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5
Optic Nerve, Chiasmal, and Hypothalamic Tumors
JOANN ATER, NANCY J. TARBELL, AND EDWARD LAWS, JR.
Gliomas are the most common tumors in the opticnerve, chiasmal,
and hypothalamic regions of the cen-tral nervous system (CNS). As
such, they are the fo-cus of this chapter. For completeness, the
less com-mon tumors of these regionsmeningiomas
andcraniopharyngiomasare also covered. Germ celltumors can also
occur in this region but are discussedin Chapter 7.
GLIOMAS
Gliomas that affect the optic nerves, chiasm, and hy-pothalamus
represent a unique type of tumor with avariable clinical course.
Histologically, most othermidline astrocytomas of childhood are of
the pilo-cytic subtype. These gliomas are among the neo-plasms of
the nervous system whose tumor type andprognosis are age related.
Except for infants, theprognosis for patients with these tumors is
inverselyrelated to age at onset, with older individuals havinga
poorer prognosis. In infancy, tumors affecting theoptic pathways
can be malignant in their course, al-though the reasons for this
are not known. Gliomasof the optic nerves and chiasm are strongly
associ-ated with neurofibromatosis type 1. Several large se-ries
report obvious signs of neurofibromatosis in asmany as 54% of
affected children (Alvord and Lofton,1988; Hoyt and Baghdassarian,
1969; Listernick etal., 1988; Packer et al., 1983; Manera et al.,
1994).Gliomas affecting the hypothalamus and anterior third
ventricle are also strongly associated with neurofi-bromatosis
and may be found in tuberous sclerosis,another hereditary
condition.
The pathology of optic pathway gliomas runs thegamut from very
benign astrocytomas, considered bysome to be hamartomas, to tumors
that are glioblas-toma multiforme. The typical histologic picture
of aglioma of the optic nerve is one of dense
arachnoidproliferation around an infiltrating pilocytic glioma,with
thin hair-like tumor cells intermixed among thefibers of the optic
nerve itself. The low-grade gliomasthat tend to affect the optic
chiasm, anterior third ven-tricle, and hypothalamus frequently are
characterizedas juvenile pilocytic astrocytomas, having few
mitoses,no malignant features, or degenerative changes suchas
Rosenthal fibers. Despite their relatively benignhistology, these
tumors can progress and cause con-siderable morbidity in young
children. Occasionally,anterior third ventricle tumors are
discovered in con-junction with tuberous sclerosis; these tumors
aregenerally noninfiltrating, relatively benign subependy-mal giant
cell astrocytoma (see Chapter 3). Overall,approximately 4% to 5% of
optic pathway tumors arefrankly malignant, and those usually have
many of thecharacteristics typical of glioblastoma multiforme.The
tumors with malignant histology occur mostcommonly in adolescents
and older individuals.
In addition to patient age, anatomic distinctionsare extremely
important in the evolution and prog-nosis of these tumors. Optic
nerve gliomas can beconveniently grouped into two major categories:
the
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anterior optic nerve glioma, which primarily affectsthe optic
nerve or nerves; and the posterior opticnerve glioma, usually
centered in the optic chiasm.Obviously, tumors in both categories
affect the visualsystem, but the two types differ in pace and
progres-sion. Anterior optic nerve gliomas, which usually oc-cur in
childhood, are ordinarily quite benign andprogress very slowly.
Some of these tumors do notprogress at all or progress over many
years. Poste-rior optic nerve gliomas, which occur in very
youngchildren or older individuals, tend to form largermasses and
present with more symptoms. These tu-mors may become large enough
to affect the physi-ology of the hypothalamus and/or obstruct the
ante-rior third ventricle, producing hydrocephalus. Ininfants who
present with optic nerve or chiasmalgliomas, the spectrum ranges
from indolent tumorsto aggressive tumors that can spread throughout
theoptic pathway from the globe back to the occipitalcortex.
Tumors arising primarily in the hypothalamus oranterior third
ventricle are less common and less of-ten associated with
neurofibromatosis. Hamartoma-tous lesions also occur in the
hypothalamus and inthe interpeduncular fossa. More typical juvenile
as-trocytomas can occur in this region, along with stan-dard
anaplastic astrocytomas and other malignantforms.
Clinical Presentation
Optic gliomas occur primarily in children, with morethan 71%
diagnosed in patients younger than 10 yearsof age and 90% diagnosed
during the first twodecades of life (Dutton, 1991). The tumors can
rangefrom mild fusiform enlargement of the optic nerve ornerves
within the orbit to very large, globular exo-phytic masses that
extend from the chiasm and arevirtually indistinguishable from a
primary hypothala-mic tumor.
In one series, more than 60% of optic pathway tu-mors involved
the optic chiasm (Tenny et al., 1982).The signs and symptoms in
children with optic path-way tumors who presented to The University
of TexasM. D. Anderson Cancer Center between 1975 and1993 are
listed in Table 51 (Manera et al., 1994).The clinical picture of a
patient with a lesion affect-ing the optic nerves, chiasm, or
hypothalamus is usu-ally one of progressive visual loss. In
unilateral opticnerve tumors, this begins as a unilateral loss of
op-
tic nerve function; in other tumors, mixed variants ofoptic
nerve and chiasmal patterns of visual loss canoccur, with an
asymmetric bitemporal hemianopsiabeing the most common finding in a
chiasmal glioma.
In addition, behavioral changes, possibly relatedto elevated
intracranial pressure or hypothalamic in-volvement, are prominent.
