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Show STATE OF THE ART Imaging Nuances of Perineural Spread of Head and Neck Malignancies Mohannad Ibrahim, MD, Hemant Parmar, MD, Dheeraj Gandhi, MD, and Suresh K. Mukherji, MD Abstract: Perineural spread is a common growth pattern of head and neck malignancies. Recognizing this pattern by imaging is important for two reasons: 1) it may be the only evidence of malignancy; and 2) its presence in conjunction with a mass converts management from surgical resection to radiation or chemotherapy. High field strength magnets and thin sections with high resolution and fat suppression now allow earlier diagnosis of this entity, but even with these imaging developments, familiarity with the relevant anatomy and the subtle alterations on MRI are necessary to identify this condition. (/ Neuro- Ophthalmol 2007; 27: 129- 137) First reported in 1862 by Neumann et al ( 1) in a patient with primary carcinoma of the lower lip that extended along the mental nerve, perineural spread ( PNS) of tumor is a pathologic process by which neoplasms spread along the neural sheath along perineural or endoneural tissues or perineural lymphatics to reach often distant locations. PNS differs from " perineural invasion," which refers to microscopic perineural or endoneural tumor confined to the main tumor mass. Perineural invasion is impossible to detect by imaging whereas PNS can be seen by the trained interpreter using modern neuroimaging techniques. PNS may occur with any head and neck malignancy, including salivary gland tumors and mucosal and skin carcinomas. Although adenoid cystic carcinomas of the minor or major salivary glands are notorious for producing PNS, squamous cell carcinomas of mucosal or cutaneous origin are also frequently associated with PNS ( 2- 4). The second and third divisions of the trigeminal nerve and the descending ( mastoid) segment of the facial nerve are the most commonly involved pathways of PNS Department of Radiology, Division of Neuroradiology, University of Michigan Health System, Ann Arbor, Michigan. Address correspondence to Hemant Parmar, MD, Department of Radiology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI; E- mail: parurad@ hotmail. com or hhparmar@ umich. edu because of their extensive subcutaneous distributions in the head and neck. The first trigeminal division ( ophthalmic nerve) is the pathway of PNS for periorbital and orbital tumors. PNS most commonly occurs in an retrograde direction from the skin surface toward the intracranial cavity, but it can also occur in an antegrade direction. Patients with PNS may have symptoms related either to the original tumor site, to the effect of PNS on the spreading pathway, or to the effect on remote destinations of the PNS. In the presence of a tumor mass, it is important for the interpreting radiologist to detect PNS before the initiation of therapy because its presence can turn a resectable tumor into an unresectable tumor. The presence of PNS can result in alteration of the surgical ports, conversion from resection to biopsy, and conversion from surgery to radiation and/ or chemotherapy ( 5). Common causes for missing the diagnosis of PNS include lack of familiarity with the head and neck cancers that cause PNS, lack of knowledge of the anatomy of their common routes of spread ( Fig. 1, Tables 1, 2), suboptimal imaging, and lack of familiarity with the imaging nuances of PNS. PERTINENT ANATOMY Trigeminal Nerve The trigeminal nerve, the largest of the cranial nerves ( 6), has three divisions: ophthalmic, maxillary and mandibular ( Fig. 1). The ophthalmic division ( Fig. 2), the smallest division, is formed by the convergence of the nasociliary, lacrimal, and frontal nerves. It provides sensory innervation of the conjunctiva, eye and orbit, bridge of the nose, forehead and ethmoid and frontal sinuses ( 7,8). The maxillary division of the trigeminal nerve carries sensory innervation from the maxilla, palate, upper lip, cheek, nasal cavity, nose, and nasopharynx ( 7,8). The infraorbital nerve is joined by the zygomatic and superior alveolar nerves in the pterygopalatine fossa ( PPF) to form the maxillary nerve ( Fig. 1). Palatine nerves from the hard