. The influence of radio-iodine treatment on survival has not been tested in a randomized trial. Its use did not predict for survival in an uncontrolled study of treatment outcome. The long-term side effects of 131I therapy in children are unclear, although post-radiation tissue atrophy in growing tissues and the increased risk of thyroid tumours after external beam thyroid irradiation are well known.

Medical care/chemotherapy

Reduction of thyroid tissue stimulation by thyroxine/tri-iodothyronine suppression of TSH production is used as preoperative preparation. Cytotoxic chemotherapy has not been widely used in these tumours. However, responses to single-agent therapy with etoposide, carboplatin, or cisplatin, and combination therapy with methotrexate and Adriamycin, bleomycin, or vincristine have been reported.

Prognosis

Reports frequently describe thyroid cancer in children as being aggressive with nodal metastases and frequent pulmonary metastases. The indolent nature of the majority of papillary and follicular TCs is associated with a 99 per cent overall 5-year survival (Table 26.1) in UK population-based figures. Series report up to 20 per cent recurrence rates. Deaths due to such tumours have been reported up to 30 years from diagnosis, and the standardized mortality ratio in patients aged <15 years at diagnosis has been calculated as 11.2. Prognostic variables in uncontrolled trials are limited to age at diagnosis, nodal invasion, and degree of tumour differentiation, with more differentiated tumours having a better prognosis. DNA aneuploidy has been associated with increasing age and tumour malignancy, but did not act independently on the prognosis of 125 adult patients. MTCs have a worse prognosis with only 50 per cent survival.

Salivary carcinomas

Salivary gland masses may include benign adenomas, haemangioma, lymphangioma, or malignant tumours such as mucoepidermoid carcinoma, acinic cell carcinoma, adenocarcinoma, soft tissue sarcoma, and leukaemic or lymphomatous infiltrates. Oral carcinoma in childhood may be 10 times as common in Bangladesh as it is in the UK, and some cases may be linked to chewing betel nut and tobacco. In the United States, the incidence among Black children is three times that among White children.

Clinical presentation and investigation

Clinical presentation is with a localized mass with or without facial pain and/or a facial palsy in parotid tumours. Regional lymph nodes may be involved at presentation. Investigation with facial radiography and CT/MRI scanning should be performed to define local tumour extension prior to surgery. A closed or incisional biopsy is not recommended. Staging investigations for distant spread to lung, liver, brain, and bone should be performed in high-grade tumours once the diagnosis has been confirmed histologically.

Pathology

Pleomorphic adenomas are well circumscribed benign solitary lesions; they rarely invade the gland capsule. The most common malignant salivary gland tumour type is the mucoepidermoid carcinoma, followed by acinic cell carcinoma, adenoid cystic carcinoma, and adenocarcinoma. Tumours are graded from I to III according to the level of differentiation.

Treatment

The primary aim of treatment is to achieve complete surgical excision. In the parotid gland, preservation of the facial nerve is highly desirable. Radiotherapy to areas of residual disease may be considered as an alternative to creating a facial palsy, as the cosmetic disfigurement may be less from radiotherapy if considerable facial growth has already occurred. Limited responses to chemotherapy using cisplatin, doxorubicin, 5-fluorouracil, cyclophosphamide, and vinorelbine given alone or in combination have been reported in adult patients. The best response rates reported used a combination of three or four of these drugs. Whether such response rates would be better in children is not reported. It does raise the possibility that chemotherapy might be used in individuals where the facial nerve is involved in order to attempt to make the tumour resectable without sacrificing the nerve.

There is a high incidence of local recurrence in both benign and malignant tumours. Evidence of incomplete resection or disseminated tumour justifies consideration of repeated surgery or radiotherapy if the disease is localized. Chemotherapy should be considered if the disease is disseminated, as this has been shown to produce durable remission and symptomatic relief.

Laryngeal carcinoma

Laryngeal carcinoma is extremely rare in childhood. It occurs most frequently after irradiation of juvenile laryngeal papillomatosis. Presentation is with cough, hoarseness, haemoptysis, stridor, and dysphagia. The tumours present later when located above the vocal cords. Diagnosis is made with microlaryngoscopy. Evidence for distant metastases should be sought with CT/MRI scanning of the chest and bone scanning. Tumours secondary to laryngeal papillomatosis are believed to metastasize rarely.

The rarity of this tumour in childhood has prevented the development of an established treatment approach. Preservation of the larynx is generally a high priority. Laser surgery, partial or total laryngectomy with or without local irradiation, may be employed depending upon the stage of the lesion. Overall survival of 59 per cent has been reported with such an approach. The inhibition of laryngeal growth coupled with the increased risk of secondary laryngeal and thyroid malignancies after irradiation makes the investigation of chemotherapy in these tumours in childhood a high priority. Reports of children being treated with chemotherapy are few, but responses have been noted. A recent review of adult trials of chemotherapy concluded that the use of induction therapy is feasible and delays development of distant metastases, although local and regional control are not improved and overall survival is unchanged. Concomitant chemotherapy and radiotherapy does produce superior survival in adults but remains experimental.

Angiofibroma

This tumour of adolescence occurs almost exclusively in males, suggesting an endocrine aetiology although this is not proven. The tumour is a mixed fibroblastic vascular tumour which is believed to be mesenchymal in origin. It commonlyarises in the nasoororopharynx and invades local surrounding hard and soft tissues; metastases are rare. It has been reported to invade the orbit, maxilla, and hard and soft palate as well intracranially. Clinical presentation is commonly with a unilateral facial swelling, obstructed nares, and recurrent epistaxis. Visualization of the tumour by anterior or posterior rhinoscopy reveals a dark red glistening tumour, warning of its extreme vascularity. Differential diagnosis includes inflammatory polyps, glomus jugulare tumour, capillary haemangioma, and fibromyxoma. Histologic examination is required to confirmthis, but biopsy isnot recommended. Treatment ismainly restrictedtosurgical resection using conventional or laser techniques. Some tumours are suitable for embolization. Local recurrences can occur. Case reports of tumour regression produced by hormone blockers and chemotherapy (flutamide, Adriamycin and DTIC) may justify trial of these approaches in extensive unresectable or recurrent cases. Stilboestrol and radiation have been used, although short- and long-term side effects in children limit the acceptability of these treatments.