Irritability, depression, so-cial withdrawal, somnolence, and
aggressive behav-ior have been reported. Because of the
frequentinvolvement of the suprasellar-hypothalamic region,children
with optic nerve tumors of these areas canalso present with
endocrine abnormalities. Althoughendocrine manifestations can occur
with any of thesuprasellar lesions, such presentations are
particu-larly common in lesions that arise in the hypothala-mus or
floor of the third ventricle. The hypothalamicdysfunction produced
by these lesions can range fromvarying forms and degrees of
hypopituitarism to en-docrine-active syndromes produced by tumors
thatsecrete hypothalamic-releasing factors. Tumors thataffect the
physiology of the appropriate nuclei in thehypothalamus or of the
pituitary stalk can result indiabetes insipidus. Finally,
hypothalamic hamartomasthat present in the interpeduncular fossa
are also as-sociated with precocious puberty. In a report of
33children with optic chiasmatic-hypothalamic tumors,5 (14%) of 33
presented with symptoms of endocrinedysfunction and 14 (56%) of 25
demonstrated en-docrine abnormalities on laboratory
evaluation.Growth hormone deficiency was the most
commonabnormality, followed by precocious puberty, delayedpuberty,
and diabetes insipidus. In addition, 7 (21%)of 33 patients failed
to thrive and had the diencephalicsyndrome (Rodriguez et al.,
1990), which is charac-terized by severe emaciation and an
inability to gainweight even when caloric intake is adequate
(Russell,1951).
Evaluations of endocrine function in children withdiencephalic
syndrome usually reveal normal thyroidfunction and elevated levels
of cortisol and growth hor-mone. Usually the child is young at the
time of diag-nosis and frequently has been subjected to
extensivefailure-to-thrive evaluations before the diagnosis ismade.
Because the only neurologic findings on exam-ination may be
decreased visual acuity, visual field cuts,optic atrophy, or
nystagmus, which are difficult to eval-uate in a child younger than
3 years, these signs maybe overlooked in a less than thorough
examination.
The association of optic nerve gliomas with neu-rofibromatosis
is well known. Optic nerve gliomas ac-
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count for only 4% to 8% of all brain tumors in child-hood
(Pollock, 1994), but as many as 70% of the op-tic nerve glioma
cases are found in individuals withneurofibromatosis type 1 (Stern
et al., 1979). In aprospective study of children referred to a
neurofi-bromatosis clinic who had no specific ocular com-plaints,
15% were found to have optic nerve gliomas,30% unilateral, 30%
bilateral, and 40% involving theoptic chiasm (Listernick et al.,
1989). In addition, allchildren who had plexiform neurofibromas of
theeyelid and glaucoma were found through compre-hensive
neuroimaging to have optic nerve gliomas.Whether the natural
history of these tumors in chil-dren with neurofibromatosis is the
same or differentfrom the rest of the population remains
controver-sial.
Prognosis and Natural History
The natural history of optic pathway tumors has beendebated for
nearly a century, with some early inves-
tigators (Hoyt and Baghdassarian, 1969) believingthat these
tumors are not neoplasms, but rather arehamartomas that do not grow
continuously. From theliterature, however, it is clear that the
clinical courseof optic pathway tumors can be quite variable,
rang-ing from rare reports of spontaneous tumor regres-sion
(Brzowski et al., 1992), to tumors that remainstable for life, as
suggested by Hoyt and Baghdassar-ian (1969), to aggressive tumors
that over time carryconsiderable risk of visual loss and death
(Alvord andLofton, 1988). Several factors have now been identi-fied
that at diagnosis predict favorable and poor out-comes (Kanamori et
al., 1985). Table 52 summa-rizes these factors.
Most investigators have divided optic pathway tu-mors into two
groups: anterior optic nerve gliomaswith isolated optic nerve
enlargement and posterioroptic nerve gliomas with optic chiasmal
involve-ment. Ten to 20 year survival rates are excellent
(ap-proximately 90%) for patients with optic nerve tu-mors (Weiss
et al., 1987) and more variable (40%
160 PRIMARY CENTRAL NERVOUS SYSTEM TUMORS
Table 51. Optic Pathway/Hypothalamic Tumors Referred to the
Pediatric Brain TumorClinic at The University of Texas M. D.
Anderson Cancer Center, 1980 to 1993*
No. %
Demographics
Total 60 100
Neurofibromatosis (NF) 31 54
Male 34 57
Female 26 43
Symptoms at diagnosis
Decreased visual acuity or blindness 28 47
Visual field deficit 12 20
Nausea/vomiting 17 46
Headache 19 32
Failure to thrive and diencephalic syndrome 6 10
Behavioral problems (irritability, social 12 20withdrawal,
somnolence, aggressive behavior)
No symptoms with NF 12 7
Endocrine complaints 4 7
Radiographic findings
Multilobular suprasellar-optic chiasmal masses 35 58
Optic nerve and chiasmal swelling 17 32
Isolated optic nerve 6 10
Hydrocephalus 23 38*Median age at diagnosis was 5.2 (range, 0.75
to 14.3) years.
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to 90%) for those with optic chiasmal tumors(Packer et al.,
1983; Pierce et al., 1990; Horwichand Bloom, 1985; Tao et al.,
1997). Upon carefulexamination, it can be observed that chiasmal
in-volvement that is not extensive and not associatedwith a large
exophytic mass may also carry an ex-cellent prognosis. The
characteristics of tumors withthe worst prognosis include early
onset in infancy,hypothalamic symptoms, signs of
hydrocephalus,presence of diencephalic syndrome, third ventricu-lar
involvement, and large chiasmal tumors extend-ing posteriorly. It
is most difficult to determine thebest treatment for young children
with these char-acteristics because aggressive treatment with
sur-gery and irradiation do not necessarily lead to thebest
survival rates or the best quality of life (Jan-noun and Bloom,
1990).