and soft palate ascend through the greater and lesser palatine canals. They are joined in the PPF by nasopharyngeal and posterior nasal cavity branches. Thus, the PPF J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 129 J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 Ibrahim et al Greater and lesser palatine nerves Lingual nerve Gasserian ganglion Greater superficial petrosal nerve Mandibular nerve Facial Nerve Chorda tympani nerve Inferior Alveolar nerve FIG. 1. Schematic diagram of the normal anatomy of the trigeminal ( fifth cranial) and facial ( seventh cranial) nerves, including their normal course through different neural foramina, branching patterns, and communicating nerves. is considered an important " relay station," connecting the infratemporal fossa ( masticator space), nasopharynx, palate, sinus, nasal cavity, orbit, face, and the middle cranial fossa ( Fig. 3A- B). Bounded posteriorly by the pterygoid plates, anteromedially by the palatine bone, and TABLE 1. Skull foramina and spaces and their transcoursing cranial nerves Skull Foramen/ Space Superior orbital fissure Foramen rotundum, pterygopalatine fossa Foramen ovale Mandibular foramen Stylomastoid foramen Transcoursing Cranial nerve Ophthalmic division of trigeminal Maxillary division of trigeminal Mandibular division of trigeminal Inferior alveolar nerve Facial nerve anteriorly by the maxillary bone, it communicates laterally with the infratemporal fossa via the pterygomaxillary fissure. It connects medially with the nasal cavity via the sphenopalatine foramen and with the orbit via the inferior orbital fissure. It connects with the cranial compartment via the foramen rotundum, which carries the maxillary nerve ( Fig. 4C) and the Vidian nerve canal ( Fig. 4C), which carries the parasympathetic Vidian nerve ( Fig. 1) ( 7,8). The mandibular division ( Fig. 4D) of the trigeminal nerve provides sensory innervation to the chin and lower lip, floor of the mouth, tongue, side of the head and scalp, and meninges ( 8,9). The motor root travels with it to innervate the muscles of mastication, tensor tympani muscle, tensor veli palatini, mylohyoid muscle, and anterior belly of the digastric muscle ( 7- 9). The lingual nerve carries general sensation from the anterior two- thirds of the tongue ( 8). The mental nerve enters the mandible through the mental foramen. It runs in the mandibular canal, where it is joined by dental branches to form the inferior alveolar nerve, which exits the mandible through the mandibular foramen on the medial side of the mandibular ramus ( 8,9) 130 © 2007 Lippincott Williams & Wilkins Perineural Spread of Malignancy J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 TABLE 2. Sites of origin of malignancy and cranial nerves commonly involved by perineural spread Site of Origin of Malignancy Forehead, eye, ethmoid and frontal sinuses, lacrimal gland Mid and lateral face, palate, maxilla, sinonasal region, nasopharynx Nasopharynx, masticator space, parapharyngeal space Lower lip, chin, floor of mouth Parotid gland Cranial Nerve involved by Perineural Spread Ophthalmic division of trigeminal Maxillary division of trigeminal Mandibular division of trigeminal Inferior alveolar nerve Facial nerve ( Fig. 6A- B). All of these branches coalesce below the skull base to form the main mandibular trunk. The auriculotemporal ( AT) nerve ( Fig. 7A) supplies sensation to the temporomandibular joint, external auditory canal, and the adjacent scalp. The three divisions of the trigeminal nerve enter the cranium through the superior orbital fissure ( ophthalmic), foramen rotundum ( maxillary), and foramen ovale ( mandibular) ( Table 1). The ophthalmic and maxillary nerves travel in the lateral wall of the cavernous sinus, inferior to the third and fourth cranial nerves ( 7,8). The sensory trigeminal ganglion resides in Meckel's cave ( Figs. 4D and 5 A), a small invagination in the floor of the middle cranial fossa at the posterior margin of the cavernous sinus. The three divisions converge into a larger sensory root and a smaller motor root, which enter the anterolateral aspect of the mid- pons ( 7,8) ( Fig. 5A- C). FIG. 2. Perineural spread ( PNS) of forehead squamous cell carcinoma