Ameloblastoma (adamantimoma)

In childhood these tumours may be benign or malignant. They most commonly arise in the mandible and maxilla, although they are occasionally reported in the long bones. The facial presentation has been associated with enamel development of the teeth and primordial or dentigerous cysts. Infection, irritation, and nutritional deficiency have been suggested as possible aetiologic factors. Radiographs of the tumour reveal an osteolytic solitary cystic lesion. The treatment of choice is local tumour excision. Local recurrences are more common in the mandible than the maxilla. Radiotherapy has produced tumour responses, and sensitivity to chemotherapy has been reported with a wide variety of conventional agents. Pulmonary metastases have been reported many years after treatment of the primary lesion warranting modality therapy.

Chordoma

This rare tumour is thought to develop from remnants of the notochord and presents as a slow-growing locally invasive lobulated mass. It is more common in boys than girls and can arise anywhere within the axial skeleton, although it is most common in the spheno-occipital and sacrococcygeal regions. It can also occur in vertebral and extra-axial sites such as the facial bones, sinuses, and mediastinum. There is a tendency for chordomas of childhood to be intracranial and more aggressive. Metastatic spread occurs in 10 per cent of patients as a late event, but is much lower in intracranial tumours. A recent report has identified loss of heterozygosity for the retinoblastoma gene in highly aggressive chordomas.

Clinical presentation is often late, with a prolonged history of symptoms related to tumour invasion or pressure on local structures. Investigation with radiography and CT/MRI scans will define the extent of the tumour. Treatment has been with a combination of local excision and radiotherapy. The restrictions on wide surgical excision imposed by the tumour site lead to a high incidence of local recurrence and a poor prognosis. The use of high radiation doses, close to the limits of normal tissue tolerance, has produced measurable responses and is reported to improve survival compared with surgery alone. More recently, computer-guided radiation techniques including proton beam therapy have been employed to provide highly focused high-dose radiotherapy in unresectable cases, although in skull base tumours this is associated with a significant risk of temporal lobe necrosis. The use of chemotherapy has been reported occasionally, with mixed responses. It is not known whether preoperative shrinkage in sensitive cases may improve surgical resection rate and permit less extensive radiation fields. In our view the risks of extensive surgery and radiation justify a trial of preoperative tumour shrinkage in patients where there is no immediate risk of neurologic deterioration.

Thoracic tumours

Thymoma

Thymoma and thymolipoma account for <10 per cent of all thymic tumours. The incidence of thymoma has decreased in recent years, almost certainly because some cases registered in the past were T-cell lymphoma. The incidence of benign thymolipoma is unknown as they are not ascertained by cancer registries. Thymolipoma is a mixed epithelial and lipomatous tumour which is slow growing and benign. It has characteristic appearances on CT and MR and can reach massive size prior to discovery. Thymoma is an epithelial tumour which can be encapsulated or locally invasive. Metastatic spread is rare.

Clinical presentation

Presentation is often incidental upon chest radiography or with superior vena cava obstruction. Breathlessness, mistaken for asthma, is reported. In adulthood, paraneoplastic syndromes such as myasthenia gravis, pure red cell aplasia, hypo-gammaglobulinaemia, finger clubbing, and new bone formation occur. Reports of EBV in tumour tissue suggest an aetiologic role similar to that in nasopharyngeal carcinoma.

Other causes of thymic masses include lymphoma, carcinoid tumour, and germ cell tumour. As the treatment of choice of thymoma is surgical, diagnostic biopsy is recommended prior to definitive surgery. Histologic grading can separate tumours into well-differentiated (low-grade) tumours and carcinomatous (high-grade) tumours, although this classification is not well validated in children.

Surgery

Surgical/pathologic staging from adult practice is used to dictate therapeutic approaches as follows.

·  Stage 1 tumours (encapsulated): no adjuvant therapy is recommended.

·  Tumours with local residual disease involving fat, pleura, or pericardium (stage 2): local radiotherapy.

·  More extensive local invasion, involving lung, bones, etc. (stage 3): consider both radiotherapy (50–60 Gy) and adjuvant chemotherapy.

Adjuvant chemotherapy

For children, mediastinal radiotherapy is likely to be associated with considerable late morbidity linked to the subsequent growth and development of irradiated structures (e.g. lung, heart, bone marrow, sternum and ribs, and thoracic spine). Such risks must be balanced in individual cases with the response to chemotherapy and surgical staging of the tumour. Regimens using cisplatin, cyclophosphamide, and doxorubicin have been shown to be effective as neo-adjuvant treatment aimed at optimising surgical resection.

Primary lung and pleural tumours

Tumours of the lung and pleura are most commonly secondary to other neoplasms. Their anatomic location dictates the nature of their clinical presentation and helps predict the likely tumour type.

Clinical presentation

In childhood and adolescence, the majority of tumours are peripherally located and present with symptoms or signs of chest-wall involvement such as chest and shoulder pain or Horner syndrome. Centrally located tumours are more likely to present with signs of bronchial obstruction, such as wheeze, recurrent infection, haemoptysis, and superior vena cava obstruction.

