American Association of Neuropathologists
2013 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.
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
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
T1+contrast
T1+contrast
FLAIR
Intraoperative Smear
200X
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.”
200X
400X
200X
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
MIB-1
Neurofilament
CD 68
GFAP
CD 34
p53
Summary of IHC and Special Stains
• 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
So we have an…
• 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
Differential Diagnosis
Diagnosis
• Glioblastoma (Granular Cell Subtype), WHO
Grade IV
Granular Cell Astrocytoma (GCA)
• 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
Differential Diagnosis of 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
IHC and Special Stain Profile
• 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
Genetic/Molecular 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
Grading and Prognosis
• 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
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.