In evaluating the effects of the tumor itself and thetreatment
of optic chiasmal gliomas, the series fromSan Francisco (Hoyt and
Baghdassarian, 1969; Imesand Hoyt, 1986) is useful because of its
long-termfollow-up period and its evaluation of the actualcauses of
death. In the original 1969 report, 8 of 28patients were dead, and
at follow up 15 years later 8more had died, leaving only 12 (46%)
of 28 surviv-ing at a median follow up of 20 years. Nine of the
16deaths occurred in patients with neurofibromatosis;
only two of these patients had died of their chiasmaltumors. The
remaining died of other malignantgliomas of the brain,
neurofibrosarcomas of periph-eral nerves, or complications of
management of cer-vical neurofibromas. Of the seven who died
withoutneurofibromatosis, five died as a result of tumor andthree
died of unrelated medical illnesses. Of those pa-tients treated
with radiation, 4 of 14 patients died be-cause of their tumor,
whereas only 5 of 14 who didnot receive radiation died, 1 from
tumor and 4 fromother causes.
On the basis of these data, no benefit from radio-therapy (RT)
could be demonstrated. In addition, therisk of death from tumor was
greatest in the early follow-up period. However, most other
investigatorshave concluded that RT does improve survival anddoes
prolong the interval before disease progression(Alvord and Lofton,
1988; Pierce et al., 1990; Hor-wich and Bloom, 1985; Tao et al.,
1997). For exam-ple, in a series of 26 children with chiasmal
gliomastreated with RT at the Joint Center for Radiation Ther-apy,
60% had objective tumor shrinkage that oc-curred gradually over a
period of 5 years. Vision ei-ther improved or stabilized in 72.7%
of the children.The 15 year overall survival rate was 85.1% and
free-dom from progression was 82.1%, with median fol-low up of 108
months (Tao et al., 1997).
Optic Nerve, Chiasmal, and Hypothalamic Tumors 161
Table 52. Classification of Optic Glioma by Factors Influencing
Prognosis
FAVORABLE PROGNOSIS
Age at onset Early childhood to adolescence
Clinical features Visual loss with laterality
Slowly progressive or arrested course
Incidental finding in child with neurofibromatosis
No symptoms of endocrine dysfunction or hydrocephalus
Does not have diencephalic syndrome
Radiographic features Intrinsic optic nerve and/or chiasmal
location
POOR PROGNOSIS
Age at onset Infancy to early childhood and adulthood
Clinical feature Hypothalamic symptoms and/or signs of
increasedintracranial pressure
Severely affected vision in both eyes
Radiographic features Large exophytic chiasmal tumor with
posterior extension
Extension into third ventricle
HydrocephalusAdapted from Kanamori et al. (1985) and Alvord and
Lofton (1988).
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Management of Optic Gliomas
The literature abounds with inconsistencies, contro-versy, and
disparate conclusions about the progno-sis, natural history, and
management of optic path-way gliomas. Although only 4% to 8% of
childhoodbrain tumors originate from the optic tract, the
po-tential morbidity of these tumors and their treatmentin the face
of good survival rates has resulted in ex-tensive literature about
the best forms of treatment tooptimize cure rates and minimize
morbidity. How-ever, because of the relative infrequency of
occur-rence of these tumors and their heterogeneous be-havior
related to patient age and tumor location andsize, most series have
not reported numbers adequateto allow definitive conclusions about
this relativelyrare subgroup of gliomas, and randomized trialscould
not be conducted with them. Furthermore, asSutton et al. (1995)
aptly stated, It is unlikely thatany single modality (surgery, RT,
or chemotherapy)will be the optimum treatment for all children
withhypothalamic/chiasmatic astrocytoma. The challengefor the
future is to determine the most appropriatetreatment for each
patient, based on rate of tumorprogression, age, radiographic
demonstration of ex-tension of tumor, prior therapy, and
visual/endocrinestatus. It is therefore extremely difficult to
arrive atany standard recommended treatment for these tu-mors.
Recognizing that controversies exist, we haveadapted the following
guidelines for the evaluation,treatment, and follow up of children
with optic path-way gliomas.
Diagnosis
The evaluation of patients with optic pathway gliomasinvolves a
thorough family history, an accurate as-sessment of visual status,
evaluation for signs andsymptoms of increased intracranial
pressure, and de-lineation of the patients endocrine status,
looking for both hypopituitarism and endocrine-active syn-dromes.
Physical examination should be directed to-ward these points,
noting the presence of papilledemaor optic atrophy, deficiencies in
visual acuity or vi-sual fields, and the general intellectual and
neuro-logic state of the patient. Careful attention should bepaid
to growth and development parameters and tothe presence of any
lesions suggestive of neurofibro-matosis or tuberous sclerosis. For
asymptomatic chil-dren with neurofibromatosis with no previous
diag-nosis of optic glioma, routine screening with imagingor visual
evoked potentials is not warranted, and tests
should be determined by findings on clinical exami-nation
(Gutmann et al., 1997).
Diagnostic evaluation consists of appropriate lab-oratory
testing, including measurement of pertinentpituitary hormones, a
formal visual examination andmeasurement of acuity and visual
fields, and imagingdiagnosis, which currently rests on magnetic
reso-nance imaging (MRI) with gadolinium enhancementfor the most
accurate delineation of the lesions in-volved.
In children with neurofibromatosis and optic nerveenlargement,
characteristic findings on MRI or com-puted tomography (CT) scans
are adequate to allowdiagnosis. Unless there is a history of acute
visual lossor neurologic changes, these such patients can
beevaluated and followed up for objective evidence ofprogression.
The baseline and follow-up evaluationsshould include complete
physical and neurologic ex-amination, careful ophthalmologic
examination, in-cluding visual fields and MRI, or CT scan
evaluations.The MRI scan is superior to the CT scan for detect-ing
change, relationship of tumor to the optic chiasm,and tumor
extension into adjacent brain. Visualevoked potentials can be
useful if the baseline valueis normal and can be very sensitive in
detecting dis-ease progression. Once vision is impaired, however,we
have not found the visual evoked potentials to bevery useful,
especially when visual field defects arepresent. Unfortunately, for
young, uncooperative chil-dren the visual evoked potential studies
were not asuseful as we had hoped. For very young children, themost
useful evaluation of vision appears to be thatperformed by a child
neurologist or pediatric oph-thalmologist.
