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Second malignancies in children: the usual suspects?
European Journal of Radiology 37 (2001) 95 – 108 www.elsevier.nl/locate/ejrad
Second malignancies in children: the usual suspects? John Moppett a, Anthony Oakhill a,*, Andrew W. Duncan b a b
Department of Paediatric Oncology, Bristol Royal Hospital for Sick Children, St. Michael’s Hill, Bristol BS2 8BJ, UK Department of Paediatric Radiology, Bristol Royal Hospital for Sick Children, St. Michael’s Hill, Bristol BS2 8BJ, UK Received 23 October 2000; accepted 10 November 2000
Abstract The aim of this article is to provide an up to date review of second malignant neoplasms (SMN’s) following treatment for childhood cancer, referring to their incidence, the role of genetic factors, and how the primary malignancy and treatment received influence the type, site and prognosis of SMN’s. The role of genetic factors will be discussed as far as they impact upon a predisposition to later development of SMN’s. The primary malignancies that have important associations with SMN’s will then be discussed, in particular Hodgkin’s disease, retinoblastoma and acute lymphoblastic leukaemia. The important second malignancies will be highlighted, including tumours of the CNS and thyroid, osteosarcoma, secondary acute myeloid leukaemia and melanoma. Emphasis will be put upon identifying which patients are most likely to suffer from these tumours. An important part of the article are case histories. These are provided in combination with illustrations as a useful adjunct to the text, with a particular emphasis on radiological features, diagnosis and screening. Finally, the important but different roles of causal agents, in particular chemotherapy and radiotherapy are highlighted. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Paediatric; Oncology; Radiology; Secondary tumours
1. Introduction Treatment for childhood cancer is often seen as one of the major success stories of modern medicine. Indeed there are many eminently curable childhood tumours that were uniformly fatal less than 50 years ago. Sadly, the increasing incidence of second malignant neoplasia (SMN’s) is one of the least desirable consequences of improved therapy for first malignancies. The aim of this article is to review current knowledge about SMN’s with particular reference to the role of aetiological factors and the clinical features of second malignancies, thus providing a rationale for the radiological followup of these children. Second malignancies are not common and many children must be followed to gain a realistic perspective on the characteristic features of these tumours. Many years often elapse before the occurrence of a SMN, requiring vigilance and long-term follow-up if they are to be recognised for what they are. Inevitably current * Corresponding author. Tel.: +44-117-9285451; fax: + 44-1179285682. E-mail address: [email protected] (A. Oakhill).
reports of SMN’s reflect the consequences of medical practice many years ago, making future predictions for current patients uncertain.
2. Incidence Several methods of expressing the risk of second malignancy are used in the literature. Clinicians and in particular patients wish to know the absolute risk of developing a second tumour for an individual. This figure is complicated however by the fact that at long follow-up intervals, the absolute population risk of developing cancer becomes quite high. Thus for example, the background population risk of malignancy after 45 years of follow-up of an ‘at risk’ population is almost 6% [1]. Epidemiologists therefore prefer to express risk in terms of relative risk. Relative risks are a powerful measure of the importance of contributing factors but can be less useful clinically. Thus whilst the 1000 fold relative risk of developing a second tumour in children with a CNS tumour and neurofibromatosis is highly significant, [2] the 51% absolute risk that a child with hereditary retinoblastoma has of developing a
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second tumour in the next 50 years is perhaps more easily understood [3]. Overall somewhat in excess of 1000 second malignant neoplasia following treatment for childhood malignancy have been reported in the literature. Exact risks are hard to quantify. In large cohort studies with long follow-up times, 5– 10% of children treated for first malignancy have developed subsequent second tumours [4,5]. These figures do not however represent the risk to current patients. The makeup of these cohorts is somewhat different to current survivors of childhood cancer therapy. In particular acute leukaemia is significantly under-represented in the groups with the longest follow-up, [1] as survival rates for ALL were poor until the late 1960’s. The risk seems to be higher for those children treated since the inception of modern intensive multiagent chemotherapy, suggesting that the incidence of second malignancies is due to rise further in the future [1]. In general terms the risk factors for developing second malignancies can be divided into patient (type of first tumour, age at diagnosis of first tumour, and certain genetic factors) and treatment (radiotherapy and chemotherapy) related.
3. Important genetic factors Over recent years, many genes involved in the development of cancer have been discovered and the mechanisms behind their function elucidated. As a result of this process, it has become possible to explain why cancer appears to be particularly common in some families. The most well-known family cancer syndrome associated with childhood malignancy is Li-Fraumeni syndrome (L-FS) [6], which is due to the autosomal dominant inheritance of germline p53 mutations [7]. P53 is a tumour suppressor gene that is involved in many adult tumours. In L-FS, children have a predisposition to develop rhabdomyosarcoma, soft tissue and bone sarcomas, brain tumours, acute leukaemia, adrenocortical cell carcinoma and early onset breast cancer [8]. Family members have a 50% chance of developing a malignancy by the age of 30 [9]. L-FS is however, rare. Germline p53 mutations (not all cases of which strictly fit the criteria for a diagnosis of L-FS) are found in at most 10% of cases of soft-tissue sarcoma and rhabdomyosarcoma, [10] and 3% of osteosarcomas [11]. Other family cancer syndromes are associated with childhood tumours such as Turcot syndrome (the association of CNS tumours, especially medulloblastoma, with colon cancer) [12], ataxia telangectasia (an autosomal recessive germline mutation of the ataxia telangectasia gene which predisposes affected individuals to the
development of immunodeficiency and subsequently leukaemias and B-cell lymphomas) and the phakomatoses [13,2]. Of these only neurofibromatosis type 1(NF-1) is common, affecting 1 in 2500 individuals. Children with NF-1 have an increased risk of developing many different tumours; in particular optic pathway gliomas and peripheral nerve sheath tumours [14,15]. Children with NF-1 who receive radiotherapy for a primary CNS tumour have a very high relative risk of developing a second CNS tumour [2]. The risk of second malignancy following modern first-line treatment for optic pathway gliomas (vincristine and carboplatin) is unknown. Overall, despite the many genes now associated with cancer syndromes, evidence to date still suggests that they represent a small minority of paediatric tumours, and do not play a significant role numerically in the development of secondary tumours.
4. Primary malignancies that have important associations with second malignant neoplasia
4.1.1. Hodgkin’s disease A significant amount of information regarding second malignancies following Hodgkin’s disease is available because a good cure rate has been achieved for many years, resulting in many long-term survivors. Most studies report cohorts in which more than 90% of children have received radiotherapy [16,17]. The increasing use of protocols that avoid radiotherapy for the majority of children may significantly alter the pattern of second malignancies in the future [17]. The largest study to date in this condition gives a relative risk for all SMN’s of 27, which equates to a 6.5% absolute risk of solid tumour (which represent 81% of all SMN’s) at 15 years from diagnosis [17]. Amongst the solid tumours, breast cancer was the single commonest (almost 50% of solid tumours in women). Carcinoma of the thyroid and basal cell carcinoma are also common [16]. Significant associations with therapy received are seen. Secondary leukaemia was associated with chemotherapy, particularly alkylating agents, whilst breast cancer only occurs in patients who have received radiation therapy, and almost always within or at the margin of the radiation field [16]. There is a particularly high risk of breast cancer for those girls treated between the ages of 10 and 16, the period when breast tissue is proliferating [16,17]. There is also good evidence that chemotherapy is additive to the effects of radiotherapy in increasing the risk of solid tumours [18]. It is notable that whilst the risk for secondary leukaemia reaches a plateau after 14 years, the risk of secondary solid tumours keeps rising, reaching nearly 30% at 30 years [16]. Thus, lifelong vigilance is required
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for children who have been treated for Hodgkin’s disease, especially those who received radiotherapy [17].
4.2. Retinoblastoma Retinoblastoma is the classical tumour model in which genetics and treatment received have both been shown to play their part in the development of second malignant neoplasia. There are two forms of retinoblastoma, sporadic and hereditary [19]. They differ both in their presentation and genetics. The underlying defect in all retinoblastoma tumours is defective functioning of the retinoblastoma tumour suppressor gene Rb, found on the long arm of chromosome 13 [20]. Normal cells carry two Rb alleles and both must be inactivated for a tumour to develop. The Rb gene product is involved in cell cycle checkpoint control and its absence allows the uncontrolled proliferation of abnormal cells [21,22]. Familial cases of retinoblastoma carry a germline deletion of one of their Rb alleles, meaning that a single spontaneous mutation of the remaining Rb allele is sufficient to cause a tumour to develop. Spontaneous cases on the other hand do not carry germline mutations, and two independent mutation events are thus required for a tumour to arise. The clinical consequences of this are that hereditary retinoblastoma occurs at a younger age and many patients present initially with bilateral disease [19]. Hereditary retinoblastoma has a well-recognised association with second malignancies, particularly osteosarcoma [23], an association not seen in sporadic retinoblastoma. Osteosarcoma represents over one third of the second malignancies arising in hereditary retinoblastoma patients [24]. Estimates of incidence vary considerably but the largest study to date puts the cumulative incidence of second malignancy at 50 years from diagnosis at 51% [3]. Other tumours that are commonly seen in hereditary retinoblastoma include melanoma, brain tumours and soft tissue sarcomas [24,1]. An association between radiation dose received and the incidence of secondary osteosarcoma and soft tissue sarcomas is seen in retinoblastoma [3], suggesting that radiation plays a part in the increased frequency at which these tumours arise. However, a significant minority of secondary tumours in retinoblastoma arise outside the radiation field [25], and an increased incidence of secondary osteosarcoma is also seen in those children who do not receive radiotherapy [26]. Molecular studies have shown that many osteosarcomas that arise in children with hereditary retinoblastoma also harbour loss of heterozygosity at the Rb locus, suggesting a common etiological mechanism [27]. Loss of heterozygosity at the Rb locus has also been found in some sporadic osteosarcomas and osteosarcoma cell lines. It is postulated that loss of both Rb
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alleles in the eye leads to retinoblastoma whilst their loss in bone tissue leads to the development of osteosarcoma. Rb mutations are commonly detected in a wide variety of common adult tumours such as breast and small cell carcinoma of the lung [28,29]. The lack of association between these tumours and retinoblastoma suggests that the Rb mutations in these tumours play a different role, unlike the essential one they have in the pathogenesis of retinoblastoma and some osteosarcomas.