along the ophthalmic division of the trigeminal nerve. Postcontrast axial CT scan shows markedly enhancing cancer in the right frontal region ( arrows). There is marked enhancement and thickening of the right ophthalmic trigeminal division ( arrowheads). Facial Nerve The facial nerve has multiple functions and a complicated course ( 7) ( Fig. 1). It supplies motor innervation to the muscles of facial expression, the stylohyoid muscle, the posterior belly of the digastric muscle, and the stapedius muscle; taste sensation to the anterior two- thirds of the tongue; and general sensation to the skin on and adjacent to the ear. Arising from the lateral aspect of the pontomedul-lary junction as a large motor segment and a small sensory segment, it runs anterolaterally in the cerebellopontine angle cistern and then along the antero superior aspect of the internal auditory canal. In the inner and middle ear, the facial nerve is divided into the following segments: labyrinthine, anterior genu, tympanic, posterior genu, and mastoid ( Fig. 8A- E). The greater superficial petrosal nerve ( Fig. 4E) arises from the geniculate ganglion and runs FIG. 3. Pterygopalatine fossa ( PPF) involvement in adenoid cystic cancer of the hard palate. A. Precontrast axial T1 MRI shows loss of the normal hyperintense fat pad in the right pterygopalatine fossa ( arrowheads) compared with the normal left side ( arrow). B. Postcontrast T1 axial MRI with fat suppression shows enhancement in the right pterygopalatine fossa suggestive of tumor. The PPF acts as an important relay station for PNS of head and neck 131 J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 Ibrahim et al FIG. 4. Maxillary and mandibular trigeminal division involvement in maxillary squamous cell carcinoma. A. Postcontrast T1 coronal MRI shows a large enhancing mass in the right maxilla ( arrows) that has invaded the floor of the right orbit and hard palate. B. Precontrast T1 axial MRI shows that the mass ( large arrows) extends posteriorly and invades and replaces the normal fat pad of the right pterygopalatine fossa ( arrowhead). Compare with the normal left side ( small arrows). C. Postcontrast T1 coronal MRI shows enhancement and enlargement of the right maxillary division of the trigeminal nerve and the nerve of the Vidian canal ( arrows), which lies inferior and medial to the trigeminal nerve. Compare with the normal nerves on the opposite side ( arrowheads). D. More posterior postcontrast T1 coronal MRI shows enhancing soft tissue in the right Meckel's cave, which has replaced the normal cerebrospinal fluid ( CSF) signal ( large arrows). Compare with the normal left Meckel's cave ( small arrows). The tumor has spread in an antegrade fashion to involve the mandibular division of the right trigeminal nerve ( arrowhead). Compare with the normal mandibular nerve in the opposite foramen ovale ( arrowhead). E. Postcontrast T1 axial MRI with fat suppression shows enhancement along the right greater superficial petrosal nerve ( arrows), a branch of the facial nerve. Compare with the normal nonenhancing nerve on the left side ( arrowheads). 132 © 2007 Lippincott Williams & Wilkins Perineural Spread of Malignancy J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 FIG. 5. Cavernous sinus and root entry zone abducens ( sixth cranial) nerve involvement in oral cavity squamous cell carcinoma. A. Post-contrast T1 axial MRI shows a large mass in the left Meckel's cave and cavernous sinus { double arrow). The mass extends along the cisternal segment of the trigeminal nerve and infiltrates the pons { arrowhead). B. Postcontrast T1 coronal MRI shows enhancement and thickening of the left trigeminal nerve { arrow) and enhancement at the root entry zone of the abducens nerve { arrowhead). anteromedian^ to exit through the facial hiatus. The stapedius muscle nerve and the chorda tympani nerve arise from the proximal and distal portions of the mastoid segment, respectively. The facial nerve exits through the stylomastoid foramen and then continues into the parotid gland where it divides into five branches and supplies the muscles of facial expression. Communication Between Trigeminal and Facial Nerves A number of small distal branches