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Cite this article: Cox CS, Stallworth DG, Ahmed KA, Wadsworth JT, Wenig B, et al. (2017) Perineural Tumor Spread Involving the Trigeminal and Facial Nerves: A Review of Critical Imaging Findings. Ann Otolaryngol Rhinol 4(5): 1177.

*Corresponding author

John A Arrington, Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, Tampa, FL, USA, Email:

Submitted: 29 May 2017

Accepted: 13 July 2017

Published: 15 July 2017

ISSN: 2379-948X

Copyright© 2017 Arrington et al.

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Keywords• Perineural tumor• Larynx• Pharynx• Head and neck cancers

Research Article

Perineural Tumor Spread Involving the Trigeminal and Facial Nerves: A Review of Critical Imaging FindingsChad S Cox, Dexter G Stallworth, Kamran A Ahmed, J Trad Wadsworth, Bruce Wenig, Christine H Chung, and John A Arrington*Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, USA

Abstract

Perineural spread (PNS) represents tumor dissemination along a nerve and is seen in 2-5% of head and neck cancers with trigeminal nerve (CN V) and the facial nerve (CN VII) involvement being most common. PNS has significant prognostic and therapeutic implications and is a well-known mechanism of head and neck cancer dissemination that has been adequately described in the literature but is too often overlooked and undetected on routine imaging studies. Vigilance and a heightened awareness of PNS by clinicians and radiologists is critical to avoid unnecessary delays in the diagnosis of perineural spread in head and neck cancer patients. Assessment and detection of perineural spread should be considered a routine part of the imaging evaluation of the head and neck. Evaluating for evidence of PNS must be considered as important as delineating the primary tumor or detecting metastatic cervical lymph nodes on imaging studies of head and neck cancer patients. Familiarity with common symptoms resulting from perineural spread involving the motor and sensory divisions of the trigeminal and facial nerve as well as a basic understanding of the imaging anatomy of the nerves is necessary to prevent a delay in diagnosis of PNS.

INTRODUCTION

Perineural spread (PNS) represents tumor dissemination along a nerve and is seen in 2-5% of head and neck cancers [1] with trigeminal nerve (CN V) and the facial nerve (CN VII) involvement being most common [2,3]. Head and neck malignancies represent a diverse group of neoplasms arising from the oral cavity, larynx, pharynx, salivary glands, and nasal passages. Head and neck can-cers are responsible for approximately 4% of all malignancies in the United States [4]. Dissemination of head and neck cancers most commonly occurs through local extension and lymphatic spread to regional cervical lymph nodes with hematogenous and perineural spread being less common. Squamous cell carcinoma (SCC) repre-sents approximately 90% of head and neck cancers and is the most prevalent head and neck tumor to have PNS with a reported inci-dence of 2-30% [5-7]. Given the prevalence of skin cancer, PNS is most commonly seen with cutaneous SCC. Adenoid cystic carcinoma (ACC) constitutes 10% of salivary gland tumors but only makes up approximately 2% of head and neck cancers. ACC has the highest relative incidence of perineural dissemination with a reported inci-dence of approximately 60% [8-11]. Mucosal SCC including palatial and nasopharyngeal carcinoma (NPC), lymphoma, melanoma, basal cell carcinoma, and other salivary gland tumors such as mucoepi-dermoid carcinoma are also known to demonstrate PNS [5,12,13].

Even though PNS is a well-known and documented method of spread of head and neck cancers, it remains often overlooked and underdiagnosed on routine preoperative and surveillance imaging. Perineural spread significantly impacts prognosis and management of head and neck carcinomas. Appropriate and op-timal treatment of head and neck cancers requires scrutiny of preoperative imaging studies for evidence of PNS prior to initi-ating therapy. Perineural spread almost always alters treatment and management of head and neck carcinomas. Overlooking and failing to detect PNS on preoperative imaging studies can result in unnecessary or inadequate surgery and ineffective therapy. Radiologists and clinicians involved in the care and management of head and neck cancer patients must be vigilant for imaging or clinical evidence of PNS. Radiologists need to be familiar with the regional anatomy and distribution of the branches of the trigemi-nal and facial nerve and the imaging findings of PNS. Clinicians must be aware of the common presenting symptoms of PNS and be able to differentiate these symptoms from other benign causes such as Trigeminal neuralgia and Bell’s palsy.

