Harbor UCLA Neuro-Radiology Case 8


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Harbor UCLA Neuro-Radiology Case 8

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  • Lamia Britt and Taylor Mackey
  • Low power showing sheets of tumor cells M normal brain and tumor sheet molecular layer on folium
  • Tumor with calcification of vascular wall (unusual for medulloblastoma)
  • Classkc pnet nice round nuclei, no nucleoli small clear lightly eosinophili cytoplasm no rosettes or paslisading so not ependymoma uniform sheets of tumor
  • Classkc pnet nice round nuclei, no nucleoli small clear lightly eosinophili cytoplasm no rosettes or paslisading so not ependymoma uniform sheets of tumor
  • Harbor UCLA Neuro-Radiology Case 8

    1. 1. HARBOR UCLA NEURO CASE # 8 Anton Mlikotic, MD, Department of RadiologyMarcia Cornford, MD, PhD, Department of PathologyLos Angeles CountyDepartment of Health Sciences
    2. 2. Clinical presentationThe patient is a 28 month-old baby girl presenting withprogressive ataxia and lower extremity weakness, whofailed to achieve developmental milestones.
    3. 3. The screening non-enhanced CT study of the brain revealed a midline posterior fossa mass ofheterogeneous density containing calcifications. There is complete effacement of the fourthventricle 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)
    4. 4. 3 CThis sagittal T1-weighted image shows a mass of heterogeneous though predominantly isointense signalwith respect to the brain, centered in the posterior fossa (arrows), with compression of the fourth ventricleand cerebellum (C) and dilatation of the third ventricle (3). There is significant mass effect upon the brainstem as well, with flattening of the pons and medulla oblongata.
    5. 5. 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.
    6. 6. 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 thetentorial incisura, marked by the arrows.
    7. 7. 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 cerebellarpeduncle (arrow), which is surrounded by the mass. Following intravenous delivery of gadoliniumcontrast (right) , there is minimal appreciable enhancement.
    8. 8. Diffusion weighted images demonstrate evidence for restriction, a finding associated withmasses that have compact cells with a high nuclear to cytoplasmic ratio.
    9. 9. Differential DiagnosisAn 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
    10. 10. T NAt low power, the specimen in paraffin stained with haematoxolin and eosin shows sheets of tumorcells (T), with invasion of normal cerebellar white matter (N).
    11. 11. Clusters of microcalcifications are present , both within the stroma and in the capillary walls (arrows)
    12. 12. 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
    13. 13. For comparison, in another patient, the above pattern of Homer-Wright rosette formation withcentral fibrillary material in another patient is a typical, though inconsistent feature.
    14. 14. IMHC staining for synaptophysin shows uptake by the tumor both peripherally within the cellmembrane (top, right) and internally within the cytoplasm (bottom, right).
    15. 15. This section of tumor best demonstrates synaptophysin positivity, where the immunohistochemicalmarker concentrates at synaptic connections.
    16. 16. The tumor shows positivity for glial fibrillary acidic protein (GFAP).
    17. 17. There are scant areas of uptake of the IMHC CD99 marker, although it is largely negative.
    18. 18. Staining with IMHC CD-34 shows uptake by both stromal and capillary endothelial components.
    19. 19. A BThe IMHC Ki-67 marker uptake demonstrates a highly variable proliferation index, with areasof both high (A) and low (B) mitotic activity.
    20. 20. There is marked uptake of Ki-67 by this portion of tumor, with a proliferation index of >25%,indicating a high grade neoplasm.
    21. 21. Summary of Histopathologic FindingsThe specimen demonstrates a “small blue cell” neoplasm, lacking rosetteformation and palisading features. The nuclei are, on average, larger andmore variegated in size, and the cytoplasmic component is more abundantthan usual .IMHC marker localization helps to confirm diagnosis. There is synaptophysinlocalization, at the cell surface, within the cytoplasm, and especially at thesynaptic connections. The tumor also shows areas of positivity for glialfibrillary acidic protein (GFAP) and CD-34 uptake of both the stromal andendothelial components. Of note, there is lack of true IMHC CD99 localization,and additional staining with INI-1 , a nuclear antigen marker, was negative.
    22. 22. MedulloblastomaMedulloblastoma is a highly malignant primary brain tumor that usuallyforms in the vicinity of the fourth ventricle, between the brainstem andcerebellum. It is the most common pediatric central nervous systemmalignancy of the posterior fossa in children (38% of all pediatric posteriorfossa tumors), occurring more frequently in males and most commonly beforethe age of 10. It accounts for 6% to 8% of all central nervous system tumorsand 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.
