Clinical presentation, diagnosis, and risk stratification of medulloblastoma

INTRODUCTION — Medulloblastomas are the most common malignant brain tumor of childhood and occur in the cerebellum. The disease is rare after the fourth decade of life.

The epidemiology, clinical presentation, diagnosis, and risk stratification of medulloblastoma in children and adults will be discussed here. The histopathology, molecular pathogenesis, treatment, prognosis, and delayed complications in survivors are discussed separately. (See "Histopathology, genetics, and molecular groups of medulloblastoma" and "Treatment and prognosis of medulloblastoma".)

EPIDEMIOLOGY — Approximately 500 children are diagnosed with a medulloblastoma each year in the United States [1,2]. Medulloblastoma is the most common malignant brain tumor of childhood, accounting for approximately 10 percent of all primary tumors of the central nervous system among children less than 19 years of age. The peak incidence is between five and nine years of age. Approximately 70 percent of patients are diagnosed before the age of 20. There is a slight increase in incidence between the ages of 20 to 24 years, and the disease is rare after the fourth decade, consistent with its embryonal origin.

Approximately 5 to 6 percent of medulloblastomas overall, with significant variation by molecular subtype, occur in association with a cancer predisposition syndrome such as nevoid basal cell carcinoma syndrome (NBCCS), caused by germline mutations in the patched-1 (PTCH1) gene; Li-Fraumeni syndrome, caused by mutations in the tumor protein p53 (TP53) gene; or familial adenomatous polyposis (FAP), caused by inactivating mutations in the adenomatous polyposis coli (APC) gene (table 1) [3]. Mutations in these genes predispose to the development of medulloblastoma through defects in pathways important in the pathogenesis of both sporadic and inherited tumors. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Genetic predisposition'.)

CLINICAL FEATURES

Symptoms — Medulloblastomas most commonly present with symptoms representative of increased intracranial pressure, including nocturnal or morning headaches, nausea, vomiting, and altered mental status. Symptoms usually evolve over a period of weeks to a few months.

Tumors in the midline may cause gait ataxia or truncal instability, whereas tumors in the lateral cerebellar hemispheres are more likely to cause limb clumsiness or incoordination. Dizziness and double vision are common symptoms that can be caused by cerebellar, brainstem, or cranial nerve involvement.

Physical examination — Neurologic examination findings depend upon the location of the tumor within the posterior fossa and the extent of hydrocephalus. Patients with midline tumors typically exhibit truncal or gait ataxia, manifested by a broad-based gait or difficulty with heel-to-toe walking. Head titubation (bobbing) and nystagmus are also common. Patients with lateral cerebellar tumors may exhibit dysmetria on finger-to-nose testing, intention tremor, and difficulty with heel-to-shin testing. (See "Detailed neurologic assessment of infants and children", section on 'Coordination'.)

Cranial nerve deficits may occur in conjunction with these signs, either from direct involvement of specific nerves or from cranial nerve dysfunction due to increased intracranial pressure impacting the brainstem. As an example, elevated intracranial pressure can induce dysfunction of the abducens nerves, causing diplopia especially with lateral gaze. (See "Detailed neurologic assessment of infants and children", section on 'Cranial nerves'.)

Prolonged elevation of intracranial pressure can lead to papilledema and complete or partial loss of vision. (See "Evaluation and management of elevated intracranial pressure in adults".)

Neuroimaging — MRI typically reveals a contrast-enhancing midline or paramedian cerebellar tumor that often compresses the fourth ventricle (image 1) [4]. Most tumors are iso- or hypointense on T1-weighted images and heterogeneous on T2-weighted images [5]. Gadolinium enhancement is often heterogeneous, and there may be regions of necrosis, hemorrhage, or cystic changes [4,6]. Hydrocephalus may be present secondary to obstruction at the level of the fourth ventricle.