of the trigeminal nerve serve as terminal conduits for branches of other cranial nerves, especially the facial nerve, creating communications that can form pathways for PNS. The major communication pathways are the Vidian ( Fig. 4C and 9A), chorda tympani, and auriculotemporal ( AT) nerves ( Fig. 7A). The greater superficial petrosal nerve arises ( Fig. 4E) from the geniculate ganglion and passes under the trigeminal cistern ( Meckel's cave) near the foramen lacerum ( 7,10). It receives sympathetic fibers from the deep petrosal nerve surrounding the internal carotid artery to become the nerve of the Vidian canal. This nerve passes anteriorly to the pterygopalatine fossa where it gives multiple parasympathetic branches to synapse in the ganglion and then innervate the lacrimal gland and the palatine and nasal mucosa ( 7,10). The chorda tympani nerve, which carries taste sensation from the anterior two- thirds of the tongue and controls secretion of the submandibular and sublingual glands, arises from the mastoid segment just above the FIG. 6. Inferior alveolar nerve involvement in lower lid squamous cell carcinoma. A. Postcontrast T1 axial MRI shows enhancement of the tumor along the inferior alveolar nerve { arrows). The inferior alveolar nerve in this case was involved owing to antegrade tumor spread along the mandibular division of trigeminal nerve. Compare with the normal fat on the opposite side { black arrows). Enhancement and reduced bulk of the pterygoid and masseter muscles { white arrowheads) suggest late subacute denervation changes. B. Axial CT scan in another patient with oral cavity squamous cell carcinoma shows mild enlargement and erosion of the left inferior alveolar nerve foramen { large arrows), compared with the normal right side { small arrows). 133 J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 Ibrahim et al FIG. 7. Auriculotemporal nerve involvement in right parotid gland adenoid cystic carcinoma. Precontrast T1 axial MRI displays a hypointense parotid mass ( arrows) with a linear hypointense structure posterior to the mandibular ramus suggestive of PNS along the expected course of the right auriculotemporal nerve ( arrowheads). Note the fatty replacement of the parotid gland from prior radiation. stylomastoid foramen and joins the lingual branch of the mandibular nerve. The AT nerve is formed by upper and lower nerve roots that arise from the mandibular division and traverses immediately posterior to the mandibular ramus. The AT nerve then pierces the parotid fascia and divides into anterior and posterior rami, both of which communicate with the facial nerve just posterior to the masseter muscle ( 7,11). CLINICAL FEATURES PNS may be detected at the time of detection of the original tumor mass, but more commonly it is noted when symptoms created by PNS occur months to years after excision of the primary tumor. Unfortunately, 30%- 45% of patients with PNS are initially asymptomatic, allowing for extensive subclinical spread ( 12). Factors associated with PNS from cutaneous cancers include male gender, tumor size > 2 cm, location on the face, and previous treatment of the original lesion ( 3,13,14). Knowledge of the pertinent anatomy allows the prediction of the pathways of perineural tumor spread ( Table 2). Tumors of the forehead, eye, ethmoid and frontal sinuses, and lacrimal gland typically extend along the ophthalmic division. The maxillary division is an important route of spread for tumor from the mid and upper lateral face, palate, maxilla, sinonasal region, and nasopharynx. The mandibular division carries tumors of the nasopharynx, masticator space, and parapharyngeal space ( 5). Tumors of the lower lip, chin, and floor of the mouth often travel in the inferior alveolar nerve, and tumors of the tongue can extend along the lingual nerve to reach the cavernous sinus ( 5). Tumors of the parotid gland follow the facial nerve or the AT branch of the mandibular trigeminal segment. Clinical evidence of PNS is usually sensory: hypesthesia, burning, knife- like, or stinging pain ( 2). Facial and masticator weakness is typically a later sign. PNS is a poor prognostic factor associated with increased risk of local recurrence and nodal