Radiation :"/ C/e

,_' 't,

Oncology Australasian Radiology (2001) 45, 472-482 " Li;

Diagnosis and management of astrocytomas,

oligodendrogliomas and mixed gliomas: A review
David GWalker1* and Andrew H Kaye 2
'Department of Neurosurgery, Royal Brisbane Hospital, Herston, Queensland and 2Department of Neurosurgery, Department of Surgery,
University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria, Australia

SUMMARY
Low-grade gliomas are a diverse group of neoplasms which, as the name implies, are thought to arise from glial cells.
Common among this group are astrocytomas (low-grade astrocytoma; LGA), oligodendrogliomas and mixed gliomas.
Among these, LGA is the commonest low-grade glioma and, occasionally, although incorrectly, the terms are
used interchangeably. Advances in imaging technology have improved the accuracy of preoperative diagnosis. The
management of low-grade gliomas is controversial. Recent evidence suggests that previously considered standard
therapy (i.e. surgery plus radiotherapy) may not be in the patient's best interests. A review of the available published
research concerning low-grade gliomas is therefore timely.
Key words: astrocytoma; diagnosis; low-grade glioma; mixed glioma; oligodendroglioma; radiotherapy, surgery;
treatment.

ASTROCYTOMAS astrocytomas, which have a different age distribution, location

Low-grade astrocytomas (LGA) are common brain neoplasms
that primarily affect young adults. Although these patients often
have a reasonably long survival, most patients will ultimately
succumb to their tumours. Low-grade astrocytomas are slow
growing astrocytic neoplasms with a high degree of cellular
differentiation that diffusely Infiltrate nearby brain. These lesions
generally affect young adults and have a tendency to progress
to hlgher-grade astrocytomas. The management of LGA, in
terms of making a diagnosis, the timing and extent of surgery
and the benefits of adJuvant therapy, remain controverSial. The
evidence for alternative management approaches is presented
in this revtew.
The term astrocytoma, unless otherwise specified, usually
refers to low-grade diffuse astrocytomas of adulthood. Some
authors refer to these as 'well-dlfferentlated astrocytoma' or
'fibrillary astrocytoma' " but this latter designation Is used more
commonly for the respective histological subtype of LGA.
Low-grade astrocytomas must be differentiated from pllocytic
and biology.
Epidemiology, location and pathology
Low-grade astrocytomas represent approximately 15% of
gliomas In adults and 25% of all gliomas of the cerebral
hemispheres In children.2 The average incidence of these
tumours has been calculated at slightly less than 1 per 100 000
population per year for bot~ children and adults. 3.4 The peak
incidence is In young adults between age 30 and 40 years
(25% of all caseS).5 Approximately 10% occur below the age of
20 years, 60% between 20 and 45 years of age, and about
30% over 45 years. There Is a Slight predominance In males,
constituting approximately 60% of cases.l!,8
Low-grade astrocytomas may develop In any region of the
central nervous system (ONS) but most commonly develop
supratentorlally in the cerebrum of both children and adults.
The bralnstem is the next most common site, while these
tumours are distinctly uncommon in the cerebellum. Within the

OGWalker PhD, FRACS; AH Kaye FRACS.

Correspondence: DG Walker. Department of Neurosurgery, Royal Brisbane Hospital. Herston Road, Herston, Old 4006.

Email: dividgwalker@ozemail.com.au

Present address: Neuro-Oncology Fellow, Department of Neurosurgery, Brigham and Women's Hospital, Childrens' Hospital, Boston, USA.

Submitted 17 0cI0ber 2000; resubmitted 23 May 2001; accepted 15 June 2001.

