HK J Paediatr (new series) 2006;11:3-12

Review Article
Recent Advances in Childhood Brain Tumours

GCF CHAN

Abstract Brain tumours are the second commonest form of childhood malignancy. In Hong Kong, around 25 to 40
children below 15 years are diagnosed to have various types of brain tumours each year. But the term
"brain tumour" in fact includes a heterogeneous group of tumours and their classification, diagnostic criteria,
treatment modalities and outcome have undergone major changes in the past 2 decades. In this review, the
objectives are to provide brief and update information on various developments in these areas. These will
include: 1) the recent consensus in the classification of childhood brain tumours; 2) the current epidemiology
of children with brain tumours, both locally and aboard; 3) the current hypotheses on the pathogenesis of
some common paediatric brain tumours; 4) the common presenting features of the commonest types of
childhood brain tumours locally; 5) the current diagnostic and therapeutic approaches and lastly; 6) the
commonly encountered long-term sequalae among paediatric brain tumours survivors. In summary, many
common forms of childhood brain tumours found locally can be cured nowadays. Current challenge is to
further improve the outcome in those with poor outcome and minimise therapy related toxicity in those
with good prognosis.

Key words Brain tumours; Children

Classification of Childhood Brain Tumour proposed classification system. First, it is quite complicated
and many of the tumours types are not commonly seen in
The classification of brain tumours has been constantly paediatric age group (i.e. most of the meningioma,
revised over times and the latest update version was the intracranial mesenchymal and haematopoietic neoplasms).
WHO classification year 2000 version.1 The basis of most Secondly, there are overlaps in the terminology due to
classifications was primarily based on the histological historical reason. For example, neuroblastoma found in the
characteristics with some consideration on the genetic adrenal and sympathetic ganglions region is a very distinct
background and embryonal origin. It has been quite disease entity in terms of origin, genetic aberration and
confusing for paediatricians or even oncologists to clinical behaviour as compare to neuroblastoma in the
comprehend totally due to several problems with the supratentorial region or in the olfactory region. Thirdly,
there are detailed subclassifications of some tumour
types (i.e. 15 subclassifications for meningioma and 4
Children Centre of Paediatric Cancer & Blood Diseases, subclassifications for ependymoma and medulloblastoma
Department of Paediatrics and Adolescent Medicine, The each) and many of which do not carry any actual or definite
University of Hong Kong, Queen Mary Hospital, 102 differences in terms of clinical behaviour and treatment
Pokfulam Road, Hong Kong, China outcome.
GCF CHAN MD, FHKAM(Paed), FRCPCH(UK) Clinically, another simplified version of classification
has been proposed primarily for coding purposes so easier
Correspondence to: Dr GCF CHAN
data accrual and analysis can be performed in a population
Received September 16, 2005 bases. This is known as International Classification of
4 Childhood Brain Tumours

Childhood Cancer (ICCC-3)2 and it classifies the common Epidemiology of Paediatric Brain Tumour
childhood brain tumours into a grouping of astrocytoma,
other glioma, ependymoma, primitive neuroectodermal In most countries and ethnic group, brain tumour is the
tumour (PNET), and miscellaneous intracranial & second commonest group of childhood malignancy.7-12 But
intraspinal tumours. This approach has also been adopted there are variations in the relative incidence of different
by the SEER (Surveillance, Epidemiology & End Result) tumours types. This can be due to either referral bias or
for data collection and analysis purpose. difference in the classification method. Ethnic difference
Some WHO classifications information can also applies has also been described such as the higher incidence of
with clinical relevance in paediatric brain tumours, for germ cell tumour in the Japanese population.13,14 There is
example, astrocytomas can further be classified according so far no population-based data on the incidence of different
to their histological features into grade I to IV (grade I, types of brain tumours in Chinese children found in the
pilocytic astrocytoma; grade II, low grade glioma; grade indexed English literature. Based on the Hong Kong
III, anaplastic astrocytoma; grade IV, glioblastoma Paediatric Haematology/Oncology Study Group
multiforme) and this has remarkable correlation with the (HKPHOSG) and Hong Kong Cancer Registry (HKCR)
clinical aggressiveness and outcome. database from Jan 1999 to Dec 2003, there were a total of
PNET of the central nervous system (CNS) should also 131 children with brain tumours diagnosed in Hong Kong
be clearly separated from the peripheral PNET. Peripheral (GCF Chan, HKPHOSG Annual Workshop Report 2004).
PNET is closely related to Ewing's sarcoma (EWS) and Based on the estimated mid-year children population (<15
majority of them shares the t(11;22) abnormality and years) of 1.1 millions by 2001 population census and
expresses Mic-2 antigen.3 EWS usually arises from the bone excluding one patient originally coming from outside Hong
and peripheral PNET usually arises from soft tissues all Kong and 5 children older than 15-year-old (n=126). The
around the body. In contrary, PNET of the CNS comprises annual incidence of brain tumours for Chinese Children in
a group of embryonic tumours arising from different parts Hong Kong is 22.9/million children/year. The comparison
of the brain.4 Histologically, they are quite similar to each of histological types with the Western population4,5 can be
other but they can be differentiated from each other by found in Figure 1. Similar to Japan, we have a much higher
location. For example, medulloblastoma arises from the incidence of germ cell tumours in the brain than the Western
vermis of the cerebellum, supratentorial PNET arises from population. The slight smaller incidence in the astrocytoma
the cerebral hemisphere, pineoblastoma arises from the and higher incidence in the PNET group can be either due
pineal gland, etc. However, recent microarray study showed to the change in histological classification over the past 2
that CNS PNETs have distinct gene expression profiles and decades or to a genuine ethnic variation. This can be
therefore the differences do not lie on the location alone.5 confirmed when our database became large enough for
Among the "miscellaneous intracranial tumour", germ cell further verification.
tumours are the one that we should pay more attention to The most common histological type of brain tumours in
due to its relative high incidence locally. Germ cell tumours children remains to be astrocytomas as shown in different
can further be divided into germinomatous and non- reported series. They can be further subdivided into different
germinomatous groups.6 The non-germinomatous group grades (i.e. Grade I to IV) and different locations (i.e.
includes yolk sac tumour (ectodermal sinus tract tumour), cerebral, brainstem). The relative frequency of each subtype
choriocarcinoma, embryonal carcinoma, benign and in our patients' cohort is shown in Figure 2. Concerning
malignant teratoma and mixed type. It is important to about the location of all the brain tumours, around 40-50%
differentiate them for their clinical behaviour especially in of the childhood brain tumours are originated from
terms of response to treatment and prognosis is not infratentorial territory and medulloblastoma is the
identical. Together with the ependymoma and benign commonest form of tumour arising from this region. Other
craniopharyngioma, the ICCC groupings already include relatively common infratentorial brain tumours in childhood
the vast majority of paediatric brain tumours that we include juvenile pilocytic astrocytoma, ependymoma and
encountered clinically. These groupings also carry a better brain stem glioma. More than 95% of brain stem gliomas
clinical correlation in terms of their response to treatment are high-grade astrocytoma and locate mainly in the pontine
and prognosis. region. Germ cell tumours mainly arise from the mid line
Chan 5

