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American Association of Neuropathologists 2013 Diagnostic Slide Session

This case report discusses a rare epithelioid neoplasm with granular cell features that mimicked sarcoid. The patient presented with eye swelling and neurological symptoms. The pathology findings and immunohistochemical profile are described, along with the differential diagnosis. The genetic/molecular profile is also discussed.

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American Association of Neuropathologists 2013 Diagnostic Slide Session

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  1. American Association of Neuropathologists2013 Diagnostic Slide Session CPT Alan George, D.O.1 Gregory N. Fuller, M.D., Ph.D.2 Lauren A. Langford, M.D., Dr.med.2 MAJ Amy Zingalis, M.D.1 Lt Col Derek A. Mathis, M.D.1 1San Antonio Military Medical Center (SAMMC) 2Section of Neuropathology, M.D. Anderson Cancer Center, Houston, TX

  2. Disclosures • None Disclaimer: The views expressed are those of the authors and do not reflect the official policy or position of the United States Air Force, United States Army, Department of Defense, or the U.S. Government.

  3. History • 76 y/o M with subacute onset of left eye swelling, proptosis, ptosis. No pain, redness, or discharge. Ophthalmology rx’d antibiotics; no improvement. Also reports occasional tremor in hands x 3 months and generalized feeling of fatigue and balance problems. Denies headache or difficulty with speech • Past medical/surgical history: hypertension, hyperlipidemia, cardiac ablation for ventricular tachycardia, seasonal allergies

  4. Radiology and Orbit Pathology • MRI for eye work-up finds “Two adjacent enhancing lesions versus heterogeneous enhancement within a single mass in the right temporal lobe with associated diffuse edema and sulcal effacement throughout the right temporal lobe” • Focal blooming artifact consistent with internal hemosiderin components • Findings concerning for primary CNS tumor given the infiltrative appearance, essentially solitary focus of disease within the right temporal lobe, and internal calcification on the comparison CT • Left orbit biopsy pathology = non-caseating granulomatous inflammation, suggestive of sarcoid

  5. T1+contrast T1+contrast FLAIR

  6. Intraoperative Smear 200X

  7. Intraoperative Findings • Smear: Hypercellular with mostly cytologically bland granular cells, some foci of high vascularity, occasional enlarged hyperchromatic “naked” nuclei • Frozen section: granular background, relatively bland nuclei, acellular areas (necrosis?), and foci of increased vascularity • Intraoperative Diagnosis = “Lesional tissue present; differential diagnosis includes neoplasm, reactive process, vascular malformation” • Neurosurgeon was present at microscope: “OK, I’ll just take out all the rest of the enhancing stuff and stop.”

  8. 200X

  9. 400X

  10. 200X

  11. H&E Vast majority of resected tissue shows an epithelioid neoplasm with relatively bland nuclei, abundant granular cytoplasm, prominent cell-cell borders Mitoses are extremely rare (1-2 total on all slides) Foci of microvascular proliferation Very rare eosinophilic granular bodies Minor component with appearance of infiltrating low grade glioma No necrosis

  12. MIB-1

  13. Neurofilament

  14. CD 68

  15. GFAP

  16. CD 34

  17. p53

  18. Positive IHC: GFAP, CD34 (strong peripheral), p53 (some), S-100, CD68 (focal, weak), MIB-1 = 2-3% Negative IHC: Neurofilament, synaptophysin (pale blush at SAMMC; negative at MD Anderson), CD163, IDH-1 (R132H), cytokeratin (CAM5.2) Special stains: PAS(+) with and without diastase No significant pericellular reticulin Summary of IHC and Special Stains

  19. Epithelioid, infiltrative, GFAP-positive tumor with: mostly bland cytology, abundant granular cytoplasm, and prominent cell-cell borders rare EGBs minor component resembling infiltrating low grade glioma extremely rare mitoses and MIB-1 = 2-3% foci of microvascular proliferation areas of enhancement on MRI …incidentally found in an older patient being worked up for an orbital mass with histopathologic features suggestive of sarcoid So we have an…

  20. ? Differential Diagnosis

  21. Glioblastoma (Granular Cell Subtype), WHO Grade IV Diagnosis

  22. Prominent granular cell component Cytoplasmic granules = lysosomes by EM Large round to oval cells with distinct cell-cell borders, often forming homogeneous sheets Nuclei are usually bland, round to oval, vary in size, may be eccentrically located, with occasional small nucleoli Tumors can be entirely granular but usually contain a mixed granular and conventional astrocytoma component Granular Cell Astrocytoma (GCA)

  23. Macrophage-rich lesions: Infarcts Demyelinating disease Infections, including progressive multifocal leukoencephalopathy Tumors: Granular cell tumor of the neurohypophysis/infundibulum Metastatic tumors with granular cytoplasm Differential Diagnosis of GCA

  24. Cytoplasmic granules are PAS(+) and diastase resistant GFAP(+) Can be low (<30%) or negative Also (+): OLIG2, CD68, S-100, EMA, vimentin, ubiquitin MIB-1 usually very low or negative Ours has strong peripheral CD34 IHC and Special Stain Profile

  25. Nothing specific for GCA, but: Loss of 9p and 10q in most Some with TP53 mutations or combined p14 and p16 deletions Higher frequencies of loss of heterozygosity at 1p, 9p, 10q, 17p, 19q than conventional infiltrating astrocytomas EGFR amplification and MGMT promoter methylation have been reported in granular cell [our MGMT was negative for methylation] No IDH-1 or IDH-2 mutations reported Genetic/Molecular Profile

  26. Grading is according to the usual infiltrating astrocytoma criteria: WHO grade II – IV Prognosis appears significantly worse than for corresponding grade conventional astrocytomas; most patients die within a year Grade III GCA survival ~ 1/3 of conventional grade III astrocytoma Grading and Prognosis

  27. References 1. Brat DJ, Scheithauer BW, Medina-Flores R, Rosenblum MK, Burger PC. Infiltrative astrocytomas with granular cell features (granular cell astrocytomas): a study of histopathologic features, grading, and outcome. Am J Surg Pathol. 2002; 26:750-7. 2. Geddes JF, Thom M, Robinson S, Revesz T. Granular cell change in astrocytic tumors. Am J Surg Pathol. 1996; 20:55-63. 3. Shi Y, Morgenstern N. Granular Cell Astrocytoma. Archives of Pathology & Laboratory Medicine. 2008; 132: 1946-1950. 4. Joo M, Park SH, Chang SH, Kim H, Choi CY, Lee, CH, Lee BH, Hwang, YJ. Cytogenetic and molecular genetic study on granular cell glioblastoma: a case report. Human Pathology 2013; 44:282-288. 5. Schittenhelm J, Psaras T. Glioblastoma with granular cell astrocytoma features: a case report and literature review. Clinical Neuropathology 2010; 29: 323-329. 6. Castellano-Sanchez AA, Ohgaki H, Yokoo H, Scheithauer BW, Burger PC, Hamilton RL, Finkelstein SD, Brat DJ. Granular cell astrocytomas show a high frequency of allelic loss but are not a genetically defined subset. Brain Pathology 2003; 13(2):185-94. 7. Joseph NM, Phillips J, Dahiya S, Felicella MM, Tihan T, Brat DJ, Perry A. Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants. Modern Pathology 5 October 2012 advance online publication. *Radiographs and tissue photomicrographs performed at San Antonio Military Medical Center.

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