Malignant Peripheral Nerve Sheath Tumors of the Orbit: a Clinicopathologic Study Of' Eight Cases*

MALIGNANT PERIPHERAL NERVE SHEATH TUMORS OF THE ORBIT: A CLINICOPATHOLOGIC STUDY OF' EIGHT CASES*

BY Frederick A. Jakobiec, MD, Ramon L. Font, MD (BY INVITATION) AND Lorenz E. Zimmerman, MD

INTRODUCTION SOLITARY NEUROFIBROMAS AND SCHWANNOMAS (BENIGN PERIPHERAL NERVE sheath tumors) are well recognized orbital neoplasms, constituting together about 2% of such tumors; another 2% of orbital tumors is represented by diffuse and plexiform neurofibromas associated with von Reck- linghausen's neurofibromatosis."2 The isolated tumors are slow growing, well tolerated lesions that usually develop in adults in the retrobulbar tissues; surgical removal, as with cavernous hemangioma, is generally highly successful due to their encapsulation or circumscription. The presence of preoperative pain or hypesthesia, and the usual absence of postoperative pareses of the extraocular muscles, suggest that many of these tumors arise from branches of the ophthalmic division of the trigeminal nerve rather than from the oculomotor nerves.3 The extreme rarity of malignant peripheral nerve sheath tumors of the orbit is indicated by the fact that there have only been three reports comprising four tumors in the ophthalmic literature over the past 20 years.4-6 In his series of 764 orbital neoplasms, Henderson' encountered two nerve sheath malignancies, both in patients with neurofibromatosis; Kennedy's series2 of 820 lesions did not include an instance ofthis entity.

*From the Departments of Ophthalmology and Pathology, The Manhattan Eye, Ear and Throat Hospital, and the Departments of Ophthalmology and Pathology, the Columbia- Presbyterian Medical Center (Dr Jakobiec); the Department ofOphthalmic Pathology, the Armed Forces Institute of Pathology (Drs Font and Zimmerman); the Departments of Ophthalmology and Pathology, Baylor University College of Medicine (Dr Font); and the Departments of Ophthalmology and Pathology, Georgetown University Medical School (Dr Zimmerman). TR. AM. OPHTH. SOC. Vol. LXXXIII, 1985 Orbital Nerve Sheath Tumors 333 We report herein eight well documented cases of malignant peripheral nerve sheath tumors of the orbit drawn from the Registry of Ophthalmic Pathology at the Armed Forces Institute of Pathology. Our studies disclose that these are highly malignant tumors, often spreading intracranially and capable of metastases. They have a distinctive proclivity to develop from the supraorbital branch ofthe trigeminal ophthalmic nerve; all ofour tumors, and two of those published earlier,5'6 presented in the anterior- superior orbit, usually under uneroded skin of the superonasal quadrant. In this article we report the salient clinical and pathologic features of our lesions, and discuss how they may be distinguished from other malignancies of the orbital region. Many terms have been employed in the past for malignancies arising from peripheral nerves: neurogenic sarcoma, neurofibrosarcoma, malignant schwannoma, and malignant neurilemmoma. We have adopted the term "malignant peripheral nerve sheath tumor" because it is not clear whether all of these tumors arise from the Schwann cell.7 Other possibil- ities include the perineural cell, the endoneural cell, and the epineural fibroblast. Particularly in malignancies, manifest evidence of Schwann cell differentiation may not be detectable at the ultrastructural level, 7-11 or even by the application of immunohistochemical methods for the identification of Schwann cell markers. 1215

REPORT OF A SERIES

CASE 1 In 1963, a 19-year-old white man presented with a 1 cm subcutaneous nodule in the left upper lid near the inner canthus. It was described as a cystic structure that had been present for many years. The patient gave the history of multiple traumas about the left orbit in his youth. Because the lesion was so unprepossessing, the tissue was not submitted for pathologic examination after surgical removal. Six months later the tumor recurred, measuring 2.0 x 1.0 x 0.5 cm. The diagnosis was either an atypical histiocytoma or a neurofibrosarcoma. A second recurrence was treated after only 1 month had elapsed. Since it was discovered, during the dissection of the tumor down to the bone, that the supraorbital foramen had become involved, it was elected to perform a craniotomy, during which a portion of the superonasal orbital bony rim was excised along with a 10 x 15 cm orbital mass that was attached directly to a thickened supraorbital nerve. A portion of involved orbital roofwas also excised. The bony defect in the anterior cranial fossa was closed with a stainless steel screen and skin graft. It was noted at the comple- tion of the surgery that the cut end ofthe remaining frontal nerve left in the deep orbit was thickened. In October of 1964, a large nodule was removed from the superomedial lid and brow regions. One month later a right preauricular lymph 334 Jakobiec et al node became enlarged; biopsy disclosed metastatic tumor. Thereafter, the left eye began to protrude with diplopia in all fields of gaze. Multiple nodules appeared on the forehead and lid, including a 1 cm nodule located somewhat lateral to the midline on the forehead. A second craniotomy was performed in 1964 to remove the intraorbital tumor, which had extended through the superior orbital fissure into the middle cranial fossa. In 1966, the patient received 6000 rads of radiotherapy for the residual intracranial tumor. During the following year he developed seizures, which were initially well controlled by medication, but subsequently became more intractable. The skin over the bony defect in the orbital roof broke down from the irradiation, with prolapse of the meninges and brain. The patient developed signs of increased intracranial pressure, and a brain ab- scess formed that was caused by pseudomonas and proteus species. He died in April of 1968 from transtentorial herniation. At autopsy, a tumor was found in the middle cranial fossa. The left trigeminal nerve roots were invaded up to the left lateral pons.

