Morphologically similar tumors arising in the pineal region are termed pineoblastomas, and those arising in other CNS locations are called primitive neuroectodermal tumors (PNETs).

With aggressive surgery, craniospinal radiotherapy and chemotherapy, more than 50% of children with medulloblastoma can be expected to be free of disease 5 years later. However, treatment for this disease often results in significant endocrinological and intellectual sequelae.

Pathophysiology: Medulloblastoma is a cerebellar tumor arising predominantly from the cerebellar vermis. The histogenesis of medulloblastoma remains controversial.

One view suggests that the cell of origin derives from the external granular layer of the cerebellum. This is supported by the finding that the proliferation of precursor neurons in this layer is controlled by sonic hedgehog, whose receptor PTCH is mutated in a subset of sporadic medulloblastomas. Another hypothesis proposes that medulloblastomas have more than one cell of origin. This is based on studies showing differential immunoreactivity to a neuronal calcium-binding protein that is not expressed in the external granular layer and to a beta-tubulin isotype that is expressed in the neuronal cells of the ventricular matrix and external granular layer. Recent studies suggest that medulloblastoma expression of neurotrophin (NT3) and its cognate receptor, Trk C, may modulate the behavior of these tumors by inducing apoptosis, thereby retarding tumor progression and resulting in a more favorable prognosis.

As the tumor grows, obstruction of cerebrospinal fluid (CSF) passage through the fourth ventricle generally occurs, resulting in hydrocephaly. The tumor may spread contiguously, to the cerebellar peduncle and/or the floor of the fourth ventricle; anteriorly, to the brainstem; inferiorly, to the cervical spine; or superiorly, above the tentorium. It also may spread via the CSF intracranially or to the leptomeninges and spinal cord. Of all the pediatric CNS neoplasms, medulloblastoma has the greatest propensity for extraneural spread, especially to bone and bone marrow; however, the rate of such events is less than 4%.

Frequency:

• In the US: Approximately 250 new patients are diagnosed annually.

• Internationally: Exact figures are not known. In general, brain tumors occur at a rate of 2.5-4 per 100,000 at-risk children per year. Of these, approximately 18% are medulloblastoma.

Mortality/Morbidity: Risk group stratification is continuing to evolve but is currently based on 3 principal features, including age, extent of postoperative residual disease, and the metastasis stage (M stage) derived from the Chang classification staging system. In the M stage classification, M0 = no gross subarachnoid or hematogenous metastasis; M1 = microscopic tumor cells found in CSF; M2 = gross nodular seeding in cerebellum, cerebral subarachnoid space, or in the third or fourth ventricles; M3 = gross nodular seeding in spinal subarachnoid space; and M4 = extraneuraxial metastasis.

The specific risk groups based on this classification scheme are defined below.

• Average-risk disease: This risk group is defined as patients older than 3 years who are at stage M0 with less than 1.5 cm² of residual tumor postoperatively. The 5-year survival rate for this group is currently 78%.
• Poor-risk disease: This risk group is defined as patients older than 3 years who are at stage M1-M4 and/or with more than 1.5 cm² of residual tumor postoperatively. The 5-year survival rate for this group is currently 30-55%.
• Infants: This group is defined as patients younger than 3 years. This group has the worst prognosis, regardless of M stage and extent of postoperative residual disease. The 5-year survival rate is approximately 30%; however, patients with metastatic disease do considerably worse.

Long-term effects: Despite successful treatment, a significant number of patients have neurocognitive and endocrinologic deficits. Although most long-term survivors have normal intelligence, many subsequently develop learning difficulties that require individualized educational programs. Biochemical growth deficiency is observed in 70-80% of patients, and some degree of growth impairment is present in well over half of patients after treatment. Thyroid and gonadotropin hormonal deficiency also may occur. Craniospinal radiation, a mainstay of treatment, has been implicated as a major cause of these deficits.

Race:

• No racial predisposition exists.

• The latest data from the Surveillance, Epidemiology, and End Results (SEER) program showed that patients aged 0-14 years in the United States have an incidence rate per million population of 5.7 in whites and 5 in blacks.

Sex:

• US incidence per 1 million population for patients aged 0-14 years is 6.1 for boys and 4.5 for girls.

Age:

• Peak age of incidence is 3-5 years. Approximately 80% of patients are diagnosed in the first 15 years of life.

