If This Is Not Glioblastoma, Then What Is

3/28/2016

I have no conflicts of interest in relation to this presentation. 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 [email protected]

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 44:1256‐72, 1979. • Burger PC; Vogel FS; Green SB; Strike TA: Glioblastoma multiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer 56:1106‐11, 1985. • 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, 1988. • …. Dr. Karsner addressed me, “Well, go ahead and make the incision.” I did without difficulty and also Senile dementia of Alzheimer’s type and Down’s syndrome without difficulty removed the tumor and placed it on the cutting board. Dr. Karsner added, “Well, cut it.” I • Teaching monograph on degenerative and demyelinating diseases did, and he said, “What do you see and what does it mean?” And then he added, “Let me clarify, ‘I did not say • Subacute diencephalic angioencephalopathy 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 • Cerebrovascular diseases, including granulomatous angiitis, hemorrhagic white matter infarction was a benign granulosa cell tumor. Dr. Karsner said, “Son, no matter what branch of medicine you enter, • Frozen section interpretation in surgical neuropathology 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 • Gamma‐L‐glutaminyl‐4‐hydroxybenzene (GHB) effect on the thyrosinase‐containing cells of the mouse which he added when he apologized and said, “I have a dinner date and must leave early.”

1 3/28/2016

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, widely‐ infiltrative; leptomeningeal infiltration rare • Relatively acute presentation; within months

2 3/28/2016

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 LOCATION

• Ring enhancing lesions: • Involvement of corpus callosum (if not necessarily a butterfly lesion): Glioblastoma, metastatic carcinoma, abscess, demyelinating Glioblastoma, metastatic carcinoma, lymphoma, tumefactive pseudotumor ….lymphoma, toxoplasmosis demyelination • Heterogeneously‐enhancing mass: • Multiplicity: High‐grade neoplasm vs. nonneoplastic processes Metastases, lymphoma, infections (bacterial or amebic abscesses, • Cyst and (homogeneously‐)enhancing mural nodule: toxoplasmosis) Pilocytic astrocytoma, ganglioglioma, angiocentric glioma, • Superficial: Metastases pleomorphic xanthoastrocytoma • Deep white matter: Lymphoma, infection

3 3/28/2016

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

PXA Findings commonly associated with low‐grade lesions

Synapto.

Retic.

4 3/28/2016

PXA with PXA anaplastic features

GFAP Synapto.

Neu‐N Ki‐67

Ganglioglioma PXA with anaplastic features

5 3/28/2016

Anaplastic Ganglioglioma Ganglioglioma

CD34

Syn. Neu‐N

Anaplastic Ganglioglioma with glial Ganglioglioma overgrowth vs. entrapped neurons

Ki‐67 BRAF V600E

6 3/28/2016

Microscopy Special Stains Molecular Clinical Location Growth Radiology GB -Astrocytic GFAP IDH mutation GB -Acute focal deficits; >50 Anywhere, deep, Infiltrative Ring- or heterogeneous -Necrosis, vascular proliferation ATRX loss -Long history with corpus callosum enhancement, irregular TP53 mutation recurrences; involvement young adult EGFR amplification PTEN mutation Giant cell GB -Relativelt younger -Well-circumscribed (5th decade) Giant cell GB -Giant cells -Reticulin -TP53 mutation -IDH wt

PXA -Pleomorphic GFAP BRAF V600E -Giant cells (Synaptophysin) PXA Long history with seizures; Temporal lobe, superficial Well-circumscribed; Cyst and enhancing mural -Mitoses, necrosis, vascular proliferation -Reticulin first few decades leptomeningeal nodule involvement

GG -Ganglion cells GFAP (background) BRAF V600E -Giant cells Synaptophysin -Mitoses, necrosis, vascular proliferation CD34 GG Long history with seizures; Temporal lobe, superficial Well-circumscribed Cyst and enhancing mural (Neu-N) first few decades nodule

