Case Study 60

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Case Study 60

• Kenneth Clark, MD

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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.

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(No Transcript)
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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.

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Question 2

• What does the T2 FLAIR signal signify?

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Answer

• Edema

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Question 3

• What does the surrounding edema tell you about
  this lesion?

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Answer

• That it is infiltrating and very likely a
  neoplasm.

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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

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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
  whorl-like formations. Sparse mitotic figures are
  seen. Giant and sparse multinucleate cells are
  seen.
• A. Neoplastic
• B. Favor metastatic tumor versus glioma

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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 HE slide

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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.

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Question 5

• What is your differential diagnosis based on
  these findings?

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Answer

• High grade glioma
• Metastatic melanoma
• Metastatic carcinoma

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Question 6

• What immunohistochemical stains would you order
  to better characterize this lesion?

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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

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Question 7

• Based on the results of the HE 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 peri-vascular distribution.
• Ki67 proliferation index 10-15
• EGFR strong positive membrane staining

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Answer

• Glioblastoma, epithelioid variant, WHO grade 4

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Question 8

• Would any molecular studies be useful in better
  characterizing this neoplasm? If so, which
  studies?

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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

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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?

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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.

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Question 10

• Does the epithelioid variant have prognostic
  significance?

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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).

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Question 11

• Are there any histologic subtypes of glioblastoma
  that have prognostic implications?

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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.

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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.
  541397-1401.
• Misra A, et al. Array comparative genomic
  hybridization identifies genetic subgroups in
  grade 4 human astrocytoma (2005). Clin Cancer
  Res. 112907-2918.
• 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. 101219-226.
• Ohgaki H, et al. Genetic pathways to
  glioblastoma a population-based study (2004).
  Cancer Res. 646892-6899.