Medulloblastoma Diagnosis and Treatment

Abstract

Medulloblastoma is the most common malignant brain tumor in children. About 16–20% of all primary brain tumors in children are medulloblastoma, and it accounts for about 40% of all cerebellar tumors in childhood. The incidence of medulloblastoma peaked in those aged 9 years and younger. Some of the most common clinical symptoms of medulloblastoma are headache, vomiting, vertigo, and ataxia. Additional manifestations that may occur include lethargy, irritability, motor or cranial nerve impairment, gaze-palsy, sphincter disorders, and back pain in those with spinal metastases. Imaging tests can help determine the location and size of the brain tumor. A computerized tomography (CT) scan or magnetic resonance imaging (MRI) may be done immediately. It is uncommon to do a biopsy, but it may be recommended if the imaging studies are not typical of medulloblastoma. The treatment for medulloblastoma depends on several factors, including clinical conditions of the patient and the size and location of the tumor. Treatment methods for medulloblastoma usually include surgery followed by radiotherapy, chemotherapy, or both. Treatment for medulloblastoma focuses on removing as much of the tumor as safely possible and relieving intracranial pressure. This three-part approach, surgery, radiotherapy, and chemotherapy, can increase the survival of patients by up to 75%.

1. Introduction

Medulloblastomas are embryonal tumors of the posterior fossa. They are the most common malignant brain tumors in pediatric patients. First described by Cushing and Bailey in 1925, these tumors derive from discrete neuronal lineages based on molecularly defined subgroups. Children and teenagers under the age of 16 are primarily involved. It can rarely occur in adults. Medulloblastoma in adults is usually diagnosed between the ages of 20 and 44.

Medulloblastomas account for approximately 20% of brain tumors in children and 1% of primary central nervous system in adults [1]. Medulloblastoma exhibits a bimodal distribution in children. Children age 4–9 years old had the highest incidence at 44%, followed by adolescents (10–16 years old) at 23%, and only a 12% incidence in infants/toddlers (0–3 years old). There is an overall male gender predilection with a male-to-female ratio that differs between molecular subgroups. Medulloblastoma affected males 1.5 times more than females [1].

There is no clear etiology for medulloblastoma. An association between medulloblastoma and viral infections, for example, early John Cunningham (JC) viral infections or human cytomegalovirus (CMV) infections in childhood, has been reported. The majority of medulloblastomas occur as sporadic cases. However, hereditary conditions have been associated with medulloblastoma, including (1) Gorlin syndrome, (2) blue rubber-bleb nevus syndrome, (3) Turcot syndrome, (4) Rubinstein–Taybi syndrome, and (5) Li-Fraumeni syndrome.

The five histologic subtypes of medulloblastoma include:

(1) Classic MB (2) desmoplastic-nodular (D/N) MB, (3) large-cell anaplastic (LC/A) MB, (4) melanotic MB, and (5) Medullomyoblastoma [1].

The classic types account for approximately 70% of medulloblastomas. They have a high invasive tendency and possess occasional neuroblastic differentiation. Desmoplastic variants are less aggressive than classic ones and account for 15% of medulloblastomas. Large-cell anaplastic medulloblastomas constitute approximately 10% of medulloblastoma, are typically located in the cerebellar vermis, and are highly aggressive. This type of MB has high mitotic and apoptotic activity and large areas of necrosis. The prognosis is poor and survival time is short after diagnosis. The last two variants are rare and comprise 5% of medulloblastomas [1]. The most recent WHO classification of central nervous system tumors has divided medulloblastoma into four molecular subgroups: Wingless-activated (WNT), sonic hedgehog-activated (SHH), Group 3 and Group 4. Each subgroup has distinguished molecular, demographic, and clinical characteristics. The WNT medulloblastoma is the rarest subgroup, accounting for 10% of all medulloblastomas, and is the subgroup with the best prognosis. The SHH subgroup accounts for 30% of all medulloblastomas and is characterized by aberration in the SHH signaling pathway. Group 3 tumors account for 25% of all medulloblastoma cases and this subgroup has the poorest prognosis. Group 4 tumors account for 35% of all medulloblastomas; this subgroup is the most common. These tumors have an intermediate prognosis, similar to the SHH subgroups (see Appendix A) [2].

2. Clinical presentation

Patients with medulloblastoma can present with variable manifestations. Clinical Symptoms often progress over several weeks to months, and it is not uncommon for patients to have an extended symptomatic period before initial diagnosis. The clinical manifestation of medulloblastoma is generally nonspecific; it presents with symptoms of a rapidly growing posterior fossa tumor [3].

Medulloblastoma symptoms can vary depending on several factors, including a person’s age, the size of the tumor, the anatomic location of the tumor, the presence of disseminated disease, and the presence of hydrocephalus. The most common presentation concerns raised intracranial pressure, including headache, vomiting, and lethargy. The younger, nonverbal patient presents with behavioral change. Symptoms in younger children include listlessness, irritability, and vomiting. The complaint of older children and adults is headache, especially upon awakening in the morning. Vomiting without nausea is common in the morning since being recumbent increases intracranial pressure [4].