(a) (b)

Abbreviations: Astro: astrocytoma (including all grades and brain stem), PNET: primitive neuroectodermal tumours (including
supratentorial and medulloblastoma), Epen: ependymoma, Cranio: craniopharyngioma, GCT: germ cell tumours, HKPHOSG: Hong
Kong Paediatric Haematology & Oncology Study Group, HKCR: Hong Kong Cancer Registry.

Figure 1 (a) Comparing incidence of childhood brain tumours of Western series (Yates, 1979, n=704; Duffner & Cohen, 1986, n=887)
(b) with the frequency of different types of childhood brain tumours in Hong Kong (HKPHOSG & HKCR, Jan 1999-Dec 2003, n=131), it
showed that we have a higher incidence of germ cell tumours. The differences in astrocytoma and PNET may be due to the differences in
histological classification between different era. However, such trends remain when we compared ours with the latest SEER data.

structures of the brain in particularly over the pineal region.

Whereas ependymoma characteristically arising from the
para-ventricular areas along the whole CNS system. All
these characteristics are similar to what have been described
in the Western literature.

Current Understanding of the Pathogenesis

The amount of knowledge about brain tumour biology

increased exponentially over the past decade. The advances
in molecular biological technology facilitated this
development. Great amount of translational research
findings have been generated but consistent correlation with
clinical observations still requires the verification of large
prospective studies. Due to the heterogeneity of the tumour
Figure 2 Relative frequency of different subtypes of types, it will not be surprised to see different models being
astrocytomas in Chinese children and adolescent (n=46), postulated. Astrocytoma and medulloblastoma will be cited
HKPHOSG-99-03. here as an example to illustrate some of these hypotheses.
6 Childhood Brain Tumours