History:

• Although 70-90% of patients present with a history of headaches, emesis, and lethargy, these symptoms are generally intermittent and subtle. Duration of symptoms for 3 months or more before diagnosis is common.
• Increased intracranial pressure (ICP)

• Early symptoms are secondary to increased ICP. The classic triad consists of morning headaches, vomiting, and lethargy. Headache consists of head pain present upon arising that is relieved by vomiting and gradually lessens during the day. Cushing triad (ie, hypertension, bradycardia, and hypoventilation), an uncommon finding in children with increased intracranial pressure, usually indicates impending herniation.

• Initial signs of increased ICP are usually subacute, nonspecific, and nonlocalizing.

• School-aged children may complain of vague intermittent headaches and fatigue. They may demonstrate declining academic performance and personality changes.

• Infants may present with irritability, anorexia, and developmental delay.

• Cerebellar dysfunction

• With increasing tumor size and invasion into the surrounding brain tissue, more characteristic symptoms appear.
• One symptom is progressively worsening ataxia involving the lower extremities, often with relative sparing of the trunk and upper extremities.

• Brain stem deficits: Tumor infiltration of the brain stem or increased ICP may result in diplopia and multiple other cranial nerve findings, such as facial weakness, tinnitus, hearing loss, head tilt, and stiff neck.

• Metastatic disease: Uncommonly, patients may present with back pain or leg weakness secondary to spinal metastasis.

Physical:

• The earliest signs are nonlocalized and caused by increased ICP. Later signs are generally due to tumor invasion of the surrounding tissue.
• Increased ICP

• Funduscopic evaluation reveals papilledema or optic pallor in infants.

• Palsy of cranial nerve VI resulting in the inability to abduct one or both eyes is common.

• Infants may have the "setting sun" sign. This is demonstrated by impaired upgaze and seemingly forced downward deviation of the eyes.
• Measurement of head circumference in infants with open cranial sutures also may reveal macrocephaly.

• Cerebellar findings: Localized deficits in truncal steadiness, upper extremity coordination, and gait are common.

• Brain stem findings

• Invasion into the brain stem may cause loss of conjugate gaze (gaze palsy) or the inability to adduct one eye on attempted lateral gaze. This is observed most commonly in combination with deficits of cranial nerves V, VII, and IX.

• Invasion into the cerebellopontine angle results in facial weakness and hearing loss, often with associated unilateral cerebellar deficits.

Causes:

• Environmental: Epidemiological studies investigating parental occupational exposures, environmental exposures and maternal nutritional intake have not proven a direct link between such factors and the development of childhood brain tumors.

• Familial and heritable disease

• Medulloblastoma is associated with recessively inherited Turcot and ataxia-telangiectasia syndromes.

• As many as 5% of patients with autosomal dominant nevoid basal cell carcinoma (Gorlin) syndrome develop medulloblastoma. These tumors demonstrate loss of heterozygosity at band 9q22-q23, the region containing the PTCH tumor suppressor gene associated with Gorlin syndrome.

• Genetic associations: The most frequent cytogenetic abnormality in sporadic medulloblastoma is an isochromosome 17q [i(17q)]. Of tumors analyzed, 40-50% have a deletion of the short arm of chromosome 17, implicating the presence of a tumor suppressor gene that maps to 17p, which is distinct from the p53 gene. Alternatively, a gene on 17q may be related to transformation because of increased copy number.

Lab Studies:

• The routine pretreatment laboratory evaluation includes CBC, electrolytes, liver, and renal function tests. Baseline thyroid function studies and viral titers also are recommended.

Imaging Studies:

• Computerized tomography

• A CT scan of the head with and without contrast has more than 95% sensitivity for the detection of brain tumors.
• On CT, prominent hydrocephalus and a solid, homogeneous, isodense to hyperdense, contrast-enhancing, midline cerebellar mass are characteristic of (although not diagnostic of) medulloblastoma.

• Magnetic resonance imaging

• Head and spinal MRI with and without gadolinium should be performed in all patients with CT or clinical findings consistent with medulloblastoma.
• Other midline posterior fossa tumors, such as cerebellar astrocytoma and ependymoma, may have a similar appearance on CT.
• MRI can be useful in such instances by better demonstrating the anatomic origin and extent of tumor.

• Preoperative and postoperative MRI is required for detection and measurement of residual disease following surgical resection. Postoperative MRI evaluation should be performed within 72 hours of surgery to delineate residual tumor from the postsurgical inflammatory changes that are visualized on MRI at this time.

• Spinal MRI is the most sensitive method available for detection of spinal cord metastasis.

• Bone scan: Because medulloblastoma can metastasize outside the CNS, especially to bone, a bone scan with plain film correlation may be useful in symptomatic patients.