Often, symptoms such as vomiting cause the patient to undergo a workup of the gastrointestinal tract for a long time prior to consideration of the CNS. Double vision may be developed by stretching of the 6th nerve caused by hydrocephalus. The sixth cranial nerve can be compressed at the petroclival ligament, resulting in diplopia and lateral gaze palsy caused by hydrocephalus. More commonly, visual disturbances result from papilledema; however, they also may originate from cranial nerve palsy (most commonly CN IV or VI). Papilledema may be present in as many as 90% of patients. The fourth cranial nerve is usually compressed by direct tumor extension into the cerebral aqueduct. Fourth cranial nerve dysfunction causes the greatest difficulty when eyes are rotated medially and depressed (i.e., going downstairs).

Examination of the extraocular muscles may detect nystagmus, which can be related to a lesion of the cerebellar vermis. Although this sign is nonspecific since Medulloblastoma is most commonly located midline, unilateral dysmetria is less common in the cerebral signs than either truncal ataxia or a wide-based gait. Recent symptoms are easily observable on tandem gait. In children, the tumor most commonly involves the cerebellar vermis and causes gait ataxia more readily than unilateral symptoms [4].

Desmoplastic medulloblastoma is more common in adults. This type of tumor usually arises in the cerebellar hemisphere, and signs of ipsilateral cerebellar dysfunction in the arm or the leg are more common. Torticollis and head tilt can be a manifestation of accessory nerve or trochlear nerve palsy caused by direct tumor compression. Also, head tilt and neck stiffness, caused by meningeal irritation, are complications of tonsillar herniation below the foramen magnum. Spreading of medulloblastoma to the spinal cord may cause the following symptoms: Back pain, inability to control the bowel and bladder, difficulty in gait, and severe weakness from tumor compression of the spinal cord or nerve roots (e. g., radiculopathy) [4].

3. Diagnosis

Medulloblastoma (MB) remains a challenging entity due to its aggressive nature, particularly when affecting pediatric populations. The diagnosis and subsequent classification of MB are pivotal in determining appropriate treatment strategies and predicting patient outcomes. The intricate diagnostic process involves a series of essential steps that collectively contribute to a comprehensive understanding of the tumor.

The clinical evaluation of a patient suspected of having MB is crucial in establishing a baseline for further investigations. The clinical presentation of medulloblastoma is generally nonspecific and is similar to that of other posterior fossa tumors. Symptoms such as persistent headaches, unexplained nausea, vomiting, and neurological deficits often prompt medical attention, leading to a detailed assessment of the individual’s medical history and presenting complaints. This initial stage sets the foundation for the subsequent diagnostic modalities and treatment decisions [5].

Imaging studies, including MRI and CT scans, play a central role in the visualization and characterization of MB. These imaging modalities not only help locate the tumor but also provide essential information regarding its size, extent of invasion, and involvement of critical structures.

Because of the heterogeneous nature of MB, it has heterogenous features on MRI. The tumor can demonstrate variable T1 and T2 intensities and different enhancement patterns. It may have calcification, hemorrhagic area, and cyst formation (Figure 1). MRI features and tumor location can predict MB subgroups. Magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) maps provide new prospects to correlate imaging findings to medulloblastoma subtypes. The lowest and highest ADC values were observed in classic medulloblastomas and LC/A medulloblastomas, respectively [6, 7]. Tumor location was also found to be correlated with molecular subtypes. MRI features and tumor location can predict MB subgroups toward the cerebellar peduncle/cerebellopontine angle cistern originating from the lower rhombic lip. SHH subgroup had cerebellar hemisphere localization, and Group 3 and Group 4 originated from the vermis. Group 4 are characteristically nonenhancing tumors in the midline/fourth ventricle site, and this characteristic differentiates it from group 3 [8].

Figure 1.

A: Brain MRI T1 sagittal. B: T2 sagittal. C: T1 axial. D: T2 axial. E: FLAIR axial. F: DWI axial. G: ADC axial. H: T1 axial with contrast. MRI reveals the midline cerebellar mass, filling the fourth ventricle and compressing the brainstem and cerebellum. The tumor has a low signal on the T1 sequence compared with the surrounding normal cerebellum, mild hyperintensity on T2, heterogeneous enhancement, cystic/necrotic component, and diffusion restriction, manifested by high B1000 and low ADC value, indicating high tumor cellularity. The finding suggest medulloblastoma.

Leptomeningeal dissemination diagnosis is essential. Failure to detect leptomeningeal dissemination is one of the main reasons for treatment failure.

A whole-axis MRI with contrast or/and CSF cytology should be performed to detect leptomeningeal dissemination (Figure 2). Whole-axis MRI is often done preoperatively to evaluate metastatic disease. If preoperative whole-axis MRI was not performed, it is recommended to be performed more than 2 weeks after surgery [9]. CSF cytology test is the golden standard for the detection of leptomeningeal dissemination. CSF can be collected intra-operatively or through Lumbar puncture 2–4 weeks after surgery [10]. When MRI and CSF cytology results are in accordance, the diagnosis is more accurate, but these results are frequently not in accordance [11, 12]. Advances in high-resolution mass spectrometry (MS) techniques and CSF proteomics have enabled the identification of small amounts of cancer cells in CSF, although its clinical usage remains to be validated [13].

Figure 2.

