Perineural tumor spread (PNS) is a well-recognized entity in head and neck cancers and represents a mode of metastasis along nerves. The trigeminal and facial nerves are most affected by PNS, and their connections are reviewed. MRI is the most sensitive modality for detecting PNS, and their anatomy and interconnections are reviewed. MRI is the most sensitive modality for detecting PNS, and imaging features of PNS and important imaging checkpoints are reviewed. Optimal imaging protocol and techniques are summarized as well as other entities that can mimic PNS.
Key points
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Perineural tumor spread (PNS) is a well-recognized mode of metastasis in head and neck cancers.
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Adenoid cystic carcinoma of the minor or major salivary glands is most likely to develop PNS; however, squamous cell carcinoma represents more cases overall, as it is more common.
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PNS most commonly affects the trigeminal and facial nerves and their connections.
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MRI is the most sensitive modality for detection of PNS.
Introduction
Perineural tumor spread (PNS) of head and neck cancer was first described in the 1800s. , However, it was not until 1963 when Ballantyne and colleagues published 80 cases exhibiting this manner of spread that physicians realized that PNS occurred more often than previously thought.
It is important to distinguish between perineural invasion (PNI) and PNS. PNI is a histologic finding, when tumor cells lie within any of the layers of the nerve sheath or when tumor cells surround more than 33% of the circumference of the nerve. However, PNS describes extension of malignancy beyond the confines of the primary tumor via neural conduits and represents gross, radiologically evident large nerve involvement. PNS is a mode of metastasis rather than a histologic feature.
Of the head and neck tumors that spread via the perineural route, ACC of the minor or major salivary glands has the greatest propensity for PNS with a prevalence of up to 56%. However, given that ACC is rare, representing 1% to 3% of head and neck cancers, cutaneous and mucosal squamous cell carcinomas are responsible for the highest number of PNS cases even though they have a relatively lower propensity for neural involvement. Desmoplastic melanoma is also known to have a propensity to invade nerves. Additional tumors that can develop PNS include mucoepidermoid and basal cell carcinomas, sarcomas, lymphoma, and leukemia. ,
The pathogenesis of PNS remains poorly understood. However, it is known that PNS is a dynamic process involving active crosstalk between tumor and nerve cells. Once a tumor cell interacts with a nerve cell, axonal migration may be a key element of PNS. Axonal growth is a complex process that requires neurotrophic growth factors. The best characterized family of neurotrophic factors, or neurotrophins, is that comprising nerve growth and brain-derived neurotrophic factors NT3 and NT4/5.
Clinical symptoms of PNS include pain, paresthesia, dysesthesias, weakness, and paralysis; however, up to 40% of patients with PNS are asymptomatic. Patients presenting with multiple cranial neuropathies may suggest more central involvement such as the cavernous sinus, spread from one cranial nerve (CN) to another, or leptomeningeal disease. ,
Diagnosing the presence of PNS is important as it correlates with decreased disease-free survival, increased risk of tumor recurrence, and higher morbidity and mortality. Williams and colleagues proposed a system of classifying PNS based on MRI into 3 zones: zone 1, peripheral; zone 2, central/skull base; and zone 3, cisternal. Surgery combined with radiotherapy portends the best outcome in zone 1 and zone 2, and surgery should be avoided with zone 3 due to a higher likelihood of treatment failure and tumor spread. Bakst and colleagues recommend adjuvant radiation in the following settings:
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Cutaneous SCC of the head and neck with extensive microscopic or involvement of large-caliber nerves
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Aggressive salivary gland cancers such as ACC or salivary duct carcinoma containing microscopic PNI
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Mucosal SCC with extensive microscopic PNI
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Any primary tumor demonstrating clinical or radiographic PNS
Pertinent anatomy
The trigeminal and facial nerves are most likely to be involved with PNS, with the highest prevalence along the maxillary division of CN V. , , The trigeminal nerve originates from 4 nuclei located in the lateral pons including 3 sensory nuclei (principal pontine sensory nucleus, the mesencephalic nucleus, and the spinal trigeminal nucleus) and a single motor nucleus. From the lateral pons CN V emerges as separate rootlets and continues as a main trunk on each side within the prepontine cistern to Meckel’s cave. , Meckel’s cave, or the trigeminal cavity, is a cerebrospinal fluid–filled dural pouch posterolateral to the cavernous sinus that houses the trigeminal (gasserian) ganglion along the lateral and anterior wall of Meckel’s cave. From here, the nerve divides into the ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions ( Fig. 1 ).
V1 travels via the lateral cavernous sinus wall and then through the superior orbital fissure to the orbit. V2 travels through the cavernous sinus and exits the skull base through foramen rotundum. The infraorbital nerve travels from the infraorbital cutaneous surface posteriorly in the infraorbital canal in the orbital floor where it connects with the superior alveolar branches and extends through the retro antral fat pad toward the PPF. The greater and lesser palatine nerves integrate into the infraorbital nerve located within the PPF.
V3 exits the skull base through foramen ovale without entering the cavernous sinus into the masticator space. The main trunk divides into a small anterior division (giving off masseteric, deep temporal, lateral pterygoid motor branches, and buccal nerve sensory branch) and large posterior division. The auriculotemporal nerve (sensory to temporal scalp, secretomotor to parotid gland) arises from 2 roots of proximal posterior division. The posterior division then divides into terminal branches: lingual nerve (sensory to tongue) and inferior alveolar nerve (IAN). The IAN traverses the mandibular canal supplying the mandibular teeth and gingiva giving off the mental nerve, which exits via the mental foramen on the lateral aspect of the mandibular body supplying the skin of the chin and lower lip.
