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:

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.