A: Spine MRI T2. B: MRI T1 with contrast, fat sat (fat saturation). Diffusely bulky spinal cord, with shows extensive heterogeous enhancement. Multiple surface and nodular enhancing lesions in the spinal cord. These represent metastatic involvement of medulloblastoma.

Histological analysis, achieved through examining a tissue biopsy sample, remains the cornerstone in definitively diagnosing MB. The microscopic evaluation of tissue sections enables pathologists to identify the distinct cellular features characteristic of MB, including high mitotic activity and a propensity for rapid growth. This histopathological confirmation is essential for initiating appropriate treatment protocols tailored to the specific tumor subtype [14].

Advancements in molecular testing have significantly enhanced our understanding of MB biology by allowing for the classification of tumors into distinct genetic subgroups. These subgroups, including the WNT-activated, SHH-activated, Group 3, and Group 4 subtypes, exhibit unique genetic alterations that influence disease behavior, treatment response, and overall prognosis. Molecular profiling has revolutionized the field of neuro-oncology by guiding personalized therapeutic interventions based on the tumor’s molecular characteristics [15].

In conclusion, the complex diagnostic pathway for MB necessitates a multidisciplinary approach encompassing clinical, radiological, histological, and molecular assessments. By integrating these diverse modalities, healthcare providers can achieve a comprehensive understanding of tumor biology, guide personalized treatment strategies, and optimize patient outcomes in managing this formidable pediatric brain malignancy.

4. Prognosis of MB

MB, a highly aggressive brain tumor primarily affecting the pediatric population, presents a complex set of challenges in terms of prognosis and treatment outcomes. Progresses in demonstrative imaging, pathology, and molecular biology coupled with advancements in neurosurgical approaches, radiotherapeutic strategies, and systemic treatments over the last two decades have significantly improved survival results for MB [16]. Notwithstanding these advancements, the 10-year mortality rate of MB is 34.6% in children [16]. Traditionally, MB patients are classified into standard-risk and high-risk groups based on clinical presentation, extent of residual disease after definitive surgery, histopathological group of the tumor, and biological or molecular characteristics of tumor cells [17, 18]. The 5-year survival rate of standard-risk patients aged ≥3 years old with current treatment is more than 70%. High-risk patients aged ≥3 years have a 5-year event-free survival (EFS) rate of around 70% for patients with metastatic BM treated with intensified chemotherapy regimens. Children beneath 3 years of age have a 5-year progression-free survival (PFS) rate of 30–90%, depending on tumor histology in this age group [17, 18].

The large cell/undifferentiated and classical subtypes have a poor prognosis, whereas the extensive nodular and desmoplastic/nodular MB have a better prognosis [17, 18].

The wingless/integral (WNT) subgroup has a good prognosis, the sonic hedgehog (SHH) subgroup and group 4 have an intermediate prognosis, while subgroup 3 has a poor prognosis [17, 18]. A recent meta-analysis suggests that the histologic characteristics of MB, molecular subgroups of MB, GTR, and radiotherapy are the most important prognostic factors associated with survival in patients with MB [19]. Epigenetic modifications, including DNA methylation patterns and chromatin remodeling, have emerged as critical determinants of MB prognosis. Specific epigenetic signatures within tumor cells have been associated with distinct molecular subgroups and survival outcomes. Epigenetic profiling provides a deeper understanding of the underlying molecular mechanisms driving tumor progression and may serve as a prognostic biomarker for risk stratification and treatment selection [20].

The immune system’s role in mediating antitumor responses and shaping disease prognosis is a rapidly evolving area of research in MB. Immune checkpoint inhibitors, adoptive T-cell therapy, and other immunotherapeutic strategies have shown promise in harnessing the host immune response to target MB cells. The immunosuppressive nature of the tumor microenvironment, characterized by regulatory T cells and myeloid-derived suppressor cells, poses challenges for effective immune activation. Novel immunotherapies aimed at modulating the immune response hold the potential for improving prognosis and long-term outcomes in MB patients [21].

The treatment of MB, which typically includes surgery, radiation therapy, and chemotherapy, can lead to significant treatment-related adverse events affecting the patient’s quality of life and long-term prognosis. Neurocognitive deficits, endocrine dysfunction, and secondary malignancies are among the potential complications associated with standard treatment protocols [22].

In conclusion, the prognosis of MB is influenced by a complex interplay of clinical, molecular, and environmental factors. A comprehensive understanding of the prognostic markers is essential for tailored treatment planning, prognostic assessments, and the continuous advancement of therapeutic strategies in managing this aggressive pediatric brain tumor.

5. Treatment

Treatment of medulloblastoma requires coordinated care by a neurosurgeon, neuro-oncologist, radiation oncologist, neuroradiologist, and neuropathologist. The current standard of care involves maximal safe surgical resection followed by risk-adapted craniospinal irradiation (for noninfant patients) and adjuvant chemotherapy. The goals of surgical management of medulloblastoma include maximal safe resection, obtaining tissue diagnosis, relieving mass effect, and treating symptomatic hydrocephalus. The extent of resection required has been closely studied, and residual tumor >1.5 cm² has been associated with worse overall survival and progression-free survival [23, 24].