SEGA Radiation necrosis vs. recurrent/residual GB: ‐ Enhancement in the wall of the resections cavity ‐ PET

TTF‐1

7 3/28/2016

Tumefactive Lymphoma demyelination; demyelinating pseudotumor (Beware of LFB/PAS NF 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 3/28/2016

Recommended References Recommended References General Glioblastoma, cont’d • WHO Classification of Tumours of the Central Nervous System. Editors: Louis DN, et al, 4th. Edition, IARC, Lyon, 2007. • Perry A, et al: Malignant Gliomas with Primitive Neuroectodermal Tumor‐like Components: A Clinicopathologic and Genetic Study of 53 Cases. • Practical Surgical Pathology: A Diagnostic Approach. Editors: Perry A, Brat DJ, Churchill Livingstone, Philadelphia, 2010. Brain Pathol 2008. • Perry A, et al: Small Cell Astrocytoma: An Aggressive Variant That Is Clinicopathologically and Genetically Distinct from Anaplastic • Horbinski C: To BRAF or not to BRAF:Is That Even a Questions Anymore? J Neuropathol Exp Neurol 2013. Oligodendroglioma. Cancer 2004. • Horbinski C: What do we know about IDH1/2 mutations so far, and how do we use it? J Neuropathol Exp Neurol 2013. • Appin CL, et al: Glioblastoma with Oligodendroglioma Component (GBM‐O): Molecular Genetic and Clinical Characteristics. Brain Pathol 2013. • 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:10.1111/bpa.12336. Seunggu JH, et al: Clinical Characteristics and Outcomes for a Modern Series of Primary Gliosarcoma Patients. Cancer 2010. • Oh JE, et al: Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma. Brain Pathol 2015. Glioblastoma

• Rodriguez FJ, et al: Epithelial and Pseudoepithelial Differentiation in Glioblastoma and Gliosarcoma: A Comparative Morphologic and Ganglioglioma Molecular Genetic Study. Cancer 2008. • Blümcke I, Wiestler OD: Gangliogliomas: An Intriguing Tumor Entity Associated With Focal Epilepsies. J Neuropathol Exp Neuron 2002. • Kleinschmidt‐DeMasters BK, et al: Epithelioid Versus Rhabdoid Glioblastomas are Distinguished by Monosomy 22 and • Majores M: Tumor Recurrence and Malignant Progression of Gangliogliomas. Cancer 2008. • Horbinski C: Isocitrate Dehydrogenase 1 Analysis Differentiates Gangliogliomas from Infiltrative Gliomas. Brain Pathol 2011. Immunohistochemical Expression of INI‐1 but not Claudin 6. Am J Surg Pathol 2010. • Kleinschmidt‐DeMasters BK, et al: Epithelioid GBMs Show a High Percentage of BRAF V600E Mutation. Am J Surg Pathol 2013. Pleomorphic Xanthoastrocytoma • Joseph NM, et al: Diagnostic implications of IDH1‐R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants. • Ida CM, et al: Immunohistochemistry is highly sensitive and specific for detection of BRAF V600E mutation in pleomorphic Modern Pathol 2012. xanthoastrocytoma. Acta Neuropathol Comm 2013. • Miller CR, Perry A: Glioblastoma: Morphologic and Molecular Genetic Diversity. Arch Pathol Lab Med 2007. • Ida CM, et al: Pleomorphic Xanthoastrocytoma: Natural History and Long‐Term Follow‐Up. Brain Pathol 2015.

Recommended References Neuroradiology • Burger PC, et al: Diagnostic Synergy in Radiology and Surgical Neuropathology: Neuroimaging Techniques and Interpretive Guidelines. Arch Pathol Lab Med 1998. • Burger PC, et al: Diagnostic Synergy in Radiology and Surgical Neuropathology: Radiolographic Findings of Specific Pathologic Entities. Arch Pathol Lab Med 1998.

9