Malignant peripheral nerve sheath tumor at the cerebellopontine angle treated with Gamma Knife radiosurgery: case report and review of the literature

Abstract

BACKGROUND AND IMPORTANCE

Malignant peripheral nerve sheath tumor (MPNST) is a rare lesion that may arise de novo or develop from an existing benign neurofibroma. Very rarely, MPNST may develop from an existing schwannoma. Intracranial MPNST is rare, and most commonly affects thevestibulocochlear nerve. Surgery is the mainstay of treatment for these lesions, but gross total resection is often difficult given the proximity of adjacent neurovascular structures. Gamma knife radiosurgery (GKS) may represent a useful adjunct to subtotal resection or biopsy of these lesions, but its use for this tumor type has not been well defined.

CLINICAL PRESENTATION

The patient, who had a long history of progressive sub-clinical hearing loss, presented with facial droop and decreased facial sensation. Imaging revealed a large left cerebellopontine angle tumor extending into the internal auditory canal. The mass was subtotally resected, and pathology revealed a malignant peripheral nerve sheath tumor. The patient underwent fractionated external beam radiotherapy two months later to the resection cavity, followed by Gamma Knife radiosurgery (GKRS) to the residual tumor. Follow up imaging eight months after GKRS revealed a substantial reduction in tumor size. The patient has remained clinically stable.

CONCLUSION

GKS may be a useful adjunct to multimodality treatment for malignant tumors of the CPA, such as MPNST, after subtotal resection and/or radiotherapy. Close ongoing follow up with periodic MR imaging is essential to monitor for recurrence.

1 INTRODUCTION

Primary malignant peripheral nerve sheath tumor (MPNST) is a rare intracranial entity [1, 2], reported as case reports only throughout the neurosurgical literature [2]. Most commonly affecting the vestibulocochlear nerve, intracranial MPNST presents in a similar manner to other cerebellopontine angle (CPA) tumors, although with the potential for rapid progression and worse overall prognosis. Surgical resection remains the primary treatment for malignancy at the CPA, but due to the proximity of critical neurovascular structures, complete resection is often not possible. Radiation therapy and chemotherapy have been used as adjunctive treatments for intracranial MPNST [3, 4], but Gamma Knife radiosurgery (GKS) has been rarely described as a treatment option for this pathology [4-8].

2 CASE REPORT

The patient is a 57 year old female who presented in July 2011, with a several month history of left-sided facial droop, sensory disturbance over the left V1 and V2 distribution, dizziness with head movements, and intermittent subjective visual disturbance. This occurred on a background of chronic hearing loss for at least 10 years prior to presentation. Imaging revealed a large left cerebellopontine angle tumor extending into the internal auditory canal (Figure 1). At surgery, a soft, friable tumor that was densely adherent to the brainstem, facial and vestibulocochlear nerves was encountered, and a subtotal resection was performed.Histopathologic findings (Figure 2) revealed a hypercellular neoplasm composed of spindle-shaped cells with pleomorphic nuclei and variable cytoplasmic clearing.Myxoid areas and intermixed collagen bundles were seen throughout the tumor and many areas revealed a fasciculated-like appearance. Mitotic activity was focally brisk and the Ki-67 proliferation index was very high. Based on histologic findings the main differential diagnosis included a solitary fibrous tumor, synovial sarcoma (monophasic type), and MPNST. By immunohistochemistry (IHC), tumor cells were immunoreactive for Bcl-2, but negative for pankeratin, CD34 and CD99 ruling out the possibility of a solitary fibrous tumor. Despite the lack of expression of MIC-2 (CD99) and CD34, the diagnosis of synovial sarcoma was considered. Based on the presence of an exclusive translocation for synovial sarcomas: t (X;18)(p11.2-q11.2) that generates a fusion between the SYT gene and one member of the SSX family gene, IHC and fluorescent in-situ hybridization (FISH) assay for an SYT rearrangement were done. Although the tumors cells were positive for SYT protein by IHC, FISH assays did not show evidence for a signal disruption. An increased number of intact signals were noted by FISH, which may explain the SYT protein immunoreactivity by IHC. SYT expression has been reported in at least 20% of cases [9]. Finally the patchy positivity for S-100, the immunoreactivity for collagen IV, and tumor positivity for CD56 (N-CAM) supported the diagnosis of MPNST without evidence of necrosis (WHO Grade III).Postoperatively, the patient developed diplopia, requiring tarsorrhaphy.