5.1 Management of hydrocephalus

Hydrocephalus is a ubiquitous presenting feature in children with medulloblastoma. Hydrocephalus is common, occurring in 71–90% of children with posterior fossa tumors. Hydrocephalus after tumor resection occurs in 10–36% of cases, with a worldwide average of 30%. At times, it may require emergent intervention with external ventricular drainage (EVD) placement.

More commonly, patients will be symptomatic but not presenting in extremis and can be managed preoperatively with a short course of high-dose dexamethasone to treat peritumoral edema and with placement of an EVD at the time of surgical resection of the tumor. Although many patients require (cerebrospinal fluid) CSF diversion at the time of surgery, treatment with a ventriculoperitoneal shunt (VPS) or endoscopic third ventriculostomy (ETV) prior to tumor resection is not recommended because approximately 25% of patients require permanent CSF diversion. The risk of hydrocephalus requiring permanent CSF diversion in children with medulloblastoma may be higher in younger patients, patients with larger tumors, patients with metastatic disease, and patients with more severe or longstanding hydrocephalus. Patients with WNT subgroup tumors may also be at lower risk of requiring permanent CSF diversion [23, 24].

5.2 Surgery for medulloblastoma

Surgical resection is complete under general intravenous and endotracheal anesthesia. Patients are generally prone with the head fixed in a 3- or 4-pin cranial fixation device and the neck slightly flexed. In infants, the head may be positioned on a horseshoe headrest, taking care of pad-dependent areas and avoiding eye pressure. Care must be taken to avoid kinking the endotracheal tube with the neck flexed. This can be avoided by using a nasal endotracheal intubation technique or selecting an endotracheal tube less susceptible to kinking. Communication and coordination with the neurasthenia team is critical. First, a midline posterior fossa exposure is completed, exposing at minimum from the inion to C2. Dissection is undertaken in the midline avascular plane, and the cervical musculature is dissected from the occiput, bifid spinous process, and lamina of C2 in a subperiosteal fashion. Great care is taken in exposing C1, and a C1 laminectomy may be required, depending on the caudal extent of the tumor and the degree of acquired tonsillar herniation (Video 1, B2n.ir/g22558). Meticulous hemostasis should be achieved before opening the dura in a Y-or V-shaped fashion (Figure 3). Bleeding from the occipital sinus can be managed with Hemoclips (Teleflex Incorporated), which often can be removed at the end of the surgical procedure, thereby avoiding artifacts on postoperative MRI. A midline cerebellar vermian or inferior telovelar tonsillar approach can be used for midline tumors. In telovelar approach, the fourth ventricle is entered through the cerebellomedullary fissure, which is the virtual space between the medulla oblongata’s posterior aspect and the tonsils’ anterior surface.

Figure 3.

(Schematic image) posterior fossa craniotomy and tumor exposure. A midine skin incision is made extending from just above the inion to the level of the spinous process of C2 (A). Bilateral burr holes are made and a craniotomy is performed incorporating the posterior rim of the foramen magnum (B). The dura is opened using a Y-shaped incision and the inferior cerebellum and brainstem are exposed. Care has to be taken to protect the posterior inferior cerebellar arteries (C). The dorsal surface of the tumor is exposed by divisionof the distal portion of the vermis (D). Posterior fossa and brainstem after tumor resection.

The medullotonsillar space of the cerebellomedullary fissure and the uvulotonsillar space are sharply dissected to release the tonsils from the uvula and the medulla oblongata bilaterally. The telachoroidea is incised from the foramen of the magendie and then followed laterally to the foramen of the Luschka on both sides [24, 25]. This natural corridor provides access to the fourth ventricle without splitting the cerebellar vermis. A second advantage of this approach is the excellent view of the lateral recess of the ventricle and the exposure of the foramen of Luschka. The fourth ventricle is entered by splitting of the cerebellar vermis in the transvermian route. In this approach, the inferior vermis of the cerebellum is incised, and then the two halves of the vermis are retracted in opposite lateral directions. The inferior vermis is split on the suboccipital surface. The incision extends a variable distance through the uvula, pyramid, tuber, and folium of the vermis, depending on the location and size of the lesion. The following steps are in order: Retracting the two halves of the lower vermis laterally, then opening the telachoroidea and then inferior medullary velum, exposing the full length of the floor from the aqueduct to the obex. Total excision with minimal complications is the goal of the surgical tratment of the patients [24, 25].

Compared to the telovelar approach, it might offer a slightly better angle to reach the rostral part of the fourth ventricle. However, the transvermian approach is possibly associated with a higher rate of neurological complications [24, 25].

Both these routes may be useful for lesions that originate from the vermis. Identification of the floor of the fourth ventricle and brainstem is of critical importance in medulloblastoma surgery (Figures 4 and 5).

Figure 4.

Operative appearance of medulloblastoma prior to removal. Tumor is seen emanating from the fourth ventricle and displacing the cerebellar tonsils upward.

Figure 5.

At the completion of tumor resection, the floor of the fourth venticle is visualized.

