HARBOR UCLA NEURO CASE # 8

Anton Mlikotic, MD, Department of RadiologyMarcia Cornford, MD, PhD, Department of

Pathology

Los Angeles CountyDepartment of Health Sciences

The patient is a 28 month-old baby girl presenting with progressive ataxia and lower extremity weakness, who failed to achieve developmental milestones.

Clinical presentation

The screening non-enhanced CT study of the brain revealed a midline posterior fossa mass of heterogeneous density containing calcifications. There is complete effacement of the fourth ventricle and prepontine cistern with dilatation of the temporal horns of the lateral ventricle (left). The mass secondarily results in significant obstructive hydrocephalus with areas of periventriculartrans-ependymal edema. (right)

This sagittal T1-weighted image shows a mass of heterogeneous though predominantly isointense signal with respect to the brain, centered in the posterior fossa (arrows), with compression of the fourth ventricle and cerebellum (C) and dilatation of the third ventricle (3). There is significant mass effect upon the brain stem as well, with flattening of the pons and medulla oblongata.

C

3

FLAIR images reveal a high water content of the neoplasm with foci of dark signal correspondingto calcifications and vascular flow voids. Note the periventricular areas of high signal related totrans-ependymal flow of cerebrospinal fluid secondary to long standing ventricular obstruction.

The coronal T2-weighted image also indicates that the tumor has a high water content, demonstrated byincreased signal intensity. Also, the mass extends into the supratentorial compartment through the tentorial incisura, marked by the arrows.

Prior to gadolinium contrast administration (left), the mass is predominately low in signal intensityon T1-weighted imaging, with scattered foci of bright and dark signal. Note the superior cerebellar peduncle (arrow), which is surrounded by the mass. Following intravenous delivery of gadoliniumcontrast (right) , there is minimal appreciable enhancement.

Diffusion weighted images demonstrate evidence for restriction, a finding associated with masses that have compact cells with a high nuclear to cytoplasmic ratio.

An infratentorial pediatric neoplasm carries the following differential considerations:

Astrocytic lineage

Juvenile pilocytic astrocytoma

Brain stem glioma

Non-glial, Embryonal lineage (Primitive Neuroectodermal Tumor)

Medulloblastoma

Medullomyoblastoma

Atypical teratoid / rhabdoid tumor

Ependymal lineage

Ependymoma

Anaplastic ependymoma

Differential Diagnosis

At low power, the specimen in paraffin stained with haematoxolin and eosin shows sheets of tumor cells (T), with invasion of normal cerebellar white matter (N).

T

N

Clusters of microcalcifications are present , both within the stroma and in the capillary walls (arrows)

At higher power, there are uniform sheets of tumor with cells containing pleomorphic nuclei and moreabundant cytoplasm than usual for this entity. No rosette formation or cellular palisading is appreciated.

For comparison, in another patient, the above pattern of Homer-Wright rosette formation with central fibrillary material in another patient is a typical, though inconsistent feature.

IMHC staining for synaptophysin shows uptake by the tumor both peripherally within the cell membrane (top, right) and internally within the cytoplasm (bottom, right).

This section of tumor best demonstrates synaptophysin positivity, where the immunohistochemicalmarker concentrates at synaptic connections.

The tumor shows positivity for glial fibrillary acidic protein (GFAP).

There are scant areas of uptake of the IMHC CD99 marker, although it is largely negative.

Staining with IMHC CD-34 shows uptake by both stromal and capillary endothelial components.

The IMHC Ki-67 marker uptake demonstrates a highly variable proliferation index, with areasof both high (A) and low (B) mitotic activity.

B

A

There is marked uptake of Ki-67 by this portion of tumor, with a proliferation index of >25%,indicating a high grade neoplasm.

Summary of Histopathologic Findings

The specimen demonstrates a “small blue cell” neoplasm, lacking rosette formation and palisading features. The nuclei are, on average, larger and

more variegated in size, and the cytoplasmic component is more abundant than usual .

IMHC marker localization helps to confirm diagnosis. There is synaptophysin localization, at the cell surface, within the cytoplasm, and especially at the synaptic connections. The tumor also shows areas of positivity for glial fibrillary acidic protein (GFAP) and CD-34 uptake of both the stromal and endothelial components. Of note, there is lack of true IMHC CD99 localization, and additional staining with INI-1 , a nuclear antigen marker, was negative.