LOW-GRADE GLIOMAS
cerebrum, they arise roughly In proportion to the relative mass
of the different lobes; hence, the frontal lobe is the commonest
location, followed by the temporallobe.e
Because of their infiltrative nature, LGA usually demonstrate
blurring of anatomical boundaries. Generally there Is distortion
but not destruction of the Invaded structures. 7 Mass lesions may
be present, both In grey or white matter, but they are Indistinct
and changes such as cysts, and areas of firmness or softening
may be seen. Cystic change commonly appears as a focal
spongy area with multiple cysts of varying size, occasionally
causing a gelatinous appearance. Uncommonly, a single large
cyst fiNed with clear fluid may be present, particularly In
gemlstocytic subtypes. Focal calcification may be present
occasionally and extension into contralateral structures,
particularly the frontal lobes, is often observed.8,8
Pathological grading
The most widely used pathOlogical grading systems in current
use are the Worid Health Organization (WHO) and the St
Anne/Mayo systems. Low-grade astrocytomas correspond to
WHO grade 11 astrocytomas.s WHO grade i astrocytomas
include pllocytic astrocytomas and subependymal giant cell
astrocytomas. The St AnnelMayo grading system lO generally
classifies LGA as astrocytoma grade 2, which requires one
histological criterion, usualiy nuclear atypia. Rarely, LGA
without nuclear atypia occur and these are designated as
astrocytoma grade 1 uSing the St AnnelMayo system.
Mkroscopk appearance
Low-grade astrocytomas are composed of well-dlfferentlated
neoplastic astrocytes on a background of loose, often micro
cystic, tumour matrix. There Is a moderate Increase In cellularity
and occasional nuclear atypia. Mltotlc figures are generally
absent but a single mitosis does not Imply the diagnoSis of a
higher-grade tumour. 9 Mltotlc activity In LGA has been shown to
affect prognosis (discussed later In Prognostic factors').
Three histological sublypeS of astrocytoma are commonly
described: (i) fibrillary; (11) gemlstocytlc; and {liO protoplasmic
astrocytoma. Fibrillary astrocytoma is the most frequent variant
of LGA. These are composed predominantly of fibrillary neo
plastic astrocytes. The occasional or regional occurrence of
gemistocytic astrocytes Is also compatible with this diagnoSis.
Gemlstocytlc astrocytomas are predominantly composed of
gemistocytlc neoplastlc astrocytes. The histological picture is
dominated by piump, eoSinophilic, glassy cell bodies of angular
shape. This variant appears particUlarly prone to progresSion
to higher gradesl1 and, hence, is thought to have a worse
prognosis. Protoplasmic astrocytoma is a rare variant com
posed of astrocytes showing a small cell body with few flaccid
processes with a low content of glial filaments. Mucoid
degeneration and microcyst formation Is common and they tend
to occur In the cortex of adults.12 In the largest series thus far
473
published, Prayson and Estesl2 described 16 patients with
protoplasmic astrocytoma with a mean age of 21 years. 'TWelve
were men and four were women. Tumours occurred mostly In
the temporal and frontal lobes. It is not possible to ascertain
whether the prognosis Is any different to that of LGA based on
this small series.
Oinical presentation and imaging findings
COmmon presenting symptoms of LGA Include epUepsy,
headache, mental changes and focal neurological deficlt. I S,14
Epilepsy Is the presenting symptom in more than half of all
caseS. 14 Headache and focal neurological deficit occur less
frequently. and signs of raised Intracranial pressure with papill
oedema are uncommon. 13
In recent years the diagnostic procedures of choice have
become CT and MR lmaglng. Magnetic resonance imaging Is
the most sensitive test available to diagnose LGA. In a typical
case, CT scanning reveals a non-enhancing lesion whose
density is lower than that of the surrounding brain. Amass effect
upon surrounding ventricular structures is common. If enhance
ment does occur, It Is generally faint and homogeneous. On
MAl. the lesion typically presents as a Iow-Intensity area of the
TI-weighted (T1 W) images, whereas there Is almost always an
increase In signal intensity corresponding with an increased
relaxation time on Trweighted (T2W) images. The area of
increased signal is usually homogeneous and well circum
scribed with no evidence of haemorrhage or necrosis. 15
Enhancement on MR imaglng may also sometimes occur.
Overall, enhancement on. CT or MAl occurs in between 8%
and 15% of caseS. IS-18 Daumas-Duport et aJ. have shown that
rumour cells are likely to extend beyond the CT and MA-deflned
abnormalities? Aecently, it has been suggested that dynamic
contrast enhanced T2W MAl may Identify more malignant areas
within an astrocytoma.IS
There may be a role for positron emission tomography
(PET) In the diagnosis and treatment of these patients. ALGA
will be hypometabollc and therefore 'cold' on PET scanning.
However, when dedifferentiation occurs to a more malignant
state, this area will be hypermetabolic and will appear as a
'hot' spot on PET scanning. This Information may be valuable In
determining a Site for biopsy and perhaps determining the
aggressiveness of therapy.20,21 Magnetic resonance spectros
copy may also provide additionallntormatlon with regard to the
grade of astrocytic tumours.22
Prognostic factors
Clinical and surgical factors
The median survival time after surgical intervention is in the
range of 6-8 years. with marked variation. Many studies have
been published on the subject of prognostic factors for LGA. For
instance. in the largest study published to date, Laws et al.
found the following factors impor1ant to prolonged survival:
474
(i) gross total surgical removal; (I/) lack of preoperatlve neuro
logical deficit; (iD) long duration of symptoms prior to surgery;
(iv) seizures as a presenting symptom; and (v) having had
surgery In recent decades. 5
Almost all authorities lNOUld agree that young age at the
time of diagnosis Is by far the most Important factor correlating
with long survlval.5.ZI-29 Seizures are correlated with a better
prognosis while focaJ deficit and change in personality are
Indicative of a worse prognosls.6.29.30 The beneficial effect of a
good clinical condition at diagnosis is well documented. 51,24
Hence, patients who present with a focal neurological deflclt211 or
with evidence of raised Intracranial pressure with papilloedema
have a worse outlook than those presenting with epilepsy.!!,'&
A recent study combining the results from three institutions
Identified pretreatment factors to be the most important In terms
of predicting outcome. 31 Using these factors (i.e. age < 40 years,
Karnofsky performance score > 70 and absence of enhance
ment on eT or MRI), these Investigators Identified four groups
of patients with statistically different median survivals. The
extent of surgery and whether radiotherapy was immediate or
delayed did not affect SUrvival.
The effect of the extent of surgery on survival for patients
with LGA is controversial. Soffletti et af. found a longer survival
in those with gross surgical removal,29 but others have not found
that the extent of surgical resection corresponds with the length
of survival.'!!,31,32 Most, but not all, studies have Indicated
that patients who receive a biopsy only have a worse survival
compared to resectlon. 17."
Tumour and biological factors
Pr90perative tumour volume An important finding of the
recent randomlzed trial on radiation In the treatment of LGA"
has been the finding that tumour volume is an Important
predictor both of overall survival and progression-free survival.
Others have also demonstrated that large tumours behave less
favourably.34.35
Cell proliferation markers Several studies have identified
that low-grade gliomas identified as having a higher mitotic
activity have a poorer prognosis. Low-grade astrocytomas with
a BUdR labelling index> 1%311.37 or a MIB-1 labelling Index of
> 8%38 represent a subset with a poorer prognosis. although
In another study, however, Ki-67 labelling was found not to
correlate with prognosis. 39 DNA ploidy. as determined by flow
cytometry has not been able to Identify patients with worse
outcomes. 37
Genetic characteristics It is likely that the tendency for
progression of LGA and, ultimately. patient survival is
dependent on the genetic make-up of the tumour. Mutations
of the p53 tumour suppressor gene are frequent genetic
aberrations in astrocytomas,40 but their predictive value Is
DG WALKER AND AH KAYE
Incompletely understood. Neoplasms with p53 gene muta
tions appear to progress to higher grades earlier and more
frequentlY,41A2 although the evidence is not convlncing.43 Some
studies have shown a worse prognosis for patients whose
tumours showed Immunoreactivity for p53 protein (indicative
of a mutation),44 whereas others have not.39'" In the future, It
seems likely that a genetic profile of a tumour will be deter
minable, which will enable more accurate prediction of natural
history and response to treatment than currently available. This
is a valid reason to obtain a tissue diagnosis of all suspected
cases at presentation, as future technologies may be applicable
to today's patients, especially if samples of their tumour are
available for analysis.
ProgreSSion of low-grade astrocytoma
The cause of death in the majority of patients with LGA is
progression to higher grade tumours.l& Progression to higher
grades occurs more rapidly in older patients - in a recent study.
'age at diagnosis' demonstrated a strong negative correlation
with 'interval to anaplastic progresslon'.48 As in ott)er neoplasms,
the development of astrocytomas and their progression to higher
grades is characterized by a multlstep progression and
accumulation of genetic abnormallties.47 There Is also a con
siderable body of evidence to suggest that more than one
genetic type of diffuse astrocytoma exists.48.49 Intratumoral
genetic heterogeneity is likely to be a prominent feature of astro
cytoma molecular genetlcs,so being reflected by well-descrlbed
histological variability within IndMdual astrocytomas. 1
Within a given tumour. multiple subpopulatlons are likely to
have evolved and those subpopulatlons that progress will have
acquired a growth advantage. 51 Eventually, one would expect
these more active cell populatlons to overtake the more indolent
cells of the LGA, thus leading to a hlgher-grade tumour. While
studying LGA that had recurred, Muller et af. found that 14% of
tumours were unchanged, 55% were anaplastic astrocytomas
and that 3O'Yo were glioblastoma multiformes.52 They concluded
that approximately two-thirds of tumours will progress, but It
was not possible to predict hlstologlcally which tumours would
progress. Progression to higher-grade tumours has been well
documented in other series al$O,5.14.17.25,29It is difficult to predict
what influences this phenomenon, although tumour volume is
probably an important parameter. 28,35 The Implication of these
studies may be that one should attempt to remove as many of
the LGA cells as possible. These tumour cells have minimal
genetic alterations and, if left in situ, over time they may
accumulate further genetic changes that could allow them to
become more malignant; for example, loss of the CDKN2 gene
on chromosome9p.S3
Methods of treatment
There Is considerable controversy as to the most appropriate
management of LGA. The key questions which have arisen are:
LOW-GRADE GLIOMAS
1. Is surgery indicated? If so, should maximal excision be
attempted?
2. Is there a role for adJuvant radiotherapy and/or chemo
therapy?
Randomized trials regarding management of LGA have
been published only recendy,33.54-a> yet many questions remain
unanswered. The conclusions of these trials are that:
1. There is no survival difference between those patients
receiving low-dose (45 Gy) and high-dose (59 Gy) radiotherapy;
2. Those patients receiving high-dose radiotherapy have a
lower quality of life.
3. There is unlikely to be any difference in overall survival
between those patients given radiotherapy at diagnosis or when
tumour progression occurs.
Delayed treatment
The option of observation or non-treatment of a patient with a
LGA may be Justified if the risks of treatment (surgery and/or
radiation) are greater than the risks of medical treatment of the
presenting symptom, usually seizures. This course, however,
depends on an accurate diagnosis on clinical and Imaglng
grounds excluding other treatable conditions, and that the
outcome Is ultimately Independent of the timing of treatment
Patients selected for observation usually have good prog
nostic features - they are often young, have no or minimal
neurological deficit and usually present with seizures. The
attraction of a period of observation in such patients Is In avoiding
the possible untoward effects of treatment. Although the risks of
surgery have decreased with the advent of recent technological
advances, morbidity and mortality are still related to tumour
location.57 Patients with deep tumours or tumours in the eloquent
cortex are at significant risk of neurological deterioration from
surgical resection or biopsy. 58 These risks need to be balanced
against the chance of obtaining an accurate diagnosis.
From an oncological perspective, surgery should be carried
out as soon as possible In the course of a malignancy, yet It has
never been proven that earlier treatment of LGA produces an
increase in survival as measured from the time of diagnosis.s9
There Is a risk of mlsdlagnosls on imaging data80 but, In studies
addressing this question, a delay in making management
decisions has not seemed to affect the outcome. For example,
Rajan et al. did not find any difference in outcome between
patients with verified and unverified LGA.61 Additionally,
because many patients present with no neurological deficits
and because operative Intervention In some locations carries a
significant risk of postoperative morbidity, delayed surgery may
be more desirable. Recht et al. compared a group of patients
who had an imaging diagnosis of LGA and no surgery to those
who had immediate surgical interventlon.62 They found no
difference in survival or in the incidence of progression between
the groups and thus concluded that deferring surgery did not
worsen outcome.
475
If a decision is made to observe a patient with suspected
LGA, a strategy must be In place to detect progressive disease,
which would then require more aggressive therapy. Progression
is generally heralded by a new onset of seizures or worsening of
seizures, or Impairment of neurological functlon. 2O
Imaglng studies are not always accurate in the diagnosis of
LGA.60 In addition, a minority of cases of anaplastic astro
cytoma and even glioblastoma multlforme (GBM) do not show
enhancement on imaglng.63 AdJuvant therapy Is recommended
In higher-grade tumours and, therefore, it seems Justified to
obtain a precise pathological diagnosis if possible. van Veeien
et al. came to a similar concluslon. 64 In a recent series, Afra
et al. described a worse prognOSis in patients with a shorter
preoperatlve hislDry who were re-operated on, and therefore
summlzed that dedifferentiation to higher grades may be
delayed by early radical surgery.
The risk of wrongly selecting a young patient for observation
with a non-enhanclng, high-grade tumour&O may be off-set by
the fact that the survival of young patients with high-grade
tumours Is better than that of older patients with low-grade
tumours. Hence, age may be more important In predicting
outcome when other factors are equal (small size, no mass
effect, lack of raised intracranial pressure and normal neuro
logical function).asYet it seems unlikely that In those individuals
who are young and are wrongly selected for a period of
observation, that their individual outcome would have been as
good had they received early aggressive treatment.
Surgical options
Stereotactic biopsy Stereotactic biopsy is an accurate and
safe method for the diagnosis of LGA.18 Framed or frameless
stereotactic techniques can be used, with either CT or MRI
guidance. Because MRI is more sensitive in detecting LGA, this
Is probably the Investigation of choice. The use of contrast Is
essential if previous images have shown enhancement. Multiple
biopsies should be taken to Increase accuracy and these can
be done usually with a single traJectory.18.66 The addition of PET
scanning may guide the biopsy of more suspicious areas.2O
Lunsford et al. advocated stereotactic biopsy followed by
radiotherapy as the treatment of choice for LGA.18 The overall
median survival of their series of 35 cases was 9.8 years, which
compares favourably with other series In which cytoreductlve
surgery was employed. 5,25,28 Also, their rates of mortality and
morbidity were significantly lower than those of a surgical
series;'6,25,26.30.57 however, their series was small.
Because astrocytomas are heterogeneous in nature,
stereotactic biopsy, theoretically at least, may be inaccurate by
underestimating the malignancy of a mass lesion. In addition,
because even high-grade astrocytomas may not enhance on
imaging studies,63 the more anaplastic areas of a tumour may ~.
not be biopsled. Stereotactic biopsy may also mlsdlagnose )
ollgoastrocytoma as a pure LGA. The accurate diagnosis of
476
ollgoastrocytoma Is important because they respond favourably
to chemotherapy.87 Sampling error, therefore, may be a sig
nificant problem.
Stereotactic biopsy is clearly not the treatment of choice In
the presence of mass effects, either clinically or radlologically.
Craniotomy and debulklng is more appropriate In this Instance.
Cytoreductlve surgery Most, but not all, retrospective
studies Indicate that gross total removal of LGA results in a
longer survival tor patients compared to those who have not had
cytoreductive surgery. IS For Instance, Janny et a/. 13 showed a
5 and 10 years' survival of 87.5% and 68.2% In LGA resected
completely compared to 57% and 31.2% with incomplete or no
surgical resection. Berger et al. showed that the patients most
at risk of tumour recurrence and malignant progression were
those with larger preoperative tumours and residual tumour
postoperatlvely.35 However, because these are unselected,
retrospective and non-randomlzed series, such studies are
flawed as in cases in which gross total removal was not
attempted, the tumour may well have been infiltrating into deep
and Important structures, and this may have affected survival
more than the extent of surgery itself. Despite this, the general
oncological principle of trying to remove as many neoplastlc
cells as possible would seem appropriate in instances In which
this can be done with minimal risk of producing a postoperative
neurological deficit. A recent review, however, failed to dem
onstrate a survival advantage with a greater extent of
resectlon.ea In a series of 78 patients that we studied in 1999,
there was an overall median survival of 8.1 years.so There
appeared to be a survival advantage following macroscopic
surgical excision with a 10 years' survival of 70% compared to
42% In patients who received biopsy only.
There is a clear benefit to the patient In the short-term in
terms of neurological function and quality of life in the presence
of mass effects and raised Intracranial pressure. Debulklng is
recommended, particularly if the tumour Is In an accessible
position. This approach may also avoid chronic steroid usage
and its Inherent side-effects.
Cytoreductlve surgery has the advantage of providing larger
tumour specimens for histological analysis. Therefore, there is
much less likelihood of underestimating the grade of the tumour
or missing an oIigoastrocytoma. With a greater amount of
tumour available, genetic analysis may also be possible.
Theoretically, the fewer the number of cells present after
surgery, the less chance of genetic progression of the
remaining tumour cells and the more effective adjuvant
radiotherapy may be. These theoretical advantages have been
questloned. 1&,66
The role of postoperative radiation therapy
The role of radiation therapy in the treatment of LGA remains
controversial. Although the majority of studies have found that
DG WALKER AND AH KAYE
radiation therapy Is beneficial when added to surgery in the
treatment of LGA,5,29,70-73 and although radloresponsiveness can
be demonstrated both in vitr074 and in vivo, 18,75,76 only recently
have properly conducted trials existed.33,55,5G Indeed, radio
logical response may not be associated with a better outcome. 76
The retrospective studies available show no uniformity of
patients, tumour pathologies or pathological classifications; nor
of radiation dose or volume or In the extent of surgical removal
and, for the most part, no control group of patients exists. The
recent series studied by Mansur et al. provides an exampleP
Yet, despite the lack of supportive data, Immediate post
operative radiotherapy is often advocated. 77
The series studied by Laws et al. is probably the largest
group of LGA and Includes 461 patients.s The investigators
interpreted the data as showing a beneficial effect of radical
surgery and a beneficial effect of radiation therapy only In those
patients with an otherwise poor prognosis. Piepmeier tevlewed
the results of radiation therapy of 60 patients with LGA, and
failed to demonstrate a beneficial effect. t6 Haovever, with a mean
time of just less than 5 years, this may not have been long
enough to demonstrate an effect. Medbery et al. compared a
group of 50 patients who received postoperative radiotherapy
with 10 who did not.78 There appeared to be a slight SUrvival
advantage for those patients with Incompletely resected
tumours who received radiotherapy postoperatlvely. A recent
Japanese study argued that the extent of surgery as well as
radiation had a beneficial effect on sUrvival. 70
In 1989, Shaw et al. reviewed data from the Mayo Clinic,
reporting on 91 patients with diffuse astrocytomas and mixed
gliomas,7 The 5 years' survival for those receiving high
dose radiotherapy (> 53 Gy) was 68%, whereas the survival
rate was 47% for those who received low-dose radiotherapy
53 Gy) and 38% who did not receive radiotherapy. The 10
year survival rates were 39%, 21% and 11%, respectively.
Their study is often cited as evidence for the efficacy of
radiotherapy In the treatment of these tumours. Yet, the data
within their study Is not supportive. Problems with the study
Include the fact that it Is a retrospective analysis, there Is
incomplete follow up of patients, and that the study group Is
heterogeneous in nature (astrocytomas are grouped together
with mixed gliomas). Even more problematic Is the fact that,
regardless of whether patients received radiotherapy or not,
and what dose was given, the study was not randomlzed.
Selection bias may, theretore, be a significant confounding
variable in the results given. Even with these shortcomings,
the study failed to shaov an effect for radiotherapy in patients
younger than 34 years.
Others, however, have advocated higher radiation doses;
that Is, 72.6 Gy delivered In a twice dally tractlonatlon scheme. 80
In this uncontrolled, non-random/zed series, the 5 and 7 year
progression-free survival were both 70%. The rate of long-term
complications, however, was not reported.
LOW-GRADE GLIOMAS
Whltton and Bloom were unable to conclude whether
postoperative radiotherapy was effective in the treatment of
LGA after reviewing the results of 88 adult patients treated at
the Royal Marsden Hospltal,8l as were Janny et al. In a French
series.la In the series studied by Vertoslck et al., the median
survival of the entire group was 8.2 years, but there was no
significant difference between the patients who received
radiotherapy and those who did not,17 selective radiotherapy
has been advocated for cases In Which only partial resection
was performed. 82
Recent studies and the future role of radiotherapy
In the European Organization for Research and Treatment
of Cancer (EORTC) Study published recently, no difference
in outcome could be found between low-dose (45 Gy over
5 weeks) and hlgh-dose radiation of LGA (59.4 Gy over
6 weeks).3S A later fOIlcm up showed those In the higher dose
group had a lower quality of Ilfe.54 Early results Indicate that
While there may be a Slightly reduced rate of progreSSion, there
was no difference in survival between patients who were given
radiotherapy either immediately after surgery or when the
tumour progressed. Similar to the EORTC Study, the North
Central Cancer Treatment Group (NCCTG) randomlzed
patients after surgery to 50.4 Gy or 64.8 Gy. There appeared to
be no difference in survival rates between the two groups.56
Radiotherapy techniques have become more sophisticated
in recent years, such that the amount of radiatiOn that normal
brain might receive could, theoretically at least, be significantly
reduced, such as by 3D-conformal and inverse treatment
planning. sa Such techniques may allow dose escalation.
Stereotactic radiosurgery has also been used in the treatment
of LGA by Pozza et al.84 They demonstrated a radlofoglcal
response in 12 of 14 patients. Also, re-Irradiation has been
reported in a patient with LGA with an interval period of
8.5 years. il& Apparently no III effects were caused by the second
course of radiotherapy.
Cerebral radiation therapy is not without side-effects;88
hence, careful consideration should be given prior to Its
administration. For instance, in a recent series of patients with
Icm-grade oligodendroglioma or mixed gliomas treated with a
median of 59.4 Gy, more than one-third of patients developed
dementia or radiation necrosls.B7 Risks of radiotherapy Include
neurocognitive impairment In long-term survivors of LGA.ss
Radiation at moderate doses (45-59 Gy) are unlikely to
produce severe side-effects In the short term.89 yet the long
term results are uncertain. The recently published EORTC trial
clearly demonstrated a worse outcome In terms of quality of life
In patients who received 59.4 Gy CNer 6 weeks compared to
those who received 45 Gy over 5 weeks.54 This multicentre,
randomized trial (EORTC 22844) compared groups of patients
diagnosed with Icm-grade glioma (astrocytomas, oligodendro
gliOmas and mixed gliomas were included, perhaps a short
477
coming of the study) receiving either 45 Gy or 59.4 Gy
postoperatlvely. There was no difference in overall survival
between the groups and no difference In progression-free
survival. Those that received the higher dose reported a lower
level of functioning and a greater amount of fatigue and malaise,
insomnia and emotional dysfunction.54 Another possible
problem with the EORTC study Is that It relied on a voluntary
patient questionnaire and, therefore, has Inherent selection
bias. A recent study has also suggested that radiation therapy
was associated with anaplastic changes In LGA in chlldren. 90
Delayed radiation therapy
Deferring radiation therapy until recurrence or progression Is a
viable option in patients with an otherwise good prognosis after
early histological diagnosis with either stereotactic biopsy or
cytoreductlve surgery.ll1.91 This delays any potential slde-effects
of radiation unttl it Is clearly necessary. Patients with a good
prognosiS may benefit from this approach.31 ,91 The second
randomlzed EORTC trial on radiation therapy was designed to
address the issue of early or delayed radiatiOn therapy. The final
results have not been publiShed as yet, but early Indications are
that, in terms of survival, there were equivalent results for
Immediate and delayed postoperatIVe radiotherapy. SI
The role of chemotherapy
Although some studies have shown a survival benefit for
patients treated with adjuvant chemotherapy,lI2 a prospective,
randomlzed trial has shown that there was no beneflfS and,
therefore, presently there is no proven role for chemotherapy
In the treatment of diffuse LGA. Studies have shown, hem
ever, that chemotherapy Is of use In treating patients with
oligodendrogliomas or oIlgoastrocytomas.- Occasionally,
intracyst chemotherapy may be useful for recurrent cysts
associated with LGA. 96 Chemotherapy may have a role in the
treatment of pilocytlc (WHO grade I) astrocytOmas. (For review,
see Freeman et al.91)
Outcome and conclusions
Before the MRI era, studies would indicate that a typical 5 year
survival rate Is approximately 40-50% and a 10 year survival
rate is 20-30%.5 Two recent studies may Indicate that early
diagnosis with CT and MR Imaglng may improve survival, with
a median survival rate now of 7.5 years and a 5 year survival
of 65% and 10 year survival of 40%.17.25 This does not Imply,
however, that earlier diagnosis has had any Impact on the
natural history of the disease.
The management of LGA is controversial and outcome is
dependent on multiple factors, not only on the treatment
instituted but also the variable Intrinsic biology of the tumours
themselves. We would recommend tissue diagnosiS in all
cases of suspected LGA. In patients with surglcany accessible
tumours, or those with mass effect on Imaging and clinical
478
grounds, craniotomy and cytoreductlve surgery should be
instituted. Stereotactic biopsy only Is a viable option in tumours
in eloquent regions with no mass effect or enhancement
on Imaging. In general, radiation therapy can be delayed until
there is evidence of progressive or recurrent disease. A more
aggressive early approach Is recommended for those who are
over 40 years of age, who clinically have neurological impair
ment or raised Intracranial pressure, or who have enhancing
tumours.on CT or MR lmaging.
OLlGODENDROGUOMAS
After astrocytomas, oligodendrogliomas are the next most
common form of glioma in adults. They represent neoplastlc
transformation of ollgodendrocytes, which form myelin within
the CNS. Oligodendrogliomas have a predilection for the frontal
lobes, are frequenUy calcified, often present with seizures and
have a characteristic 'fried egg' appearance on mlcroscopy.
Epidemiology
Oligodendrogliomas were originally thought to comprise
approximately 4% of primary brain tumours.M However, current
immunohistochemical techniques have demonstrated that
many tumours with the histological appearance of astrocytoma
lack glial fibrillary acidic protein (GFAP) staining, partly or
completely and, as such, are now diagnosed as either mixed
ollgoastrocytomas or oligodendrogliomas, respectively. Using
these criteria, the incidence of oligodendrogliomas has
Increased.9$They have a slight male preponderance with a peak
incidence of around 40 years of age, with a smaller peak at
around 10 years of age. 100,101
Clinical presentation and imaging findings
Seizures are the presenting symptom in 50-80% of caseS.98.100
Other symptoms Include raised Intracranial pressure and focal
signs, both of which are less common. Many imaglng character
Istics of oligodendroglioma are similar to those of astrocytoma.
Most often, they are seen as deep, white matter lesions that
Infiltrate widely. On CT and even plain X-rays, calCification is
frequently seen. Particularly characteristic is a gyriform or
ribbon-like pattern of calcification. Magnetic resonance Imaging
is not diSSimilar to that of astrocytomas.
Pathology
Oligodendrogliomas occur most frequently in the frontal
lobes,'02 but may occur anywhere within the CNS, including the
spinal cord.100. lOO Macroscopically, these tumours are often pink
to red, friable masses. There may be an apparent plane
between the tumour and normal brain at surgery; moreso than
diffuse astrocytomas. 1Focally, the neoplasm is often extremely
cellular, grey and fleshy and therefore simulates a more
anaplastic lesion. Oligodendrogliomas may visibly alter the
cerebral cortex because they diffusely infiltrate grey matter.
DG WALKER AND AH KAYE
The microscopic recognition of a typical oligodendroglioma
Is not difficUlt given an appearance of uniform sheets of cells
with similar cell shape and size. Calcification Is frequent, both In
the tumour itself and the surrounding cerebral cortex. A helpful
diagnostic feature Is the appearance of perlneuronal satel
litoSis, subpial accumUlation and perivascular aggregation. 1.82
Often present are delicate angulated segments of capillaries, .
giving a 'chicken wire' appearance. Oligodendrogliomas also
have a tendency for intratumoral haemorrhage. The 'fried egg'
artefact Is a distinctive feature of many oligodendrogliomas and
Is created by autolytic Imbltlon of water accompanying delayed
fixation, forming clear perinuclear halos. However, these typical
histological features are not always present and previous
estimates that oligodendrogliomas represent approximately
5% of primary brain tumours Is likely to be a significant
underestimate. II1105
Treatment
Historically, treatment of oligodendrogliomas has been based
on gross surgical resection followed by radiotherapy. Many
of the controversies that apply to the definitive management of
LGA also apply to oligodendrogliomas In terms of the role of
surgery, Its timing and extent, and the role of postoperative
radiotherapy.
The extent of surgery correlates with survival In most
serles. 81 ,98,101 For example, In the Mayo Clinic experience, Shaw
et al. showed that In patients with gross resection there was a
median survival of 12.6 years and a 5 and 10 yearsurviva/ of
74% and 59%, compared to a median survival of 4.9 years and a
5 and 10 year survival of 48% and 260/0 in thOse who underwent
subtotal resectlon. '01 However, as with LGA, the evidence that
the extent of surgery itself results in Improved survival, as
opposed to other patient and tumour-related factors, Is lacking.
Some studies have not shown a beneficial effect of extent of
surgical resection on survival for oligodendroglioma.100 Given the
controversy, we believe that for an oligodendroglioma of low
grade, If poSSible, gross surgical resection should be performed,
It Is likely to potenUate adjuvant radiotherapy and/or chemo
therapy, to allow a decrease In radiotherapy portal size and to
increase the diagnostic accuracy by decreasing sampling error.
A recent series by Sun et al. reported the outcomes of
patients with oligodendroglioma and mixed gliomas.100 In that
series, the median survival was 16.7 years. The investigators
found no difference in survival in those patients having early or
delayed treatment, or the chOice of treatment on disease-free or
. overall survival. Chemotherapy was given to many of these
patients and was associated with significant acute toxicity In
almost half of patients, and radiation therapy produced late
neurotoxicity in more than one-third. Sun et al. argued for
deferring treatment untO clinically necessary.
Recent reports have shown that oligodendrogliomas are
chemosensitive.95.101-109 PCV (procarbazine, CCNU, vincristine)
LOW-GRADE GLIOMAS
is most widely used, allhough melphalan and thiotepa may
be equally effective. lOB Therefore, chemotherapy should be
strongly considered In patients with subtotal resection or in
those who have anaplastic or otherwise aggressive tumours
(I.e. large, mass effects with extensive radiological appear
ance). In those with stable, non-enhanclng disease who are
Clinically well, a period of observation before chemotherapy Is
justified.
Chemotherapy can be associated with slgnllicanttoxlclty.
Temozolomlde, an oral agent with a low Incidence of side
effects, may be wen suited to the treatment of low-grade
gliomas, including oligodendrogliomas. 110
The role of radiotherapy is controversial. Although often
considered standard therapy, some studies have shown no or
marginal survival benefit for patients given postoperative
Irradlatlon.lol,1II Wallner et al. showed a distinct advantage
for patients who received greater than 45Gy of postoperative
radiotherapy. m In other series, a survival advantage has also
been shown, particularly for patients who had undergone
subtotal resection. 113,114 Undegaard et al., however, showed no
advantage for those who had total macroscopic resection. 113
In fact, they believed that it Is detrimental in these patients, who
otherwise have a good prognosis. They also showed no benefit
from 50 to 60 Gy as opposed to 40-50 Gy and, therefore,
recommended the lower dose regimen if radiotherapy was to be
used. On the basis of these and similar series, postoperative
radiotherapy Is generally recommended,lIs yet the evidence for
Its efficacy, as for LGA, Is not well substantiated. Therefore,
when analysing this data, knowing that the survival benefit
of postoperative radiotherapy Is uncertain and long-term
neurocognltlve slde-effects are likely, and knowing that PCV
chemotherapy Is likely to produce a response, the primary
modality after surgery could be chemotherapy. Radiotherapy
can then be delayed for anaplastic transformation or recur
rence. Alternatively, If chemotherapy is to be delayed and
reserved for tumour progression. PCV should be administered
first and followed by radiotherapy.
The EORTC and NCCTG randomlzed trials concerning the
role of radiotherapy In the treatment of low-grade glioma
included patients with oligodendroglioma and mixed gliomas.
Hence, the results of these trials can probably be applied to
oligodendrogliomas a1so.54-56
MIXED GLIOMAS
Mixed gliomas are composed of more than a single type
of neoplastlc glial cell. criteria for their diagnosis are difficult
to define, but it is generally accepted that the essential char
acteristic is phenotypic heterogeneity. not necessarily blphaslc
tumours. By far the most common are ollgoastrocytomas.
OIlgoastrocytomas are defined as tumours with geo
graphically distinct areas of unequivocal oligodendroglioma and
astrocytoma coexisting.' They are WHO grade 11 lesions.
479
Varying opinions for the minimum astroglial component for the
diagnosis exist, including at least 1%,"6 25%117 and 50%.118
More recently, it has been suggested that the microscopic
presence of at least one x100 field of oligodendroglioma Is
sufficient for the diagnosis of oIigoastrocytoma, rather than
astrocytoma. 105
The epidemiology, clinical presentation and Imaging
findings are similar to that of pure oligodendroglioma. The
prognostic significance of this tumour Is uncertain. The overall
outcome of patients with ollgoastrocytoma Is not predicated
on the astrocytoma component. 195 In their series from the
Mayo Clinic, Shaw et al. showed a median survival of 6.3 years
and a 5 and 10 year survival rates of 58% and 32%,
respectively. m It is likely that overall, the outlook is some
where between LGA and pure ollgodendroglloma. 95 Both pure
oligodendroglioma and ollgoastrocytoma respond to chemo
therapy.SS,too Pure tumours are likely to be more chemo
sensltlve95 and, given this, the degree to which the tumour has
oligodendroglioma cells probably dictates Its chemosensitivity
and prognosiS.
CONaUSION
Low-grade gliomas are slow-growing lesions with an indolent
natural history, especially In young patients In good clinical
condition. A cautious approach to treatment Is both prudent
and supported by evidence. However, surgery, radiation and
chemotherapy are evolving to become safer. The role of these
treatment modalHies will require further review In the future.
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glioma in adults: An analysis 01 prognostic lactors and timing d
radiation. JCfin 0nc0I1997; 15: 1294-301.
92. Watne K, Hannisdal E. Nome 0 et al. Combined intra-arterial
chemotherapy followed by radiation in astrocytomas. J Neurooncol
1992; 14: 73-80.
93. Eyre HJ, Crowlay JJ, Townsend JJ et al. A randomized trial 01
radiotherapy versus radiotherapy plus CCNU for incompletely
resected low-grade gliomas: A Southwest Oncology Group study.
J Neurosurg 1993; 78: 909-14.
94. Schiffer D. Dutto A, Cavalla P et al. Prognostic factors in oligo
dendroglioma C8nJ Neurol Sci 1997; 24: 313-19.
95. Soffietti R., Ruda R.. Bradac GB. Schiffer D. PCV chemotherapy
for recurrent oligodendrogliomas and oligoastrocylomas. Neuro
surgery 1998; 43: 1066-73.
96. Disabato JA, Handler MH. Strain JD. Fleitz JM. Foreman NK.
Successful use 01 intracavitary bleomycin for low grade astro
cytoma tumor cyst. Pediatr NfiItIrosurg 1999; 31: 246-50.
97. Freeman CR, Farmer JP. Mantes J. Low-grade astrocytomas in
children: Evolving management strategies (review}. Int J Radiation
OncoIBiolPhys1998;41:979-87.
96. Mork SJ. Undegaard KF, Ha/vorsen TB et al. Oligodendroglioma:
Incidence and biological behavior in a defined population.
JNeurOfWrg 1985; 63:881-9.
99. Holt AM. Maravitla KR. Supratentol1al gliomas: Imaging.ln:Wilkins
RH. Rengachary SS (eds). Neu(OfWrgery. McGraw-HiII, New York,
1996;881-9.
100. Chin HW. Hazel JJ. Kim TH. Webster JH. 06godendrogliomas.
I: A clinical study d cerebral oligodendrogliomas. Cancer 1960; 45:
1458-66.
101. Shaw EG. Scheithauer BW. O'Fallon JR. Tazetaar HO. Davis DH.
Oligodendrogliomas: the Mayo Clinic experience. J Neurosurg
1992;76:428-34.
102. Russetl D. Rubinstein LJ. Pathology of Tumors of the Nervous
System. 5th edn. Williarns & Wilkins. Baltimore. 1989.
103. Merchant TE. Nguyen O. Thompson SJ. Reardon DA, Kun LE,
Sanford RA. High-grade pedialric spinal cord turnors. Pediatr
Neurosurg 1999; 30: 1-5.
104. Ushida T. Sonobe H. Mizobuchi H, Toda M. Tani T. Yamamoto H.
Oligodendroglioma of the 'widespread' type in the spinal cord.
Childs Nerv Syst 1998; 14: 751-5.
DG WALKER AND AH KAYE
105. Coons SW. Johnson pc, Scheithauer BW, Yates AJ, Pearl OK.
Improving diagnostic accuracy and interobserver concordance in
the classification and grading of primary g60mas. Cancerl997; 79:
1381-93.
106. Sun ZM. Genka S, Shitara N, Akanuma A. Takakura K. Factors
possibly influencing the prognosiS of oligodendroglioma. Neuro
surgery1988; 22: 886-91.
107. Caimcross JG. Macdonald OR. Successful chemotherapy for
recurrent malignant oligodendroglioma Ann Neurof 1988; 23:
360-4.
108. Cairncross JG, Macdonald DR. Ramsay DA. Aggressive oligo
dendroglioma: A chemosensitive tumor. Neurosurgery 1992; 31:
78-82.
109. Glass J, Hochberg FH. Gruber ML. Louis DN, Smith D. Rattner B.
The treatment of oligodendrogliomas and mixed oligodendro
glioma-astrocytomas wilh PCV chemotherapy. J Neurosurg 1992;
76:741-5.
110. Cairncross JG. Understanding low-grade glioma N6tlrology 2000;
54:1402-3.
111. Reedy DP. Bay JW, Hahn JF. Role of radialion therapy in the
treatment of cerebral ofigodendroglioma: An analysis of 57 cases
and a lilerature review. NeurOfWrgery1983; 13: 499-503.
112. Wallner KE. GonzaJes M. Sheline GE. Treatment d oligodendro
gliomas with or without postoperative irradiation. J Neurosurg
1988; 68: 684-8.
113. Lindegaard KF. Mark SJ. Eide GE et al. Statistical analysis of
clinicopathofogical features. radiotherapy, and survival in 170
cases 01 oligodendroglioma J N6tlrosurg 1987; 67: 224-30.
114. Shimizu KT. Tran LM, Mark RJ. Setch MT. Management of
oligodendrogliomas. Radiologyl993; 186: 569-72.
115. Plunkett SR. Conventional radiotherapy for specific central
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.Neurosurgery. McGraw-HRI. New "1brk. 1996; 184s-:s5.
116. Kim L. Hochberg FH. Thornton AF et al. Procarl:Iazine. lomustine.
and vincristine (PCV) chemotherapy for grade III and grade IV
oligoastrocytomas. J Neurosurg 1996; 85: 602-7.
117. Mark SJ, Ha/vorsen TB, Lindegaard KF, Eide GE. Oligodendro
glioma: Histologic evaluation and prognosis. J Neuropathol Exp
Neurol1966; 45: 65-76.
118. Hart MN. Petito CK. EaI1e KM. Mixed gliomas. cancer 1974; 33:
134-40.
119. Shaw EG. Scheithauer SW, O'Fallon JR, Davis DH. Mixed
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Neurosurgery 1994; 34: 577-82.
 CHAPTER 152
I '