    23. 23. Medulloblastoma: Clinical PresentationSymptoms result from secondary increased intracranial pressure due to blockageof the fourth ventricle and present less than months before diagnosis. Headache andpersistent vomiting are common, and truncal ataxia accompanied by spasticity, resultfrom 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 nervealong the anterior margin of the fourth ventricle. Other findings may reflect distalmetastatic seeding to the brain or spinal cord.
    24. 24. Medulloblastoma: ImagingThe tumor is characteristically high in density on unenhanced CT studies,reflecting the compactness of the tumor cell, which has a high nuclear tocytoplasmic ratio. It is typically heterogeneous, related to the presence ofcystic degeneration or necrosis, hemorrhage, and calcification. The mass ischaracteristically midline in children, often arising from the cerebellar vermis. In adults, a more lateral location is typical in the posterior fossa. The massusually incites vasogenic edema in the surrounding brain tissue, and thedegree of contrast enhancement is variable, though most commonlyhomogeneous. Secondary obstructive hydrocephalus results from compressionof the fourth ventricle.On MR, the mass is isointense to hypointense relative to white matter on T1weighted 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 motionof water molecules in cells with low cytoplasmic content.
    25. 25. Medulloblastoma: ImagingAt the time of diagnosis, over 30% of cases show evidence ofleptomeningeal spread, both in the brain and the spine.The differential diagnosis in children includes ependymoma, pilocyticastrocytoma, and atypical teratoid / rhabdoid tumor. Otherconsiderations are metastasis, hemangioblastoma, astrocytoma,lymphoma, and dysplastic cerebellar gangliocytoma.
    26. 26. Medulloblastoma: HistogenesisAlthough currently classified as a subset of primitive neuroectodermal tumor(PNET), originating from immature or embryonal cells at their earliest stageof development, the exact cell of origin or “medulloblast” is unknown, and mayarise from cerebellar stem cells that are prevented from differentiating intonormal cell types. Molecular genetics have isolated a gene deletion on the longarm of chromosome 17, distal to the p53 gene, and genetic profiling hasdemonstrated a molecular profile that is distinct from other PNET neoplasms.
    27. 27. Medulloblastoma: HistologyOn gross inspection, medulloblastomas have a variable appearance. Theymay present as discrete, firm masses or may be soft and less well defined.Histologically, medulloblastomas are small, blue-cell tumors that mayresemble other entities, such as pineoblastomas. The presence of HomerWright rosettes, with central neurofibrillary processes, is a hallmark finding,but is not always present. Mitotic activity is conspicuous, and necrosis mayoccur both on the cellular level (apoptosis) and in confluent fields.Large cell or anaplastic medulloblastoma has a closely packed cellarrangement, similar to the usual type of medulloblastoma, however the nucleihave increased diameters and the nucleoli are prominent. This variant alsoshows striking immunohistochemical staining for synaptophysin.In contradistinction, atypical teratoid / rhabdoid tumors have a less overallorganized appearance and show only scant, focal areas of synaptophysin andGFAP uptake. This tumor also shows uniform positivity for CD-99 andnegativity for INI-1(integrase interactor 1), a tumor suppressor gene normallyexpressed but lost in malignant rhabdoid tumors and epithelioid sarcomas.
    28. 28. 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
    29. 29. 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
    30. 30. Medulloblastoma: Subtype classificationThe 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 fibers3- 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.
    31. 31. Medulloblastoma: Subtype classification4- Large cell medulloblastoma is the least common form (4% of cases), and is characterizedby 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 “largecell anaplastic variant.”Other less common subtypes include medullomyoblastoma and melanotic medulloblastoma.
    32. 32. Medulloblastoma: Treatment / PrognosisTreatment begins with maximal resection of the tumor, and the addition of radiation tothe entire neuroaxis and chemotherapy may permit a 5 year survival in over 80% ofcases. Prognosis worsens however with a very young presentation (less than 3 years ofage), an inadequate degree of resection, or with distal spread.
    33. 33. Post-operative imagingFollowing surgical debulking of the non-enhancing tumor, the residual tumor burden isbest appreciated on the diffusion weighted images. Approximately 80 to 90% was successfullremoved, and the portion that was closely adherent to the brainstem was preserved. A smallamount of intraventricular hemorrhage is also noted.
    34. 34. 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.
    35. 35. MR SpectroscopyIn 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 specificfor medulloblastoma and related PNET tumors. AJNR March, 2006; 27: 560-572
    36. 36. 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.