From the Archives of the AFIP

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1 AFIP ARCHIVES 1613 CME FEATURE See accompanying test at /education /rg_cme.html LEARNING OBJECTIVES FOR TEST 6 After reading this article and taking the test, the reader will be able to: Recognize the distinguishing imaging features of medulloblastoma. Identify the characteristic imaging appearances of medulloblastoma in children and adults, including the presence of dissemination. Describe the direct correlation of the imaging appearance of medulloblastoma with its gross pathologic and histologic appearance. From the Archives of the AFIP Medulloblastoma: A Comprehensive Review with Radiologic-Pathologic Correlation 1 Kelly K. Koeller, CAPT, MC, USN Elisabeth J. Rushing, COL, MC, USA Medulloblastoma is the most common pediatric central nervous system malignancy and the most common primary tumor of the posterior fossa in children. This highly malignant neoplasm occurs more frequently in males and usually before 10 years of age. Clinical symptoms and signs are generally brief, typically less than 3 months in duration, and reflect the strong predilection of this tumor to arise within the cerebellum, most often in the vermis. Although much less common, the disease may also occur in adults, usually in the 3rd and 4th decades of life. Surgical resection, radiation therapy, and chemotherapy have substantially lowered the mortality associated with this tumor, with 5-year survival rates now commonly well above 50%. Still, both dissemination at the time of diagnosis and recurrence remain obstacles in achieving a cure. The tumor has characteristic hyperattenuation on unenhanced computed tomographic scans that reflects the high nuclear-cytoplasmic ratio seen at histologic analysis. The tumor typically appears heterogeneous on images, findings that are related to cyst formation, hemorrhage, and calcification and that are even more pronounced with magnetic resonance (MR) imaging. Evidence of leptomeningeal metastatic spread is present in 33% of all cases at the time of diagnosis and is well evaluated with contrast-enhanced MR imaging of the brain and the spine. Although controversial, postoperative surveillance with MR imaging is performed at most institutions in the hope of facilitating a better outcome. With continued research, treatment of these common neoplasms should improve, perhaps even achieving a cure in the future. Abbreviation: CSF cerebrospinal fluid Index terms: Brain neoplasms, Medulloblastoma, Neoplasms, in infants and children, ; 23: Published online /rg From the Departments of Radiologic Pathology (K.K.K.) and Neuropathology (E.J.R.), Armed Forces Institute of Pathology, 14th St at Alaska Ave, Bldg 54, Washington, DC ; Departments of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md (K.K.K.); and Department of Pathology, George Washington University, Washington, DC (E.J.R.). Received July 17, 2003; revision requested July 30 and received August 14; accepted August 15. Address correspondence to K.K.K. ( [email protected]). The opinions and assertions contained herein are the private views of the authors and are not to be construed as official nor as representing the views of the Departments of the Navy, Army, or Defense.

2 1614 November-December 2003 RG f Volume 23 Number 6 Introduction In the 78 years since the initial report, few neoplasms have been debated and scrutinized in the world s literature as much as the medulloblastoma. With a near 100% mortality rate initially, it represented a neurosurgeon s worst nightmare an aggressive neoplasm located in one of the most challenging sites in a young child, who is almost certain to die from the disease within a matter of months or less. From these stark beginnings, substantial improvement in survival has been made because of a combination of several factors: (a) the implementation of radiation therapy to counter the rapid growth of the tumor; (b) improvements in neurosurgical equipment and technique that allowed greater accessibility to the posterior fossa and permitted a greater chance of gross total surgical resection; (c) the development of chemotherapy protocols that strive to optimize prevention of recurrence and minimize the chance of metastatic dissemination; and (d) the advent of modern cross-sectional imaging techniques, especially magnetic resonance (MR) imaging, that have completely changed the method of assessment for follow-up in affected patients. Using case material from the Thompson Archives of the Department of Radiologic Pathology at the Armed Forces Institute of Pathology, we present the spectrum of cross-sectional imaging manifestations of this common tumor and a comprehensive summation of the history, pertinent clinical findings, pathologic characteristics, histogenesis, and prognosis associated with this tumor. Salient demographic and imaging features of medulloblastoma are listed in Table 1. Epidemiologic Characteristics Medulloblastoma is a highly malignant neuroepithelial tumor of the posterior fossa that is predominantly seen in children but may also occur in adults (1,2). Although it accounts for 6% 8% of all central nervous system tumors and 12% 25% of such tumors in the pediatric age group, it constitutes only 0.4% 1% of all adult central nervous system tumors (1,3 6). Medulloblastoma is the most common malignant central nervous system tumor in children and the second most common pediatric brain neoplasm, following only astrocytoma. It accounts for up to 38% of all pediatric posterior fossa tumors and represents the most common pediatric posterior fossa tumor overall (7,8). From the single largest collection (532 cases) of medulloblastoma as part of the National Cancer Institute s Surveillance, Epidemiology, and End Results (SEER) program, boys are more commonly affected (61.5%) (1). The overall mean age at diagnosis for all age groups is about 13 years (median age, 9 years), with most (77.4%) patients presenting before 19 years of age (1). Within this younger group of patients, the mean age at diagnosis is 7.3 years with small peaks at 3 years and 7 years (1). When medulloblastoma occurs in adults, variably described in the literature as those older than years of age, most (63%) manifest in patients years of age (9,10). It is rare in patients older than 50 years of age, and the oldest patient on record was 73 years old at the time of diagnosis (9 11). Occasional familial cases have been reported (12). First-degree relatives of patients with medulloblastoma also appear to have increased rates of cancer (4). By far, the cerebellum is the most common location for medulloblastomas (94.4% of cases in the SEER study), and most ( 75%) of these arise in the midline cerebellar vermis (1,2). More lateral locations within the cerebellar hemisphere are typical when these tumors manifest in older children, adolescents, and adults. This difference in location is thought to be related to the migration of undifferentiated cells from the posterior medullary velum in a lateral and superior direction (1,5). Early in life, these cells are still located close to the midline and theoretically would give rise to midline tumors in the cerebellar vermis. Later in life, the cells have migrated further laterally, and, accordingly, the tumors that arise during this period of time would be expected to be within the cerebellar hemisphere, away from midline (13). Brain stem infiltration is common (33% of 144 cases in a series reported by Park et al) (14). Other less common locations include the fourth ventricle (3% of cases), other areas of the brain (2.1%), and the spinal cord (0.6%) (1). The reported incidence of medulloblastoma ranges from one per 178,000 to one per 201,000 children aged 19 years or younger (4). From the Connecticut Tumor Registry, the prevalence of the tumor was noted to increase in the late 1950s and early 1960s, only to return to its baseline level thereafter (4). It is speculated that polio vaccine,

