Cerebellopontine Angle Tumor Composed of Schwann and Meningeal Proliferations

Acoustic neuromas are benign intracranial tumors that originate from Schwann cells along the vestibular division of the eighth cranial nerve. With an incidence of 1 in 100 000, acoustic neuromas are relatively uncommon; however, they represent approximately 10% of all intracranial tumors and more than 80% of cerebellopontine angle (CPA) tumors.^{1 - 3} Each year, 2000 to 3000 new cases of acoustic neuromas are diagnosed within the United States. Acoustic neuromas predominantly occur sporadically and unilaterally but may present with other intracranial tumors or bilaterally as part of the complex syndrome of neurofibromatosis 2 (NF2).^{4 - 5}

Neurofibromatosis 2 is primarily an inherited, autosomal dominant disease, the hallmark of which is the occurrence of bilateral acoustic neuromas. The current diagnostic criteria for NF2 are met when an individual has either the characteristic bilateral acoustic neuromas or a first-degree relative with NF2 and one of the following: a unilateral acoustic neuroma before the age of 30 years or the presence of 2 tumors (neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity).^{5 - 6} Approximately 50% of NF2 cases are the result of de novo mutations.^{1 ,7} In these sporadic cases, NF2 may only be diagnosed in patients with bilateral acoustic neuromas.^{4 - 5} However, NF2 may display phenotypic heterogeneity. Multiple intracranial and spinal tumors, rapid progression of symptoms, and early death characterize severe forms of NF2. Mild NF2 features late onset, fewer tumors, and a slower progression of symptoms.^{1 ,7 - 8} Also, some affected members of families with mild NF2 may not develop acoustic neuromas.⁷ Within the literature, there has been some debate that the current diagnostic criteria for NF2 may be too narrow.^{1 ,4 - 5 ,7}

We describe a patient who did not have a family history of NF2 and did not fulfill the current diagnostic criteria, but he was noted to have 2 rare findings that are seen almost exclusively in patients with NF2. Both findings were noted incidentally during treatment of his nasopharyngeal carcinoma. The first finding was the occurrence of an acoustic neuroma concomitant with a spinal nerve schwannoma. The second finding was noted during excision of the CPA lesion, which was notable for both Schwann and meningeal cells, supporting the diagnosis of a mixed tumor. Individually, to our knowledge, these findings have been noted only once before in association with sporadic unilateral acoustic neuromas.^{9 - 10} Herein, we discuss differentiation between sporadic unilateral acoustic neuromas and NF2 tumorigenesis.

A 48-year-old man was diagnosed as having a nasopharyngeal carcinoma. His medical history was significant for radiation therapy for chronic otitis media at the age of 2 years. He was treated with combined-modality radiation therapy and chemotherapy. Incidentally, in a discussion of the ototoxic effects pertaining to his chemotherapy, the patient noted long-standing hearing loss in the left ear that began as sudden bilateral hearing loss in 1983 (at the age of 32 years). His hearing loss resolved on the right side, although his hearing loss in the left ear had persisted, with some progression.

Before treatment was begun, computed tomographic scans were obtained for radiation treatment planning. The scans revealed 2 densely enhancing lesions. One was noted in the left CPA; the other was an intradural, extramedullary mass located in the upper cervical canal. Magnetic resonance imaging revealed a mixed enhancing and nonenhancing mass within the left CPA that extended along the seventh and eighth cranial nerves. Magnetic resonance imaging scans of the cervical spine lesion demonstrated an enhancing mass at the level of the second cervical vertebra (C2) that was intradural and extramedullary and projected along the left nerve root, consistent with a schwannoma or neurofibroma (Figure 1, Figure 2, and Figure 3).

After successful treatment of the patient's nasopharyngeal carcinoma, surgical treatment of the patient's CPA tumor was begun. A translabyrinthine approach to the CPA was used. The facial nerve was found to be splayed over the tumor. Posterolaterally, portions of the tumor were cystic and calcified. In the region near the brainstem, the tumor appeared to infiltrate the facial nerve and a portion of the brainstem itself. It was also noted to be very adherent to the facial nerve. It was completely removed except for a portion of its capsule. The facial nerve was stimulated at 0.1 mA at the end of the case.

Frozen-section examination of the left CPA mass revealed proliferation of hyperchromatic spindle cells with tapered ends, Verocay bodies, and numerous psammoma bodies. Some regions of tissue displayed a whorled pattern. Ancient change was seen focally with large, bizarre nuclei. Vascular proliferation and abnormal vessels were also noted. Sections including meningioma cells were distinctly separated from the schwannoma cells (Figure 4).