4.3. Acute lymphoblastic leukaemia Whilst other conditions are more classically associated with second malignancies, ALL is a significant cause of SMN’s because of its high incidence in childhood and the good overall survival rates achieved with modern intensive chemotherapy [1]. The pattern of SMN’s following treatment for ALL is significantly different to that for Hodgkin’s disease and retinoblastoma. Central nervous system tumours and secondary leukaemias predominate, with new lymphomas and thyroid malignancies also common [30 –33]. The quoted incidence varies from 2.5 to 3.3% at 15 years from diagnosis [30,31]. Risk of second malignancy is clearly linked to treatment received, with an increased risk of a SMN in those receiving radiotherapy [30]. Almost all secondary brain tumours and thyroid malignancies occur in prior radiation fields [30,34]. Radiotherapy related tumours have an increasing incidence over time whilst chemotherapy related tumours tend to plateau after 5 years from diagnosis of the primary malignancy [34,31]. SMN’s are also more common in those treated at an early age (B 5 years at diagnosis of leukaemia) [34,30 –32]. Epipodophyllotoxin treatment is associated with the occurrence of secondary AML (see below) [33]. For the first 5 years after treatment, secondary AML is the likeliest second malignancy (though relapse remains the most common malignancy found), being superseded thereafter by brain tumours due to the longer latency of CNS tumours relative to secondary AML [31].
5. Important second malignant neoplasia
5.1. CNS tumours It has traditionally been thought that neural tissue is relatively insensitive to the tumorigenic effects of ionising radiation [35]. The data regarding CNS tumour risk in atomic bomb survivors for example is equivocal, [35] unlike the increased risk in this population for many
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other tumour types [36,37]. The clearest evidence for an association between radiation and CNS tumours in the general population comes from children who received low dose scalp irradiation for tinea capitis [38]. Followup studies of these children have clearly shown an increased risk of CNS tumours [38]. The highest risk is for secondary benign tumours but an increased risk of malignant tumour also exists [38]. The majority of these tumours are meningiomas (Figs. 1 and 2) [39]. When compared to meningiomas in the general population (which have a preponderance in middle aged females), they appear to be more aggressive histologically, have no sex bias and appear at younger age [40,35]. The interval between exposure and subsequent tumour development is longest for benign tumours and shorter for malignant neoplasia [35]. Generalising data from
these cohorts to children treated therapeutically is difficult. Whole brain radiation exposure in the tinea capitis group is less uniform, and the doses, usually 1–2 Gy are significantly lower than therapeutic doses used today [35]. Several large cohort studies have recently reported clearly increased risks of secondary CNS tumours following treatment for childhood malignancy [2,31,32]. The clearest risk is in patients with prior radiotherapy to the CNS. (Fig. 3) This risk is both dose and age dependent. Increasing dose of radiation and younger age at exposure are both strong independent risk factors [2,32]. There is also a significantly increased risk of secondary CNS tumour following treatment for a first CNS tumour (Fig. 4) [2]. Clear increased risk of a secondary CNS tumour is also seen for children with
Fig. 1. An asymptomatic 22 year old male who had acute lymphoblastic leukaemia (ALL) at 3 years of age and had received cranial irradiation. He had been part of a survey, by magnetic resonance imaging, of long-term survivors of acute lymphatic leukaemia treated with cranial irradiation [39]. (a) Sagittal; and (b) coronal T1 weighted MRI brain scans following intravenous contrast shows an enhancing mass arising from the inferior margin of the tentorium on the right side, consistent with and subsequently proved to be an anaplastic meningioma. No specific features, but young age of patient is suggestive of secondary tumour. If Magnetic Resonance Angiography (MRA) is performed, it may show vasculitis which would indicate radiation change and provide strong circumstantial evidence of the tumour being of a secondary nature.
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Fig. 1. (Continued)
neurofibromatosis [2], and retinoblastoma [3], strongly suggesting that genetic factors play a role in the risk of developing CNS tumours. Some papers have shown weak links between chemotherapy and subsequent CNS tumour risk [1] whilst others do not [2]. It therefore remains unclear whether the increasing use of chemotherapy for CNS tumours will affect the long-term incidence of secondary tumours. As regards the clinical features of secondary CNS tumours following childhood cancer therapy, meningioma is the commonest, as seen in the tinea capitis cohorts [35]. Likewise, secondary meningiomas tend to show more aggressive histological features [40]. Despite this. the clinical outcome appears good [32]. However, other more aggressive tumours such as glioblastoma multiforme, and anaplastic or other high-grade astrocytomas represent roughly 50% of the tumours occurring following childhood ALL (Fig. 5) [39] and these tumours have a very poor prognosis [2]. Benign tumours develop later than malignant ones [32]. Overall, the risk of developing a secondary CNS tumour appears to be 0.5% at 15 years overall, 2% at 15 years for children with CNS tumours and 1.39% at 20 years for children with ALL [2]. Adjacent extracranial secondary tumours will also result as a consequence of cranial irradiation (Figs. 6 and 7) [39,32].
Fig. 2. A 23 year old female who had previously had ependymoma of cerebellum at 12 years of age and was treated by radiotherapy. Eleven years post treatment, she presented with malignant meningioma. CT scan following intravenous contrast shows multiple malignant meningiomas on the falx and peripherally on the left side. There had been a previous craniotomy in the frontal parietal region on the left side for removing a previous malignant meningioma. No specific features but multiple lesions suggest secondary tumours.
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the standard population risk [34,41]. This is in part due to the relative rarity of thyroid tumours in the general population and partly due to some particular associations between treatment and thyroid cancers. Thyroid malignancies have a well-known association with exposure to radiation. Cohort studies of atomic bomb survivors; children exposed to radiation from the Chernobyl disaster; and children treated with radiation for tinea capitis, enlarged tonsils and enlarged thymus
Fig. 3. Fourteen year old male with rhabdomyosarcoma of the left orbit at 8 years, treated by chemotherapy and radiotherapy and presented 5 years post treatment. MRI scan T1 weighted after contrast enhancement shows multifocal astrocytoma in the frontal region. There was a further lesion in the cerebellum.
Fig. 4. Twenty year old female who had an astrocytoma at 3 years of age and was treated by radiotherapy. She presented 17 years post treatment. Sagittal MRI scan T1 weighted post contrast shows multifocal glioblastoma.
5.2. Thyroid tumours The cumulative increased risk of developing a secondary thyroid malignancy compared to the general population risk is one the highest of all second malignancies. Estimates of the risk vary from 53 to 80 times
Fig. 5. A 20 year old male who had ALL at 11 years and chemotherapy. Two years later he relapsed and received radiotherapy. Nine years post treatment, 7 years post radiotherapy, he presented with headaches and seizures. He was a patient who was in the group for survey [39] but presented prior to his scan appointment. MRI scan T1 weighted (a – b) following intravenous contrast. This shows ring enhancement of the mass in the posterior temporal region, which was proven to be an anaplastic astrocytoma.
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Fig. 6. Twenty-two year old male who had ALL at 5 years and had received cranial radiotherapy. (a) Coronal T2 weighted MRI shows a heterogeneous mass in the ethmoid air cells extending into the nasal cavity destroying the conchae. This was an alveolar rhabdomyosarcoma. Mucosal thickening is seen in the maxillary antra. This patient had 1 year previously been surveyed [39]. (b) Axial T2 sequence shows mild mucosal thickening in the ethmoid sinuses. One year later he presented with facial pain and a repeat MRI (c) showed extensive tumour in the ethmoid air cells. Screening survivors of ALL who have received cranial irradiation has shown to be of value [39]. The difficulty in a screening programme however is when it should begin, the frequency and when they become risk free. Two cases illustrated in this article show that they may present between or before the surveys.
all show a significant increase in thyroid cancers [42,38,43,37]. The cancers are almost all papillary thyroid carcinomas and many carry gene rearrangements producing the RET/PTC oncogene [44], a subtype usually limited to thyroid carcinoma in children under 10 years of age. The thyroid is exquisitely sensitive to radiation, with increased tumour risks occurring after
very low dose radiation exposure [37]. The above studies have also shown an association between age of exposure to radiation and future risk, with radiation exposure below the age of two carrying the greatest risk [42]. Likewise, cohort studies of children treated for primary malignancies have shown an increased risk of
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subsequent thyroid carcinoma and adenoma [34]. Most but not all cases arise in or near to the radiation field in children treated with radiotherapy [41]. The thyroid is sufficiently radiosensitive for the dose of radiation received at the thyroid following craniospinal irradiation for CNS leukaemia to be tumorigenic. Tumours in-
Fig. 8. This is a 15 year old girl who was diagnosed as having a fibrosarcoma of the nasopharynx at the age of 3 years. She was treated with chemotherapy but was found to be unresponsive. She then received radiotherapy. She presented 12 years later with swelling of the right side of the neck. (a) A longitudinal ultrasound scan showed a mass in the right lobe of the thyroid, which was slightly hypoechoic compared with the surrounding thyroid tissue, with a lucent halo around it. These features suggest a benign follicular adenoma but are not pathognomonic. (b) The axial MRI T2 weighted scan shows the high signal well defined thyroid nodule, which was subsequently shown to be a follicular adenoma. Early radiotherapy of the gland is associated with both benign and malignant thyroid masses.