3 RG f Volume 23 Number 6 Koeller and Rushing 1615 Table 1 Characteristics of Medulloblastoma Prevalence Age Gender Male (62%) Location Clinical symptoms and signs Therapy Histologic subtype Prognosis CT appearance About 1 in 200,000; 6% 8% of all CNS tumors; 12% 25% of pediatric CNS tumors; 0.4% 1% of adult CNS tumors; most common malignant CNS tumor in children; up to 38% of all pediatric posterior fossa tumors Overall median age, 9 years; in children less than 10 years of age mean age is 7.3 years (small peaks at 3 and 7 years). Most affected adults are years old; rarely seen in patients older than 50 years Cerebellum (94%). At least 75% are in vermis, especially in children, with hemispheric location more common in older children and adults. Fourth ventricle (3%), rest of brain (2%), and spinal cord (0.6%) can be involved Usually brief duration ( 3 mo); headache, truncal ataxia, spasticity, and sixth nerve palsy common Surgical resection with adjuvant radiation therapy and chemotherapy Classic, most common by far; desmoplastic, predilection for adults; nodular, grapelike appearance on images, probably better prognosis; large cell/ anaplastic, worst prognosis 50% 80% survival at 5 years (in general); prognosis better in year-old patients, in females, with gross total resection and cerebellar hemisphere location; recurrence very common with poorer prognosis Hyperattenuated almost always (89%); most reliable imaging feature for distinguishing medulloblastoma from pilocytic astrocytoma MR imaging appearance Iso- to hypointense on T1-weighted images, variable signal intensity on T2- weighted images, more heterogeneous than CT appearance, almost always enhances Special features Increased rate of secondary malignancies; association with nevoid basal cell carcinoma containing the neoplasm-inducing papovavirus simian virus 40 from 1955 to 1961, may have played a role in the increased prevalence during this interval (4). Curiously, one report noted a seasonal increased prevalence, peaking in July, August, September, and October, based on the birth month of patients with medulloblastoma (15). Clinical Characteristics Typical clinical histories are usually brief and reflect the aggressive biologic behavior of the tumor. Most (75%) patients have symptoms for less than 3 months (14,16). Headache (generalized or localized to the suboccipital region) and persistent vomiting (without or with nausea) are common symptoms (14,16). Seizure activity is uncommon and may herald metastatic spread (16). Truncal ataxia, secondary to destruction of the cerebellar vermis, is the most common objective clinical sign and is frequently accompanied by spasticity (14,16). Other common clinical signs include papilledema (related to hydrocephalus), nystagmus, limb ataxia, and dysdiadokokinesis, with the last two findings reflecting a more laterally located mass within the cerebellar hemisphere (14,16). One-third of patients have positive Babinski and Hoffmann signs (16). Abducens nerve palsy, resulting from compression of the relatively exposed nucleus of the sixth cranial nerve along the anterior margin of the fourth ventricle, is also a common manifestation of the extraventricular tumor extension (16). Rare clinical findings include sudden neurologic deterioration and death secondary to acute hemorrhage into a medulloblastoma and spinal cord compression resulting from diffuse cerebrospinal fluid (CSF) seeding (14,16,17). Therapy Surgical resection and reestablishment of normal CSF flow remain the cornerstones of treatment of medulloblastoma in virtually all cases (1). With numerous technical improvements in neurosurgical techniques, equipment, and postoperative care and the development of a reliable operative staging system in 1969 (Table 2), the overall

4 1616 November-December 2003 RG f Volume 23 Number 6 Table 2 Chang Classification for Cerebellar Medulloblastoma Stage Tumor stage T1 T2 T3a T3b T4 Metastasis stage M0 M1 M2 M3 M4 Feature Less than 3 cm diameter; limited to vermis, roof of fourth ventricle, or hemisphere More than 3 cm diameter; invades one adjacent structure or partially fills fourth ventricle Invades two adjacent structures or completely fills fourth ventricle with extension into cerebral aqueduct, foramen of Luschka, or foramen of Magendie Arises from floor of fourth ventricle or brain stem; fourth ventricle completely filled Spreads to involve cerebral aqueduct, third ventricle, midbrain, or upper cervical spinal cord No evidence of metastasis Tumor cells in CSF Gross nodular seeding of brain CSF spaces Gross nodular seeding of spinal CSF space Extraneural spread operative mortality rate associated with these predominantly posterior fossa masses has plummeted from 50% in the mid-1900s to less than 10% today (16,18,19). The tumor is very radiosensitive, and radiation therapy has been used since Bailey and Cushing (20) documented the initial cases. Not surprisingly, the combination of surgery and radiation therapy is most commonly used (1). The institution of presymptomatic craniospinal radiation therapy is probably the single most important factor responsible for the improved survival rates in these patients compared with those in the 1960s and early 1970s (1 4,14,21). Currently, radiation doses of 54 Gy to the posterior fossa, Gy to the whole brain, and Gy to the spine are typically employed in fractionated form (22 25). Unfortunately, radiation therapy is not without substantial side effects. Radiation therapy has been implicated in the development of telangiectasia or cavernous malformation, which is easily detected on conventional T2-weighted MR images as focal hypointense regions confined to the radiated field (26 28). Because radiation therapy induces luminal narrowing that leads to increased venous pressure and occlusion, it is believed that venous restrictive disease is the most likely cause for development of these vascular malformations (28). On the arterial side, radiation injury induces hyalinization and fibrinoid necrosis within small arteries and arterioles, which leads to endothelial proliferation and occlusion (26,27). Although more commonly seen in patients receiving chemotherapy (eg, methotrexate), even mineralizing microangiopathy may occur in patients treated with radiation therapy alone (29). Even more serious is radiation therapy s staggering effect on the immature developing central nervous system of a young child. Impaired cognitive function, intellectual deterioration, and growth retardation are seen in virtually all treated patients in this group (14,24). Atrophy, especially of the posterior portions of the corpus callosum, is seen in over half of the cases (51%) (29,30). Calcification (28% of cases) and white matter abnormalities (26%) are also common, particularly in patients younger than 3 years of age (29,31). Consequently, craniospinal radiation therapy is strictly avoided in children younger than 2 years of age unless there is documented evidence of CSF dissemination or recurrence (21,32). Since the 1980s, the role of adjuvant chemotherapy in the treatment of childhood medulloblastoma has steadily increased for several reasons. The use of either preoperative or postoperative chemotherapy is associated with an increase in survival rates in high-risk children with medulloblastoma (ie, those with fourth ventricle invasion and children less than 2 years of age) and in patients with recurrent or advanced disease (1,33). It also allows a reduction in the radiation therapy dose to the whole brain and spinal cord in patients with nondisseminated disease and is used