Tumors of the Central Nervous System in

Children and Adolescents
SHIAO Y. woo, M.D., AND LUCIUS F. SINKS, M.D.

EPIDEMIOLOGY fusion over nomenclature and cO,ntroversy over histologic

grading of certain types of tumors. One classification is
Primary tumors of the central nervous system are the
shown in Table 152.1. For astrocytomas the degree of ma
most commonly seen solid tumors in children andadoles
lignancy has been graded by several different systems.
cents and the second most common malignancy in this age
group, second only to leukemia. The incidence in the age, Glioblastoma multiforme is the highest grade or most ma
group of 0-14 years is 6.5I1QO,OOO. The median age for lignant form. Grading of malignancy has also been applied
infratentorial tumors varies from 3 to 8 years depending to ependymomas and medulloblastomas.
The tumor types most com~only seen in children and c
on the tumor type, and the median age for supratentorial
tumors varies from 9 to 17 years. Thus, infratentorial tu adolescents include cerebellar astrocytoma, medulloblas
0:
mors are more common in children'under 10 years of age, toma, brain stem glioma, ependymoma, cerebral hemi
01
and supratentorial tumors become increasingly more com spheric astrocytoma, craniopharyngioma, and optic glioma.
aJ
mon in adolescents. In general, there is a preponderance cc
of males over females. Whites exceed nonwhites for deaths PATHOGENESIS di
fr~m medulloblastoma and ependymoma; the reverse is Pi
true for glioma. Metastatic brain tumors are uncommon There are very exciting developments currently taking
jul
in this age group. place which relate molecular genetic studies to the con rej
ventional neuropathologic classification. Preliminary work ris
ETIOLOGY has been recently reported identifying the stage of malig ga:
The etiology for the majority of tumors of the central nancy of glioblastomas to specific genotypic changes. There '
~
nervous system is unknown. will undoubtedly be much more work in this area which nei
Basal cell nevus syndrome, a genetic disorder, is asso has the potential benefit of selecting specific genotypic' or
ciated with an increased risk of medulloblastoma. Hered subtypes oftumors which conceivably will allow more spe atr.
itary factors also play a role in brain tumors associated cific therapy to be developed.
with neurofibromatosis, tuberous sclerosis, von Hippel
Landau's disease, and retinoblastomas. Li and Fraumeni Table 152.1. T.
have described several families in which different"mem Classification of primary brain tumors awa
bers developed soft tissue sarcoma, brain tumor breast diffe
cancer, and osteosarcoma. Supratentorial
> '

Cerebral hemisphere . brai

Embryonic maldevelopment can result in certain tu cula
Astrocytoma (including glioblastoma multiforme)

mors, such as epidermoids', dermoids, teratomas and cra Ependymoma

tom:
niopharyngiomas. ' Oligodendroglioma pseu
Although viruses and carcinogens can clearly induce Spongioblastoma
?rain tumors in animals, their role in the tumorigenesis Choroid plexus papilloma
In the central nervous system of humans is not established. Teratoma Sk
Th~re .is, however, some evidence to support that ionizing Pinealoma cent!
radiabon to the head may be,etiologicalIy associated with Sella/chiasma cran:
the development of brain tumors, as evidenced from an Craniopharyngioma postE
increased incidence ofbrain .tumors in children who re Pituitary adenoma ings
Optic glioma
ceive radiation to the scalp for tinea capitis. calci
Infratentoriai
The predilection of certain tumor types to specific sites Brain stem
giom
~n the central nervous system suggests local vulnerability'
Glioma/astrocytoma (including glioblastoma multiforme)

m areas of nervous tissue which may not be morphologi Ependymoma .

cally recognizable. Teratoma Th.

Cerebellum
most
PATHOLOGIC CLASSIFICATION Medulloblastoma
brain
There is no general agreement on the precise pathologic Astrocytoma pecia:
classification of primary brain tumors. There is also con~ Spongioblastoma only,

1574
 Chapter 1521 Central Nervous System Tumors In Children' and Adolescents
CLINICAL SIGNS AND SYMPTOMS
The clinical manifestations of brain tumors are related
10 increased intracranial pressure and to the location of
the turnor. .
Elevation of intracranial pressure is the result of cere
bral edema, hydrocephalus from obstruction of cerebro
.,,,,kl_."Y"'"' fluid flow or, les8 frequently, of the volume of the
tumor itself. Headache is a common' symptom and char
acteristically occurs in the mo~ing and is accompqied,
and often relieved, by vomiting. Headache is a less com
mon complaint in young children compared to olderchil
dl'en and adolescents. The child may instead present with
"irritability, malaise, somnolence, and even changes in per
sonality. Cranial enlargement can occur in infants in whom
s!1tures have not yet fused.'Papilledema is a clear
sign ofincreased intracranial pressure; a sixth nerve palsy
. can also occur, giving rise to diplopia. Occa,sionally a sud
'. den increase in intracranial pressure can cause impending
. herniation and present as an emergency with coma and
changes in vital signs and various neurologic deficits.
A hemispheric turnor can cause seizures, hemiparesis,
or loss of cortical sensation. Tumors at the hypothalaD;lic
or pituitary region can give rise to visual field disturb
ances, endocrine abnormalities, diabetes insipidus, pre
cocious puberty, hypersoIQnia, hyperphagia, or a
aiencephalic syndrome of failure to thrive and emaciation.
Pineal turnors classically present with paralysis of con
jugate upward gaze, absent pupillary reaction to light, and
con retraction nystagmus. Brain stem tumors frequently give
I"Ork
rise to multiple cranial nerve palsies, long tract signs, and
tUg- .
gait problems. Tumors in the cerebellum can cause nys
'. tagmus, ataxia, gait abnormalities, and dysdiadochoki
nesia. Some spinal cord tumors ean produce paraparesis
or nerve root pain, sensory loss, muscle weakness, and
atrophy.
DIAGNOSTIC StUDIES
The first steP. in the diagnosis of brain tumor is clinical
awareness. Brain tumor should always be included in the
differential diagnosis of a space-occupying lesion in the
brain besides brain abscess, congenital malformation, vas
cular lesion, subdural hematoma, intracerebral hema
toma, parasitic infestation, lead encephalopathy, and
pseudotumor cerebrii. . MagnetiC Resonance Imaglng and Positron Scan
Plain X-Ray of the Skull
Skull x-rays are normal in many children and adoles
cents with brain tumors. Sometimes signs of raised intra
cranial pressure such as suture separation, erosion of the
posterior clinoid process, and increased convolution mark
ings on the inner table ofthe skull may be present. Tumor
calcifications occur most frequently in craniopharyn
giomas and occasionally in gliomas and ependymomas.
Computed Tomography
The computed tomographic (CT) scan of the head is the
most useful single tool for the diagnosis and follow-up of
brain tumors. It is noninvasive, quick, and sensitive, es
pecially when coupled with contrast enhancement. It not
only localizes the tumor and outlines its characteristics,
1575
but also demonstrates the presence or absence of hydro
cephalus.
Radlonuclide Brain Scan
The brain scan is used much less often now since the
introduction of the CT scan; However, sometimes it may
be of use in co~rming Bupratentoriallesions.
Pneumoencephalogram
This invasive procedure is rarely uled; however, it de
lineates small pineal tumors, optic gliomas, hypothalamic
turnors, and intraventricular .and paraventricular tumors
well.
Cerebral Angiography
Cerebral angiography also is far less frequently used
than. previously, being an invasive procedure. However, it
may be necessary to UBe it to differentiate between arte
riovenoUs malformations and brain turnors when there is
still doubt after the other studies. In addition, it supplies
useful information to the surgeon regarding blood supply .
to t:k&-twnor.
~amination of the Cerebrospinal Fluid
A lumbar puncture is generally not advisable in a pa
tient with raised intracranial pressure. However, exami~
nation of the cerebrospinal fluid can provide useful
information regarding turnor seeding along the cereln;o
spinal pathway. The polyamines in the cerebrospinal fluid ~,
have been found to be useful tumor markers for the ac
tivity of medulloblastomas. Serial monitoring of polya
mine levels can aid in the detection of turnor recurrence.
Alfllfetoprotein and/or ~~human chorionic gonadotro
phin (jj.HCG) can also be detected in the cerebrospinal
fluid of patients with germ cell tumon oftho pinGal "linG,
and Ilr!! thGret'ore U!l(!ful markers fur diagnosis and follow
tip.
Myelography
Myelography is a useful procedure for the diagnosis of
spinal canal turnors. It can be used also for the detection
of metastases of certain brain tumors, such as medullo
blastomas.
Magnetic resonance imaging (MRI) now provides su
perior imaging of the central nervous system than does
the CT scan. It is particularly useful for the detection and
monitoring of brain stem and other posterior fossa tumors.
The positron scan can provide information on the differ~
ential metabolism of the different regions of the brain. It
is the most reliable noninvasive tool for distinguishing
between recurrent brain tumor and radiation necrosis.
Evoked Potential
Brainstem auditory evoked potential study has been re
pOrted to be very useful in monitoring the progress of chil
dren with braiJistem glioma after therapy. Visual evoked
potential has not been stu4ied extensively but may be
useful in patients with optic glioma.

