Epidemiology

Medulloblastoma is a highly malignant CNS tumor that arises from the cerebellum. It is the most common primary malignant intracranial childhood neoplasm, accounting for 25% of all childhood tumors.²⁰⁰ More than 80% of medulloblastomas are diagnosed in children during the first 15 years of life, the median age at diagnosis being 5 years. In adults (patients ≥ 16 years of age), medulloblastomas are much less common, accounting for < 1% of all adult brain tumors.²⁰¹ The incidence of adult medulloblastomas is approximately 0.5 per million per year, and decreases with increasing age.²⁰² The etiology of medulloblastomas is not known. Given the rarity of adult medulloblastomas, published studies of these patients are retrospective.

Pathology

Medulloblastomas are tumors consisting of small round blue cells.²⁰³ Histologically, about half of these tumors have recognizable cell lines combined with undifferentiated components. The two main medulloblastoma variants are the classical and desmoplastic. The latter variant has large amounts of reticulin and collagen. A relationship between prognosis and the degree of cellular differentiation has been proposed, but although some reports suggest that the more undifferentiated tumors are associated with a better outcome than those with predominant astrocytic differentiation, others suggest that differentiation imparts a better prognosis.²⁰³ At present, there is no consensus regarding prognosis as it relates to histology.

Clinical Presentation

Because of its posterior fossa location, medulloblastoma often produces hydrocephalus and symptoms of increased ICP, as well as cerebellar signs (eg, truncal and limb ataxia, nystagmus). Papilledema also can be noted on examination. Disease may exist as nodular lesions outside the primary site anywhere within the neuraxis, including the spine and supratentorial cerebrum, and may involve the CSF, as detected by positive cytology results. Occasionally, there may be disease beyond the CNS at the time of the original diagnosis, most often in the bone and/or soft tissue structures, including the lymph nodes.

Diagnostic Neuroimaging

The imaging modality of choice is MRI. Lesions are usually iso- to hypointense on T1WI, have variable signal on T2WI, and frequently demonstrate contrast enhancement. These tumors tend to be homogenous in appearance, with occasional cystic or necrotic areas. Because of the high rate of neuraxis dissemination, MR imaging of the entire brain and spine in the setting of a posterior fossa lesion is recommended. Figure 83-10 shows the typical appearance of a medulloblastoma arising out of the fourth ventricle in both the axial and coronal planes.

Figure 83-10

Magnetic resonance imaging appearance of a fourth ventricular medulloblastoma. A, Lesion in the sagittal plane. B, Lesion in the coronal plane.

Prognostic Factors

The 5-year overall survival rates range from 58% to 84%,^204–208 which are comparable to those of childhood medulloblastoma patients; 5-year progression-free survival rates range from 40%²⁰⁴ to approximately 61%.^207,208 Reported median survivals have varied from 6 years²⁰⁵ to 17.6 years.²⁰²

For pediatric medulloblastoma patients, therapeutic strategies and survival expectations differ between standard- and poor-risk groups. Poor-risk adult medulloblastoma patients have one or more of the following clinical factors: > 25% of tumor remaining after resection, evidence of brainstem invasion, tumor cells present in the CSF, or evidence of distant metastases. Prados and colleagues retrospectively evaluated 26 poor-risk and 21 standard-risk adult medulloblastoma patients, and found that 5-year overall survival and disease-free survival rates significantly differed between the risk groups (overall survival: 81% vs 54%; disease-free survival: 58% vs 38%).²⁰⁴ These findings were comparable to those of childhood medulloblastoma patients, suggesting that treatment decisions may also be modified based on risk groups. Le and colleagues also noted a statistically significant difference in overall survival.²⁰⁵ Kunschner and colleagues did not find a statistically significant difference in progression-free survival rate or median survival, although only 3 of 16 poor-risk patients had metastatic disease, which may have accounted for the long median survival (approximately 8.2 years) of the poor-risk patient group.²⁰⁸

A number of individual prognostic factors have been evaluated in adult medulloblastoma patients, particularly those that are known to be predictive in pediatric medulloblastoma patients, such as patient age at diagnosis, M stage, and extent of resection. In contrast to childhood medulloblastomas, these factors have not been found to be significantly predictive in adults. Age, which is a very important prognostic factor in the pediatric medulloblastoma population, has not been found to be a significant independent prognostic variable for adults. Age may be relevant in subsets of the adult medulloblastoma population, as was noted in one study in which the effect of older age was most pronounced in male patients with localized disease.²⁰⁵ M0 stage was reported to be highly significantly (p = .0005) associated with improved disease-free survival,²⁰⁶ but a subsequent study did not find a significant association (p = .68).²⁰⁹ One study found GTR to be significantly associated with improved disease-free survival and posterior fossa tumor control.²⁰⁹ However, other series did not find this association.^205,206,208