5 RG f Volume 23 Number 6 Koeller and Rushing 1617 Figure 1. Medulloblastoma. Photograph of an autopsy specimen sectioned in the midline shows a fairly well-circumscribed mass (m) of the superior cerebellar vermis. Figure 2. Classic medulloblastoma. Photomicrograph (original magnification, 400; hematoxylin-eosin stain) of a classic medulloblastoma reveals monomorphic sheets of closely apposed small cells with a high nuclear-cytoplasmic ratio, occasionally interrupted by neuroblastic rosettes (arrows). Figure 3. Desmoplastic-nodular medulloblastoma. Photomicrograph (original magnification 400; hematoxylin-eosin stain) of a desmoplastic-nodular medulloblastoma shows a prominent nodule, or pale island, (I) containing small, uniform neurocytic cells with abundant cytoplasm. Smaller pale islands surround the dominant nodule. The internodular zones often contain abundant reticulin and are populated by more atypical cells. to delay the onset of radiation therapy in young children (32,34,35). It is highly likely that the role of chemotherapy in the treatment of this tumor will expand and be refined in the future (25,36). The role of adjuvant postoperative therapy in adult patients with the disease is less certain, as both standard-risk and poor-risk patients have approximately the same rate of disease-free survival (37). Pathologic Characteristics At gross inspection, medulloblastomas have a variable appearance. Some are firm and discrete masses, whereas others may be soft and less well defined (Fig 1) (2). On occasion, prominent hemorrhage may also occur (2). The World Health Organization classifies medulloblastoma as a grade IV lesion and recognizes four major subtypes of the tumor: classic, desmoplastic, extensively nodular with advanced neuronal differentiation, and large cell (2). Other less common subtypes include medullomyoblastoma and melanotic medulloblastoma (10,38). The classic subtype is defined by dense, sheetlike growth of cells with hyperchromatic roundto-oval nuclei accompanied by increased mitotic activity and conspicuous apoptosis (Fig 2) (2). Areas of necrosis are less common. Neuroblastic or Homer-Wright rosettes, consisting of neoplastic cell nuclei disposed in a radial arrangement around fibrillary processes, are common features (2). The desmoplastic subtype is characterized by nodular reticulin-free pale islands that are surrounded by reticulin-staining collagen fibers (Fig 3) (2). This tumor subtype was originally described as a circumscribed arachnoidal cerebellar sarcoma, a term that is now obsolete (39).

6 1618 November-December 2003 RG f Volume 23 Number 6 Figure 4. Large cell anaplastic medulloblastoma. Photomicrograph (original magnification 400; hematoxylin-eosin stain) of a large cell anaplastic medulloblastoma demonstrates characteristic cells with large nuclei containing prominent nucleoli (arrowheads), accompanied by conspicuous apoptosis and numerous mitoses. A third subtype medulloblastoma with extensive nodularity and advanced neuronal differentiation occurs primarily in children less than 3 years of age and is associated with a grapelike nodularity seen on cross-sectional images (2). Intranodular cellular uniformity, accompanied by a fine fibrillary matrix and occasional mature ganglion cells, are typical. This variant is also known by the term cerebellar neuroblastoma (40). Finally, the large cell medulloblastoma is the least common form (about 4% of cases). The salient morphologic features include large round nuclei with prominent nucleoli, nuclear molding, and abundant cytoplasm (Fig 4) (2). This form carries the poorest prognosis of the four major histologic subtypes (2). Some authorities have also reported an anaplastic type with some features similar to the large-cell variant including its poor prognosis (41). Accordingly, it is sometimes called the large cell anaplastic variant (42). As debate continues among neuropathologists, some authorities have merged some of these subtypes into hybrid forms based on their morphologic similarity and comparable clinical outcome. This has led to the description of a nodular/desmoplastic form, medulloblastoma with neuroblastic or neuronal differentiation, and even medulloblastoma with glial differentiation (41,42). It is clear that the naming and categorization of these tumors is an evolving process, and more data and discussion are likely required to reach a consensus about the nomenclature of these lesions. The entity previously known as lipomatous medulloblastoma is now designated cerebellar liponeurocytoma (43). The World Health Organization working group considers this lesion a distinct clinicopathologic entity with an overall good prognosis. In contrast to medulloblastoma, this low-grade neuronal tumor usually occurs in much older patients (range, years) and does not require adjuvant postoperative therapy in most, if not all, cases (44). This lesion has a distinctive imaging appearance, being seen on cross-sectional images as a cerebellar mass containing areas of attenuation or signal intensity similar to those of fat (45). A plethora of chromosomal abnormalities has been identified in medulloblastomas. The most common (30% 45% of cases) is the loss of genetic material from chromosomal arm 17p (46). This site is apparently the location of a suppressor gene, the removal of which allows for the expression of the tumor (46). Absence of this structure has also been linked with medulloblastomas with aggressive biologic behavior compared with those medulloblastomas without this genetic loss (47). Other identified chromosomal abnormalities in medulloblastomas, by either gains or losses, include chromosomes 1, 8, 9, 10, 11, and 16 (47). Histogenesis The cell of origin for a medulloblastoma has been controversial since Bailey and Cushing (20) first described the initial 29 cases in 1925 and noted its affinity to grow from the roof of the fourth ventricle. They hypothesized that the tumor arose from a medulloblast, an undifferentiated embryonal cell located in the external granular layer of the cerebellum that could then give rise to other formative cells. Although an attractive theory in its time, no neuroanatomic proof of this cell was ever identified, and the theory was subsequently abandoned (2). The three existing theories of medulloblastoma histogenesis also focus on the concept of an undifferentiated cell with the capacity to differentiate into other cell lines (2). The first proposes that the external granular layer itself is the site of origin. Cells located along the roof of the fourth ventricle and posterior medullary velum migrate laterally and upward to form this layer. This theory is supported by the observation of certain gene mutations in sporadic medulloblastoma that