At diagnosis, it is often unclear from the patientshistory how
rapidly visual change is occurring; there-fore, for the first 6
months to 1 year, we perform radiographic and physical examinations
every 3months. If no change is observed, evaluation inter-vals can
be safely decreased to yearly. For childrenwithout
neurofibromatosis, these guidelines can alsobe followed in cases of
isolated optic nerve enlarge-ment. When tumor progression is
identified, optionsfor further treatment include surgery,
radiation, andchemotherapy. The pros and cons of these ap-proaches
are discussed separately.
Surgery
When a suprasellar mass is present at diagnosis, sur-gical
resection or biopsy is usually recommended.
162 PRIMARY CENTRAL NERVOUS SYSTEM TUMORS
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The extent of resection depends on the extent and lo-cation of
the tumor. A biopsy is necessary to confirmthe diagnosis in
patients who present with a suprasel-lar-hypothalamic mass.
Frequently, the origin of thetumor cannot be determined by
radiography, andcraniopharyngiomas may be indistinguishable
fromsuprasellar germinomas. Because management ofthese two entities
differs somewhat, a definitive diag-nosis is needed.
In addition, careful surgical removal from the chi-asm of the
portion of the tumor that is exophytic cansometimes improve vision
by relieving external pres-sure on the adjacent optic nerve (Oakes,
1990).Sometimes surgical debulking can also relieve hy-drocephalus.
These goals must, however, be balancedagainst the risks of
increased visual loss and in-creased postoperative hypothalamic
dysfunction,which can result in a disturbed sleepwake cycle,
dis-torted appetite and thirst, hyperactivity, memory dys-function,
and panhypopituitarism.
The indication for surgery varies with the type andlocation of
the tumors affecting the optic pathways.For the typical unilateral
optic nerve glioma locatedwithin the orbit, the indication for
surgery is pro-gressive visual loss and progressive proptosis.
Sur-gery is generally the treatment of choice when thereis loss of
vision in an eye without extension of tumorinto the chiasm.
Surgical excision of the lesion whenit has not reached the optic
chiasm can be curative,but the eye remains blind. Current surgical
techniquesallow for preservation of the globe and a good cos-metic
result. Patients known to have optic nervegliomas with little
proptosis and preserved functionalvision can be evaluated with
periodic imaging stud-ies and visual assessments. If there is any
evidence ofthe tumor extending toward the optic chiasm, treat-ment
should be planned early. When surgery is indi-cated, the operation
involves a frontal craniotomy andunroofing of the orbit, sectioning
of the optic nerveat its junction with the globe, and removal of
the op-tic nerve, including its intracanalicular segment up toits
junction with the optic chiasm. Results are excel-lent provided
that the tumor is totally excised and theremaining optic nerve is
free of disease.
Astrocytomas that involve the optic chiasm cannotbe resected
without causing significant visual impair-ment. Unfortunately, the
characteristics of this type oftumor, as shown by neuroimaging
scans, are still notspecific enough to allow a histologic diagnosis
with-out biopsy. In these cases, the goal is to perform asafe but
effective biopsy of the lesion without pro-
ducing additional visual impairment. This is ordinar-ily
accomplished with a frontotemporal type of cran-iotomy using
microsurgical techniques for the tumorbiopsy. Some tumors in this
region are large enoughso that the exophytic component extending
from thechiasm produces obstructive hydrocephalus; in suchcases, a
tumor debulking that preserves the portioninvolving the optic
chiasm can be accomplished torelieve the ventricular obstruction.
This procedurecan be performed accurately and safely using
carefulmicrosurgical techniques. There are reports of
verysatisfactory results of removal of some hypothalamichamartomas
using similar techniques, with reversalof some of the endocrine
deficits, particularly preco-cious puberty.
Despite the risks, several neurosurgical groupshave advocated
radical resection as primary treatmentfor children with
hypothalamic gliomas. Wisoff et al.(1990) reported a series of 16
children with chias-matic-hypothalamic tumors treated with radical
re-section, with 11 of 16 alive and well 4 months to4.5 years after
surgery, most without other therapy.Infants were most likely to
progress after surgery andrequire other therapy. It is evident that
significant sur-gical judgment and skill are necessary to deal
withthese difficult lesions, as the dysfunction produced by
overzealous resections can have serious, life-threatening
consequences, such as memory loss, in-appropriate thirst, and
severe diabetes insipidus,which can ultimately result in an
individuals requir-ing constant care. In addition, of 11 children
with di-encephalic syndrome after surgical intervention in anM. D.
Anderson Cancer Center series (Manera et al.,1994), 9 (82%)
eventually became obese and suf-fered multiple endocrine deficits.
The progression tomorbid obesity and endocrine deficits can also
occurafter RT and during the natural course of tumor pro-gression,
but the manifestation is usually not acute.
When the tumor is infiltrative, extensive, and diffi-cult to
remove in bulk, hydrocephalus may be treatedwith a shunting
procedure. Depending on the cir-cumstances, one can consider either
a ventricu-loperitoneal or a ventriculocisternal (Torkildsen)type
of shunt procedure.
In summary, we recommend a conservative surgi-cal approach
primarily for diagnosis. Once the diag-nosis is made, children who
exhibit favorable char-acteristics are followed up until signs of
tumorprogression occur. For those who show
unfavorablecharacteristics (Table 52), either RT or chemo-therapy
is recommended for most, depending on the
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age of the individual. For patients who have extensivetumors
invading the hypothalamus, extending to thethird ventricular
region, with massive infiltrationalong the optic tracts, or with
clear-cut evidence ofrapidly progressive disease at the time of
diagnosis,a delay in treatment is not recommended. However,in those
few cases of tumors where surgical decom-pression and improvement
of vision have occurred,especially in young children, very close
follow upwithout intervention until objective signs of progres-sion
occur is also an acceptable alternative.