 1576 Section 0 / Childhood Cancer
SPECIFIC TUMORS
Infratentorlal Tumors
MEDULLOBLASTOMA
Medulloblastomas acco\1Ilt for about one-quarter of all
pediatric brain tumors. The majority of cases occur before
the age of 15; some are seen in adults.
In children medulloblastoma is usually a midline turnor
found in the vermis. The tumor tends to be located more
laterally in older children and adolescents. In addition to ,
invading the neighboring structures, such as the cerebel
lar hemisphere and the fourth ventricle, the tumor also
has a propensity to seed the meninges and spread the
cerebrospinal fluid through the entire neuroaxis to involve
the cerebrum and spinal cord (drop metastasis). Medul
loblastoma can also metastasize outside the central ner
vous system to the peritoneal cavity (occasionally via
ventricular-peritoneal shunt), bone, bone marrow: lymph
nodes and rarely, the liver. The vertebrae, long bones, ribs,
and skull are common skeletal areas of metastases. The
incidence of extra-central nervous system metastases has
been reported as less than 5% in the literature but is now
believed to be as high as 20% with long-term follow-ups
of patients.
Surgery is the primary mode of therapy. The tumor,
,however, is often not completely resectable. Nonetheless,
even a partial resection, in addition to providing a speci
men for histologic diagnosis, can reduce the tumor burden
thereby rendering radiotherapy and/or chemotherapy the
.~ oretically more effective. Surgical decompression of ob
structive hydrocephalus by a ventricular-peritoneal shunt
also frequently improves symptoms. Surgical resection,
unfortunately, has seldom led to cure.
Medulloblastomas are radiosensitive tumors. Postop
erative irradiation of the craniospinal axis has produced
5-year survival rates of approximately 50% and 10-year
survival rates of about 35%.
The recommended dose ofradiation to the posterior fossa
is generally 4500-5500 cGy; to the supratentorium::about
3500 cGy; and to the spinal cord, 2400-4000 cGy. The price
of high-dose irradiation to the brain and spine, however,
is not insignificant, particularly in the very young. The
undesirable late effects include possible diminished ver
tebral growth, endocrine dysfunction, learning problems,
and secondary oncogenesis. Woo et aI. in a pilot study did
not find increased spinal recurrence when the radiation
dose to the spine was reduced to 2400 cGy. A study from
Children's Memorial Hospital/Northwestern University also
showed that 2500 cGY neuroaxis irradiation was adequate
for early-stage patients. However, a small pilot study from
Milan, Italy, using radical resection, radiation to the pos
terior fossa only, and chemotherapy (both systemic and
intrathecal) reported spinal failure in three out of four
patients. It therefore seems inappropriate to omit neu
roaxis irradiation but more advisable to reduce the dose
of radiation in selected patients. The Pediatric Oncology
Group (POG) is currently evaluating children with T1TzMo
~ medulloblastoma by a randomized study of 2340 cGy or
3600 cGy to the spine. In addition, electron instead of
photon is being used more frequently to treat the spine. ' 11
As opposed to photon, the depth of penetration of electrons b
is governed by its energy (within a certain energy range). tE
It is therefore possible to limit the dose of radiation to <, pl
!
structures anterior to the spine by selecting an electron a]
beam of the appropriate energy, thereby minimizing the bl
acute and possibly the chronic side effects of radiation. In se
children less than 2 or 3 years of age, neurotoxicity from w
cranial irradiation has been reported to be greater than di
in older children, probably because of the increased sen di
sitivity of the developing brains to the late effects of ra st
diation. There have been small pilot studies from several Sil
institutions including M.D. Anderson Hospital, St. Jude h~
Children's Research Hospital, and Dana-Farber Cancer in
Institute using postoperative chemotherapy and delayed ra
radiotherapy in these young children. The preliminary cu
results are encouraging. A POG study is now in progress . '/"
to determine if the use of postoperative cyclophosphamide bI:
and vincristine in children less'than 36 months of age will ch
permit the delay of cranial irr"diation for 12 months in do
children 2-3 years old at diagnosis and 24 months for those ca
less than 2 years o l d . ' , in;
Several chemotherapeutic agents, when used alone or Cl:
in combination, have demonstrated activity against re bh
current medulloblastoma. These include vincristine, 15,
methotrexate, 1,3-bis-(2-chloroethyl)-I-nitrosourea (BCNU), wi
chloroethyl-cyclohexyl-nitrosourea (CCNU), cyclophos ale
phamide, nitrogen mustard, procarbazine, VM-26, VP-16, vis
cis-platinum and carbo-platinum. The role ofadjuvant che pr(
motherapy has been explored in several studies. On the or1
basis of the results of a pilot study carried out at the Royal reI
Marsden Hospital in London, the International Society of grf
Pediatric Oncology (SlOP) in 1976 randomized patients beE
with medulloblastoma to receive, after surgical resection,
either craniospinal irradiation or radiotherapy and che . Tat
motherapy with vincristine and CCNU. In the last anal. Chi
ysis, 286 patients were evaluable, and the 5-year disease
free survival was 54% for patients who received chemo T,
therapy and 43% for those who did not (p = .08). The
advantage ofchemotherapy was observed in boys, children
under 2 years of age, patients with T3/ T4 lesions, those
with brainstem involvement, and patients with grossly
incomplete resection ofthe primary tumor. The Children's
Cancer Study Group (CCSG) in 1976 started a study al
most identical to the SlOP study, with the exception that
prednisone was added to vincristine and CCNU in the
chemotherapy arm. Although there was no significant dif
ference in terms of survival between the two therapeutic
approaches when the entire group was analyzed, chemo
therapy appeared to be beneficial for patients with T3/ T4 .
f
,
or Ml-Ma disease. The 5-year event-free survival for pa
T4
tients with T 3 IT4 disease was 58% in the chemotherapy
arm versus 41% in the nonchemotherapy arm. A pilot study f Mo
using surgery, craniospinal irradiation (with the spinal
dose reduced to 2400 cGy) and intermediate-dose metho Ml
trexate (500 mg/m2) and BCNU showed a disease-free sur M2
vival of 60% 27-84 months from diagnosis (median-41
months). There was no excessive toxicity or increased rate
of spinal recurrence. There are therefore indications that M3
adjuvant chemotherapy may be advantageous in the treat M4
 Chapter 152/ Central Nervou$ System Tumors in Children and Adolescents
: ment of at least some subsets of patients with medullo
'blastoma. Recently there has been also considerable in
terest in applying chemotherapy early in the treatment
;;program, that is, soon after surgery and before radiother- ,
tapy. In a West German pilot study, vincristine, procar
"bazine, and intermediate-dose methotrexate were given
raoon after surgery. and radiotherapy was delayed until
, week 11. Toxicity was reported as tolerable and the ra
.dii:Jtherapy did not appear to be compromised. The 4-year
disease-free survival was approximately 50%. Several larger
ra studies by SlOP, CC sa, and poa are in progress using a
raj ;<~ similar strategy. Preliminary analysis of the SlOP trial
lde' has not demonstrated clear-cut advantage of a brief but
~er intensive chemotherapy course after surgery but before
red" radiotherapy. The role of biologic response modifiers is also
try . currently being investigated.
~5$ ,
Several prognostic factors are recognized for medullo
de blastoma. Children under 3 years fare less well than older
'ill children, perhaps in part because ofthe need to reduce the
in " dose of radiation in the younger children and in part be
se cause ofa higher incidence of cerebrospinal fluid dissem
ination of tumor. Girls have a better prognosis than boys.
or Chang et aI. have devised a staging system for medullo
e blastoma which appears to have prognostic value (Table
e, 152.2). A decrease in survival has been found in patients
1), with Ta / T4 or Ml-Ma disease. Brainstem involvement is
s also a bad prognostic sign. Patients who have the grossly
S, visible primary tumor completely resected have a better
- prognosis than those whose tumors are partially resected
. or.biopsied only. The resectability of the tumor is probably
relatedtq the extent of the disease. Recently, a histologic
grading sYstem which reportedly hRi prognostic value has
been propaeed. Most current studies use some oraH of
I,
Table 151.2.
Chang classification for medUlloblastoma
Tl Tumor less than 3 cm in diameter and limited to the
classic midline position in the vermis, the roof of the
fourth ventricle, and, less frequently, the cerebellar
hemispheres.
T2 TUmor 3 cm or greater III diameter, further invading one
adjacent structure or partially filling the fourth ventricle.
Ta This stage is divided into TaA and T3B.
TaA: Tumor further invading two adjacent structures or
completely filling the fourth ventricle with extension
into the aqueduct of Sylvius, foramen of Magendie,
or foramen of LuscAka, thus producing marked
internal hydrocephalus.
TaB: Tumor arising from the floor of the fourth ventricle or
f~'
brain stem and filling the fourth ventricle.
T4 Tumor further spreading through the aqueduct of Sylvius
to involve the third ventricle or midbrain, or extending to
the upper cervical cord.
f:- Mo No evidence of gross subarachnoid or hematogenous
metastasis. . cephalus. The primary treatment for brainstem glioma is
Ml Microscopic tumor cells found in cerebrospinal fluid.
M2 Gross nodular seeding demonstrated in cerebellar,
cerebral subarachnoid space, or the third or lateral
ventricles. . to the primary tumor. Comparable survival rates have
Ma Gross nodular seeding in spinal subarachnoid space.
M4 Metastases outside the cerebrospinal axis.
1577
these prognostic factors to categorize patients into differ
ent prognostic groups and apply different therapeutic
strategies to them.
CEREBELLAR ASTROCYTOMA
The classical juvenile cerebellar astrocytoma is usually
a low-grade well-differentiated astrocytoma which con
tains microcysts, Rosenthal flbers,and sometimes a rural
nodule. The treatment of choice is surgical excision. Com
plete excision results in cure in the great majority (more
than 90%) of patients. Even partial removal is often fol
lowed by a prolonged period of symptom control and Bur
. viva!; therefore, postoperative radiotherapy Can be withheld
in many cases. However. if the residual tumorafter sur
and
.... gery is large symptomatic, radiotherapy should be
considered. A report from Stanford showed a 12year sur
vival and freedom from relapse of 60% in children who
received Po.stoperative radiotherapy for large, incom
pletely resected cerebellar tumors. Radiotherapy is also of
benefit in patientswith symptomatic recurrence in a sur
gically inaccessible site such as the brainstem. There is a
type of..diffi:tse cerebellar astrocytoma which has features
of higher grade of malignancy such Ri high cell density,
. necrosis, and perivascular pseudorosettes. The prognosis
is worse in patients with this form of cerebellar astrocy
toma and postoperative irradiation is usually indicated.
The role of chemotherapy is not well established. .
BRAINSTEM GLIOMA
The brainstem glioma represents about 10-15% of all
primary brain tumors in children. The term glioma is
used instead of Qther more precise patholoiic terms be- .
cause in the past, Burgle!l explorAtion and btOP9Y were
seldom done in most patients because of the hazards
involved in tumor biopsies in the brainstem. The diag
nosis of brainsteln glioma. is usually made with the' aid
'of eT scan or MRl. With improvements in CT-guided
stereotactic neurosurgical techniques, some investiga
tors have advocated surgical biopsy of the tumor to as
. certain the histologic grade of the tumor, since this may
have prognostic importance. On the other hand, it has
been shown that the biopsy sample might not be rep
resentative of the entire tumor, and pathology exami
nation at autopsy not infrequently revealed a higper
histology grade than that of the biopsy specimen. More
over, the majority ofbrainstem gliomas eventually cause
. death regardiess of their initial histologic grade, al
though the rate of progression may be slower in the well
differentiated tumor than in glioblastoma .
Surgical evacuation of cysts or excision of exophytic tu
morscan produce improvement in symptoms. However,
commonly the only surgical procedure performed in some
patients is the shunting procedure for obstructive hydro
. radiation therapy. A controversy exists as to whether ra
diotherapy should be directed to the primary site plus a
margin or to the whole brain initially followed by a boost
been achieved with both forms of radiotherapy, and the
major site of failure after either form of radiotherapy is
1578 Section 0 I Childhood Cancer
the brainstem. A usual radiation dose range for conven
tional fractional radiation therapy is 5000-5600 cGy, and
it is not clear that brainstem glioma shows a clear dose
response to radiation therapy in the usual dose range.
Although conventional radiation therapy often produces
symptomatic response, the 5-year survival is generally
around 20%. Currently, hyperfractionated radiation ther
apy is being studied. The rationale for hyperfractionated
irradiation is that multiple fractions per day may selec- ,
tively spare normal central nervous system tissues, and
therefore a higher total radiation dose can theoretically
be delivered to the tumor without increasing the incidence
of late complications. Indeed, POG used 110 cGy twice a
day at 4- to 6-hr intervals to a total dose of 660 cGy and
found no increase in toxicity. Unfortunately, there was no
apparent improvement in survival with this radiation dose
compared with historical control. POG is currently esca
lating the total dose to 7020 cGy. At the Children's Hos
pital of Philadelphia, a pilot study using 120 cGy of
radiation, twice a day, 5 days a week to a total dose .of
6480 cGy was done, again showing no excessive acute or
subacute toxicity, but also no increase in efficacy. On the
other hand, at the University of California, San Francisco,
two fractions per day each of 100 cGy were delivered in
72 fractions to a total tumor dose of 7200 cGy over a 7
week period. A recent update appears to show a 50% pro
longation ofsurvival when compared to a group of children
with brainatem glioma treated by conventional radiation
therapy in CCSG. There was again no increase in the
incidence of radiation necrosis. However, there was an
unexpected observation of prolonged lymphocytopenia as
sociated with opportunistic infections in a few patients.
Nonetheless, the result is encouraging and needs confir
mation. The role of hyperfractionated radiation therapy
should be further explored. The use ofradiation sensitizers
has not been extensively studied in brainstem glioma, al
though a CCSG pilot study incorporating mi80nidazole and
hydroxyourea did not demonstrate any survival benefit.
The role of chemotherapy is not established.J main~ be
cause of a lack of highly effective agents, .aJthough re
sponses to BCND, CCNU, procarbazine, methotrexate, and
cis-platinum have been reported. Dexamethasone, a syn
thetic steroid, has been very useful in controlling tumor
igenic edema, causing symptomatic improvement in many
patients. In limited trials of adjuvant or neoadjuvant che
motherapy for brainstem glioma, no significant benefit
from the chemotherapy has been demonstrated. At pres
ent chemotherapy is generally used for palliation. None
theiess, efforts to find more effective chemotherapeutic
agents for this disease should continue.
The prognosis is partially related to the histologic grade
of the tumor, with glioblastomas being generally rapidly
progressive and uniformly fatal. Tumors arising in the
midbrain and thalamus, sometimes grouped under
brainstem glioma, fare better than those arising in the
pons or medulla. It has been reported that a short clinical
history, widespread brainstem dysfunction, a hypodense
tumor on pre-enhancement CT scan, and a diffuse tumor
on MR images are also poor prognostic factors for brain
stem glioma.
EPENDYMOMA
Ependymomas arise frO\ll ependymal cells and can occur
ilifratentorially' and supratentorially; In, children, infra
tentorial ependymomas are more common than supraten
torial ependymomas, and account for about 8-10% of
posterior fossa tumors. The tumor usually arises from the
floor of the fourth ventricle and extends to the neighboring
structures. The histologic grading oftumor, although non
uniform among pathologists, appears to have prognostic
significance. Ependymomas are thought to behave fre-'
quently like medulloblastomas in that they may seed the
cerebrospinal pathway and may even spread outside the
central nervous system. However, the incidence of cere
brospinal seeding seems to relate to both histologic grade
and site-high-grade infratentorial ependymomas have a
higher risk of spinal metastasis than low-grade supraten
torial ependymomas. .
The standard treatment of ependymoma is surgical re
section followed by radiotherallY' Diez et a1. at Buenos
Aires Children's Hospital have found that extensive sur
gical dissection at the floor of the fourth ventricle con
tributed to postoperative brainstem dysfunction and death,
and have cautioned against this practice. Because of the
aforementioned low risk of cerebrospinal metastasis of low t
grade supratentorial, ependymomas, some investigators I
have suggested that irradiation of the entire cerebrospinal
t
axis is not necessary in these patients. For infratentorial t
ependymomas, most oncologists would recommend cra
t
niospinal irradiation with a boost to the~ initial tumor ~d
and areas of gross disease. The radiation dose range IS
v
similar to that for medulloblastoma. In general, a radia a
tion dose in excess of 4500 cGy to the primary tumor site
fi
is recommended. Five-year survival figures of 50-70% have g
been reported. However, about 50% of patients with high
tl
grade tumors fail locally. with current treatment pro d
grams. Children with supratent~rial epen~ymo~as ~p v.
pear to fare better than those with infratentonal pmnB?es. r!
Recurrent ependymomas have shown response to mtro Cl
soureas, methotrexate, epipodpphyllotoxin, vincristine, cis iJj
platinum, and carboplatinum, but the chemotherapy sal
bl
vage rate is poor. The role of adjuvant chemotherapy has bl
also not been fully established. Some children with epen
5
dymomas were included in the SlOP medulloblastoma study, di
but clear benefit of adjuvant CCNU and vincristine could to
not be demonstrated. A study from M.D. Anderson Hos
w:
pital on infants with ependymoma, however, show d that
some infants treated with surgery and MOPP (mtrogen
7 10:
bI
mustard, vincristine, procarbazine, and prednisone) ~he
Tl
motherapy could have a prolonged disease-free surVIVal to
without any radiation therapy. This observation will need
at
confirmation by a larger cooperative group study. wi
f do
Supratentorial Tumors do:
ral
CEREBRAL ASTROCYTOMA to
COl
Astrocytomas account for 10% of all brain tumors in
children but represent about one-third of all supratento wi
rial tumors of childhood. The most malignant form of as dil
trocytoma, namely, glioblastoma multiforme (Grade IV wi
 Chapter 152 I Centra. Nervous System Tumors In Children and Adolescents
astrocytoma), is less frequently seen in children than in
.adults.
The treatment of supratentorial astrocytoma depends '
on the histologic wading of the tumor. For 'a very low
grade astrocytoma (Grade I), surgical resection is the
treatment of choice. Radiotherapy is frequently rese~ed
for the treatment of recurrence. For the more malignant .
astrocytoma, radical surgery has been either ineffective
or fraught with excessive morbidity andlor mortality. In
fact,less than 20% of patients with glioblastoma are likely
to be suitable for radipal resection because of the extent
Of location of the tumor. Even with tUmors which grossly
appear to be resectable, it is often difficult during surgery
to differentiate the tumor edge and normal brain tissue.
. Nonetheless, laser and stereotactic technology have im
proved the armamentarium of the neurosurgeon. Inves
tigators at the Mayo Clinic are studying a sophisticated
and laborious CT-guided technique for the surgical resec
tion of high-grade astrocytomas in adult patients. Long
term follow-up of a sufficient number of patients Will be
needed to prove the benefit of this procedure. Currently
the established role. of surgery is in biopsy of the tumor
for histologic diagnosis, resection (partial or total) of the
tumor bulk where feasible, and decompression of the ven
tricles to reduce the intracranial pressure when necessary.
FOf selected patients there is a suggestion of a survival
benefit after reoperation following initial surgery, radio
therapy (teletherapy and/or brachytherapy), and chemo
therapy.
Radiotherapy of 5000-6000 cGy can improve the sur
vival of some patients with malignant astrocytomas. Stage
L-
and Stein reported 5-year survival rates of 40% and 15%
for Grades II and m astrocytomas, respectively, after sur
gery and irradiation. Sheline, after reviewing data from
the University of California, San Francisco, and selected
data from the literature, concluded that the 5-year sur
vival rate for Grade III astrocytoma is near zero without
radiotherapy but about 20% with radiotherapy. The effi
cacy Qf radiotherapy in glioblastoma multiforme is far less
impressive. Survival may be prolonged in a few patients,
but the cure rate is excea~ingly low. Children with glio
blastoma appear to fare 'better than adults, with reported
5-year survival figures up'to 25% after conventional ra
diotherapy. In a Stant'ord series of children with astrocy
toma followed up to 14 years from diagnosis, 38% of children
with cerebral astrocytoma (of all histologic grades) were
long-term survivors, although all the patients with glio
blastoma ultimately died of their disease (Figure 152.1).
The survival benefit of radiotherapy for glioblastoma seems
to be limited to the first 2 years following presentation,
at least in adults. Ninety percent of glioblastomas recur
within a 2 cm margin of the primary site after radiation
done up to 6000 cGy, suggesting that recurrent radiation
doses are inadequate to eradicate the primary tumor. Higher
radiation doses may improve tumor control but ate likely
to produce severe side effects, such as brain necrosis. A
controversy exists as to whether whole brain irradiation
with a boost to the tumor volume or more localized irra
diation to the tumor site or margin is needed in patients
with high-grade astrocytomas. In the Stanford series, a
1579
~ 100
..J
t eo
aJ
~ ~o
38%
~ 40 I
w I
........ Cerebellum
(.)
Thalamus a Hypolho!omus
ffi'
Il..
20
. _.-
-
._._.
Cerebrum
Spinal Cord
--- Brolnstem
2 4 6 8 10 12 14 16
YARS
Figure 152.1. Survival as a function of site of primary tumor in
children with astrocytoma. (Reproduced with permission from
Woo SY, Donaldson SS, Cox RS: Astrocytoma in children-14
years' experience at Stanford University Medical Center. J Clin
Onco/6:1001-1007.1988.)
definite benefit for whole brain irradiation could not be
demonstrated in children. Patients at the University of
California, San Francisco treated by Hmited fi@lds also had
median survival similar to that of children treated to the
whole brain in the Brain Tumor Study Group studies. Thus,
in children who have had clear delineation of the tumor
by modem high-quality imaging techniques, it seems rea
sonable to limit the volume ofirradiation to the brain in
order to reduce long-term toxicity.
Several approaches to improve the efficacy of radio
therapy have been studied. Fast neutrons have been shown
to sterilize malignant brain tumors, but the toxicity to
surrounding normal brain has been devastating. The role
of helium ions, neon ion, and pions is still being explored.
Electron affinic sensitizers, such as misonidazole, and hal
ogenated pyrimidine;; have been studied in adults with
high-grade gliomas, but their use in children has been very
limited. Interstitial brachytherapy with high-activityP25
has been evaluated at the University of California, San
Francisco, in a few children with recurrent astrocytoma.
Although responses could .be demonstrated, the definitive
role of brachytherapy in the primary treatment of malig
nant astrocytoma in children is still unknown. Interstitial
hyperthermia has not been studied in children. Hyper
fractionated radiotherapy has been studied in adults,
showing some promise. The experience with hyperfrac
tionated radiotherapy in children is very limited. Inves
tigators in Alberta, Canada, have treated six children either
with 3500-4000 cGy in 45 fractions in 3 weeks plus a boost
of 1400 cGy in 10 fractions in 2 weeks, or with 6000 cGy.
in 75 fractions over 5 weeks. They have not encountered
excessive toxicities, and four children were alive from less
than 2 years to 4 years from diagnosis. It therefore seems
reasonable to further explore the role ofhyperfractionated
high-dose radiotherapy. ,~.
Recurrent malignant astrocytomas have shown re
sponse to a number of chemotherapeutic agents such as
BCNU, CCNU, procarbazine, vincristine, cytosine arabi
 1580 Section 0 I Childhood Cancer
noside, dimethyl-tri-azenoimidazole, carboxamide, meth
.~
'otrexate, epipodophyllotoxin cis-platinum, and aziridinyl
\
,
benzoquinone (AZQ). The Brain Tumor Study Group have
performed several randomized studies to test the efficacy
of adjuvant chemotherapy. Thus far, it appears that BCND
may l;lenefit a subset' of patients, as evidenced by a sig
I
nificantly higher 18-month survival rate in patients who
received radiation and BCND than patients who did not
receive BCND. The CCSG also reported a prelimiDary study
demonstrating a disease-free survival benefit using ad
juvant chemotherapy with vincristine, CCNU, and pred
nisone in children with astrocytoma. In the CCSG series,
children with glioblastoma who received radiation and
chemotherapy had a 5-year disease-free survival rate of
42% compared with a 6% disease-free survival in children
who received radiotherapy only. CCSG is currently inves
tigating the role of "eight-in-one" chemotherapy in chil
dren with high-grade astrocytoma. The potential usefulness
of interferon, interleukin-2Ilymphokine-activated killer
cells, and 125I-Iabeled monoclonal antibody to epidermal
growth factor receptor is being studied in adults.
In adult patients, several prognostic factors have been
reported. These factors include patient age, histologic grade,
presence of giant cells, extent of surgical removal, per
formance status at diagnosis, duration of symptoms, his
tory of seizures, and presence or absence of rapid ancon
sciousness, speech disorder, and motor symptoms. In
children, age and sex are not significant prognostic factors.
The impact of performance status and neurologic symp
toms has not been systematically evaluated. Jenkin has
shown, no difference in survival among children with ce
rebral hemisphere astrocytomas arising in different sites.
The most important prognostic factor in children with as
trocytoma who have long-term follow-up, current therapy
is inadequate for more than half of the children with as
trocytoma. Continued efforts in designing innovative clin
ical trials using multimodality therapy are needed. Areas
of research include brachytherapy, new radiation sensi
tizers, high-dose hyperfractionated radiotherapy'_ f$.ereo
tactic radiotherapy, intra-arterial che'tnotherapy,
hyperthermia, and biologic response modifiers. In addi
tion, it has become apparent that the disease and its treat
ment can have significant impact on the physical,
intellectual. psychologic, and endocrine function of chil
dren, and further long-term studies in those areas should
be conducted.
PINEAL TUMORS
A variety oftumors can occur at the pineal region. These
tumors include tumors arising from pineal parenchyma
(pineoblastoma and pineocytoma), germ cell tumors such
as germinoma, choriocarcinoma, endodermal sinus tumor,
teratoma, and tumors from the surrounding tissue (glioma, .
ganglioneuroma, meningioma, and hemangiopericytoma).
In children germinoma and pineoblastoma are the most
common pineal tumors encountered. Pineoblastoma has
been reported to be associated with bilateral retinoblas
toma-the so-called trilateral retinoblastoma.
Surgical excision of pineal tumors has generally been
difficult and associated with significant morbidity and
mortality. In the past, most pineal tumors were not biop
sied and treated with radiotherapy only. With improve
ment in stereotactic techniques, neurosurgeons are more
willing to perform biopsy especially if the pathology in
fluences the radiotherapy technique. On the other hand,
there have been reports of increased incidence of cerebro f
spinal fluid dissemination of pineal tumors after biopsy. t
Radiotherapy with tumor doses of 5000 cGy or higher i:
is effective. For germinoma:s, whether the entire cranio
spinal axis needs to be irradiated or not is subject to debate.
Experience in Kyoto and the University of California,
Francisco, seems to indicate a low incidence of spinal
ure even in patients whose tumors were biopsied.
tigators in these institutions do not recommend
prophylactic craniospinal irradiation unless there is
spillage at surgery, positive cerebrospinal fluid cvt:OlOJ'CV.
or documented subependymal and subarachoroid
tasis. On the other hand, ma:ny oncologists still
craniospinal irradiation as t~ 'Standard treatment.
sometimes encounters a clinical situation in which
histologic diagnosis is unknown and the cerebrospinal
cytology, tumor markers, and myelogram are negative.
frequently used clinical approach is to irradiate the pri ral
mary tumorto 2000cGy and repeat the CT or MID, scan. wii
If there has been substantial reduction in the tumor size, . is 1
the tumor is most probably a germinoma and one can
administer another 3000 cGy to the whole brain or to
craniospinal axis. If there is no response, then
is continued to the same field to a total dose of uV'JV-'VUUU;;
cGy.
Pineal germinomas and pineoblastomas have been
ported to respond to cis-platinum-containing chl~mother~
apeutic regimens, In general, patients with pIrleOltllastoIII8
fare worse than those with germinoma, and children
pineal endodermal sinus tumor have poor prognosis.
germinoma, long-term survival of 70-80% has been
ported. The role of a(ljuvant chemotherapy is cwrrerttlf
under study.
OPTIC GLIOMA
Optic gliomas are rare tumors which can affect the
nerve or optic chiasma or extend into the brain itSelf.
mlijority of tumors are slow-growing, low-grade
tomas, although low-grade glioblastomas ofthe
have been reported. There is a distinct association
glioma with neurofibromatosis. The diagnosis of
gliomas in children may precede clinical mlllnil'es!;al
of neurofibromatosis.
The natural course and therapy of optic gliomas
controversial because of the slow-growing nature of
tumor. Complete excision of the tumor is frequently
ficult, especially for tumors extending into or beyond
optic chiasma. However, incomplete excision can
times produce prolonged symptomatic improvement.
diotherapy has been reported to cause ,",V'cL'"'''-'''
improvement in patients whose tumors cannot be
pletely resected. Experience with chemotherapy in
tumor is limited.
 Chapter 152 / Central Nervous System Tumors in Children and Adolescents
CRANIOPHARYNGIOMA
Craniopharyngioma is thought to arise from a remnant
of Rathke's pouch and is located in the suprasellar region.
ltis usually a slow-growing tumor which may have a cystic
'. component and is nearly always calcifieq. Because of the
location ofthe tumorit can cause complex symptomatology
, from visual defects, endocrine dysfunction, and raised in
tracranial pressure. The tumor location has also resulted
in significant surgical morbidity following aggressive ex
cision of the tumor.
A commonly accepted treatment approach is limited sur
gery such as aspiration of "crankfllase oil" material (con
taining cholesterol crystals) from the tumor cyst followed
by radiotherapy to approximately 5000-5500 cGy. An im
aspect oBhe management of craniopharyngioma
, is the meticulous postoperative management of endocrine
problems. Although 5-year survival rates of up to 75%
been reponed for aggressive surgery, about' 40% of
patients subsequently relapsed. With limited surgery and
radiotherapy, surgical morbidity is reduced and 5-year
survival of 75~85% has been achieved in reported series.
Recurrent tumors after initial surgery can also be sue
cessfullytreated with radiotherapy. Recently stereotactic
radiosurgery has been used in a few children in Sweden
" with encouraging results. The usefufness ofchemotherapy
is unknown.
Intraspinal Tumors
Primary spinal cord tumors are rare in children. Low
, grade astrocytomas, other forms of gliomas, and ependy
momas are the usual variety seen most commonly. The
signs and liymptomlil doplilnd on the site of involvement,
Cervical and upper thoracic spinal' tumors give rise to
weakness or sensory changes of an upper limb. With tu
1Ml'S at the lumbar region involving the cauda equina,
, there is pain (rom nerve root irritation, lower limb w~ak~
ness, and bowel and bladder symptoms. Complete surgical
resection usually is not possible. When there is a cystic
component of the tumor, aspiration of the cyst can have a
significant palliative effe<\t. Radiotherapy is the preferred
treatment, and experience\with chemotherapy is limited.
Patients with spinal cord a'strocytoma may survive for a
long time despite persistence or recurrence of tumor. Re
, cunence can also be detected beyond 5 years from diag
nosis; In the Stanfprd series, a 60% long-term survival was
reported.
References
1. Finlay J, Sposto R, Evans A, Ertel I, Jenkin D, Hammond D:
Current status of the Children's Cancer Study Group (CCSG)
1581
brain tumor trials. Society ofPediatric Oncology 18th Annual
Meeting Abstracts 36, 1986. '
2. Freeman Cll, Krischer J, Sanford RA, Burger PC, Cohen M.
Norris D: Hyperfractionated radiotherapy in brain stem tu
mors: results of a Pediatric Oncology Group Stud,y.lnt J Ra
diat Oncol Bioi Phys 15:3U-318, 1988.
3. Harasiadis L, Chang CH: Medulloblastoma in children: a cor
relation between stagi.ni and results of treatment. Int J Ra
diat Omol BioI Phys 2:833-841, 19'7'7.
4. James CD, Caribom E, Dwnanski J, Hansen MF, Norden
slrjold M, CoUina vp. Cavenee WK: Gimomic alterations in
glioma malignancy stages. Presented at the meeting of the
American Association ,oecancer Reaearch, New Orleans, 1988.
5. Li FP, Winston n, Gimbrere K: Follow-up of children with
brain tumors. Cancer 64:135-J38, 1984. ,
G. Unatadt D, Ward WM, Edwards EBB, Hudgina Rd, Sheline
GE: Radiotherapy of primary intracranial gertninomas: the
case against routine cranioSpinal irradiation. rnt J Radiat
Oncol BioI Phys 15:291-297. 1988.
7. Maor MII, Fields RS, Hogstrom KR, van Eys J: Improving
the therapeutic ratio of craniospinal irradiation in medullO
blastoma.lnt J Rq.diat OncolBiol Phys 11:687-697, 1985.
8. Marks JE, Adler SJ: A comparative study of ependymomas
by site of origin.lnt J Radiat Oncol Bial Phys 8:37-43, 1982.
9. Packer RJ, Sutton LN, Rorke LB, Littman.PA, Sposto R,
Rose~JG, Bruce DA, Schut L: Prognostic importance of
ceiktlar differentiation in medulloblastoma of children. J
NeutosU1'g 61:296-301, 1984.
10. Phuphanich S, Edwards MS, Leven VA, VestiJ.ys PS, Ward
WM, Davis RL, Wilson CB: Supratentorial malignant gliomas
of childhood. Results of treatment with radiation therapy and
chemotherapy. J Neurosurg'60:495-499, 1984.
11. Hochberg FH, Pruitt A: Assumptions in the radiotherapy of
glioblastoma. Neurology 30:907-911,1980.
12. Sheline GE: The importance of distinguishing tumor grade
in malignant gliomas: treatment and prognosis.lnt J Radiat
Oncol Bioi Phys 1:781-786. 1976. ,
13. Walker MD, Alexander E Jr, Hunt WE, et al: Evaluation of
BCNU and/or radiotherapy in the treatment of neoplaatic
gliomas: QOOllUl'lltivlI CUniGAI trilll, J NllurfJ8urg 49i888",343 1
1978.
14. Woo SY, McCullough 0, Sinks LF: Primary therapy of med
, ulloblaatoma with ilu,fgery. radiation and methotrexate and
BCNtJ-A pilot study. In Walker MD, Thomas DOT (eils):
Biolqgy of Brain Tumor. Boston, Martil'lUs N'ijhoff, 1986,
pp 429-432.
15. Woo SY, Donaldson SS, Cox RS: Astrocytoma in children
14 years' experience at Stanford University Medical Center.
J Clin OncoI6:1001-1007, 1988.
Selected Readings
AlIen JC, BloomJ, Ertel I, Evans A, Hammond D, Jones H, Levin
V, Jenkin D, Spo$to R, Wara W: Brain tumors in children:
Current cooperative and institution chemotherapy trials in newly
diagnosed and recurrent disease. Semin Oncol13: 110-122, 1986
Review of many of the Children's Cancer Study Group and
Memorial Sloan-Kettering brain tumor trials.
Cohen ME, Duffner PK: Brain Tumors in Children-Principle$
ofDiagnosis and Treatment. New York, Raven, 1984-An ex
cellent overall review of pediatric neuro-oncology.
Mealey J, Hall PV: Medulloblastoma in children. J Neurosurg
46:56, 1977-One of the classic papers in medulloblastoma.
 LOCALlSEO NEUROLOGICAL DISEASE AND ITS MANAGEMENT B. SPINAL CORD AND flOOTS