Perineural spread (PNS) and Perineural invasion (PNI)

Perineural spread must be differentiated from perineural in-vasion (PNI). These are not interchangeable or equivalent terms. Perineural invasion cannot be visualized with imaging and rep-resents microscopic tumor in or around nerves at the primary tumor location. PNI does not imply tumor spread or dissemina-

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tion of tumor from the primary site of origin. Histologically, PNI can be diagnosed when the primary carcinoma has direct contact with the perineurium of a nerve, surrounds a nerve, and/or dem-onstrates neural invasion [14]. Perineural spread and perineural tumor spread (PNTS) are equivalent terms describing true spread or dissemination of tumor along a nerve. PNS represents mac-roscopic disease and can be visualized with imaging and is best visualized and evaluated with magnetic resonance imaging (MRI) rather than computed tomography (CT) [2,3].

Clinical Significance

Both PNI and PNS adversely affect prognosis resulting in de-creased survival. The 8th edition of American Joint Committee on Cancer now recognizes that perineural tumor invasion is part of the T category for SCC elevating the lesion to T3 classification. Pa-tients with Perineural spread have a higher incidence of regional lymph node metastases, local recurrence, and distant metastases [15-19]. Patients with both clinical symptoms and imaging evi-dence of perineural spread have the highest rates of local recur-rence and lower rates of disease specific survival [15]. If PNS is confirmed or is suggested on preoperative imaging, the extent of surgical resection necessary to obtain clear surgical margins will be altered, and adjuvant therapy, neck dissection, and/or a larger radiation field will need to be considered [5,8,18-20].

Pathogenesis

The mechanism of perineural tumor spread is still not com-pletely understood. Perineural spread was once thought to rep-resent spread via direct invasion along low resistant planes or through lymphatics of the epineurium. It is now known that perineural spread is not related to direct invasion, hematogenous dissemination or lymphatic dissemination [14,15]. Currently, it is believed that perineural dissemination is a complex reciprocal interaction between the tumor and the nerves themselves [14]. There are many potentially important molecular factors involved in this interaction including neurotrophic factors like nerve growth factor, brain derived nerve growth factor, neurotrophins, growth factors and axonal guidance molecules [15,21,22]. The neoplasm must be able to respond appropriately to these sig-nals from the neural microenvironment to disseminate along the nerves [15]. This microenvironment is currently thought to be one of the key determining factors in PNS with in vitro models suggesting that reciprocal signals between tumor and nerve are necessary to stimulate and promote PNS [8,23-27].

Critical Anatomy and Clinical findings

The anatomy as well as the sensory and motor functions of the trigeminal and facial nerve is intricate and complex. Detection and diagnosis of PNS requires vigilance and a heightened awareness of PNS by radiologists and clinicians in combination with a basic understanding of the anatomy and physiology of the trigeminal and facial nerve. While up to 40% of patients with PNS are asymp-tomatic, common sensory symptoms of PNS include formication, pain, paresthesia, and numbness in the distribution of the trigemi-nal nerve. Motor symptoms include trouble swallowing and weak-ness in the muscles of mastication when the mandibular division of the trigeminal nerve is involved and weakness in the muscles of facial expression when the facial nerve is involved [28-30]. Clini-

cal symptoms from trigeminal and facial nerve PNS are nonspe-cific and can overlap common clinical findings of entities such as trigeminal neuralgia, Bell’s palsy, and stroke. It is critical for the treating clinician to include PNS in the differential diagnosis of pain, paresthesia, and numbness in patients with a current or past history of head and neck cancer to avoid unnecessary delay in the diagnosis and treatment of perineural tumor spread.

