I have no conflicts of interest in relation to this presentation. Vogel FS & Burger PC 3/28/2016

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1 IF THIS IS NOT GLIOBLASTOMA, THEN WHAT IS IT? Murat Gokden, MD Department of Pathology/Neuropathology University of Arkansas for Medical Sciences Little Rock, AR I have no conflicts of interest in relation to this presentation.. Dr. Karsner addressed me, Well, go ahead and make the incision. I did without difficulty and also without difficulty removed the tumor and placed it on the cutting board. Dr. Karsner added, Well, cut it. I did, and he said, What do you see and what does it mean? And then he added, Let me clarify, I did not say what do you know about ovarian tumors? What have you been told, what have you read about ovarian tumors? I described the physical characteristics of the mass as best I could and suggested that perhaps it was a benign granulosa cell tumor. Dr. Karsner said, Son, no matter what branch of medicine you enter, when you approach a patient and have the opportunity to see a disease process, always ask yourself, what do I see and what does it mean?.. On many occasions, I have followed Dr. Karsner s suggestion even that which he added when he apologized and said, I have a dinner date and must leave early. Vogel FS & Burger PC Burger PC; Mahley MS Jr; Dudka L; Vogel FS: The morphologic effects of radiation administered therapeutically for intracranial gliomas: a postmortem study of 25 cases. Cancer 44: , Burger PC; Vogel FS; Green SB; Strike TA: Glioblastoma multiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer 56: , Eby NL; Grufferman S; Flannelly CM; Schold SC Jr; Vogel FS; Burger PC: Increasing incidence of primary brain lymphoma in the US. Cancer. 62:2461 5, Senile dementia of Alzheimer s type and Down s syndrome Teaching monograph on degenerative and demyelinating diseases Subacute diencephalic angioencephalopathy Cerebrovascular diseases, including granulomatous angiitis, hemorrhagic white matter infarction Frozen section interpretation in surgical neuropathology Gamma L glutaminyl 4 hydroxybenzene (GHB) effect on the thyrosinase containing cells of the mouse 1

2 Goal & Objectives Goal: To identify histologic mimics of glioblastoma Objectives: Review the classical clinical, radiologic and histologic features of glioblastoma Learn the characteristic clinical, radiologic and histologic findings that alert to the presence of another lesion List the main lesions in the differential diagnosis of glioblastoma and their distinguishing findings Describe the differential diagnostic work up of glioblastoma and their mimics GLIOBLASTOMA (GB) 15% of all intracranial neoplasms; 50 60% of all astrocytic tumors Cerebral hemispheres with involvement of deep structures, widelyinfiltrative; leptomeningeal infiltration rare Relatively acute presentation; within months 2

3 GB, HISTOLOGIC VARIABILITY (i.e., MULTIFORME) GB, NOS Small cell GB Giant cell GB With PNET like differentiation With oligodendroglioma component Rhabdoid/epithelioid GB Glandular/adenoid GB, epithelial and/or mesenchymal metaplasia Gliosarcoma RADIOLOGIC MIMICS Ring enhancing lesions: Glioblastoma, metastatic carcinoma, abscess, demyelinating pseudotumor.lymphoma, toxoplasmosis Heterogeneously enhancing mass: High grade neoplasm vs. nonneoplastic processes Cyst and (homogeneously )enhancing mural nodule: Pilocytic astrocytoma, ganglioglioma, angiocentric glioma, pleomorphic xanthoastrocytoma LOCATION Involvement of corpus callosum (if not necessarily a butterfly lesion): Glioblastoma, metastatic carcinoma, lymphoma, tumefactive demyelination Multiplicity: Metastases, lymphoma, infections (bacterial or amebic abscesses, toxoplasmosis) Superficial: Metastases Deep white matter: Lymphoma, infection 3

4 HISTOLOGIC MIMICS Pleomorphic xanthoastrocytoma (PXA) vs giant cell GB (GG) Subependymal giant cell astrocytoma (SEGA) Anaplastic oligodendroglioma vs small cell GB Metastatic small cell carcinoma/pnet embryonal tumors vs GB with PNETlike differentiation Metastatic carcinoma vs GB with epithelioid features Abscess vs. GB with inflammatory reaction vs infections (ameba, toxoplasma vs other necrotic lesions such as granulomata) Infarct vs GB (granular cell) vs demyelinating pseudotumor/tumefactive demyelination Sarcoma/gliosarcoma/malignant meningioma vs GB Radiation necrosis/reactive gliosis vs. residual/recurrent GB Pleomorphic xanthoastrocytoma (PXA) (GG) Suspect something lower grade: Cystic component Prominent leptomeningeal surface involvement Well circumscription Eosinophilic granular bodies Rosenthal fibers Calcifications Findings commonly associated with low grade lesions PXA Synapto. Retic. 4