7 RG f Volume 23 Number 6 Koeller and Rushing 1619 Figure 5. Medulloblastoma in a 6-year-old girl with a 10-day history of nausea and vomiting. (a) Axial CT image shows a heterogeneous hyperattenuated mass in the right cerebellar hemisphere. (b) On an axial T1-weighted MR image, the mass has homogeneous hypointensity compared with normal cerebellar signal intensity. (c) On an axial T2-weighted MR image, the mass is heterogeneous with surrounding vasogenic edema. (d) Contrast-enhanced axial T1- weighted MR image shows heterogeneous enhancement of the mass. are also responsible for control of developing neurons in this layer and by the observation of neuronal differentiation in some medulloblastomas (1,13,48,49). The second theory espouses the concept that all medulloblastomas are actually primitive neuroectodermal tumors (PNETs). This theory is supported by the observation that many medulloblastomas share common histologic features with supratentorial PNETs (50). However, recent investigations have revealed genetic differences between the two tumor types, casting some doubt on this theory (2). The third hypothesis proposes that medulloblastomas may have more than one cell of origin. This theory is supported by the expression of immunoreactivity in two different cell types, one that is found associated with the developing ventricular system and the other that is found in cells derived from both the ventricular matrix and the external granular layer. It is proposed that this theory could account for the classic medulloblastoma arising from the ventricular matrix cell line, whereas desmoplastic medulloblastomas arise from the external granular layer (2). Imaging Features Computed Tomography The classic computed tomographic (CT) appearance of a medulloblastoma is a hyperattenuated, well-defined vermian cerebellar mass with surrounding vasogenic edema, evidence of hydrocephalus, and homogeneous enhancement on contrast material enhanced images in a child less than 10 years of age (Figs 5, 6) (16,51,52). From data collected on 420 patients in three studies,

8 1620 November-December 2003 RG f Volume 23 Number 6 Figure 6. Medulloblastoma in a 3-year-old boy with a 1-month history of progressively worsening clumsiness, ataxia, headache, nausea, and vomiting. Developmental delay in speech and motor skills was also present. Papilledema was noted on physical examination. (a) Axial CT image shows a nearly homogeneous hyperattenuated mass in the posterior fossa midline. A thin crescent of the fourth ventricle (arrowheads) is noted along the anterior margin of the mass. (b) On an axial T1-weighted MR image, the mass is hypointense compared with the surrounding normal cerebellum. (c) On an axial T2-weighted MR image, the mass shows mild hyperintensity compared with surrounding normal brain tissue. (d) Contrast-enhanced axial T1-weighted MR image shows intense but mildly heterogeneous enhancement of the mass. (e) Photograph of the resected specimen highlights the soft friable nature of the mass, characteristic of a medulloblastoma. 89% of all medulloblastomas demonstrated at least some hyperattenuation compared with normal cerebellar attenuation on nonenhanced CT scans (16,51,53). In a review of 233 patients, Nelson et al (53) found that 95% had marginal vasogenic edema and 97% had at least some enhancement (Fig 5). However, variance from this imaging appearance is common, seen in about 40% of all cases (51,53,54). Cyst formation (59% of cases) and calcification (22%) (Figs 7, 8) were common in the study by Nelson et al (53). Other less common atypical features include ill-defined margins, absence of vasogenic edema or hydro- cephalus, hypoattenuation, hemorrhage, absence of enhancement on contrast-enhanced images, and the appearance of primary leptomeningeal dissemination (Fig 9) (16,51,53,54,56).

9 RG f Volume 23 Number 6 Koeller and Rushing 1621 Figure 7. Medulloblastoma in a 4-year-old boy with a 2-week history of headaches and vomiting. (a) Axial CT image shows a heterogeneous mass in the posterior fossa midline. Soft-tissue portions are hyperattenuated whereas more cystlike areas are hypoattenuated. (b) On an axial T1-weighted MR image, the mass has similar heterogeneity. (c) Axial T2- weighted MR image demonstrates mild hyperintensity of the soft-tissue section and marked hyperintensity of the cystlike compartment. Note that the signal intensity of the cystlike portion (arrows) is even more intense than that of CSF, indicating that it is not simple fluid. (d) Contrast-enhanced axial T1-weighted MR image shows heterogeneous enhancement within the soft-tissue segment. Figure 8. Medulloblastoma in a 10-yearold boy. Axial CT image shows a heterogeneous hyperattenuated mass in the midline of the posterior fossa. Focal areas of hyperattenuation (arrows) represent calcification, an occasional manifestation of this disease. (Reprinted, with permission, from reference 55.)

10 1622 November-December 2003 RG f Volume 23 Number 6 Figure 9. Medulloblastoma in a 4-year-old boy with a 2-month history of ataxic gait. On day of admission, he hit his head on the floor and presented comatose to the emergency department. (a) Axial CT image shows a heterogeneous mass in the cerebellar vermis. Areas of hyperattenuation (arrowheads) are secondary to hemorrhage. The fourth ventricle is not seen. (b) Axial T1-weighted MR image shows mild hyperintensity in the hemorrhagic regions; otherwise the mass is predominantly hypointense. (c) Axial T2-weighted MR image reveals marked hypointensity in the hemorrhagic zones. These features are consistent with intracellular methemoglobin. (d) Contrast-enhanced axial T1-weighted MR image demonstrates heterogeneous but intense enhancement of the nonhemorrhagic portions. (e) Sagittal T1-weighted MR image shows complete filling of the fourth ventricle and upward extension of the posterior fossa mass through the cerebral aqueduct (arrow) into the third ventricle.