SPINAL ;CORD AND ROOTS

Disorders localised to the spinal cord or nerve roots are detailed below, but. note that many
diffuse neurological disease processes also affect the cord (see Section V, e.g. multiple
sclerosis, Friedreich's ataxia).
SPINAL CORD AND ROOT COMPRESSION
As the spinal canal is a rigidly enclosed cavity, an expanding disease process will eventually
cause cord and/or root compression.
Causes dural
TUMOURS ____ pruna
.
ry :::~extraintradural (extramedullary)
secondary .........Intramedu 11ary.

INFECTION ____ acute,. e.g.

staphylococcal_ extradural
chromc - TB . - intradural
DISC DISEASE AND SPONDYLOSIS

AVM } extradural
HAEMATOMA ( spontaneous' ( intradural
trauma intramedullary
extradural
CYSTIC LESIONS / ' intradural - arachnoidal
"- intramedullary - syringomyelia
Manifestations of cord or root compression depend upon the following:

Site of lesion within the spinal canab Interruption of

an expanding lesion outside the cord produces descending motor
signs and symptoms from root and segmental tracts
damage.
ROOT lower motor neuron (l.m.n.) and
sensory impairment appropriate to the
distribution of the damaged root.
SB(;MENTAL _ l.m.n. and sensory
I. impairment appropriate
t to segmental level.
Interruption of ascending sensory and
descending motor tracts produces sensory
impairment and an upper motor neuron
(u.m.ri.) deficit below the level of the lesion.
Lesions withiJ;l. the cord (intramedullary)
produc:e only segmental signs and symptoms.

376
 LOCALISED NEUROLOGICAL DISEASE AND ITS MANAGEMENT B. SPINALCORb.A:Nl:':ff6~fS

SPINAL CORD AND ROOT COMPRESS-roil .

Level of the lesion: a lesion above the Ll . Intervertebral

vertebral body may damage both the cord foramina
and its roois. Below this, only roots are
damaged.
Cervical
segments
Vascular involvement: whether neuronal
damage results from mechanical Inretching or
is secondary to arterial ischaemia or venous
obstruction remains uncertain. On occasions,
clinical findings indicate cord damage well Thoracic
beyond the level of the compressive lesion; segments
this implies a distant ischaemic effect due to Thoracic
blood vessel compression at the lesion site. roots
1-12
Speed of onset: speed of compression Lumbar
affects the clinical pictUre. Despite segments
producib.g upper motor neuron damage, a Sacral
rapidly progressive cord lesion often segments
produces a 'flaccid paralysis' with. loss of
reflexes and absent plantar responses. This
state is akin to 'spinal shock' seen following
trauma. Several days or weeks may elapse
before tone returns accompanied by the (After BING A.
expected 'upper motor neuron' signs. Local Diagnosis
in Neurological
Disease 15 00.)
Coccygeal root

Clinical features
These depend on the site and level of the compressive lesion.

____ - ROOT severe, sharp, shooting, burning pain radiating into

PAIN
,/ the cutaneous distribution or muscle group supplied by the
root; aggravated by movement, straining or coughing.

_--=.---.:----- SEGMENTAL - continuous, deep aching pain radiating into

whole leg or one half of body; not affected by movement.

... "
continuous, dull pain and tenderness over the
.......... BoNE-
affected area; mayor may not be aggravated by movement.
LOCALlSED'N"EtJROLOGICALDISEASE AND ITS MANAGEMENT-B. SPINAL CORD AND ROOTS

SPt)\JAL'COR'D AND ROOT 'COIVIPRESSION

NEUROLOGICAL EFFECTS

LATERAL COMPRESSIVE LESION Root/segmental damage

MUSCLE WEAKNESS in groups supplied by the
Corticospina I Dorsal columns - gracile
and cuneate nuclei '
involved root and segment with LOWER MOTOR
tract
'NEURON (l.m.n.) signs: - wasting; - loss of tone;
- fasciculation; - diminished or absent reflexes.
N.B. motor deficit is seldom detected with root
lesions above CS and from T~ to Ll.
SENSORY DEFECT of all modalities or
hyperaesthesia in area supplied by the root, but
overlap from adjacent roots may prevent
detection. '
Lateral spinothalamic Long tract signs and symptoms
tract Partial (Unilateral) cord lesion (Brown
Sequard syndrome)
BROWN MOTOR DEFICIT - dragging of the leg: In high
SEQUARD cervical lesions weakness of fmger movements
SYNDROME is noted on the side of the lesion.
Ipsilateral
UPPER MOTOR NEURON (u.m.n.) signs
root/segmental
signs (maximal on side of lesion):
weakness .in a 'pyramidal' distribution, i.e.
arms extensors predominantly affected;
legs - flexors predominantly affected.
increased tone, clonus; - increased reflexes;
extensor;. plantar response.
SENSORY DEFICIT numbness may occur on the
same side-as the lesion and a burning
Ipsilateral
dysaesthesia on the opposite side.
pyramidal
,/ weakness joint position sense and accurate touch
and localisation (two point discrimination)
impaired impaired on side of lesion.
Contral~teral joint position pinprick and temperature sensation impaired
impairment sense and on opposite side.
of pain and, accurate touch
'temperature localisation
sensation

In practice., cord damage is seldom restricted to one side. Usually a mixed picture occurs, with
anasymfnetric distribution of signs arid symptoms.
nairiage to sympathetic pathways in the T1 root or cervical cord causes an ipsilateral
Horner's syndrome (page 141).
BLADDER symptoms are infrequent and only occur when cord dainage is bilateral.
378 Precipitancy or difficulty in starting micturition may precede .retention.
 LOCALISED NEUROLOGICAL DISEASE AND ITS MANAGEMENT B. SPINAL CORD AND ROOTS

SPINAL-CORD AND ROOT COMPRESSION;.;;.

NEUROLOGICAL EFFECTS

LATERAL COMPRESSIVE LESION (contd)

Long tract damage complete cord lesion
MOTOR DEFICIT: the speed of cord cOInpression
affects the clinical picture. Slowly growing lesions
present with difficulty in walking;
the legs may 'jump' at night. Examination
reveals u.m.n. signs often with an
asymmetric distribution. Rapidly progressive
lesions produce 'spinal shock' - the limbs are flaccid, power
and reflexes diminished or absent and plantar responses are Impairment of all
absent or extensor. sensory modalities
up to the level of
SENSORY DEFICIT: involves all modalities and occurs the lesion.
up to the level of the lesion.
BLADDER: patient first notices difficulty in initiating Power and reflexes
diminished or
micturition. Retention follows, associated with
absent
incontinence as automatic emptying occurs.
Constipation is only noticed after a few days. Some
patients develop priapism (painful erection).
CENTRAL CORD LESION

Segmental damage: A central lesion initially damages

the second sensory neuron crossing to the lateral
spinothalamic tract; pain and temperature sensations are
impaired in the distribution of the involved segment. As
the lesion expands, anterior horn cells are also involved
and a l.m.n. weakness occurs.
'CAPE' sensorY
deficit
Long tract effects: further lesion expansion damages
the spinothalamic tract and corticospinal tracts, the
most medially situated fibres being involved first. With
lesion in the cervical region, the sensory deficit to pain
and temperature extends downwards in a 'CAPE' -like
distribution. As the sacral fibres lie peripherally in the
lateral spinothalamic tract, SACRAL SPARING can occur,
even with a large lesion. Involvement of the
Sacral corticospinal tracts produces u.m.n. signs and symptoms
sparing in the limbs below the level of the lesion. The bladder
is usually involved late.
In the cervical cord, symp~thetic involvement may
produce a unilateral or bilateral Horner's syndrome.
 t.0CAl:ISEDNEUROlGGICAL DISEASE AND ITS MANAGEMENT B.SPINAL CORD AND ROOTS

SPINAL CO,R'D AND ROOT COMPRESSION
NEUROLOG'ICAL ,EFFECTS

LOWER CORD (CONUS) CAUDA EQUINA LESIONS

Root or segmental lesions may involve the upper part of the cauda equina
and produce root/segmental and long tract signs as described on the
previous page, e.g. an expanding proximal L4 root lesion causes weakness
/ and wasting of the foot dorsiflexors, sensory deficit over the inner calf, an
increased ankle jerk and an extensor plantar response. Bladder involvement
tends to occur late.
"",
The lower sacral roots are involved early,
producing loss of motor and sensory
/ bladder control with detrusor paralysis.
Overflow incontinence ensues. Impotence
and faecal incontinence may be noted. A
l.m.n. weakness is found in the muscles
supplied by the sacral roots (foot
plantarflexors and evertors), the ankle
jerks are absent or impaired and a sensory
deficit occurs over the 'saddle' area. 'Saddle' area.
VERTEBRAL COLUMN
If a spinal cord or root lesion is suspected look for:
- Scoliosis,
. . . loss of lordosis
. or . . ~ - su ests root lrntatlOn
. . .
itmJtatJon of strazght leg ramng gg
Paravertebral swelling . . .' .
'T' d b ' - suggests mahgnant disease or infectIOn
- .I. en erness on one percusSIOn
- Restricted spinal mobility - suggests bone, disc or root involvement
Sacral dimple or tuft of hair - suggests spina bifida occulta/dermoid.

SPINAL CORDAND ROOT COMPRESSION ~.,

INVESTIGATIONS
STRAIGHT X-RAY On the ANTERO-POSTERIOR views look for:
Pedicle erosion } - suggests malignant
.J "...'" i with or without a extradural tumour
~;;;::::==f',ItI:::;;~ I paraspinal mass
v '
,,/ -:?.. O-O~c:--
.
I'
;;::t~Ib::'-_'" Thinning
of the
pedicle and - suggests
longstanding
intradural!
intramedullary
expansion.

380
 LOCALISED NEUROLOGICAL DISEASE AND rtsMANAGEMENT B, SPINAL CORD AND ROOTS

SPINAL CORD AND ROOT COMPRESSlON',

INVESTIGATIONS

STRAIGHTX-~Y (contd) ~
On the LATERAL vtew , ~~ _ ~ 'Scalloping' of the
a<---P"
L-J:J'~/. Collapse of the vertebral
"body suggests
~ posterior surface of the
..J " "'\.. vertebral ?od~ indicates a

tJ malignant infiltratt,'on
G ,':--0
,,\. lo~standing Intradural

SJ
~>}~, ~ /
/ or osteoporosis
(If the disc. spac~ is
~
) ~
les19n

Q ~ u:
FtlOyed, mrecnon
IS more likely)
'
"_Narrow disc spa.ce, narrow
-~-canal and hypertrophic
W-facet joints ,support a

~ ClX'
I r ~ diagnosis of disc disease

O I

...