CASE 2 In February of 1962, a 52-year-old white man had a "sebaceous cyst" removed from the superomedial aspect of the left upper lid above the medial canthus. There was no ulceration of the surface epithelium, and histopathologic examination of the lesion revealed a malignant tumor infiltrating the deep dermis and adjacent orbicularis striated muscle but sparing the surface epidermis. Because the tumor had been incompletely excised, the patient received a course of postoperative irradiation. In August and September the lesion recurred twice, again without evidence of surface breakdown, and was excised on these occasions. Another recurrence in 1963 resulted in repeat radiotherapy. In 1964, there was obvious left orbital involvement with diplopia in all fields of gaze and 4 mm of relative left proptosis. Radiotherapy was tried a third time to no avail, and in June of 1964, a left orbital exenteration was performed with exploration of the left ethmoidal, frontal, and sphenoidal sinuses. The tumor was described in the operative report, and by the pathologist who grossed the exenteration specimen, as an encapsulated, firm, grey-white mass originating from the old cutaneous scar and extending deep into the orbit along its medial aspect. There were focal areas ofmyxomatous change and yellow flecks within the mass. The tumor grew supero- laterally across the medial rectus muscle; it could be peeled offwith ease from this structure as well as from the superior rectus muscle, eyeball, and optic nerve, to which it was approximated and nonadherent. Intraoperative and pathologic evaluation failed to disclose any evidence of sinus involvement. Because of metastases to the left submandibular and anterior cervical lymph nodes, a left radical neck dissection was also carried out. One year following surgery, the patient appeared to be free of tumor, but thereafter began to develop progressive neurologic symptoms of right-sided weakness, vertigo, and difficulty swallowing. In the spring of 1966, the patient was admitted to the hospital with bronchopneumonia and further deterioration in his neurologic status. He died of staphylococcal bronchopneumonia. At autopsy, a tumor was discovered in the middle cranial Orbital Nerve Sheath Tumors 335 fossa, adjacent to the superior orbital fissure, the sphenoid bone, and the optic foramen. The tumor was discovered infiltrating the Virchow-Robin's spaces and the brain parenchyma. The tumor was also present in the region of the left pons and cerebellum. Extracranial metastases were present bilaterally in the hilar nodes and the lungs. The left periorbital skin and large cavity formed by the exenteration and sinusectomies were free of tumor.

CASE 3 A 49-year-old white man presented in July of 1967 with a subcutaneous swelling in the superomedial region of the right upper lid. The overlying skin was intact, and after excision, the tumor was interpreted histopathologically as a sweat gland carcinoma. In the spring of 1968, the tumor was rebiopsied after a recurrence became obvious; at the time of surgery the tumor was discovered to have extended into the anterior orbit and to be partially cystic, leading the surgeon to the conclusion that it might be a "neurilemmoma." The biopsy, however, was again read as a carcinoma. A trial ofradiotherapy failed to produce significant regression in the tumor, as would have been expected with a carcinoma. By November of 1968, the right orbit had become massively involved; the globe was displaced downward and the lids were edematous and closed (Fig 1). The right orbit was exenterated. Examination of the specimen disclosed homogeneous, firm, greyish- white fasciculated tumor tissue extending to the posterior surgical margin (Fig 2). The oval tumor mass included in the specimen was centered superonasally in the orbital contents, creating a generally circumscribed nodule measuring 3.0 x 2.6 x 1.8 cm that was easily separated from the superior rectus muscle. Since tumor was known to have been left behind in the deep orbit, a craniotomy was performed in March, 1969. Tumor tissue was noted to extend through the superior orbital fissure into the middle cranial fossa, where it enveloped the right cavernous sinus. The sinus was entered, to reveal that the tumor had preferentially extended along the ophthalmic division of the trigeminal nerve, expanding this structure as well as the Gasserian ganglion. During surgery, it was estimated that approximately 15 ml of residual intraorbital and intracranial tumor was removed. The patient showed no signs of local recurrence, but died in the hospital in November of 1970 from a massive gastrointestinal hemorrhage associated with a multinodular, enlarged liver. At autopsy, the right orbit, adjacent meninges, and brain were free of tumor. The liver nodules had been caused by cholangiocarcinoma. The slides of this tumor were reviewed at the Armed Forces Institute of Pathology (AFIP) and the tumor was established to be totally unrelated to the earlier orbital malignancy.

CASE 4 In March of 1975, a 55-year-old white man complained ofpain about the right eye and orbit with tearing; redness and a slight prominence of the right eye were also noted. He had had a scar and a small lump superomedially in the right upper lid and brow for many years, which he dated from an accident with a crowbar; there 336 Jakobiec et al

FIGURE 1 One year after the removal of a superonasal subcutaneous lesion misinterpreted as a sweat gland carcinoma, this 50-year-old man returned with massive involvement of right orbit causing swelling and closure of eyelids (case 3).

was also numbness of the forehead in the distribution of V-1 that the patient related to the same accident. The vision was 20/20 in both eyes, with 3 mm of relative right proptosis. A venogram revealed compression and displacement of the right supeAior ophthalmic (orbital) vein, compatible with a mass lesion. The remainder of the workup was unremarkable. The patient refused arteriography and exploratory surgery. For a while systemic steroids helped to control the pain, but in July of 1975, worsening of the pain led to exploration of the right orbit, during which no tumor could be found. In January of 1976, the patient developed a right comeal abrasion that was quite extensive yet painless; it was then discovered that he had complete anesthesia of the entire right side of his face (Fig 3, top). Because offear of corneal ulceration due to neuroparalytic keratitis, the lids were sewn together to protect the cornea; a small "incidental" lump of the right Orbital Nerve Sheath Tumors 337

FIGURE 2 Exenterated orbital contents show a tumor situated in superior orbit. Lesional tissue is present at posterior margin of resection. A craniotomy was performed, and tissue extending through superior orbital fissure was extirpated. Patient died 1 year later of an unrelated cholangiocarcinoma. Postmortem examination of orbital and adjacent cranial regions failed to disclose any residual tumor (case 3).

upper lid was removed, which revealed a malignancy. This finding led to a computerized tomographic study of the skull, which disclosed a mass in the right cranial fossa (Fig 3, bottom). Arteriography was again negative. A craniotomy and biopsy of the tumor established its histologic identity to the tumor in the right upper lid. The patient died 9 months later.

CASE 5 A 75-year-old white woman developed a tumor in the left medial and superonasal orbital region, which was excised in January 1966. A recurrence was treated with wide local excision and skin grafting in October of 1967. A second recurrence was removed in August of 1969, but by March of 1971, definite evidence of intraorbital involvement was present in the forms of left ptosis and proptosis (Fig 4). The orbit was surgically explored and a well localized tumor measuring 27 x 13 x 5 mm was found superomedially in the anterior orbit. At surgery, it was noted that the supraorbital nerve was considerably thickened and extended from the intraorbital tumor across the supraorbital rim onto the forehead as a cord-like structure. The patient was treated with radiotherapy and Velban postoperatively, and has had no recurrence during a 5-year follow-up. 338 Jakobiec et al

FIGURE 3 Top: A 55-year-old man complained of pain about the right eye. Nine months later, he developed a right corneal abrasion which was extensive but painless, and was found to have complete anesthesia of right side offace and a mass located superior to right globe. Bottom: Axial computed tomogram of a recurrent orbital tumor demonstrates intracranial extension into middle cranial fossa (arrows) (case 4). Orbital Nerve Sheath Tumors 339

FIGURE 4 Appearance ofa 78-year-old woman who had experienced two recurrences ofan initially left anterior superonasal lesion, now exhibiting evidence of deep orbital invasion with proptosis and lateral displacement of globe (case 5).