Radiation
Most modern reports utilizing megavoltage RT docu-ment an
advantage for patients who have progressivechiasmal gliomas (Pierce
et al., 1990; Horwich andBloom, 1985; Wong et al., 1987; Tao et
al., 1997).Radiation therapy is generally the treatment of
choicefor symptomatic chiasmatic/hypothalamic gliomas inolder
children. Many recent series report excellentsurvival after
RTgenerally 90% at 10 years (Pierceet al., 1990; Horwich and Bloom,
1985; Tao et al.,1997). However, deaths can occur from disease
pro-gression many years after treatment, and, thus, long-term
follow up is critical in the management of thisdisease.
Outcome in terms of vision is an important mea-sure of treatment
success for chiasmal/hypothalamicgliomas. Following RT, vision is
improved in approx-imately one-third of patients, with most
patients ex-periencing visual stabilization (Pierce et al.,
1990;Tao et al., 1997). This success in maintaining or im-proving
vision is possible only if treatment is initiatedbefore severe
visual damage has occurred. Therefore,documented visual
deterioration is a major indica-tion for the prompt initiation of
therapy.
The overall survival rate for patients with optic sys-tem
gliomas is excellent. However, conventional RThas been associated
with significant morbidity. Mostradiation fields cover not only the
tumor bed (tumorvolume) but also tissues thought to be at risk for
mi-croscopic disease to allow for uncertainty in tumordefinition
and for inconsistencies in the daily treat-ment set-up (target
volume). The tolerance of thenormal brain parenchyma and its
vascular and sup-porting structures becomes, therefore, the
limitingparameter of external-beam therapy, and the risks of acute
and long-term sequelae are major dose-limiting factors. Permanent
radiation injury can in-
clude pituitary-hypothalamic dysfunction as well asmemory and
intellectual deficits. Young children areat greater risk than
adults (Glauser and Packer, 1991;Ellenberg et al., 1987; Ater et
al., 1999). After irra-diation, 72% of children treated at the
Joint Centerfor Radiation Therapy developed new onset of
hy-popituitarism, most commonly growth hormone de-ficiency in 59%,
with panhypopituitarism in 21% (Taoet al., 1997).
With conventional fractionation schedules (1.8Gy/day), total
doses of 50 to 54 Gy are consideredstandard for the treatment of
optic gliomas. Late ef-fects appear in a predictable manner in
terms of ra-diation dose, volume, and fractionation.
Fractionationexploits the differences in response to irradiation
be-tween normal brain and tumor tissue; normal tissuestolerate
multiple small doses of irradiation much bet-ter than they tolerate
a single, large fraction.
Until recently, greater precision in the delivery ofconventional
RT was limited by an incomplete diag-nostic definition of tumor
volumes, unsophisticatedtreatment planning systems, and imprecise
immobi-lization devices. Computed tomography and MRI nowprovide
much improved delineation of CNS neo-plasms, and three-dimensional
treatment planningsystems are currently available. These
technologicaladvances allow for accurate focal administration of
adose to the target area and have thus promoted thewidespread use
of radiosurgery techniques.
Stereotactic Radiosurgery
Stereotactic radiosurgery is a highly accurate andprecise
technique that utilizes stereotactically di-rected convergent beams
of ionizing radiation to treata small and distinct volume of tissue
with a single radiation dose. The multiple-beam approach of
ra-diosurgery results in sharp dose fall-off beyond thetarget, thus
sparing adjacent normal tissue. The tech-nique must, however, be
reserved for select small le-sions because it ablates both normal
and abnormaltissue within the treatment volume. Some investiga-tors
have advocated using stereotactic radiosurgeryto reduce the
treatment volumes of discrete, well-circumscribed lesions, although
certain parameters,including the size and location of the target
volume,are associated with complications from radiosurgery(Marks
and Spencer, 1991; Loeffler and Alexander,1993; Tishler et al.,
1993). Certain intracranial le-sions cannot be treated safely or
effectively with ra-
164 PRIMARY CENTRAL NERVOUS SYSTEM TUMORS
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diosurgery once the target volume becomes relativelylarge or is
located near brain stem, retina, and theoptic pathways. For
example, the maximum radiationtolerance of the optic nerve appears
to be between 8and 10 Gy; if more than 1 cm of the eighth nerve
istreated with radiosurgery, hearing loss is predictableeven with
doses as low as 15 Gy (Tishler et al., 1993).Kjellberg and others
have published isoeffect datapredicting the incidence rates of
brain necrosis us-ing a proton facility (Kjellberg et al., 1983;
Flickinger,1989). These isoeffect curves demonstrate the
rela-tionship between tumor necrosis, radiation dose, andfield size
and demonstrate the limitations of usinglarge single fractions for
intracranial lesions that in-volve critical structures such as the
optic system.Therefore, although stereotactic radiosurgery is
precise in the administration of large single frac-tions,
complications associated with larger volumes(greater than 3 cm) and
with certain locations (brainstem, visual pathways) limit the use
of this procedurein the primary management of pediatric tumors,
par-ticularly in the management of patients with opticpathway
tumors.
Stereotactic Radiotherapy
Fractionation of the daily dose of radiation combinedwith the
precision of radiosurgical techniques may bethe optimal way to
treat relatively small, symptomaticoptic tumors that do not show
extensive involvementalong the optic tracts. Stereotactic RT is
defined asthe use of stereotactic radiosurgery hardware andsoftware
(stereotactic head frame and support sys-tem, small-field
collimators, and three-dimensionalplaning) combined with radiation
routine fractiona-tion (1.8 Gy/day) or some form of altered
fractiona-tion such as hypofractionation (a few large fractionsof
4.0 to 8.0 Gy). Basic requirements necessary toadminister
stereotactic RT include specially designedsoftware and reproducible
repeat head fixation andlocalization systems.