Trigeminal Nerve

PNS most commonly involves the trigeminal nerve secondary to its large cutaneous distribution [28,31]. CN V is a mixed mo-tor and sensory nerve which relays sensory information from the face and head and provides motor input to the muscles of mastica-tion (masseter, medial and lateral pterygoid, and temporalis). The trigeminal nerve arises from the mid pons and enters Meckel’s cave, a CSF-containing pouch in the middle cranial fossa at the posterolateral aspect of the cavernous sinus (CS). In the anterior portion of Meckel’s cave the nerve forms the trigeminal (Gasse-rian) ganglion [32]. Arising from the trigeminal ganglion are the three divisions of the trigeminal nerve: the ophthalmic (V1), the maxillary (V2), and the mandibular nerve (V3).

The ophthalmic nerve is a pure sensory nerve which courses through the lateral wall of the cavernous sinus and passes through the superior orbital fissure (SOF) to reach the orbit and provide sensory innervation to the eye, orbit and forehead [33]. In Figure 1, a cutaneous carcinoma of the forehead spreads along the right supraorbital nerve (branch of V1) thru the SOF to the cavernous sinus. Axial noncontrast T1-weighted (T1W) imaging demon-strates abnormal intermediate signal in the normal high signal intensity fat along the right supraorbital nerve in the superior and medial quadrant of the right orbit. The perineural tumor enhances with contrast on T1W fat suppressed images.

The maxillary nerve (V2) is also a pure sensory nerve and courses more inferiorly to V1 in the lateral wall of the cavernous sinus. It exits the middle cranial fossa via the foramen rotundum (FR) and enters the pterygopalatine fossa (PPF). In the PPF, the maxillary nerve gives rise to the infraorbital nerve (ION) which enters the orbit through the inferior orbital fissure (IOF). It cours-es along the inferior aspect of the orbit to exit through the in-fraorbital foramen and provide sensation to the middle 1/3 of the face including the upper lip, medial cheek, and nose [33]. Figure 2 and 3 demonstrate perineural tumor involving V2. In Figure 2, perineural tumor involves a markedly enlarged ION on the right. Figure 3 demonstrates perineural tumor involving right V2 from the pterygoid palatine fossa to foramen rotundum and the cavern-ous sinus without enlargement of the nerve. This case also dem-onstrates involvement of the vidian nerve (branch of VII) which will be discussed later.

The mandibular nerve (V3) is the largest trigeminal division and is a mixed nerve providing motor input to the muscles of mas-tication as well as sensation to the lower 1/3 of the face including the chin, lower lip, floor of mouth, and the side of the head [33]. It is the only branch of the trigeminal nerve that does not course through the cavernous sinus. After branching from the trigeminal ganglion, the mandibular nerve immediately courses inferiorly through the foramen ovale (FO) into the infratemporal fossa (ITF). Within the masticator space (MS), the mandibular nerve gives off

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Figure 1 A-H. Coronal T1W MRI without (A,C) and with (B,D,F) contrast demonstrate and axial T1W MRI without (G) and with (E,H) contrast demonstrate PNS extending from cutaneous SCC along right supraorbital nerve (blue block arrows) in the superior orbit thru the superior orbital fissure to cavernous sinus (white block arrows). Note that the tumor is seen best on noncontrast T1W images (A,C,G) because the normal high signal intensity (white) fat has abnormal intermediate signal intensity (dirty fat).

anterior motor branches which innervate the muscles of mastica-tion. The posterior trunk divides into the auriculotemporal nerve (ATN) and the inferior alveolar nerve (IAN). The auriculotempo-ral nerve provides sensory innervation for the lateral face. The inferior alveolar nerve enters the mandibular foramen (MF) and provides sensory information to the lower teeth and gingiva while traversing the mandibular canal and exiting the mental foramen to supply sensory information to the chin. The auriculotemporal nerve and inferior alveolar nerve are critical terminal branches of V3. Figures 4 and 5 demonstrate PNS involving V3. In Figure 4, a NPC spreads along V3 and demonstrates abnormal enhancement and enlargement of V3 on the left. Axial CT image demonstrates enlargement of the left FO. In Figure 5, enhancing perineural tu-mor involves V3 at the foramen ovale, gasseian ganglion, and in the lateral pontine cistern.