It is useful to place a cotton patty at the ventral aspect of the tumor covering the floor of the fourth ventricle, as a marker to avoid extending the tumor resection to the brainstem. The margins of the tumor are dissected with a microsurgical technique to expose the interface between the tumor and the cerebellum. Samples of the tumor are taken for pathology review and diagnosis, and the tumor is internally debulked with suction and with a cavitation ultrasonic surgical aspirator. After the surgical resection, the cotton patty placed at the beginning of the resection, protecting the underlying fourth ventricle, should again be identified. The resection cavity is then inspected for any residual tumor before removal of the cotton patty. It is noteworthy that intraoperative neuromonitoring can be used to identify key structures. Continuous monitoring of the corticospinal and corticobulbar tract can be performed by recording motor-evoked potentials from limb muscles and facial muscles. Sensory pathways can be evaluated using somatosensory evoked potentials. Lateral/hemispheric tumors require a cordectomy through the overlying cerebellar cortex. Subsequently, tumor dissection, internal debulking, exposure of brain-tumor interface, and inspection for residual tumor will follow a course similar to that described for midline tumors. After tumor resection, meticulous hemostasis must be achieved with hemostatic agents, careful use of bipolar cautery, warm saline irrigation, and gentle tamponade with thrombin-soaked cotton balls. The dura is closed in a watertight fashion, using duraplasty when necessary. The bone is then replaced, and the cervical paraspinous musculature is reapproximated in the midline in a multilayered fashion. If an external ventricular drain (EVD) is required prior to tumor resection, a separate smaller incision can be made for placement of an occipital EVD. Cerebrospinal fluid (CSF) diversion with an EVD in the perioperative period is useful in managing hydrocephalus, ensuring appropriate wound healing, and avoiding the occurrence of a pseudomeningocele. The EVD can often be weaned over several days to a week postoperatively. In patients where permanent CSF diversion will be needed, it is prudent to avoid delay in placing the shunt to allow the patient to proceed with adjuvant therapy [24, 25].

5.3 Recurrence

MB recurrence occurs in approximately 30% of patients and is associated with poor prognosis. It is considered a serious complication. There is a wide range of therapeutic options, such as re-irradiation, surgery, chemotherapy, and targeted therapies.

Younger patients (more commonly, patients younger than 5 years) have a higher recurrence rate, and the role of histology is unclear. One of the negative prognostic factors is the detection of MYC amplification, which affects both the development of recurrence and time to death after relapse. The presence of metastatic dissemination at diagnosis had no effect on survival after relapse. Gross total resection and the absence of a residual or < 1.5 cm² residual tumor showed a lower recurrence rate. The molecular analysis revealed that the patients within the SHH subgroup and those with DN/MBEN histology have a better prognosis. On the contrary, non-DN/MBEN (desmoplastic, extensive nodularity) or subtotal resection (STR) within the SHH subgroup were considered poor prognostic factors. Group 3 usually presented with a disseminated relapse pattern and was characterized by MYC amplification, and Group 4 demonstrated local relapse and a moderate prognosis [26].

5.4 Complications of MB surgery

Surgical resection plays a central role in the management of MB, aiming to achieve maximal tumor removal while preserving neurological function. Despite advancements in surgical techniques and perioperative care, MB surgery is associated with potential complications that can impact postoperative outcomes and patient recovery. This section explores the common complications of MB surgery, their management strategies, and their implications on patient morbidity and long-term outcomes.

5.4.1 Surgical site infections

Surgical site infection is one of the most frequently encountered complications following MB surgery. Postoperative infections can arise from various factors, including prolonged operative times and CSF leakage. Prompt recognition and appropriate management of surgical site infections are critical to prevent further complications such as meningitis or abscess formation [27].

5.4.2 CSF leakage (pseudomeningocele)

CSF leak is a common complication observed after posterior fossa surgeries, including MB resections. Inadequate dural closure and inadequate closure of muscle layer, fascia, and hydrocephalus can lead to CSF leakage. Early detection and meticulous repair of the leak are essential to prevent the development of meningitis [28].

5.4.3 Hydrocephalus

The development of hydrocephalus following MB surgery is attributed to obstructed CSF flow or impaired resorption pathways. Postoperative hydrocephalus can manifest acutely or chronically and may necessitate the placement of a ventriculoperitoneal shunt for CSF diversion. Regular monitoring and prompt intervention are crucial in managing hydrocephalus-related complications effectively [29].

5.4.4 Cerebellar mutism syndrome

Cerebellar mutism syndrome (CMS) is a rare but debilitating complication observed in children undergoing posterior fossa surgery, including MB resections. CMS is characterized by a transient loss of speech and language function, often accompanied by emotional lability, motor deficits, and cognitive impairments. Rehabilitation and multidisciplinary support are essential in managing CMS and optimizing the patient’s recovery and quality of life postoperatively [30].

5.4.5 Neurological deficits

Despite efforts to preserve neurological function during MB surgery, the procedure can result in new or exacerbated neurological deficits. Motor weakness, gait disturbances, sensory abnormalities, and cranial nerve palsies are among the potential neurological complications that may arise due to surgical manipulation or injury to adjacent vascular structures. Rehabilitation and neurorehabilitation programs are vital in facilitating recovery and function restoration in patients with postoperative neurological deficits [31].

In conclusion, understanding the potential complications associated with MB surgery is essential for healthcare providers caring for these patients. Early recognition, prompt intervention, and comprehensive postoperative management are key elements in mitigating complications, optimizing patient outcomes, and ensuring a successful recovery following surgical resection of MB.