Other Tests:

• A baseline hearing test (audiogram or BAER) is recommended because of the potential toxicity from radiation and chemotherapy. Some investigational treatment protocols may require additional tests, such as echocardiogram, pulmonary function tests, or other more specific tests, for the purposes of monitoring treatment-related toxicity.

Procedures:

• Lumbar puncture

• CSF cytologic examination is useful for the detection of microscopic leptomeningeal tumor dissemination. However, neither clinical symptoms nor negative CSF cytologic findings can be relied on to indicate the presence of nodular spinal cord disease. As many as 50% of patients with positive spine MRI studies are asymptomatic and have negative cytologic results.

• Funduscopic examination (or CT or MRI) must be performed before lumbar puncture (LP) to rule out the presence of hydrocephaly.
• In known cases of medulloblastoma, LP generally is deferred until 2 weeks postoperation to avoid the presence of tumor cells that have disseminated as a result of surgery.

• Bone marrow aspirate and biopsy

• Medulloblastoma rarely metastasizes to bone marrow.
• These tests should be reserved for patients who demonstrate abnormal peripheral blood findings that have no clear etiology.

Histologic Findings: Medulloblastomas are undifferentiated embryonal neuroepithelial tumors of the cerebellum. They are highly cellular, soft, and friable tumors composed of cells with deeply basophilic nuclei of variable size and shape, little discernible cytoplasm, and often abundant mitoses. These characteristics give the microscopic appearance of a small, round, blue cell tumor. Morphologically identical tumors arising in the pineal region are termed pineoblastomas, and those arising in other CNS locations are called primitive neuroectodermal tumors (PNETs).

Homer-Wright rosettes (ringlike accumulations of tumor cell nuclei around a neuropil-containing or fibrillary core) and pseudorosettes are variably present. These tumors express neuronal and neuroendocrine markers, including synaptophysin and neurofilament proteins.

Various degrees of glial or neuroblastic differentiation are noted, suggesting that the primitive cell of origin possesses the capacity for bipotential differentiation. A histologic variant with abundant stromal component, desmoplastic medulloblastoma, occurs dominantly in the lateral cerebellar areas of adolescents and adults.

Medical Care:

• Standard therapy consists of aggressive surgery followed by radiation to the entire craniospinal axis with boost to both the primary tumor site and focal CNS metastatic sites. Recently, adjuvant chemotherapy also has been shown to be beneficial.
• Radiation therapy

• Average-risk disease
  • Reducing the amount of craniospinal radiation in an attempt to decrease morbidity without jeopardizing survival appears to be successful in this group. In a recent report by the International Society of Pediatric Oncology, children with average-risk medulloblastoma randomly received either the standard 36 Gy or a reduced dose of 24 Gy to the neuraxis. It was found that no statistical difference in progression-free survival rates was demonstrated between the groups as long as the initiation of radiotherapy was not delayed by the administration of chemotherapy before radiation.
  • The current dose for average-risk medulloblastoma patients enrolled on Children's Cancer Group (CCG) trials is 23.4 Gy to the craniospinal axis followed by 32.4 Gy boost directly to the primary tumor site. In both the poor-risk and average-risk groups, the total radiation dose to sites of known disease is 55.8 Gy.

• Poor-risk disease
  • The current recommendation is 36 Gy to the craniospinal axis, followed by a boost of 19.8 Gy to the primary tumor site and an additional 19.8 Gy to focal metastatic sites. The amount of boost that can be given is limited by the presence of the optic nerves within the radiation field or if more than two thirds of the supratentorial compartment volume is within the radiation field.
  • Spinal disease that is visible after 30.6 Gy of the prescribed 36 Gy to the craniospinal axis receives an additional boost up to a total of 45 Gy if the tumor is located above the termination of the spinal cord and up to 50.4 Gy if the tumor is located below the termination of the cord.
• Infants
  • Radiotherapy for patients younger than 3 years, the poorest risk group, remains controversial. Because the effects of radiotherapy on intellectual development are most severe in this age group, attempts have been made to delay or omit radiation by using chemotherapy. However, in the most recent CCG study, infants receiving chemotherapy alone had a 29% 3-year progression-free survival rate for those without dissemination and only 11% for those with metastasis. The Pediatric Oncology Group (POG) reported that, in infants with medulloblastoma treated initially with chemotherapy followed by delayed radiation, the 2-year progression-free survival rate was 34%.
  • Trials are currently underway to avoid or delay radiotherapy in this population by using cycles of high-dose chemotherapy followed by autologous stem cell rescue.