Dose-optimization treatment using stereotactic RTor other
conformal techniques has now become routine for lesions that are
well controlled by con-ventional RT. These RT techniques may become
thetreatment of choice for many diseases such as in-completely
resected craniopharyngioma, pituitary ad-enoma, and small optic
pathway tumors. The radia-tion dose to nearby nontarget volume
structures vitalfor memory (mesial temporal lobe), for
endocrine
function (hypothalamic-pituitary axis), and for nor-mal
structural development (skull, mandible, and softtissues of the
scalp) is markedly reduced with thesetechniques. This technique of
dose optimization isparticularly important in the pediatric
population. Formany pediatric intracranial tumors, focal RT
tech-niques will largely replace conventional RT in orderto reduce
the long-term side effects of therapy (Dun-bar et al., 1994;
Loeffler et al., 1999).
In general, the use of stereotactic techniques asdefinitive
treatment should be restricted to lesionsthat (1) are distinct on
imaging scans, (2) are of rel-atively small volume, and (3) are
noninvasive or non-infiltrating. Although stereotactic techniques
do notreplace large-field RT in the treatment of widely
in-filtrating or seeding tumors, it is clear that conven-tional RT
is no longer acceptable for a large sub-group of patients who have
more focal intracranialtumors.
Chemotherapy for Optic Chiasmal Tumors
The use of chemotherapy for low-grade astrocytomasin children,
especially optic chiasmal-hypothalamictumors, has been investigated
at several medical cen-ters. In 1977, Packer and the group at
Childrens Hos-pital of Philadelphia started to treat patients
youngerthan 6 years of age newly diagnosed with intracranialvisual
pathway gliomas with combination chemother-apy. Their justification
for this approach was that thebeneficial effects of radiation on
vision could not beconfirmed in their patient population as only 1
of 21children demonstrated visual improvement after RT(Packer et
al., 1983). In addition, these investigatorsfound that progressive
neurologic deterioration andvisual loss did occur in patients who
received radia-tion late in the course of their disease, usually 5
to10 years after diagnosis.
Between 1977 and 1988, 32 children younger than6 years of age
were treated with vincristine and actin-omycin D chemotherapy as
initial therapy after diag-nosis. At last report, 10 (31%) remained
free of pro-gressive disease and had not required additionaltherapy
(Janss et al., 1995). For those whose diseaseprogressed, the median
time was 27 months after theinitiation of treatment. Ten year
overall survival forthe entire group was 85% because of the success
ofsalvage treatment.
Various chemotherapeutic agents, including lo-mustine;
vincristine; a combination of procarbazine,
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lomustine, and vincristine; and
cisplatin-containingcombinations, have been somewhat effective in
pa-tients with recurrent low-grade gliomas (Edwards etal., 1980)
and have been utilized for optic chiasmaltumors. In an M. D.
Anderson Cancer Center trial ofnitrogen mustard, vincristine,
procarbazine, andprednisone (MOPP) given to children younger than3
years of age with low-grade astrocytomas; six chil-dren either had
hypothalamic or brain stem lesions.With a median follow up of more
than 7 years, all pa-tients survived with stable disease. However,
five ofsix eventually received RT for tumor progression at amedian
of 1 year after diagnosis (Ater et al., 1988).
Combination chemotherapy with 6-thioguanine,procarbazine,
dibromodulcitol, lomustine, and vin-cristine has been substituted
effectively for RT for chil-dren with chiasmal and hypothalamic
astrocytomas.Investigators at the University of California at
SanFrancisco (Petronio et al., 1991) initially reported re-sults
for 19 infants and children (median age, 3.2years) with chiasmal
and hypothalamic gliomas who received chemotherapy, 12 at diagnosis
and 7 atthe time of tumor progression. Most received 6-thioguanine,
procarbazine, dibromodulcitol, lomus-tine, and vincristine
chemotherapy, and two receivedother combinations. Of the 18
patients with evaluabledisease initially managed with chemotherapy,
tumorsin 15 (83%) either responded to therapy or stabi-lized. With
a median follow-up period of 18 months,all are surviving; disease
progressed in only 4 of 15and was successfully treated with
radiation. Vision ini-tially improved or stabilized in 16 (88%)
patients.This series was updated in 1997 and now includes agroup of
42 children with a mean age of 5 years. Themedian time to
progression was 132 weeks, with a 5year survival rate of 78% (95%
CI, 60% to 87%) (Pra-dos et al., 1997).
In low-grade hypothalamic and chiasmal gliomas,the criteria used
to evaluate the usefulness of the che-motherapy are different from
those in the usual phaseII studies that assess tumor response. For
low-gradeastrocytomas, prolonged stable disease has been
con-sidered a response by some investigators. Friedmanand the
Pediatric Oncology Group (1992) studied theresponse of pediatric
brain tumors to carboplatin.Based on results from 13 children with
clearly pro-gressive, low-grade astrocytomas of the optic path-way,
third ventricle, thalamus and suprasellar region,and temporal
region, in which 73% achieved stabledisease and one had a partial
response, Friedmans
group determined that carboplatin is active againstlow-grade
astrocytomas. The duration of stable dis-ease in this subgroup of
patients ranged from 3months to greater than 68 months (median,
40months).
A multi-institutional group studied the combina-tion of weekly
low-dose carboplatin plus vincristinegiven for low-grade gliomas
(Packer et al., 1993,1997). At the most recent report, 78 children
withnewly diagnosed progressive low-grade gliomas witha median age
of 3.1 years were treated with this reg-imen. Fifty-eight were
chiasmatic-hypothalamic in lo-cation, and the remainder occurred in
other loca-tions. Forty-five (56%) children had objective
tumorresponse. Tumor response did not correlate withlength of
disease control. The only significant factorpredictive of outcome
was age, with a 2-year pro-gression-free survival rate for children
younger than5 years at start of treatment of 81% compared with58%
in older children ( p 0.01) (Packer et al.,1997).