Recently established genetic profiles of various grades of syndrome (RTS). RTS is associated with microdeletions on
astrocytoma suggested an association between the chromosome 16p13.3 in which is the gene responsible for
biological behaviour with the events in genetic aberrations the production of human CREB (cAMP response element)
such as activation of oncogenes 15 and inactivation of binding protein or CBP (CREB binding protein).25 CBP is a
putative tumour suppressor genes.16 Activation of multiple transcriptional co-activator that functions in many signal
oncogenes such as EGFR (epidermal growth factor receptor transduction pathways. It interacts with SHH signaling
or c-erB1), 17 PDGFRα (platelet derived growth factor pathway mentioned above as a co-activator of Gli
receptor alpha)18 genes in the same tumour are associated (Glioblastoma-1) family of transcription factor, in
with high-grade characteristics with rapidly progressed particularly Gli-1.26 Another familial condition known as
clinical course. On the other hand, loss of heterozygosity Turcot syndrome, which results from mutation of APC or
at certain loci on chromosomes 10 (i.e. PTEN/MMAC-1, DNA mismatch repair genes are also associated with the
phosphate and tension analog/mutated in multiple advanced development of medulloblastoma.27
cancers-1 at 10q23) and 17 (i.e. p53 gene at 17p13.1) To summarise the current understanding on the genetic
leading to loss of proliferation regulation has been linked background of the 2 commonest types of childhood brain
to the progression of anaplastic astrocytoma to glioblastoma tumours, a diverse genetic mechanism has been identified.
multiforme.19,20 This information can help us to understand more about their
For medulloblastoma, loss of chromosome 17p distal to pathogenesis or even prognostic significance. The known
TP53 and isochromosome 17q is the commonest chromosomal or genetic aberrations associated with either
cytogenetic abnormality. Familial linkage studies identified good or bad clinical outcomes are listed in Table 1. The
association between nevoid basal cell carcinoma syndrome various inherited syndrome associated with the
(NCCCS, also known as Gorlin syndrome) and the development of brain tumours are listed in Table 2.
development of medulloblastoma. NBCCS is caused by a
germline mutation of a putative germline tumour suppressor
gene on chromosome 9q31.21,22 The gene involved is known Pattern Recognition of Common Presenting
as Patched (Ptc), which is a transmembrane receptor for Features of Childhood Brain Tumours
the secreted ligand Sonic Hegehog (SHH) intracellular
signaling pathway.23 So far, the desmoplastic variant of In general, presenting symptoms of brain tumours are
medulloblastoma that accounts for 10-20% of sporadic closely related to the topographic location of the lesions,
medulloblastoma cases is also characterised by mutations such as long tract sign for patients with tumour affecting
in the Ptc pathway.24 Interestingly, we have a much lower the cortical spinal tract, different forms of visual field defect
incidence of this particular type of medulloblastoma locally for optic tract tumour, etc. This is mainly the pattern for
(1.5%, 2/131). Another condition that is prone to the supratentorial tumours affecting the different parts of the
development of medulloblastoma is Rubinstein-Taybi cerebral hemisphere. Supratentorial astrocytoma and

Table 1 Prognostic factors related to genetic or chromosomal changes in various types of childhood brain tumours
Types of tumours Poor prognosis factors Good prognostic factors
High grade astrocytomas Mutated or over-expression of P53 -1p*, -19q*
Over-expression of MIG-1
Medulloblastoma & PNET Over-expression of c-Myc Over-expression of Trk-C
Over-expression of ErbB-2 & ErbB-4
Ependymoma +1q +7, +9, +18,
-3, -6, -15
Meningioma LOH: -1p, -10q, -14q Over-expression of E-cadherin
Del CDKN2A (9p21)
Abbreviations: + gain of chromosome, - loss of chromosome, Del: deletion, LOH: loss of heterozygosity
* Good prognostic correlation found in adults patients but no such association found in paediatric patients.
(Information adopted from the 10th International Symposium on Paediatric Neuro-Oncology, London, June 9-12, 2002.)
Chan 7

Table 2 Familial syndrome & brain tumours

Syndrome Gene Encoded protein Gene dysfunction Brain tumours commonly found
Neurofibromatosis I NF-1 Neurofibromin Tumour suppressive - Optic glioma
(17q11.2) gene - Low grade glioma
Neurofibromatosis II NF-2 Merlin or Tumour suppressive - Meningioma
(22q11.2) Schwannomin gene - Acoustic neuroma
Turcot syndrome APC Adenomatous Disrupted Wnt - Medulloblastoma
(associated with colonic (5q21) polyposis coli signaling results in
cancer with polyposis (APC) protein increase c-Myc &
in the colon) cyclin D expression
(oncogenes)
Turcot syndrome hMLH1 / hMLH1 / hPMS2 DNA mismatch - Glioblastoma
(associated with colonic hPMS2 proteins repair genes and
cancer with no polyposis cause microsatellite
in the colon, HNPCC) instability
Tuberous sclerosis TSC1 Hamartin / Tuberin Tumour suppressor - Astrocytoma
(9q34) / gene - Ependymoma
TSC2
(16p13.3)
Von Hippel-Lindau VHL P
VHL30 & PVHL19 Cell cycle and - Haemangioblastoma
syndrome angiogenesis control
Cowden syndrome PTEN PTEN/MMAC-1 Tumour suppressive - Dysplastic gangliocytoma of cerebellum
(Lhermitte-Duclos (10q23.3) protein gene - Meningioma
disease)
Li-Fraumeni syndrome p53 p53 protein Tumour suppressive - Astrocytoma
(17p13.1) gene - Medulloblastoma
- Choroids plexus carcinoma
- Ependymoma
Gorlin syndrome Ptc Ptc transmembrane Tumour suppressive - Medulloblastoma
(9q31) receptor gene
Rubinstein-Taybi -16p13.3 CBP Tumour suppressive - Medulloblastoma
syndrome gene
Familial retinoblastoma Rb pRb Tumour suppressive - Retinoblastoma
syndrome (13q14) gene - Pineoblastoma
Families with increase INK4 p16 & p19ARF Tumour suppressive - Astrocytoma
melanoma & brain (9p21) proteins gene
tumours (p16 &
p19ARF)
Pallister-Hall syndrome Gli3 Transcription factor - Hypothalamic hamartoma
(7p13)
Abbreviations: HNPCC, hereditary non-polyposis colorectal cancer; hMLH1 / hPMS2: Human postmeiotic segregation genes 1 & 2; TSC1 & TSC2: tuberous
sclerosis consortium genes 1 & 2; VHL: Von Hippel-Lindau gene; PTEN: phosphate & tension analog gene; MMAC-1: mutated in multiple advanced cancers);
Ptc: patched gene; CBP: CREB binding protein; Rb: retinoblastoma gene; pRb: retinoblastoma protein; INK4: inhibitors of CDK4 & CDK6.
(Information adopted from the 10th International Symposium on Paediatric Neuro-Oncology, London, June 9-12, 2002.)
8 Childhood Brain Tumours