Fig. 7. A 12 year old male with an astrocytoma of the third ventricle at 1 year who had received radiotherapy. At 11 years post treatment, he presented with the astrocytoma in the cervical spinal cord at the edge of the RT field. The tumour was pylocytic unlike the primary tumour, and therefore thought to be secondary to radiotherapy. MRI T2 weighted scans (a) sagittal (b) coronal, show a regular expansion of the cord in the upper cervical region which was shown to be an astrocytoma. Tumours more often arise at the edge of the radiation field, probably due to the fact that the cells are totally destroyed in the centre whereas peripherally the dose is such that, rather than being lethal, they damage the cell. This may induce genetic change with malignant potential.
duced by high-dose therapeutic radiation, like those following low dose treatment for tinea capitis often contain RET/PTC mutations [34]. Intriguingly there also appears to be an independent association between neuroblastoma as the primary malignancy and later development of thyroid carcinoma, despite the absence of RET/PTC mutations in neuroblastoma [45,34]. This link persists even for those infants not treated with radiotherapy [34]. Unsurprisingly, the primary tumours most often are associated with secondary thyroid malignancies are those involving radiation to the anterior neck, in particular Hodgkin’s disease [16], leukaemia [31] and bone marrow transplantation [46]. Ultrasonography has been recommended as a sensitive non-invasive follow-up investigation to screen for thyroid abnormalities in children who have received head and neck irradiation [47] (Fig. 8).
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5.3. Osteosarcoma
6. Secondary AML
Osteosarcoma is one of the commonest second malignant neoplasia following childhood malignancy [1]. Its association with retinoblastoma has already been discussed. Whilst 25% of secondary osteosarcomas follow treatment for retinoblastoma [26], the majority occur following radiotherapy for other solid tumours, particularly Ewing’s tumour, rhabdomyosarcoma, neuroblastoma, Wilms’ tumour and Hodgkin’s disease [48,26,49]. Radiation induced osteosarcomas almost always arise in the irradiated bone (Figs. 9 – 12) [50] whilst those that do occur in previously un-irradiated patients are found in the usual sites of predilection for osteosarcomas, namely the long bones, particularly around the knee [26]. Studies have found an association between prior alkylating agent and anthracycline therapy and osteosarcoma [26,49] (Fig. 13); [51,52]. Latent periods can be considerable, ranging from under 6 years to more than 20 years in one study [48]. The highest risk of secondary osteosarcoma is thus to be found in those treated for retinoblastoma, Ewing’s sarcoma and other soft tissue sarcomas, and those treated with both high dose radiation and chemotherapy [49]. Secondary osteosarcoma has a poor prognosis due to its aggressive behaviour [48].
Therapy related AML has a very clear association with prior chemotherapy. It was initially described following intensive chemotherapy for ALL and lymphomas [53]. It soon became clear that the epipodophyllotoxins (etoposide and tenoposide), were leukaemogenic. Latterly it has been found that all topoisomerase II inhibitors (a group which includes doxorubicin, mitoxantrone and dactinomycin as well as the epidophyllotoxins) can induce the same form of AML, which is now known as topoisomerase II inhibitor related leukaemia [53]. These associations have been made because of the unique features of topoisomerase II inhibitor related leukaemia. It contains a balanced translocation involving chromosome 11 at 11q23. The gene involved in all these translocations is the MLL gene (mixed lineage leukaemia). This form of leukaemia has a short latency, occurring between 30 and 34 months after treatment. It is unclear whether there is a dose-related increase in risk, but the risk is schedule dependent, being highest for weekly or biweekly dosing and less for more regular dosing [33,54].Secondary AML is important because it is the commonest secondary tumour after treatment for ALL, and because although most patients enter remission following treatment, long-term survival is rare, even following bone marrow transplantation [53,33].
6.1. Melanoma
Fig. 9. Twelve year old female with cerebellar astrocytoma at 6 years, received radiotherapy. Six years post treatment she presented with chondroblastic osteosarcoma of the petrous bone. The axial CT scan shows destruction of the right mastoid bone with complete loss of aeration due to tumour invasion.
The association between melanoma as a second malignancy and childhood cancers is an interesting one. The evidence for the role of environment ionising radiation in the development of melanoma is equivocal. The commonest risk factors for the general population are exposure to ultraviolet radiation, history of sunburn at an early age and the presence of high numbers of benign naevi. The strongest associations between primary malignancies and subsequent melanoma are for Hodgkin’s disease [55], retinoblastoma [56] and bone marrow transplant recipients [46]. Whilst some secondary melanomas develop in radiation fields, the significance of this is unclear. Chemotherapy increases the number of benign naevi in patients treated for haematological disease [57,58]. It has been postulated that the underlying mechanism in ultraviolet induced melanoma is immunosupression. Long-term defects in immune function in patients with Hodgkin’s disease and those undergoing bone marrow transplant are seen, and this may explain the increased melanoma risk. Support for this idea is seen in the increased risk of melanoma in renal transplant recipients [59]. The melanomas found in children treated for retinoblastoma have not been found to contain mutations of the Rb gene and this association remains unexplained [56].
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Fig. 10. Sixteen year old male with Non-Hodgkin’s Lymphoma of the caecum presented with intussusception at 9 years old. (a) Barium enema shows a filling defect in the caecum. He received radiotherapy and 7 years later presented with (b) osteosarcoma of the left ilium in the sacroiliac joint at the edge of the radiation field, indicated by the sclerosis. (c) There were also numerous exostoses on the iliac crest. Radiation-induced osteocartilaginous exostoses occur in 12% of cases at an average age of 7 years [50]. Rarely do they themselves become malignant although the adjacent irradiated bone may give rise to osteosarcoma as in this patient.
7. Important causal agents
7.1. Radiation Although there may be less radiotherapy in modern treatment protocols than in the past, it is clear from the previous discussions that radiotherapy is responsible for many secondary cancers. In particular, brain tumours, thyroid malignancies, bone sarcomas and breast cancer in young girls treated for Hodgkin’s disease are clearly linked to prior radiotherapy. In many cases, a dose
effect can also be shown, as can particular windows of risk — younger age at the time of CNS radiotherapy and radiation to the thyroid, radiation to the breast during puberty for example. Other SMN’s that are linked to prior radiotherapy include soft tissue sarcomas and non-melanoma skin cancer. A key characteristic of radiation-induced neoplasia that differentiates them from others is the latency of onset. Unlike tumours associated with chemotherapy, radiation induced tumours tend to have a longer latency, the incidence increases gradually over time,
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reaching a plateau late if at all. Thus continued vigilance is required throughout the life of the patient. Indeed we do not yet know the true lifetime incidence of radiation induced second malignancies as few patients have yet reached old age.
7.2. Chemotherapy
Fig. 11. Thirteen year old female with rhabdomyosarcoma of the calf at 9 years. She received chemotherapy, radiotherapy and surgery. (a) Shows the lower limb one year before, with evidence of osteotomy and orthopaedic fixation device. (b) One year later, shows bone destruction and spicular bone formation typical of osteogenic sarcoma at the radiation site.
The role of chemotherapeutic agents is more difficult to discern than that of radiotherapy as most children treated with chemotherapy receive multiple agents. Evidence that multiagent chemotherapy plays a role in the development of SMN’s is strong. A collaborative Nordic cohort study [1] shows an increase in risk of SMN over time that mirrors the developments in childhood cancer therapy; the increased risk of SMN following treatment for a primary tumour in the pre-chemotherapy era increases further in the modern era of multi-agent chemotherapy. (Relative risk of SMN following primary tumour diagnosed 1943 – 1959= 2.6; relative risk of SMN following primary tumour diagnosed after 1975= 6.9). Cyclophosphamide, in addition to contributing to the general risk of malignancy caused by chemotherapy has a specific recognised association with transitional cell carcinoma of the bladder [60]. Whilst this association is most commonly seen following treatment for adult tumours, it can occur following treatment for childhood malignancy. There is an increased risk with higher doses of cyclophosphamide. The tumours themselves tend to have an aggressive phenotype. The specific role of topoisomerase II inhibitors in relation to secondary AML has already been mentioned.