CASE 6 A 30-year-old white woman, with pigmented spots on the face and sun-exposed skin consistent with xeroderma pigmentosum, developed in 1973, several melan- otic lesions of her lids, and a rapidly growing left conjunctiva lesion that was biopsied and diagnosed as a malignant melanoma (Fig 5, top). One year later, proptosis developed on the right side, caused by a mass located above and medial to the right globe (Fig 5, bottom). Excisional biopsy established the diagnosis of a malignant peripheral nerve tumor. Four months later in January of 1975, a recurrence ofthe right orbital tumor was noted in the superomedial portion of the orbit. Chemotherapy was administered. 340 Jakobiec et al

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FIGURE 5 Top: A 30-year-old woman with xeroderma pigmentosum developed a left inferior conjunc- tival and lid melanoma. Bottom: One year later, there is evidence of a right superonasal palpable orbital tumor. Orbital Nerve Sheath Tumors 341

FIGURE 6 A 63-year-old woman, known since childhood to have neurofibromatosis, developed a subcutaneous nodule above the left medial canthus (case 7).

CASE 7 In 1966, a 63-year-old white woman with neurofibromatosis since childhood, observed a slowly growing nodule at the upper border of the left medial canthus, causing tearing (Fig 6). She did not seek medical attention until 1969 when the mass had achieved the size of a walnut. The mass was excised and diagnosed as a neurofibroma with malignant change. A local recurrence developed in 1970; the patient refused radical surgery and was treated with 6000 rads of radiotherapy. A recurrence in 1972 was treated with 3,7000 rads of radiotherapy; subsequently, ulceration and induration developed on the skin ofthe medial canthus. The tumor was removed surgically and measured 27 x 17 x 15 mm. X-ray studies showed infiltration of the paranasal sinuses. The patient was reported to have died in February of 1975.

CASE 8 A 28-year-old black American man, known to have had von Recklinghausen's disease for over 10 years, had been aware of lumps on his skin for 20 years. The first of these that he could recall was located above his right eye. Over a 6-month period, the latter began to grow much larger displacing the proptosed right eye downward (Fig 7, top). He had also developed loss oflight perception in the right eye. The orbital contents were exenterated (Fig 7, bottom). Postoperatively, 342 Jakobiec et al

FIGURE 7 Top: A 28-year-old black man with a diagnosis for 10 years of von Recklinghausen's disease had a long-standing lump above the right eye. He developed massive right proptosis over a 6-month period. Bottom: Exenterated orbital contents show firm white areas that were composed of cartilage, as well as fleshy areas (case 8). Orbital Nerve Sheath Tumors 343 pulmonary metastasis was observed, and a local recurrence appeared in the incision site at the orbital rim. Six months later the patient died. PATHOLOGIC FINDINGS All cases in the Registry of Ophthalmic Pathology at the AFIP up to 1975 (the year the first author left the AFIP) carrying the diagnoses of malignant schwannoma, neurofibrosarcoma, malignant neurilemmoma, and neurogenic sarcoma were reviewed; eight cases were selected that on reevaluation of the clinical and pathologic material were deemed accept- able for inclusion in this study. Dr Franz Enzinger, Chairman of the Department of Soft Tissue Pathology at the AFIP, examined all of the cases and confirmed the accuracy of the diagnoses. Exenteration specimens were processed at the AFIP for cases 3 and 8. Slides prepared from the cervical metastases in cases 1 and 2 were also reviewed at the AFIP, as well as the autopsy slides from case 3. Special stains prepared on paraffin blocks made available to the AFIP included Masson's trichrome, Wilder's reticulin, the Fontana reaction for melanin, alcian blue and mucicarmine for mucus, and the Bodian for axons. Table I summarizes the various architectural and cytologic features encountered among the eight lesions. The cell types composing the major patterns were either spindle shaped or epithelioid. The epithelioid cells consistently failed to stain for melanin with the Fontana reaction. Indi- vidual lesions could exhibit diverse features, and were often biphasic and even multiphasic in their characteristics. The two malignancies arising in patients who had von Recklinghausen's neurofibromatosis (cases 7 and 8) had the most mesenchymal appearances-the malignant cell population displaying a predominance of spindle cells. In the malignant plexiform pattern (Fig 8), swollen nerve bundles were infiltrated by either epithelioid cells or spindle cells. The tumor cells generally infiltrated the centers of nerve bundles with intact perineuria, but invasion of the surrounding soft tissues was also seen. A mixture of pre-existent benign cells and invasive malignant cells was observed within the nerve bundles (Fig 9); the latter appeared to be increased in number. In regions where most ofthe nerve architecture was obliterated, wavy bundles of cells suggestive of a nerve remnant with Schwannian elements contained axon cylinders as revealed with the Bodian stain (Fig 9, bottom). Axon cylinders and their enveloping Schwann cells were particularly well preserved in the middle of the intact nerve bundles (Fig 10). In the neurotubular pattern, plump spindle cells with well defined eosinophilic cytoplasm lepidically outlined lumina, which were devoid of 344 Jakobiec et al

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FIGURE 8 Top: Malignant plexiform pattern of peripheral nerve sheath tumor shows multiple swollen nerve bundles, delimited by intact but thickened perineuria (H&E, x 60). Bottom: Clus- ters of hyperchromatic epithelioid cells infiltrate center of nerve bundles (H&E, x 90). 346 Jakobiec et al

