Keywords
malignant peripheral nerve sheath tumor - nonvestibular schwannoma - radiation associated
malignancy - stereotactic radiosurgery
Introduction
Schwannomas originate from the Schwann cells surrounding the peripheral nerves, including
cranial nerves III to XII. More than 40% of nonsyndromic benign solitary schwannomas
are located in the head and neck region.[1] The most frequently involved cranial nerve is the eighth nerve, and vestibular schwannomas
account for 8% of intracranial tumors.[2] Nonvestibular schwannomas are rare and constitute < 0.5% of all intracranial tumors.[3] Most of the skull base schwannomas arise from the sensory nerves; purely motor nerve–associated
schwannomas are very rare and often associated with von Recklinghausen disease (neurofibromatosis
[NF]1).[4]
Surgical resection has been considered the standard treatment for the management of
nonvestibular schwannomas.[2]
[5] Similar to the evolution of treatment modalities for vestibular schwannomas, radiosurgery
has become an alternative treatment modality in recent years for the management of
nonvestibular schwannomas.[3]
[6]
[7]
[8] Radiation-associated secondary malignancy or malignant transformation for the treatment
of vestibular schwannomas is a rare but potentially deadly phenomenon.[9]
[10]
Case Report
Clinical Presentation
The patient was a 52-year-old man who underwent right suboccipital craniectomy for
resection of a vestibular schwannoma in 1992 at an outside hospital (20 years prior
to current presentation). He was also found to have a T1-enhancing mass in the left
high cervical/skull base area located in between the external and internal carotid
arteries. It was assumed to be a vagal schwannoma. The patient had a complete loss
of hearing and transient facial weakness on the right after the surgery in 1992.
He had not had regular follow-up for the left lesion since 1992. In 2003, he presented
with choking and difficulty with swallowing. His symptoms were attributed to the lesion
on the left, measured at 1.8 × 1.6 × 1.9 cm on magnetic resonance imaging (MRI). He
was found to have left vocal cord paralysis. He underwent CyberKnife radiosurgery
of the left high cervical/skull base lesion at an outside hospital in November 2003
without a biopsy. The targeted volume was 5.7 cm3 with minimum doses of 13 Gy and maximum doses of 15 Gy targeted to the tumor. A dose
of 13.6 Gy was conformed to the 85% isodose line. The patient was subsequently followed
with serial MRI scans, and there was radiographic evidence of slight tumor shrinkage
up to 2009 (dimension 1.5 × 1.6 × 1.7 cm). His symptoms improved but with residual
hoarseness of his voice. The left lesion was considered as treated with the CyberKnife
because no growth of the lesion was noted for 6 years. He had no further follow-up
until 9 weeks prior to the current presentation (June 2012) when he presented with
increasing hoarseness, coughing, nausea, and headaches. Repeat imaging showed enlargement
of his left neck/skull base lesion with decreased central contrast enhancement (dimension
3.9 × 2.1 × 2.0 cm). Computed tomography (CT) of the chest did not show evidence of
metastasis. He was referred to the senior author (LNS) for a second opinion and management
([Fig. 1]).
Fig. 1 Magnetic resonance imaging scans of the patient, 4 months (2004) after CyberKnife
treatment. (A) T1-weighted postcontrast axial view showing a left cervical/skull base
lesion (thin arrow) located between the external carotid artery (line) and the internal
carotid artery (thick arrow). (B) T1-weighted postcontrast coronal view showing the
tumor (arrow) 5.5 years (2009) after CyberKnife treatment. (C) T1-weighted postcontrast
axial view showing the lesion (arrow) with a slight decrease in size. (D) T1-weighted
postcontrast coronal view showing the lesion 8.5 years (2012) after CyberKnife treatment.
(E) T1-weighted postcontrast axial view showing the lesion (arrow) with increased
size and hypointensity in the center, consistent with necrosis. (F) T1-weighted postcontrast
coronal view showing the lesion (arrow). (G) Fine-cut T1-weighted postcontrast axial
view showing the lesion with a tail extending through the hypoglossal canal (thin
arrow) and abutting the jugular foramen (thick arrow). (H) Fine-cut T2-weighted axial
view again showing the lesion with a tail extending through the hypoglossal canal
(arrow).