11 RG f Volume 23 Number 6 Koeller and Rushing 1623 Figure 10. Medulloblastoma in a 6-year-old boy with recurrent headaches. (a) Axial T1- weighted MR image shows a heterogeneous soft-tissue mass (arrows) in the right cerebellar hemisphere with an associated peripheral cystlike region. The soft-tissue portion is hypointense relative to the normal cerebellum. Several focal areas of fluidlike hypointensity are noted within the mass. (b) Axial T2-weighted MR image shows that the soft-tissue component is slightly hyperintense relative to the normal cerebellum. The fluidlike areas are again noted. (c) Contrast-enhanced axial T1-weighted MR image demonstrates intense but heterogeneous enhancement of the soft-tissue portion. The nonenhancing regions represent either cystic degeneration or necrosis. affect therapeutic decisions in favor of chemotherapy or reduced-dose radiation therapy (57). The presence of falcine calcification in children with medulloblastoma may be a marker for nevoid basal cell carcinoma. Because patients with this tumor tend to develop numerous basal cell carcinomas in irradiated fields, scrutiny of CT studies in such patients is warranted, since it may MR Imaging At MR imaging, the typical appearance of a medulloblastoma is iso- to- hypointense relative to white matter with short repetition time/short echo time pulse sequences and variable signal intensity relative to white matter with long repetition time pulse sequences (58). Even greater degrees of heterogeneity among these lesions are described for those seen on MR images than on CT scans (58). As with CT, nearly all enhance following the intravenous administration of contrast material, but the enhancement is usually heterogeneous (Figs 10 13) (58). MR spectroscopy in cases of medulloblastoma typically shows elevated choline peaks, reduced N-acetyl aspartate and creatine peaks, and occasionally elevated lipid and lactic acid peaks, a characteristic spectrographic

12 1624 November-December 2003 RG f Volume 23 Number 6 Figure 11. Medulloblastoma in a 4-month-old boy with irritability and vomiting. Physical examination revealed increased head circumference, bulging fontanelle, and left gaze preference. (a) Axial CT image shows a hyperattenuated heterogeneous mass in the midline of the posterior fossa with nearly complete effacement of adjacent cisternal spaces. (b) On an axial T1-weighted MR image, the mass is heterogeneous with focal areas of hyperintensity mixed with isointense signal. (c) On an axial T2-weighted MR image, the mass has mild hypointensity compared with gray matter and contains scattered areas of moderate hypointensity that correspond to regions of hemorrhage. (d) Contrast-enhanced sagittal MR image shows intense plaquelike enhancement of the mass with superior displacement of the straight sinus (arrowheads).

13 RG f Volume 23 Number 6 Koeller and Rushing 1625 Figure 12. Medulloblastoma in a 10-month-old boy with nausea and vomiting for several months and recent onset of lethargy and failure to meet developmental milestones. (a) Axial CT image shows a heterogeneous mass involving the cerebellar vermis and hemisphere with extension toward the left cerebellopontine angle. The soft-tissue portion near midline is hyperattenuated, whereas the fluidlike compartment is more lateral and posterior in location. (b) Axial T1-weighted MR image reveals mild hypointensity of the soft-tissue portion with moderate hypointensity in the cystlike region. This latter signal intensity is more hyperintense relative to normal CSF, thereby indicating that it is not simple fluid but likely contains proteinaceous debris or possibly hemorrhage. The extension through the left foramen of Luschka (arrow) is better seen. (c) Axial T2-weighted MR image demonstrates heterogeneity within the soft-tissue portion. (d) Contrast-enhanced axial T1-weighted MR image shows peripheral rim enhancement of the cystlike portion and more solid enhancement within portions of the soft-tissue section. At surgery, the mass was seen to extend through the left foramen of Luschka.

14 1626 November-December 2003 RG f Volume 23 Number 6 Figure 13. Medulloblastoma in a 3-year-old boy with a 1-week history of headache, vomiting, and difficulty walking at night. Papilledema was noted on physical examination. (a) Axial CT image shows a homogeneous hyperattenuated mass arising in the cerebellar vermis. A thin crescent of the fourth ventricle is visible along the ventral margin of the mass. (b) Axial T1-weighted MR image reveals the nearly homogeneous hypointense mass. Note a small focal area of marked hypointensity (arrowhead). (c) Axial T2-weighted MR image demonstrates diffuse hyperintensity of the mass and focal marked hyperintensity (arrowhead) of the area previously noted in b. This area represents either cystic change or necrosis. There is minimal surrounding vasogenic edema. (d) Contrast-enhanced axial T1-weighted MR image shows linear enhancement within the mass, but a large portion of it does not enhance. signature for a neuroectodermal tumor but not necessarily specific for medulloblastoma (59). Foraminal extension from the fourth ventricle to involve the cerebellopontine angle, cisterna magna, and other cisternal compartments may occur but is not common. Involvement of the cerebellopontine angle by a medulloblastoma was noted in only 3% of 233 cases evaluated with CT in the series reported by Nelson et al (53) However, in a much smaller cohort evaluated with MR imaging, 14% of medulloblastoma cases demonstrated foraminal extension (60). It may be that foraminal extension is more common than reported, since most of the cases recorded in the literature were evaluated with CT rather than MR

15 RG f Volume 23 Number 6 Koeller and Rushing 1627 Figure 14. Medulloblastoma in a 33-year-old man with a 6-month history of headache and 2-week history of ataxia, vertigo, and vomiting. (a) Axial T1-weighted MR image shows predominantly hypointense masses that involve both cerebellar hemispheres. There is an ill-defined area (arrows) of nearly isointense signal along the posterior margin of the left cerebellar mass. Linear areas that are isointense (arrowheads) relative to normal cerebellar tissue are noted along the ventral margin of the left hemispheric mass. These areas bear some resemblance to the striated pattern seen in dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), with the exception that the axis is perpendicular to that typically seen in the latter disease. (b) Axial T2-weighted MR image reveals predominant hyperintensity of the masses. An area of mild hypointensity suggestive of soft tissue can be seen along posterior margin of left hemispheric mass. (c) Contrast-enhanced axial T1-weighted MR image demonstrates intense enhancement of the soft-tissue portion. imaging. At least three reported cases of medulloblastoma involved the porus acusticus and simulated the imaging appearance of a vestibular schwannoma (6,61). Striking grapelike nodularity characterizes the CT and MR imaging appearances of the medulloblastoma with extensive nodularity (62). Increased uptake on iodine-123 metaiodobenzylguanidine (MIBG) imaging studies has been reported in this subtype. The degree of uptake was more than that seen in classic medulloblastoma and may indicate the neuronal differentiation known to be present within this variant (62). Medulloblastomas occurring in the adult population tend to manifest as poorly defined masses located in the cerebellar hemisphere (Figs 14, 15) (13). Only 28% are located in the cerebellar vermis (6,9,10,13). When they occur in the vermis, they usually have well-defined margins and appear similar to those seen in children (9,13). Cystlike regions are more commonly seen (82% of cases) in medulloblastomas in adults than in those that occur in children and reflect the presence of either cystic degeneration or necrosis (13).

