1. Case Study 9 Craig Horbinski, M.D., Ph.D.

2. The patient is a 26 year-old female. MRI with contrast was done. What do you see? Question 1

3. T1 with contrast

8. Multiple extra-axial dural-based tumors (note the dural tails), right cerebellopontine angle tumor, C1 intraspinal canal tumor. Answer

9. Question 2 What are the extra-axial dural-based tumors most likely? What about the CPA tumor? The C1 intraspinal canal tumor?

10. 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 sausage- shaped and like to occupy the central canal or one of the ventricles.

11. Question 3 What is the overall diagnosis in this patient (i.e. what disease produces all the aforementioned tumors)?

12. 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.

13. 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.here

14. 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.

15. Question 5 What is the diagnosis? What stains would you do to confirm the diagnosis?

16. Answer Meningioma. Routine immunostains include EMA (80% are focally positive, 100% of schwannomas are negative) and Ki67 (assesses proliferation index).

17. Question 6 What WHO grade would you assign it?

18. 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 sheet- like growth pattern. It's close to being a grade 2, but not quite there.

19. 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, Ki67EMAKi67

20. 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.

21. Question 8 What does grade mean in this setting, anyway? What does it imply for a typical patient? For this patient?

22. 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 10- 15% 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.

23. Question 9 What are the official criteria for NF2? (Yes, this is fair game for the general pathology boards.)

24. 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.

25. Question 10 What is the most common deletion seen in this tumor? (Another high-yield boards question.)

26. Answer Deletion on chromosome 22q (del 22q).

27. Question 11 What key gene is on this region of deleted DNA? What does it do?

28. 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.