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Brain tumors are the most common of the
solid tumors in children. It is the second most common neoplasm of
childhood (next to leukemia group) and accounts for 20% of all pediatric
cancers. In developed countries, it is the second most commonest cause of
death, next only to trauma. The incidence rate of benign and malignant
brain tumors in children (age 0-19 years) is 3.7 cases per 100,000. The
rate is higher in males (3.9 per 100,000) than in females (3.5 per
100,000).
Hospital based statistics show brain
tumor is the third common illness for admission in Pediatric
Neurosurgical ward, hydrocephalus and trauma being the first and second
common illnesses.
The
highest incidence of CNS cancer is among children age 7 and younger. Rates
are slightly higher in boys than in girls.
Rates
are higher in white children than in black children. This difference
between the races is seen primarily among boys and young children.
In
the last 2 decades stastics have shown a steady rise in incidence of
pediatric brain tumors of 1% per year, which can only be partly be
explained by better diagnostic methods.
Pathology:
During
fetal life and the first two years, supratentorial tumors are more
common. Tumors in infancy are often found in the midline structures,
which are phylogenetically older.
Between
3 and 15 years infratentorial growth is much more frequent. Cellular
factors, like persisting pluripotent cells in the posterior fossa, are
postulated. Another explanation is the different amount of time neoplasms
like medulloblastoma and cerebellar astrocytoma, need to develop.
Typical
histological types are primitive neuroectodermal tumors are mixed
gliomas, which are rare neoplasms in adults.
There
are secondary germinal areas in the subependymal layer of the lateral
ventricles, in the subpial germinal layer and in the external granular
layer of the cerebellum, where postnatal cell proliferation continues
during the first six months of extrauterine life. Tumors like
medulloblastoma, PNET and ganglioglioma are found in these regions.
Some
brain tumors are much more aggressive in infancy, while others, in
particular optic gliomas, show a better prognosis in young patients.
The
most common primary brain tumors in children are primitive
neuroectodermal tumors/medulloblastoma in ages 0-9, astrocytoma in ages
10-14, and pilocytic astrocytoma in ages 15-19.
The
brain cancers occurring most often in children and adolescents,
generally, fall into three main groups:
Astrocytomas, which
arise from astrocytes. Astrocytomas may grow anywhere in the brain or
spinal cord, but in children, they occur in the brain stem, the cerebrum,
and the cerebellum. Astrocytomas account for nearly 68% of CNS
malignancies in children. Pilocytic astrocytomas account for 30% of all
infratentorial tumors in childhood, and 80% of pilocytic astrocytomas are
found in the posterior fossa. Brainstem
tumors are most commonly diagnosed in children, in whom they account for
10% to 20% of the primary brain tumors.
Pilocytic astrocytomas account for 30%
of all infratentorial tumors in childhood, and 80% of pilocytic
astrocytomas are found in the posterior fossa.
Primitive
neuroectodermal tumors (PNET), which are thought to develop from primitive
nerve cells that normally do not remain in the body after birth. PNETs
include medulloblastomas. These tumors account for about 21% of childhood
CNS cancers.
Ependymomas, which
usually develop in the cells lining the ventricles. These tumors account
for about 9% of CNS tumors in children.
Neuroblastoma
and lymphoma are usually located outside the CNS, but can also be found
as primary CNS neoplasms. With a growing number of immunodeficiency
patients related to HIV or bone marrow transplantation, CNS lymphoma may become
more important.
Genetic
alterations seem to play a more important role than environmental
influences.
An
analysis of 200 cases of childhood brain tumors presents the following
results:
First
degree relatives do not snow a higher incidence of CNS tumors
First
born children with higher birth weights have a greater tendency to
develop a brain tumor
15%
of the mothers suffered from allergies
possible
virus related oncogenesis in cases of live polio vaccine (
medulloblastoma )or zoonosis
5%
occurred after radiation
37.5%
of the ependymomas occurred after miscarriages 18% in others.
Posterior
fossa tumors occurred more often after difficult labor(dystocia).