ependymoma are the common groups of tumour present hypopituitarism is one of the common presenting features
this way. Seizure as a whole is uncommon in children with with visual field defect. Of interest, the visual field defect
brain tumours. It accounts for <5% of the presenting does not necessary presents as bitemporal hemianopsia
symptoms of brain tumours in our children. When it occurs, (chiasmatic involvement) and a minority of patient may
it is most commonly associated with low-grade astrocytoma have other form of visual field defect such as unilateral
or oligodendroglioma in the supratentorial region, and homonymous hemianopsia due to the involvement of the
temporal lobe seems to be the commonest site in our local optic tract posteriorly.
experience.
Tumours arise from the infratentorial region particularly
at the vermis of the cerebellum region often present with Current Diagnostic and Treatment Modalities
symptoms of increase intracranial pressure. That is because
of the forward expansion of the mass often compresses the Diagnostic Modalities
narrow 4th ventricle anteriorly and induce obstructive With the advances of the imaging techniques, CT scan
hydrocephalus. Interestingly, the headache and vomiting and MRI scan are now the 2 main tools in the diagnosis of
can occur rather subtlely. Affected child may complaint of brain tumours in children. In general, MRI can provide a
headache upon waking up in the morning with or without more details and thorough assessment of the brain
vomiting. The symptoms can often be relieved after parenchyma but it takes a longer time to capture the
vomiting and the recurrence of symptoms may take several information. Adequate and longer sedation may be
days or even week. There may not be any symptoms in necessary for young children. There are no more roles for
between attack. Observative parents or teachers may be able some of the older forms of imaging such pneumatogram
to pick up deterioration in handwriting or gait occasionally and myelogram in the modern paediatric oncology service.
in older children. Frequent headache, vomiting, trunkal They have been totally replaced by either CT or MRI scans
ataxia or even cranial nerves deficit (mainly 6th and 7th by now.
cranial nerve) are symptoms related to more advanced While it is relatively satisfactory for either CT scan or
disease. The non-specific initial signs and symptoms MRI to provide diagnostic information, there are problems
provide explanation why brain tumours in this region often at time to differentiate the residual tumour from post-
present late. In contrary, brainstem glioma seldom presents treatment scarring or inflamed tissues. Newer build-in
with sign of obstructive hydrocephalus. A triad of symptoms modalities such as MR spectroscopy may be helpful in this
namely multiple cranial nerves deficit (>90% occurs in the aspect. Especially the multi-voxels MR spectroscopy may
pons therefore mainly affects 5th, 6th, 7th & 8th); long be theoretically helpful even for small size lesions. But it
tract sign (involvement of the corticospinal tract) and ataxia remains to be an investigatory tool at the moment and still
(involvement of the cerebellar tract) and without sign of could not produce reliable finding in periventricular areas.
increase intracranial pressure are strongly suggestive of Positron Emission Tomography (PET) can assess the
pontine glioma. functional status of a tumour by checking its glucose
Another characteristic pattern of presentation is related isotopes uptake. It is quite sensitive and can provide
to the germ cell tumour. Since it is mainly arising from additional information to the conventional CT or MRI
mid line, in particularly at the pineal and hypothalamic imaging. However, false positive findings do exist19 and it
region, endocrine disturbances such as precocious puberty, does not provide spatial relationship between the lesions
diabetes insipidus may be the initial symptoms. Headache and normal brain structure. Proper correlation with
and vomiting due to obstructive hydrocephalus of the 3rd conventional imaging is therefore mandatory. Currently, a
ventricle or chiasmatic visual field defect may be noted in newer modality, which combines the CT scan and PET scan
more advanced stage. Diencephalic symptoms (wasting via digital technology that can solve the anatomical
despite good appetite) and Gilastic seizure (inappropriate correlation problem but the resolution of the CT scan
laughter episodes) are relatively uncommon but is appears to be less refined in this setting.
characteristically associated with either germ cell or other However, the gold standard of confirming the diagnosis
types of tumour (i.e. hypothalamic harmatoma) arising from remains to be histological examination. Therefore biopsy
the mid line region of the brain. Some suprasellar tumour is required in most situations. The exception will be
such as craniopharyngioma often has a long presenting brainstem glioma. It is because >90% of them are high grade
history due to its benign nature. Growth failure due to astrocytoma which diffusely involves the pontine area,
Chan 9