The facial nerve or CN VII arises from the posterior pons. Its fibers loop around the ipsilateral abducens nucleus and create the facial colliculus at the anterior wall of the fourth ventricle. , The nerve then continues through the lateral pons and exits the brainstem at the lateral pontomedullary junction. The cisternal segment then traverses the cerebellopontine angle cistern and enters the internal auditory canal into the temporal bone and advances through the anterior otic capsule as the labyrinthine segment, through the middle ear cavity as the anterior genu and horizontal tympanic segment, posterior genu, and then the descending mastoid segment inside the mastoid section of the temporal bone. The nerve exits the temporal bone via the stylomastoid foramen into the parotid gland, dividing the parotid gland into the deep and superficial lobes. Within the parotid gland, the nerve splits into 5 branches: temporal, zygomatic, buccal, marginal mandibular, and cervical (see Fig. 1 ). , These branches split up into various branches to innervate the facial muscles to provide motor function and facial expression.
Various interconnections exist between the facial and trigeminal nerves, which enables tumors to travel between them. An important interconnection involves the greater superficial petrosal (GSP) nerve, which provides parasympathetic innervation from fibers that originate from the nervus intermedius, to the lacrimal gland, palate, nasal cavity, and nasopharynx. The GSP nerve then joins with the deep petrosal nerve to form the vidian nerve, also known as the nerve of the pterygoid canal. The vidian nerve then travels through the vidian (pterygoid) canal into the pterygopalatine fossa to connect the preganglionic fibers in the pterygopalatine ganglion. Near the PPF assorted postganglionic fibers connect with branches of V2. PNS along the GSP nerve typically occurs after tumor has reached the PPF and can then extend retrograde along the vidian nerve to the GSP nerve ( Fig. 2 ). Direct extension of tumor in Meckel cave to the GSP nerve can also occur because of their proximity.
Another important connection between CN V and VII involves the auriculotemporal nerve, which arises as 2 roots from the posterior division of V3 soon after it exits the skull base via foramen ovale. These 2 roots then encircle the middle meningeal artery and merge into a single nerve to pass by the posterior border of the mandibular ramus/condylar head into the parotid gland. Intraparotid secretomotor branches and sensory innervation of the auricle and temporal skin region are provided by this nerve. Within the parotid gland, the auriculotemporal rami crosses with the facial nerve.
PNS has also been described along the sixth CN and greater auricular nerve. , The greater auricular nerve provides sensory innervation to the skin overlying the parotid gland, mastoid process, and outer ear. It originates from branches of the C2 and C3 spinal nerves ( Figs. 3 and 4 ).
Imaging modalities and features
MRI is the most sensitive modality for detecting perineural spread of tumor due to its superior soft tissue contrast resolution. In Nemzek and colleagues, the sensitivity for detecting PNS with 1.5 T MRI was 95%, although sensitivity for identifying the entire extent of involvement was less at 63%. In Hanna and colleagues, the sensitivity and specificity for detecting PNS of ACC at the skull base for MRI were 100% and 85%, respectively, compared with 88% (sensitivity) and 89% (specificity) for computed tomography (CT).
CT is less sensitive than MRI in detecting PNS because it relies on indirect/secondary features such as neural foramen enlargement and erosions that occur in later disease stages. CT is, however, more sensitive than MRI to detect the neural foramen bony enlargement and erosions. CT is useful to guide biopsy of suspected PNS and helpful as an alternative to MRI if the patient has implants that preclude MRI.
PET/CT can detect PNS; however, it generally has low sensitivity due to lower spatial resolution and partial-volume effects and false-positive results secondary to inflammation and treatment effects. PNS appears as a linear or curvilinear area of F-fluorodeoxyglucose (FDG) uptake along the course of CNs ( Fig. 5 ).
There are key features that enable identification of PNS, and they can be separated into 2 major categories: primary or direct findings and secondary or indirect findings. Direct findings describe the features that demonstrate the infiltration of nerve fibers or nerve sheath by tumor such as nerve thickening/enlargement and nerve enhancement. Indirect findings are those that develop after there has been tumor accumulation along a nerve, which then result in neural foramen widening and/or erosion, loss of fat around a nerve, and denervation changes in muscles ( Table 1 ).
| Direct Features | Indirect Features |
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Nerve Enhancement
Disruption of the blood-nerve barrier by tumor results in increased vascular permeability and capillary leakage of contrast, resulting in enhancement on imaging. An enhancing nerve can be compared with the contralateral nerve to detect asymmetries, as PNS typically occurs unilaterally. False-positive enhancement can occur for several reasons including asymmetries from patient head positioning and normal enhancement along a nerve due to perineural venous plexus, which may mimic PNS. In these cases, the proximity of a nerve to the primary malignancy should be considered to ascertain if additional features of PNS are present to increase diagnostic confidence. Normal nerve ganglia enhancement such as that of the gasserian (CN V) and geniculate (CN VII) ganglia can be confounded with PNS.
Nerve Thickening/Enlargement and Loss of Fat Around Nerve
The diameter of a nerve enlarges as tumor cells infiltrate and proliferate along the nerve; this enables detection of PNS by comparing the thickness of a nerve versus the contralateral (normal) nerve. Coronal images are particularly helpful for assessing CN V branches. Fat surrounds cranial nerves along much of their extracranial courses and within neural foramina. Increased size of a nerve progressively obliterates the surrounding fat pad, and this serves as another feature of PNS. Both features, nerve enlargement and loss of fat around a nerve, can be appreciated well on both CT and MRI ( Figs. 6 and 7 ).