5.5 Radiation therapy

Radiation has long been recognized to have an important role in the treatment of medulloblastoma, both to delay or prevent recurrence and to control metastatic disease. Work over several decades led to the adoption of a regimen of 35–36 Gy to the neuraxis and a boost to 54–55.8 Gy to the posterior fossa. It was shown that such a strategy led to consistent improvements in survival, the focus shifted to studying dose-reduction strategies for lower-risk patients to limit late toxicities. Currently, radiation protocols are tailored based on patient age and risk of relapse.

5.5.1 Risk-adapted therapy

Risk stratification: Patients older than 3 years old and have a tumor size<1.5 cm² after surgery are classified as the average-risk group. The presence of >1.5 cm² of tumor after resection and large cell anaplastic histology are considered a high-risk group. The recent molecular subgrouping of medulloblastoma will undoubtedly affect future risk-adapted treatment protocols [32, 33].

The low-risk group with a survival higher than 90% includes patients with non-metastatic WNT MB or non-metastatic Group 4 MB with genetic events such as loss of chromosome 11 or gain of chromosome 17 comprises patients with non-metastatic SHH MB with tumors without a TP53 mutation or MYCN amplification. Those with non-metastatic and non-MYC Group 3 MB are classified as the standard-risk group (survival of 75–90%). Patients with a metastatic noninfant, TP53 wild-type–type and MYC–amplified non-mastatic SHH MB and metastatic Group 4 MB are considered as high-risk and have a survival rate of 50–75%. The very high-risk group is considered as patients with SHH MB harboring TP53 mutations, or Group 3 MB with metastasis and has a survival rate of less than 50%. The patients with WNT and Group 4 may benefit from dose-reduced radiation with stable intellectual outcomes [32, 33].

For children older than 3 years old, postoperative radiation is performed as a standard of care. Average-risk patients may receive 23.4 Gy CSI and a higher boost of 55.8 Gy to the tumor bed, usually combined with weekly doses of cytostatic drugs as radiosensitizer 30 days after surgery. At the same time, those classified as high-risk patients are treated with 36 Gy CSI and an additional boost to 54 Gy to the tumor bed or posterior fossa and focal sites of metastases. The adverse sequelae, most deleterious in the youngest patients (<3 years), precludes using the approaches above in infants and young children. Therefore, in children younger than age 3 years, attempts are made to omit or delay radiation therapy or limit the use of focal radiation only. Because radiation dose-reduction studies have shown unfavorable outcomes with high relapse rates, primary chemotherapy followed by delayed radiation therapy is commonly employed for infants. Other groups defer irradiation to the time of first recurrence or after patients reach age 3 years or beyond [32, 33].

Alternative radiation technologies: Recently, the role of proton beam radiotherapy in treating medulloblastoma has been explored. With proton beam radiotherapy, the area targeted for radiation can be focused much more precisely, allowing the same dose of radiation to be administered with less effect of radiation to surrounding tissue. Proton beam radiotherapy also limits radiation to the spinal vertebral bodies, reducing late effects of scoliosis and short stature and exposure of the heart, lungs, and gastrointestinal tract. Additionally, if lower doses of radiation can be applied to critical areas of neurogenesis in the developing brain, a neurocognitive benefit to proton radiation may exist [32, 33].

5.5.2 Side effects of radiation therapy

Both short-term side effects and late toxicities limit radiation therapy for medulloblastoma. Short-term side effects include hair loss, fatigue, nausea, and vomiting, which can complicate or limit the successful completion of therapy. Late toxicities have become more apparent as long-term survival rates have drastically improved in recent decades. These late side effects include neurocognitive effects, neuropathy, endocrine abnormalities, growth retardation, scoliosis, hearing loss, cardiac toxicity, cerebrovascular disease, and secondary cancer. Neurocognitive effects are present in the majority of patients treated with CSI for medulloblastoma and include a severe reduction in their quality of life. Shorter attention span, slower processing, and memory disturbances contribute to a decline in executive ability and lower educational attainment. The main factor predictive of poor neurocognitive outcome is the young age at the time of diagnosis and treatment for medulloblastoma. Endocrine effects may include growth hormone deficiency, hypothyroidism, and early-onset puberty. Secondary malignancies are of significant concern as childhood medulloblastoma survivors live longer. These tumors include meningioma, malignant glioma, osteosarcoma, and myelodysplastic syndromes. However, alopecia and radiation necrosis are more common with proton radiation [32, 33].

5.6 Chemotherapy

Whereas historical treatment of medulloblastoma consisted of surgical resection followed by radiotherapy, multiagent cytotoxic chemotherapy regimens have evolved as a key adjunct therapy since 1970. Current chemotherapy regimens are risk-adapted, with differing strategies for average-risk children, high-risk children, and infants who undergo radiation-sparing protocols. Cytostatic drugs must pass the blood–brain barrier, and common chemotherapeutic agents are cisplatin, vincristine, cyclophosphamide, and lomustine.

