Case 1 -
Glioblastoma, Granular Cell Variant, WHO Grade IV
Arie Perry, University of California, San Francisco, San Francisco, CA
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This 51-yo woman presented with new onset of headaches and left hemiparesis. MRI studies revealed a 5 x 3 x 3.5 cm. partially cystic, partially solid contrast enhancing right temporo-parietal mass with surrounding edema and a roughly 1 cm midline shift to the left. The lesion was in close proximity to the lateral ventricle and the radiologist favored a high-grade ependymoma or astrocytoma. A craniotomy and open biopsy was performed.
Case 1 - Slide 1
Case 1 - Figure 1
Post-gadolinium T1-weighted MRI demonstrating a rim enhancing mass in the right temporo-parietal white matter, including a periventricular region. Evidence of mass effect includes right to left midline shift and compression of the right lateral ventricle.
Case 1 - Figure 2
Area of pallor with abundant clear foamy cells mimicking macrophages, as well as perivascular lymphocytic cuffing. This focus resembles active inflammatory demyelinating disease.
Case 1 - Figure 3
Higher magnification image of histiocyte-like clear foamy cells with mild nuclear atypia and increased mitotic activity.
Case 1 - Figure 4
Focus of tumor cells with granular eosinophilic cytoplasm.
This case represents a rare variant of glioblastoma which can be particularly challenging
diagnostically, due to the relatively bland cytological features of tumor cells and their resemblance to
either foamy macrophages or to the low-grade granular cell tumor of the pituitary and other sites. In
most cases, there are at least some foci showing conventional features of diffuse astrocytoma, but in
some, deceptively bland appearing granular cells constitute the only cell type. The differential
diagnosis for such cases in the posterior fossa of children is discussed below.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Sections revealed a hypercellular infiltrate composed predominantly of cells with foamy clear
cytoplasm suggestive of macrophages. At higher magnification, some degree of nuclear pleomorphism is
noted, along with fairly brisk mitotic activity and foci of microvascular proliferation. Histochemical
and immunohistochemical studies revealed that these large foamy cells were positive on stains for PAS
with diastase, CD68 (weak), GFAP, EMA, Olig2, and p53 protein. The Ki-67 labeling index was markedly
elevated and a stain for neurofilament protein highlighted numerous entrapped axons, consistent with an
infiltrative pattern. Tumor cells were negative for the R132H mutant form of IDH1, cytokeratin cocktail,
AE1/AE3, low molecular weight keratin, CK7, CK20, synaptophysin, chromogranin, and PAX-8.
- Tumefactive inflammatory demyelinating disease
- Granular cell GBM
- Steroid treated CNS lymphoma
- Infectious Process
- Metastatic granular cell tumor or carcinoma (e.g., RCC)
- Histiocytic disorder
Glioblastoma, Granular Cell Variant, WHO Grade IV
Granular cell astrocytomas (GCA) were first described by William Markesbery and colleagues in 1973 and
were originally thought to represent an intracerebral form of granular cell tumor, analogous to those
encountered systemically and in the pituitary gland . However, it later became evident that these
were distinctive highly aggressive neoplasms with overlapping features to those of diffuse astrocytomas,
along with the presence of transitional forms cytologically
GCA are defined as diffuse
astrocytic neoplasms with at least 30% of tumor cells containing lysosome-rich granular cells. The
latter are often deceptively bland cytologically and may resemble either foamy macrophages or more
eosinophilic granular tumor cells. As such, they may engender a wide differential diagnosis (discussed
below), especially for cases that are nearly entirely composed of granular cells or are only focally
sampled on stereotactic needle biopsies.
Roughly 50-60 GCA have been reported in the literature to date and the demographics are typically
those of diffuse astrocytomas in general. Nearly all cases have presented as contrast enhancing cerebral
masses in middle age to older adults, with men outnumbering women about 2:1. However, rare pediatric,
cerebellar, or spinal examples have also been reported. Although they can be stratified from WHO grades
II to IV based on current criteria for astrocytomas, the clinical behavior has been almost uniformly
dismal, with the great majority of patients succumbing to their disease in less than a year. The reasons
for this are unclear, although it suggests that perhaps these represent variants of glioblastoma
regardless of whether or not microvascular proliferation and necrosis are seen. In that respect, only a
subset have been analyzed genetically, but they seem to share many alterations seen in conventional
high-grade astrocytomas; these include losses of heterozygosity (LOH) involving chromosomes 1p, 9p, 10q,
17p, and 19q, with the 9p and 10q losses being nearly universal. Occasional cases harbor TP53 mutations
or biallelic inactivation of CDKN2A (p16). In contrast, EGFR gene amplifications have not been found to
date and the mutant IDH1-R132H protein has not been expressed immunohistochemically in the rare cases
tested so far.
Since the tumor cells are lysosome-rich, they are typically PAS and CD68 (KP1) positive. However, the
latter stain is typically less intense than ordinary macrophages and more specific markers of histiocytic
lineage, such as CD163 are typically negative. Similarly, GCA cells do not appear to be immunoreactive
with the PGMI clone of CD68. For reasons that are not entirely, GCA tumor cells are also usually EMA
positive, but in a cytoplasmic rather than membrane pattern. In most, the astrocytic histogenesis is
manifested by GFAP expression, although rare examples harbor only weak positivity or may even be
negative. As such, other glioma markers, such as the Olig2 transcription factor may additionally be
Because of the often bland cytology and foamy macrophage- like cytoplasm, non-neoplastic entities may
be considered in the differential, especially tumefactive demyelinating disease, cerebral infarct, or
infections. However, the immunohistochemical markers discussed above can be utilized to delineate the
astrocytic nature of these tumor cells and in most cases, foci of more conventional astrocytoma can be
identified as well. The same is true for considerations such as steroid treated lymphoma and histiocytic
disorders. In those with greater cytological atypia, metastatic carcinoma may also be a consideration,
especially renal cell carcinoma which typically has granular and clear cells. Although the strong EMA
expression can be misleading in this differential consideration, GCA are consistently negative for
cytokeratins, have an infiltrative rather than solid pattern (as evidenced by entrapped neurofilament
positive axons), and are also positive for glial markers, such as GFAP and Olig2.
Giant cell astrocytoma represents a rare and aggressive subtype of diffuse astrocytoma, which can pose
considerable diagnostic challenges. Awareness of this variant and its immunoprofile will prevent
misdiagnosis of other diagnostic considerations, particularly non- neoplastic entities characterized by
macrophage-rich infiltrates. The explanation for the unusually aggressive biology despite a deceptively
bland cytology awaits further studies.
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