Male gender was reported to be significantly predictive of worse overall survival in one study,²⁰⁵ but not in subsequent series.^208,209 Unlike tumors arising in childhood, adult medulloblastomas have higher incidences of the desmoplastic compared to the classic histologic variant (30%) and lateral cerebellar location compared to the midline (30% to 40%).²⁰⁶ However, medulloblastoma location has not been reported to be a significant prognostic variable, and the desmoplastic variant has been noted by most studies to also not have prognostic value. Carrie and colleagues did report a statistically significant trend (p = .03) for improved event-free survival, but central pathologic review was not performed. Other variables noted to be significant positive prognostic factors include higher postoperative functional status^206,207 and the absence of hydrocephalus and ventriculoperitoneal shunt.^204–206 MDM2 overexpression, but not TP53 gene mutation, was found in one study to be statistically significantly associated with worse survival in adult medulloblastoma patients.²¹⁰ The data concerning molecular markers in adult medulloblastomas is exceedingly scant. Definitive prognostic factors, both clinical and molecular, need to be delineated in order to optimize treatment for adult medulloblastoma patients.

Treatment

The goal of surgery is to remove all visible tumor. Survival of adult medulloblastoma patients may be influenced by the extent of residual disease following surgery, particularly for patients without evidence of dissemination. Treatment of associated hydrocephalus can be managed by external drainage with tumor decompression, tumor decompression alone, or by the use of various shunting procedures.

Craniospinal axis radiation therapy is the standard of care for the treatment of adult medulloblastoma patients, as medulloblastomas are quite radiosensitive. Standard radiation doses to the craniospinal axis involve delivering 35 to 45 Gy to the brain and 30 to 40 Gy to the spine, with a dose of 54 Gy to the primary tumor site. Long-term adult medulloblastoma survivors who were previously treated with whole-brain radiation were found to have below-average IQs and notable deficits in memory, visuospatial skills, reasoning, and arithmetic.²¹¹

In contrast to childhood medulloblastoma, the role of chemotherapy in adult medulloblastoma patients is undetermined. A number of chemotherapy regimens used for pediatric medulloblastoma patients have been evaluated, including the 8-in-1 regimen, vincristine with CCNU, and CCV (cisplatinum, CCNU, and vincristine). In their study, Prados and colleagues found that those patients who received adjuvant chemotherapy (mostly nitrosourea-based regimens) had a statistically significantly longer survival as compared to those who did not receive adjuvant chemotherapy.²⁰⁴ However, other series did not find any significant survival benefit for adjuvant chemotherapy.^{205,207–209} There may be a defined role for chemotherapy in adult medulloblastoma patients, but issues such as timing (when to give chemotherapy), which specific therapeutic agents to use, and who will most benefit from chemotherapy still need to be resolved.

Recurrence

The recurrence rate for medulloblastomas in adults is approximately 50% to 60%.^204–209 The median time-to-tumor progression (TTP) is approximately 30 months,²⁰⁷ and the median survival after recurrence has been reported to be approximately 1.3 years.²⁰⁶ The most common site of recurrence is the posterior fossa. Other sites of recurrence include the spine, CSF, supratentorial cerebrum, bone, and other extraneural sites. Late recurrences are more common in adults than in children. In one study, 59% of all recurrences occurred more than 2 years after treatment,²⁰⁹ whereas, in general, 75% of childhood medulloblastoma recurrences occur within the first 2 years after treatment.²¹² Recurrences as late as 14 years after treatment have been reported.²⁰¹ Thus, long-term monitoring is important for adult medulloblastoma patients.

Conclusion

Adult medulloblastoma patients have traditionally been managed with therapies used to treat pediatric medulloblastoma patients based on the assumption that these tumors behave similarly in both populations. However, adult medulloblastomas have notable differences, such as higher frequencies of lateral cerebellar location, desmoplastic histology, and late recurrences. Although the 5-year overall survival rates are comparable between the adult and pediatric population, the prognostic factors that are well defined in childhood medulloblastoma patients have not been definitively established in adult medulloblastoma patients. Currently, the management of adult medulloblastoma patients involves a thorough staging work-up (including brain and whole-spine MRI and CSF cytology analysis), as complete a resection as possible, and postoperative CSA irradiation. Nitrosourea-based chemotherapy is reserved for recurrent disease, as adjuvant chemotherapy has not been definitively shown to have significant benefit in adult medulloblastoma patients. Other treatment modalities, such as radiosurgery, may also have a role in certain medulloblastoma patients. Because of its infrequent occurrence, the majority of data about adult medulloblastomas is derived from retrospective studies. Prospective studies evaluating are needed to accurately define significant prognostic factors and treatment regimens for adult patients with medulloblastomas.