surgical biopsy of the pontine area carries high morbidity chemotherapy + cranial RT (omitting the spinal RT). We
and mortality and the result will not alter the prognosis adopted the chemotherapy based approach so we can
of this group of patients. Another example is non- minimise the impact of spinal RT on a growing child. With
germinomatous germ cell tumour with elevated serum αFP both of these approaches, the long-term event free survival
or β-HCG secretion; actual benefit of biopsy remains can reach 90%. 36 Whereas the non-germinomatous
controversial in this setting. performed less well with a survival rate of about 60%,37
chemotherapy is often the main stay of the therapy with or
Treatments Modalities without cranial RT. Our local treatment results for
Surgery, radiation therapy and chemotherapy are the germinomatous GCT are similar to that of the other
3 main forms of therapeutic modalities and whether they countries but our non-germinomatous GCT seems to have
have to be applied singly or in combination depending on a better survival, this may be a bias observation due to our
the type and stage of the brain tumours. relative small sample size. Except for malignant teratoma
For medulloblastoma, except for a few localised or some form of mixed germ cell tumour, the role of surgery
completely excised tumours which may be treated with is mainly for diagnostic purpose.
surgery and radiation therapy alone, combination of For gliomas, low-grade tumours (Grade I & II) are treated
surgery/radiation therapy/chemotherapy are often time with surgery alone. Grade I glioma such as pilocytic
indicated. 28 For the chemotherapy regimen, by using astrocytoma has a very good long-term survival of >90%
cisplatinum, CCNU and vincristine on 6 weekly basis for if it is completely excised.38 However, when it located in
8 cycles, an 86% 5-year-event free survival has been the unresectable area such as the optic chiasma or thalamic
achieved for standard risk group of patients.29 But cranio- area, the long term outcome is guarded. The role of
spinal irradiation upfront with weekly vincristine is another chemotherapy and RT on unresectable low-grade gliomas,
key element of this regimen. Latest result suggested that though controversial, has been tested with some
reduced dose radiation therapy could achieve similar result.30 encouraging preliminary results in recent year.39,40 For high-
It appears that cisplatinum-based chemotherapy with up- grade tumours, the survival remains dismal up to the current
front radiation therapy produced similar results in our local moment. Basically surgical excision is the main form of
patient cohort as well, a 83% 4-year-event free survival treatment follows by local high dose RT. The long-term
has been recorded so far (HKPHOSG 2004 workshop). For survivors are rarity if there is any. The estimated median
those with high-risk features which includes: 1) more than survival of anaplastic astrocytoma and glioblastoma
1.5 cm residual tumour volume after surgery and 2) those multiforme are usually measured in months. 41 The role
with leptomeningeal metastasis, megatherapy followed by of chemotherapy remains questionable; recently
autologous marrow transplant rescue has been shown to temozolamide was found to induce response in a quarter
produce a reasonably good result. Children <3-year-old is of patients tested.42 There is a strong association between
another poor risk group for radiation therapy has to be the status of the DNA repair enzyme O6-methyl-guanine-
postponed to after 3 year of age in order to avoid DNA-methyl-transferase (MGMT) and the outcome of
neurological damage on a developing brain. 31,32 As a TMZ-based chemotherapy.43 While other approaches such
consequence, relapse during treatment is more frequent. as high dose tamoxifen, megatherapy followed by
Regimen included intensive chemotherapy followed autologous transplant did not produce any good evidence
autologous transplant seems to produce better result. The of response. Another novel modality is by using by using
role of autologous transplant as a consolidation to tumour lysate challenged autologous activated T-cells or
conventional therapy in these settings has to be verified by dendritic cells as tumour vaccine.44-46 This remains to be an
further study.33 experimental approach and has to be conducted on a clinical
For germ cell tumour (GCT), the treatment approach trial basis.
depends on the histological subtypes. In general, with the For ependymoma, the role of chemotherapy remains
exception of malignant teratoma, GCT is chemo- and RT controversial.47,48 The main form of treatment is surgery
sensitive. In recent years, platinum based chemotherapy and local RT. The outcome is highly correlated with the
regimens with the combination of other agents such as presence of residual disease after surgery or not.49 In our
bleomycin, etoposide or vinblastine are the standard limited experience, we found that supratentorial tumours
approach.34,35 For intracranial germinomatous GCT, it can that were completely excised, the long-term survival can
either be treated with craniospinal RT alone or reach 70-80% but for those with residual disease or with
10 Childhood Brain Tumours

