Given its origin in the cerebellum with the propensity of locally spreading into the fourth ventricle, patients most often present with a combination of cerebellar signs like clumsiness, gait disturbances, and obstructive hydrocephalus, for example, early morning headaches, nausea/vomiting, double vision, or blurry vision.

Since the majority of medulloblastomas arse in the fourth ventricle, obstructive hydrocephalus is not uncommon. These patients may present with emesis, headache, and lethargy. Time from symptom onset to diagnosis is usually short, usually two to three months.[11][20]

Almost all patients have early signs of elevated intracranial pressure that is associated with headache early in the morning and relieved over the course of the day. Patients with Cushing triad usually have impending herniation and need immediate treatment.

The tumor in the cerebellum can also lead to ataxia and truncal unsteadiness. If the brain stem is involved, it may lead to cranial nerve palsies that may present as diplopia, hearing loss, facial weakness, and head tilt.

Fundoscopy may show optic pallor or papilledema. Paralysis of the abducens nerve may lead to an inability to abduct the eye. The sun setting sign may be seen in some infants. Measurement of the head circumference in infants may reveal macrocephaly.

Investigations should include routine laboratories, including thyroid function tests.

Computed tomogram (CT) of the brain may reveal a mass in the 4th ventricle. Most medulloblastomas are contrast-enhancing. Hydrocephalus is common in most patients.

Magnetic resonance imaging (MRI) is performed in all patients as it demonstrates the anatomy better than CT scan. MRI is often used to detect post-surgical residual disease. Spinal MRI is also useful for detecting metastatic spinal lesions.

Other tests include audiometry prior to starting cisplatin treatment. Echocardiogram and pulmonary function tests are obtained as a baseline prior to the start of chemotherapy.

A lumbar puncture may reveal leptomeningeal tumor spread. But despite a positive MRI, cerebrospinal fluid (CSF) may be normal. Prior to a lumbar puncture, fundoscopy is done. Following surgery, lumbar puncture is delayed for at least 2 weeks because the surgery may have caused tumor dissemination, leading to a false-positive result.

Current treatment modalities for medulloblastoma combine surgical resection with chemotherapy and radiation. By traditional risk stratification, cure rates in the average-risk group reached three-quarters of patients. However, post-surgical treatment-related neurologic, cognitive, and endocrinologic sequelae, including intellectual retardation and growth hormone deficiency, remain a source of morbidity in up to 80% of survivors. The high-risk group experienced up to 50% mortality due not only to the presence of extraneural metastases at diagnosis but also due to their young age at diagnosis, which poses significant limitations to their therapeutic options, namely lower doses of radiation and chemotherapeutic agents.[1]

Newer subgroup classification systems have facilitated the development of more targeted therapeutics aimed at disrupting signal transduction pathways critical to phenotypic transformation. These are currently under clinical investigation:

SHH Subgroup

The SHH pathway is activated by the binding of Sonic Hedgehog to its receptor Patched 1 (PTCH1), which activates downstream signaling via a key mediator Smoothened (SMO). The most widely studied targeted therapeutic agents today are SMO inhibitors, i.e., cyclopamine, HhAntag, vismodegib, saridegib, and sonidegib.[21][22][23][24] Sonidegib (NCT01708174) and vismodegib are currently in phase 2 clinical trials in patients with relapsed SHH subgroup medulloblastoma.[25]

WNT Subgroup

The key step in WNT signal transduction leading to malignant transformation is a lack of degradation of beta-catenin due to mutations at key amino acid residues that are normally destined for phosphorylation. Hence, new drugs have been developed to target steps in downstream signaling by beta-catenin. These include naturally-occurring protein phosphatase inhibitors, cantharidin, norcantharidin, and ginkgetin.[26][27][28][29] However, given the benign prognosis of patients in this subgroup (five-year overall survival > 90%), current efforts are being aimed at limiting cytotoxic therapies such as radiation dosing (NCT02724579).

Non-SHH/WNT Subgroup

Unfortunately, not much is known about the signaling pathways implicated in non-SHH/WNT subgroup medulloblastoma. As a result, targeted therapeutics have yet to be developed for this type of medulloblastoma. Promising strategies currently under investigation include myc inhibition, cell cycle checkpoint inhibitors, and histone deacetylase (HDAC) inhibitors.[30][31][32][33]

• Choroid plexus carcinoma
• Ependymoma
• Teratoma

Surgery aims to excise as much tumor as possible and to relieve the obstruction of the CSF. However, care should be taken during surgery as the tumor is friable and can quickly disseminate. Following surgery, more than 40% of patients have residual neurological deficits. Besides cerebellar dysfunction, others may develop mutism, cranial nerve palsies, and hemiparesis. Some symptoms do reverse with time, but extensive rehabilitation is required. At least 50% will have permanent deficits.

In most patients, a ventriculoperitoneal shunt is necessary for the relief of hydrocephalus. Some patients may obtain benefits from an endoscopic third ventriculostomy. Besides central venous access for medications, an Ommaya reservoir for chemotherapy is often used. However, all these procedures have risks, and technical complications are common.