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FIGURE 10 Surviving Schwann cells with Schmidt-Lantermann clefts (arrows) enveloping axon cylinders are separated by malignant cells infiltrating nerve bundles (Bodian stain, x 220). 348 Jakobiec et al axons or mucosubstances (Fig 11). The lining spindle cells often delami- nated into the central lumina. The neurotubule formations were frequently quite elongated, and occasionally were only partially canalized. In the pseudoglandular pattern, small nests and cords of epithelioid cells were separated by a mucopolysaccharide-rich stroma. The overall pattern suggested an epithelial malignancy (Fig 12). Rarely were the cells set in a hyalinized stroma. High power microscopy revealed that the cellular nests did not possess a true lumen, but rather were solid, cellular aggregates formed by three to five cells. Occasionally, a lumen might be simulated by central necrosis or drop-out of cells, but in these formations the walls were generally two to three cells thick rather than a monolayer of true adeno-units (Fig 13, top). The alcian blue and mucicarmine stains were negative. Adjacent to the solid nests and pseudoglandular units, individual cells were suspended in a loose and mildly inflamed stroma, and sometimes displayed bizarre cytomorphologic features, including multinucleation of pleomorphic epithelioid cells and strap-like spindle cells with clearly visible, longitudinal, cytoplasmic filaments failing to manifest cross-striations (Fig 13, bottom). The alveolar-organoid pattern was encountered as an architectural modification of tumors featuring a prominent epithelioid cell component. In one lesion, the subdivisions were created by thick trabeculae of collagen and blood vessels; the enclosures contained a mixture of spindle and epithelioid cells (case 2) (Fig 14, top). In the other lesion, tumor cells were packed in small compartments surrounded by thin reticulin fibers (Fig 14, bottom left). Nonorganoid sheet-like arrangements of mitotically active epithelioid cells were found in other fields of these two tumors and in the other three tumors featuring epithelioid cells (Fig 14, bottom right). In lesions possessing a fascicular spindle cell component, there was only a mild tendency for palisading of nuclei and the cells frequently had conspicuous cytoplasm (Fig 15, top). The nuclei were oval and more pleomorphic in comparison with those in a fibrosarcoma. In the two lesions with the best developed spindle fascicular pattern (cases 3 and 7), there was prominent necrosis, with palisading of the surrounding spindle cells (Fig 15, bottom). Necrosis in other tumors was surrounded by epithelioid cells. In case 8, heteroplastic cartilage was discovered in intimate association with a malignant spindle cell neoplasm (Fig 16, top). The latter had arisen in the field of a benign orbital plexiform neurofibroma (Fig 16, bottom). A careful study of many sections prepared from the exenteration specimen failed to disclose any striated muscle elements. Aft "OP,

FIGURE 11 Neurotubular pattern composed of plump spindle cells lining elongated pseudolumens. No axon cylinders were demonstrated in centers of these formations (H&E, top, x 200; bottom, x 305). 350 Jakobiec et al