surgically inaccessible tumour, the survival rate would be radiation therapy targets at the tumour bed will further ablate
much lower. We adopted the combination approach of using whatever residual function left. Proper assessment pre- and
surgery + local RT + chemotherapy locally. post-therapy will guide the replacement strategy. Partial
Despite being a benign tumour, craniopharyngioma has endocrine defect may occur sometimes in patients receiving
a high recurrence rate with significant long-term whole brain cranial irradiation with radiation dose of more
consequence in children.50,51 After either surgery or RT alone, than 3000 cGy.58
close to 30% will relapse. Current thought is to avoid Residual motor impairment and inco-ordination is a
overzealous intention in excising the tumour surgically.52 common finding of childhood brain tumours in particularly
Additional therapy includes repeated surgery or intralesional those affecting the cerebellum. In contrary, epilepsy is
chemotherapy if there is a cystic cavity inside the tumour.53 commoner in supratentorial tumours. Patients with large
If the size of the tumour remains small, ablative RT in the tumour, incompletely resected tumour or after extensive
form of gamma or X-knife can be attempted. surgery are at a greater risk of developing epilepsy. 59
Chronic subdural haematoma can occur as a consequence
of excessive shunting within a short period of time leading
Common Long-term Sequalae of Paediatric to excessive negative pressure intracranially.60 It can be
Brain Tumours Survivors managed conservatively if it is mild or change to a low-
pressure shunt system or to ventricular-atrium shunt. Recent
As the survival rate of children with brain tumours trends is to avoid installing permanent VP shunt in children
improved over the past decade, a number of long-term with resectable brain tumours, an external shunt can be used
complications either associated with the initial effect of the during the acute phase instead. While mild degree of
disease or as a consequence of the treatment. leukomalacia can commonly be detected in brain tumour
Defect in cognitive function in the forms of short-term survivors using newer mode of MRI examination,61 severe
memory, abstract thinking, calculation and other high radio-necrosis and leucomalacia is uncommon but does
intellectual function are relatively common in childhood occur and carry significant morbidity.62
brain tumour survivors. The cause may be multifactorial.
Study demonstrated that the baseline intelligent
assessments of children with medulloblastoma prior to the Summary
commencement of treatment were already lower than the
control group.54 That means the effects of the local tumour Brain tumours, being the second commonest group of
infilatration; its associated hydrocephalus or direct pressure childhood malignancy, is a heterogeneous group of disease.
effect may already have an impact on the brain function. Though with a complicated histological classification
The other confounding factor is high dose cranial irradiation. systems currently, it can be simplified into several key
It has been shown to have an adverse effect on a developing groups in paediatric population. The diagnosis of brain
brain. Children were found to have lower IQ score and poorer tumours in children are often delayed due to their subtle
school performance than the age matched control.54,55 The clinical signs and symptoms and lack of awareness of the
effect of systemic chemotherapy and chronic hospitalisation relative non-specific presenting patterns. With the advances
on IQ score is less clear. However, cis-platinum, carbo- in the diagnostic tools and treatment modalities, the
platinum and ifosphamide had all been shown to have neuro- prognosis of many childhood brain tumours (such as
toxicity. High frequency hearing impairment is a common medulloblastoma, germ cell tumour) improved drastically
finding of children receiving platinum based chemotherapy. over the past decade. Some tumour types such as high-grade
In case of medulloblastoma, the booster radiation field glioma remains to be a therapeutic challenge for both adult
targeted at the posterior fossa also inadvertently hit on the and paediatric oncologists. The understanding of the
part of temporal lobe and inner ear canal, which may make pathogenesis of brain tumours by the recent advances in
the hearing impairment worse.56,57 molecular biology may help us to look for possible novel
Permanent multiple endocrine deficiency in form of and targeted treatment modality. This may hopefully
hypopituitarism and diabetes insipidus is a common finding improve the treatment outcome of those poor risk brain
of germ cell tumours and craniopharyngioma. The defect tumours and minimise the treatment-induced complications
is partly or wholly caused by the tumour. The subsequent of those good risk brain tumours in the future.
Chan 11

References glioblastoma multiforme. Cancer Res 1997;57:4183-6.

