Hot on the Trail of the One-in-a-Million Brain Tumor

The odds are exceedingly slim that you'll ever see an intracranial MPNST. With no established treatments and tough clinical dilemmas, you don't want to. But 3 recent case reviews and new insights from biology suggest this rare tumor may finally be vulnerable.

How would you treat a malignant peripheral nerve sheath tumor (MPNST) affecting an intracranial nerve? Not many people know, at least offhand. The good news is that the odds are very slim you'll ever see one: The annual incidence of MPNST is below one in a million, and those arising inside the cranium are even more rare.

You would probably hope never to see one. MPNSTs are aggressive tumors, and the median overall survival for intracranial MPNST is a meager 9 months. A review published in Radiation Oncologylast month says there are "no established therapeutic approaches," but there are "therapeutic dilemmas." Foremost among them is whether to use radiation, which can help to eradicate these rare tumors but has also been implicated in the malignant transformation that causes them (and second primaries of the same type are a feature of this tumor).

If you did have to treat a case, more than likely you'd do what others have done: Survey the literature first, and report your case afterwards. It's noteworthy that this extraordinarily rare malignancy has been the subject of 3 reviews within the last 2 years, 2 of them within the last 2 months. The total number of such cases in the international literature is 43.

Prognostic factors

This was enough for authors of the latest review (from the University Hospital of Bonn, Germany) to establish favorable prognostic indicators for intracranial MPNST: Female gender, the accomplishment of gross total resection (possible in fewer than half of reported cases), and adjuvant radiotherapy. There have been too few cases to even analyze the impact of tumor grade and size. But so far it doesn't seem to matter whether the MPNST has arisen spontaneously or secondary to neurofibromatosis, as it commonly does.

After their literature review, the Bonn authors decided to offer postoperative stereotactic radiotherapy to their 64-year-old male patient, despite the fact that about 42% of cases of malignant transformation in their literature review had a history of radiation, and even though their own patient's tumor appeared to result from malignant transformation of a benign schwannoma. The possibility that radiation can trigger transformation is controversial, and the ability of stereotactic radiotherapy to target the tumor while sparing normal tissue was too attractive to forgo. Also, previous reviews have suggested a survival benefit from radiotherapy in MPNSTs of all sites. (It did not show a benefit in their own multivariate analysis, perhaps because numbers were too small.)

The man in the Bonn study was alive without recurrence 12 months after surgery, and his doctors recommend resection of the tumor plus adjuvant radiotherapy for intracranial MPNSTs. Doctors from the University of Montreal hospital reached the same conclusion in a similar review of intracranial MPNST published in October in Auris, Nasus, Larynx (without case study). The third review, published in March 2009 by pathologists from the Mayo Clinic, described their experience with 17 cases.

An oncogene and a SERM

Earlier this year, radiologists in Japan published MRI criteria for distinguishing MPNST from benign neurofibromas, based on 41 cases of MPNST. Fortunately for all involved, some biologists are also on the case.

Last year University of Cincinnati biologists reported finding a gene (EYA4 or "eyes absent," first identified in fruit flies) whose expression is specifically upregulated in MPNST but not in the benign tumors from which they often derive. Inhibiting its expression reduced tumor cell migration and adhesion in vitro and increased tumor cell necrosis in a xenograft model.

Closer to the clinic, a report last month in Neuro-Oncology from a team at the University of Alabama in Birmingham reveals that varying concentrations of tamoxifen inhibit cell proliferation and induce cell death in xenografts of MPNST, probably by an estrogen-independent mechanism. They suggest following up with a clinical trial.

What we can all hope for is a response so dramatic that the outcome will be evident in our lifetimes.