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DISCUSSION Enzinger and Weiss'2 have provided an excellent comprehensive review of the clinical and pathologic features of malignant tumors of peripheral nerves throughout the body. They point out that such malignancies ac- count for only 10% ofall soft tissue sarcomas, and that less than halfoccur with neurofibromatosis. Patients with von Recklinghausen's disease have a 3% to 13% chance of developing a malignant peripheral nerve tumor, often after latent periods of 10 to 20 years. Most ofthe patients with these malignancies are between 20 and 50 years of age at presentation, with a distinct tendency for patients with von Recklinghausen's disease to develop these lesions at an earlier age. Males predominate when the tumor arises in the setting ofvon Recklinghausen's disease, but there is roughly an equal sex distribution for the tumors that arise in isolation from this syndrome. Patients have symptoms ofpain and swelling developing over a several month period, and the lesions are usually represented by large fusiform or eccentric masses developing in the major nerve trunks, such as the sciatic nerve, the brachial plexus, and the sacral plexus. These involvements lead to the distinctive anatomical sites of predilection- namely, the proximal portions ofthe upper and lower extremities and the trunk. In contrast with neurilemmomas (benign schwannomas), which have a tendency to arise in the head and neck region, malignant peripheral nerve sheath tumors generally spare this locale. Reported survival rates for patients with malignant peripheral nerve sheath tumors have ranged from a low of 30% for those occurring in association with von Recklinghausen's disease, to 75% for the isolated lesions; a review of the AFIP material, however, disclosed a 47% 5-year survival rate for lesions uncomplicated by neurofibromatosis. When metastases develop, charac- teristically to the lungs, they are usually detected within 2 years of the patient's initial presentation. In 1971, Schatz5 reported a benign orbital neurilemmoma (schwannoma) in a patient with von Recklinghausen's neurofibromatosis that underwent a sarcomatous degeneration. A 27-year-old woman gave a 6-week history ofthe appearance ofa right superior orbital lesion that had caused some pain. A transcranial orbitotomy was performed, and an 356 Jakobiec et al "encapsulated" mass incorporating the supraorbital nerve was encountered. A rapid recurrence of the tumor several months later necessitated an exenteration followed by radiotherapy. The patient died 21 months later, and an autopsy revealed metastases to the lung and mediastinum. Three years later Grinberg and Levy6 reported a 47-year-old male with a 1 year history of tingling and numbness of the left brow accompanied by pain. Physical examination disclosed anesthesia in the distribution of the left supraorbital nerve, and the nerve itself was palpably swollen and tender. At operation, 33 mm of the left supraorbital and ophthalmic trigeminal nerves were excised, through the superior orbital fissure and up to the cavernous sinus. Fifty-one hundred rads of radiotherapy were given postoperatively, and the authors reported no recurrence during a 9-month follow-up. Of Henderson's' two patients with long-standing histories of neurofibromatosis, one developed, at age 37, a malignant transformation of an orbital lesion, and lived through multiple recurrences over an 8-year period until death occurred. In his other patient, a malignant degeneration occurred at age 76, and after 7 years of multiple recurrences, the patient was reported to be still alive. Our series considerably amplifies the clinical picture of malignant peripheral nerve sheath tumors ofthe orbit, which is nontheless very similar to the cluster of findings described in the previous two reports.5'6 In common with the previous patients, our patients typically had their lesions develop in the superior-medial aspect of the orbit immediately beneath the lid and canthal skin, which was not eroded. The lesions appeared innocuous clinically, and a suspicion of malignancy was never entertained at the outset. The lesions were frequently described as "cystic. " The right and left orbits were equally involved; in our series, five men and three women were affected. At the time of presentation, the patients ranged in age from 19 to 75 years, with half the patients being younger than 50 years of age. Only two of the patients were known to have von Recklinghausen's neurofibromatosis. While the initial presentation was unprepossessing, after an incomplete excision, there was a cres- cendo in the clinical course. Recurrences were rapid, occurring from 3 to 6 months after the initial surgery. Three patients had three recurrences. By the time major ablative surgery was resorted to, it was generally too late to eradicate the tumor completely. Multiple administrations of high doses of radiotherapy were unavailing. Five of our patients are known to have died from their disease, at intervals after presentation of 1 year, 11/2 years, 4 years, and 5 years (two cases). Besides the superomedial anterior orbital location of the lesions, be- tokening an origin from the supraorbital nerve (a terminal branch of the Orbital Nerve Sheath Tumors 357 ophthalmic division of the trigeminal), further neurotropism was evi- denced by posterior intracranial spread toward the middle cranial fossa. Some patients were noted at presentation or upon recurrence to have anesthesia or hypesthesia in the involved divisions of the trigeminal nerve. Loss of the trigeminal supply to the cornea resulted in corneal breakdown from a neuroparalytic keratitis in one of our patients. Clini- cally, and at the time of surgery, the supraorbital nerve, as it extended posteriorly into the deep orbit, and also anteriorly across the forehead, could be observed or palpated to be grossly enlarged. The case histories of patients 1 through 4 depict the inexorable spread of tumor into the middle cranial fossa; at autopsy in cases 1 and 2, involvement of the trigeminal nerve as far back as the pons was demonstrated. In addition to producing death from intracranial extension, these tumors were able to metastasize to regional lymph nodes and eventually to the mediastinum and lungs. It should be mentioned that malignant peripheral nerve neoplasms have been reported in the retro-orbital divisions of he trigeminal nerves, as well as in the Gasserian ganglion16"17; in one of these cases, intraneural extension of tumor cells to the pons was established by computed tomography. 17 In such cases, facial and periocular pain or hypesthesia develop without proptosis. The histopathologic features of the lesions in this series were quite varied, as summarized in Table I. The clinical propensity of the tumor cells to extend along the trigeminal nerve divisions was confirmed in the pathologic specimens. Four lesions showed a prominent malignant plexiform pattern, in which the tumor cells expanded the compartments of the involved nerve bundles. While these nerve bundles appeared to be increased in number over their normal anatomical distribution in the superomedial orbital region, it is difficult to know whether a true plexiform neurofibroma pre-existed in these lesions, or whether the nerve units proliferated secondary to invasion by the tumor cells. Two patients gave histories of trauma sustained to the superomedial orbital region where their tumors later developed. It could be speculated, but not satisfactorily proved, that a traumatic neuroma was the precursor for the development of the malignant peripheral nerve tumors in these traumatized patients. After the malignant plexiform pattern, the neurotubular pattern found in two patients' lesions was the most distinctive. Plump spindle cells lining elongated cavities imparted the appearance of Schwann cells abortively trying to create enclosures for nonexistent axon cylinders. In the alveolar and pseudoglandular patterns, an epithelial malignancy was simulated by small clusters ofepithelioid cells suspended in a mucopolysaccharide-rich stroma, or else delimited by delicate or thick collagenous trabeculae. No 358 Jakobiec et al true lumens were found, and mucosubstances secreted by the tumor cells could not be demonstrated by the alcian blue and mucicarmine stains. Three of the lesions were biphasic, featuring both spindle and epithelioid cells. The epithelioid cells were usually diffusely arranged, but in two cases, there was an organoid pattern wherein groups of cells were surrounded by collagenous trabeculae or reticulin-positive fibers. The spindle cells generally had abundant cytoplasm and oval nuclei, rather than the pointed nuclei typical of fibroblasts. In areas of necrosis, there was a tendency for the tumor cells to palisade, a feature shared with malignant glial tumors of the central nervous system. A subtle cytologic feature that may be helpful in the diagnosis of these lesions was their fine nuclear chromatin stippling and small nucleoli. This chromatinic particu- lation bears a striking resemblance to that of other neuroectodermal or neural crest-derived neoplasms. In all of our lesions there was no question about malignancy, because of the high mitotic rate and frequent nuclear pleomorphism. Incompletely excised benign orbital schwannomas and neurofibromas can recur; the absence of cellular pleomorphism and mitotic activity in the recurrences should rule out a malignant degeneration. Enzinger and Weiss'2 state that the vast majority of peripheral nerve sheath malignancies are of the spindle cell-fascicular type, and that the major differential diagnosis in soft tissue pathology concerns fibrosarcoma. Clinical and anatomical data can help to distinguish spindle cell malignant peripheral nerve sheath tumors from fibrosarcoma--e.g., the development ofthe tumor in the setting ofvon Recklinghausen's neurofibromatosis, the relationship of the tumor to a major nerve trunk or plexus, and the predilection of the tumor to grow along the perineurium of the nerve of origin. Malignant peripheral nerve sheath tumors arising in neurofibromatosis usually are ofthe spindle cell type12'18; occasionally, heteroplastic elements such as cartilage and bone may be found, as well as the very rare expression of rhabdomyoblastic differentiation (Triton tumor). 9 In our two patients with von Recklinghausen's disease, the malignant outgrowth was composed of mitotically active spindle cells, and a similar cellular composition was discovered in the two malignancies arising in the orbits of patients with neurofibromatosis in Henderson's series. 1 In one of our two patients with von Recklinghausen's disease (case 8), heteroplastic cartilage was also found in association with a malignant spindle cell neoplasm and a pre-existent benign plexiform neurofibroma. Compared with the spindle cells of fibrosarcoma, those in a malignant peripheral nerve sheath tumor have less fascicular regimentation (absence of the herringbone pattern of fibrosarcoma), and the poor parallel Orbital Nerve Sheath Tumors 359 orientation of the tumor cells often gives way to alternating myxoid regions. The nuclei of fibrosarcoma cells are straight and pointed, whereas in a malignant peripheral nerve sheath tumor, the nuclei are wavy, buckled, or comma shaped, and when cut en face, they appear asymmet- rically oval. In contrast to the bipolar processes of fibrosarcoma cells, in malignant peripheral nerve sheath neoplasms, the cells are frequently multipolar with entangled processes, which impart an indistinct fibrillary background. Hyaline bands and focal nodules set in a looser myxoid stroma are more in keeping with a malignant peripheral nerve sheath tumor than a fibrosarcoma. Finally, there is generally less collagen pro- duced in a malignant peripheral nerve sheath tumor, although reticulin fibers may be abundant due to basement membrane-like material in the interstitices. While fewer than 10% of patients with malignant peripheral nerve sheath tumors have unusual differentiations besides a spindle cell proliferation, our orbital lesions, paradoxically, more often exhibited distinctive and unusual morphologic aspects. Once the pathologist is aware of the malignant plexiform, alveolar/organoid, pseudoglandular, neurotubular, and epithelioid cell variants, particularly when there is a biphasic relationship of spindle cells and epithelioid cells, the diagnosis can be much more readily made than in the case ofisolated spindle cell lesions of the orbit that don't immediately appear to be neurogenic. Both the malignant spindle cells and epithelioid cells of peripheral nerve sheath sarcomas stain negatively for melanin by the Fontana reaction, and are generally bereft ofglycogen granules, which are more frequently found in amelanotic melanoma, leiomyosarcoma, and rhabdomyosarcoma. Besides the lack of a Triton tumor in our series, we also had no examples of so-called glandular malignant schwannoma, which may contain mucin-se- creting elements.20 The neurotubular pattern found in two of our tumors comes the closest to this morphologic variant, but no evidence of mucin secretion was discovered in the lumens created by the plump spindled Schwann cells. The striking elongation of the neurotubular units, the lining of spindle cells rather than columnar or cuboidal cells, and the absence of mucin production help to rule out adnexal carcinomas. Another feature which is useful in confirming that a spindle cell malignancy is of nerve sheath origin is the discovery of a pre-existent or associated benign nerve sheath tumor, overwhelmingly a neurofibroma. In our cases 7 and 8, either an earlier biopsy, or the exenterated orbital contents, revealed such a feature. Jakobiec and Jones21 have reported a diffuse myxoid neurofibroma that underwent multiple orbital recurrences, until a malignant spindle cell nerve tumor was spawned in the 360 Jakobiec et al patient's sixth decade. In contrast to neurofibromas, neurilemmomas (benign schwannomas) are considered to be relatively immune to malignant degeneration.'2 In this regard, the case reported by Schatz5 of a malignant degeneration in an orbital neurilemmoma is problematic. In examining the published photomicrographs of this case, one cannot be completely sure whether the lesion was a schwannoma or a cellular neurofibroma; furthermore, in certain fields of a classical neurofibroma, focal Schwann cell proliferations can be observed, including the production of organoid or tactile bodies.2' Electron microscopic studies of orbital and nonorbital peripheral nerve sheath tumors have disclosed that neurofibromas are composed of cells possessing perineural cell features rather than Schwann cell features.7,21-23 These characteristics include an overall bipolar spindle shape, interrupted segments ofbasement membrane material (but usually not banded basement membrane material or Luse bodies), pinocytotic vesicles at the plasmalemma, cytoplasmic filaments, and a scarcity of cytoplasmic organelles (short segments of rough surfaced endoplasmic reticulum and a few mitochondria). Benign schwannomas or neurilemmomas, on the other hand, are usually predominantly composed of Schwann cells, exhibiting myriad delicate and elongated cellular processes, abundant and frequently reduplicated linear basement membrane material, banded basement membrane material (Luse bodies), mesaxon and pseudomesaxon formation, and cytoplasmic filaments and neurotub- ules. The expression of these distinctive Schwann cell characteristics in malignant peripheral nerve sheath tumors is often absent, with only a minority of cells displaying entangled, slender cellular processes, and basement membranes.712'2' Even the epithelioid variant of malignant peripheral nerve sheath tumors may or may not show clear-cut Schwan- nian features.9-" Immunohistochemical methods for the delineation of S-100 protein, which is present in the cytoplasm of Schwann cells, melanocytes, and nevus cells, is almost constantly present in benign peripheral nerve sheath tumors, but only episodically in malignancies.12-15 One of us (FAJ) has examined by electron microscopy a myxoid neurofibroma of the orbit, which was the soil for the development of a malignant spindle cell proliferation. 24The ultrastructural features ofthe cells in the benign myxoid area were those of a perineural cell; the malignant spindle cell proliferation displayed the same but attenuated morphologic features. This case further underscores the value of adhering to the more noncommital term of malignant peripheral nerve sheath tumor rather than malignant schwannoma. Ifthe most frequent precursor lesion for the development of a malignant peripheral nerve sheath tumor is the neuro- Orbital Nerve Sheath Tumors 361 fibroma (and hence the most frequent precursor cell would be the perineural cell),7 it should not be surprising that the malignant tumor cells often fail to demonstrate Schwannian features. After primary orbital fibrosarcoma (itself at least as rare as neurogenic sarcoma), the remainder of the differential diagnoses includes the following entities: rhabdomyosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, and alveolar soft part sarcoma.25 In reviewing earlier reported cases of orbital peripheral nerve malignancies, Hender- son1 noted their frequent occurrence in younger individuals. It would seem likely that many of these patients actually had embryonal rhabdomyosarcomas, which can produce a neuroid appearance through the al- ternation of spindled and myxoid regions. Porterfield and Zimmerman26 noted in their retrospective review of orbital rhabdomyosarcomas that a common earlier misdiagnosis had been neurofibrosarcoma. Leiomyosar- coma of the orbit frequently has a prominent vasculature with perithelial cuffing of the malignant cells; the trichrome stain will reveal intense cytoplasmic fuchsinophilia and longitudinal noncrossed filaments. Lipo- sarcoma often has a distinctive plexiform vascular pattern, and one must discover vacuolized lipoblasts among the constituent cells. Malignant fibrous histiocytoma should exhibit the storiform pattern and often has multinucleated histiocytic cells. The two cases reported by Mortada4 of malignant neurilemmomas ofthe orbit may well be examples ofmalignant fibrous histiocytomas, in that one of his lesions contained multinucleated giant cells. Finally, alveolar soft part sarcoma can be distinguished from an epithelioid malignant nerve tumor by virtue of the demonstration of periodic acid-Schiff-positive, diastase-resistant, crystalline cytoplasmic inclusions in the former. The optimal management of orbital malignant peripheral nerve sheath tumors depends upon an early and accurate pathologic diagnosis. It is hoped that the data presented above will facilitate more rapid diagnosis in the future. In view of the propensity of these lesions to grow along the ophthalmic divisions of the trigeminal nerve toward the Gasserian ganglion and other cranial structures, orbital exenteration with removal of the greatest extent of the trigeminal nerve is probably the best management. A combined exenteration and craniotomy would be required for an extensive extirpation ofthe trigeminal nerve. While malignant peripheral nerve sheath tumors arising in patients with neurofibromatosis are considered to have a worse prognosis than those arising in isolation,'2 this differential prognosis probably does not obtain in the orbit, because ofthe short distance between the orbital structures and nerves and the intracranial compartments. Before proceeding with radical surgery, a systemic 362 Jakobiec et al workup for metastases should be performed; regional lymph node metastases may also occur, particularly in the epithelioid cell variants. Postop- erative radiotherapy coupled with chemotherapy may improve the results ofradical surgery.27 Earlier reports on the ineffectiveness of radiotherapy dealt with bulky tumors and antiquated methods. 12 Improvident radiotherapy may rarely produce malignant peripheral nerve sheath tumors on its own, or provoke a malignant transformation in an incompletely excised benign tumor.28 It should be emphasized that the best chance for local cure of an orbital malignant peripheral nerve sheath tumor is at the time of first surgery, because after recurrences, there is an almost unavoidable spread intracranially.