~ .I..

-
i ..... -
~'
- ' Expansion of
the intervertebral
or lumbar spinal stenosis
(but not diagnostic)

it! foramina suggests neurofibroma

On OBUQUE views G '->'-- ,

..... ' Narrowing from osteophytic encroachment
'. indicates possible root compression

~~
(but often seen in asymptomatic elderly patients)

MRI
This is now the investigation of choice for spinal
disease, whether this lies within or outwith the dura
or the spinal cord. Clinical examination and straight .
X-rays may suggest the level of the lesion and guide
the level of examination. If this fails to detect a
lesion, then further imaging must cover the whole
length of the cord since occasionally the site of
compression lies many segments higher than the
clinical signs indicate. The examination must involve
both Tl and T2 weighted images, the former often
repeated with gadolinium enhancement. Sagittal or
coronal views are of value in outlining a section of the
spinal cord or the cervical medullary junction. On
displaying an abnormality ata particular site, axial
views at selected levels may provide additional Coronal T2 weighted
information, MRI differentiates a syrinx (page 387) MRI showing an in
or a cystic swelling within the spinal cord from a tradural, extramedullary
solid intramedullary tumour (page 386). , lesion (ependymoma)
LOCALLSED~EUROLQGJCALDISEAS.E..ANDIJS MANAGEMENTS. SPINAL CORD AND ROOTS

SPI,NAt;CORDAND ROOT COMPRESSION

INVESTIGATIONS

MYELOGRAPHY
If MRI is unavailable, myelography is used to screen the spinal cord and the cauda equina. TIris will identify the
level of a compressive lesion and indicate its probable site i.e. intradural, extradural.
Extradural Intradural
PARTIAL i COMPLETE EXTRAMEDULLARY INTRAMEDULLARY
BLOCK I BLOCK BLOCK BLOCK
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
Dura lifted off 'Ragged' edge to I Cord displaced
I
vertebral body contrast material I to one side
I Contrast material is
at site of block 'Shoulder' of . splayed around the
contrast material dilated cord
Even with an apparent 'complete' block, sufficient contrast medium may be 'coaxed' beyond the lesion to
determine its upper extent. If not, a cervical puncture may be necessary.
Radio~opaque markers on the skin surface at the site of the block are a useful operative guide.
Lesions in the lumbar and sacral regions require a 'radiculogram', outlining the lumbosacral roots.

CT SCAN/CT MYELOGRAPHY
It is impractical to use this as a screening investigation for cord compression, but if the level of interest is known,
CT scanning provides useful additional information.
Plain CT with,axial cuts will clearly demonstrate bone
Vertebral body eroded by tumour erosion, osteophytic outgrowth and thickened facet joints
causing narrowing of the spinal canal or intel'1/"ertebral
foramen. Axial cuts will also demonstrate disc disease of the
lumbosacral spine, show the relationship of any paraspinal
mass to the vertebral body and intervertebral foramen and
Displaced identify the extraspinal extent of an intraspinal lesion, e.g.
thecal sac neurofibroma.
'containing CT m:Jlelography with axial cuts (CT performed either 6-12
hours after !pUrine myelography or immediately after
contrast intrathecal injection of just a few mls of contrast)
medium demonstrates clearly the degree of spinal cord or nerve root
compression.

If cord compression is suspect then lumbar puncture and CSF

, " " ", " in cord analysis should await imaging.
compression. Abnonnalities frequently CSF protein: often increased, especially below a complete
occur, bUt lumbarpuriciUre.may block. '
precipitate neurological deterioration, CSF ~1l count: a marked leucocyte count suggests an
presUIIlably due to the; creation "of a infective cause" abscess or tuberculosis.
382 preSS1)re gradient. CSF cytology may reveal tumour cells
 LOCALISED NEUROLOGICAL ,DISEASE AND ITS MANAGEMENT B. SPINAb..-GOR~ANi:)ROQ:rS.

SPINAL CORD AND ROOT COMPRESSION

TUMOURS
Incidence: The table shows the number of patients with histologically confirmed tumours
admitted to the Institute of Neurological Sciences, Glasgow, over a 5-year period
(population 2.7 millions). Tumour types differ in adults and children and are considered
separately.
Adults Children
:J;XTRADURAL (78cro) EXTRADURAL (18%)
Metastasis 118 Metastasis 1
Myeloma 19 Lymphoma 1
Neurofibroma 15
Lymphoma 14
Others 7
INTRADURAL (18%) INTRADURAL (64%)
Meningioma 22, I>ernnoid/epidernnoid 6
Schwannoma 13 Others 1 (Table adapted
Others 4 from Adams.
INTRAMEDULLARY (4ht) INTRAMEDULLARY (18cro) Graham and
Doyle: Brain
Astrocytoma 8 Astrocytoma 2 Biopsy, 1982)
Others . 1
Pathology: .The pathological features of spinal tumours match those of their intracranial
counterparts (see page 294);
METASTATIC TUMOUR
Occurs in 5 % of all cancer patients and accounts for 50% of adult acute myelopathies.
Primary site: Usually breast, lung, prostate or kidney.
Metastatic site: Thoracic vertebrae most often involved, but metastasis may occur at 'any
site and may be multiple.
Clinical features: Bone pain and tenderness are common features usually preceding limb
and autonomic dysfunction. .
Investigations: Plain radiology may be diagnostic as osteolytic lesions or vertebral
collapse are preseQ.t in most cases. MRI or myelography will identify extradural
compression and help exclude or confirm multiple level disease.
Management . '
In the previous decade, numerous patients with spinal cord compression were subjected
to a <decompressive' laminectomy followed by radiotherapy. Since metastatic tumour
usually involves the vertebral body and pedicles, removal of the spinous processes and the
lamina served only to increase instability. Not surprisingly results were extremely poor;
Most now feel that radiotherapy is the appropriate initial treatment, once the diagnosis is
established, unless known radioresistance or a rapidly deteriorating neurological condition
enforces the need for surgt.'cal decompression, Major operative procedures are inappropriate
in the elderly, in patients with paraplegia of > 6-12 hours duration, and inpatients with a,
diBnlaI prognosis fromtheir primary tumour (e.g. small cell bronchial carcinoma). In such
patients, if medication fails to control pain, a palliative course of radiotherapy may help~ .
, Aims of To establish a diagnosis if not already known '. ., '
sur~cal ~ To decompress ~~s~~ cor~. yetmaint:ain sta.bility ,of vertebral column ,
t~eatment .. To produce stabIhty If mstabilitycauses exceSSIve pam .. .
 lOCAUSEDNEUROLOGICAL DISEASE AND rrs MANAGEMENT B. SF'INAL CORD AND ROOTS

SPINAL CORD AND ROOT COMPRESSION

Techniques

Biopsy - needle biopsy of a paraspinous mass or

POSTBROLAn!RAL AJ'PROACH
trochar biopsy of infiltrated bone (costo-transversectomy):
/ Several ribs are
Surgical
decompression
/IV resected along
with the transverse
FOR TUMOUR INVOLVING THE processes.
V1!RTBBRAL BODY OR THE
PEDICLB-
Collapsed vertebral
ANTERIOR TRANsTHORACIC body removed
/
DBOOMPImssxON: Provides excellent /
/
exposure of the vertebral bodies, but /
/
requires the more e.xteusive procedure of
a thoracotomy; Usually reserved for
patients with the best outcome e.g. -
breast carcinoma.
Acrylic block
POR TUMOUR LYING POSTERIOR ins~dand
TO THE CORD OR ONLY INVOLVING'THE secured with k
LAMINA AND SPINOUS PROCIlSSBS wires or with a
metal plate
\
\
\
LAMlNBCTOMY: Removal of
the lamina and spinal processes.
SUGGESTED SCHEME

OF MANAGEMENT

~UlANT ~ N~ known NBlIDLB BIOPSY of IRADI01'HllRAPi .,

~TIENTS . . prunary Iinfiltrated
paraspinal mass
bone
or /. I
I
Known primary ---~======~-" further'deterioration
I