Pathology

Rare pulmonary tumour types include adenomas and carcinomas, whilst rare types of pleuropulmonary tumours include pulmonary blastoma, neuroepithelioma (Askin tumour), or malignant mesothelioma.

Investigation

Imaging with chest radiography, CT/MRI scanning, and bone scanning is necessary to delineate the site and extent of the tumour as well as the number of distant metastases.

Pleuro-pulmonary blastoma

Pleuro-pulmonary blastoma (PPB) is a distinct clinicopathologic entity which occurs almost exclusively in childhood. It is an embryonic lung tumour consisting of gland-like structures lined with non-ciliated epithelium and surrounded by mesenchymatous stroma, mimicking the appearances of developing lung. It is found equally in both sexes. Trisomy 2 has been reported as have elevated levels of AFP. Despite failing to find abnormalities of TP53, family studies suggest that PPB heralds predisposition to dysplastic or neoplastic disease in 25 per cent of cases. Nearly a third of cases reported have been in association with congenital lung cysts, justifying a surgical approach to their management at diagnosis. The tumours grow aggressively and metastasize early. Primary surgical resection may be complicated by local recurrence. Recent case reports of the use of chemotherapy suggest that responses may be possible, justifying its consideration in tumours which are considered primarily inoperable. A proposed strategy would be to adopt an approach to therapy similar to that used in soft tissue sarcoma of preoperative chemotherapy followed by delayed surgery in order to optimize the chances of complete surgical resection.

Pulmonary adenomas

This term covers a variety of slow-growing tumours with low malignant potential including: carcinoid tumour, mucoepidermoid carcinoma, and cylindroma. They most commonly occur in the main bronchi. Primary treatment of these tumours is by surgical resection.

Lung carcinoma

Such carcinomas are well documented in childhood and are equally represented in both sexes. Histologically, they are most commonly undifferentiated bronchoepidermoid or adenocarcinomas. Lung carcinomas in children are more commonly located peripherally. Their aggressive nature and late presentation may explain the presence of metastases early in their clinical course. Treatment has followed adult guidelines with resection of operable tumours. The use of modern chemotherapy has an established role in the management of adult patients with smallcell lung carcinoma, resulting in a significant prolongation of survival in the majority and cure in a small percentage. Its role in the neo-adjuvant setting is being explored; cisplatin, VP16, gemcitabine, paclitaxel, carboplatin, vinorelbine, and docetaxel all have activity. Novel biologic agents are being investigated with mixed success. Radiotherapy has been used palliatively with some effect.

Breast tumours

The very significant difficulties in assessment and surgical approaches, and the need to support a young patient during diagnosis, treatment, and follow-up, justify referral for assessment of such problems to a paediatric oncology center linked to a collaborating multidisciplinary breast cancer team. Most breast tumours in children are benign. Breast lumps in early adolescence or childhood can be due to premature thelarche, juvenile papillomatosis, fibroadenoma, and, rarely, malignant tumours such as juvenile secretory carcinoma, fibro-, rhabdo-, and liposarcomas, and cystosarcoma phylloides. The benign tumours are more likely to show fluctuations in size and tenderness during the menstrual cycle. Secondary malignant tumours have been reported, as have rare presentations of soft tissue sarcoma and lymphoma. Secondary breast cancers are more common in young women after thoracic wall irradiation. Ultrasound-guided needle biopsy is recommended. Histologic diagnosis is difficult in view of the variable appearance of the developing breast. However, in situ studies of oestrogen and progesterone receptors may help to identify hormonally dependent and independent tissues. Areas of secretory carcinoma have been reported within fibroadenoma and juvenile papillomatosis. The rarity of breast tumours in this age group justifies a national/international pathology review process in order to standardize diagnostic criteria before rational treatment programmes can evolve.

Phylloides tumour

Phylloides tumour is a rapidly growing tumour which is most commonly benign, although histology is not always predictive (15 per cent are malignant). Five per cent of all tumours occur during adolescence, and they are not reported in males. Treatment by surgical resection is recommended. In metastatic cases, chemotherapy and radiotherapy have been effective. Longterm follow-up is recommended as there is a sustained risk of recurrence.

Breast carcinoma

Fewer than 0.1 per cent of breast carcinomas occur in children aged <15 years. Malignant tumours are most commonly juvenile secretory carcinomas for which conservative primary surgical resection is recommended, after which long disease-free periods have been observed with occasional late relapses. Their clinical behaviour is one of slow growth with multiple recurrences. Patients with juvenile secretory carcinomas aged <12 years seem to have a better prognosis than older adolescents. Undifferentiated carcinomas have been reported and have a much poorer prognosis, justifying an aggressive multimodality approach to treatment with surgery, chemotherapy, and radiotherapy. The use of radiation has been limited to the treatment of localized unresectable disease.

Malignant mesothelioma

Prognosis

Malignant mesothelioma arises from the mesothelial layer of the pleura, peritoneum, pericardium, and tunica vaginalis. The incidence of mesothelioma is very low in children's tumour registries. Histopathologic classification within these childhood cancer registries is complicated by the lack of a specific internationally recognized disease code coupled with a lack of consensus of histopathologic features. In most childhood cases there is a predominant tubular papillary pattern with solid areas, whilst some tumours show foci of single cells. Immunor-eactivity for cytokeratin, epithelial membrane antigen, and vimentin is characteristic. It is not possible to grade these tumours histologically. Peritoneal tumours are often multicystic and have a reduced capacity to metastasize, tending to recur locally.

Biology

Chromosome loss from overlap regions 1p21–p22 and 9p21–p22 have been reported, together with other areas of chromosome loss on 3p, 6q, 14,16,18, and 22. WT1 tumour suppression gene is expressed in the mesothelial lining during embryologic development. Mutations of WT1 have been detected in some sporadic mesotheliomas. These observations suggest that there is a multiple step process to tumour development.