SUMMARY Eight adult patients with malignant peripheral nerve sheath tumors ofthe orbit are described. Only two of the patients were known to have von Recklinghausen's neurofibromatosis. The typical clinical history included the development ofa mass in the superonasal quadrant ofthe orbit, which was palpable immediately beneath the skin ofthe lid. There was a definite tendency for the lesions to arise in, or grow along, the supraorbital nerve-including posteriorly through the superior orbital fissure to the Gasserian ganglion, and even as far posteriorly along the trigeminal root- lets to the pons. Delays in pathologic diagnosis, which beclouded the true nature of the process, led to multiple recurrences, eventuating in five known fatalities out of the eight patients. In addition to intracranial extension, pulmonary metastases and regional cervical metastases were encountered. Once recognized for their diagnostic value, the histopathologic patterns are highly distinctive: biphasic populations of spindled and epithelioid cells; sheets of epithelioid cells or clusters demarcated by delicate reticulin fibers or thicker collagenous trabeculae; malignant plexiform patterns; and neurotubular patterns. Pure spindle cell populations were encountered only in the two patients with von Recklinghausen's disease, and in each, either a pre-existent benign neurofibroma or a coexistent plexiform neurofibroma was found in the pathology specimens. The best management of this condition depends upon early clinical and pathological recognition, leading to radical surgery, which usually con- sists of orbital exenteration combined with intracranial extirpation of as much of the trigeminal nerve as possible. Postoperative radiotherapy and chemotherapy after radical surgery might also be advisable. Orbital Nerve Sheath Tumors 363