]- '~=~e~=~:':bral _.. ----- --1 I

~
d;,e:!:~o~
NON-AMBUlANT
PATIENTS
and duration of. body not involved) I
limb weakness
and prognosis of
~~~~~;):::;;:;::::;::::;-_ _ _~ISRADFI=OTHE=:;::RAPY=":'....JI...JII
l=NBlIDLE BIOPSY
primary tumour - I NO FURTHER TREATMENT I- - - - - - - - -
Prognosis:,Outcome depends on the nature of the primary tumour. Mean survival after surgery and radiotherapy
ranges from 6 months for lung carcinoma to 45 months for prostatic and thyroid carcinoma.

MYELOMA
This m.ai.ignant condition usually affects older age groups. It is often muitifocal, involving the vertebral bodies,
pelvis,-ribs and skull, but solitary tumours may occur ('plasmacytoma'). Spinal cord compression occurs in 15% of
patients With myeloma and rarely without vertebral body involvetl"ent due to intradural deposits. If suspect, look
for characteristic changes in the plasma immunoglobulins and for Bence-Jones-protein in the urine. An isotope
bone scan may be less informative than a radiological skeletal survey. Bone marrow shows infiltration of plasma
cells. Serum calcium levels may be high.
Management is as for metastatic tumour with additional chemotherapy. The prognosis is variable but patients
384 may survive many years with.a solitary plasmacytoma.
 LOCALISED NEU ROLOG ICALDISEASE AND .ITSMANAGEMENTB.:SP1NAU:OaCiAc~bROOTS
. . , -:,'"
,,- .. -",

"--." ""~' "<:..:;>.

SPINAL CORD AND ROOTCOMP,R~SSrON

MENINGIOMA
Spinal meningiQmas tend to occur in elderly patients
and are more common in females than in males. They
usually arise in the thoracic region and are almost
always intradural. Slow growth often permits
considerable cord flattening to occur before symptoms
become evident. MRI or CT myelography will identity
the lesion.
The operative aim is complete removal. Results are
usually good, but if the tumour arises anteriox:ly to ,the
cord, excision- of the dural origin is difficult, if not
impossible, and recurrence may result.
SCHWANNOMA/NEUROFmROMA
.Schwannomas are slowly growi:ri.g benign tumours Nerve root
occurring at any level and arising from the posterior entering
nerve roots. They lie either entirely within the spinal tumour ~.",_r. _
canal or 'dumbbell' through the intervertebral
fQramen, on occasions presenting as a mass in the
thorax or posterior abdominal wall.
Neurofibromas are identical apart from their
microscol.'ic app~ce (page 295) and their
association with multiple neurofibromatosis CVon
Recklinghausen~s disease NFI - see page 540) - look
for cafe au lait patches in the skin.
Schwannomas tend to occur in the 30-60 age group.
Typically they present with root pain. Root signs andl Neurofibroma 'dumbbelling'
or signs of cord cotnpression may follow. through intervertebral foramen
MRI or CT-myelography identifies an intradural/
extramedullary lesion. Oblique X-rays may show
fOraminal enlargement; eT scan will delineate any
extraspinal extension (see page 382). Complete
operative remqval is feasible but the nerve root of
origin is inevitably sacrificed. Overlap from adjacent
nerve roots usually minimises any resultant
neurological deficit.
b.OCAblSED NE-UROLOGICAL DISEASE AND ITS MANAGEMENT B. SPINAl.: CORD AND ROOTS

SPINAL CORD AND ROOT COMPRESSION

INTRAMEDULLARY TUMOURS
Intrinsic tumours of the spinal cord occur infrequendy. In the Glasgow series (Table, page 383) almost'aIl were
slowly growing astrocytomas (grades I and II) although other series repon an equal incidence of ependymomas.
Cystic cavities may lie within the tumour or at the upper or lower pole. Benign lesions include
haemangioblastoma, lipoma, epidennoid, tuberculoma and cavernous angioma.
Clinical features
The onset is usually gradual. Segmental pain is common. hlterruption of the decussating fibres of the lateral
spinothalamic tract causes loss of pain and temperature sensation at the level of the involved segments.
Tumour expansion and involvement of the anterior hom cells produces a
lower motor neuron weakness of the corresponding muscle groups;
conicospinal track involvement produces an upper motor neuron weakness
below the level of the lesion. The sensory deficit spreads downwards'
bilaterally, the sacral region being the last to become involved. '

Investigations

Straight X-rays occasionally show widening of the

interpediculat distance or 'scalloping' of the vertebral

TI weighted
bodies. Myelography confirms the.presence of an sagittalMRI
intramedullary lesion, but MRI provides most
showing
infonnation, differentiating tumour from
syringomyelia, and identifying the extent of the
intramedullary
lesion and the presence of any associated cysts.
lesion

Management

When an intrinsic cord tumour is suspected, an exploratory laminectomy is required. An attempt is made to

obtain a diagnosis either through a longitudinal midline cord incision or by needle biopsy. Cystic cavities within a

tumour or an associated syringomyelia may benefit from aspiration. With some ependymomas and benign lesions,

a plane of cleavage is evident and partial or even total removal is possible. Attempted removal of low.. grade

astrocytomas carries less encouraging results and operation is contraindicated in malignant tumours. After tumour

biopsy or removal, radiotherapy is often administered, but its value is unc\!nain.

EPENDYMOMA OF THE CAUDA EQUINA

Over 50% of spinal ependymomas o.ccur around the cauda equina and present with a central cauda equina

SPINAL CYSTIC LESIONS

Ente~genons cysts: cy~ts with a

mUCOid content are occaSionally found \,
0 ::

CJ'
:s--
syndrome (page 380). Operative removal combined with radiotherapy usually gives good long-term results,

although metastatic seeding occasionally occurs through the CSF.

, u:;;
. ;.: '. -
!i. :! i:
-
Intramedullary cystic lesion:
syringomyelia (see over) or cystic
cavitation within a glioma.

lying ventral0: dorsal. to the cord. They '\ '\

are often aSSOCIated With vertebral
i:::
,,-.-::1
-~ :::'::: Ara~oid cysts: ara~oid POUch..es
filled With contrast medium are
malfonna~on or other congenital , \., ~ occasionally found incidentally dUring. '
abnormality, and are thought to anse :,i:; myelography. These may seal off,
from remnants of the neuroenteric 'i', producing CSF filled cysts. They occur
canal. 1~ predominaotly'in the thoracic region
}~ and sometimes cause cord compression.
Children with extradural arachnoid
Epidermoid/dermoid cysts: may be _ - - - - - - cysts frequently develop kyphosis; the
of developmental origin or may follow causal relationship remains unknown. In
implantation from a preceding lumbar aokylosing spondylitis lumbosacral cysts
386 puncture procedure, produc!! a cauda equina syndrome.
 CHAPTER 152
I '

Tumors of the Central Nervous System in

Children and Adolescents ' '
SHIAO Y. WOO, M.D., AND LUCIUS F. SINKS, M.D.

EPIDEMIOLOGY fusion over nomenclature and controversy over histologic

Primary tumors of the central nervous system are the
most commonly seen solid tumors in children andadoles
cents and the second most common malignancy in this age
group, second only to leukemia. The incidence in the age
group of 0-14 years is 6.5/1QO,OOO. The median age for
infratentorial tumors varies from 3 to 8 years depending
grading of certain types of tumors. One classification is
shown in Table 152.1. For astrocytomas the degree of ma
lignancy has been graded by several different systems; ,
Glioblastoma multiforme is the highest grade or most ma
lignant form. Grading ofmalignancy has also been applied
to ependymomas and medullolJ1astomas.
\

on the tumor type, and the median age for supratentorial The tumor types most commonly seen in children and
tumors varies from 9 to 17 years. Thus, infratentorial tu adolescents include cerebellar astrocytoma, medulloblas
toma, brain stem glioma, ependymoma, cerebral hemi o
mors are more common in children' under 10 years of age, o
and supratentorial tumors become increasingly more com spheric astrocytoma, craniopharyngioma, and optic glioma.
a
mon in adolescents. In general, there is a preponderance
ofmales over females. Whites exceed nonwhites for deaths d
PATHOGENESIS'
frqm medulloblastoma and ependymoma; the reverse is P
true for glioma. Metastatic brain tumors are uncommon There are very exciting developments currently taking ju
in this age group. place which relate molecular genetic studies to the con rE
ventiomil neuropathologic classification. Preliminary work
ri
ETlOLOGY has been recently reported identifying the stage of maIig- ' gf
nancy of glioblastomas to specific genotypic changes. There "

The etiology for the majority of tumors of the central ta

will undoubtedly be much more work in this area which

nervous system is unknown. nE

Basal cell nevus syndrome, a genetic disorder, is asso has the potential benefit of selecting specific genotypic'

or

ciated with an increased risk of medulloblastoma. Hered subtypes of tumors which conceivably will allow more spe at:
itary factors also play a role in brain tumors associated cific therapy to be devel6ped.
with neurofibromatosis, tuberous sclerosis, von Hippel
Landau's disease, and retinoblastomas. Li and Fraumeni Table 152.1.
have described several families in which differenf'"mem Classification of primary brain tumors aw
bers developed soft tissue ~arcoma, brain tumor, breast dif
cancer, and osteosarcoma. Supratentorial
Cerebral hemisphere
bra
Embryonic maldevelopment can result in certain tu cuI
Astrocytoma (including glioblastoma multiforme)
mors, such as epidermoids, dermoids, teratomas, and cra Ependymoma ton
niopharyngiomas. Oligodendroglioma pse
Although viruses and carcinogens can clearly induce Spongioblastoma
brain tumors in animals, their role in the tumorigenesis Choroid plexus papilloma
in the central nervous system of humans is not established. Teratoma 8
There is, however, some evidence to support that ionizing Pinealoma cam
radiation to the head may be ,etiologically associated with Sella/chiasma craI
the development of brain tumors, as evidenced from an Craniopharyngioma post
increased incidence of brain tumors in children who re Pituitary adenoma ings
Optic glioma , calc
ceive radiation to the scalp for tinea capitis.
Infratentorial
The predilection of certain tumor types to specific sites Brain stem

gion
in the central nervous system suggests local vulnerability' Glioma/astrocytoma (including glioblastoma multilorme)

in areas of nervous tissue which may not be morphologi Ependymoma

cally recognizable. Teratoma

Cerebellum

PATHOLOGIC CLASSIFICATION Medulloblastoma

Astrocytoma

There is no general agreement on the precise pathologic

Spongioblastoma

classification of primary brain tumors. There is also con~

1574
 Chapter 1521 Central Nervous System Tumors in Children and Adolescents
CLINICAL SIGNS AND SYMPTOMS
The clinical manifestations of brain tumors are related
to increased intracranial pressure and to the location of
the turnor. '
Elevation of intracranial pressure is the result of cere
bral edema, hydrocephalus from obstruction of cerebro
spinal fluid flow or, less frequently, of the volume of the
tumor itself. Headache is a common' symptom and char
acteristically occurs in the morning and is accompanied.
and often relieved. by vomiting. Headache is a less com
mon complaint in young children compared to older chil
dren and adolescents. The child may instead preeent with
irritability, malaise, somnolence, and even changes' in per
sonality. Cranial enlargement can occur in infants in whom
s?turea have not yet fused. 'Papilledema is a clear
sign ofincreased intracranial pressure; a sixth nerve palsy
can also occur, giving rise to diplopia. Occasionally a sud
',' den increllSe in intracranial pressure can cause impending
herniation and present as an emergency with coma and
. changes in vital signs and various neurologic deficits.
: A hemispheric turnor can cause seizures, hemiparesis,
or losS of cortical sensation. Tumors at the hypothalarnic
'. or pituitary region can give rise to visual field disturb
ances, endocrine abnormalities, diabetes insipidus, pre
cocious puberty, hypersolllnia, hyperphagia, or a
aiencephalic syndrome of failure to thrive and emaciation.
Pineal turnors classically present with paralysis of con
jugate upward gaze, absent pupillary reaction to light, and
con
retraction nystagmus. Brain stem tumors frequently give
vork
rise to multiple cranial nerve palsies, long tract signs, and
dig
gait problems. Tumors in the cerebellum can cause nys
Ilere
tagmus, ataxia, gait abnormalities, and dysdiadochoki
~ich
nesia. Some spinal cord tumors can produce paraparesis
or nerVe root pain, sensory loss. muscle weakness, and
.pe-
atrophy.
DIAGNOSTIC STUDIES
The first ste~ in the diagnosis of brain tumor is clinical
awareness. Brain tumor should always be included in the
differential diagnosis of a space-occupying lesion in the
brain besides brain absceSs, congenital malformation, vas- .
cular lesion, subdural hematoma, intracerebral hema
toma, parasitic infestation, lead encephalopathy. and
pseudotumor cerebrii. . Magnetic Resonance Imaglng and Positron SeEm
Plain X-Ray of the Skull
Skull x-rays are normal in many children and adoles
cents with brain tumors. Sometimes signs of raised intra
cranial pressure such as suture separation, erosion of the
posterior clinoid process. and increased convolution mark
ings on the inner table of the skull may be present. Tumor
calcifications occur most frequently in craniopharyn
giomas and occasionally in gliomas and ependymomas.
Computed Tomography
The computed tomographic (CT) scan ofthe head is the
most useful single tool for the diagnosis and follow-up of
brain tumors. It is noninvasive. quick, and sensitive, es
pecially when coupled with contrast enhancement. It not
only localizes the tumor and outlines its characteristics,
1575
but also demonstrates the presence or absence of hydro
cephalus.
Radionuclide Brain Scan
The brain scan is used much less often now since the
introduction of the CT scan. However, sometimes it may
be of use in copfirming supratantoriallesions.
Pneumoencephalogram
This invasive procedure is rarely used; however, it de
lineates small pineal turnors, optic gliomas, hypothalamic
tumore, and intraventricular .and paraventricular tumors
well.
Cerebral Angiography
Cerebral angiography also is far less frequently used
than previously, being an invasive procedure. However, it
may be necessary to use it to differentiate between arte
riovenous malformations and brain turnors when there is
still doubt after the other studies. In addition, it supplies
useful information to the surgeon regarding blood supply .
to tae.tamor.
Examination of the Cerebrospinal Fluid
A lumbar puncture is generally not advisable in a p~
tient with raised intracranial pressure. However, exami
nation of the cerebrospinal fluid can provide useful
information regarding turnor seeding along the cerebl;o
spinal pathway_ The polyamines in the cerebrospinal fluid ~\
have been found to be useful turnor markers for the ac
tivity of medulloblastomas. Serial monitoring of polya
mine levels can aid in the detection of turn~r recurrence.
Alfafetoprotein and/or ~.human chorionic gonadotro
phin (~-HCG) can also be detected in the cerebrospinal
fluid of patientIf with pm c!lll t"mar~ oftho plnealgland,
and are th41'efore useful markers tor diagnosis and follow
tip.
Myelography
Myelography is a useful procedure for the diagnosis of
spinal canal tumors. It can be used also for the detection
of metastases .of certain brain tumors, such as medullo
blastomas.
Magnetic resonance' imaging (MRI) now provides su
perior imaging of the central nervous system than does
the eT scan. It is particularly useful for the detection and
monitoring of brain stem and other posterior fossa tumors.
The positron scan can provide information on the differ
ential metabolism of the different regions of the brain. It
is the most reliable noninvasive tool for distinguishing
between recurrent brain turnor and radiation necrosis.
Evoked Potential
Brainstem auditory eVQked potential study has been re
ported to be very useful in monitoring the progress of chil
dren with brainstem glioma after therapy _Visual evoked
potential has not been stU/lied extensively but may be
useful in patients with optic glioma.

 1576 Section 0 I Childhood Cancer
SPECIFIC TUMORS
~ Infratentorial Tumors
MEDULLOBLASTOMA
Medulloblastomas accollnt for about one-quarter of all
pediatric brain tumors. The majority of cases occur before
the age of 15; some are seen in adults.
In children medulloblastoma is usually a midline tumor
found in the, vermis. The tumor tends to be located more
laterally in older children and adolescents. In addition to ,
invading the neighboring structures, such as the cerebel
lar hemisphere and the fourth ventricle, the tumor also
has a propensity to seed the meninges and spread the
cerebrospinal fluid through the entire neuroaxis to involve
the cerebrum and spinal cord (drop metastasis). Medul
loblastoma can also metastasize outside the central ner
vous system to the peritoneal cavity (occasionally via
ventricular-peritoneal shunt), bone, bone marroW, lymph
nodes and rarely, the liver. The vertebrae, long bones, ribs,
and skull are common skeletal areas of metastases. The
incidence of extra-central nervous system metastases has
been reported as less than 5% in the literature but is now
believed to be as high as 20% with long-term follow-ups
of patients.
Surgery is the primary mode of therapy. The tumor,
however, is often not completely resectable. Nonetheless,
even a partial resection, in addition to. providing a speci
men for histologic diagnosis, can reduce the tumor burden
/,,---,\
thereby rendering radiotherapy and/or chemotherapy the
oretically more effective. Surgical decompression of ob
structive hydrocephalus by a ventricular-peritoneal shunt
also frequently improves symptoms. Surgical resection,
unfortunately, has seldom led to cure.
Medulloblastomas are radiosensitive tumors. Postop
erative irradiation of-the craniospinal axis has produced
5-year survival rates of approximately 50% and lO-year
survival rates of about 35%.
The recommended dose of radiation to the poster!oJ; f?ssa
is generally 4500-5500 cGy; to the supratentorium, about
3500 cGy; and to the spinal cord, 2400-4000 cGy. The price
of high-dose irradiation to the brain and spine, however,
is not insignificant, particularly in the very young. The
undesirable late effects include possible diminished ver
tebral growth, endocrine dysfunction, learning problems,
and secondary oncogenesis. Woo et a1. in a pilot study did
not find increased spinal recurrence when the radiation
dose to the spine was reduced to 2400 cGy. A study from
Children's Memorial HospitallNorthwestern University also
showed that 2500 cGY neuroaxis irradiation was adequate
for early-stage patients. However, a small pilot study from
Milan, Italy, using radical resection, radiation to the pos
terior fossa only, and chemotherapy (both systemic and
intrathecal) reported spinal failure in three out of four
patients. It therefore seems inappropriate to omit neu
roaxis irradiation but more advisable to reduce the dose
of radiation in selected patients, The Pediatric Oncology
Group (POG) is currently evaluating children with TlT2Mo
~ medulloblastoma by a randomized study of 2340 cGy or
3600 cGy to the spine. In addition, electron instead of
photon is being used more frequently to treat the spine. , tl
As opposed to photon, the depth of penetration of electrons b
is governed by its energy (within a certain energy range). t4
It is therefore possible to limit the dose of radiation to , p
structures anterior to the spine by selecting an electron i a
beam of the appropriate energy, thereby minimizing the b
acute and possibly the chronic side effects of radiation. In sc
children less than 2 or 3 years of age, neurotoxicity from 'W
cranial irradiation has been reported to be greater than d;
in older children, probably because of the increased sen- di
sitivity of the developing brains to the late effects of ra- at
diation. There have been small pilot studies from several si
institutions including M.D. Anderson Hospital, St. Jude h~
Children's Research Hospital, and Dana-Farber Cancer iD
Institute using postoperative chemotherapy and delayed r.;
radiotherapy in these young children. The preliminary Ct
results are encouraging. A POG study is now in progress
to determine if the use of postoperative cyclophosphamide bI
and vincristine in children less'than 36 months of age will ct
permit the delay of cranial irra.,diation for 12 months in d(
children 2-3 years old at diagnosis and 24 months for those ca
less than 2 years old. in
Several chemotherapeutic agents, when used alone or Cl
in combination, have demonstrated activity against re- bl
current medulloblastoma. These include vincristine, 15
methotrexate, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), wi
chloroethy l-cyclohexy l-ni trosourea (C CNU) , cycl ophos- all
phamide, nitrogen mustard, procarbazine, VM-26, VP-16, vil
cis-platinum and carbo-platinum. The role of adjuvant che- pr
motherapy has been explored in several studies. On the or
basis of the results of a pilot study carried out at the Royal re:
Marsden Hospital in London, the International Society of gr
Pediatric Oncology (SlOP) in 1976 randomized patients be
with medulloblastoma to receive, after surgical resection,
either craniospinal irradiation or radiotherapy and cbe . Ta
motherapy with vincristine and CCNU. In the last anal~ Ch
ysis, 286 patients were evaluable, and the 5-year disease-
free survival was 54% for patients who received chemo- Tt
therapy and 43% for those who did not (p = .08). The
advantage of chemotherapy was observed in boys, children
under 2 years of age, patients with T3 I T 4 lesions, those T2
with brainstem involvement, and patients with grossly
incomplete resection of the primary tumor. The Children's T3
Cancer Study Group (CCSG) in 1976 started a study al
most identical to the SlOP study, with the exception that
prednisone was added to vincristine and CCNU in the
chemotherapy arm. Although there was no significant dif
ference in terms of survival between the two therapeutic
approaches when the entire group was analyzed, chemo
therapy appeared to be beneficial for patients with Tal T4
T4
or MI-Ma disease. The 5-year event-free survival for pa
tients with Tal T4, disease was 58% in the chemotherapy
arm versus 41% in the nonchemotherapy arm. A pilot study [ Mo
using surgery, craniospinal irradiation (with the spinal
dose reduced to 2400 cGy) and intermediate-dose metho M,
trexate (500 mg/m2) and BCNU showed a disease-free sur M2
vival of 60% 27-84 months from diagnosis (median-41
months). There was no excessive toxicity or increased rate
of spinal recurrence. There are therefore indications that Ms
adjuvant chemotherapy may be advantageous in the treat- M4

 Chapter 1521 Central Nervous System Tumors in Children and Adolescents 1577

". ment of at least some subsets of patients with medullo these prognostic factors to categorize patients into differ
'blastoma. Recently there has been also considerable in ent prognostic groups and apply different therapeutic
, terest in applying chemotherapy early in the treatment strategies to them. '
~:program, that is, soon after surgery and before radiother ,
::i apy. In a West German pilot study, Vincristine, procar . CEREBELLAR ASTROCYTOMA
j bazine. and intermediate~ose methotrexate were given The classical juvenile cerebellar astrocytoma is usually
:: soon after surgery, and radiotherapy WIlS delayed until a low-grade well-differentiated astrocytoma which con
.. week 11. Toxicity was reported as tolerable and the ra taills microeysts, Rosenthal fibers, and sometimes a rural
" diotherapy did not appear to be compromised. The 4-year nodule. The treatment of choice is surgical excision. Com
,en~ ~" . disease-free survival was approximately 1)0%. Several larger plete excision results in cure in the great majority (more
ra studies by SlOP, CCSG, and POG are in progress using a , than 90%) of patients. Even partial removal is often fol
,ra!. similar strategy. Preliminary analYlil of the SIOP trial lowed by a prolonged period of symptom control and sur
Ide has not demonstrated clear-cut advantage of a brief but , 'vival; therefore, postoperative radiotherapy can be withheld
cer intensive chemotherapy course after surgery but before in many cases., However. if the residual tumor 'after sur
led radiotherapy. The role of biologic response modifiers is also . gery is large and symptomatic, radiotherapy should be
Uj' ,,' currently being investigated. considered. A report from Stanford showed a 12-year 8Ur~
ess ' .". Several prognostic factors are recognized for medullo vival and freedom from relapse of 60% in children who
[de '.blastoma. Children under 3 years fare less well than older received PO,stoperative radiotherapy for large, incom
rill t. children, perhaps in part because of the need to reduce the pletely resected cerebellar tumors. Radiotherapy is also of
in t dose of radiation in the younger children and in part be benefit in patientswith symptomatic recurrence in a sur
lBe cause of a higher incidence of cerebrospinal fluid dissem gically inacc.essible site such as the brainstem~ There is a
ination of tumor. Girls have' a better prognosis than boys. type cf..aiffuse cerebellar astrocytoma which has features
or , Chang et al. have devised a staging system for medullo of higher grade of malignancy such as high cell density,
'e- blastoma which appears to have prognostic value (Table necrosis, and perivascular pseudorosettes. The prognosis
,e, 152.2). A decrease in survival has been found in patients is worse in patients with this form of cerebellar astrocy
1), with Tal T4 or MI-Ma disease. Brainstem involvement is toma and postoperative irradiation is usually indicated.
s- also a bad prognostic sign. Patients who have the grossly The role of chemotherapy is not well established.
6, c, visible primary tumor completely resected have a better
e i" prognosis than those whose tumors are partially resected BRAINSTEM GLIOMA
le ;; or biopsied only. The resectability of the turnor is probably The brainstem glioma represents about 10-15% of all
il relatedtq the extent of the disease. Recently, a histologic primary braintumors in children. The term glioma is
)f grading aylitem which reportedly has prognostic value hall used instead of qther more precise pathologie term. be
:s been proposed. Most current studies use some or all of Cause in the past, surgical explora.tion and biopsy wel'@
seldom done in most patients because of the hazards
Table 152.2.
involved in tumor biopsies in the brainstem. The diag
Cllang olassiflcatiOn fOr medulloblastoma,
or
nosis brainstem glioma is usually made with the' aid
of eT scan or MRI. With improvements in CT-guided
T, Tumor less than 3 cm in diameter and limited to the stereotactic neurosurgical techniques, some investiga