7.3. BMT
Fig. 12. Eighteen year old male with Ewing Sarcoma of the humerus at 7 years old and treated with chemotherapy and radiotherapy. Eleven years post treatment he presented with osteosarcoma at the same site. (a) Radiograph shows the humerus post treatment where there are radiation changes but no evidence of bone destruction. (b) One year later there is extensive destruction in the humeral shaft indicating malignancy, which was proven to be osteosarcoma at biopsy.
In is perhaps unsurprising that bone marrow transplantation, which commonly combines treatment with high dose alkylating agents and total body irradiation is associated with SMN’s. Children transplanted for aplastic anaemia, especially Fanconi syndrome carry a high risk of secondary tumours post-transplant [61]. For all types of primary malignancy, there are high risks of secondary solid tumours. These include brain tumours, thyroid carcinoma, tumours of the mouth (tongue, salivary and parotid glands) and melanoma [46,62].With the exception of melanoma and carcinoma of the tongue, all these tumours are associated with ionising radiation. There is also a significant association between BMT and EBV associated post-transplant lymphoproliferative disease (PTLD) [46]. BMT is unique amongst childhood cancer treatments in the degree of immunosupression it causes. EBV associated PTLD, like melanoma is also common following renal transplants. Immunosupression is thought to be the mechanism underlying the development of PTLD, melanoma and carcinoma of the tongue [46].
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Fig. 13. Eighteen year old male with Hodgkin’s Lymphoma of the mediastinum at 17 years. Received no radiotherapy, only chemotherapy. Six months post treatment he presented with a small lump in the forearm. Radiographs (a) show a rather unusual looking lesion on the diaphysis of the ulna reminiscent of a sessile osteochondroma although its location is somewhat unusual. (b) Six months later chondroblastic osteogenic sarcoma is seen at the site of the ‘exostosis’. Any unusual appearance of an exostosis, particularly in this location and not in the metaphyseal region, in a patient with known malignancy with radiotherapy or chemotherapy, raises the suspicion that this may be a secondary tumour and would warrant having an MRI. Malignant change in the solitary osteochondroma is rare, 1%, and when it occurs it usually manifests itself as a chondrosarcoma, although osteosarcoma can occur in adjacent bone. A cartilage cap of 3 cm should raise the suspicion of malignancy, especially if there is disruption of its surface [51]. Any high signal on T2 sequences in the medullary cavity beneath the osteochondroma, or surrounding the cap suggesting oedema, is abnormal, and may be an early sign of malignant transformation and merits biopsy [52]. Rapid increase in size is also an ominous sign. Hodgkin’s disease and osteosarcoma are well-known associations although the time interval between the presentation of these tumours is unusually short in this patient.
8. Summary It is clear that almost all children treated for childhood cancer are at risk of subsequent second tumours. However, within this group several key risk groups can be identified. The largest number of SMN’s will occur in children treated for ALL. Amongst these, it is those with CNS leukaemia and those treated with CNS radiotherapy or epipodophyllotoxins that are at greatest risk. Primary CNS tumours represent the other large risk group, with secondary CNS tumours the likely second tumour. Other groups meriting particular note due to their high individual risk of second malignancy are those treated for retinoblastoma, Hodgkin’s disease and neurofibromatosis. A small number of children with familial cancer syndromes are also at significant risk and merit close observation.
9. Conclusion Having attempted to tease out the different roles played by primary tumour type, genetics and treatment modality, in concluding it is appropriate to draw all
these factors together. Radiotherapy and chemotherapy have a combined effect and in the majority of children both play their part in increasing the risk of second tumours. Immunosupression also plays an important role in some contexts. The role of genetic factors is less clear. Whilst for some tumours, notably retinoblastoma and CNS tumours in the phakomatoses, a genetic link is clear, genetic causes have not been implicated in the majority of second tumours. Whether a clearer understanding of tumour biology in the future will increase the role played by genetics remains to be seen. For the moment then the usual suspects, radiation and certain chemotherapeutic agents remain the prime cause of second malignancies. In this context, all children who have received these treatments remain at risk and continued surveillance is warranted. Perhaps the future looks brighter than the current increasing incidence of SMN’s would suggest. There is a significant lead-time between the effects of treatment and later development of secondary tumours. Many of the treatment alterations being undertaken today have the potential to decrease the future risk of SMN’s. In particular, the trend away from the use of cranial radiation for the majority of children with leukaemia,
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and the decreasing role that radiotherapy has in Wilms’ tumour and Hodgkin’s disease should improve the outlook for these patient groups.
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[16] Bhatia S, Robison LL, Oberlin O, Greenberg M, Bunin G, Fossati-Bellani F, Meadows AT. Breast cancer and other second neoplasms after childhood Hodgkin’s disease [see comments]. N Engl J Med 1996;334:745– 51. [17] Metayer C, Lynch CF, Clarke EA, Glimelius B, Storm H, Pukkala E, Joensuu T, van Leeuwen FE, van’t Veer MB, Curtis RE, Holowaty EJ, Andersson M, Wiklund T, Gospodarowicz M, Travis LB. Second cancers among long-term survivors of Hodgkin’s disease diagnosed in childhood and adolescence. J Clin Oncol 2000;18:2435– 43. [18] van Leeuwen FE, Klokman WJ, Veer MB, Hagenbeek A, Krol AD, Vetter UA, Schaapveld M, van Heerde P, Burgers JM, Somers R, Aleman BM. Long-term risk of second malignancy in survivors of Hodgkin’s disease treated during adolescence or young adulthood. J Clin Oncol 2000;18:487– 97. [19] Knudson AG, Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820–3. [20] Squire J, Gallie BL, Phillips RA. A detailed analysis of chromosomal changes in heritable and non-heritable retinoblastoma. Hum Genet 1985;70:291– 301. [21] Buchkovich K, Duffy LA, Harlow E. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 1989;58:1097– 105. [22] Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995;81:323– 30. [23] Abramson DH, Ellsworth RM, Kitchin FD, Tung G. Second nonocular tumors in retinoblastoma survivors. Are they radiation-induced? Ophthalmology 1984;91:1351– 5. [24] Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 1986;53:661– 71. [25] Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology 1988;95:1583– 7. [26] Newton WA, Jr., Meadows AT, Shimada H, Bunin GR, Vawter GF. Bone sarcomas as second malignant neoplasms following childhood cancer. Cancer 1991;67:193– 201. [27] Hansen MF, Koufos A, Gallie BL, Phillips RA, Fodstad O, Brogger A, Gedde-Dahl T, Cavenee WK. Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. Proc Natl Acad Sci USA 1985;82:6216– 20. [28] Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 1988;241:353–7. [29] T’Ang A, Varley JM, Chakraborty S, Murphree AL, Fung YK. Structural rearrangement of the retinoblastoma gene in human breast carcinoma. Science 1988;242:263– 6. [30] Loning L, Zimmermann M, Reiter A, Kaatsch P, Henze G, Riehm H, Schrappe M. Secondary neoplasms subsequent to Berlin– Frankfurt– Munster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy. Blood 2000;95:2770– 5. [31] Neglia JP, Meadows AT, Robison LL, Kim TH, Newton WA, Ruymann FB, Sather HN, Hammond GD. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 1991;325:1330– 6. [32] Walter AW, Hancock ML, Pui CH, Hudson MM, Ochs JS, Rivera GK, Pratt CB, Boyett JM, Kun LE. Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol 1998;16:3761– 7. [33] Winick NJ, McKenna RW, Shuster JJ, Schneider NR, Borowitz MJ, Bowman WP, Jacaruso D, Kamen BA, Buchanan GR. Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide [see comments]. J Clin Oncol 1993;11:209– 17.
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[34] de Vathaire F, Hardiman C, Shamsaldin A, Campbell S, Grimaud E, Hawkins M, Raquin M, Oberlin O, Diallo I, Zucker JM, Panis X, Lagrange JL, Daly-Schveitzer N, Lemerle J, Chavaudra J, Schlumberger M, Bonaiti C. Thyroid carcinomas after irradiation for a first cancer during childhood. Arch Intern Med 1999;159:2713–9. [35] Ron E, Modan B, Boice JD, Jr., Alfandary E, Stovall M, Chetrit A, Katz L. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 1988;319:1033– 9. [36] Little MP, Muirhead CR, Haylock RG, Thomas JM. Relative risks of radiation-associated cancer: comparison of second cancer in therapeutically irradiated populations with the Japanese atomic bomb survivors. Radiat Environ Biophys 1999;38:267– 83. [37] Ron E, Lubin JH, Shore RE, Mabuchi K, Modan B, Pottern LM, Schneider AB, Tucker MA, Boice JD, Jr. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res 1995;141:259–77. [38] Ron E, Modan B. Benign and malignant thyroid neoplasms after childhood irradiation for tinea capitis. J Natl Cancer Inst 1980;65:7– 11. [39] Laitt RD, Chambers EJ, Goddard PR, Wakeley CJ, Duncan AW, Foreman NK. Magnetic resonance imaging and magnetic resonance angiography in long term survivors of acute lymphoblastic leukemia treated with cranial irradiation. Cancer 1995;76:1846– 52. [40] Soffer D, Gomori JM, Siegal T, Shalit MN. Intracranial meningiomas after high-dose irradiation. Cancer 1989;63:1514– 9. [41] Tucker MA, Jones PH, Boice JD, Jr., Robison LL, Stone BJ, Stovall M, Jenkin RD, Lubin JH, Baum ES, Siegel SE. Therapeutic radiation at a young age is linked to secondary thyroid cancer. The Late Effects Study Group. Cancer Res 1991;51:2885– 8. [42] Farahati J, Demidchik EP, Biko J, Reiners C. Inverse association between age at the time of radiation exposure and extent of disease in cases of radiation-induced childhood thyroid carcinoma in Belarus. Cancer 2000;88:1470–6. [43] Ron E, Modan B, Preston D, Alfandary E, Stovall M, Boice JD, Jr. Thyroid neoplasia following low-dose radiation in childhood. Radiat Res 1989;120:516–31. [44] Santoro M, Thomas GA, Vecchio G, Williams GH, Fusco A, Chiappetta G, Pozcharskaya V, Bogdanova TI, Demidchik EP, Cherstvoy ED, Voscoboinik L, Tronko ND, Carss A, Bunnell H, Tonnachera M, Parma J, Dumont JE, Keller G, Hofler H, Williams ED. Gene rearrangement and Chernobyl related thyroid cancers. Br J Cancer 2000;82:315–22. [45] de Vathaire F, Francois P, Schlumberger M, Schweisguth O, Hardiman C, Grimaud E, Oberlin O, Hill C, Lemerle J, Flamant R. Epidemiological evidence for a common mechanism for neuroblastoma and differentiated thyroid tumour. Br J Cancer 1992;65:425– 8. [46] Socie G, Curtis RE, Deeg HJ, Sobocinski KA, Filipovich AH, Travis LB, Sullivan KM, Rowlings PA, Kingma DW, Banks PM, Travis WD, Witherspoon RP, Sanders J, Jaffe ES, Horowitz MM. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol 2000;18:348– 57.