16 1628 November-December 2003 RG f Volume 23 Number 6 Figure 15. Medulloblastoma in a 37-year-old man with a 1-month history of progressively severe headaches and episodes of dizziness. (a) Axial T2-weighted MR image shows hyperintense cerebellar masses (arrows) within both hemispheres. (b) Contrast-enhanced axial T1-weighted MR image reveals mild enhancement of the right cerebellar mass and subtle enhancement of the left cerebellar mass. Medulloblastomas in adult patients are often the desmoplastic histologic type, which is prone to late recurrence (13,63). Imaging of desmoplastic medulloblastoma demonstrates a cerebellar mass that extends to the overlying meninges, where it incites an intense desmoplastic reaction, occasionally with abnormal leptomeningeal enhancement (64). When this occurs, the imaging appearance may mimic that of a meningioma (6). Medulloblastomas in adult patients typically show isointense T2 signal that most likely reflects the degree of hypercellularity, high nuclear-tocytoplasmic ratio, and, in the desmoplastic type, a fibrocollagenous matrix (6). On contrast-enhanced images, these tumors usually have slightly less enhancement compared with the intense enhancement seen in pediatric medulloblastomas (6,13). Differential Diagnosis The most likely alternative consideration for a hyperattenuated midline cerebellar mass in a child is an ependymoma. In contrast to a medulloblastoma, an ependymoma is typically calcified and often extends from its common fourth ventricular origin through the foramen of Luschka into the adjacent cerebellopontine cistern (65). For childhood masses that are within the cerebellar hemisphere, a pilocytic astrocytoma is the most likely tumor that must be differentiated from a medulloblastoma. Hyperattenuation on nonenhanced CT scans is the signature imaging feature of the vast majority of cerebellar medulloblastomas and reflects the compact nature of the tumor seen at histologic study (13). According to Barkovich (59), this CT finding also accounts for the single most reliable imaging feature with which to distinguish a medulloblastoma from a pilocytic astrocytoma. Since cells of a pilocytic astrocytoma contain abundant cytoplasm and form a less compact matrix, they tend to be hypoattenuated on nonenhanced CT scans unless calcification or hemorrhage is also present. Other considerations in the differential diagnosis include metastasis, hemangioblastoma, astrocytoma, lymphoma, and dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease). Metastasis is the most common cerebellar mass in the

17 RG f Volume 23 Number 6 Koeller and Rushing 1629 adult population and has a variety of appearances (66). Hemangioblastoma is the most common primary neoplasm of the cerebellum in adults (6). The majority (60%) of these tumors have the classic imaging appearance of a cystic mass with an enhancing mural nodule and should be readily distinguishable from a medulloblastoma. However, when the hemangioblastoma is in a solid or mixed form, its imaging appearance is nonspecific and it will be more difficult to differentiate from a medulloblastoma. Both lesions tend to be peripherally located. The presence of flow voids and intense enhancement on contrastenhanced images may help correctly identify a hemangioblastoma (6). About 10% of all central nervous system lymphomas occur in the cerebellum. Hypointensity on T2-weighted images is characteristic of these lesions, which also tend to be periventricular in location (67). The striated cerebellum is the classic imaging appearance of dysplastic cerebellar gangliocytoma, which carries the eponym of Lhermitte- Duclos disease (68). In support of the belief that this lesion is a hamartoma, it usually does not have surrounding vasogenic edema or enhancement and is not hyperattenuated on nonenhanced CT scans. The striped appearance is classic but not all lesions will have this imaging manifestation (69). There is one case report of a medulloblastoma that had an imaging appearance mimicking a nonclassic appearance of a dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) (70). The appearances of hyperattenuation on CT scans and contrast enhancement of the cerebellar mass on T1-weighted MR images in that case provided clues to the correct diagnosis. Metastasis Leptomeningeal Seeding Subarachnoid seeding is common in medulloblastomas, occurring in up to 33% of all patients at the time of initial diagnosis (18). Some investigators believe that the prevalence of CSF seeding may be actually much higher and perhaps present in all patients with the disease (17,71). Ventriculoperitoneal shunt involvement is common (20% of cases) and may lead to metastatic spread in the abdominal cavity (1). Numerous studies have shown that patients with evidence of CSF spread have a poorer prognosis compared with those in whom it is absent (72). Therefore, its detection is crucial to optimal patient management, and those who review these imaging studies must be aware of its imaging manifestations. Spread via the leptomeninges is the usual path of extension and leptomeningeal involvement of the spinal cord is the most common site of spread, ostensibly as a result of CSF flow from the posterior fossa into the spinal axis (1,4). Supratentorial involvement frequently involves the frontal and subfrontal regions and can be found anywhere CSF is present (eg, cranial cisterns and ventricles) (14). CT findings suggestive of leptomeningeal spread include sulcal and cisternal effacement, ependymal-subependymal enhancement, widened tentorial enhancement, and communicating hydrocephalus (73). Both conventional myelography and CT myelography markedly improved the detection and depiction of the true extent of metastatic disease and can still be used today in cases in which MR imaging is not feasible (74,75). Nerve root thickening, nodularity, thecal sac irregularity, and spinal cord enlargement are readily detected in these examinations. However, all of these studies have been supplanted by contrast-enhanced MR imaging as the current imaging study of choice to evaluate patients for this condition. Besides obviating the intrathecal injection of contrast material, contrast-enhanced MR imaging is more sensitive than CT myelography in the detection of these lesions (Figs 16, 17) (76 78). Nodular enhancement of the spinal cord surface or nerve roots, clumped nerve roots, and diffuse enhancement of the thecal sac are common findings. Because the normal flow of CSF from the cisterna magna travels first along the posterior margin of the spinal cord before returning to the cistern along the ventral surface of the spinal cord, most metastases are found along the posterior margin of the spinal cord as the greatest concentration of malignant cells would be expected to be found there (74,75).