Some
reports show that many children with brain tumors live in rural areas
implicating zoonosis as a potential risk factor.
Rubella
infection is associated with medulloblastoma.
Cerebral
tumors as secondary malignancies after radiotherapy are reported in 1%.
Familial tumors seem to be limited to one or two generations.
There
is a high risk in patients with phakomatoses to develop neoplasms of the CNS, in particular
neurofibromatosis.
Benign tumors are rare. Among benign
tumors, craniopharyngiomas
are common; the meningiomas are rare.
Clinical features:
Brain tumors can be easily missed and
diagnosis delayed fro several weeks as their clinical features viz,
headache, vomiting and seizures mimic common illnesses like systemic
fever, gastroenteritis and CNS infections. Awareness among parents,
paramedical personnel and family physicians and pediatricians and easy
access to imaging study for all sections of population will be the most
important step in minimizing the delay in diagnosis.
Early morning headache causing early
arousal from bed, vomiting which is not associated with systemic febrile
illness should be investigated when present for more than 3 - 4 days.
Central vomiting has the features of being forceful, without nausea /
anorexia and often relieving the headache; upon completion of vomiting,
the child desires to finish eating.
Headache is the presenting symptom in
more than 50% of children with brain tumors.
Papilledema
on fundoscopy is seen in 40% of supratentorial tumors and 65% of
infratentorial tumors. Papilledema itself does not cause any visual
symptom for several weeks but the finding of papilledema galvanizes the
neurologic examination.
While headache, vomiting and choked disc
are the cardinal triad of intracranial hypertension, 30% of pediatric
brain tumors at specific locations present with focal neurologic signs
without overt ICT; seizures, generalized or focal are the presenting
early symptom in about 20% of supratentorial tumors.
Visual symptoms in optic nerve-chiasmal gliomas,
endocrine disturbances in suprasellar tumors, early gait disturbances in
vermian tumors, cranial nerve dysfunction in brain stem gliomas when
encountered should be investigated appropriately and neuroimaging ordered
to avoid delay in the diagnosis.
Clinical progression in temporal profile
is the hallmark of SOL.
Child's brain has plasticity and
language disturbances are very unusual even in left hemispheric lesions.
Large tumors in non-eloquent locations
may cause only minimal behavioral changes and cause delay in diagnosis.
Macrocrania may be the presenting
symptom in infants.
Diagnosis:
Today CT and MRI are the two modalities
with high accuracy of anatomic diagnosis of brain tumors. In many
situations both are complimentary to each other. While CT scan is quick
taking less than 5 minutes to complete the study, MRI takes a much longer
time and may not be possible in very sick children. Patient monitoring
during the procedure is very difficult in an MRI while this is possible
while doing a CT scan. MRI is four times more expensive than a CT scan.
The undisputed advantage of MRI are the
high sensitivity and the superb anatomical delineation by 3 planar images
which guide the neurosurgeon to plan the surgical procedure. While both
CT and MRI do not give a clue to the pathologic diagnosis in many
patients, CT is more often specific to histology. Germinomas and
medulloblastomas are iso or hyper dense in plain CT scan while
astrocytomas are always hypo dense. Calcification is seen better in CT
than in MRI; tumor hemorrhage is better seen in MRI than in CT. In many
situations the preoperative histological diagnosis may not be essential
as it is determined by the HPE of the surgical specimen.
The crux of the problem lies in lesions
situated in the brainstem, hypothalamus etc where even CT guided
stereotactic biopsy carries high risk especially when the possibility of
tuberculoma is entertained. Trial therapy with ATT and repeat CT after 6
to 8 weeks has been employed by many neurosurgeons in our country.
Examination of CSF for malignant cells
in medulloblastomas and for biological markers in pineal region tumors
help in staging these tumors. Tumor markers, such AFP, and human HCG,
help in monitoring response to therapy, and in follow ups.
Management:
Surgery:
Surgery is indicated in most
patients, and is the primary treatment.