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[47] Crom DB, Kaste SC, Tubergen DG, Greenwald CA, Sharp GB, Hudson MM. Ultrasonography for thyroid screening after head and neck irradiation in childhood cancer survivors. Med Pediatr Oncol 1997;28:15– 21. [48] Bechler JR, Robertson WW, Meadows AT, Jr., Womer RB. Osteosarcoma as a second malignant neoplasm in children. J Bone Joint Surg [Am] 1992;74:1079– 83. [49] Le Vu B, de Vathaire F, Shamsaldin A, Hawkins MM, Grimaud E, Hardiman C, Diallo I, Vassal G, Bessa E, Campbell S, Panis X, Daly-Schveitzer N, Lagrange JL, Zucker JM, Eschwege F, Chavaudra J, Lemerle J. Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood. Int J Cancer 1998;77:370– 7. [50] Ozonoff MB. Paediatric Orthopaedic Radiology. London: WB Saunders, 1992. p. 604– 689. [51] Woertler K, Lindner N, Gosheger G, Brinkschmidt C, Heindel W. Osteochondroma MR imaging of tumor-related complications. Eur Radiol 2000;10:832– 40. [52] Moore SG, Dawson KL. Tumours of the musculoskeletal system. In: Cohen MD, Edwares MK, editors. Magnetic Resonance in Children. Philadelphia: BC Decker, 1990. p. 825– 911. [53] Pui CH, Relling MV. Topoisomerase II inhibitor-related acute myeloid leukaemia. Br J Haematol 2000;109:13– 23. [54] Pui CH, Relling MV, Rivera GK, Hancock ML, Raimondi SC, Heslop HE, Santana VM, Ribeiro RC, Sandlund JT, Mahmoud HH. Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. Leukemia 1995;9:1990– 6. [55] Tucker MA, Misfeldt D, Coleman CN, Clark WH, Jr., Rosenberg SA. Cutaneous malignant melanoma after Hodgkin’s disease. Ann Intern Med 1985;102:37– 41. [56] Corpron CA, Black CT, Ross MI, Herzog CS, Ried HL, Lally KP, Andrassy RJ. Melanoma as a second malignant neoplasm after childhood cancer. Am J Surg 1996;172:459– 61. [57] Hughes BR, Cunliffe WJ, Bailey CC. Excess benign melanocytic naevi after chemotherapy for malignancy in childhood. BMJ 1989;299:88– 91. [58] Baird EA, McHenry PM, MacKie RM. Effect of maintenance chemotherapy in childhood on numbers of melanocytic naevi. BMJ 1992;305:799– 801. [59] Greene MH, Young TI, Clark WH, Jr. Malignant melanoma in renal-transplant recipients. Lancet 1981;1:1196– 9. [60] Travis LB, Curtis RE, Glimelius B, Holowaty EJ, van Leeuwen FE, Lynch CF, Hagenbeek A, Stovall M, Banks PM, Adami J. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst 1995;87:524– 30. [61] Socie G, Henry-Amar M, Bacigalupo A, Hows J, Tichelli A, Ljungman P, McCann SR, Frickhofen N, Veer-Korthof E, Gluckman E. Malignant tumors occurring after treatment of aplastic anemia. European Bone Marrow Transplantation– Severe Aplastic Anaemia Working Party. N Engl J Med 1993;329:1152– 7. [62] Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, Travis LB, Horowitz MM, Witherspoon RP, Hoover RN, Sobocinski KA, Fraumeni JF, Jr., Boice JD, Jr. Solid cancers after bone marrow transplantation [see comments]. N Engl J Med 1997;336:897– 904.
Second malignancies in children: the usual suspects? John Moppett a, Anthony Oakhill a,*, Andrew W. Duncan b a b
Department of Paediatric Oncology, Bristol Royal Hospital for Sick Children, St. Michael’s Hill, Bristol BS2 8BJ, UK Department of Paediatric Radiology, Bristol Royal Hospital for Sick Children, St. Michael’s Hill, Bristol BS2 8BJ, UK Received 23 October 2000; accepted 10 November 2000
Abstract The aim of this article is to provide an up to date review of second malignant neoplasms (SMN’s) following treatment for childhood cancer, referring to their incidence, the role of genetic factors, and how the primary malignancy and treatment received influence the type, site and prognosis of SMN’s. The role of genetic factors will be discussed as far as they impact upon a predisposition to later development of SMN’s. The primary malignancies that have important associations with SMN’s will then be discussed, in particular Hodgkin’s disease, retinoblastoma and acute lymphoblastic leukaemia. The important second malignancies will be highlighted, including tumours of the CNS and thyroid, osteosarcoma, secondary acute myeloid leukaemia and melanoma. Emphasis will be put upon identifying which patients are most likely to suffer from these tumours. An important part of the article are case histories. These are provided in combination with illustrations as a useful adjunct to the text, with a particular emphasis on radiological features, diagnosis and screening. Finally, the important but different roles of causal agents, in particular chemotherapy and radiotherapy are highlighted. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Paediatric; Oncology; Radiology; Secondary tumours
1. Introduction Treatment for childhood cancer is often seen as one of the major success stories of modern medicine. Indeed there are many eminently curable childhood tumours that were uniformly fatal less than 50 years ago. Sadly, the increasing incidence of second malignant neoplasia (SMN’s) is one of the least desirable consequences of improved therapy for first malignancies. The aim of this article is to review current knowledge about SMN’s with particular reference to the role of aetiological factors and the clinical features of second malignancies, thus providing a rationale for the radiological followup of these children. Second malignancies are not common and many children must be followed to gain a realistic perspective on the characteristic features of these tumours. Many years often elapse before the occurrence of a SMN, requiring vigilance and long-term follow-up if they are to be recognised for what they are. Inevitably current * Corresponding author. Tel.: +44-117-9285451; fax: + 44-1179285682. E-mail address: [email protected] (A. Oakhill).
reports of SMN’s reflect the consequences of medical practice many years ago, making future predictions for current patients uncertain.
2. Incidence Several methods of expressing the risk of second malignancy are used in the literature. Clinicians and in particular patients wish to know the absolute risk of developing a second tumour for an individual. This figure is complicated however by the fact that at long follow-up intervals, the absolute population risk of developing cancer becomes quite high. Thus for example, the background population risk of malignancy after 45 years of follow-up of an ‘at risk’ population is almost 6% [1]. Epidemiologists therefore prefer to express risk in terms of relative risk. Relative risks are a powerful measure of the importance of contributing factors but can be less useful clinically. Thus whilst the 1000 fold relative risk of developing a second tumour in children with a CNS tumour and neurofibromatosis is highly significant, [2] the 51% absolute risk that a child with hereditary retinoblastoma has of developing a
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second tumour in the next 50 years is perhaps more easily understood [3]. Overall somewhat in excess of 1000 second malignant neoplasia following treatment for childhood malignancy have been reported in the literature. Exact risks are hard to quantify. In large cohort studies with long follow-up times, 5– 10% of children treated for first malignancy have developed subsequent second tumours [4,5]. These figures do not however represent the risk to current patients. The makeup of these cohorts is somewhat different to current survivors of childhood cancer therapy. In particular acute leukaemia is significantly under-represented in the groups with the longest follow-up, [1] as survival rates for ALL were poor until the late 1960’s. The risk seems to be higher for those children treated since the inception of modern intensive multiagent chemotherapy, suggesting that the incidence of second malignancies is due to rise further in the future [1]. In general terms the risk factors for developing second malignancies can be divided into patient (type of first tumour, age at diagnosis of first tumour, and certain genetic factors) and treatment (radiotherapy and chemotherapy) related.