Physical examination at the time of current presentation showed a right hearing loss;
other cranial nerve functions were intact with no focal neurologic findings. He had
one brown spot on the skin of his back. He also had several subcutaneous fibromas.
Reportedly, several of his relatives also have subcutaneous fibromas. However, there
is no definitive family history of NF. The patient had not had any testing to prove
a diagnosis of NF.
Surgical Treatment
The patient underwent left upper cervical and preauricular transfacial exposure in
conjunction with an otolaryngology surgeon. The tumor was completely resected using
microsurgical techniques and under the guidance of neuronavigation. Intraoperatively,
the tumor was found to originate from the hypoglossal nerve inferiorly and extending
superiorly to the jugular foramen. The tumor was encapsulated, with whitish color
and very firm consistency. The splayed nerve fascicles of the hypoglossal nerve showed
only a very weak response to intraoperative direct stimulation of 1 ampere. After
the tumor was removed in a gross-total fashion, no signal was detected on direct stimulation
of the hypoglossal nerve. Good stimulation of the spinal accessory nerve was present.
Postoperative imaging was consistent with gross-total resection ([Fig. 2]).
Fig. 2 Intraoperative microscopic views of the tumor resection. (A) The inferior border
of the tumor (arrow) is in continuity with the hypoglossal nerve (asterisk). (B) The
inferior border of the tumor (arrow) is being dissected away from the hypoglossal
nerve (asterisk). (C) The whitish firm tumor is being lifted from the hypoglossal
nerve (asterisk). (D) The superior border of the tumor (arrow) is being dissected
away from the area of the jugular foramen. (E) The tumor is being removed in total
from the resection cavity. (F) The intraoperative view after the removal of the tumor
showing the hypoglossal nerve (asterisk) and the resection cavity from which the tumor
was removed (arrow). (G) Postoperative magnetic resonance imaging scan T1-weighted
postcontrast axial view showing the cavity from which the previously enhancing lesion
was removed (arrow). (H) Coronal view again showing the removal of the lesion (arrow).
Pathologic Examination
Hematoxylin and eosin–stained sections of the tumor specimen showed pleomorphic spindle
cell neoplastic proliferation with atypical nuclei arranged in intersecting fascicles
and separated by varying amounts of collagenous stroma ([Fig. 3A, B]). Dense connective tissue was attached to the tumor containing invested myelinated
nerves and scattered inflammatory cells. Occasional bizarre multinucleated neoplastic
cells, multiple mitoses (5/10 high-power fields), and extensive central necrosis were
present ([Fig. 3A, B, D]). Immunohistochemical study of the neoplasm showed diffuse immunopositivity for
S-100 protein ([Fig. 3C]) and p53 upregulation in < 25% of the neoplastic cells. There was no cytokeratin
7, HMB45, Melan-A, or microphthalmia transcription factor (markers for melanocyte
differentiation) expression. The final diagnosis was malignant peripheral nerve sheath
tumor (MPNST). The case was also sent to an expert pathologist in another institution
for review, and he concurred with our pathologic diagnosis.
Fig. 3 Histopathologic analysis of the tumor. (A, B) Microphotograph of the hematoxylin
and eosin (H&E)-stained resected tumor tissue exhibits neoplastic spindle cells with
marked pleomorphism and fasciculated architecture of alternating cellularity. Necrosis
is also present (asterisk in A); (C) Immunohistochemical stain for S-100 shows strong
positive staining in the neoplastic cells. (D) H&E-stained tissue shows increased
mitotic activity (arrows). Magnifications: (A) ×200; (B–D) ×400.
Hospital Course
Immediately after surgery, the patient displayed transient mild tongue deviation,
but his tongue returned to midline position on protrusion 24 hours after surgery.
His left vocal cord remained paralyzed but with a paramedian position. He was able
to tolerate a dysphagic diet without evidence of aspiration.
He was referred to a soft tissue oncologist as well as a radiation oncologist for
further management. He was also referred to a medical geneticist for screening for
NF gene mutations.
Adjuvant Therapy
About 3 months after his surgery, the patient received 25 fractions of daily conventional
radiation to his neck around the surgical site for a total of 50 Gy. He also underwent
one session of boost gamma knife radiosurgery of 10 Gy to the 50% isodose line.