classic midline position in the vermis, the roof of the tors have advocated surgical biopsy of the tumor to as
fourth ventricle. and. less frequently. the cerebellar
hemispheres. ,
certain the histologic grade of the tumor, since this mar.
In
T2 Tllmor 3 cm or greater diameter, further invading one have prognostic importance. On the other hand, it has
adjacent structure or partially filling the fourth ventricle. been shown that the biopsy sample might not be rep
Ta This stage is divided into TaA and T3B. resentative of the entire tumor, and pathology exami
T3A: Tumor further invading two adjacent structures or nation at autopsy not infrequently revealed a higp,er
completely filling the fourth ventricle with extension histology grade than that of the biopsy specimen. More
into the aqueduct of Sylvius. foramen of Magendie. over, the majority of brainstem gliomas eventually cause
or foramen of Luschka, thus producing marked death regardless of their initial histologic grade, al
internal hydrocephalus. though the rate of progression may be slower in the well
TaB: Tumor arising from the floor of the fourth ventricle or differentiated tumor than in glioblastoma.
brain stem and filling the fourth ventricle.
Surgical evacuation of cysts or excision of exophytic tu
T4 Tumor further spreading through the aqueduct of Sylvius
to involve the third ventricle or midbrain, or extending to mors .can produce improvement in symptoms. However,
the upper cervical cord. commonly the only surgical procedure performed in some
Mo No evidence of gross subarachnoid or hematogenous patients is the shunting procedure for obstructive hydro
metastasis. ' cephalus. The primary treatment for brainstem glioma is
M, Microscopic tumor cells found in cerebrospinal fluid. radiation therapy. A controversy exists as to whether ra
M2 Gross nodular seeding demonstrated in cerebellar, diotherapy should be directed to the primary site plus a
cerebral subarachnoid space, or the third or lateral margin or to the whole brain initially followed by a boost ..~
ventricles. . to the primary tumor. Comparable survival rates have
Ma Gross nodular seeding in spinal subarachnoid space. been achieved with both forms of radiotherapy, and the
M4 Metastases outside the cerebrospinal axis,
. ~. major site of failure after either form of radiotherapy is
 1578 Section 0 I Childhood Cancer

the brainstem. A usual radiation dose range for conven EPENDYMOMA

tional fractional radiation therapy is 5000-5600 cGy, and
Ependymomas arise fro~ ependymal cells and can occur
it is not clear that brainstem glioma shows a clear dose
infratentorially and supratentorially: In. children, infra
response to radiation therapy in the usual dose range.
tentorial ependymomas are more common than supraten
Although conventional radiation therapy often produces
torial ependymomas, and account for about 8-10% of
symptomatic response, the 5-year survival is generally
posterior fossa tumors. The tumor usually arises from the
around 20%. Currently, hyperfractionated radiation ther
floor of the fourth ventricle and extends to the neighboring
apy is \>eing studied. The rationale for hyperfractionated
structures. The histologic grading of tumor, although non
irradiation is that mUltiple fractions per day may selec- ,
uniform among pathologists, appears to have prognostic
tively spare normal central nervous system tissues, and
significance. Ependymomas are thought to behave fre- .
therefore a higher total radiation dose can theoretically
quently like medulloblastomas in that they m83' seed the
be delivered to the tumor without increasing the incidence
cerebrospinal pathway and may even spread outside the
of late complications. Indeed, POG used 110 cGy twice a
central nervous system. However, the incidence of cere
day at 4- to 6-hr intervals to a total dose of 660 cGy and
brospinal seeding seems to relate to both histologic grade
found no increase in toxicity. Unfortunately, there was no
and site-high-grade infratentorial ependymomas have a
apparent improvement in survival with this radiation dose
higher risk of spinal metastasis than low-grade supraten
compared with historical control. POG is currently esca
torial ependymomas. .
lating the total dose to 7020 cGy. At the Children's Hos
The standard treatment of ependymoma is surgical re
pital of Philadelphia, a pilot study using 120 cGy of
section followed by radiotheraflY' Diez et a1. at Buenos .
radiation, twice a day, 5 days a week to a total dose .of
Aires Children's Hospital have found that extensive sur
6480 cGy was done, again showing no excessive acute or
gical dissection at the floor of the fourth ventricle con
subacute toxicity, but also no increase in efficacy. On the
tributed to postoperative brainstem dysfunction and death,
other hand, at the University of California, San Francisco,
and have cautioned against this practice. Because of the f
two fractions per day each of 100 cGy were delivered in
aforementioned low risk of cerebrospinal metastasis of low f
72 fractions to a total tumor dose of 7200 cGy over a 7
grade supratentorial, ependymomas, some investigators 1
week period. A recent update appears to show a 50% pro
have suggested that irradiation of the entire cerebrospinal l
longation of survival when compared to a group of children
axis is not necessary in these patients. For infratentorial t
with brainstem glioma treated by conventional radiation
ependymomas, most oncologists would recommend cra t
therapy in CCSG. There was again no increase in the
niospinal irradiation with a boost to the' initial tumor b~
~, incidence of radiation necrosis. However, there was an
and areas of gross disease. The radiation dose range IS v
unexpected observation of prolonged lymphocytopenia as
similar to that for medulloblastoma. In general, a radia a
sociated with opportunistic infections in a few patients.
tion dose in excess of 4500 cGy to the primary tumor site fi
Nonetheless, the result is encouraging and needs confir
is recommended. Five-year survival figures of 50-70% have g
mation. The role of hyperfractionated radiation therapy
been reported. However, about 50% of patients with high tI
should be further explored. 'fhe use of radiation sensitizers
grade tumors fail locally. with current treatment pro d
has not been extensively studied in brainstem glioma, al
grams. Children with supratentorial ependymomas ap v
though a CCSG pilot study incorporating misonidazole and
pear to fare better than those with infratentorial primaries.
hydroxyourea did not demonstrate any survival benefit.
Recurrent ependymomas have shown response to nitro c~
The role of chemotherapy is not established" mainI,- be
soureas methotrexate, epipodophyllotoxin, vincristine, cis it
cause of a lack of highly effective agents, although re
sponses to BCNU, CCNU, procarbazine, methotrexate, and
platin~, and carboplatinum, but the chemotherapy sal bl
vage rate is poor. The role of adjuvant chemotherapy has bI
cis-platinum have been reported. Dexamethasone, a syn
also not been fully established. Some children with epen 5
thetic steroid, has been very useful in controlling tumor
dymomas were included in the SlOP medulloblastoma study, di
igenic edema, causing symptomatic improvement in many
but clear benefit of adjuvant CCNU and vincristine could to
patients. In limited trials of adjuvant or neoadjuvant che
not be demonstrated. A study from M.D. Anderson Hos wi
motherapy for brainstem glioma, no significant benefit
pital on infants with ependymoma, however, showed that 101
from the chemotherapy has been demonstrated. At pres
some infants treated with surgery and MOPP (nitrogen bl
ent, chemotherapy is generally used for palliation. Non~ mustard, vincristine, procarbazine, and prednisone) che
theless, efforts to find more effective chemotherapeutIc Tl
motherapy could have a prolonged disease-free survival to
agents for this disease should continue.
without any radiation therapy. This observation will need at
The prognosis is partially related to the histologic grade confirmation by a larger cooperative group study.
ofthe tumor, with glioblastomas being generally rapidly wi
progressive and uniformly fatal. Tumors arising in the do
midbrain and thalamus, sometimes grouped under
Supratentorial Tumors do:
brainstem glioma, fare better than those arising in the ral
pons or medulla. It has been reported that a short clinical CEREBRAL ASTROCYTOMA to
history, widespread brainstem dysfunction, a hypodense COl
Astrocytomas account for 10% of all brain tumors in
.~ tumor on pre-enhancement CT scan, and a diffuse tumor children but represent about one-third of all supratento wi'
on MR images are also poor prognostic factors for brain rial tumors of childhood. The most malignant form of as diE
stem glioma. wil
trocytoma, namely, glioblastoma multiforme (Grade IV
 Chapter 1521 Central Nervous Syatem Tumors In Children and Adolescents
astrocytoma), is less frequently seen in children than in
.' adults.
The treatment of supratentorial astrocytoma depends '
ra , . On the histologio srading of the tumor. Fora very low
!n grade astrocytoma (Grade I), surgical resection is .the
of .' . treatment of choice. Radiotherapy is frequently reserVed
m
;he " for the treatment of recurrence. For the more malignant
~ ~o
ng
astrocytoma, radical surgery has been either ineffective
38%
)fi
or fraught with excessive morbidity andlor mortality. In
~ 40 I
tic .. fact, less than 20% of patients with glioblastoma are likely
W ._..... Cerebellum
re
he
to be suitable for radical resection because of the extent
or location of the tumor. Even with tumors which grossly
he . appear to be resectable, it is often difficult during surgery
~e
to differentiate the tumor edge and normal brain tissue.
o 2 4 6 8 10 12 14
de Nonetheless, laser and stereotactic technology have im
proved the armamentarium of the neurosurgeon. Inves
n tigators at the Mayo Clinic are studying a sophisticated
Figure 152.1. Survival as a function of site of primary tumor in
and laborious CT-guided technique for the surgical resec
children with astrocytoma. (Reproduced wIth permission from
'&
tion of high-grade astrocytomas in adult patients. Long
os
term followup of a sufficient number of patients will be
Onco/6:1001-1007,1988.)
:r needed to prove the benefit of this procedure. Currently
n- the established role of surgery is in biopsy of the tumor
h, 'for histologic diagnosis, resection (partial or total) of the
tumor bulk where feasible, and decompression of the ven
tricles to reduce the intracranil!l,l pressure when neCClS81l'Y,
rs For selected patients there is 8. suggestion of a survival
d benefit after reoperation following initial surgery, radio
il therapy (teletherapy andlor brachytherapy), and chemo
1 therapy.
d Radiotherapy of 5000-6000 cGy can improve the sur
is vival of some patients with malignant astrocytomas. Stage
l and Stein reported 5-year survival rates of 40% and 15%
e for Grades II and III astrocytomas. respectively, after sur
e gery and irradiation. Sheline, after reviewing data from
l
the University of California, San Francisco, and selected
I
data from the literature, concluded that the 5-year sur
vival rate for Grade III astrocytoma is near zero without
I. radiotherapy but about 20% with radiotherapy. The effi
cacy of radiotherapy in glioblastoma multiforme is far less
impressive. Survival may be prolonged in a few patients,
but the cure rate is exceepingly low. Children with glio
blastoma appear to fare better than adults, with reported
5-year survival figures upto 25% after conventional ra
diotherapy. In a Stanford series of children with astrocy
toma followed up to 14 years from diagnosis, 38% of children
with cerebral astrocytoma (of all histologic grades) were
long-term survivors, although all the patients with glio
blastoma ultimately died of their disease (Figure 152.1).
The survival benefit of radiotherapy for glioblastoma seems
to be limited to the first 2 years following presentation,
at least in adults. Ninety percent of glioblastomas recur
within a 2 cm margin of the primary site after radiation
done up to 6000 cGy, suggesting that recurrent radiation
doses are inadequate to eradicate the primary tumor. Higher
radiation doses may improve tumor control but are likely
to produce severe side effects, such as brain necrosis. A
controversy exists as to whether whole brain irradiation
with a boost to the tumor volume or more localized irra
diation to the tUIDor site or margin is needed in patients
with high-grade astrocytomas. In the Stanford series, a
1679
~ 100
::J
~ 10
Q..
o
ffi'
Q..
20
. -.-
.-.-.
Thalamus El Hypolhalamu&
Cerebrum
Spinal Cord
--- Braln.lem
o~--~--~--~~--~--~--~----~~
16
YEARS
Woo SY, Donaldson SS, Cox RS: Astrocytoma in children-14
years' experience at Stat'lford University Medical Centsr. J Clin
definite benefit for whole brain irradiation could not be
demonstrated in children. Patients at the UniV'ersity of
Oalifornia, Ban Francisco treated by limited fields also had
median survival siruilar to that of children treated to the
whole brain in the Brain Turnor Study Group studies. Thus,
in children who have had clear delineation of the tumor
by modern high-quality imaging techniques, it seems rea
sonable to limit the volume of irradiation to the brain in
order to reduce long-term toxicity.
Several approaches to improve the efficacy of radio
therapy have been studied. Fast neutrons have been shown
to sterilize malignant brain tumors, but the toxicity to
surrounding normal brain has been devastating. The role
of helium ions, neon ion, and pions is still being explored.
Electron affinic sensitizers, such as misonidazole, and hal
ogenated pyrimidine!,! have been studied in adults with
high-grade gliomas, buUheir use in children has been very
limited. Interstitial brachytherapy with high-activity P2&
has been evaluated at the University of California, San
Francisco, in a few children with recurrent astrocytoma.
Although responses could be demonstrated, the definitive
role of brachytherapy in the primary treatment of malig
nant astrocytoma in children is still unknown. Interstitial
hyperthermia has not been studied in children. Hyper
fractionated radiotherapy has been studied in adults,
showing some promise. The experience with hyperrac
tionated radiotherapy in children is very limited. Inves
tigators in Alberta, Canada, have treated six children either
with 3500-4000 cGy in 45 fractions in 3 weeks plus a boost
of 1400 cGy in 10 fractions in 2 weeks, or with 6000 cGy
in 75 fractions over 5 weeks. They have not encountered
excessive toxicities, and four children were alive from less
than 2 years to 4 years from diagnosis. It therefore seems
reasonable to further explore the role ofhyperfractionated
high-dose radiotherapy.
Recurrent malignant astrocytomas have shown re
sponse to a number of chemotherapeutic agents such as
BCND, CCNU, procarbazine, vincristine, cytosine arabi
1580 Section 0 I Childhood Cancer
noside, dimethyl-tri-azenoimidazole, carboxamide, meth
"Otrexate, epipodophyllotoxin cis-platinum, and aziridinyl
benzoquinone (AZQ). The Brain Tumor Study Group have
performed several randomized studies to test the efficacy
of adjuvant chemotherapy. Thus far, it appears that BCNU
may genefit a subset' of patients, as evidenced by a sig
nificantly higher I8-month survival rate in patients who
received radiation and BCNU than patients who did not
receive BCNU. The CCSG also reported a preliIIliiurry study
demonstrating a disease-free survival benefit using ad
juvant chemotherapy with vincristine, CCNU, and pred
nisone in children with astrocytoma. In the CCSG series,
children with glioblastoma who received radiation and
chemotherapy had a 5-year disease-free survival rate of
42% compared with a 6% disease-free survival in children
who received radiotherapy only. CCSG is currently inv:es
tigating the role of "eight-in-one" chemotherapy in chil
dren with high-grade astrocytoma. The potential usefulness
of interferon, interleukin-2/1ymphokine-activated killer
cells, and 125I-Iabeled monoclonal antibody to epidermal
growth factor receptor is being studied in adults.
In adult patients, several prognostic factors have been
reported. These factors include patient age, histologic grade,
presence of giant cells, extent of surgical removal, per
formance status at diagnosis, duration of symptoms, his
tory of seizures, and presence or absence of rapid uncon
sciousness, speech disorder, and motor symptoms. In
children, age and sex are not significant prognostic factors.
The impact of performance status and neurologic symp
toms has not been systematically evaluated. Jenkin has
shown. no difference in survival among children with ce
rebral hemisphere astrocytomas arising in different sites.
The most important prognostic factor in children with as
trocytoma who have long-term follow-up, current therapy
is inadequate for more than half of the children with as
trocytoma. Continued efforts in designing innovative clin
ical trials using multimodality therapy are needed. Areas
of research include brachytherapy, new radiation sensi
tizers, high-dose hyperfractionated radiotherap..Y.._~tereo
tactic radiotherapy, intra-arterial che'motherapy,
hyperthermia, and biologic response modifiers. In addi
tion, it has become aPparent that the disease and its treat
ment can have signific~nt impact on the physical,
intellectual, psychologic, and endocrine function orchil
dren, and further long-term studies hi those areas should
be conducted.
PINEAL TUMORS
A variety of tumors can occur at the pineal region. These
tumors include tumors arising from pineal parenchyma
(pineoblastoma and pineocytoma), germ cell tumo:rs such
as germinoma, choriocarcinoma, endodermal sinus tumor,
teratoma, and tumors from the surrounding tissue (glioma,
ganglioneuroma, meningioma, and hemangiopericytoma).
In children germinoma and pineoblastoma are the most
common pineal tumors encountered. Pineoblastoma has
been reported to be associated with bilateral retinoblas
toma-the so-called trilateral retinoblastoma.
Surgical excision of pineal tumors has generally been
difficult and associated with significant morbidity and
mortality. In the past, most pineal tumors were not biop
sied and treated with radiotherapy only. With improve
ment in stereotactic techniques, neurosurgeons are more
willing to perform biopsy especially if the pathology in
fluences the radiotherapy technique. On the other hand, I
there have been reports of increased incidence of cerebro ,f
spinal fluid dissemination of pineal tumors after biopsy.. t
Radiotherapy with tumor doses of 5000 cGy or higher i:
is effective. For germinOm8:S, whether the entire cranio c
spinal axis needs to be irradiated or not is subject to debate.
Experience in Kyoto and the University of California, g
Francisco, seems to indicate a low incidence of spinal fail~': tl
ure even in patients whose tumors were biopsied. Inves b:
tigators in these institutions do not recommend , pi
prophylactic craniospinal irradiation unless there is tumor " is
spillage at surgery, positive cerebrospinal fluid cytology, ' pl
or documented subependymal and subarachoroid metas, , hI
tasis. On the other hand, many oncologists still consider '.
craniospinal irradiation as t~ 'Standard treatment.
sometimes encounters a clinical situation in which
histologic diagnosis is unknown and the cerebrospinal
cytology, tumor markers, and myelogram are negative.
frequently used clinical approach is to irradiate the pri .
mary tumor to 2000 cGy and repeat the CT or MRI, scan. .
If there has been substantial reduction in the tumor
the tumor is most probably a germinoma and one can then
administer another 3000 cGy to the whole brain or to the
craniospinal axis. If there is no response; then ilT'>ln!iSltjnn
is continued to the same field to a total dose ofuv'vv--vuvv:;
cGy.
Pineal germinomas and pineoblastomas have been
ported to respond to eis-platinum-containing ch!~mc}thllr
apeutic regimens. In general, patients with pineoblastoma
fare worse than those with germinoma, and children
pineal endodermal sinus'tumor have poor prognosis.
germinoma, long-term survival of 70-80% has been
ported.The role of adjuvant chemotherapy is ""T.,."'n.~jv
under study.
OPTIC GLIOMA
Optic gliomas are rare tumors which can affect the
nerve or optic chiasma or extend into the brain itself.
majority' of tumors are slow-growing, low-grade
tom as, although low-grade glioblastomas of the optic
have been reported. There is a distinct association of
glioma with neurofibromatosis. The diagnosis of
gliomas in children may precede clinical m2rnilfesltatil)n$
of neurofibromatosis.
The natural course and therapy of optic gliomas
controversial because of the slow-growing nature of
tumor. Complete excision of the tumor is frequently
ficult, especially for tumors extending into or beyond
optic chiasma. However, incomplete excision can
times produce prolonged symptomatic improvement.
diotherapy has been reported to cause \;Vl", ..,,,aau"i
improvement in patients whose tumors cannot be
pletely resected. Experience with chemotherapy in
tumor is limited.
 Chapter 152/ Central Nervous System Tumors in Children and Adolescents
CRANIOPHARYNGIOMA
Craniopharyngioma is thought to arise from a remnant
QfRathke's pouch and is located in the suprasellar region.
IUs usually a slow-growing turnor which may have a cystic
.' component and is nearly always calcified. Because of the
location ofthe tumor-it can cause complex symptomatology
~om visual defects. endocrine dysfunction, and raised in
tracranial pressure. The turnor location has also resulted
in significant surgical morbidity following aggressive ex
cision of the tumor.
A commonly accepted treatment approach is limited sur
gery such as aspiration of "crankca.se oil" material (con
!aining cholesterol crystals) from the tumor cyst followed
.byradiotherapy to approximately 5000-5500 cGy. An im
aspect ofthe management of craniopharyngioma
: is the meti~ulous postoperative management of endocrine
: problems. Although 5-year survival rates of up to 75%
have been reported for aggressive surgery, about 40% of
patients subsequently relapsed. With limited surgery and
radiotherapy, surgical morbillity is reduced and 5-year
survival of 75~85% has been achieved in reported series.
Recurrent turnors after initial surgery can also be suc
cessfully treated with radiotherapy. Recently stereotactic
radiosurgery has been used in a. few children in Sweden
with encouraging results. The usefulness of chemotherapy
is unknown.
Intraspinal Tumors
Primary spinal cord tumors are rare in children. Low
grade astrocytomas, other forms of gliomas, and ependy
momas are the usual variety seen most commonly. The
ligns and l.Iymptomi depend on the lite of involvoment.
Cervical and upper thoracic spinai tumors give rise to
wea.kness or sensory changes of an upper limb. With tu:'
more at the lumbar region involving the cauda equina,
there is pain from nerve root irritation, lower limb w~ak
'ness, and bowel and bladder symptoms. Complete surgical
resection usually is not possible. When there is a cystic
. component of the tumor, aspiration of the cyst can have a
significant palliative efIec~. Radiotherapy is the preferred
treatment, and experience'with chemotherapy is limited.
Patients with spinal cord a'strocytoma may survive for a
. long time despite persistence or recurrence of tumor. Re
currence can also be detected beyond 5 years from diag
nosis. In the Stanford series, a 60% long-term survival was
reported.
1. Finlay J, Sposto R, Evans A, Ertel I, Jenkin D, Hammond D:
Current status of the Children's Cancer Study Group (CCSG)
1581
brain tumor trials. Society ofPediatric Oncology 18t/!. Annual ...~
Meeting Abstracts 36,1986. '.
2. Freeman C:ij., Krischer J, Sanford RA, Burger PC, Cohen M.
Noms D: Hyperfractionated radiotherapy in brain stem tu
mors: results of a Pediatric Oncology Group Studf.lnt J Ra
diat Oncol Biol Phys 15:3U-318, 1988 .
3. Harasiadis L, Chang CH: Medulloblastoma in children: a cor
relation between staging and results of treatment. IntJ Ra
diat Oncol BioI Phys 2:888-841, 1977.
4. James CD, Caribom E, Dumanski J, Hansen MF, Norden
skjold M, Collins VP, Cavenee WK: Genomic alterations in
glioma malignancy stages. Presented at the meeting of the
American Association ,of Cancer Research, New Orleans, 1988.
5. Li FP, Winston n, Gimbrere K: Follow-up of children with
. brAin tumors. Cancer 54;135-~S8. 1984.
, 6. Linstadt.D, Ward WM, Edwards EBB, Hudglns RJ, Sheline
GE: Radiotherapy of primary intracraniai germinoroas: the
case against routine craniospinal irradiation. Int J Radiat
Oncol Bioi P.kys 15:291-297, 1988. .
7. Maor MH, Fields RS, Hogstrom KR, van Eys J: Improving
the therapeutic ratio of craniospinal irradiation in medullo
blastoma. Int J RC}diat Oncol-Biol Phys 11:687-697, 1985.
8. Marks JE, Adler SJ: A comparative study of ependymomas
by site of origin.lnt J Radiat Oncol Bioi Phys 8:37-43, 1982.
9. Packer RJ, Sutton LN, Rorke LB, LittmanPA, Sposto R,
RosenstodtJG, Bruce DA, Schut L: Prognostic importance of
canular differentiation in medulloblastoma of children. J
Neu'rosurg 61:296-301, 1984.
10. Phuphanich S, Edwards MS, Leven VA, Vestnys PS, Ward
WM, Davis RL, Wilson CB: Supratentorial malignant gliomas
of childhood. Results oftreatment with radiation therapy and
chemotherapy. J Neurosurg'60:495-499, 1984.
11. Hochberg FH, Pruitt A: Assumptions in the radiotherapy of
glioblastoma. Neurology 30:907-911, 1980.
12. Sheline GE: The importance of distinguishing tumor grade
in malignant gliomas: treatment and prognoeis.lnt J Radiat
Oncol Bioi Phys 1:781-786, 1976. ,
13. Walker MD, Alexander E Jr, Hunt WE, et all Evaluation of
BCNU and/or radiotherapy in the treatment of neoplastic
glioma!!: cooperattvlllllinillll trial, J N'"rtJBurB 48:38&...,343,
1978.
14. Woo SY, McCullough D, Sinks LF: Primary therapy of med
'. ulloblastoma with surgery, radiation imd methotrexate and
BeNU-a pilot iitudy.ln Walker MD, Thomas DOT (eds):
Biolqgy of Brain Tumor. aoston, Martinus Nijhoff, 1986;
pp 429-432.
15. Woo SY, Donaldson SS, Cox RS: Astrocytoma in children
14 years' experience at Stanford University Medical Center.
J CUll. Onco16:1001-1007, 1988.
Selected Readings
AlIen JC, Bloom J, Ertel I, Evans A, Hammond D, Jones H. Levin
V, Jenkin D, SpO!!to R, Wara W: Brain tumors in children:
Current cooperative and institution chemotherapy trials in newly
diagnosedandrecurrentdisease.SeminOncol13:110-122,1986
Review of many of the Children's Cancer Study Group and
Memorial Sloan-Kettering brain tumor trials.
Cohen ME, Duffnel' PK: Brain Tumors in Children-Principles
of Diagrwsis and Treatment. New York, Raven, 1984-An ex
cellent overall review of pediatric neuro-oncology.
Mealey J, Hall PV: Medulloblastoma in children. J Neurosurg
46:56, 1977-0ne of the classic papers in medulloblastoma.