Case Study 60
Kenneth Clark, MD
Question 1
• This is a 78-year-old woman with a history of
CREST syndrome and hypothyroidism who
reports 1 month history of neurocognitive
decline, personality changes and a mild
headache. An MRI of the head was obtained.
• Describe the MRI findings.
Axial T1
Axial T1 + Contrast
Coronal T2 FLAIR
Axial T2 FLAIR
Coronal T1 + Contrast
Answer
• Large cystic mass lesion within the right frontal
lobe white matter. The lesions show solid areas
of diffuse contrast enhancement as well as
regions of peripheral rim enhancement. The
lesion shows marked surrounding FLAIR signal
and associated mass effect.
Question 2
• What does the T2 FLAIR signal signify?
Answer
• Edema
Question 3
• What does the surrounding edema tell you about
this lesion?
Answer
• That it is infiltrating and very likely a neoplasm.
Question 4
• A small biopsy was obtained and submitted for
intra-operative examination. The surgeon
specifically mentions a concern for lymphoma
(based on the neuroradiology). Describe the
findings. How would you report to the surgeon?
• Click here to see the smear
Answer
• The smear shows a highly cellular lesion
comprised of markedly pleomorphic, large,
epithelioid cells which are loosely cohesive and
appear to be attached to central vascular
structures. The cells show round-to-ovoid nuclei
with coarsely distributed chromatin, indistinct
nuceoli and abundant bright eosinophilic
cytoplasm. Numerous cells are wrapped by
neighboring tumor cells, forming peculiar whorllike formations. Sparse mitotic figures are seen.
Giant and sparse multinucleate cells are seen.
• A. Neoplastic
• B. Favor metastatic tumor versus glioma
Question 5
• Based on the intra-operative diagnosis, the
surgeon resects the lesion and submits it for
pathologic examination. How would you
describe the histology?
• Click here to see the H&E slide
Answer
• The tissue shows confluent sheets of neoplastic
cells that have an epithelioid appearance. The
cells show moderate nuclear pleomorphism and
relatively abundant pale pink cytoplasm. There
are numerous cells that appear to be wrapped
by neighboring tumor cells, forming unusual
looking concentric structures. Scattered mitotic
figures are seen. Endothelial proliferation is
seen. No necrosis is evident.
Question 5
• What is your differential diagnosis based on
these findings?
Answer
• High grade glioma
• Metastatic melanoma
• Metastatic carcinoma
Question 6
• What immunohistochemical stains would you
order to better characterize this lesion?
Answer
•
•
•
•
GFAP, IDH1, Vimentin, p53, EGFR (glioma)
S100, MelanA, HMB45, Tyrosinase (melanoma)
Pankeratin, AE1/3 (carcinoma)
CD3, CD20 (r/o lymphoma since surgeon is
specifically concerned about this)
• Ki67 (proliferation index)
• Click to view vimentin, GFAP, S100, AE1/3, p53,
EGFR, Ki67
Question 7
• Based on the results of the H&E and immunostains (see
below) what is your diagnosis?
•
•
•
•
•
•
•
•
•
GFAP & vimentin – strongly positive in tumor cells
S100 – positive in tumor cells
AE1/3 – light staining of tumor cells
P53 - highlights one minute focus of clonality, while the majority of
the tumor is negative
Tyrosinase, HMB45, pancytokeratin - negative
IDH1 - negative.
CD3 & CD20 reveal scattered positive cells, with a prominent perivascular distribution.
Ki67 – proliferation index 10-15%
EGFR – strong positive membrane staining
Answer
• Glioblastoma, epithelioid variant, WHO grade 4
Question 8
• Would any molecular studies be useful in better
characterizing this neoplasm? If so, which
studies?
Answer
• Fluorescence In Situ Hybridization (FISH)
– 1p/19q deletion
– P16 deletion
– EGFR amplification
• LOH
– 1p, 19q, 9p (p16), 10q (PTEN), 17p (Tp53)
• IDH1 mutational analysis
Question 9
• Molecular studies show the following results:
–
–
–
–
–
–
–
–
1p – NO deletion
19q – Deleted
23% p16 deletion by FISH
No EGFR amplification (chromosome 7 hyperploidy
rate 33%)
33% 9p deletion by PCR (LOH)
0% p53 deletion by PCR (LOH)
100% 10q deletion by PCR (LOH)
Negative for IDH1 or IDH2 mutation
• How would you interpret these?
Answer
• Loss of 10q is the most frequent genetic
abnormality associated with de novo
glioblastomas (60-80%). Also, deletion of 19q
occurs in approximately 25% of primary
glioblastomas. A subset of glioblastomas have
also been shown to have the co-presence of
gain of chromosome 7 with loss of chromosome
10. Likewise, the molecular data support the
diagnosis of glioblastoma.
Question 10
• Does the epithelioid variant have prognostic
significance?
Answer
• No. Glioblastoma was historically called
glioblastoma multiforme, referring to the wide
range of histologic appearances. The
importance of specifying the subtype is only in
distinguishing it from other histologically similar
tumors (carcinomas, for instance).
Question 11
• Are there any histologic subtypes of
glioblastoma that have prognostic implications?
Answer
• Giant cell glioblastoma has some distinction
from other variants of glioblastoma in that it they
show very high levels of p53 mutations (80-90%,
less than 30% for conventional primary
glioblastomas) and they grow in an expansile
manner (rather than infiltrative), resulting in fairly
well-circumscribed borders. Some recent reports
have indicated that giant cell glioblastoma offers
a more favorable prognosis than other forms of
glioblastoma.
References
• Louis D, Ohgaki H, Wiestler O, Cavanee W. WHO Classification of
Tumours of the Central Nervous System. IARC: Lyon 2007.
• Von Deimling A, et al. Loci associated with malignant progression in
astrocytomas: a candidate on chromosome 19q1 (1994). Cancer
Res. 54:1397-1401.
• Misra A, et al. Array comparative genomic hybridization identifies
genetic subgroups in grade 4 human astrocytoma (2005). Clin
Cancer Res. 11:2907-2918.
• Shinojima N, et al. The influence of sex and the presence of giant
cells on post-operative long-term survival in adult patients with
supratentorial glioblastoma multiforme (2004). J Neurosurg.
101:219-226.
• Ohgaki H, et al. Genetic pathways to glioblastoma: a populationbased study (2004). Cancer Res. 64:6892-6899.