20. Mercer WE, Shields MT, Lin D, Appella E, Ullrich SJ. Growth
1. Kleihues P, Louis DN, Scheithauer BW, et al. The WHO suppression induced by wild-type p53 protein is accompanied
classification of tumors of the nervous system. J Neuropathol by selective down-regulation of proliferating-cell nuclear
Exp Neurol 2002;61:215-25; discussion 226-9. antigen expression. Proc Natl Acad Sci U S A 1991;88:1958-
2. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. 62.
International Classification of Childhood Cancer, third edition. 21. Farndon PA, Del Mastro RG, Evans DG, Kilpatrick MW.
Cancer 2005;103:1457-67. Location of gene for Gorlin syndrome. Lancet 1992;339:581-2.
3. Ladanyi M, Lewis R, Garin-Chesa P, et al. EWS rearrangement 22. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine
in Ewing's sarcoma and peripheral neuroectodermal tumor. (Baltimore) 1987;66:98-113.
Molecular detection and correlation with cytogenetic analysis 23. Johnson RL, Rothman AL, Xie J, et al. Human homolog of
and MIC2 expression. Diagn Mol Pathol 1993;2:141-6. patched, a candidate gene for the basal cell nevus syndrome.
4. Rorke LB. The cerebellar medulloblastoma and its relationship Science 1996;272:1668-71.
to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 24. Pietsch T, Waha A, Koch A, et al. Medulloblastomas of the
1983;42:1-15. desmoplastic variant carry mutations of the human homologue
5. Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of of Drosophila patched. Cancer Res 1997;57:2085-8.
central nervous system embryonal tumour outcome based on 25. Petrij F, Giles RH, Dauwerse HG, et al. Rubinstein-Taybi
gene expression. Nature 2002;415:436-42. syndrome caused by mutations in the transcriptional co-
6. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell activator CBP. Nature 1995;376:348-51.
tumors: natural history and pathogenesis. J Neurosurg 1985; 26. Leahy P, Crawford DR, Grossman G, Gronostajski RM, Hanson
63:155-67. RW. CREB binding protein coordinates the function of multiple
7. Bleyer WA. What can be learned about childhood cancer from transcription factors including nuclear factor I to regulate
"Cancer statistics review 1973-1988". Cancer 1993;71(10 phosphoenolpyruvate carboxykinase (GTP) gene transcription.
Suppl):3229-36. J Biol Chem 1999;274:8813-22.
8. McKinney PA, Parslow RC, Lane SA, et al. Epidemiology of 27. Paraf F, Jothy S, Van Meir EG. Brain tumor-polyposis syndrome:
childhood brain tumours in Yorkshire, UK, 1974-95: two genetic diseases? J Clin Oncol 1997;15:2744-58.
geographical distribution and changing patterns of occurrence. 28. Rood BR, Macdonald TJ, Packer RJ. Current treatment of
Br J Cancer 1998;78:974-9. medulloblastoma: recent advances and future challenges. Semin
9. Gjerris F, Agerlin N, Borgesen SE, et al. Epidemiology and Oncol 2004;31:666-75.
prognosis in children treated for intracranial tumours in 29. Cohen BH, Packer RJ. Chemotherapy for medulloblastomas
Denmark 1960-1984. Childs Nerv Syst 1998;14:302-11. and primitive neuroectodermal tumors. J Neurooncol 1996;29:
10. Michaelis J, Kaletsch U, Kaatsch P. Epidemiology of childhood 55-68.
brain tumors. Zentralbl Neurochir 2000;61:80-7. 30. Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of
11. Sriamporn S, Vatanasapt V, Martin N, et al. Incidence of children with medulloblastomas with reduced-dose craniospinal
childhood cancer in Thailand 1988-1991. Paediatr Perinat radiation therapy and adjuvant chemotherapy: A Children's
Epidemiol 1996;10:73-85. Cancer Group Study. J Clin Oncol 1999;17:2127-36.
12. Tu J, Li FP. Incidence of childhood tumors in Shanghai, 1973- 31. Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative
77. J Natl Cancer Inst 1983;70:589-92. chemotherapy and delayed radiation in children less than three
13. Kuratsu J, Ushio Y. Epidemiological study of primary years of age with malignant brain tumors. N Engl J Med 1993;
intracranial tumors in childhood. A population-based survey in 328:1725-31.
Kumamoto Prefecture, Japan. Pediatr Neurosurg 1996;25:240- 32. Duffner PK, Horowitz ME, Krischer JP, et al. The treatment of
6; discussion 247. malignant brain tumors in infants and very young children: an
14. Kaneko S, Nomura K, Yoshimura T, Yamaguchi N. Trend of update of the Pediatric Oncology Group experience. Neuro-
brain tumor incidence by histological subtypes in Japan: oncol 1999;1:152-61.
estimation from the Brain Tumor Registry of Japan, 1973-1993. 33. Finlay JL. The role of high-dose chemotherapy and stem cell
J Neurooncol 2002;60:61-9. rescue in the treatment of malignant brain tumors: a reappraisal.
15. Akbasak A, Sunar-Akbasak B. Oncogenes: cause or Pediatr Transplant 1999;3 Suppl 1:87-95.
consequence in the development of glial tumors. J Neurol Sci 34. Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O.
1992;111:119-33. Combined treatment with chemotherapy and radiation therapy
16. von Deimling A, Louis DN, Wiestler OD. Molecular pathways for intracranial germ cell tumors. Childs Nerv Syst 1998;14(1-
in the formation of gliomas. Glia 1995;15:328-38. 2):59-62.
17. Ekstrand AJ, James CD, Cavenee WK, Seliger B, Pettersson 35. Culine S, Droz JP. Comparative tolerability of chemotherapy
RF, Collins VP. Genes for epidermal growth factor receptor, regimens for germ cell cancer. Drug Saf 2000;22:373-88.
transforming growth factor alpha, and epidermal growth factor 36. Matsutani M. Clinical management of primary central nervous
and their expression in human gliomas in vivo. Cancer Res system germ cell tumors. Semin Oncol 2004;31:676-83.
1991;51:2164-72. 37. Brandes AA, Pasetto LM, Monfardini S. The treatment of cranial
18. Hermanson M, Funa K, Hartman M, et al. Platelet-derived germ cell tumours. Cancer Treat Rev 2000;26:233-42.
growth factor and its receptors in human glioma tissue: 38. Burkhard C, Di Patre PL, Schuler D, et al. A population-based
expression of messenger RNA and protein suggests the presence study of the incidence and survival rates in patients with
of autocrine and paracrine loops. Cancer Res 1992;52:3213-9. pilocytic astrocytoma. J Neurosurg 2003;98:1170-4.
19. Wang SI, Puc J, Li J, et al. Somatic mutations of PTEN in 39. Kidd EA, Mansur DB, Leonard JR, Michalski JM, Simpson
12 Childhood Brain Tumours