Follow-up
The patient remained at his neurologic baseline 9 months after his resection. A repeat
MRI showed no evidence of tumor recurrence.
Based on his clinical history, family history, and his physical examination, our medical
geneticist deemed the patient not meeting the diagnostic criteria for either NF1 or
2), or for schwannomatosis. He was considered potentially to be a mosaic for NF2 mutation,
and sequencing his tumor tissue could be potentially informative. The patient declined
the sequencing offer.
Discussion
Nonvestibular schwannomas are rare, and schwannomas originating from pure motor cranial
nerve such as the hypoglossal nerve are even more scarce.[3]
[4]
[11] Traditionally, surgical resection using microsurgical techniques and modern skull
base approaches has been the standard treatment modality. Only a few current case
series with more than three cases of hypoglossal schwannomas exist in the literature,[12]
[13]
[14] and the authors report 50 to 100% gross-total resection rate, no disability to 33.3%
of new cranial nerve deficits, and 8.3% tumor recurrence (1 of 12) to 100% tumor control
with the longest reported follow-up period of 14 years. There is no case of a MPNST
tumor of the hypoglossal nerve reported in the surgical series just cited.
Radiosurgery has been increasingly used in the treatment of nonvestibular schwannomas,
either as an adjuvant therapy, a salvage therapy at time of recurrence after surgical
treatment, or as the primary treatment after a diagnosis based on radiographic features.[3]
[6]
[7]
[8]
[15]
[16]
[17]
[18] Cumulative experiences have shown that radiosurgery can be an effective and safe
alternative to treat nonvestibular schwannomas, especially for relatively small tumors
without a significant mass effect on the brainstem. The longest reported follow-up
period is 210 months (no stratified data on hypoglossal schwannomas alone)[8] among the series on radiosurgery, and no case of secondary malignancy or malignant
transformation has been reported, although a theoretical risk of 0.005 to 0.1% was
mentioned.[15]
MPNST of the head and neck is reported in 8% of all the cases of a published cohort
of MPNST.[19] It is estimated that half of MPNSTs are associated with NF1.[20] Singh and Shaha[21] reported a case of cervical malignant nerve sheath tumor of the hypoglossal nerve
in a patient without known NF and identified three other cases in the literature.
Their review of the literature involving malignant nerve sheath tumors of the cranial
nerves showed that the association to NF1 is less compared with those MPNST tumors
located elsewhere. The significance of this finding is unclear. Scheithauer et al[22] reported the largest series of cranial nerve MPNSTs (no case of hypoglossal-derived
tumor). Of the cases not associated with NF1 or 2, one patient had radiation for Hodgkin
disease, one for pilocytic astrocytoma, and both patients were exposed to the radiation > 20
years prior. Two patients had spontaneous malignant transformation (vestibular schwannoma)
over a rather short period (< 1 year) without known prior radiation exposure. One
patient had a low-grade MPNST and had radiation 13 years and 15 years after the initial
presentation.
Our patient does not meet the diagnostic criteria for NF1 or 2. The patient received
radiosurgery to his left neck lesion without a prior surgical biopsy for pathologic
diagnosis. Although we do not know whether there was any malignant feature in his
original tumor, the fact that the lesion did not grow significantly 11 years after
the original discovery prior to the radiosurgical treatment, and until 8.5 years after
the CyberKnife treatment argues against a very aggressive lesion prior to the radiation
treatment.
Radiation-associated secondary malignancies or malignant transformations after the
treatment of vestibular schwannomas are very rare but well documented in the literature.[9]
[10]
[23] We cannot compare the current tumor pathology with the original lesion prior to
radiation due to no biopsy. Other characteristics of this case including history of
radiation, tumor progression within the radiation field, and a latency of 8.5 years
from the time of radiation highly suggest a potential malignant transformation associated
with the radiation treatment for a nonvestibular schwannoma. Although we cannot completely
rule out the possibility of a spontaneous malignant degeneration, the likelihood is
very low, especially in a non-NF background. We expect that as the number of cases
of nonvestibular schwannomas treated with radiation continues to grow, we may see
more reports of secondary malignancy or malignant transformation cases, even though
they are very rare occurrences overall.
Conclusions
MPNST may occur after radiation treatment of hypoglossal schwannoma.