Perinueral tumor can disseminate in either a retrograde or antegrade direction and can be bidirectional. Perineural tumor

Figure 2 A-D: T1W MRI without contrast in the sagittal (A) and coronal (B-D) plane demonstrate PNS extending from the soft tissues anterior to maxilla (black block arrow) along infraorbital nerve (white block arrow within the infraorbital canal.

most commonly spreads in a retrograde fashion from the primary tumor toward the central nervous system (CNS). PNS can also dis-seminate in an antegrade direction away from the CNS [15,34-36]. Figures 6 and 7 illustrate bidirectional perineural tumor spread. In figure 6, a parotid gland neoplasm extends along the auriculo-temporal nerve (branch of V3) in a retrograde direction to the masticator space extending to the level of the posterior trunk divi-sion of the mandibular nerve into the auriculotemporal and infe-rior alveolar nerve. The perineural spread continues in a retro-grade direction along the mandibular nerve to the skull base and foramen ovale but also spreads in an antegrade direction to the mandible along the inferior alveolar nerve. Figure 7 demonstrates both retrograde and antegrade PNS by a lip carcinoma. The prima-ry lip carcinoma extends in a retrograde fashion along branches of V2 thru the infraorbital canal to PPF and continues thru foramen rotundum to involve the cavernous sinus, gasserian ganglion, and cisternal segment of the left trigeminal nerve. Perineural tumor then spreads along V3 in an antegrade direction thru foramen ovale along the left mandibular nerve.

Facial Nerve

The facial nerve controls the muscles of facial expression, and functions in conveying taste from the anterior two-thirds of the tongue and oral cavity. CN VII arises from the mid pons and courses through the cerebellopontine angle cistern to enter the in-ternal auditory canal. It continues through the petrous portion of the temporal bone until it exits the stylomastoid foramen where it eventually pierces the parotid gland fascia and divides into its five terminal branches [37]. In figure 8, PNS involves the left facial nerve from the stylomastoid foramen to the IAC.

Communications between the Trigeminal Nerve and the Facial Nerve

There are extracranial communications between the facial and trigeminal nerve which can serve as pathways for PNS to in-volve both nerves. These patients can have both trigeminal and facial nerve symptoms from PNS. There are three major connec-

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Figure 3 A-L: T1W axial MRI with (A,C,I,J) and without (B,D) contrast, T1W coronal CE FS (E-H), and T1W sagittal CE FS images demonstrate PNS involving the right PPF (blue block arrow). Note the normal fat filled PPF on the left with abnormal enhancing soft tissue within the right PPF. Tumor extends along V2 thru foramen rotundum (small white arrows) to cavernous sinus (white block arrow) as well along vidian nerve (white block arrow) to involve the facial nerve (black block arrow) in the temporal bone and IAC.

Figure 4 A-D: Axial T1W MRI without (A) and with (B) contrast, axial T2W FS, MRI (C) and axial CT (D) images demonstrate PNS from NPC involving V3 (blue block arrow). The left mandibular nerve is enlarged and shows abnormal increased T2 signal and enhancement. The osseous foramen ovale is widened on CT.

Figure 5 A-D: Axial (A,B) and coronal (C,D) T1W CE FS MRI images demonstrate PNS extending along V3 thru foramen ovale (blue arrow) to involve the cavernous sinus (white block arrow), the Gasserian ganglion (white small arrow) and cisternal segment of the right trigeminal nerve (black block arrows).

tions between the facial and trigeminal nerves:

1. Maxillary nerve and the vidian nerve (branch of VII) in the pterygopalatine fossa.

2. Auriculotemporal nerve (branch of V3) and the facial nerve in the parotid gland.

3. Infraorbital nerve (branch of V2) and the buccal branches of the facial nerve forming the infraorbital plexus [29,38].

The pterygopalatine ganglion is the most recognized neural communication between the trigeminal and facial nerve [3]. The maxillary branch of the trigeminal nerve courses through the pterygopalatine fossa synapsing with the pterygopalatine gan-glion before continuing thru foramen rotundum to the cavernous sinus. The facial nerve gives rise to the greater superficial petrosal nerve (GSPN) in the petrous temporal bone, which courses an-

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Figure 6 A-H: Axial MRI images without (A,D) and with (B,E) contrast and axial contrast enhance CT (C,F), and coronal MRI without (G) and with (H) contrast demonstrate PNS extending along the auriculotemporal nerve (V3) posterior to the mandible (black block arrow) to the ITF (open white arrow) and masticator space (blue arrow) with retrograde spread toward the Gasserian ganglion and CNS along mandibular nerve to the skull base and foramen ovale (white block arrow). PNS also extends along the inferior alveolar nerve to the mandible in an antegrade direction with enlargement of mandibular foramen (small black arrow).