5 PXA PXA with anaplastic features GFAP Synapto. Neu N Ki 67 PXA with anaplastic features 5

6 Anaplastic CD34 Syn. Neu N Anaplastic with glial overgrowth vs. entrapped neurons Ki 67 BRAF V600E 6

7 GB Giant cell GB Clinical Location Growth Radiology -Acute focal deficits; >50 -Long history with recurrences; young adult -Relativelt younger (5 th decade) Anywhere, deep, corpus callosum involvement Infiltrative -Well-circumscribed Ring- or heterogeneous enhancement, irregular GB Giant cell GB Microscopy Special Stains Molecular -Astrocytic -Necrosis, vascular proliferation -Giant cells GFAP -Reticulin IDH mutation ATRX loss TP53 mutation EGFR amplification PTEN mutation -TP53 mutation -IDH wt PXA Long history with seizures; first few decades Temporal lobe, superficial Well-circumscribed; leptomeningeal involvement Cyst and enhancing mural nodule PXA -Pleomorphic -Giant cells -Mitoses, necrosis, vascular proliferation GFAP (Synaptophysin) -Reticulin BRAF V600E GG Long history with seizures; first few decades Temporal lobe, superficial Well-circumscribed Cyst and enhancing mural nodule GG -Ganglion cells -Giant cells -Mitoses, necrosis, vascular proliferation GFAP (background) Synaptophysin CD34 (Neu-N) BRAF V600E SEGA Radiation necrosis vs. recurrent/residual GB: Enhancement in the wall of the resections cavity PET TTF 1 7

8 Lymphoma LFB/PAS NF Tumefactive demyelination; demyelinating pseudotumor (Beware of histiocytes!) CD20 CD3 CD3 CD68 Summary Abscess GB, while generally a straightforward diagnosis, can be mimicked by a variety of other neoplastic or non neoplastic lesions due to variable histology. Anaplastic versions of typically well circumscribed, low grade neoplasms with large/giant cells can be especially problematic. Knowledge of histologic, radiologic and clinical features of alternative lesions is crucial in avoiding over diagnosis. Conscious use of special stains and molecular markers help in the differential diagnosis. 8

9 Recommended References General WHO Classification of Tumours of the Central Nervous System. Editors: Louis DN, et al, 4 th. Edition, IARC, Lyon, Practical Surgical Pathology: A Diagnostic Approach. Editors: Perry A, Brat DJ, Churchill Livingstone, Philadelphia, Horbinski C: To BRAF or not to BRAF:Is That Even a Questions Anymore? J Neuropathol Exp Neurol Horbinski C: What do we know about IDH1/2 mutations so far, and how do we use it? J Neuropathol Exp Neurol Solomon DA: Diffuse Midline Gliomas with Histone H3 K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations. Brain Pathol 2015 doi: /bpa Glioblastoma Rodriguez FJ, et al: Epithelial and Pseudoepithelial Differentiation in Glioblastoma and Gliosarcoma: A Comparative Morphologic and Molecular Genetic Study. Cancer Kleinschmidt DeMasters BK, et al: Epithelioid Versus Rhabdoid Glioblastomas are Distinguished by Monosomy 22 and Immunohistochemical Expression of INI 1 but not Claudin 6. Am J Surg Pathol Kleinschmidt DeMasters BK, et al: Epithelioid GBMs Show a High Percentage of BRAF V600E Mutation. Am J Surg Pathol Joseph NM, et al: Diagnostic implications of IDH1 R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants. Modern Pathol Miller CR, Perry A: Glioblastoma: Morphologic and Molecular Genetic Diversity. Arch Pathol Lab Med Recommended References Glioblastoma, cont d Perry A, et al: Malignant Gliomas with Primitive Neuroectodermal Tumor like Components: A Clinicopathologic and Genetic Study of 53 Cases. Brain Pathol Perry A, et al: Small Cell Astrocytoma: An Aggressive Variant That Is Clinicopathologically and Genetically Distinct from Anaplastic Oligodendroglioma. Cancer Appin CL, et al: Glioblastoma with Oligodendroglioma Component (GBM O): Molecular Genetic and Clinical Characteristics. Brain Pathol Seunggu JH, et al: Clinical Characteristics and Outcomes for a Modern Series of Primary Gliosarcoma Patients. Cancer Oh JE, et al: Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma. Brain Pathol Blümcke I, Wiestler OD: s: An Intriguing Tumor Entity Associated With Focal Epilepsies. J Neuropathol Exp Neuron Majores M: Tumor Recurrence and Malignant Progression of s. Cancer Horbinski C: Isocitrate Dehydrogenase 1 Analysis Differentiates s from Infiltrative Gliomas. Brain Pathol Pleomorphic Xanthoastrocytoma Ida CM, et al: Immunohistochemistry is highly sensitive and specific for detection of BRAF V600E mutation in pleomorphic xanthoastrocytoma. Acta Neuropathol Comm Ida CM, et al: Pleomorphic Xanthoastrocytoma: Natural History and Long Term Follow Up. Brain Pathol Recommended References Neuroradiology Burger PC, et al: Diagnostic Synergy in Radiology and Surgical Neuropathology: Neuroimaging Techniques and Interpretive Guidelines. Arch Pathol Lab Med Burger PC, et al: Diagnostic Synergy in Radiology and Surgical Neuropathology: Radiolographic Findings of Specific Pathologic Entities. Arch Pathol Lab Med

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