While leukemias are the most common type of malignancy to afflict the pediatric population, brain tumors are the most common solid tumors in this age group. Medulloblastoma is the most common malignant brain tumor in children constituting nearly 20% of all pediatric brain tumors. It is categorized as an embryonal neuroepithelial tumor of the cerebellum.
This is a high-grade tumor that has a propensity to spread via the cerebrospinal fluid.
Within the first few years of diagnosis, mortality approximates 15%; however, cure rates can reach as high as 60% with current therapeutic modalities. Surgical resection preceded and/or followed by radiation and chemotherapy is the mainstay of therapy, with five-year survival rates of between 50% to 90%. This wide range is multifactorial, owing in part to age at diagnosis, the presence of metastases at diagnosis, and a histologic variant of medulloblastoma. Regardless of long-term survival, treatment-related cognitive, neurologic, and endocrinologic effects remain a debilitating concern and an impetus for the search for further therapeutic modalities.
There is no clear etiology to medulloblastoma. Some studies have found a link between maternal diet and blood/immune disorders during pregnancy. Others report an association with viral infections, for example, early John Cunningham (JC) viral infections or human cytomegalovirus (CMV) infections in childhood.
Medulloblasotms may have a familial association and are also known to be associated with:
Examining data from the Surveillance, Epidemiology, and End-Results (SEER) database from 1973 through 2007, the annual incidence for medulloblastoma was reported at six per million children, in other words, approximately 450 new pediatric cases per year. Children age 4 to 9 years old had the highest incidence at 44%, followed by adolescents (10 to 16 years old) at 23%, and only a 12% incidence in infants/toddlers (0 to 3 years old). Pediatric incidence was calculated to be ten-fold higher than adult incidence. Medulloblastoma affected males 1.5 times more than females.
Thought to originate from the granule cell precursors in the external germinal layer (EGL) of the developing cerebellum, tumor growth starts in the fourth ventricle and can grow to occupy it completely. After that, the tumor spreads to the cerebellar vermis and the brainstem, seeding the craniospinal axis. Medulloblastoma is a highly malignant tumor with a propensity for local invasion and distant metastatic spread through the subarachnoid system (i.e., within the brain and along the spinal cord, also known as "drop mets").
Extraneural metastases in pediatric medulloblastomas are an infrequent occurrence (approximately 7%). The most frequent sites of extraneural metastasis in children include bone (78%), lymph nodes (33%), liver (15%), and lungs (11%). The average time to develop after maximal surgical resection is approximately 20 months. Survival in these cases is dismal and in most cases, can be less than six months.
Notably, the most common cytogenetic mutation encountered in medulloblastoma is isochromosome 17q, resulting from the loss of the short arm (p) with a resultant gain of genetic material from the long arm (q). Also, deletions in the short arm have also been frequently reported, leading to loss of heterozygosity of 17p, (i.e., 17pLOH). Interestingly, the tumor suppressor gene, TP53, which is located on chromosome 17p, is rarely mutated in medulloblastoma. Thus, the search for putative tumor suppressor genes on chromosome 17p in the context of medulloblastoma is ongoing.
The five histologic subtypes encountered in medulloblastoma include:
In classic medulloblastoma, sheets of small round cells, possessing a high nuclear-to-cytoplasmic ratio, are noted. They have a high invasive tendency and possess occasional neuroblastic differentiation. The classic type constitutes approximately 70% of medulloblastomas. Nodules of tumor cells displaying neurocytic differentiation on a collagen-rich matrix characterize the desmoplastic variant; these tumors are less aggressive than the classic variant and account for 15% of medulloblastomas. Large-cell anaplastic medulloblastomas, as the designation suggests, demonstrate features of anaplasia. These features are large tumor cells with abundant cytoplasm, pleomorphic nuclei, and prominent nucleoli. These tumors are typically located in the cerebellar vermis and are highly aggressive, demonstrating high mitotic and apoptotic activity with large areas of necrosis. Consequently, the prognosis is especially poor with short survival times after diagnosis. They constitute approximately 10% of medulloblastomas. The last two variants are rare and make up the remaining 5% of medulloblastomas.
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.
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.
CT of the brain may reveal a mass in the 4th ventricle. Most medulloblastomas are contrast-enhancing. Hydrocephalus is common in most patients.
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. ECHO and pulmonary function tests are obtained as a baseline prior to the start of chemotherapy.
Lumbar puncture may reveal leptomeningeal tumor spread. But despite a positive MRI, CSF fluid 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.
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:
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. Sonidegib (NCT01708174) and vismodegib are currently in phase 2 clinical trials in patients with relapsed SHH subgroup medulloblastoma.
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. 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).
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.
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 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.
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. 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. 
Using a combination of molecular profiling and histology, the World Health Organization (WHO) presently divides medulloblastoma into five subtypes :
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, 2 WNT, 4 SHH, 3 group 3 and 3 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.
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.  [Level V][Level 5]
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