Aetiology

In adults, environmental exposure to asbestos (crocidolite) with a latent period of 12–20 years is a well-recognized aetiologic mechanism. It is estimated to account for over half of cases in adults, predominantly in males. In the absence of asbestos exposure, the sex ratio of adult cases is probably close to 1:1. Childhood mesothelioma is fairly equally represented in both sexes. It is not commonly associated with asbestos exposure, although asbestos bodies have been identified in children. A study in the USA failed to identify geographical clustering of childhood cases, although a cluster of cases in the West Midlands, UK, has been identified and remains to be explained. The SV40-contaminated poliomyelitis vaccine has been implicated in the aetiology of mesothelioma, although this was not supported in recent follow-up studies. Of some concern is the number of reports of mesothelioma occurring as a second malignant neoplasm in survivors of childhood as well as adult cancers. The first tumours in the childhood cases were predominantly Hodgkin disease and Wilms tumour.

Clinical presentation

Clinical presentation is most commonly pleural (75–85 per cent), with initial chest pain and subsequent shortness of breath and cough as pleural effusions develop. Peritoneal presentation is with abdominal distension and/or intestinal obstruction. Sixty-five per cent of peritoneal malignant mesotheliomas occur in girls. Multicystic tumours can present with free-floating cystic masses. Congenital presentation has been reported. Detailed imaging of pleural/peritoneal spaces, lung, and bone should be performed with CT/MRI, ultrasound, and scintigraphy scanning. Positron emission tomography has been helpful in monitoring cavitary tumour responses during therapy.

Treatment

Successful treatment is dependent upon complete surgical excision, particularly in the multicystic tumour types, although local recurrence is common and repeated resections may be necessary. Systemic chemotherapy has been used; the agents reported to be active include doxorubicin, cisplatin, cyclophosphamide, mitomycin-C, ifosfamide, and vincristine. Intracavitary treatment with cisplatin and bleomycin have been used to control recurrent effusions, although this may lead to the development of extensive abdominal adhesions. The use of intracavitary instillations of radioactive gold or phosphorus is being investigated.

Abdomen

Gastric carcinoma

One to two per cent of gastric carcinomas occur in people aged <30 years of age, and 3 per cent of these are in the paediatric age group. They may be associated with immune deficiency states or with features of ataxia telangiectasia. Clinical presentation is often late, with weight loss, iron deficiency anaemia, and anorexia. Barium studies or endoscopy and tumour biopsy will confirm the diagnosis. The tumours are usually unresectable, having a tendency to disseminate early and invade locally. Radiotherapy is of little value in view of the low radiation tolerance of the surrounding structures. Promising results with a variety of chemotherapy regimes have been reported, including VAC and FAM (5-fluorouracil, Adriamycin, and mitomycin) and cisplatin alone and in combination with 5-fluorouracil, Adriamycin and etoposide. Neoadjuvant chemotherapy is being explored. Intraperitoneal cisplatin has been used in view of the presence of malignant cells in peritoneal washings in up to one-third of patients at surgery. Good anti-emetic therapy is important for the use of chemotherapy in upper gastrointestinal neoplasms if the treatment is to be tolerated. The optimistic reports of chemotherapy in adult patients indicate the need to explore its role as primary treatment of such poor prognosis childhood tumours.

Pancreatic tumours

Benign tumours of the pancreas are either dermoid cysts or cystadenomas. Malignant tumours of the pancreas occur more commonly and are equally distributed between the sexes. There are four main tumour types: pancreatoblastoma, papillary cystic neoplasm (Frantz's neoplasm), islet cell tumours, and adenocarcinoma.

Clinical presentation

Clinically, these tumours present with abdominal pain, an upper abdominal mass, symptoms of disturbed exocrine pancreatic function (diarrhoea, weight loss), duodenal obstruction (vomiting, weight loss), or symptoms related to endocrine products of the tumour such as gastric ulceration, hypoglycaemia, endocrine disturbance, or diarrhoea. Obstructive jaundice is less common in childhood (one-third of patients) than in adults (two-thirds of patients).

Investigation

Locating the mass in the pancreas is best performed by ultrasound, CT/MRI scanning (Fig. 26.2), arteriography, and sometimes endoscopic retrograde cholangiopancreatography (ERCP). Tumours are most common in the head of the pancreas. Identifying tumours arising from the pancreas as opposed to the liver or other retroperitoneal structures can be difficult. A cytologic diagnosis may be made at ERCP from pancreatic fluid. A variety of tumour markers have been used for diagnosis (carcino-embryonic antigen, AFP, and pancreatic oncofetal antigen). Pancreatic peptides have also been used (Table 26.4).

Pancreatoblastoma

Pancreatoblastoma is the most common malignant neoplasm of the pancreas in early life. The mean age at presentation is 4.5 years; it rarely occurs after 10 years of age. There is a predominance of Asian case reports in the literature.

Pathology

Embryologically there are great similarities between the development of the liver and pancreas from the foregut, and these similarities are mirrored in nature of the embryonic tumours of these organs. Pancreatoblastoma tumours are frequently large and well circumscribed. Microscopically, pancreatoblastoma is a dense epithelial cellular tumour with acinar differentiation and ‘squamoid corpuscles’. The tissue is frequently lobulated by fibrous stroma. Cystic change and calcification are described. Immunocytochemically, pancreatoblastoma is positive for a1-antitrypsin, AFP, and glucose-6-phosphatase. It is a malignant tumour with local invasion, with metastatic disease to local lymph nodes, liver, and lung in up to 35 per cent in one series. It is associated with Beckwith–Wiedemann syndrome and may be associated with elevated levels of serum AFP which might constitute a useful tumour marker.

