Harbor UCLA Neuro-Radiology Case 8

1. HARBOR UCLA NEURO CASE # 8
Anton Mlikotic, MD, Department of Radiology
Marcia Cornford, MD, PhD, Department of Pathology
Los Angeles County
Department of Health Sciences

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

3. 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 periventricular
trans-ependymal edema. (right)

4. 3
C
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.

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

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

7. Prior to gadolinium contrast administration (left), the mass is predominately low in signal intensity
on 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 gadolinium
contrast (right) , there is minimal appreciable enhancement.

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

10. Differential Diagnosis
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

11. T
N
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).

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

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

14. 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.

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

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

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

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

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

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

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

22. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. Immunohistochemical Profiles for Non-glial Embryonal Neoplasms
CD-9 Desmin/
Neoplasm GFAP Vimentin EMA NSE Synaptophysin S-100 CD99
9 Actin
Medulloblastoma focal - - + + - - - -
Medulloepithelioma rare + - - - - - - -
Atypical Teratoid /
focal + + + variable - + + +
Rhabdoid Tumor
Medullomyoblastoma - - - - + * - + - -
Ependymoblastoma rare + - - - - - + -
Supratentorial PNET focal - - - - + - - +
* Positivity for neuroectodermal cells only
Information derived from Pathologyoutlines.com and Manual of Basic Neuropathology, 4th Edition

32. Immunohistochemical Profile for Medulloblastoma
Marker Endothelial Stromal
component component
VEGF + +
CD 31 + -
CD 34 + +
FACTOR 8 + -
GFAP - Occasionally
EMA - -
CYTOKERATIN - -
VIMENTIN - +
ERYTHROPOEITIN - Occasionally
NSE - +
VEGF = Vascular endothelial growth factor
GFAP = Glial fibrillary acidic protein
EMA = Endothelial membrane antigen
NSE = Neuron specific enolase
Information derived from Pathologyoutlines.com and Manual of Basic Neuropathology, 4th Edition

33. 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.

34. 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.

35. 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.

36. 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 successfull
removed, and the portion that was closely adherent to the brainstem was preserved. A small
amount of intraventricular hemorrhage is also noted.

38. 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.

40. 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 more
rapidly 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

41. 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.