JR, Perry A. The Efficacy of Radiation Therapy in the in children and adults: systematic analysis of 121 cases with
Management of Grade I Astrocytomas. J Neurooncol 2005; in long-term follow-up. Clin Endocrinol (Oxf) 2005;62:397-409.
press. 52. Thompson D, Phipps K, Hayward R. Craniopharyngioma in
40. Gnekow AK, Kortmann RD, Pietsch T, Emser A. Low grade childhood: our evidence-based approach to management. Childs
chiasmatic-hypothalamic glioma-carboplatin and vincristin Nerv Syst 2005;21(8-9):660-8.
chemotherapy effectively defers radiotherapy within a 53. Cavalheiro S, Dastoli PA, Silva NS, Toledo S, Lederman H, da
comprehensive treatment strategy -- report from the multicenter Silva MC. Use of interferon alpha in intratumoral chemotherapy
treatment study for children and adolescents with a low grade for cystic craniopharyngioma. Childs Nerv Syst 2005; in press.
glioma -- HIT-LGG 1996 -- of the Society of Pediatric Oncology 54. Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM.
and Hematology (GPOH). Klin Padiatr 2004;216:331-42. Intellectual outcome after reduced-dose radiation therapy plus
41. Prados MD, Levin V. Biology and treatment of malignant adjuvant chemotherapy for medulloblastoma: a Children's
glioma. Semin Oncol 2000;27(3 Suppl 6):1-10. Cancer Group study. J Clin Oncol 2001;19:3470-6.
42. Yung WK. Temozolomide in malignant gliomas. Semin Oncol 55. Packer RJ. Radiation-induced neurocognitive decline: the risks
2000;27(3 Suppl 6):27-34. and benefits of reducing the amount of whole-brain irradiation.
43. Stupp R, van den Bent MJ, Hegi ME. Optimal role of Curr Neurol Neurosci Rep 2002;2:131-3.
temozolomide in the treatment of malignant gliomas. Curr 56. Anderson NE, Sheffield S, Hope JK. Superficial siderosis of
Neurol Neurosci Rep 2005;5:198-206. the central nervous system: a late complication of cerebellar
44. Wheeler CJ, Black KL. Dendritic cell vaccines and immunity tumors. Neurology 1999;52:163-9.
in glioma patients. Front Biosci 2005;10:2861-81. 57. Huang E, Teh BS, Strother DR, et al. Intensity-modulated
45. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. radiation therapy for pediatric medulloblastoma: early report
Vaccination with tumor lysate-pulsed dendritic cells elicits on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys
antigen-specific, cytotoxic T-cells in patients with malignant 2002;52:599-605.
glioma. Cancer Res 2004;64:4973-9. 58. Duffner PK. Long-term effects of radiation therapy on cognitive
46. Wood GW, Holladay FP, Turner T, Wang YY, Chiga M. A pilot and endocrine function in children with leukemia and brain
study of autologous cancer cell vaccination and cellular tumors. Neurologist 2004;10:293-310.
immunotherapy using anti-CD3 stimulated lymphocytes in 59. Gerstle de Pasquet E, Pietra M, Iniquez RA. Epileptic seizures
patients with recurrent grade III/IV astrocytoma. J Neurooncol as an early complication of neurosurgery. Acta Neurol Latinoam
2000;48:113-20. 1976;22(1-4):144-51.
47. Maksoud YA, Hahn YS, Engelhard HH. Intracranial 60. Mori K, Maeda M. Risk factors for the occurrence of chronic
ependymoma. Neurosurg Focus 2002;13:e4. subdural haematomas after neurosurgical procedures. Acta
48. Packer RJ. New insights into childhood ependymomas. Curr Neurochir (Wien) 2003;145:533-39; discussion 539-40.
Neurol Neurosci Rep 2005;5:107-9. 61. Khong PL, Kwong DL, Chan GC, Sham JS, Chan FL, Ooi GC.
49. Agaoglu FY, Ayan I, Dizdar Y, Kebudi R, Gorgun O, Diffusion-tensor imaging for the detection and quantification
Darendeliler E. Ependymal tumors in childhood. Pediatr Blood of treatment-induced white matter injury in children with
Cancer 2005;45:298-303. medulloblastoma: a pilot study. AJNR Am J Neuroradiol 2003;
50. L e n a G, P a r e d e s A P, S c a v a r d a D , Gi u s ian o B . 24:734-40.
Craniopharyngioma in children: Marseille experience. Childs 62. Khong PL, Ng KC, Kwong DL, Ooi GC, Chan GC. Cortical
Nerv Syst 2005;21(8-9):778-84. laminar necrosis in childhood intracranial germ cell tumor
51. Karavitaki N, Brufani C, Warner JT, et al. Craniopharyngiomas survivors. Pediatr Blood Cancer 2005;44:412-5.