Treatment

Pancreatoblastoma is potentially a curable malignancy, with survival rates of 50–80 per cent being reported. The higher survival rates are in patients who have had complete resections. The largest series reports an overall 58 per cent survival rate. The similarity to hepatoblastoma and the successes of multimodality approaches to treatment in the SIOPEL studies of that tumour, coupled with the evidence for chemosensitivity in pancreatoblastoma, justify the proposal to adopt a similar multidisciplinary approach; the high-risk strategy of SIOPEL 2 being most suitable. Primary resection should be reserved for localized tumours which are considered easily resectable. Biopsy is followed by a trial of chemotherapy and delayed resection for those deemed initially unresectable.

Table 26.4. Pancreatic endocrine tumours: cell types, ectopic hormones and clinical presentation

Cell type

Hormone secreted

Tumour type

Clinical presentation

A

Glucagon

Glucagonoma

Adult

B

Insulin

Insulinoma

Hypoglycaemia

C

Gastrin

Gastrinoma

Peptic ulceration, Zollinger–Ellison syndrome

D

Somatostatin

Somatostatinoma

Primarily adult

D1

Vasoactive intestinal polypeptide (VIP)

VIPoma

Diarrhoea

Papillary cystic tumour of pancreas (Frantz's tumour)

Papillary cystic tumour of pancreas (PCTP) has been variously referred to by a heterogeneous collection of terms, and varying degrees of malignant behaviour are described. It is a relatively slowly growing tumour predominantly affecting girls (one-third occur at <16 years of age) and young adult women.

Fig. 26.2 MRI scan showing a pancreatic tumour (insulinoma).

Pathology

PCTP is typically encapsulated and associated with pancreatic inflammation, pseudocyst formation, and calcification. Mitoses are rare, although capsular invasion is common and may extend to the duodenum and hepatic portal vein. Microscopically it consists of solid and papillary components. The solid elements typically form rosettes and degenerate into cysts. The papillary components stain positively for periodic acid–Schiff reagent. Immunocytochemically, the tumours stain positively for a1-antitrypsin and a1-antichymotrypsin. Studies of oestrogen and progesterone receptors may be justified in some cases as they may provide an option for therapy in difficult cases.

Treatment

Surgical resection for both primary tumour and any metastases is the treatment of choice, justifying extensive surgical procedures to achieve this. Chemotherapy and radiotherapy have been reported to be effective. However, these treatments are generally restricted to those with residual or metastatic disease.

Islet cell tumours

Islet cell tumours are endocrine tumours. They are the least common group of tumours of the pancreas and secrete either insulin or gastrin. They are most commonly solitary and benign. Individuals with MEN type 1 may present with adenomatosis of the pancreas. In the case of insulinomas, a plasma glucose-to-insulin ratio >1, with a normal C peptide, is diagnostic. The tumour may be difficult to localize and is most commonly benign. Gastrinomas are diagnosed by the identification of elevated serum gastrin levels. They are more commonly malignant although they grow slowly. Treatment for these tumours is by surgical resection where the tumour is solitary and resectable. Multiple or metastatic tumours are best treated medically to control exocrine or endocrine symptoms.

Carcinoma of pancreas

As in adults, ductal adenocarcinoma followed by acinar cell carcinoma are the most common types. Cases have been described in patients aged as young as 3 weeks. Surgical resection provides the only hope of cure. Chemotherapy (usually 5-fluorouracil, gemcitabine) produces partial responses, as does radiotherapy. However, survival benefit is yet to be demonstrated. Some authors believe that children may have a better prognosis than adults.

Adrenal cortical carcinoma

Adrenal carcinoma (ACC) accounts for 0.2 per cent of childhood malignancies with an international incidence of 0.5–1 per million. It is more common in girls than boys (1.5:1) and has a bimodal age distribution, with a peak incidence in early childhood and adolescence. In early childhood the ratio of girls to boys is at least 2:1. A 5-year survival of 38 per cent is reported by the CCRG in the childhood age range (Table 26.1).

Aetiology and biology

There is clear evidence of a genetic aetiology for many cases of ACC. It is one of the tumours linked to the family cancer syndrome originally described by Li and Fraumeni. The presence of ACC in such families is rare, but it occurs 100 times more frequently than would be expected by chance. Most families with classic Li–Fraumeni syndrome have a germ-line mutation of TP53. As 50 per cent of cases with ACC have germ-line mutations of TP53, the diagnosis of ACC in a family is likely to be the first sign of a familial cancer predisposition justifying consideration of referral for genetic counselling. ACC is also associated with two tissue-overgrowth syndromes: hemi-hypertrophy and Beckwith–Wiedemann syndrome. A possible metabolic aetiology is suggested by the association with a previous history of salt-losing congenital adrenal hyperplasia. Finally, an environmental toxic aetiology is suggested by a study of parental toxic exposures in children identified with ACC within the Manchester Children's Tumour Registry and the observation of a threefold increase in population incidence in southern Brazil compared with international incidence. St Jude's Children's Research Hospital has established an international ACC paediatric tumour register.

Clinical presentation

Clinical presentation is with virilization/precocious puberty (90 per cent), abdominal mass (60 per cent), Cushing syndrome (<50 per cent), or a combination of these. Occasionally rapidly growing carcinomas present with abdominal pain, weight loss, fever, and an abdominal mass in the absence of endocrine disturbances.