Enhancing nodules or more linear patterns of enhancement may be evident in the ventricles, over the surface of the brain, or in the spinal canal, indicative of leptomeningeal dissemination (image 2). In cases of spinal involvement, MRI typically shows linear or nodule enhancement along the pial surface of the spinal cord and/or drop metastases within the cauda equina.

Adults are more likely to have cerebellar hemisphere tumors than are children, and the desmoplastic variant, which is more common in adults, may lack uniform contrast enhancement [6].

Medulloblastomas may be missed on computed tomography (CT) scan. The classic CT finding is a hyperdense mass on an unenhanced study that markedly enhances after the injection of contrast medium [6].

Cerebrospinal fluid — Approximately one-third of medulloblastomas metastasize throughout the central nervous system following CSF pathways. In these cases, cytopathologic examination of the lumbar CSF may reveal neoplastic cells. Elevated protein and a mild pleocytosis are often seen in association with a positive cytology, but these findings are nonspecific.

A positive lumbar CSF cytology either pre- or postoperatively predicts for an increased rate of relapse and poor outcome [7,8]. However, negative cytology does not exclude a more advanced stage of disease.

Lumbar puncture must be deferred until after surgery in the majority of patients due to the presence of increased intracranial pressure and/or obstructive hydrocephalus. Postoperative staging lumbar puncture should be delayed until 10 to 14 days after surgery to avoid confounding results from surgical blood products and debris. (See "Lumbar puncture in children", section on 'Contraindications' and 'Extent of disease evaluation' below.)

DIAGNOSIS — A diagnosis of medulloblastoma requires histopathologic confirmation at the time of surgical resection. Biopsies are not routinely performed in patients suspected of having a medulloblastoma by imaging, because maximal safe resection is an integral part of the management and prognosis of medulloblastoma as well as other posterior fossa tumors. (See "Treatment and prognosis of medulloblastoma", section on 'Surgery'.)

The histopathology of medulloblastoma is discussed separately. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Histopathology'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of a cerebellar mass in a child includes other tumors with a predilection for the cerebellum, the most common of which are pilocytic astrocytoma, ependymoma, and atypical teratoid/rhabdoid tumor (ATRT). While each of these entities is ultimately distinguished from medulloblastoma by findings on surgical histopathology, certain imaging findings may help to differentiate among these tumors:

●Pilocytic astrocytomas are typically cystic with a mural nodule or centrally necrotic with a thick rim of enhancing tissue; if cysts are present in medulloblastomas, they are typically small and multiple rather than solitary [9].

●Ependymomas usually originate from the ependymal surfaces of the ventricles and may grow to fill the fourth ventricle and extend inferiorly through the foramen of Magendie or laterally through the foramen of Luschka. Foraminal extension has been rarely reported in medulloblastoma but is much less common [9].

●ATRTs are much rarer than medulloblastomas but can have a similar appearance on MRI. Compared with medulloblastomas, ATRTs are more likely to involve the lateral hemispheres or cerebellopontine angle and contain intratumoral hemorrhage [10]. Suspicion for ATRT should also be higher in children less than three years old at presentation.

Advanced MRI characteristics are also helpful. Decreased apparent diffusion coefficient (ADC) values, a marker of high cellularity, are characteristic of medulloblastoma and ATRT but not typically ependymoma or pilocytic astrocytoma [11,12].

In an adult with a cerebellar mass lesion, the differential diagnosis also includes metastatic tumors originating from a systemic primary tumor, which are rare in childhood.

EXTENT OF DISEASE EVALUATION — Spine MRI and lumbar puncture for cerebrospinal fluid (CSF) cytology should be performed in all patients as part of the extent of disease evaluation. Medulloblastomas rarely metastasize outside of the nervous system at diagnosis, and therefore systemic staging (eg, CT of the chest, abdomen, and pelvis; positron emission tomography [PET]; bone scan) is not required at the time of diagnosis unless presenting or localized symptoms suggest dissemination outside of the central nervous system.