Figure 7 A-I: Primary lip carcinoma extends in a retrograde direction along infraorbital nerve (V2) thru infraorbital canal to PPF and continuing thru foramen rotundum to the cavernous sinus and the gasserian ganglion. Perineujral tumor spreads then extends along V3 in an antegrade direction thru foramen ovale along the mandibular nerve. T1W coronal image (A) and axial without (B) and with (C) contrast demonstrate the tumor (small black arrow) in the subcutaneous fat anterior to the maxilla. T1W CE FS coronal images (D-G) demonstrate PNS involving left ION (small white arrow), PPF (blue arrow), foramen rotundum (black block arrow), and cavernous sinus (open arrow). Tumor also involves left V3 in foramen ovale (white block arrow). Axial T1W CE FS images (H,I) also demonstrate the left cavernous sinus and V3 involvement at foramen ovale. Figure H also demonstrates involvement of cisternal segment of left trigeminal nerve (Bent black arrow).

teromedially to exit the superior surface of the temporal bone. It continues as the vidian nerve in the pterygopalatine canal to enter the pterygopalatine fossa where it synapses with the pterygopala-tine ganglion. In figure 3, perineural tumor spreads along the right maxillary nerve to the PPF and continues along V2 to the cavern-ous sinus but also extends along the right vidian and GSPN to in-volve the facial nerve in the temporal bone and IAC. PNS involv-ing the vidian nerve is underappreciated and underdiagnosed. In 2000, a retrospective analysis of the CTs and MRIs of 98 untreated patients with head and neck cancer, revealed 10 patients with PNS of the vidian nerve [2].

The auriculotemporal nerve arises from V3 has several con-nections with the facial nerve in the parotid gland providing an-other neural connection that allows PNS to involve both the fa-cial and trigeminal nerves (figure 6). Clinically, in the setting of perineural spread along the auriculotemporal nerve, the patient can present with periauricular pain, temporomandibular joint (TMJ) dysfunction or TMJ tenderness [29].

Imaging

In patients with head and neck cancer, imaging is crucial to the diagnosis of perineural dissemination, evaluating the extent of the disease, guiding treatment, and post treatment surveil-lance. MRI with contrast is the gold standard for detecting and

evaluating perineural tumor spread with a reported sensitivity of 95% [39,40]. CT can also demonstrate findings of PNTS and is best utilized to evaluate for widening of osseous skull base fo-ramen. While FDG PET/CT has limited special resolution for the evaluation of perineural dissemination, PNS can be diagnosed on FDG PET/CT [5]

The key imaging findings of PNS are as follows:

Abnormal enhancement (figure 3,8) and/or enlargement (fig-ure 2,4,5) of a nerve or abnormal linear or curvilinear enhance-ment (figure 6) along the course of cranial nerve V or VII. Contrast enhanced (CE) and fat suppressed (FS) T1W MR images (T1W CE FS) are best to evaluate for abnormal enhancement and enlarge-ment of a nerve (figure 3-6) and is the key sequence to diagnosing perineural tumor spread on imaging [2,41].

Loss of normal fat planes that surround cranial nerves (Fig-ures 1,6,7). Cranial nerves within and below the skull base fo-ramen normally have fat surrounding the nerve. The loss of the normal fat around cranial nerves within and/or below the skull base foramen is an important secondary sign of PNS [42,43]. This finding can be seen on both CT and MRI and when interpreting scans on head and neck cancer patients, a routine imaging search must include visualizing normal fat surrounding the branches of the trigeminal nerve at the skull base foramen and fissures. For the trigeminal nerve this includes the foramen ovale and rotun-dum, as well as the superior and inferior orbital fissure, and the pterygoid palatine fossa (Figure 3). Precontrast T1-weighted

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(T1W) MR images without fat suppression is the best sequence for evaluating the fat planes surrounding the nerves. On T1W im-aging, fat has homogeneous high signal intensity. When perineural tumor spreads along the nerve, there is loss of this normal high signal intensity and the fat appears “dirty” with areas of abnormal decreased signal indicating tumor infiltration2 (figure 1,3).