Partly because of variability in prognostic factorssuch as age,
the most effective regimen cannot begleaned from these single-arm
studies. Therefore, anational randomized trial in the Childrens
CancerGroup (CCG) is currently underway testing the effi-cacy of
chemotherapy for progressive low-gradegliomas in children younger
than 10 years old, com-paring the carboplatin-vincristine regimen
to theCCNU-based regimen reported by Prados et al.(1997).
Neuropsychological and endocrine outcomeof children treated with
chemotherapy will also beevaluated in this trial.
Long-term Follow-up and Complications of Therapy
The use of chemotherapy for hypothalamic-chiasmalgliomas is
gaining support not only because of thepreviously mentioned risks
of extensive surgery butalso because of the consequences of
conventional RT.For young patients, there is a risk of increased
en-docrine deficits and intellectual impairment follow-ing RT
delivered to the hypothalamic region (Mooreet al., 1992; Ater et
al., 1997, 1999; Tao et al., 1997).Serial IQ scores before
radiation showed no decline,but among those receiving radiation, IQ
scores fell amedian of 12 points from baseline ( Janss et
al.,1995). Also, several reports (Rajakulasingam et al.,1979;
Mitchell et al., 1991) have recognized the risk
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of radiation-induced moyamoya vascular change inthe suprasellar
region, which can result in vasospasm,transient ischemic-type
episodes, seizures, andstrokes. The actual incidence of moyamoya is
notknown, but it may be higher than suspected becausethe symptoms
may also be attributed to progressivedisease. The risk of moyamoya
appears to be relatedto the patients age at radiation, and the
condition hasbeen seen generally in children receiving
radiationbefore 3 years of age or in association with
neurofi-bromatosis type 1 (Poussaint et al., 1995).
When patients experience new symptoms that sug-gest progressive
disease, especially many years aftertreatment, MRI or CT scans can
provide essential in-formation, but definitively distinguishing
progressivedisease from another cause can remain difficult. Attimes
the MRI scan can be diagnostic, revealing hem-orrhage, stroke, or
tumor growth. However, in a re-port by Epstein et al. (1992), three
children with chi-asmatic-hypothalamic gliomas who had symptoms
oftumor progression 9.5, 11.5, and 2 years after RTwere found to
have misleading radiographic findings.Neuroradiographic studies
including angiographyshowed large mass lesions. These were presumed
tobe tumor recurrences and chemotherapy was initi-ated. However, on
autopsy of two and biopsy of thethird, the bulk of the mass was
found to consist ofnumerous vessels of variable size. The authors
pro-posed that these lesions probably represented in-corporation of
the rich vasculature in the chiasmalregion into the tumor, which
underwent degenera-tion secondary to radiation therapy (Epstein et
al.,1992). Further prospective evaluation of the vascularphenomenon
associated with these tumors and theirtreatment is needed.
MENINGIOMAS
Clinical Presentation
Meningiomas can occur anywhere within the craniumand are related
to the arachnoid cap cells of the pac-chionian granulations, where
spinal fluid is absorbedinto the venous sinuses. Meningiomas arise
fromthese structures and are attached to the dura. Theyoccur most
commonly in females, and several differ-ent subtypes of meningioma
can specifically affect thevisual apparatus and the hypothalamus.
Arising pe-ripherally, meningiomas may grow out of the optic
nerve sheath itself. These tumors tend to involve thedura of the
optic nerve and ultimately strangulate thenerve; they may also
occlude the blood supply to the ophthalmic artery. Direct surgery
on these tumorsusually results in devascularization of the optic
nerveand blindness. The indications for surgery are pro-gressive
visual loss and proptosis, similar to the sce-nario with optic
nerve gliomas but with a less favor-able prognosis, as meningiomas
can extend readilyfrom the intraorbital segment of the optic
nervesheath through the optic canal to involve the in-tracranial
dura.
Meningiomas may also arise from the dura aroundthe optic foramen
in which case these lesions maystrangulate the optic nerve and
affect the ophthalmicartery. Both optic nerve sheath meningiomas
andmeningiomas of the optic foramen can be bilateral.This is most
commonly seen in optic foramen menin-giomas where tumor cells may
bridge from one op-tic foramen to the other or may arise as two
sepa-rate, nearly symmetric, lesions around the opticforamen. More
common are meningiomas that arisefrom the dura of the planum
sphenoidale or the tu-berculum sellae. The former cause optic
nerve-typevisual loss, compressing the optic nerves from aboveand
pushing them inferiorly. The latter tend to besuprasellar tumors
and may affect either the opticnerves or the optic chiasm or both.
Some menin-giomas arise from the dura of the diaphragma sellaeand
also act like suprasellar tumors, producing chi-asmal-type visual
loss and sometimes compressingthe pituitary stalk, causing
distortions of pituitary-hypothalamic function. Tumors arising from
the duraof the inner third of the sphenoid wing commonly in-volve
both the cavernous sinus (and the nerves withinit) and the optic
nerve on the same side. Patients af-flicted with these tumors may
present with double vi-sion, ptosis, pupillary abnormalities, and
optic nerve-type visual loss.
Management
Diagnosis
As with gliomas affecting the optic nerves and chiasm,patients
with meningiomas in similar regions needcareful documentation of
their visual function and vi-sual fields. Basic laboratory tests
that include hor-monal evaluations are important. The
diagnosticimaging method of choice is an MRI scan with
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gadolinium contrast, which clearly shows the menin-gioma and
frequently its areas of origin from the dura.Such scans accurately
reveal the effects of the tumoron the surrounding anatomy and help
guide the sur-geon in devising a safe and effective approach.
Surgery
Indications for surgery of meningiomas generally arethose of
progressive enlargement of the tumor alongwith the progressive
visual and neurologic signs thatmay accompany such growth. A number
of menin-giomas reach a certain size and stop growing, so
anargument can be made for careful follow up in somecases.