3. Important genetic factors Over recent years, many genes involved in the development of cancer have been discovered and the mechanisms behind their function elucidated. As a result of this process, it has become possible to explain why cancer appears to be particularly common in some families. The most well-known family cancer syndrome associated with childhood malignancy is Li-Fraumeni syndrome (L-FS) [6], which is due to the autosomal dominant inheritance of germline p53 mutations [7]. P53 is a tumour suppressor gene that is involved in many adult tumours. In L-FS, children have a predisposition to develop rhabdomyosarcoma, soft tissue and bone sarcomas, brain tumours, acute leukaemia, adrenocortical cell carcinoma and early onset breast cancer [8]. Family members have a 50% chance of developing a malignancy by the age of 30 [9]. L-FS is however, rare. Germline p53 mutations (not all cases of which strictly fit the criteria for a diagnosis of L-FS) are found in at most 10% of cases of soft-tissue sarcoma and rhabdomyosarcoma, [10] and 3% of osteosarcomas [11]. Other family cancer syndromes are associated with childhood tumours such as Turcot syndrome (the association of CNS tumours, especially medulloblastoma, with colon cancer) [12], ataxia telangectasia (an autosomal recessive germline mutation of the ataxia telangectasia gene which predisposes affected individuals to the
development of immunodeficiency and subsequently leukaemias and B-cell lymphomas) and the phakomatoses [13,2]. Of these only neurofibromatosis type 1(NF-1) is common, affecting 1 in 2500 individuals. Children with NF-1 have an increased risk of developing many different tumours; in particular optic pathway gliomas and peripheral nerve sheath tumours [14,15]. Children with NF-1 who receive radiotherapy for a primary CNS tumour have a very high relative risk of developing a second CNS tumour [2]. The risk of second malignancy following modern first-line treatment for optic pathway gliomas (vincristine and carboplatin) is unknown. Overall, despite the many genes now associated with cancer syndromes, evidence to date still suggests that they represent a small minority of paediatric tumours, and do not play a significant role numerically in the development of secondary tumours.
4. Primary malignancies that have important associations with second malignant neoplasia
4.1.1. Hodgkin’s disease A significant amount of information regarding second malignancies following Hodgkin’s disease is available because a good cure rate has been achieved for many years, resulting in many long-term survivors. Most studies report cohorts in which more than 90% of children have received radiotherapy [16,17]. The increasing use of protocols that avoid radiotherapy for the majority of children may significantly alter the pattern of second malignancies in the future [17]. The largest study to date in this condition gives a relative risk for all SMN’s of 27, which equates to a 6.5% absolute risk of solid tumour (which represent 81% of all SMN’s) at 15 years from diagnosis [17]. Amongst the solid tumours, breast cancer was the single commonest (almost 50% of solid tumours in women). Carcinoma of the thyroid and basal cell carcinoma are also common [16]. Significant associations with therapy received are seen. Secondary leukaemia was associated with chemotherapy, particularly alkylating agents, whilst breast cancer only occurs in patients who have received radiation therapy, and almost always within or at the margin of the radiation field [16]. There is a particularly high risk of breast cancer for those girls treated between the ages of 10 and 16, the period when breast tissue is proliferating [16,17]. There is also good evidence that chemotherapy is additive to the effects of radiotherapy in increasing the risk of solid tumours [18]. It is notable that whilst the risk for secondary leukaemia reaches a plateau after 14 years, the risk of secondary solid tumours keeps rising, reaching nearly 30% at 30 years [16]. Thus, lifelong vigilance is required
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for children who have been treated for Hodgkin’s disease, especially those who received radiotherapy [17].
4.2. Retinoblastoma Retinoblastoma is the classical tumour model in which genetics and treatment received have both been shown to play their part in the development of second malignant neoplasia. There are two forms of retinoblastoma, sporadic and hereditary [19]. They differ both in their presentation and genetics. The underlying defect in all retinoblastoma tumours is defective functioning of the retinoblastoma tumour suppressor gene Rb, found on the long arm of chromosome 13 [20]. Normal cells carry two Rb alleles and both must be inactivated for a tumour to develop. The Rb gene product is involved in cell cycle checkpoint control and its absence allows the uncontrolled proliferation of abnormal cells [21,22]. Familial cases of retinoblastoma carry a germline deletion of one of their Rb alleles, meaning that a single spontaneous mutation of the remaining Rb allele is sufficient to cause a tumour to develop. Spontaneous cases on the other hand do not carry germline mutations, and two independent mutation events are thus required for a tumour to arise. The clinical consequences of this are that hereditary retinoblastoma occurs at a younger age and many patients present initially with bilateral disease [19]. Hereditary retinoblastoma has a well-recognised association with second malignancies, particularly osteosarcoma [23], an association not seen in sporadic retinoblastoma. Osteosarcoma represents over one third of the second malignancies arising in hereditary retinoblastoma patients [24]. Estimates of incidence vary considerably but the largest study to date puts the cumulative incidence of second malignancy at 50 years from diagnosis at 51% [3]. Other tumours that are commonly seen in hereditary retinoblastoma include melanoma, brain tumours and soft tissue sarcomas [24,1]. An association between radiation dose received and the incidence of secondary osteosarcoma and soft tissue sarcomas is seen in retinoblastoma [3], suggesting that radiation plays a part in the increased frequency at which these tumours arise. However, a significant minority of secondary tumours in retinoblastoma arise outside the radiation field [25], and an increased incidence of secondary osteosarcoma is also seen in those children who do not receive radiotherapy [26]. Molecular studies have shown that many osteosarcomas that arise in children with hereditary retinoblastoma also harbour loss of heterozygosity at the Rb locus, suggesting a common etiological mechanism [27]. Loss of heterozygosity at the Rb locus has also been found in some sporadic osteosarcomas and osteosarcoma cell lines. It is postulated that loss of both Rb
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alleles in the eye leads to retinoblastoma whilst their loss in bone tissue leads to the development of osteosarcoma. Rb mutations are commonly detected in a wide variety of common adult tumours such as breast and small cell carcinoma of the lung [28,29]. The lack of association between these tumours and retinoblastoma suggests that the Rb mutations in these tumours play a different role, unlike the essential one they have in the pathogenesis of retinoblastoma and some osteosarcomas.
4.3. Acute lymphoblastic leukaemia Whilst other conditions are more classically associated with second malignancies, ALL is a significant cause of SMN’s because of its high incidence in childhood and the good overall survival rates achieved with modern intensive chemotherapy [1]. The pattern of SMN’s following treatment for ALL is significantly different to that for Hodgkin’s disease and retinoblastoma. Central nervous system tumours and secondary leukaemias predominate, with new lymphomas and thyroid malignancies also common [30 –33]. The quoted incidence varies from 2.5 to 3.3% at 15 years from diagnosis [30,31]. Risk of second malignancy is clearly linked to treatment received, with an increased risk of a SMN in those receiving radiotherapy [30]. Almost all secondary brain tumours and thyroid malignancies occur in prior radiation fields [30,34]. Radiotherapy related tumours have an increasing incidence over time whilst chemotherapy related tumours tend to plateau after 5 years from diagnosis of the primary malignancy [34,31]. SMN’s are also more common in those treated at an early age (B 5 years at diagnosis of leukaemia) [34,30 –32]. Epipodophyllotoxin treatment is associated with the occurrence of secondary AML (see below) [33]. For the first 5 years after treatment, secondary AML is the likeliest second malignancy (though relapse remains the most common malignancy found), being superseded thereafter by brain tumours due to the longer latency of CNS tumours relative to secondary AML [31].
5. Important second malignant neoplasia
5.1. CNS tumours It has traditionally been thought that neural tissue is relatively insensitive to the tumorigenic effects of ionising radiation [35]. The data regarding CNS tumour risk in atomic bomb survivors for example is equivocal, [35] unlike the increased risk in this population for many
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other tumour types [36,37]. The clearest evidence for an association between radiation and CNS tumours in the general population comes from children who received low dose scalp irradiation for tinea capitis [38]. Followup studies of these children have clearly shown an increased risk of CNS tumours [38]. The highest risk is for secondary benign tumours but an increased risk of malignant tumour also exists [38]. The majority of these tumours are meningiomas (Figs. 1 and 2) [39]. When compared to meningiomas in the general population (which have a preponderance in middle aged females), they appear to be more aggressive histologically, have no sex bias and appear at younger age [40,35]. The interval between exposure and subsequent tumour development is longest for benign tumours and shorter for malignant neoplasia [35]. Generalising data from
these cohorts to children treated therapeutically is difficult. Whole brain radiation exposure in the tinea capitis group is less uniform, and the doses, usually 1–2 Gy are significantly lower than therapeutic doses used today [35]. Several large cohort studies have recently reported clearly increased risks of secondary CNS tumours following treatment for childhood malignancy [2,31,32]. The clearest risk is in patients with prior radiotherapy to the CNS. (Fig. 3) This risk is both dose and age dependent. Increasing dose of radiation and younger age at exposure are both strong independent risk factors [2,32]. There is also a significantly increased risk of secondary CNS tumour following treatment for a first CNS tumour (Fig. 4) [2]. Clear increased risk of a secondary CNS tumour is also seen for children with
Fig. 1. An asymptomatic 22 year old male who had acute lymphoblastic leukaemia (ALL) at 3 years of age and had received cranial irradiation. He had been part of a survey, by magnetic resonance imaging, of long-term survivors of acute lymphatic leukaemia treated with cranial irradiation [39]. (a) Sagittal; and (b) coronal T1 weighted MRI brain scans following intravenous contrast shows an enhancing mass arising from the inferior margin of the tentorium on the right side, consistent with and subsequently proved to be an anaplastic meningioma. No specific features, but young age of patient is suggestive of secondary tumour. If Magnetic Resonance Angiography (MRA) is performed, it may show vasculitis which would indicate radiation change and provide strong circumstantial evidence of the tumour being of a secondary nature.