The spinal leptomeninges are a frequent site of spread, with involvement at presentation in 20 to 25 percent of patients. Contrast-enhanced MRI of the spine and lumbar CSF cytology are used to assess the craniospinal axis for evidence of tumor dissemination; the combination of both tests is more sensitive than either one individually [13,14].

Many patients are not candidates for a lumbar puncture prior to surgery due to the extent of disease in the posterior fossa. If lumbar CSF cytology is not obtained preoperatively, it is important to wait 10 to 14 days after surgery to avoid potential contamination of the specimen with surgical debris and blood products. Similarly, the interpretation of a spinal MRI obtained soon after surgery may be difficult due to the challenge of distinguishing between subdural blood products and drop metastases. Therefore, spine MRI should be performed pre-operatively (ideally) or delayed for 10 to 14 days if performed postoperatively.

RISK STRATIFICATION — There is an evolving understanding of prognostic factors and risk stratification in medulloblastoma. Historically, the most important factors affecting outcome have been the extent of disease, the amount of residual tumor postoperatively, and the age of the patient at diagnosis. Additional studies have highlighted the importance of both molecular markers and histopathology in determining prognosis [15-17], and these now form the basis for better pretreatment risk stratification.

Extent of disease — The modified Chang criteria, which are based upon the size of the primary tumor and the extent of nervous system and extraneural spread, have historically been useful in estimating prognosis, which is progressively worse in the presence of more advanced disease (table 2) [18]. The utility of T staging in the modern era is unclear, however, and most experts use M staging alone for medulloblastoma.

The importance of the presence of metastases was illustrated in a trial of 188 children with medulloblastoma [19]. Patients without metastatic disease (M0) had a significantly higher five-year progression-free survival (PFS; 70 versus 57 percent with M1 and 40 percent with M2, M3, or M4 disease). Similar results were noted in a second series of 173 consecutive patients with medulloblastoma, 84 percent of whom were less than 15 years old [20]. The five-year survival of those with M0 or M1 disease was 78 percent compared with 21 percent in patients with M2 or M3 involvement.

Extraneural metastases are rare, particularly in the modern era. In a review of the literature that identified 119 patients with M4 disease, the median age was 16 years, and the median time to diagnosis after initial presentation was 16 months [21]. Bone was the most common site of extraneural disease and was present in 84 percent of cases. In approximately one-half of patients, central nervous system involvement was present at the time of extraneural relapse. Negative prognostic factors included the presence of lung or liver metastases, the presence of central nervous system disease, and a shorter interval between original diagnosis and the development of these metastases.

Extent of resection — Extent of resection and the amount of residual disease postoperatively have historically been thought to be prognostic, with children who have ≥1.5 cm² residual tumor as assessed by MRI having a worse prognosis. The importance of this cutoff is being reassessed in the molecular era, however [22].

Age at diagnosis — The relationship between age and outcome in medulloblastoma is nonlinear, with patients at the extremes of the age distribution (ie, infants/young children and adults) fairing worse than those in the middle.

Young age at diagnosis has a negative impact on both long-term survival and quality of life in survivors. In earlier case series, children younger than age five years with medulloblastoma, and particularly those younger than three, were found to have a significantly poorer prognosis. This was illustrated by one series, in which the estimated five-year PFS was 32 percent in children between age 1.5 and 3 years versus 58 percent in those 3 and older [19]. Reduction or elimination of radiation in very young children, necessitated by the toxicity of radiation to the developing nervous system, may have contributed to their overall poor prognosis. Subsequent series have shown that young children with desmoplastic nodular medulloblastoma (DNMB) or medulloblastoma with extensive nodularity (MBEN) have higher rates of survival [16]. (See "Treatment and prognosis of medulloblastoma", section on 'Infants and young children'.)