metastasis and reduced survival ( 3,15,16). Many treatment failures are related to unrecognized PNS ( 17). PATHOGENESIS The pathogenesis of PNS of head and neck neoplasms has not been not fully elucidated. In 1905, it was theorized that tumor cells spread along nerves via perineural lymphatics ( 18). In 1952, Mohs and Lathrop ( 19) noted that some tumors demonstrate an affinity for nerve sheaths, with cancer cells located just beneath the perineurium. The authors suggested that the rich vascular network associated with nerves may provide a nutritional factor that promotes perineural growth and that the cleavage plane between the nerve and its sheath would provide a path of least mechanical resistance for tumor spread. With intraneural injection of contrast medium and tumor cells in animals, Larson et al ( 20) demonstrated that PNS occurs along the path of least resistance of the neural planes rather than via the perineural lymphatic vessels. A noncontiguous flow of tumor cells could not be demonstrated and the contrast medium did not actively flow after injection had ceased, implying a lack of lymphatic flow Gandour- Edwards et al ( 21) demonstrated that adenoid cystic carcinoma expresses the adhesion molecule N- CAM, a membrane- bound glycoprotein of the immunoglobulin supergene family that mediates cell- to- cell adhesion, especially in neuroectodermal tissues. In a study of 66 patients, Vural et al ( 22) found N- CAM expression in 93%> of patients with PNS; in contrast, only 36% of the patients without PNS expressed N- CAM. IMAGING FEATURES MRI is the imaging modality of choice for detecting PNS because of its high degree of soft tissue resolution and multiplanar capability. Expertly interpreted MRI can correctly predict the presence of PNS with 95% sensitivity but can only map the entire extent of spread in 63% ( 23). CT is helpful in detecting subtle cortical bone erosion. 134 © 2007 Lippincott Williams & Wilkins Perineural Spread of Malignancy J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 FIG. 8. Facial nerve involvement by right parotid gland mucoepidermoid carcinoma. A. Postcontrast T1 axial MRI shows a large hypointense mass in the right parotid gland { arrows). B- C. Postcontrast T1 axial MRI with fat suppression shows mild enlargement and marked enhancement along the mastoid segment ( B), and tympanic and anterior genu segments of the right facial nerve ( C) { arrows). D. Coronal high- resolution CT scan of the right temporal bone shows mild enlargement and cortical irregularity of the mastoid segment of the right facial nerve canal { arrows). E. Coronal CT scan of the left temporal bone shows a normal facial nerve canal { arrows). FIG. 9. Enlargement and destruction of skull base foramina by PNS ( three different cases). A. Retrograde spread of adenoid cystic cancer of the left maxillary sinus along the Vidian nerve { arrows). The tumor initially spread into the pterygopalatine fossa along the branches of the maxillary nerve and then extended into the Vidian nerve canal. A coronal CT scan shows smooth expansion of the left Vidian canal. Note the normal fat density in the right Vidian canal for comparison. B. Marked enlargement of the right palatine foramina { arrows) owing to antegrade spread of orbital lymphoma. The tumor reached the pterygopalatine fossa via the inferior orbital fissure and then spread in an antegrade fashion into the palatine foramina. Note the normal appearance of the palatine foramina on the left { larger arrowhead indicates the greater palatine foramen; smaller arrowhead indicates the lesser palatine foramen). C. Enlargement of the left foramen ovale { large arrows) due to PNS along the mandibular division of the trigeminal nerve. Compare with the normal right foramen ovale { small arrows). Enlargement, erosion, and destruction of a cranial nerve foramen and canal are relatively late signs of PNS. They can be seen on CT scanning as well as MRI; CT scanning is more sensitive for detection of early cortical bone erosions. 