Pathology

Differentiating histologically between adenoma and carcinoma is difficult as features of malignancy, including frequent mitoses, cellular pleomorphism, and vascular invasion, may be seen in both categories. A modification of the Weiss criteria based upon atypical mitoses, confluent necrosis, and nuclear grade is believed by some to predict clinical outcome. However, tumour size is more widely accepted as a predictor of tumour behaviour; tumours of weight <100–150 g and diameter >5–6 cm or volume >200 ml are more likely to be malignant. In the author's view, this assumption is counter-intuitive. A preferable assumption would be that all tumours have malignant potential if left to grow untreated, which is supported by the adverse prognostic factors of older age at presentation, increased urinary steroid excretion, and delays in diagnosis.

Investigation

Investigations are directed at clarifying the endocrine status by differentiating between Cushing disease, congenital adrenal hyperplasia, and adrenal tumours. Adrenal carcinomas are associated with markedly elevated basal urinary 17 ketosteroid production (>40 mg/24 h), and urinary androgens, plasma levels of cortisol, dihydroepiandrosterone sulphate, and 17-hydroxy progesterone may be raised. ACTH levels are low because of pituitary suppression. It is important to determine the endocrine profile in order to monitor response to treatment. Imaging with abdominal ultrasound and CT/MRI scans will permit definition of tumour size and local and distant spread (Fig. 26.3). Vascular invasion of the inferior vena cava may occur and its demonstration is important prior to surgical removal.

Surgery

Primary surgical removal is the treatment of choice and may be curative for smaller tumours. Patients with residual disease are seldom cured. Staging criteria are given in Table 26.5.

Endocrine management

In tumours characterized by excess hormone production, great care is needed to manage steroid deficiency in the postoperative period. Treatment with mitotane (o, p0-DDD) has been used to control steroid side effects and has been reported to reduce primary and secondary tumour size. Response rates reported are 19–34 per cent in adults and 30 per cent in the most recent study in children. No reports claim curative success with this treatment. In a large adult study it was not shown to improve survival. Mitotane is administered orally (starting dose 0.5 g) and is associated with a range of troublesome symptoms including vomiting, diarrhoea, neurologic disturbances, lethargy, dizziness, somnolence, and muscle weakness. Careful monitoring is essential. It is most effective when the serum level >14 mg/l. Concomitant mineralocorticoid and glucocorticoid therapy may need to be intensified during mitotane therapy since deaths from adrenal insufficiency, despite replacement therapy, have been reported.

Fig. 26.3 CT scans showing an adrenal tumour with calcification.

Table 26.5. Anatomical staging systems for adrenal carcinoma

Stage 1

Total excision of tumour, volume <200 cm3
Absence of metastases and normal hormone levels after surgery

Stage 2

Microscopic residual tumour, tumour volume >200 cm3
Absence of metastases yet persistently elevated adrenocortical hormone levels after surgery

Stage 3

Gross residual or inoperable tumour

Stage 4

Distant metastases

Chemotherapy

Cytotoxic chemotherapy has generally been restricted to the treatment of relapse. Responses have been reported with combination regimens such as 5-fluorouracil, Adriamycin, and cisplatin, streptozotocin and mitotane, CAP (cyclophosphamide, Adriamycin, and cisplatin), OPEC/OJEC (cisplatin, carboplatin, vincristine, VM26, VP16, and cyclophosphamide), cisplatin and etoposide, and cisplatin and etoposide in combination with mitotane. The precise role of chemotherapy in clinical management, despite this evidence of tumour sensitivity, is not established in the literature. However, the importance of complete resection coupled with demonstrable chemosensitivity would justify a trial of preoperative treatment in large and predictably unresectable tumours.

Radiotherapy

Radiotherapy has been used to eradicate residual disease. However, secondary tumours within the irradiation field have been reported which in the presence of a high risk of genetic cancer predisposition suggests an enhanced sensitivity to radiation-induced second tumours, especially in the breast in girls.

Colon and rectal carcinoma

Epidemiology and pathology

Almost all of the 1 per cent of cases of colorectal malignancy that arise in patients aged <30 years are carcinoma. It is almost unheard of in infancy, and the majority of cases that are reported occur during adolescence where boys are affected twice as commonly as girls. Predisposing factors such as familial adenomatous polyposis, Turcot syndrome, and ulcerative colitis are recognized but accounted for a minority of reported cases in the literature.

Clinical presentation

Clinical presentation is with vague abdominal pain, rectal bleeding, weight loss, altered bowel habit, and abdominal distension. Screening is not possible in the childhood population; delays in diagnosis are frequent and <50 per cent have the diagnosis made prior to operation. The majority of tumours occur in the sigmoid and rectum. Barium enema, colonoscopy, and biopsy are the optimal diagnostic investigations in suspected cases. Histologically, the tumours are most frequently mucus-secreting adenocarcinomas (50 per cent) or are poorly differentiated, hence the high incidence of rapidly disseminated disease. Sixty to eighty per cent present with Duke stage C or D involvement at diagnosis and are often inoperable.

Treatment

As in adult practice, successful treatment of colon cancer depends upon complete surgical resection. Adult studies of systemic chemotherapy have identified that high-dose 5-fluorouracil combined with leucovorin and irinotecan improves survival of more advanced stage patients. Intra-arterial or portal chemotherapy has been used for hepatic metastases but the results are inconclusive. Chemotherapy produces responses in >50 per cent of cases in childhood but they are not sustained. The overall survival is poor, with 5-year survival rates <10 per cent.

Successful treatment of rectal carcinoma in adult practice is again based upon the extent of surgical resection. There is controversy surrounding the optimal method of defining margins of resection. Preoperativeradiotherapycan improve resection rates in 35–75percentof patients but seemstobelesseffectiveaftersurgery. Mostrecently, biologictherapiestargetingepithelialgrowth factor receptor and vascular endothelial growth factors are being combined with conventional chemotherapy and are producing improved and sustained responses in refractory patients.