ACKNOWLEDGMENTS We would like to express our appreciation to Drs Olga Litricin, Terrence Makley, Alan Putterman, and Ingolf Wallow, for allowing us to include their patients in this series.

REFERENCES 1. Henderson JW: Orbital Tumors, ed 2. New York, Brian C Decker, 1980, pp 276-279. 2. Kennedy RE: An evaluation of 820 orbital cases. Trans Am Ophthalmol Soc 1984; 82:134-157. 3. Krohel GB, Rosenberg P, Wright J, et al: Localized orbital neurofibromas. Am J Ophthalmol 1985; 100:458-464. 4. Mortada A: Solitary orbital malignant neurilemmoma. Br J Ophthalmol 1968; 52:188-190. 5. Schatz H: Benign orbital neurilemmoma: Sarcomatous transformation in von Reckling- hausen's disease. Arch Ophthalmol 1971; 86:268-274. 6. Grinberg MA, Levy NS: Malignatn neurilemmoma of the supraorbital nerve. Am J Ophthalmol 1974; 78:489-492. 7. Erlandson RA, WoodruffJM: Peripheral nerve sheath tumors: An electron microscopic study of 43 cases. Cancer 1982; 49:273-287. 8. Taxy EB, Battifora H, Turjillo Y, et al: Electron microscopy in the diagnosis of malignant schwannoma. Cancer 1981; 48:1381-1391. 9. Alvira MD, Mandybur TI, Menefee MG: Light microscopic and ultrastructural obser- vations of a metastasizing malignant epithelioid schwannoma. Cancer 1976; 38:1977-1982. 10. Vuia 0: Morphologic aspects of the neurofibrosarcoma (neurogenic sarcoma). Eur Neurol 1977; 16:1-10. 11. Taxy JB, Battifora HB: Epithelioid schwannoma: diagnosis by electron microscopy. Ultrastruct Pathol 1981; 2:19-27. 12. Enzinger FM, Weiss SW: Soft Tissue Tumors. St. Louis, CV Mosby Co, 1983, pp 625-656. 13. Stefansson K, Wollmann R, Jerkovic M: S-100 protein in soft-tissue tumors derived from Schwann cells and melanocytes. Am J Pathol 1982; 106:261-268. 14. Weiss SW, Langloss JM, Enzinger FM: Value of S-100 protein in the diagnosis of soft tissue tumors with particular reference to benign and malignant Schwann cell tumors. Lab Invest 1983; 49:299-308. 15. Messmer EP, Font RL: Applications of immunohistochemistry to ophthalmic pathology. Ophthalmology 1984; 91:701-707. 16. Hedeman LS, Lewinsky BS, Lochridge GK: Primary malignant schwannoma of the Gasserian ganglion. J Neurosurg 1978; 48:279-283. 17. Liwnicz BH: Bilateral trigeminal neurofibrosarcoma. J Neurosurg 1979; 50:253-256. 18. Guccion JG, Enzinger FM: Malignant schwannoma associated with von Recklinghau- sen's neurofibromatosis. Virchows Arch Pathol Anat 1979; 383:43-57. 19. WoodruffJM, Chernik NL, Smith MC, et al: Peripheral nerve tumors with rhabdomyo- sarcomatous differentiation (malignant 'Triton" tumors). Cancer 1973; 32:426-439. 20. Woodruff JM: Peripheral nerve tumors showing glandular differentiation (glandular schwannomas). Cancer 1976; 37:2399-2341. 21. Jakobiec FA, Jones IS: Neurogenic tumors, in IS Jones, FA Jakobiec (eds): Diseases of the Orbit. Hagerstown, MD, Harper & Row, 1979, pp 371-416. 22. Jakobiec FA, Font R, Iwamoto T: Diagnostic ultrastructural pathology of ophthalmic tumors, in FA Jakobiec (ed): Ocular and Adnexal Tumors. Birmingham, AL, Aescu- lapius Publishing Co, 1978. 364 Jakobiec et al 23. McDonald P, Jakobiec FA, Iwamoto T: Benign peripheral nerve sheath tumors of the lacrimal gland. Ophthalmology 1982; 90:1403-1413. 24. Jakobiec FA: Malignant orbital peripheral nerve sheath tumor arising in association with a myxoid neurofibroma in a child. Case presentation to the Verhoeff Society, April 28-29, 1984, Washington, D.C. 25. Jakobiec FA, Font RL: Diseases of the orbit, in WH Spencer (ed): Ophthalmic Pathol- ogy: An Atlas and Textbook. Philadelphia, WB Saunders, 1985, vol 3, chap 12. 26. Porterfield JF, Zimmerman LE: Orbital rhabdomyosarcoma: A clinicopathologic study of 55 cases. Virchows Arch Pathol Anat 1962; 335:329-341. 27. Storm FK, Eilber FR, Mirra J, et al: Neurofibrosarcoma. Cancer 1980; 45:126-129. 28. Foley KM, Woodruff JM, Ellis FT, et al: Radiation-induced malignant and atypical peripheral nerve sheath tumors. Ann Neurol 1980; 7:311-318.