The natural history and response to treatment of medulloblastoma may differ in older as compared with younger children. In a retrospective review of 72 patients between the ages of 10 and 20 years at the time of diagnosis, five-year overall and event-free survival rates of 78 and 70 percent, respectively, were similar to those observed in younger children [23]. However, relapses were often delayed, with a mean time to relapse of three years. Furthermore, treatment in this older cohort was associated with frequent severe toxicity, including ototoxicity (45 percent), peripheral neuropathy (71 percent), hematologic toxicity (95 percent), and weight loss (73 percent).

Histopathology — The World Health Organization classification of brain tumors divides medulloblastoma based upon histopathologic criteria into several variants, including classic, desmoplastic/nodular, desmoplastic with extensive nodularity, large cell, or anaplastic (table 3). (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Histopathology'.)

Histopathology is an important prognostic factor, particularly in young children. The impact of histopathology was studied in a cohort of 260 children less than five years of age who were treated on national protocols in Europe and the United States [16]. Even after accounting for stage (presence of metastases and residual disease), patients with DNMB or MBEN histologies have a significantly better event-free and overall survival compared with the classic form of medulloblastoma on multivariate analysis. By contrast, those with large cell or anaplastic variants had a significantly worse prognosis.

Molecular markers — Analysis of molecular features in medulloblastoma offers important insights into the prognosis, and it may provide opportunities to individualize treatment for patients with medulloblastoma. Based on integrative genomic studies, medulloblastoma can be divided into four molecular groups, which have divergent cell histology, genetics, clinical behavior, demographics, and patient outcomes (figure 1) [15-17,24-28].

Tumors that show activation of the Wingless-related integration site (Wnt) pathway have the best prognosis, whereas tumors with amplification of the MYC proto-oncogene ("group 3") have the worst prognosis. Tumors with activation of the sonic hedgehog (SHH) pathway and those in group 4 have an intermediate prognosis, with the exception of SHH tumors containing TP53 mutations, which are associated with a particularly poor prognosis. This is described in more detail separately. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Molecular groups'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Medulloblastoma is the most common malignant brain tumor of childhood, accounting for approximately 10 percent of all primary tumors of the central nervous system among children less than 19 years of age. The peak incidence is in children between five and nine years of age. (See 'Epidemiology' above.)

●Clinical features – Patients with medulloblastoma present with a combination of signs and symptoms, typically of increased intracranial pressure and cerebellar dysfunction. Common symptoms include nocturnal or morning headaches, nausea, vomiting, and gait ataxia. (See 'Symptoms' above.)

On neurologic examination, patients may exhibit papilledema secondary to increased intracranial pressure; cerebellar findings such as head titubation, nystagmus, and ataxia; and cranial nerve dysfunction. (See 'Physical examination' above.)

●Neuroimaging – MRI typically demonstrates a midline or paramedian cerebellar mass that enhances after administration of contrast and often compresses the fourth ventricle. Dilation of the ventricles secondary to obstructive hydrocephalus may be seen. (See 'Neuroimaging' above.)

●Differential diagnosis – The differential diagnosis of a cerebellar mass in a child includes other tumors with a predilection for the cerebellum, the most common of which are pilocytic astrocytoma, ependymoma, and atypical teratoid/rhabdoid tumors (ATRT); in adults, extra-central nervous system metastatic tumors should also be considered. (See 'Differential diagnosis' above.)

●Diagnosis – The diagnosis of medulloblastoma requires pathological confirmation at the time of surgical resection. Leptomeningeal dissemination is present in approximately one-third of patients at the time of diagnosis and confers a worse prognosis. (See 'Diagnosis' above.)

•Extent of disease evaluation – Spine MRI and lumbar puncture for cerebrospinal fluid (CSF) cytology should be performed in all patients as part of the extent of disease evaluation. (See 'Extent of disease evaluation' above.)

•Risk stratification – Age, extent of resection, extent of disease, histopathologic subtype, and molecular subtype are used to stratify patients with medulloblastoma into risk groups and determine appropriate therapy. (See 'Risk stratification' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Scott L Pomeroy, MD, PhD, who contributed to earlier versions of this topic review.