Pelvis

Genital tract and bladder tumours

The majority of genital tract tumours in childhood are rhabdomyosarcomas or germ cell tumours. Carcinomas may occur throughout the genital tract in girls, whilst in boys they have only occasionally been reported in the testis and bladder.

Clear cell adenocarcinoma of the vagina and cervix

An association between intrauterine exposure to diethylstilboestrol (DES) and an increased incidence of clear cell vaginal adenocarcinoma with vaginal adenosis was suspected after two case–control studies. Prospective screening of the at-risk population established an association between intrauterine DES exposure and vaginal and cervical adenosis. However, the risk for having clear cell carcinoma after intrauterine DES exposure was small (0.14–1.4 in 1000) and the evidence for a causative association with clear cell vaginal carcinoma in young women has not been clearly demonstrated. The use of DES during pregnancy was widespread in the USA but only limited in the UK, and its use was discontinued in 1971. Screening has been recommended for exposed children from the age of 14 years or menarche. Clinical presentation may otherwise occur with abnormal vaginal bleeding in the prepubertal and adolescent years.

Investigation and treatment

Presentation is with premenarchal vaginal bleeding. Diagnosis is dependent on abdominal and pelvic ultrasound/MRI and vaginal examination including colposcopy, which may necessitate an anaesthetic. Evidence for metastatic spread should be sought with chest CT and clinical evaluation of lymph nodes, including the supraclavicular region. The tumour is locally invasive and may metastasize to the lungs as well as to local and distant lymph nodes. Local treatment is dictated by the stage of the tumour at presentation. The staging system of the International Federation of Gynecology and Obstetrics (FIGO) is used. Interstitial or transvaginal radiotherapy, which spares the ovaries from ablative irradiation, is reserved for stage I lesions. More extensive disease is treated by radical surgery, followed by vaginal reconstruction, or external irradiation of the entire pelvis. The use of chemotherapy has been reserved for the treatment of recurrent disease. Responses to cyclophosphamide, melphalan, actinomycin D, 5-fluorouracil, and carboplatin have been reported.

Prognosis

Overall survival is 80 per cent (stage I, 85 per cent; stage II, 70 per cent; stage III, 50 per cent; stage IV, 0 per cent). Older patients (>19 years) do better than younger patients (<15 years), and this difference in survival is attributed to the prevalence of tubulocystic differentiation in the older age group. The extensive surgery or radiotherapy recommended in advanced stages has many long term physical and psychologic side effects which may justify the exploration of early chemotherapy if less radical local treatment could be considered after initial tumour shrinkage.

Tumours of the Fallopian tubes

Malignant tumours of the Fallopian tubes are either pure carcinomas or mixed Müllerian tumours, which are biphasic tumours containing both mesenchymal and carcinomatous elements. Conventional treatment approaches to such tumours depend upon a combination of radical surgery and radiotherapy. Chemotherapy with a wide variety of agents is currently under investigation. Anecdotal reports of responses to chemotherapy with BEP (bleomycin, VP-16, and cisplatin) in mixed Müllerian tumours justify further investigation in an attempt to reduce iatrogenic morbidity and distant failures associated with continued surgery and radiotherapy.

Transitional cell carcinoma of the bladder

Transitional cell carcinoma of the bladder occurs rarely during the first two decades of life. Gross haematuria is the most common presenting symptom. Preoperative imaging frequently detects the tumour, although cytoscopy is necessary to obtain histology. The malignancy is usually low grade and non-invasive, with a low recurrence rate. Transurethral resection or fulguration is the treatment of choice, and the prognosis is favourable. Trials of intravesical chemotherapy and local microwave hyperthermia for recurrence are being reported, with gemcitabine and carboplatin being the investigatory drugs.

Ovarian carcinoma

Adenoor cystadenocarcinomas of the ovary account for 12–18 per cent of malignant ovarian tumours in children. Their clinical presentation is with acute or chronic lower abdominal pain in the majority, together with abdominal distension and a palpable mass. Pelvic and abdominal ultrasound is important to differentiate between solid and cystic masses. Most, but not all, cystic masses are benign. Careful surgical staging is important, as is tumour monitoring with C125. Management is effectively as for adult disease. Surgery is recommended for solid, palpable, or calcified masses and for those that present with persistent fever to rule out appendix abscess. At surgery, where a tumour is suspected, oophorectomy with or without salpingectomy is recommended. Second-look procedures to monitor response are widely used. Postoperative chemotherapy with combinations of cyclophosphamide, hexamethylamine, cisplatin, and Adriamycin have been used successfully in extensive disease. A recent phase III trial in adults showed a survival advantage for a paclitaxel–cisplatin regimen, and a randomized comparison of paclitaxel with topotecan showed that topotecan performed favourably with respect to response rates and time to progression. Dose-intense and high-dose therapy with stem cell rescue have been tested in recurrent adult cases. Intraperitoneal chemotherapy is also used.

Other tumours

Melanotic primitive neuroectodermal tumour of infancy (MPNET, melanotic progonoma)

This tumour is unusual in that it is made up of two populations of cells derived from the neural crest, neuroblasts and melanocytes. Ninety-five per cent of the tumours occur in infants aged <1 year. The sites of presentation include the maxilla (60 per cent), the skull (13 per cent), the epididymis (9 per cent), the mandible (6 per cent), and the brain (6 per cent), as well as a variety of other bony and soft tissues. Urinary vanillylmandelic acid (VMA) excretion may be elevated in a small proportion of tumours. This is of no prognostic significance, but it is useful as a tumour marker. It has a favourable prognosis, with a low malignant potential (2–7 per cent) and low (10–15 per cent) local recurrence risk. Indications for adjuvant treatment are governed by the clinical nature of the tumour at presentation. Mixed responses to chemotherapy agents have been reported.

