Neurofibromatosis type 2

Abstract

Malignant schwannoma is an aggressive tumor that carries a poor prognosis despite wide excision, chemotherapy, and radiotherapy. Malignant schwannoma of the parapharyngeal space is an uncommon finding; to our knowledge, only four cases have been described in the literature during the past 30 years, and only one of them involved a patient who had clinical evidence of neurofibromatosis type 1. In this article, we describe a new case of malignant schwannoma of the parapharyngeal space in a patient who had clinical evidence of neurofibromatosis type 1. Following resection of the tumor and a total parotidectomy, the diagnosis was made on the basis of histology and immunohistochemistry. The patient underwent postoperative chemotherapy with carboplatin and UP16. However, 5 months following surgery, the tumor recurred and metastasized. The patient was then placed on a different polychemotherapeutic regimen, which was made up of 3 g/[m.sup.2] of ifosfamide, 1.5 mg/[m.sup.2] of vincristine, and 1.5 mg/[m.sup.2] of doxorubicin (IV[A.sup.2] protocol). The IV[A.sup.2] regimen slowed tumor growth, but 13 months after the initiation of therapy, the patient died of neoplastic cachexia. Although chemotherapy is generally ineffective in most cases of malignant schwannoma, we did experience some positive results with the IV[A.sup.2] protocol. Therefore, we recommend that this combination be considered as a first-line adjuvant therapy following surgery or as a first-line therapy for patients with inoperable tumors.

Introduction

Neurofibromatosis type 1 (von Recklinghausen's disease) is a hereditary illness. Clinical symptoms include cafe au lair spots, sessile or pedunculated dermal tumors, and tumors of the peripheral nerves. Neurofibromatosis is known to be complicated by malignant tumors, most of which are of soft-tissue origin. The reported incidence of transformation of neurofibromas into malignant schwannomas ranges from 3 to 30%; only a small percentage of these transformations occur in the head and neck area. (1-3)

Malignant schwannoma is a highly aggressive tumor that carries a poor prognosis. (4) It requires a precise, early diagnosis based on imaging techniques and immunohistochemical studies so that an appropriate line of treatment can be determined. For low-grade tumors, the recommended treatment is surgery. For high-grade tumors, aggressive surgical resection with wide tumor-free margins supplemented by postoperative irradiation and/or chemotherapy is recommended. (4-10) Overall, chemotherapy alone is generally considered to have little effect on survival, (11-14) but its efficacy as an adjuvant treatment has yet to be clarified.

In this article, we describe the clinical history of a young man affected by neurofibromatosis type 1 whose neurofibroma of the parapharyngeal space transformed into a malignant schwannoma. Based on our experience with this case, we can suggest a new therapeutic regimen for malignant schwannoma.

Case report

In November 1996, a 25-year-old man with diffuse neurofibromatosis type 1 and multiple cafe au lait spots was admitted to the Department of Otolaryngology for evaluation of a painful tumor mass in the left parotid gland that had caused earache and dysphagia. On examination, the tumor in the parotid area measured approximately 4 x 3 x 1.5 cm.

Magnetic resonance imaging (MRI) showed that the mass was located in the parapharyngeal space and extended into the deep lobe of the parotid gland (figure 1). A smaller mass was seen inside the left parotid. Wide resection of the tumor combined with a total left parotidectomy was carried out. The facial nerve was spared. Frozen-section examination of the tumor specimen confirmed the suspicion that it represented a neurofibroma that had transformed into a malignant schwannoma. Histologically, the tumor was made up of compact bands of polymorphous and polymetric cells with leptochromatic nuclei (figure 2). Immunohistochemical studies showed positive staining of tumor cells for vimentin and focally for S-100 protein.

[FIGURES 1-2 OMITTED]

Radio- and chemotherapy were not carried out because the histologic examination appeared to confirm that the tumor had been completely removed by wide-margin resection. However, 5 months later, in April 1997, the patient returned to us with a recurrence in the left parotid area. The mass had grown to 13 cm in diameter in only a few days. Enlarged exeresis of the recurrent lesion was performed, including removal of the ascending ramus of the mandible and the skin of the parotid area. The skin defect was reconstructed with a musculocutaneous flap taken from the pectoralis major and with a gauntlet (pedicle) flap taken from the temporalis.

In May 1997, chemotherapy with 500 mg/[m.sup.2] of carboplatin and 150 mg/[m.sup.2] of UP16 was administered. However, a few weeks later, the patient developed a new recurrence while undergoing chemotherapy, and the tumor rapidly grew to 20 cm in diameter. Computed tomography (CT) revealed that the tumor had invaded the left pterygopalatine fossa, the infratemporal fossa, and the skull base with infiltration of the petrous portion of the left temporal bone and the left cavernous sinus (figure 3).