Radiation therapy is often used for local control and management of the micrometastatic disease. Radiation is administered to the craniospinal axis. To maximize the response, it should be given within four weeks after surgery. Reducing the dose of radiation to minimize the complications is associated with higher relapse rates and poor outcomes. For those who relapse, the prognosis is dismal. At this stage, additional radiation may not help.

Patients with medulloblastoma were traditionally stratified into average-risk or high-risk groups based on three primary characteristics: (1) age, (2) extent of residual tumor post-op, and (3) degree of dissemination at the time of diagnosis. Patients who were at least three years old at diagnosis, had, at most, 1.5 cm of postoperative residual disease by MRI, and those who had no extraneural metastases were categorized as average-risk. The rest were high-risk.[1][34]

This traditional risk stratification discounted the influence of tumor histology on tumor behavior and impact on patient prognosis. Recent transcriptional profiling studies derived from microarray data of large numbers of patients with medulloblastoma revealed clusters of patients with similar transcriptomes, proteomes, and cytogenetic signatures involving unique signal transduction pathways. This has led to the currently accepted classification system of medulloblastoma into four primary subgroups: (1) SHH, sonic hedgehog, (2) WNT, wingless; (3) non-SHH/WNT group 3; and (4) non-SHH/WNT group 4.[10][34] Moreover, this system has not only augmented prognostication but has also facilitated the development of novel therapeutic options. That said, the field of medulloblastoma is ever-evolving, and there may be as many as 12 subtypes of medulloblastoma that cluster with high fidelity.[35][36] 

Using a combination of molecular profiling and histology, the World Health Organization (WHO) presently divides medulloblastoma into five subtypes[37]:

1. WNT-activated with classic histology
2. SHH-activated (wild-type TP53), with classic, desmoplastic/nodular, or large-cell/anaplastic histology
3. SHH-activated (mutant TP53), with classic or large-cell/anaplastic histology
4. non-WNT/non-SHH, group 3, with classic or large-cell anaplastic histology
5. non-WNT/non-SHH, group 4, with classic or large-cell/anaplastic histology

The outcomes depend on several factors, including age, stage, the extent of residual disease after surgery, and response to treatment. Children with WNT subtype have a good outcome, whereas those with MYCN or MYC amplification have poor outcomes. Even after successful treatment, many patients are left with permanent residual neurological and cognitive deficits. Children have difficulties with learning, and there is growth impairment. In addition, deficiency of gonadotrophin and thyroid hormones are common. The key reason for these complications is craniospinal radiation.

The five-year survivor rate for those with average risk disease is 85% as long as there is no significant residual disease and no evidence of spread.

In the high-risk group, the 5-year survival is less than 40%.

In children less than three years, survival varies from 30%-70%. Children with metastatic disease do poor, whereas those with SHH or WNT activated lesions have better survival.

Transcriptional and methylation profiling date coupled with cytogenetic aberrations and copy number variations and patient outcomes has helped subclassify medulloblastoma in as many as 12 subtypes, two WNT, four SHH, three group 3 and three group 4. The highest survival rates have consistently been seen for the WNT subgroup at 97-100% at 5 years. The SHH subgroup remains intermediate, with 5-year overall survival between 70%-88%. The non-SHH/WNT subgroups have been thought to have the worst prognosis though group 4 patients tend to do better. Group 4 MB has a 65%-85% 5-year overall survival, while group 3 MB has dismal rates between 40%-65% 5-year overall survival, with myc amplification portending the poorest outcomes.[36]

• Headaches
• Emesis
• Ataxia
• Posterior fossa syndrome
• Shunt infection/malfunction
• Bleeding
• Hemiparesis
• Neurocognitive impairment
• Somnolence syndrome
• Radiation necrosis
• Ototoxicity
• Secondary malignancies
• Chemotherapy associated complications

The patients (or more often the parents of the patients) should be educated on the prognosis of the disease and proper consent should be taken including all the risks involved, given the critical location of the tumor, before proceeding with any type of surgical intervention.

The diagnosis and management of medulloblastoma are best done by an interprofessional team that consists of a pediatrician, neurologist, neurosurgeon, oncologist, radiation therapist, and specialty trained nurses. The majority of children first present with cerebellar symptoms to the primary provider, pediatrician, or nurse practitioner. Once diagnosed the treatment modalities for medulloblastoma combine surgical resection with chemotherapy and radiation. Oncology board-certified pharmacists can consult with the oncologist on the regimens for chemotherapy, and the alternatives based on patient response. The pharmacist should also educate the patient on the management of headache and emesis. The oncology nurse is vital for patient monitoring and educating the patient and family. The oncology nurse should educate the patient on the types of treatments, their benefits, and potential complications. Mental health professionals may be important is vital as many patients develop depression and anxiety. The role of speech, occupational, and physical therapy cannot be understated. The members of the team should communicate and hold weekly meetings to determine the steps in care and ensure that the patient is receiving the current standard of care.

By traditional risk stratification, cure rates in the average-risk group reached three-quarters of patients. However, post-surgical treatment-related neurologic, cognitive, and endocrinologic sequelae, including intellectual retardation and growth hormone deficiency, remain a source of morbidity in up to 80% of survivors. The high-risk patient may have mortality in excess of 50%-75%. For those who survive, complete functional recovery may take months or even years, but an interprofessional team will optimize outcomes.[38][39][40] [Level V]