Schwannomatosis: A newly recognized tumor-predisposing condition

Neurofibromatoses are complex hereditary conditions with highly variable presentation and severity. There are two major types: NF1 and NF2, the common feature of which is a predisposition toward multiple benign nerve sheath tumors.

Recently, schwannomatosis has been recognized as an independent form of NF, distinct from NF2, which it resembles. The main clinical finding in schwannomatosis is the presence of benign neurogenic tumors in the absence of acoustic neuromas (vestibular schwannomas). In the past 5 years, schwannomatosis has been more clearly defined, but it continues to be underrecognized and often misdiagnosed.

Distinguishing schwannomatosis from NF2

The diagnostic criteria for schwannomatosis continue to evolve. Because the symptoms can be confused with NF2, it is critical that NF2 be ruled out during evaluation. Key distinguishing features are:

• Cranial nerve involvement. Bilateral acoustic neuromas are the hallmark of NF2. They may occur simultaneously or sequentially. Patients with schwannomatosis may have schwannomas on other cranial nerves but do not have acoustic schwannomas.
• Segmental subtypes. In NF2 and schwannomatosis, tumors may occur in a random distribution, but in subtypes of both disorders, tumors can be segmental in distribution—localized to a single limb or in 5 or fewer contiguous spinal segments. Although segmental distribution occurs more often in schwannomatosis than in NF2, the pattern of tumor distribution is not necessarily helpful in differential diagnosis.
• Age of onset. NF2 usually affects young adults. In contrast, schwannomatosis typically occurs in the third to sixth decades of life.
• Inheritance. NF2 is an autosomal dominant syndrome caused by mutations in the NF2 gene, and genetic testing of blood and tissue is available for its detection. Schwannomatosis is usually sporadic, and familial cases occur in fewer than 20% of patients. A mutation in 1 tumor-suppressing gene (INI1) has been identified as a factor in a very small proportion of familial schwannomatosis cases. For the majority of patients, the genetic basis of schwannomatosis is not known.

To rule out NF2, a diagnosis of schwannomatosis is made in patients with multiple schwannomas only in the following clinical situations:

• High-resolution MRI demonstrates absence of acoustic nerve tumors in persons older than 30 years
• Genetic testing rules out the NF2 genes
• No first-degree relative has NF2

Overcoming diagnostic challenges

Neural imaging can localize lesions suggestive of nerve tumor but cannot identify underlying pathology. A biopsy is required for definitive diagnosis, but nerve biopsy risks nerve damage.

Robert J. Spinner, M.D., a neurosurgeon at Mayo Clinic in Rochester, Minnesota, who specializes in peripheral nerve surgery, points out that specialized techniques used at Mayo Clinic can help determine the type and nature of peripheral nerve tumors while minimizing neurologic consequences.

Surgical advances in plexiform schwannomas

Spectrum of schwannomas in schwannomatosis

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Most schwannomas are encapsulated tumors that stem from a single, nonfunctional fascicle of a nerve that enters and exits the tumor. Typically, the tumor is in a small nonfunctional fascicle. In the hands of an experienced surgeon, resection of these conventional lesions using microsurgical techniques often has a favorable outcome.

Not all schwannomas, however, stem from a single fascicle. Some schwannomas may be multinodular or plexiform in nature, involving multiple nodules or fascicles, or both. In the majority of cases, plexiform schwannomas affect small nerves of the skin or subcutaneous tissue, but in some patients, plexiform tumors arise in major peripheral nerves. These more-complex lesions have been identified in subgroups of patients with schwannomatosis, in patients with NF2, and in those without a known syndrome.

Previously, plexiform schwannomas were thought to occur only in extreme cases, but Dr. Spinner and his colleagues note that they also may occur in what were thought to be conventional lesions (Hébert-Blouin et al. J Neurosurgery. 2010;112[2]:372-82).

High-resolution MRI can demonstrate the multifascicular involvement. These multinodular and plexiform tumors must be managed differently from conventional schwannomas and must be treated with special caution.

Total resection of the lesion results in neurologic deficit due to the loss of more fascicles, many of which, despite the presence of tumor, are still functioning. In such cases, Dr. Spinner and colleagues recommend a more conservative approach: observation in patients with minimal pain or a more limited resection of a painful dominant nodule.

Family-based research

Dr. Spinner and Dusica Babovic-Vuksanovic, M.D., a medical geneticist and the director of the Neurofibromatosis Clinic at Mayo Clinic in Rochester, Minnesota, are working together to create a registry of patients with schwannomatosis and their family members.

Patient families have not yet been studied, and Drs. Spinner and Babovic-Vuksanovic are including them to better understand the commonalities and variations in the disease. One question they hope to answer is whether there is a link between schwannomatosis and other tumor types. Their work in schwannomatosis is an example of Mayo's collaborative research and clinical commitment to patients with NF and other tumor-predisposing conditions.

Neurofibromatosis (NF) Forum

The third annual Neurofibromatosis (NF) Forum, sponsored by the Children's Tumor Foundation, will be held in Minneapolis, Minnesota, on July 29 to 31, 2011.

Mayo Clinic will host a breakout NF symposium in Rochester, Minnesota, for patients, families, and physicians during the meeting. Speakers drawn from Mayo's numerous subspecialists with NF expertise will discuss NF-related topics, including schwannomatosis. Subspecialties participating in the care of neurofibromatosis (NF) patients at Mayo Clinic include:

• Audiology
• Dermatology
• Developmental Pediatrics
• Endocrinology
• Medical Genetics
• Neurology
• Neurosurgery
• Oncology
• Ophthalmology
• Orthopedic Surgery
• Otolaryngology
• Pain Clinic
• Physical Medicine and Rehabilitation
• Plastic Surgery
• Psychology
• Radiology
• Social Services
• Speech Pathology