Ventriculo peritoneal shunt / External
ventricular drainage for hydrocephalus is indicated in posterior fossa
tumors and third ventricular SOLs as they cause early obstruction of CSF
pathway. When a tumor appears resectable in imaging studies, V P shunt
can be avoided and hydrocephalus can be managed by temporary preoperative
EVD.
Total excision of benign or
slow growing tumors is achieved wherever possible. Cerebellar
astrocytoma, most craniopharyngiomas, cerebral low grade gliomas in
non-eloquent areas, certain pineal region tumors, meningiomas, colloid
cysts, choroid plexus papilloma are some of the lesions that will be
amenable to total excision. Surgery is curative in these situations.
Subtotal excision:
Medulloblastomas, ependymomas and exophytic brain stem gliomas are the
lesions for which the neurosurgeon attempts total excision but may have
to leave parts of the tumor infiltrating the cerebellar peduncles or
floor of the fourth ventricle. All these patients need postoperative
radiotherapy. Prognosis for long term survival is better when total
excision is achieved compared to partial excision especially for
ependymomas. Debulking (partial excision or intracapsular excision): When
a tumor is highly vascular and has no definite plane of cleavage, the
surgeon resorts to debulking of the tumor in order to minimize the mass
effect of the tumor and excision of central necrotic parts of the tumor
which are less amenable to Radiotherapy and Chemotherapy
Biopsy alone is indicated for
establishing a tissue diagnosis before giving radiotherapy or
chemotherapy. open method for surface lesions, C T guided stereotactic
biopsy for deep lesions are the methods used.
Very rarely, as in brainstem tumors,
empiric radiotherapy is given after excluding the possibility of a
tuberculoma.
Resurgery for recurrent
slow growing symptomatic tumors is preferable to radiotherapy whenever
possible.
In short, when the lesion is benign or
slow growing, the neurosurgeon is very aggressive and attempts to remove
the whole tumor with all available surgical armamentarium in his hands
viz., operating microscope, micro instruments, ultrasonic surgical
aspirator, laser, viewing wand etc.
On the other hand when the tumor is
malignant or aggressive, the neurosurgeon tends to be less aggressive.
Radiotherapy:
In spite of several criticisms for
submitting children for radiotherapy,
radiotherapy continues to be the sheet anchor in the treatment of fast
growing tumors and left out slow growing tumors. Radiotherapy above the
dose of 50 Gy has been very effective in delaying the recurrence of tumor
after surgery thus increasing the survival period and disease free
interval. Once the tissue diagnosis is available from the surgical
specimen and wound healing is sound, radiotherapy is given depending on
the age of the patient and H P E. Mega voltage radiotherapy with multiple
beams using wedge filters and shields help to save not only vital areas
of the brain but also eye and skin. Interstitial brachytherapy and
Stereotactic radiotherapy are useful in specific situations.
the adverse effects of radiotherapy include:
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Early adverse effects:
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Late adverse effects
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Edema
Alopecia
Hematological
complications.
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Dose dependant
complications
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Dose independant
complications
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Psychomotor retardation,
Cranial neuropathy,
Endocrinopathy, Leucoencephalopathy
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Occurrence of second
neoplasms
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In view of significant delayed
complications in young children, radiotherapy is avoided in children
below 3 years of age especially in medulloblastoma and several studies
have shown comparable results with Chemotherapy alone.
Adjuvant therapy:
Though chemotherapy
remains mainly an adjuvant therapy after surgery and radiotherapy,
many centers are conducting trials as to use chemotherapy alone without
radiotherapy in young children in order to avoid the delayed effects of
radiotherapy. Pre-irradiation chemotherapy known as neo-adjuvant therapy
is also being tried for medulloblastomas and pineal tumors. Though
nitrosurea (CCNU or BCNU) which is cell-cycle non specific and readily
crosses the blood - brain - barrier, used as monotherapy has been proved
to improve survival, it is often combined with cell-cycle specific drugs
like Vincristine.
Protocols and prognosis for common
tumors:
Medulloblastoma :
CCNU, vincristine, cis-platin once in 4
to 6 weeks as adjuvant therapy yielded 2 year disease free survival rate
of 96% for high risk patients (T3b to T4 tumors with M1
to 3 spread in Chang's staging).