Medulloblastoma

Medulloblastoma is a highly malignant primary brain tumor that usually forms in the vicinity of the fourth ventricle, between the brainstem and cerebellum. It is the most common pediatric central nervous system malignancy of the posterior fossa in children (38% of all pediatric posterior fossa tumors), occurring more frequently in males and most commonly before the age of 10. It accounts for 6% to 8% of all central nervous system tumors and 12% to 25% of tumor subtypes in the pediatric population.

In constitutes only 0.4% to 1% of all central nervous system tumors in adults, however, presenting usually in the second or third decades of life.

Medulloblastoma: Clinical Presentation

Symptoms result from secondary increased intracranial pressure due to blockage

of the fourth ventricle and present less than months before diagnosis. Headache and persistent vomiting are common, and truncal ataxia accompanied by spasticity, result from destruction of the cerebellar vermis. Other clinical findings include papilledema, nystagmus, limb ataxia, and dysdiadokokinesis.

On examination, one third of patients have a positive Babinski and Hoffman signs. Abducens nerve palsy results from compression of the nucleus of the sixth cranial nerve along the anterior margin of the fourth ventricle. Other findings may reflect distal metastatic seeding to the brain or spinal cord.

Medulloblastoma: Imaging

The tumor is characteristically high in density on unenhanced CT studies, reflecting the compactness of the tumor cell, which has a high nuclear to cytoplasmic ratio. It is typically heterogeneous, related to the presence of cystic degeneration or necrosis, hemorrhage, and calcification. The mass is characteristically midline in children, often arising from the cerebellar vermis. In adults, a more lateral location is typical in the posterior fossa. The mass usually incites vasogenic edema in the surrounding brain tissue, and the degree of contrast enhancement is variable, though most commonly homogeneous. Secondary obstructive hydrocephalus results from compression of the fourth ventricle.

On MR, the mass is isointense to hypointense relative to white matter on T1 weighted imaging and has variable signal intensity on T2 weighted imaging. Similar to CT, the contrast enhancement of these lesions is highly variable, which may reflect the subtype of the lesion or degree of malignancy. Diffusion-weighted imaging is helpful for both diagnosis and post-operative surveillance, as the neoplasm shows high signal, reflecting restriction of the random motion of water molecules in cells with low cytoplasmic content.

Medulloblastoma: Imaging

At the time of diagnosis, over 30% of cases show evidence of leptomeningeal spread, both in the brain and the spine.

The differential diagnosis in children includes ependymoma, pilocytic astrocytoma, and atypical teratoid / rhabdoid tumor. Other considerations are metastasis, hemangioblastoma, astrocytoma, lymphoma, and dysplastic cerebellar gangliocytoma.

Medulloblastoma: Histogenesis

Although currently classified as a subset of primitive neuroectodermal tumor (PNET), originating from immature or embryonal cells at their earliest stage of development, the exact cell of origin or “medulloblast” is unknown, and may arise from cerebellar stem cells that are prevented from differentiating into normal cell types. Molecular genetics have isolated a gene deletion on the long arm of chromosome 17, distal to the p53 gene, and genetic profiling has demonstrated a molecular profile that is distinct from other PNET neoplasms.

Medulloblastoma: Histology

On gross inspection, medulloblastomas have a variable appearance. They may present as discrete, firm masses or may be soft and less well defined. Histologically, medulloblastomas are small, blue-cell tumors that may resemble other entities, such as pineoblastomas. The presence of Homer Wright rosettes, with central neurofibrillary processes, is a hallmark finding, but is not always present. Mitotic activity is conspicuous, and necrosis may occur both on the cellular level (apoptosis) and in confluent fields.

Large cell or anaplastic medulloblastoma has a closely packed cell arrangement, similar to the usual type of medulloblastoma, however the nuclei have increased diameters and the nucleoli are prominent. This variant also shows striking immunohistochemical staining for synaptophysin.

In contradistinction, atypical teratoid / rhabdoid tumors have a less overall organized appearance and show only scant, focal areas of synaptophysin and GFAP uptake. This tumor also shows uniform positivity for CD-99 and negativity for INI-1(integrase interactor 1), a tumor suppressor gene normally expressed but lost in malignant rhabdoid tumors and epithelioid sarcomas.