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Fig. 1. (Continued)
neurofibromatosis [2], and retinoblastoma [3], strongly suggesting that genetic factors play a role in the risk of developing CNS tumours. Some papers have shown weak links between chemotherapy and subsequent CNS tumour risk [1] whilst others do not [2]. It therefore remains unclear whether the increasing use of chemotherapy for CNS tumours will affect the long-term incidence of secondary tumours. As regards the clinical features of secondary CNS tumours following childhood cancer therapy, meningioma is the commonest, as seen in the tinea capitis cohorts [35]. Likewise, secondary meningiomas tend to show more aggressive histological features [40]. Despite this. the clinical outcome appears good [32]. However, other more aggressive tumours such as glioblastoma multiforme, and anaplastic or other high-grade astrocytomas represent roughly 50% of the tumours occurring following childhood ALL (Fig. 5) [39] and these tumours have a very poor prognosis [2]. Benign tumours develop later than malignant ones [32]. Overall, the risk of developing a secondary CNS tumour appears to be 0.5% at 15 years overall, 2% at 15 years for children with CNS tumours and 1.39% at 20 years for children with ALL [2]. Adjacent extracranial secondary tumours will also result as a consequence of cranial irradiation (Figs. 6 and 7) [39,32].
Fig. 2. A 23 year old female who had previously had ependymoma of cerebellum at 12 years of age and was treated by radiotherapy. Eleven years post treatment, she presented with malignant meningioma. CT scan following intravenous contrast shows multiple malignant meningiomas on the falx and peripherally on the left side. There had been a previous craniotomy in the frontal parietal region on the left side for removing a previous malignant meningioma. No specific features but multiple lesions suggest secondary tumours.
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the standard population risk [34,41]. This is in part due to the relative rarity of thyroid tumours in the general population and partly due to some particular associations between treatment and thyroid cancers. Thyroid malignancies have a well-known association with exposure to radiation. Cohort studies of atomic bomb survivors; children exposed to radiation from the Chernobyl disaster; and children treated with radiation for tinea capitis, enlarged tonsils and enlarged thymus
Fig. 3. Fourteen year old male with rhabdomyosarcoma of the left orbit at 8 years, treated by chemotherapy and radiotherapy and presented 5 years post treatment. MRI scan T1 weighted after contrast enhancement shows multifocal astrocytoma in the frontal region. There was a further lesion in the cerebellum.
Fig. 4. Twenty year old female who had an astrocytoma at 3 years of age and was treated by radiotherapy. She presented 17 years post treatment. Sagittal MRI scan T1 weighted post contrast shows multifocal glioblastoma.
5.2. Thyroid tumours The cumulative increased risk of developing a secondary thyroid malignancy compared to the general population risk is one the highest of all second malignancies. Estimates of the risk vary from 53 to 80 times
Fig. 5. A 20 year old male who had ALL at 11 years and chemotherapy. Two years later he relapsed and received radiotherapy. Nine years post treatment, 7 years post radiotherapy, he presented with headaches and seizures. He was a patient who was in the group for survey [39] but presented prior to his scan appointment. MRI scan T1 weighted (a – b) following intravenous contrast. This shows ring enhancement of the mass in the posterior temporal region, which was proven to be an anaplastic astrocytoma.
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Fig. 6. Twenty-two year old male who had ALL at 5 years and had received cranial radiotherapy. (a) Coronal T2 weighted MRI shows a heterogeneous mass in the ethmoid air cells extending into the nasal cavity destroying the conchae. This was an alveolar rhabdomyosarcoma. Mucosal thickening is seen in the maxillary antra. This patient had 1 year previously been surveyed [39]. (b) Axial T2 sequence shows mild mucosal thickening in the ethmoid sinuses. One year later he presented with facial pain and a repeat MRI (c) showed extensive tumour in the ethmoid air cells. Screening survivors of ALL who have received cranial irradiation has shown to be of value [39]. The difficulty in a screening programme however is when it should begin, the frequency and when they become risk free. Two cases illustrated in this article show that they may present between or before the surveys.
all show a significant increase in thyroid cancers [42,38,43,37]. The cancers are almost all papillary thyroid carcinomas and many carry gene rearrangements producing the RET/PTC oncogene [44], a subtype usually limited to thyroid carcinoma in children under 10 years of age. The thyroid is exquisitely sensitive to radiation, with increased tumour risks occurring after
very low dose radiation exposure [37]. The above studies have also shown an association between age of exposure to radiation and future risk, with radiation exposure below the age of two carrying the greatest risk [42]. Likewise, cohort studies of children treated for primary malignancies have shown an increased risk of
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subsequent thyroid carcinoma and adenoma [34]. Most but not all cases arise in or near to the radiation field in children treated with radiotherapy [41]. The thyroid is sufficiently radiosensitive for the dose of radiation received at the thyroid following craniospinal irradiation for CNS leukaemia to be tumorigenic. Tumours in-
Fig. 8. This is a 15 year old girl who was diagnosed as having a fibrosarcoma of the nasopharynx at the age of 3 years. She was treated with chemotherapy but was found to be unresponsive. She then received radiotherapy. She presented 12 years later with swelling of the right side of the neck. (a) A longitudinal ultrasound scan showed a mass in the right lobe of the thyroid, which was slightly hypoechoic compared with the surrounding thyroid tissue, with a lucent halo around it. These features suggest a benign follicular adenoma but are not pathognomonic. (b) The axial MRI T2 weighted scan shows the high signal well defined thyroid nodule, which was subsequently shown to be a follicular adenoma. Early radiotherapy of the gland is associated with both benign and malignant thyroid masses.
Fig. 7. A 12 year old male with an astrocytoma of the third ventricle at 1 year who had received radiotherapy. At 11 years post treatment, he presented with the astrocytoma in the cervical spinal cord at the edge of the RT field. The tumour was pylocytic unlike the primary tumour, and therefore thought to be secondary to radiotherapy. MRI T2 weighted scans (a) sagittal (b) coronal, show a regular expansion of the cord in the upper cervical region which was shown to be an astrocytoma. Tumours more often arise at the edge of the radiation field, probably due to the fact that the cells are totally destroyed in the centre whereas peripherally the dose is such that, rather than being lethal, they damage the cell. This may induce genetic change with malignant potential.
duced by high-dose therapeutic radiation, like those following low dose treatment for tinea capitis often contain RET/PTC mutations [34]. Intriguingly there also appears to be an independent association between neuroblastoma as the primary malignancy and later development of thyroid carcinoma, despite the absence of RET/PTC mutations in neuroblastoma [45,34]. This link persists even for those infants not treated with radiotherapy [34]. Unsurprisingly, the primary tumours most often are associated with secondary thyroid malignancies are those involving radiation to the anterior neck, in particular Hodgkin’s disease [16], leukaemia [31] and bone marrow transplantation [46]. Ultrasonography has been recommended as a sensitive non-invasive follow-up investigation to screen for thyroid abnormalities in children who have received head and neck irradiation [47] (Fig. 8).
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5.3. Osteosarcoma
6. Secondary AML
Osteosarcoma is one of the commonest second malignant neoplasia following childhood malignancy [1]. Its association with retinoblastoma has already been discussed. Whilst 25% of secondary osteosarcomas follow treatment for retinoblastoma [26], the majority occur following radiotherapy for other solid tumours, particularly Ewing’s tumour, rhabdomyosarcoma, neuroblastoma, Wilms’ tumour and Hodgkin’s disease [48,26,49]. Radiation induced osteosarcomas almost always arise in the irradiated bone (Figs. 9 – 12) [50] whilst those that do occur in previously un-irradiated patients are found in the usual sites of predilection for osteosarcomas, namely the long bones, particularly around the knee [26]. Studies have found an association between prior alkylating agent and anthracycline therapy and osteosarcoma [26,49] (Fig. 13); [51,52]. Latent periods can be considerable, ranging from under 6 years to more than 20 years in one study [48]. The highest risk of secondary osteosarcoma is thus to be found in those treated for retinoblastoma, Ewing’s sarcoma and other soft tissue sarcomas, and those treated with both high dose radiation and chemotherapy [49]. Secondary osteosarcoma has a poor prognosis due to its aggressive behaviour [48].
Therapy related AML has a very clear association with prior chemotherapy. It was initially described following intensive chemotherapy for ALL and lymphomas [53]. It soon became clear that the epipodophyllotoxins (etoposide and tenoposide), were leukaemogenic. Latterly it has been found that all topoisomerase II inhibitors (a group which includes doxorubicin, mitoxantrone and dactinomycin as well as the epidophyllotoxins) can induce the same form of AML, which is now known as topoisomerase II inhibitor related leukaemia [53]. These associations have been made because of the unique features of topoisomerase II inhibitor related leukaemia. It contains a balanced translocation involving chromosome 11 at 11q23. The gene involved in all these translocations is the MLL gene (mixed lineage leukaemia). This form of leukaemia has a short latency, occurring between 30 and 34 months after treatment. It is unclear whether there is a dose-related increase in risk, but the risk is schedule dependent, being highest for weekly or biweekly dosing and less for more regular dosing [33,54].Secondary AML is important because it is the commonest secondary tumour after treatment for ALL, and because although most patients enter remission following treatment, long-term survival is rare, even following bone marrow transplantation [53,33].