135 J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 Ibrahim et al FIG. 10. Entities mimicking PNS in causing enhancement or enlargement of cranial nerves. A. Schwannoma of the right oculomotor ( third cranial) nerve with extension along the interpeduncular fossa up to the brainstem { arrows). Optic nerve sheath meningioma in the right orbit { arrowheads). B. Sarcoidosis involving both oculomotor nerves { arrows). C. Breast carcinomatosis with enhancement of leptomeninges { arrowheads) and both oculomotor nerves { arrows). A preferred MRI protocol for patients with suspected PNS is the application of thin ( 2- 3 mm) section precontrast Tl and T2 and contrast- enhanced Tl image with and without fat suppression in the axial and coronal planes and with a field of view of 16- 18 cm. Precontrast Tl MRI is important for looking at involvement of the normal fat planes. Fat- suppressed postcontrast Tl MRI is important for looking at subtle enhancing lesions, which would otherwise be missed on routine postcontrast Tl MRI. CT scanning is ideally performed in 1.25 mm sections through the suspected region of abnormality, and the images are viewed in soft tissue and bone algorithms. Typical imaging findings in PNS on a CT scan include foraminal enlargement ( Fig. 9A- C), foraminal destruction ( Figs. 6B and 8D), and abnormal enhancement within the foramen or canal ( Fig. 9A). Loss of fat around the nerves or within the foramina should also be viewed as an indication of PNS. MRI findings suggestive of PNS are obliteration of fat planes around the nerve or within the foramen ( Fig. 3), nerve enhancement ( Fig. 4C), and nerve enlargement ( Fig. 4C). When disease spreads to the cavernous sinus, there is convexity of the lateral cavernous sinus wall ( Fig. 5A); when the tumor spreads to the trigeminal cistern ( Meckel's cave), there is replacement of the normal CSF signal by enhancing soft tissue ( Fig. 4D). PNS along the facial nerve will show enhancement with or without thickening of the nerve and usually extends from the parotid segment to the intracanalicular or cisternal segment ( Fig. 8B- C). It is important to remember that some portions of the facial nerve, namely the anterior genu and tympanic and mastoid segments, normally enhance on postcontrast MRI because of the presence of a normal arteriovenous plexus. Therefore, interpreting pathologic neural enhancement in the facial nerve can be tricky ( 24). An indirect sign of PNS is denervation change in the involved muscles, typically affecting those of mastication ( anterior belly of the digastric, mylohyoid, and glossal) ( 5). The imaging findings vary with the chronicity of the process. Acute and subacute denervation results in abnormal enhancement and edema- like signal changes ( hypointense on T1 and hyperintense on T2 MRI) in the affected muscles ( Fig. 6A), sometimes accompanied by increased volume of the denervated muscles. Chronic denervation results in extensive fatty replacement with Tl hyperintensity and T2 hypointen-sity and a decrease in the volume of the affected muscles. DIFFERENTIAL DIAGNOSIS Entities that can be confused with PNS by causing multiple enhancing cranial nerves include benign tumors such as schwannoma ( Fig. 10A), infections such as rhinocerebral mucormycosis and aspergillosis, granulomatous disorders such as sarcoidosis ( Fig. 10B) ( 25,26), and lepto-meningeal metastasis ( Fig. IOC). In all such cases, however, the clinical facts usually allow differentiation. CONCLUSIONS PNS from head and neck malignancies is a serious complication associated with local recurrences and decreased patient survival. Imaging is critical in these patients, but missed diagnosis is common. Accurate detection of PNS requires an understanding of the anatomy of commonly involved neural pathways. A high level of suspicion on the part of the clinician and radiologist, awareness of common imaging signs of PNS, and careful attention to imaging technique will allow earlier detection. Acknowledgment The authors thank Anne Phillips, our medical illustrator, for providing the illustration used as Figure 1. 136 © 2007 Lippincott Williams & Wilkins Perineural Spread of Malignancy J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 REFERENCES 1. Neumann E. Secondare cancroid infiltration des nerves metalis bei einem Fall von Lippincroid. Arch Pathol Anat 1862; 24: 201. 2. 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