Figure 1.

Peripheral malignant nerve sheath tumor at the cerebellopontine angle.Preoperative T1 gadolinium-enhanced MRI demonstrating left CPA tumor compressing the brainstem and extending into the internal acoustic meatus;(A) axial, (B) coronal, and (C) sagittal views.

Figure 2.

Histology of CPA MPNST.Hypercellular neoplasm with pleomorphic spindle-shaped nuclei and variable cytoplasmic clearing in the upper left area. H&E X 100 (A). Weak patchy staining for S100, X 40 (B), elevated Ki-67 proliferation labelling index, X 100 (C) and immunoreactivity for Bcl2, X 200 (D). Negative immunostaining for MIC2 (CD99), X 200 (E) and CD 34 highlighting only blood vessels but negative in tumor cells, X 100 (F). The positive staining for SYT by immunohistochemistry, X 100 (G), was not supported by FISH assay that showed however increase number of intact signals in the majority of the tumor cells (H)

Following sub-total resection, the patient completed fractionated external radiotherapy to the tumor bed over the course of 6 weeks, with a total dose of 56Gy in 28 fractions. Follow-up imaging confirmed residual tumor (Figure 3), and the patient was offered multiple treatment options including, radiosurgery, and chemotherapy. She opted for Gamma Knife radiosurgery, targeting the nodular, enhancing residual tumor. In November, 2011, the 3.4cm x 1.5cm x 2.4cmtumorvolume (total volume 8.05 cm³) was treated with a prescription dose of 15.0 Gy to the 50% isodose line (treatment volume covered 7.56 cm³). The maximum dose was 30.0 Gy (Figure 4). The right lens received a maximum dose of 0.4 Gy, and the left lens received a maximum dose of 0.7 Gy. The maximum dose to the brainstem was 18.7 Gy, with 0.01 cm³ receiving > 17.10 Gy, 0.1 cm³ receiving > 15.3 Gy, 0.5 cm³ receiving > 13.6 Gy, 1.0 cm³ receiving > 12.4 Gy, and 4.46 cm³ receiving > 8.0 Gy. The facial and glossopharyngeal nerves were not well defined on the post-contrast T1 planning studies, and were intimately involved in the tumor, so no specific dose plan was employed for these structures.

Figure 3.

T1 gadolinium-enhancedMRI performed during Gamma Knife dose planning, four months after initial decompression, demonstrates residual tumor at the left CP angle;(A) axial, (B) coronal, and (C) sagittal views.

Figure 4.

Gamma Knife dose plan, with a prescription dose of 15.0 Gy to the 50% isodose line, and a maximum dose of 30.0 Gy.

Follow-up MRI 8 months after GKS demonstrated a marked decreased in size and enhancement of the 2.5cm x 0.8cm x 2.1cm residual tumor (Figure 5). The patient remains neurologically stable with a residual House Brackmann Grade 4 facial nerve palsy and stable diminished hearing on the left.

Figure 5.

T1 gadolinium-enhanced MRI performed 8 months after GKRSdemonstrates decreased size and enhancement of the residual MPNS tumor; (A) axial, (B) coronal, and (C) sagittal views.

3 DISCUSSION

The authors report the case of a 57 year old patient who presented with a facial droop, sensory disturbance and hearing loss referable to a large left-sided CPA MPNST. MPNST is a rare entity, described in the literature mainly in case reports, and occurs most commonly between the fifth and sixth decades of life and in males [2]. It is most commonly seen in association with preexisting intraneural or plexiformneurofibromas, arising in peripheral nerves in the trunk, limbs or major neural plexuses [4]. MPNST uncommonly occurs in the intracranial cavity. In the literature to date there have been 33 reported cases of intracranial MPNST [2, 5], of which 15 occurred at the CPA and primarily affected the vestibulocochlear nerve. Due to the location of the lesion at the CPA, it is initially difficult to distinguish these lesions on imaging from other more common, benign lesions such as a vestibular schwannoma. Current imaging modalities are not able to reliably differentiate these tumors from benign cerebellopontine angle lesions; the diagnosis of intracranial MPNST thus remains a histological one. MPNST may show a variety of histologic findings, including whorls, pallisades, pseudorosettes, spindles, perineural or intraneural spread, and necrosis [10].MPNST is a sarcoma-like tumor and therefore can present histologically with multiple morphologic patterns. There is some uncertainty in the pathological diagnosis of MPNST, particularly in distinguishing these tumors from cellular schwannomas, synovial sarcoma and ossifying fibromyxoidtumor [10]. Immunohistochemistry provides additional evidence in the diagnosis of MPNST. Only 50-70% of MPNST exhibit S-100 protein staining and reactivity is grade related providing further clues in the diagnosis. Both vestibular schwannoma and MPNST may demonstrate nuclear atypia, hypercellularity, as well as locally aggressive growth [11].However, clinically MPNST typically demonstrate a much more aggressive growth pattern, often invading nearby structures such as bone and brainstem. These tumors may also develop drop metastases to the spine [2].