6.1. Melanoma
Fig. 9. Twelve year old female with cerebellar astrocytoma at 6 years, received radiotherapy. Six years post treatment she presented with chondroblastic osteosarcoma of the petrous bone. The axial CT scan shows destruction of the right mastoid bone with complete loss of aeration due to tumour invasion.
The association between melanoma as a second malignancy and childhood cancers is an interesting one. The evidence for the role of environment ionising radiation in the development of melanoma is equivocal. The commonest risk factors for the general population are exposure to ultraviolet radiation, history of sunburn at an early age and the presence of high numbers of benign naevi. The strongest associations between primary malignancies and subsequent melanoma are for Hodgkin’s disease [55], retinoblastoma [56] and bone marrow transplant recipients [46]. Whilst some secondary melanomas develop in radiation fields, the significance of this is unclear. Chemotherapy increases the number of benign naevi in patients treated for haematological disease [57,58]. It has been postulated that the underlying mechanism in ultraviolet induced melanoma is immunosupression. Long-term defects in immune function in patients with Hodgkin’s disease and those undergoing bone marrow transplant are seen, and this may explain the increased melanoma risk. Support for this idea is seen in the increased risk of melanoma in renal transplant recipients [59]. The melanomas found in children treated for retinoblastoma have not been found to contain mutations of the Rb gene and this association remains unexplained [56].
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Fig. 10. Sixteen year old male with Non-Hodgkin’s Lymphoma of the caecum presented with intussusception at 9 years old. (a) Barium enema shows a filling defect in the caecum. He received radiotherapy and 7 years later presented with (b) osteosarcoma of the left ilium in the sacroiliac joint at the edge of the radiation field, indicated by the sclerosis. (c) There were also numerous exostoses on the iliac crest. Radiation-induced osteocartilaginous exostoses occur in 12% of cases at an average age of 7 years [50]. Rarely do they themselves become malignant although the adjacent irradiated bone may give rise to osteosarcoma as in this patient.
7. Important causal agents
7.1. Radiation Although there may be less radiotherapy in modern treatment protocols than in the past, it is clear from the previous discussions that radiotherapy is responsible for many secondary cancers. In particular, brain tumours, thyroid malignancies, bone sarcomas and breast cancer in young girls treated for Hodgkin’s disease are clearly linked to prior radiotherapy. In many cases, a dose
effect can also be shown, as can particular windows of risk — younger age at the time of CNS radiotherapy and radiation to the thyroid, radiation to the breast during puberty for example. Other SMN’s that are linked to prior radiotherapy include soft tissue sarcomas and non-melanoma skin cancer. A key characteristic of radiation-induced neoplasia that differentiates them from others is the latency of onset. Unlike tumours associated with chemotherapy, radiation induced tumours tend to have a longer latency, the incidence increases gradually over time,
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reaching a plateau late if at all. Thus continued vigilance is required throughout the life of the patient. Indeed we do not yet know the true lifetime incidence of radiation induced second malignancies as few patients have yet reached old age.
7.2. Chemotherapy
Fig. 11. Thirteen year old female with rhabdomyosarcoma of the calf at 9 years. She received chemotherapy, radiotherapy and surgery. (a) Shows the lower limb one year before, with evidence of osteotomy and orthopaedic fixation device. (b) One year later, shows bone destruction and spicular bone formation typical of osteogenic sarcoma at the radiation site.
The role of chemotherapeutic agents is more difficult to discern than that of radiotherapy as most children treated with chemotherapy receive multiple agents. Evidence that multiagent chemotherapy plays a role in the development of SMN’s is strong. A collaborative Nordic cohort study [1] shows an increase in risk of SMN over time that mirrors the developments in childhood cancer therapy; the increased risk of SMN following treatment for a primary tumour in the pre-chemotherapy era increases further in the modern era of multi-agent chemotherapy. (Relative risk of SMN following primary tumour diagnosed 1943 – 1959= 2.6; relative risk of SMN following primary tumour diagnosed after 1975= 6.9). Cyclophosphamide, in addition to contributing to the general risk of malignancy caused by chemotherapy has a specific recognised association with transitional cell carcinoma of the bladder [60]. Whilst this association is most commonly seen following treatment for adult tumours, it can occur following treatment for childhood malignancy. There is an increased risk with higher doses of cyclophosphamide. The tumours themselves tend to have an aggressive phenotype. The specific role of topoisomerase II inhibitors in relation to secondary AML has already been mentioned.
7.3. BMT
Fig. 12. Eighteen year old male with Ewing Sarcoma of the humerus at 7 years old and treated with chemotherapy and radiotherapy. Eleven years post treatment he presented with osteosarcoma at the same site. (a) Radiograph shows the humerus post treatment where there are radiation changes but no evidence of bone destruction. (b) One year later there is extensive destruction in the humeral shaft indicating malignancy, which was proven to be osteosarcoma at biopsy.
In is perhaps unsurprising that bone marrow transplantation, which commonly combines treatment with high dose alkylating agents and total body irradiation is associated with SMN’s. Children transplanted for aplastic anaemia, especially Fanconi syndrome carry a high risk of secondary tumours post-transplant [61]. For all types of primary malignancy, there are high risks of secondary solid tumours. These include brain tumours, thyroid carcinoma, tumours of the mouth (tongue, salivary and parotid glands) and melanoma [46,62].With the exception of melanoma and carcinoma of the tongue, all these tumours are associated with ionising radiation. There is also a significant association between BMT and EBV associated post-transplant lymphoproliferative disease (PTLD) [46]. BMT is unique amongst childhood cancer treatments in the degree of immunosupression it causes. EBV associated PTLD, like melanoma is also common following renal transplants. Immunosupression is thought to be the mechanism underlying the development of PTLD, melanoma and carcinoma of the tongue [46].
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Fig. 13. Eighteen year old male with Hodgkin’s Lymphoma of the mediastinum at 17 years. Received no radiotherapy, only chemotherapy. Six months post treatment he presented with a small lump in the forearm. Radiographs (a) show a rather unusual looking lesion on the diaphysis of the ulna reminiscent of a sessile osteochondroma although its location is somewhat unusual. (b) Six months later chondroblastic osteogenic sarcoma is seen at the site of the ‘exostosis’. Any unusual appearance of an exostosis, particularly in this location and not in the metaphyseal region, in a patient with known malignancy with radiotherapy or chemotherapy, raises the suspicion that this may be a secondary tumour and would warrant having an MRI. Malignant change in the solitary osteochondroma is rare, 1%, and when it occurs it usually manifests itself as a chondrosarcoma, although osteosarcoma can occur in adjacent bone. A cartilage cap of 3 cm should raise the suspicion of malignancy, especially if there is disruption of its surface [51]. Any high signal on T2 sequences in the medullary cavity beneath the osteochondroma, or surrounding the cap suggesting oedema, is abnormal, and may be an early sign of malignant transformation and merits biopsy [52]. Rapid increase in size is also an ominous sign. Hodgkin’s disease and osteosarcoma are well-known associations although the time interval between the presentation of these tumours is unusually short in this patient.
8. Summary It is clear that almost all children treated for childhood cancer are at risk of subsequent second tumours. However, within this group several key risk groups can be identified. The largest number of SMN’s will occur in children treated for ALL. Amongst these, it is those with CNS leukaemia and those treated with CNS radiotherapy or epipodophyllotoxins that are at greatest risk. Primary CNS tumours represent the other large risk group, with secondary CNS tumours the likely second tumour. Other groups meriting particular note due to their high individual risk of second malignancy are those treated for retinoblastoma, Hodgkin’s disease and neurofibromatosis. A small number of children with familial cancer syndromes are also at significant risk and merit close observation.
9. Conclusion Having attempted to tease out the different roles played by primary tumour type, genetics and treatment modality, in concluding it is appropriate to draw all
these factors together. Radiotherapy and chemotherapy have a combined effect and in the majority of children both play their part in increasing the risk of second tumours. Immunosupression also plays an important role in some contexts. The role of genetic factors is less clear. Whilst for some tumours, notably retinoblastoma and CNS tumours in the phakomatoses, a genetic link is clear, genetic causes have not been implicated in the majority of second tumours. Whether a clearer understanding of tumour biology in the future will increase the role played by genetics remains to be seen. For the moment then the usual suspects, radiation and certain chemotherapeutic agents remain the prime cause of second malignancies. In this context, all children who have received these treatments remain at risk and continued surveillance is warranted. Perhaps the future looks brighter than the current increasing incidence of SMN’s would suggest. There is a significant lead-time between the effects of treatment and later development of secondary tumours. Many of the treatment alterations being undertaken today have the potential to decrease the future risk of SMN’s. In particular, the trend away from the use of cranial radiation for the majority of children with leukaemia,
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and the decreasing role that radiotherapy has in Wilms’ tumour and Hodgkin’s disease should improve the outlook for these patient groups.
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