18 1630 November-December 2003 RG f Volume 23 Number 6 Figure 16. Leptomeningeal metastatic spread from medulloblastoma in a 4-year-old boy with decreased level of consciousness and new onset of seizures. (a) Axial T2-weighted MR image shows ill-defined mild hyperintensity of the sulcal spaces bilaterally and hyperintensity within the corona radiata and external capsule region. (b) Contrast-enhanced axial T1-weighted MR image reveals diffuse bilateral leptomeningeal enhancement. (c) Contrast-enhanced coronal T1-weighted MR image shows similar features with more involvement on the right side than the left side. (d) Photograph of the brain sliced in the coronal plane correlates with the findings in c. Extensive leptomeningeal spread is evident (arrowheads). Detection of CSF seeding by means of cytopathologic analysis has been difficult, since only 15% 60% of patients with leptomeningeal metastasis have positive results (76). At least one report indicated that contrast-enhanced MR imaging is more sensitive (83%) than CSF cytologic analysis (60% 78%) in establishing the presence of CSF dissemination, even when multiple CSF samples were obtained (72). Other authors demonstrated that neither MR imaging nor CSF cytologic analysis alone is sufficient but that the two methods should be used in combination to establish the diagnosis (79). False-positive results, either from the presence of methemoglobin or from leptomeningeal irritation caused by subarachnoid blood, may be seen if MR imaging is performed within the first 2 weeks following surgery (80). For this reason, such studies should be avoided in this time frame or, alternatively and perhaps best of all, assessment of the spinal axis should be per-

19 RG f Volume 23 Number 6 Koeller and Rushing 1631 Figure 17. Leptomeningeal metastatic spread from medulloblastoma in a 3-year-old boy with lethargy, malaise, weight loss, headache, nausea, and vomiting of several weeks duration. (a) Contrast-enhanced sagittal T1-weighted MR image shows intense enhancement of a mass arising in the cerebellar vermis. Diffuse leptomeningeal enhancement (arrowheads) is also noted along the ventral margin of the brain stem and upper cervical spinal cord. (b) Contrast-enhanced sagittal T1-weighted MR image reveals thin linear enhancement (arrowheads) along the margin of the thoracolumbar spinal cord to the tip of the conus medullaris. Note also the focal collection of enhancement (arrow) in the distal margin of the thecal sac. formed preoperatively during the initial MR imaging examination (59). Although nodular leptomeningeal enhancement is more commonly seen in neoplastic disease rather than infectious meningitis, there is no specific imaging appearance for the former and it may not be possible to exclude the latter (81). At best, only 70% of MR imaging studies will show abnormal enhancement, even when positive CSF cytologic results are obtained (79). Corroboration with clinical and cytopathologic CSF findings is therefore crucial to substantiate the diagnosis of CSF dissemination from the medulloblastoma or other malignant tumors (79). Extraneural Spread While it is unusual for any central nervous system tumor to spread to remote sites, medulloblastoma has the third highest rate of extraneural metastasis, following glioblastoma multiforme and meningioma (82). The prevalence of remote spread in children is increased in patients of a younger age, of male gender, and with diffuse subarachnoid disease (83). The addition of chemotherapy to the routine treatment protocol of patients with medulloblastoma is associated with a significantly decreased prevalence of extraneural metastasis (25). Still, extraneural metastasis may manifest up to several years after initial treatment, with a median time of months (84,85). By compiling data on 119 cases reported in the literature, Rochkind et al (86) determined the overall prevalence of extraneural metastasis at 7.1% of patients with a medulloblastoma. Bone is the most common (77% of cases) extraneural site in both children and adults, followed by the lymph nodes (33%). In children, liver (15% of cases), lung (11%), and muscle (2%) are the next most common sites, whereas lung (17%), muscle (13%), and liver (10%) are the next most common sites in adults (86). Less frequently, the pancreas (4%), kidneys (2%), testes (2%), ureters