Malignant melanoma

Malignant melanoma is an aggressive skin tumour derived from melanocytes which are cells which arise in the neural crest in the fetus.

Epidemiology

In the UK, the annual incidence in childhood is about 1.2 per million with a male-to-female ratio of 0.8:1. A Swedish population-based study showed that the incidence rates for childhood malignant melanoma were stable, whilst the incidence rates for adolescents are rising in line with adult figures. In Australia, crude rates of 5 per million nationally and 10 per million in Queensland have been recorded. There is a different pattern of disease incidence between those malignant melanomas arising in childhood (<14 years) and those arising during adolescence. The malignant melanomas arising in childhood are predominantly associated with skin types susceptible to damage by ultraviolet radiation, children who have a family history of the disease, and tumours which present as a complication of a congenital melanocytic naevus. Families with a strong history of melanoma may demonstrate ‘genetic anticipation’, where successive generations have the condition diagnosed earlier than their parents. Whether this is due to improved surveillance or genuine genetic anticipation is not proven. The increasing incidence in adults and adolescence is thought to be related to enhanced skin exposure to sunlight, although the epidemiologic evidence is conflicting. Exposure to phototherapy given in infancy for hyperbilirubinaemia has not been identified as a risk factor for the development of malignant melanoma.

Clinical presentation

More than 90 per cent of childhood malignant melanomas are skin tumours. Rarely, ocular and central nervous system leptomeningeal primaries are also seen. Over half of the skin tumours are of the superficial spreading type and most other specified cases are nodular. Staging investigations looking for ‘in transit’ metastases, regional lymph node involvement, and distant metastases in lung, brain, and bones should be carried out. Cerebral metastases occur in 20 per cent of patients. The presence of brain metastases is associated with a very poor prognosis.

Pathology and prognosis

The histologic diagnosis should only be made by experienced pathologists. A recent EORTC study identified only 60 per cent of centrally referred malignant melanoma as true malignant melanomas. In adults, malignant melanomas are graded by their thickness (Breslow thickness > 3 mm) which correlates with their risk of metastatic spread. The EORTC study identified a thickness >2 mm as predictive of a higher risk of metastatic spread and fatal outcome. Overall 5-year survival rates were greater than 80 per cent (Table 26.2).

Large congenital melanocytic naevi

A study of 289 cases of large congenital melanocytic naevi (LCMN) identified only 38 (13 per cent) which developed primary cutaneous malignant melanomas, all of which arose within LCMNs located at axial sites and none within LCMNs located on peripheral (limb) sites. Two others developed malignant melanoma at uninvolved sites. A striking finding in this study was the absence of malignant melanomas in any of the many thousands of satellite lesions. Removal of LCMN is an area of controversy. Curettage or surgical removal has been performed within the first few weeks of life for cosmetic reasons, and in older children removal has been directed at preventing development of melanoma. There is little evidence that radical surgery of this sort reduces the incidence of metastatic disease.

Surgery

Newly diagnosed patients with malignant melanoma should have wide surgical excision and pathologic assessment of the lesion by an experienced pathologist. There is a place for surgical resection of solitary accessible cerebral metastases.

Drug therapy

No further therapy is recommended for completely resected thin lesions (Breslow thickness <3 mm) in adults. Adjuvant therapy with high-dose interferon given over a year has shown a 10 per cent survival advantage for locally advanced disease (Breslow thickness > 3 mm), regional lymph node involvement, or ‘in transit’ metastases. Metastatic disease in adulthood is treated with DTIC, and trials are under way to evaluate the use of chemotherapy in combination with biologic therapies such as interferon and interleukin. Such treatments are considerably more toxic than chemotherapy alone. There are no trials open in the UK specifically recruiting children. The nitrosourea analogue fotemustine is licensed for treatment of cerebral metastases in a number of countries, but not in the UK or the USA. Preliminary experience with responses to temozolomide have been reported. Twenty per cent response rates have been reported to both fotemustine and temozolomide, which are well tolerated as they are given orally.

Radiotherapy

The role of radiotherapy in cerebral metastases is controversial as few patients have sensitive disease.

Future developments

A number of conclusions can be drawn from considering these rare tumours.

There is a strong need for an individual case to be managed in the children's multidisciplinary team, supported by specialists from disciplines familiar with technical aspects of specific tumour types, for example breast cancer team, head and neck cancer team, radiotherapists, endocrinologists, urologists, gynaecologists, geneticists, neurosurgeons, maxillofacial surgeons, and upper and lower gastrointestinal teams.

Advances in therapy will be promoted by national cancer registration, central pathologic review, the development of guidelines, trials of novel therapies, and adoption of new techniques from adult practice.

The rarity of these tumours makes them attractive for research in aetiology and biology (adrenal carcinoma, thyroid cancer), new treatments (mesothelioma, pleuropulmonary blastoma), and, where relevant, publicity aimed at prevention (melanoma).

Patient/family information should be developed to reduce the sense of isolation that these families experience when their condition is referred to as ‘rare’ and they become the focus of medical curiosity.

Acknowledgements

The author would like to acknowledge the invaluable assistance of Dr Charles Stiller of the Children's Cancer Research Group, Oxford, UK, and Dr Richard Grundy of the University of Birmingham.

Bibliography

Walker DA, Grundy R, Stiller C (2002) Rare tumours of childhood. In: Souhami R, Tannock I, Hohenberger P, Horiot JC (eds) Oxford Textbook of Oncology (2nd edn). Oxford: Oxford University Press, 2669–91.



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