The primary treatment for CPA MPNST is surgical resection, but due to the invasive nature of this tumor and its frequent occurrence in close association with vital neurovascular structures, it is often difficult to achieve gross total resection [2, 5, 12, 13]. Therefore, residual tumor and recurrence is very likely and adjuvant treatment is needed. In spite of this multimodality treatment, these tumors carry a poor prognosis. Overall survival, as reported in the literature, ranges between 6 months and 2 years [3, 14-16]. MPNST-specific survival at 10 years has been reported at 31.6%, and this number further drops to 25.9% for recurrent tumors, and 7.5% for those that develop metastasis [12].

MPNST has been associated with Neurofibromatosis Type 1 and Type 2. Among patients with NF1, the lifetime risk of development of MPNST from a peripheral neurofibroma is 8-13% [17], and approximately 2/3rds of all MPNSTs occur in patients with NF1 [13]. Intracranial MPNST has been associated with NF1 in 13% and NF2 in 6% in one study [2]; there are occasional other reports of these associations but it is uncommon [18-20]. MPNST has also been described as a rare complication of radiation therapy. In one study, six of 80,000 patients who underwent radiotherapy underwent malignant transformation (2 glioblastomas, 4 MPNST) [21]. In a few reports, a presumed benign schwannoma was treated with primary SRS, but demonstrated continued growth, and was found on subsequent resection to be a MPNST [6, 18, 22-27]. It is unclear whether radiotherapy and/or SRS was a causative factor in the malignant transformation of these tumors, or whether there was an independent differentiation event.Despite these associations, the majority of intracranial MPNSTs arise sporadically, rather than in association with phacomatosis or secondary insult [2, 13].

Adjuvant treatment options for MPNST include chemotherapy and radiation therapy [3, 14-16]. External beam radiotherapy (XRT) use has been shown to increase survival and should be considered after surgical resection of the MPNST [2, 28]. In our case, XRT was used post-operatively to the resection cavity, and SRS was subsequently used as a primary treatment for the nodular, enhancing remnant of tumor. There are very few cases of SRS in the treatment of intracranial MPNST (Table 1) [4, 5, 7, 8]. Karami and colleagues [5] recently reported on the case of a 23 year old female who presented with progressive ataxia and sudden hearing loss and hemifacial paralysis, who was found to have a left CPA MPNST. Following multiple surgical procedures for tumor growth and worsening neurological symptoms, the patient received partial brain IMRT with a cumulative dose of 70 Gy in 37 fractions over 6 weeks. She subsequently underwent GKRS as a potential salvage treatment to 3 sites (tentorium, jugular foramen, and adjacent to brainstem). The dose was 16 Gy to the 50% isodose line to the left tentorium tumor (total volume 3.6 cm³), 14 Gy to the 50% isodose line to the left jugular foramen tumor (total volume 1.7 cm³), and 14 Gy to the 50% isodose line to the left brainstem tumor (total volume 6.9 cm³, with <3% of brainstem receiving >8 Gy). Follow-up MRI at 8 weeks after the last SRS treatment demonstrated shrinkage of all three lesions, and there was clinical improvement in ataxia; however, there was subsequent generalized deterioration and MRI four months after GKRS, repeat imaging demonstrated widespread recurrence. Scheithauer et al. [4] reported their series of 17 patients with MPNST of cranial nerves, of which one patient was treated postoperatively with gamma knife SRS. The patient was a 26 year old female with a left geniculate ganglion MPNST, who presented with progressive hearing impairment, facial nerve paralysis and epilepsy. Thirteen years after initial surgery, the lesion recurred and was treated with SRS at a dose of 12 Gy. A second recurrence 2 years later was treated with surgery (subtotal resection) and additional radiotherapy (total dose of 59.4 Gy). There were no neurological complications referable to SRS, although the patient developed hydrocephalus secondary to postoperative hemorrhage after the most recent surgery, requiring shunt placement. There was no information about the margin dose, treatment plan, or long-term follow-up.