MOPP regime - Nitrogen Mustard Oncovin,
Procarbazine and Prednisone had 76% 5 year survival.
Eight in one day regime - Vincristine,
CCNU, Cis-platin, Hydroxyurea, Prednisone, Cyclophosphamide, Ara-C,
Procarbazine. . Neo adjuvant therapy:
Vincristine, cis-platin and cyclophosphamide combination as pre
irradiation treatment have given good results.
For children below 3 years of age, if
there is no residual tumor, radiotherapy is avoided and instead,
chemotherapy is given unless there is evidence of local recurrence or
spinal metastases.
For recurrent medulloblastomas the
outlook is very poor. Marrow ablative high dose chemotherapy with
autologous bone marrow transplantation has been tried in some centers.
Ependymoma:
The addition of chemotherapy after
irradiation has not shown any significant benefit to the patient.
Recurrent ependymomas are treated however with cis-platin and etoposide
with marginal benefits (Stereotactic radiosurgery to local recurrence is
being tried in some centers).
High grade gliomas:
When chemotherapy - vincristine &
CCNU - is added to radiotherapy, the 5 year survival improved from 18%
without chemotherapy to 46% with chemotherapy. Eight in one day regimes
have been tried but without any significant added benefit.
Brainstem glioma and low grade gliomas:
The role of chemotherapy for these
tumors is unclear.
In recent years, minimizing the side
effects of chemotherapy, and radiotherapy, in children is an important
consideration. A better understanding of the molecular events leading to
tumor development has provided an opportunity to intervene with
experimental modalities, such as, genetherapy and immunotherapy
(they are discussed
elsewhere).
For
children with brain tumors, genetherapy offers the hope of
replacing the defective genes, amplifying the immune response to cancer.
The malignant phenotype of a brain tumor results from a series of
mutations, including genetic deletions. Therefore, the simple paradigm of
replacing a defective protein does not typically apply to children with
brain tumors. Further study is required.
Prognosis:
Pediatric
brain tumors differ from adult brain tumors in several ways: the
predominant location in the posterior fossa, tendency to present along
central neuraxis, relative delay in establishing the diagnosis, the
higher post-operative mortality rate, the adverse effects of radiation on
physical growth and mental development in young children are but some of
the peculiarities. 30 to 50% of the tumors are benign by location and by
histology and are amenable to radical resection.
Brain
tumors represent 23% of cancer-related deaths in male children under the
age of 20, and 25% of cancer-related deaths in female children under the
age of 20.
More than one half of
children diagnosed with brain tumors will survive 5 years from diagnosis.
In some subgroups of patients, an even higher rate of survival and cure
is possible. Each child's treatment should be approached with curative
intent, and the possible long-term sequelae of the disease and its
treatment should be considered when therapy is begun.
Two major subclassifications
are now being used:
1)
Average risk - Children older than 3 years of
age with posterior fossa tumors; tumor is totally or "near-totally"
(<1.5 cubic centimeters of residual disease) resected; no
dissemination.
2)
Poor risk - Children younger than 3 years of age
or those with metastatic disease and/or subtotal resection (>1.5 cubic
centimeters of residual disease) and/or nonposterior fossa location.
Factors for an unfavorable outcome include, younger age at diagnosis, brain stem involvement, subtotal
resection, and a non-posterior fossa tumor. The prognostic importance of
brain stem involvement is still being debated. These prognostic variables
must be evaluated in the context of the treatment received. Biologic
markers, such as tumor-cell ploidy, are also being evaluated and the
subcategories of disease may change over time. High TrkC mRNA expression
is an independent predictor of favorable clinical outcome.
Five-year
survival rates are highest for children and adolescents with astrocytomas
(74%), followed by other gliomas (57%), ependymomas (56%), and PNET or
medulloblastoma (55%).
Pooling
of pediatric brain tumors in a few centers will certainly yield better
results in these sick children.
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