Expansion of a fossa or canal that contains a nerve (Figures 2,4). CT is the best imaging modality for evaluating osseous struc-tures [44,45] (figure 2). The foramen rotundum and foramen ovale should be closely inspected for enlargement which would indicate PNS [2,41].

Findings related to the denervation of the muscles of mastica-tion or facial expression. When PNS involves a lower motor nerve there are imaging patterns that develop depending on the chro-

nicity of denervation which are best visualized on MRI [44,46]. Acute muscle denervation is seen as intramuscular edema with associated muscle enlargement and is best seen on T2-weighted imaging (Figure 9). In the subacute stage, the muscles will dem-onstrate milder intramuscular edema on T2-weighted imaging with no muscle enlargement. Chronic denervation results muscle atrophy and fatty infiltration of the involved musculature [45-47] (Figure 10). Chronic denervation can also be seen on CT as asym-metrical muscle atrophy.

CONCLUSIONPNS has significant prognostic and therapeutic implications

and is a well-known mechanism of head and neck cancer dissemi-nation that has been adequately described in the literature but is too often overlooked and undetected on routine imaging studies. Vigilance and a heightened awareness of PNS by clinicians and ra-diologists are critical to avoid unnecessary delays in the diagnosis of perineural spread in head and neck cancer patients.Common symptoms such as facial pain, paresthesia, and motor deficits must not mistakenly be attributed to other etiologies such as trigeminal neuralgia, Bell’s palsy, or stroke. Imaging studies must be appro-priately protocoled and scrutinized for evidence of PNS so that subtle imaging findings of perineural spread are not overlooked. While perineural spread can be suspected clinically, PNS is an im-aging diagnosis. Assessment and detection of perineural spread should be considered a routine part of the imaging evaluation of the head and neck, and the responsibility of detecting perineural spread belongs to the radiologist protocoling and interpreting the imaging study. Evaluating for evidence of PNS must be considered as important as delineating the primary tumor or detecting meta-static cervical lymph nodes on imaging studies of head and neck cancer patients. Knowledge of the position, expected course, and key anatomic landmarks of the major divisions and branches of the trigeminal and facial nerve are essential in detecting and diag-nosing perineural tumor spread. Radiologists must be diligent in their search for perineural spread when reviewing imaging stud-ies of head and neck cancer patients.

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Figure 8 A-F: PNS involving left facial nerve (yellow arrow) which demonstrates abnormal enhancement but not enlargement from IAC to Stylomastoid foramen. Noncontrast axial T1W axial and coronal images (A-C) demonstrate no enlargement of the facial nerve. Contrast enhanced T1W axial and coronal images (D-F) demonstrate abnormal enhancement of the facial nerve in the IAC and cisternal segment (D) and in the mastoid segment seen in the axial (E) and coronal (F) plane.

Figure 9 A-F: coronal T1W MRI with (A,D) and without (B,E) contrast and T2W FS (C,F) MRI demonstrate PNTS involving right V3 (yellow arrows) results in denervation and neurogenic edema involving medial ( blue arrows) and lateral pterygoid muscles (small black arrows).

Figure 10 A-B: PNTS involving left V3 resulting in chronic denervation and atrophy and fatty infiltration of the left masseter as well as the left medial and lateral pterygoid muscles. Axial T1W images at the level of the lateral Pterygoid muscles (A) and medial pterygoid and masseter muscles (B) demonstrate normal size and signal in the right muscles of mastication while the left are atrophic with fatty infiltration. Blue arrows point to the medial pterygoid muscles in A and the medial pterygoid muscles in B. Small black arrows point to masseter muscle in both A and B.

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Cox CS, Stallworth DG, Ahmed KA, Wadsworth JT, Wenig B, et al. (2017) Perineural Tumor Spread Involving the Trigeminal and Facial Nerves: A Review of Critical Imaging Findings. Ann Otolaryngol Rhinol 4(5): 1177.

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