• Chemotherapy

• Average-risk disease
  • The most encouraging results with adjuvant chemotherapy have been reported in children with nondisseminated medulloblastoma receiving 8 cycles of lomustine (CCNU), vincristine, and cisplatin chemotherapy for approximately 1 year following conventional dose radiotherapy and concomitant vincristine.
  • Latest trials indicate that children aged 3-10 years who received this regimen with reduced-dose craniospinal radiation have a superior survival rate compared to those who received standard radiation alone. The current 3-year progression-free survival rate for those receiving adjuvant chemotherapy is approximately 80%.

• Poor-risk disease
  • To improve survival rates in this group, current trials are investigating the use of high-dose chemotherapy (most commonly using carboplatin and thiotepa-containing regimens) and autologous stem cell rescue after a course of conventional craniospinal radiotherapy and chemotherapy.
  • Chemotherapeutic agents that have been found to be most effective for this disease are cisplatin, carboplatin, cyclophosphamide, and vincristine.
• Infants
  • In children younger than 3 years, there is evidence that some do respond at least partially to chemotherapy. In patients with minimal residual postoperative disease, this response may be long-lasting.
  • Ongoing trials are investigating high-dose chemotherapy (carboplatin and thiotepa) and stem cell rescue, following induction with chemotherapeutic agents similar to those used in the treatment for older children with poor-risk disease. Whether radiotherapy can be safely delayed or omitted altogether in certain subgroups has not yet been determined.

Surgical Care:

• Suboccipital craniotomy

• Because the tumor is often friable, gentle suction is used. Microdissection is used to remove adherent portions.

• Modern neurosurgical techniques permit complete or near-complete resection with little or no significant increase in morbidity and mortality rates compared to more conservative surgery.

• Because surgical estimates of the extent of resection may not be reliable, postoperative MRI evaluation for residual disease is required within several days of the procedure.

• As many as 40% of patients have some degree of new neurologic dysfunction postoperatively. One ill-defined syndrome is posterior fossa syndrome, characterized by mutism, cerebellar dysfunction, supranuclear cranial nerve palsy, and hemiparesis that occurs 12-48 hours after surgery. Resolution is expected, although it may take several weeks.

• Ventriculoperitoneal shunt: A significant number of patients require placement of a ventriculoperitoneal shunt at the time of operation (or shortly thereafter) because of unresolving obstructive hydrocephaly.

Consultations:

• As a direct result of the tumor and/or therapy, many patients are referred to occupational, physical, hearing, and speech therapists for rehabilitation of common neurologic dysfunction. Neurophthalmologists also may be consulted after successful treatment to evaluate persistent gaze palsies that may effect visual development.

• Team members for the care of all patients should include specialists from each of the following:

• Neurosurgery

• Pediatric oncology and/or neuro-oncology

• Radiation oncology

• Neurology
• Neuropsychology
• Endocrinology

Diet:

• No specific dietary restrictions or requirements are indicated.

• Patients who develop severe anorexia or weight loss as a result of therapy may need supplemental nutrition to maintain daily requirements. Most patients can tolerate enteral supplementation, but some may need parenteral support.

Activity:

• Most patients have no restrictions on activity other than limitations from neurologic deficits caused by the tumor and treatment.

• Patients with ventriculoperitoneal shunts may be restricted from performing high-impact sports (eg, diving).

Chemotherapeutic agents are continually evolving. Historically, the most active drugs have been DNA alkylators. These agents cause DNA damage and disrupt DNA replication. The agents with the longest clinical history in the treatment of medulloblastoma are vincristine, lomustine (CCNU) and cisplatin.
Drug Category: Antineoplastic agents -- These agents disrupt DNA replication, which inhibits tumor growth and promotes tumor cell death.

Further Inpatient Care:

• Admit for specific chemotherapy and for complications (eg, fever, neutropenia, infection) as a result of therapy.

Further Outpatient Care:

• Radiotherapy: Daily outpatient radiotherapy (usual dose fractions of 180 cGy/d) is performed for approximately 6 weeks.

• Physical and neurologic examination

• Careful monitoring of response and treatment-associated side effects is performed weekly during radiotherapy and at least every 2 weeks during chemotherapy.
• Reevaluation immediately before each cycle of chemotherapy is necessary to document resolution of previous treatment-related toxicities.
• Following the completion of therapy, assessments are conducted every 3 months for the first 12-18 months, every 6 months for the next 2 years, and then annually, provided no complications have occurred.