Immunohistochemical Profiles for Non-glial Embryonal Neoplasms

Neoplasm GFAP Vimentin EMA NSE SynaptophysinCD-99

Desmin/Actin

S-100 CD99

Medulloblastoma focal - - + + - - - -

Medulloepithelioma rare + - - - - - - -

Atypical Teratoid / Rhabdoid Tumor

focal + + + variable - + + +

Medullomyoblastoma - - - - + * - + - -

Ependymoblastoma rare + - - - - - + -

Supratentorial PNET focal - - - - + - - +

* Positivity for neuroectodermal cells only

Information derived from Pathologyoutlines.com and Manual of Basic Neuropathology, 4th Edition

Immunohistochemical Profile for Medulloblastoma

Marker Endothelialcomponent

Stromalcomponent

VEGF + +

CD 31 + -

CD 34 + +

FACTOR 8 + -

GFAP - Occasionally

EMA - -

CYTOKERATIN - -

VIMENTIN - +

ERYTHROPOEITIN - Occasionally

NSE - +

VEGF = Vascular endothelial growth factorGFAP = Glial fibrillary acidic proteinEMA = Endothelial membrane antigenNSE = Neuron specific enolase

Information derived from Pathologyoutlines.com and Manual of Basic Neuropathology, 4 th Edition

Medulloblastoma: Subtype classification

The World Health Organization recognizes four major subtypes of this grade 4 lesion:

1- The classic subtype is defined by dense, sheet like growth of cells with hyperchromatic, round to oval nuclei, accompanied by increased mitotic activity and apoptosis. Commonly visualized are neuroblastic or Homer-Wright rosettes, consisting of neoplastic cell nuclei in a radial arrangement around fibrillary processes.

2- The desmoplastic subtype shows nodular, reticulin-free “pale islands” surrounded by reticulin-staining collagen fibers

3- The subtype termed “medulloblastoma with extensive nodularity and advanced neuronal differentiation” occurs primarily in children less than 3 years, associated with “grapelike” nodularity that can be appreciated on cross-sectional imaging. Intranodular cellular uniformity, accompanied by a fine fibrillary matrix and occasional mature ganglion cells, is typical. This variant is termed cerebellar neuroblastoma.

Medulloblastoma: Subtype classification

4- Large cell medulloblastoma is the least common form (4% of cases), and is characterized

by large round nuclei with prominent nucleoli, nuclear molding, and abundant cytoplasm.

This subtype carries the poorest prognosis, and a variant of this form has been termed “large

cell anaplastic variant.”

Other less common subtypes include medullomyoblastoma and melanotic medulloblastoma.

Medulloblastoma: Treatment / Prognosis

Treatment begins with maximal resection of the tumor, and the addition of radiation to the entire neuroaxis and chemotherapy may permit a 5 year survival in over 80% of cases. Prognosis worsens however with a very young presentation (less than 3 years of age), an inadequate degree of resection, or with distal spread.

Post-operative imaging

Following surgical debulking of the non-enhancing tumor, the residual tumor burden is best appreciated on the diffusion weighted images. Approximately 80 to 90% was successfully removed, and the portion that was closely adherent to the brainstem was preserved. A small amount of intraventricular hemorrhage is also noted.

Answer: Contrast-enhanced imaging of the neuroaxis

Leptomeningeal metastasis occurs in 33% of cases at diagnosis. Primitive neuroectodermal tumors, such as medulloblastoma, may spread via

subarachnoid seeding. Therefore, complete contrast-enhanced imaging

of the neuroaxis should be performed to assess for distal spread.

Whether post-operative surveillance with MRI should be performed remains controversial in terms of prognosis. It may be useful though in assessing the

efficacy of adjuvant therapies to treat this disease.

MR Spectroscopy

In another patient, single voxel proton spectroscopy sampling a midline posterior fossa neoplasm,proven to be a medulloblastoma, shows an elevated choline peak, a signature for neoplasm, at 3.2 ppm. Elevated choline peaks reflect the increased turnover of cell membrane phosphatidylcholine in morerapidly dividing tumor cells. In addition, there is a taurine peak of 3.4 ppm, considered fairly specific for medulloblastoma and related PNET tumors.

AJNR March, 2006; 27: 560-572

References

• Medulloblastoma: A Comprehensive Review with Radiologic-Pathologic Correlation. Radiographics 2003; 23: 1613-1637.

• Escourolle and Poirier Manual of Basic Neuropathology: Fourth Edition. F Gray, U De Girolami, J Poirier. Pages 23-24.