Average risk: The current standard of care for classically defined average-risk children (age 3–18 years without metastasis and at least NTR) involves surgical resection followed by radiotherapy. Patients subsequently receive four to nine cycles of vincristine, cisplatin, and either lomustine (CCNU) or cyclophosphamide. These regimens result in 5-year overall survival rates of approximately 80% [32, 33].

5.6.1 High-risk children

Treatment of high-risk children harboring metastatic disease or significant residual tumors is less standardized, and most contemporary regimens used in recent clinical trials have resulted in 5-year survival rate of 50–70%. CSI plus tumor bed or posterior fossa boost combined with four to nine cycles of chemotherapy using combinations of is applied for high-risk patients. Conflicting data exist in trials comparing preradiation versus postradiation chemotherapy. Using a chemotherapy regimen consisting of three cycles of cisplatin and etoposide followed by seven cycles of vincristine and cyclophosphamide, Tarbell and associates investigated whether outcomes differed between high-risk patients when undergoing this regimen before or after radiation and found no statistically significant difference in overall survival (OS) (5-year OS of 73.1 and 76.1%, respectively). Intraventricular methotrexate has also been assessed as an adjunct to radiotherapy and cytotoxic chemotherapy for high-risk patients and resulted in 74% 5-year OS in patients 4 years of age or older with metastatic disease [32, 33].

5.6.2 Infants and young children

Because of the unacceptable toxicity of CSI on the developing brain, treatment of infants and young children with medulloblastoma typically employs chemotherapy-only approaches, with CSI reserved for use in progressive disease if the child has reached an acceptable age [32, 33].

The recognition of lower-risk infant groups based on histological subtype (DN) or molecular subtype (ish-II) has complicated the determination of ideal treatment strategies. However, it holds promise to find treatments that improve outcomes and reduce treatment-related toxicity. One approach has been to treat patients with high-dose chemotherapy combined with intrathecal methotrexate, resulting in the 5-year OS of 93% for patients with complete resection and no metastasis, 56% for patients with residual tumor but no metastasis, and 38% for patients with metastatic disease [32, 33].

5.6.3 Adverse effects of chemotherapy

Chemotherapy is associated with a variety of adverse effects, including acute events during treatment and chronic effects. Myelosuppression is extremely common, with grade 3 or 4 hematologic toxicity reported in nearly all patients, and can be a dose-limiting complication. Other acute side effects include fatigue, nausea, vomiting, anorexia, infection, and weight loss. Rarer side effects include nephrotoxicity, hepatotoxicity, cardiomyopathy, pulmonary fibrosis, and gastrointestinal toxicity. Ototoxicity resulting in sensorineural hearing loss is associated with cisplatin chemotherapy, requiring frequent monitoring and potential dose reduction. Treatment with multiagent chemotherapy may also have indirect consequences on long-term quality of life in medulloblastoma survivors [32, 33].

5.7 Novel therapies

Advances in understanding the molecular pathways that drive medulloblastoma tumorigenesis and the development of agents that block these pathways are paving the way toward targeted therapy for medulloblastoma. Inhibitors of the SHH signaling pathway, such as vismodegib or sonidegib, which target smoothened, have been trialed in SHH tumors. However, because of the importance of SHH signaling to skeletal development, SHH inhibition is restricted to mature patients skeletally. Additionally, the specific molecular alteration resulting in SHH pathway activation is important because patients with alteration downstream of smoothened (SUFU mutation or GLI2 amplification) are unlikely to respond to this therapy. The ongoing SJMB12 trial is incorporating vismodegib into maintenance chemotherapy in skeletally mature SHH subgroup patients. Other molecularly informed therapies have shown promise in preclinical trials, with some treatments, such as phosphoinositide 3- Kinase/mammalian target of rapamycin (PI3K/mTOR) pathway inhibitors, advancing to clinical trials. Various forms of immunotherapy have proved efficacious in preclinical models, and early-phase clinical trials are underway. Some studies have shown that simultaneous treatment with vaccination (such as with dendritic cells loaded autologous lymphocyte transfer) and chemotherapy improved antigen-specific T-cell activity. One of the successful approaches to treating several types of cancer is anti-HER2 chimeric antigen receptor T-cell (CAR T) therapy, and the HER2 receptor is also known to be overexpressed in medolloblastoma. Furthermore, a study titled Immunotherapy for Medulloblastoma in 2020, which was conducted by Kabir TF et al., showed that CAR T-cells could clear MB implanted in the posterior fossa in mice without any significant toxicity [33].

6. Conclusion

Medulloblastoma is the most frequent pediatric malignant CNS tumor. A multidisciplinary team that best diagnoses and manages medulloblastoma includes a pediatrician, neurologist, neurosurgeon, oncologist, radiation therapist, and specialty-trained nurses. Cerebellar symptoms are one of the first symptoms that the majority of children with medulloblastoma present to the primary provider. Once diagnosed, the treatment modalities for medulloblastoma combine surgical resection with chemotherapy and radiation. Recent molecular advances drive clinical trials and the development of novel therapies. However, there are still questions about how to best stratify treatment based on molecular findings and how best to combine targeted therapies with more traditional therapeutic mainstay. Progress and future trials will provide insight into these questions and ideally lead to better prediction of outcomes and decreased long-term deficits.