Basic surgical principles include the planning of acraniotomy
that provides excellent exposure of the le-sion with the ability to
protect and preserve normalneurologic structures. Adjuncts such as
intraopera-tive corticosteroids and mannitol to shrink the
braintemporarily are most helpful, and the surgery is car-ried out
with precise microsurgical techniques. Oc-casionally, a laser or
ultrasonic surgical aspirator al-lows the surgeon to manage
difficult tumors that mayhave a very firm consistency.
Because the vast majority of meningiomas are be-nign, surgery
may not be indicated for patients whosevision is preserved without
it when curative surgerycould produce blindness or other forms of
neuro-logic deficit. In such instances, RT has been benefi-cial in
a reasonable number of patients.
Radiation Therapy
The largest use of radiation for menigiomas has beenwith
conventional RT (Goldsmith et al., 1994). Post-operative RT is
indicated for malignant menigiomas,subtotally resected tumors,
tumors with atypical his-tologies, or multiply recurrent
meningiomas. Focusedradiosurgery also has its role in the
management ofsmall meningiomas, and many promising results havebeen
reported (Hakim et al., 1998).
CRANIOPHARYNGIOMA
Clinical Presentation
Craniopharyngiomas are developmental lesionsthought to arise
from squamous remnants of Rathkespouch. Although these tumors tend
to appear as tu-
mors of childhood, they can actually occur at any age;there are
three basic types of clinical presentation thatare age related. In
childhood, craniopharyngiomastend to be large, cystic suprasellar
lesions that pre-sent as failure of growth and development, which
arerelated to the tumors effects on the
hypothalamus.Craniopharyngiomas may also present with progres-sive
visual loss of the chiasmal type along with ob-structive
hydrocephalus in large lesions that affect thethird ventricle. In
young adulthood, craniopharyn-giomas tend to present in a fashion
similar to pituitary adenomas. In women, the
amenorrhea-galactorrhea syndrome is a common presentation andmay or
may not be associated with progressive chi-asmal-type visual loss.
Men may develop hypopitu-itarism and impotence along with visual
symptoms.In the elderly, these tumors usually present with men-tal
function changes, but may also produce increasedintracranial
pressure and visual loss.
Management
Diagnosis
Medical evaluation for craniopharyngiomas shouldinclude a
careful history and physical examination,paying particular
attention in children to their growthand development, including
secondary sexual char-acteristics, and to sexual function in older
patients.Careful evaluation of the visual system, including vi-sual
acuity and visual field determinations, should becarried out.
Laboratory evaluation should include acareful review of pituitary
hormone status. Becausecraniopharyngiomas frequently arise from the
pitu-itary stalk, some patients, particularly children, pre-sent
with diabetes insipidus; appropriate laboratorytests should be
ordered if this is one of the featuresof clinical presentation.
Patients with increased intracranial pressure usu-ally have
headaches and may have papilledema. Theimaging procedure used for
diagnosis is an MRI scanwith gadolinium contrast. This modality
usually isfairly diagnostic for craniopharyngioma. Becausemany of
these lesions are calcified, a CT scan or evena plain skull X-ray
may show the presence and posi-tion of calcified portions of the
tumor. For the eval-uation of postoperative residual disease, CT
and MRIscans are often complementary, with CT demonstrat-ing
residual calcification (not easily seen on MRI)and MRI most often
demonstrating possible residualcystic or solid
craniopharnygioma.
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Surgery
The surgical principles utilized in the management
ofcraniopharyngioma are a subject of some contro-versy. It is clear
that a proportion of these lesions,particularly cystic lesions in
children, can be totallyexcised. Ordinarily this is accomplished
using a cran-iotomy for those lesions that are suprasellar.
Thecraniotomy procedure utilized to attack a cranio-pharyngioma can
be tailored to the position and ex-tent of the lesion. Subfrontal,
frontotemporal (pteri-onal), and a variety of skull base approaches
can beutilized to approach and effectively remove these le-sions. A
scrupulous microsurgical technique is es-sential and can provide
good results in both extent oftumor removal and preservation or
restoration of vi-sion. If a craniopharyngioma is associated with
sig-nificant enlargement of the sella, then the tumor mayhave had
its origin below the diaphragma sella andmay be amenable to total
removal using thetranssphenoidal approach. For these lesions, the
sizeof the sella, whether the tumor is primarily cystic orprimarily
solid, and whether calcifications are pres-ent can be important
factors in determining the ex-tent of debulking. Many suprasellar
craniopharyn-giomas, particularly in older patients, are
intimatelyassociated with the floor of the third ventricle, the
hy-pothalamus, and the optic chiasm. In such cases, at-tempts at
total removal can produce significant neu-rologic damage; thus the
surgeon must use goodjudgment in attempting complete tumor removal.
Of-ten, it is better to remove the bulk of the tumor andto treat
the small remnants adherent to vital struc-tures with postoperative
irradiation.
Radiotherapy
Conventional RT has been effective for craniopharyn-giomas
(Hetelekidis et al., 1993). For the reasonsstated previously,
however, conventional RT is notrecommended for the immature brain
(generally,children 3 years of age or younger). Stereotactic
tech-niques include radiosurgery, stereotactic RT, and di-rect
colloid instillation into cystic craniopharyn-giomas. Radiosurgery
has been utilized for adjunctivemanagement of craniopharyngiomas.
However, be-cause the chiasm is often in close proximity, the
sameconstraints as discussed earlier apply for cranio-pharyngiomas
(Tarbell et al., 1994).
Radiosurgery should only be considered whenthere is a very small
area (less than 2 cm) of resid-
ual/recurrent tumor that is away from the optic chi-asm. Direct
instillation of colloidal radioisotopes intothe cysts of primarily
cystic tumors appears effectivewhen appropriately applied. This
technique has beenwidely used in Europe with limited experience in
theUnited States. Stereotactic radiation or conformal ra-diation
treatments using conventional fractionationmay be the safest mode
of treatment for patients witha solid component of residual
disease.
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