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

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.

• 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

History

• 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

Radiology and Orbit Pathology

T1+contrast T1+contrast

FLAIR

Intraoperative Smear

200X

• 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.”

Intraoperative Findings

200X

400X

200X

• 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

H&E

MIB-1

Neurofilament

CD 68

GFAP

CD 34

p53

• 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

• 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…

?Differential Diagnosis

• Glioblastoma (Granular Cell Subtype), WHO Grade IV

Diagnosis

• 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)

• 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

• 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

• 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

• 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

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.

References