[FIGURE 3 OMITTED]

Because of the size of the tumor and its continuous surface exudation, the patient did not wish to appear in public. Therefore, surgical debulking was carried out to improve the patient's remaining quality of life. In July 1997, the patient was started on 3 g/[m.sup.2] of ifosfamide, 1.5 mg/[m.sup.2] of vincristine, and 1.5 mg/[m.sup.2] of doxorubicin (IV[A.sup.2]). Initially, there was evidence of a partial response to chemotherapy, and for 13 mouths, this antiblastic regimen appeared to slow the growth of the tumor. However, in August 1998, the patient died of neoplastic cachexia.

Discussion

Malignant schwannoma--also known as neurogenic sarcoma, neurofibrosarcoma, malignant neurofibroma, and recently renamed malignant peripheral nerve sheath tumor--is a rare form of cancer that accounts for 5% of all soft-tissue tumors and affects 0.001% of the population. (6,7) In 25 to 70% of cases, malignant schwannoma is associated with neurofibromatosis. (3,15,17) The percentage appears to be higher in patients who have a family history of neurofibromatosis.

Malignant schwannoma usually arises in the extremities, but it can affect any part of the body. In fact, cases of malignant schwannoma have been reported in the submandibular, zygomatic, and buccal areas, in the maxillary sinus, in the nasal fossa, in the esophagus, in the thoracic vagus, in the ileal loop, in the frontoethmoid complex, and in the breast. (4,5,8,18-22) When it occurs in the head and neck area, it usually manifests as a painful, gray-white, encapsulated mass of variable size. (17)

To the best of our knowledge, only four other cases of malignant schwannoma of the parapharyngeal space have been reported in the literature during the past 30-plus years. (3,23,24) Only one of these cases involved a patient with neurofibromatosis type 1. (24)

Surgery is universally recognized as the best form of treatment. (4,6,7) Surgery should be carried out in all cases in which ample local exeresis is possible. It may be combined with a course of postop radiotherapy. (2,4,6-8,10,24-28) Radiotherapy is considered a useful palliative modality in cases in which the surrounding structures have been invaded and the tumor cannot be enucleated. (23) Radiotherapy is administered to reduce the possibility of local recurrence and to treat cases of isolated recurrence and tumors that cannot be excised. However, it is well known that malignant schwannoma is usually resistant to both radio- and chemotherapy, although chemotherapy may play a role in the treatment of surgical failures. (4,6-8,24,25,29,30) In such cases, different chemotherapeutic agents have been utilized singly or in combination. Sordillo et al (31) suggested that chemotherapy might be effective in cases of associated neurofibromatosis type 2, but the meager amount of data in the literature is frankly disheartening. (32-34) Some success has been reported, but only in isolated case reports as opposed to clinical studies. For example, Ohnishi et al described a case of malignant schwannoma of the mandibular nerve that was treated with surgery and chemotherapy; the patient had no evidence of disease at 5 years of follow-up. (27) Bruckner et al reported the complete regression of an inoperable malignant schwannoma of the posterior neck after combined-modality treatment with radio- and chemotherapy (vinblastine plus doxorubicin). (34) Athow and Kirkham observed a partial response to chemotherapy in the treatment of a malignant schwannoma of the parotid gland. (35) Most recently, Zanon et al suggested that despite the general ineffectiveness of chemotherapy, the most active drugs in the control of tumor growth in malignant schwannoma are decarbazine, doxorubicin, and ifosfamide. (21) In our patient, only (IV[A.sup.2] (our second line of therapy) appeared to control the growth of the tumor. In fact, we observed clinically that the size of the tumor remained unchanged for a long period.

We acknowledge that chemotherapy has little value in most cases, but in our experience, the IV[A.sup.2] chemotherapeutic protocol yielded a good short-term result in controlling tumor growth. Therefore, we emphasize the necessity of continuing research to find an effective adjuvant therapy, and we suggest that IV[A.sup.2] be considered as a first-line choice as an adjuvant treatment following surgery or a first-line treatment for patients with an inoperable malignant schwannoma.

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From the Department of Otolaryngology, La Sapienza University, Rome.

Reprint requests: Andrea Gallo, MD, Department of Otolaryngology, La Sapienza University, Viale dell' Universita, 00161 Rome, Italy. Phone: 39-06-4997-6808; fax: 39-06-446-0378; e-mail: andrea.gallo@uniromal.it

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