DISCUSSION DR ANDREW P. FERRY. One complaint directed against discussers of scientific papers is that, all too often, after giving a briefnod to the material just presented, they proceed to present their own papers on the subjects. This won't happen here. I've never seen a patient with this rare orbital tumor, so I'll have to confine my remarks to discussing what Doctor Jakobiec has just presented to us. He emphasized the extreme rarity ofmalignant peripheral nerve sheath tumors occurring in the orbit and cited several reports to bear out his point. Still further support for his statements regarding the rarity ofthese tumors can be found in the paper published recently by Doctor Shields and colleagues (Arch Ophthalmol 1984; 102:1606-1611), in which they encountered no tumor of this type in 645 biopsies of orbital space-occupying lesions. The only malignant peripheral nerve sheath tumor I have seen developed in the scapular area of this patient [slide] with von Recklinghausen's neurofibromatosis. The tumor proved to be fatal. Her eyes were obtained at autopsy and exhibited these characteristic Lisch nodules [slide] in both irises. Parenthetically, I should like to add that the figures Doctor Jakobiec quoted accurately from the literature concerning the chance of patients with von Recklinghausen's disease developing a malignant peripheral nerve sheath tumor (3% to 13%) seem exces- sive. In the past, these tumors (which are less uncommon elsewhere in the body than they are in the orbit) traveled most often under the name "malignant Schwan- noma." But Doctor Jakobiec has touched briefly upon the fact that it is theoreti- cally possible for these neoplasms to arise by proliferation of any of the three principal cells comprising the peripheral nerve sheaths, ie, the Schwann cell, the perineural cell, and the epineural fibroblast. In this photomicrograph of an orbital nerve [slide] spindle shaped cells are prominent. Electron microscopy facilitates determining which of the three principal types ofnerve sheath cells they are. Thus, in this electron micrograph [slide] of another specimen, it is apparent that the nerve fibers are nonmyelinated and that the nerve sheath cell in question is a Schwann cell. Schwann cells are generally considered to be of neuroectodermal origin. They sheathe axons from Orbital Nerve Sheath Tumors 365 the point where the latter emerge from the pia mater to their terminations. They are identified by their close relationship to axons and they are the principal cells of the endoneurium. In nonmyelinated nerves one or more axons are enveloped by a single Schwann cell process. The Schwann cell in myelinated nerves wraps around individual axons in a "jelly roll" fashion. Perineural cells, the second principal cell comprising the peripheral nerve sheaths, develop in concentric layers to form the perineurium that surrounds the endoneurium. Perineural cells have long, thin, bipolar cell processes isolated from each other by collagen fibrils. Whether they are ofneural crest or mesenchymal origin is still controversial, with most investigators favoring a neural crest origin. The epineural fibroblast, the third principal cell comprising the peripheral nerve sheaths, is the chief component of the epineurium, the outermost sheath encompassing several nerve fascicles. Epineural fibroblasts are regarded as being most likely of mesodermal origin according to Erlandson and Woodruff (Cancer 1982; 49:273-287). As Doctor Jakobiec has emphasized, when examining these malignant tumors it is often impossible, even with ultrastructural techniques or application of immunohistochemical methods, to determine which of the three principal components ofthe nerve sheath is giving rise to the tumor; hence the current trend to refer to these neoplasms by the more noncommittal term of "malignant peripheral nerve sheath tumor" rather than "malignant Schwannoma." Scattered about this bed of roses there are a few bare patches. Only one of the eight patients described by Doctor Jakobiec (case 4) seems to have undergone orbital computerized tomography. But this failing derives chiefly from the fact that computerized tomographic scanning was not available, or at least was not widely available, when most ofthe patients in this study were being evaluated and treated. Because so much of the patient's chance for survival depends upon what is done at the time of the initial hospitalization, it would be particularly desirable to have a clear idea of what features these tumors exhibit on computerized tomographic examination. This would help alert the surgeon to the possibility of encountering this rare tumor when he enters the orbit. Although intraoperative histopathologic examination, using the frozen section technique, of biopsy specimens will suggest the presence of a malignant peripheral nerve sheath tumor, a definite diagnosis will usually require examination of conventional, paraffin-embedded sections. Once the diagnosis is established, ap- propriate therapy is indicated. Based upon the results of the study we've just heard, in view of the propensity of these lesions to grow along the ophthalmic divisions of the trigeminal nerve toward the Gasserian ganglion and other intracranial structures, orbital exenteration with removal of the greatest extent of the trigeminal nerve is probably the best management. I enjoyed the opportunity of discussing this paper, and you don't need me to tell you that the presentation you've just heard by Doctor Jakobiec will be the definitive work on this subject for years to come. DR FREDERICK JAKOBIEC. I would like to thank Doctor Ferry for his very kind comments about this paper. The material collected represents about 20 years of 366 Jakobiec et al experience at the Armed Forces Institute of Pathology, and some of this material was also received from outside the United States. I would imagine at the present time that about two to three malignant peripheral nerve sheath tumors develop in the orbits ofpatients in the United States each year; unfortunately, it is likely that some of these cases are mistakenly diagnosed as something else. Therefore, in response to Doctor Ferry's query about what the computerized tomographic (CT) scan appearances ofthese lesions might be, it could take some time to accumulate experience. The 2-year-old patient of Doctor Albert Hornblass that I mentioned had a CT scan performed that showed a bilobed retrobulbar mass. One of the lobes was a pre-existent neurofibroma, out of which a spindle cell malignant peripheral nerve sheath tumor arose. This complex tumor is exceptional in that it did not appear to arise in relationship to the supraorbital nerve or its divisions, but probably arose from a deeper orbital branch of the ophthalmic division of the trigeminal, in view of the retention of full extraocular motility after its local excision. Many experts recommended exenteration in this case, and I'm pleased to say that the patient is free of recurrence 2 years after Doctor Homblass's surgery. I believe the key to clinical diagnosis will never reside in the CT scan appearances, but rather in the clinical features. A superonasal or orbital rim lesion, or an orbital tumor developing in a patient with von Recklinghausen's neurofibromatosis, should be suspected ofbeing a malignant peripheral nerve sheath tumor, or at least this entity ought to be in the differential diagnosis. A history ofpain, or the demonstration of hypesthesia or anesthesia in the distribution of any of the trigeminal ramifications, would be further ancillary clinical data in favor of the diagnosis ofa benign or malignant nerve sheath tumor. I hope that the pathologic features demonstrated in this paper will assist pathologists in the future to make the correct diagnosis in a timely fashion. I also hope that the emphasis I placed on the tendency of these tumors to spread intracranially through the superior orbital fissure will lead to early radical surgery, including an attempt to eradicate tumor in the cavernous sinus region. Postoperative radiotherapy and chemotherapy, after radical orbital and periorbital surgery has been performed, might also be worthwhile.