Neurofibromatosis 2 is a complex syndrome defined by multiple, contemporarily growing tumors; however, mixed tumors are thought to be a rare event.^{9 ,11} The occurrence of a mixed acoustic neuroma-meningioma has been reported fewer than 30 times^{10 - 18} since 2 cases were reported by Worster-Drought et al¹⁹ in 1937. There are several theories to explain the genesis of these mixed tumors. Neoplastic meningeal and Schwann cells may have diverged from a common cell line.²⁰ Metaplasia may have occurred in one of the neoplastic the cell lines.²¹ Alternatively, 2 distinct tumors may have converged and formed a single tumor.²²

Another explanation involves local factors that may promote the development of mixed Schwann-meningeal tumors.¹⁴ Intracranial meningiomas are found to express high levels of epidermal growth factor receptors.^{23 - 24} However, meningeal expression of epidermal growth factor has not been detected, although other factors like platelet-derived growth factor and insulin-related growth factor have been seen.^{25 - 26} A similar growth factor, schwannoma-derived growth factor, is found to activate the epidermal growth factor receptors and to stimulate growth.²⁷ Based on this finding, it has been postulated that schwannomas may stimulate the emergence of meningeal proliferation in a paracrine fashion.^{12 ,14} This theory appears contradictory to data indicating the rarity of a mixed tumor containing both Schwann and meningeal cells.^{11 - 12} However, 1 series of NF2-associated acoustic neuromas found 10 of 48 samples containing discrete meningeal proliferations or small foci of meningeal growths within the schwannomas.¹⁰ The scarcity of cases within the literature describing mixed Schwann-meningeal tumors may be the result of the difficulty in identifying these mixed tumors. Of the 10 mixed tumors that were identified histopathologically in the aforementioned series, only 3 could be identified grossly. These mixed tumors of neoplastic Schwann and meningeal cells are not unique to the auditory canal and CPA; they have been noted in the jugular foramen, frontal and temporal lobes, spinal cord, and cerebellar convexity.^{20 ,28 - 32}

Mixed acoustic neuromas have predominantly been found in association with NF2.^{10 - 18} The NF2 acoustic neuromas exhibit a predilection for histologic features not normally seen in unilateral, sporadic acoustic neuromas. Neurofibromatosis 2–associated acoustic neuromas more commonly show a lobular pattern, higher cellularity, and an association with meningeal proliferation. In contrast, unilateral acoustic neuromas infrequently display a lobular pattern, normally have lower cellularity and abnormal vasculature, and are not associated with meningiomas.¹⁰ In the case reported herein, our patient's tumor demonstrated characteristics common to both unilateral and NF2-associated acoustic neuromas. The tumor was noted to have high cellularity and meningeal growth, characteristics consistent with NF2. However, it also displayed vascular proliferation, hyalinization of vessels, and an absence of lobular structure, which are features of sporadic acoustic neuromas.

Both sporadic and NF2 acoustic neuromas are associated with a common gene.^{33 - 35} Located on chromosome 22q12, the NF2 gene encodes a tumor suppressor protein called merlin or schwannomin. Merlin is thought to connect the cytoskeleton to components of the plasma membrane and likely to be involved in cell shape, motility, and growth regulation.³⁵ Mutations in this gene are found in approximately 50% of sporadic acoustic neuromas and almost 30% of meningiomas.^{33 - 34} The NF2 gene's association with multiple tumors may suggest a larger, more prominent role in tumorigenesis. This case, involving a patient with a unilateral mixed acoustic neuroma, a spinal nerve schwannoma, and a nasopharyngeal carcinoma, does not fulfill the current clinical criteria for NF2. However, it may represent a mild, sporadic form of NF2. The clinical diagnosis of NF2 is a continuous process that may change as new tumors arise. The patient was given a presumptive diagnosis of NF2. This case may also be a demonstration of the NF2 gene's broader role in tumor initiation and progression.

Our patient's history was also complicated by a remote history of childhood radiotherapy. Childhood radiotherapy has been shown to significantly increase the risk for benign and malignant neoplasms. Irradiation of the head and neck and the subsequent development of brain tumors have been well documented.^{36 - 40} In a 30-year study of 10 000 children who underwent radiotherapy for tinea capitis, there was a marked increased risk for schwannomas (relative risk, 18.8) and meningiomas (relative risk, 9.5) in comparison to a control group from the general population and nonirradiated siblings. The intervals between irradiation to tumor diagnosis ranged from 6 to 29 years.⁴⁰ Our patient received bilateral irradiation to the mastoids for treatment of chronic otitis media when he was 2 years old. Because of the remote history of treatment, specific dosages of radiation could not be retrieved. However, doses greater than 700 rad (7 Gy) were commonly used in the treatment of chronic otitis media.³⁹ Ron et al⁴⁰ showed a dose-response relationship, with 100 rad (1 Gy) showing a relative risk of 3.0 for head and neck tumors and 200 rad (2 Gy) demonstrating a ×20 increased risk.

The present case demonstrated the unique occurrence of a CPA tumor composed of both Schwann and meningeal cells concomitant with a spinal nerve schwannoma in a patient with no family history of NF2 or nervous system tumors. Individually, both findings have been reported once before in patients without a diagnosis of NF2 but never in association. The patient's diagnosis of NF2 remains a presumptive one. Commercial genetic testing is available, although it is not definitive and remains primarily experimental. The diagnosis of NF2 depends on clinical and radiologic information. The case reported herein illustrates the potential difficulty in diagnosing NF2, a heterogeneous disease that may be acquired as often sporadically as congenitally.

Accepted for publication July 17, 2001.

Corresponding author and reprints: Bruce J. Gantz, MD, Department of Otolaryngology–Head and Neck Surgery, The University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242 (e-mail: bruce-gantz@uiowa.edu).