Case Study 9
Craig Horbinski, M.D., Ph.D.
Question 1
The patient is a 26 year-old female. MRI with contrast
was done. What do you see?
T1 with contrast
T1 with contrast
T1 with contrast
T1 with contrast
T1 with contrast
Answer
Multiple extra-axial dural-based tumors (note the dural
tails), right cerebellopontine angle tumor, C1 intraspinal
canal tumor.
Question 2
What are the extra-axial dural-based tumors most
likely? What about the CPA tumor? The C1 intraspinal
canal tumor?
Answer
The location of all these tumors dictates the most likely
diagnoses. The extra-axial dural-based tumors are most
likely meningiomas. The more intensely enhancing CPA
tumor is probably a schwannoma. The intraspinal canal
tumor is an ependymoma, which tend to be sausageshaped and like to occupy the central canal or one of the
ventricles.
Question 3
What is the overall diagnosis in this patient (i.e. what
disease produces all the aforementioned tumors)?
Answer
Neurofibromatosis type 2. The diagnosis had already
been confirmed years ago via molecular genetic testing,
but this single MRI study is pathognomonic even if you
knew nothing at all about the patient.
Question 4
No intraoperative consultation was requested. Several
tumors were resected, including a left frontal mass. The
permanent slides of this tumor arrived. What do you see?
Click here to view slide.
Answer
Hypercellular; spindle cells organized into vague whorls,
fascicles, and sheets; psammoma bodies; rare mitoses;
generally bland oval nuclei with intranuclear
pseudoinclusions and inconspicuous nucleoli.
Question 5
What is the diagnosis? What stains would you do to
confirm the diagnosis?
Answer
Meningioma. Routine immunostains include EMA (80%
are focally positive, 100% of schwannomas are negative)
and Ki67 (assesses proliferation index).
Question 6
What WHO grade would you assign it?
Answer
WHO grade 1. Despite the cellularity and presence of a
few mitoses, it's not enough to call this an atypical
meningioma, WHO grade 2. To do that, you need to see
either 4 or more mitoses per 10 high power fields OR 3 of
the following: hypercellularity, small cell change,
prominent nucleoli, sheet-like growth pattern, necrosis,
brain invasion. In this tumor there is only about 1 mitosis
per 10 high power fields with hypercellularity and a sheetlike growth pattern. It's close to being a grade 2, but not
quite there.
Question 7
The immunostains you ordered have arrived (assuming
these were the ones you ordered, anyway). Does the
Ki67 immunostain help "push" this tumor to a higher
grade? If so, how high does the index have to be? If not,
why bother doing the stain?
Click the following links to view slides: EMA, Ki67
Answer
No. Even though the estimated proliferation index is
around 10-15%, which is pretty high for a meningioma,
the criteria for upgrading it to "atypical" status does not
include Ki67 proliferation index (at least, not yet). Even
so, quite frequently the surgeons will ask what the
proliferation index is; a proliferation index this high might
very well influence the management of this
patient. Moreover, sometimes a "hot spot" of Ki67
immunoreactivity will call attention to a focus of high
mitotic activity that otherwise might have been missed on
H&E. Thus it is part of the routine workup of all
meningiomas, as well as many other brain tumors.
Question 8
What does grade mean in this setting, anyway? What
does it imply for a typical patient? For this patient?
Answer
For meningiomas, grade predicts the likelihood of
recurrence. (The main predictor is, of course, extent
of surgical resection, but grade nonetheless is
important.) Grade 1 meningiomas recur around 1015% of the time, whereas grade 2 recurs up to 40%
of the time. Grade 3 meningiomas recur up to 80%
of the time. However, these numbers are for
sporadic tumors. In this particular patient it's a little
different because she has a germline genetic disease
that will undoubtedly come back.
Question 9
What are the official criteria for NF2? (Yes, this is fair
game for the general pathology boards.)
Answer
The diagnostic criteria for NF2 can be met in 1 of 3 ways:
Bilateral vestibular schwannomas
In a patient with a first-degree relative already diagnosed with NF2,
either one vestibular schwannoma or 2 of the following: meningioma,
schwannoma of another nerve, glioma (e.g. diffuse astrocytoma or
ependymoma), cerebral calcification, lens cataracts.
2 of the following: 1 vestibular schwannoma, multiple
meningiomas, glioma (e.g. diffuse astrocytoma or ependymoma),
schwannoma of another nerve, cerebral calcification, lens cataracts.
This patient has a vestibular schwannoma plus multiple
meningiomas, so she meets the diagnostic criteria for NF2.
Question 10
What is the most common deletion seen in this tumor?
(Another high-yield boards question.)
Answer
Deletion on chromosome 22q (del 22q).
Question 11
What key gene is on this region of deleted DNA? What
does it do?
Answer
Merlin (a.k.a. schwannomin or neurofibromin 2), located
on 22q12. It's a tumor suppressor protein that inhibits
Rac-dependent signaling and STAT activation.