20 1632 November-December 2003 RG f Volume 23 Number 6 (1%), ovaries (1%), and breast (1%) may be involved (16,84,86). Peritoneal metastases may result from ventriculoperitoneal shunt transmission, although it is less likely since the incorporation of the millipore filter in the early 1970s (4,14). Interestingly, no adrenal metastasis has ever been identified in a patient with a medulloblastoma (86). Osseous lesions are usually sclerotic (65% of cases) on radiographs and CT scans (71). Lytic (35% of cases) and mixed (5%) lesions occur less often (85). On T1-weighted MR images, the lesions produce hypointensity relative to normal marrow signal intensity, with a reversion to normal signal intensity occurring as a successful response to chemotherapy (82,85). On T2-weighted MR images, iso- to hypointense signal is typical but not always present (Fig 18) (82,85). The survival rates of patients with systemic metastasis are similar to those of patients with recurrence (84). At histologic examination, systemic metastases appear to contain areas of anaplasia more frequently than do medulloblastomas overall, and transformation to a more aggressive form of medulloblastoma has been commonly noted in the metastasis compared with the original tumor (84). Postoperative Surveillance Imaging Postoperative surveillance imaging of the brain and spine in patients with medulloblastoma is routinely employed at many institutions with 3 6 month intervals during the first 5 years following initial diagnosis in the hope of detecting recurrent disease earlier. Theoretically, detecting recurrent or metastatic disease earlier would make these patients more amenable to salvage therapy and should lead to an increase in survival rate (87). However, this concept was challenged in 1994 when Torres et al (88) reported no statistical difference in the survival rate between those patients who had symptomatic recurrence and those who had an asymptomatic recurrence detected as part of surveillance screening in 23 patients. Still another study showed only intracranial recurrence in a cohort of patients whose disease was initially staged as M0 (no evidence of metastatic disease), a finding that led the authors to conclude that surveillance imaging of the spinal axis was not indicated in the absence of intracranial recurrence (89). However, other reports have championed surveillance screening, demonstrating evidence of longer median survival time and less advanced disease when recurrence occurs (72,87,90,91). Resolution of this controversy likely rests with the accumulation of more data from the continued assessment of such patients. Recurrence Rates Recurrence of medulloblastoma is unfortunately very common in both children and adults with the disease. Most recurrent disease in children develops in the first 2 years after initial treatment (72, 92). In children, recurrent disease that develops beyond the first 2 years may also occur, but it is less common with the use of chemotherapy in combination with radiation therapy (35,72,92). In adults, recurrent disease that develops beyond 2 years from the time of initial treatment is more common and may occur several years after initial presentation (93). Accordingly, close long-term follow-up is recommended for adult patients (93). Recurrence of medulloblastoma most commonly manifests as leptomeningeal enhancement or focal parenchymal nodular enhancement within the brain (92). Recurrent disease develops most frequently in the posterior fossa, with the subfrontal region being the second most common location, possibly reflecting the prone position commonly used during surgery and the use of lead blocks to spare the ocular system during radiation therapy (94,95). Dural enhancement, as a singular finding, does not necessarily indicate recurrent disease (92). Not all cases of recurrent medulloblastoma will demonstrate enhancement on contrast-enhanced images; therefore, the absence of enhancement does not exclude the presence of recurrent disease (96). As with metastatic disease, the development of recurrent medulloblastoma carries a poorer prognosis with lowered 5-year survival rates (92). Figure 18. Medulloblastoma in a 13-year-old girl with nausea, vomiting, nystagmus, and ataxia. Physical examination revealed bilateral papilledema. (a) Axial T1-weighted MR image shows a heterogeneous mass within the left cerebellar hemisphere. The mass appears to extend to the surface of the cerebellum. (b) Axial T2-weighted MR image reveals marked heterogeneity within the mass. (c) Contrast-enhanced axial T1-weighted MR image demonstrates intense enhancement of the soft-tissue portions of the mass. (d) Contrast-enhanced coronal T1-weighted MR image shows exophytic extension (arrow) of the mass into the cerebellopontine angle. Ten months after surgical resection, the patient developed a single sacral metastasis (not shown). Despite radiation therapy, she developed neck and back pain 19 months later. (e) Postlaminectomy sagittal T2-weighted MR image shows multiple areas of abnormal hyperintensity (arrowheads) involving several cervical and thoracic vertebrae, indicative of metastatic disease. (f) Bone scan obtained 1 month later reveals diffuse increased uptake in the entire cervical spine and skull base as well as the humeral head.

21 RG f Volume 23 Number 6 Koeller and Rushing 1633

22 1634 November-December 2003 RG f Volume 23 Number 6 Following therapy, patients with medulloblastoma have an increased risk for the development of secondary malignancies, a tendency that is partially attributable to the longer survival times for some patients and the use of radiation therapy and chemotherapy (36). Cases of meningioma, basal cell carcinoma, glioblastoma multiforme, thyroid cancer, cervical cancer, uterine cancer, and acute leukemias have all been noted in these patients (14,23). As treatments extend survival times for medulloblastoma patients, it is likely that secondary malignancies will be encountered (23). Prognosis and Survival Rates The prognosis for patients with medulloblastoma has improved dramatically since Before that time, the overall 5-year survival rate was only 2% 30% (16,18). Since then, individual reports have described markedly improved 5-year survival rates, between 50% and 70% in most studies and over 80% in some reports (16,18,23,31,36, 97,98). Several demographic and clinical variables are associated with improved survival rates for patients with this disease. The rate is higher for patients who are years old at the time of presentation compared with younger patients (1). Girls have a higher survival rate overall compared with boys (1). A majority of studies have indicated improved survival rates with gross total resection compared with those with subtotal resection (14,18,99). Masses located within the cerebellar hemisphere are more likely to be completely removed than those located within the cerebellar vermis, and patients with tumors in the former location tend to have a better prognosis (4,100). Most studies have indicated a better survival rate (as high as 84% in one series) for adult patients with medulloblastoma compared with children with the disease (10,37,63). This improved rate appears to be directly related to the age of the patient and is not simply a reflection of a difference in histologic type (101). Conversely, a poorer prognosis has been noted in patients who require CSF diversion through ventriculoperitoneal shunting within 30 days of surgical resection of the tumor and for those with evidence of CSF spread (18,102). No statistical difference in survival rates among patients of different races has been observed in the overall population, although this may be a reflection of the lower numbers of non-whites reported in studies (1). Although initially believed to be a reliable predictor for prognosis, tumor volume alone does not correlate with prognosis (18). There are conflicting data as to whether a specific histologic type carries an improved survival rate. Such contradiction is especially true for the desmoplastic variant, for which reports have shown both worsened and improved rates in different patient cohorts (2). Different histologic criteria applied by pathologists may account for this discrepancy. Patients with medulloblastoma with extensive nodularity appear to have a much more favorable prognosis compared with those with the classic subtype (40,41). There is widespread agreement that the large cell variant is more biologically aggressive than the classic subtype, and the former subtype is associated with a significantly lower survival rate (2). In rare cases, maturation of the neuronal component of a recurrent medulloblastoma may occur with an uncertain impact on prognosis (49). Conclusions Once virtually uniformly fatal, the prognosis for patients with medulloblastoma has improved substantially since the mid-1900s, with many longterm survivors now reported. The diagnosis and treatment of medulloblastoma cross many specialty boundaries and require skill and diligence among all who care for patients with the disease. For those engaged in imaging of such patients, one should be aware of the characteristic hyperattenuation on nonenhanced CT scans, the common location within the cerebellar vermis, and the frequent presence of leptomeningeal metastasis at the time of diagnosis. The role of contrastenhanced MR imaging has revolutionized the evaluation of affected patients, and use of this modality is now considered essential in their follow-up care. With continued refinements in radiation therapy and chemotherapy, it is hoped that a tolerable cure may be at hand in the near future. Acknowledgments: The authors gratefully acknowledge the contributions of case material from radiology residents worldwide to the Thompson Archives of the Department of Radiologic Pathology at the Armed Forces Institute of Pathology, the assistance of Janeth Amarillo and Jessica Holquin in the preparation of the images, and the assistance of Sarah Heffron in manuscript preparation. References 1. 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