Table 1.

Reported Cases of Intracranial MPNST Treated with SRS

	Author [ref.]	Year	Age	Dose Used	Location	F/U	Tumor Response	Neurological Response
1	Scheithauer [4]	2000	26	12Gy after initial recurrence 59.4Gy to residual 2yr later	CPA	N/A	Not reported	Neurologically stable
2	Van Eck [7]	2006	83	20Gy to the 50% isodose line, max dose 40Gy, tumor volume 15.2 cc	Left frontal (met from primary penile MPNST)	14 mo	97% decrease in tumor volume	Stable neurological disease at 12 mo Death from pneumonia at 14 mo
3	Rodriguez [8]	2007	17	Gamma Knife SRS with single dose 20Gy	Cavernous Sinus	9 mo	“Slight shrinkage” of mass on MRI	Neurologically stable
4	Karami [5]	2011	23	Gamma Knife SRS with 3 separate sites: 16Gy to 50% isodose line (total 3.6cc) 14Gy to 50% isodose line (total 1.7cc) 14Gy to 50% isodose line (total 6.9cc)	Left tentorium Left jugular foramen Left brainstem	28 mo	Significant decrease in tumor size at all sites Subsequent localrecurrence	Subsequent neurological decline from local and distant recurrence
5	Current report	2012	57	56Gy XRT to resection cavity 15Gy to the 50% isodose line with max 30Gy to GTV	CPA	8 mo	Significant decrease in tumor size	Neurologically stable

CPA=cerebellopontine angle; SRS=stereotactic radiosurgery; XRT=radiotherapy; GTV=gross tumor volume; cc=cubic centimeter

van Eck and colleagues [7] reported a case of a left frontal metastasis 9 years after resection of a penile MPNST, presenting with behavioral changes, amnesia and confusion. Seven months after complete resection, the tumor recurred with a volume of 15.2 cm³, and gamma knife SRS was performed with a dose of 20 Gy to the 50% isodose line. The patient was clinically stable, and imaging 9 months after SRS demonstrated a 97% reduction of tumor volume to 0.4 cm³. Three new tumors were evident on this scan (3.1 cm³ left occipital, 0.07 cm³ left temporal, 0.25 cm³ right CPA), which were each treated with GKRS at a dose of 20 Gy to the 45% isodose line. Twelve months after the first GKRS, imaging revealed tumor volume reduction and stable disease at all intracranial sites, and the patient had stable neurological status with only intermittent complaints of dizziness. Finally, Rodriguez et al [8] reported a case of a malignant trigeminal nerve sheath tumor located in the left cavernous sinus with left sphenoid sinus opacification, causing painful abducens nerve palsy in a 17 year old female. The patient underwent biopsy of the mass, and subsequent SRS at a margin dose of 20 Gy. The patient’s esodeviation improved, but still required prism correction to prevent diplopia, and there was progressive trigeminal nerve deficit over the course of 9 months’ follow-up. MRI at 9 months demonstrated slight shrinkage of the tumor.

These cases demonstrate the varied clinical course and response to treatment of intracranial MPNST, including response to SRS and radiotherapy. The radiobiologic effect of SRS has a theoretical appeal over XRT for the treatment of these lesions, and the welldemarcated plane on MR imaging between tumor and surrounding tissue permits straightforward radiosurgical planning. These factors may have contributed to the generally positive tumor response reported in the cases in the literature. Our case, along with the others treated with SRS postoperatively in the literature, demonstrates the potential efficacy of SRS as part of multimodality treatment for MPNST patients. Long-term follow up and a broader experience will shed more light on the role of SRS for these aggressive tumors.

4 CONCLUSION

Intracranial MPNST is a rare entity that, when occurring at the CPA, represents a surgical challenge due to the proximity of vital neurovascular structures. In cases of subtotal primary surgical resection, adjuvant treatment should be considered to decrease the chance of recurrence and progressive neurological decline. Stereotactic radiosurgery has the potential to augment surgical resection in subtotally resected or biopsied malignant lesions at the CPA. SRS appears to confer benefit in terms of tumor control and preservation of neurological function.

5 ACKNOWLEDGMENTS

The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

Author contribution to the study and manuscript preparation include the following. Conception and design: all authors. Acquisition of data: Sweiss, Raper. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Sheehan.