Acknowledgments

I am grateful to my colleague, Dr. Amir Azarhomayoun for his cooperation in preparing this paper.

Conflict of interest

The authors declare no conflict of interest.

Appendix A

Medulloblastoma has been recognized to be a collection of distinct diseases, namely, the four molecular subgroups of medulloblastoma: Wingless (WNT), Sonic hedgehog (SHH), Group 3, and Group 4. Beyond the differences in underlying molecular biology, these subgroups have characteristic developmental origins, clinical manifestation, radiographic appearances, histopathologic correlates, and prognoses. Thus, molecular subgrouping of medulloblastoma informs all aspects of clinical practice, from counseling patients and their families to selecting appropriate treatment protocols to the long-term follow-up of medulloblastoma patients. These subtypes have important clinical correlates that will inform patient care and clinical trial design in the future. WNT Medulloblastoma is the rarest molecular subgroup, accounting for 10% of cases, but is associated with the best clinical outcomes with over 95% 5-year survival rates in pediatric patients. These tumors arise in children 4 years of age and older through early adulthood and occur with equal frequencies in males and females. WNT tumors usually have a classic morphology; however, 3% have LC/A histology. Nuclear localization of B-catenin is a hallmark of this subgroup. Metastases are present at diagnosis in 5–10% of patients, and the association of metastasis with prognosis in this subgroup is not well understood. Although recurrence is rare in this subgroup, both local and distant metastatic patterns of recurrence have been described. WNT tumors are driven by aberrant upregulation of the canonical WNT signaling pathway, which normally plays an important role in embryonic development. WNT pathway activation leads to cytoplasmic B- catenin accumulation and eventual translocation to the nucleus, where it activates transcription factors (T-cell factor/lymphoid enhancer factor-1) and induction of gene expression of downstream targets, including c-Myc (MYC) and cyclin D1 (CCND1). WNT pathway activation results in cellular responses, including cell proliferation and migration. Interestingly, the blood–brain barrier appears to be disrupted in WNT tumors, a unique characteristic compared to other subgroups, and this has been proposed as a mechanism for these tumors often appearing hemorrhagic at the time of surgical resection and being more responsive to standard-of-care treatment with cytotoxic chemotherapy.

Group 3 medulloblastoma accounts for 25% of diagnoses and typically arises in infants and young children. Group 3 tumors occur twice as frequently in males. This subgroup was associated with high rates of metastasis at the initial presentation. Classic morphology is the most common histopathologic subtype; however, LC/A histology occurs in Group 3 more than the other molecular subgroups. This subgroup has the worst prognosis of all the molecular subgroups, with certain molecular features such as MYC amplification associated with dismal outcomes. Compared to WNT and SHH tumors, the molecular underpinnings of the remaining subgroups are less clearly defined. Group 3 tumors are highly aneuploid. Among this subgroup’s most frequent cytogenetic events are the presence of isochromosome 17 q (i17q), chromosomes 1q and 7 gains, and chromosomes 8,10q, and 16 q losses.

Group 4 Medulloblastoma is the most common subgroup, accounting for 35–40% of all medulloblastoma diagnoses. This subgroup has the strongest male predilection, occurring over three times more commonly in males. Group 4 tumors are present across all age ranges, although they are relatively rare in infants. Peak incidence occurs in middle to late childhood. Most of Group 4 tumors have classic histology; however, a handful demonstrate DN or LC/A histology. Metastasis is present at diagnosis in approximately one-third of cases. This subgroup is considered to have an intermediate prognosis. Group 4 tumors appear to have transcriptional programs resembling unipolar brush cells and glutamatergic cerebellar nuclei, suggesting that progenitor cells within these lineages are the cells of origin for this subgroup. SHH Medulloblastoma accounts for approximately 30% of medulloblastoma diagnoses; however, it is the most common subtype among infant and adult patients but is less common during childhood and adolescence. The sex distribution is approximately even, with a slight male predominance. The histopathologic appearance of SHH tumors is variable, with all subtypes reported in this subgroup. Clinical characteristics, including histopathologic features, rate of metastasis, and prognosis, are variable based on patient age and molecular features, such as TP53 mutation status. Genetic predisposition syndromes have provided important insights into the role of the SHH signaling pathway in this subgroup, and genetic counseling remains an important diagnostic consideration in these patients, with up to 40% of pediatric cases occurring in patients with a cancer predisposition syndrome. Patients with Gorlin syndrome, an autosomal dominant condition that predisposes to the development of basal cell carcinoma, medulloblastoma, and other cancerous and noncancerous tumors, harbor germline mutations in SHH pathway genes, including PTCH1 and SUFU. Both of these genes are inhibitors of downstream SHH pathway activation. Mutation in these genes results in constitutive, ligand-independent activation of the SHH pathway, which normally regulates granule cell precursor proliferation in the developing cerebellum.

Acronyms and abbreviations

MB	medulloblastoma
MRI	magnetic resonance imaging
CT	computed tomography
CSI	craniospinal irradiation
EVD	external ventricular drainage
ETV	endoscopic third ventriculostomy
CSF	cerebrospinal fluid
WNT	wingless
SHH	sonic hedgehog
D/N	desmoplastic-nodular
LC/A	large-cell anaplastic
TP53	tumor protein P 53