• Imaging studies

• To have an objective measurement of tumor response to therapy, MRI with contrast of the head is performed at the completion of radiotherapy, after every 2 cycles of chemotherapy, and at the end of therapy.

• Unless clinically indicated, follow-up MRI scans after the completion of therapy are performed in conjuncture with the physical and neurologic examination schedule.
• MRI with contrast of the spine is performed only at the completion of therapy and annually thereafter unless there has been metastatic spinal disease, in which case more frequent evaluation may be necessary.

• Laboratory studies

• Carefully monitor toxicities associated with therapy. It is necessary to perform weekly CBC during radiotherapy and chemotherapy, as well as liver function studies, electrolytes, renal function, and a hearing test before each cycle of chemotherapy and again at the end of treatment.
• Baseline studies should be obtained before the initiation of any therapy. It may be necessary to obtain these tests annually for the first 3-5 years after therapy.
• A baseline endocrinologic and neuropsychologic evaluation should be performed at the completion of therapy and annually thereafter.
• Additional tests for the purposes of monitoring specific investigational protocol treatment-related toxicity (eg, echocardiogram, pulmonary function tests, other studies) may be required according to protocol guidelines.

In/Out Patient Meds:

• Inpatient medications are dictated by the most current chemotherapeutic protocols available for the treatment of medulloblastoma. The most commonly used chemotherapeutic agents are DNA alkylators.

• Most regimens require the concomitant use of an antiemetic.

• Because of the immunosuppressive effects of chemotherapy, trimethoprim sulfamethoxazole and nystatin are commonly prescribed for prophylaxis against Pneumocystis carinii PCP pneumonia and mucocutaneous candidiasis, respectively, for the duration of treatment.

• Granulocyte colony stimulating factor (GCSF) following chemotherapy may be used in treatment regimens expected to cause marked neutropenia.

Transfer:

• Transfer to centers that can provide appropriate MRI imaging studies, neurosurgical intervention, radiotherapy, and chemotherapy may be necessary.

Deterrence/Prevention:

• Avoid exposure to ill contacts during therapy.

Complications:

• Obstructive hydrocephaly

• Neurologic impairment

• Pain secondary to metastasis

• Chemotherapy-induced effects

• Anemia

• Thrombocytopenia and increased risk for bleeding

• Neutropenia and increased risk for life-threatening bacterial, viral, and fungal opportunistic infections

• Nephrotoxicity, ototoxicity, hepatotoxicity, and neurotoxicity

• Radiation-induced effects

• Neurocognitive and endocrinologic dysfunction
• Mineralizing microangiopathy with ischemia or infarct
• Secondary CNS and thyroid malignancies

Prognosis:

• The clinical criteria used to assign prognostic risk groups is continuing to evolve but is currently based on the following 3 features: age, metastasis at presentation, and extent of postoperative residual disease.
• Metastasis stage (M stage) is derived from the Chang classification staging system, whereby M0 = no gross subarachnoid or hematogenous metastasis; M1 = microscopic tumor cells found in CSF; M2= gross nodular seeding in cerebellum, cerebral subarachnoid space, or in the third or fourth ventricles; M3 = gross nodular seeding in spinal subarachnoid space; and M4 = extraneuraxial metastasis. The CCG-921 study confirmed prospectively the unequivocal impact of metastasis at diagnosis on early tumor progression or relapse. Although the M1 stage lacked statistical power, in this study, the lower M stage correlated with improved progression-free survival rates (M0 > M1 > M2+) in children older than 3 years.
• The current risk groups are specifically defined, as follows:
• Average-risk disease: Average-risk disease is defined as patients older than 3 years who are at stage M0 with less than 1.5 cm² of residual tumor postoperatively. The 5-year survival rate for this group is currently 78%.

• Poor-risk disease
  • Poor-risk disease is defined as patients older than 3 years who are at stage M1-M4 and/or with more than 1.5 cm² of residual tumor postoperatively. The 5-year survival rate for this group is currently 30-55%.
  • All patients with nonposterior fossa tumors that are morphologically similar to medulloblastoma (PNETs) have a poor prognosis similar to patients with poor-risk medulloblastoma, regardless of dissemination.

• Infants: Infants are defined as patients younger than 3 years. This group has the worst prognosis, regardless of M stage and extent of postoperative residual disease. The 5-year survival rate is approximately 30%; however, patients with metastatic disease do considerably worse.

Patient Education:

• Patients and family members should be instructed about the care of the central venous catheter.

• Patients should be instructed about protection against infection and what to do should infection be suspected during therapy.