Perineural Tumor Spread Involving the Central Skull Base Region Hilda E. Stambuk, MD*,† Perineural spread of tumor is defined as extension of the primary tumor along tissues of the neural sheath (epineurium and perineurium) of a named nerve. Given the density of cranial nerves in the central skull base region and their extracranial communications, perineural tumor spread from a variety of sources can affect the central skull base region. Common malignancies with perineural tumor spread to central skull base include mucosal squamous cell carcinoma, adenoid cystic carcinoma, and cutaneous malignancies including melanoma. The presence and extent of tumor spread influence selection of treatment and prognosis. Appropriate imaging and interpretation, therefore, play a crucial role in detection and management of perineural tumor spread in the central skull base region. Semin Ultrasound CT MRI 34:445-458 C 2013 Published by Elsevier Inc.
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erineural spread (PNS) of tumor is a distinct growth pattern in which a malignant neoplasm spreads from a primary tumor site to a secondary site via the scaffolding of a nerve or nerve plexus. Although histologic evaluation can demonstrate microscopic tumor invasion of the central aspects of the nerve—the endoneurium, PNS is generally limited to the outer layers of the nerve sheath—the epineurium and the perineurium.1 As tumor spreads in this pattern, it extends from one anatomical compartment or space to another and escapes local treatment effects, culminating in disease persistence and progression. Given the density of the cranial nerves (CNs) in the central skull base region and their intricate communications with extracranial sites, malignancies can extend to the central skull base region from a variety of distant sites and via a number of perineural pathways. Tumors can reach the central skull base from the oral cavity, oropharynx, nasopharynx, sinonasal region, orbits, and cutaneous structures of the face and scalp. CN V, owing to its large size and extent, is the most commonly involved nerve of the central skull base region, and V2, its maxillary division, is the most commonly involved branch.2 However, perineural tumor spread can also affect V1, V3, CN III, CN IV, CN VI, and smaller nerves like the palatine Project Editor: Suzanne Byan-Parker. Tel.: þ1-205-934-4274; þ1-205-4823229 (mobile). E-mail: [email protected]. The author thank medical illustrator David Fisher for providing the conceptual, anatomic illustrations. *Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY. †Weill Cornell Medical College, New York, NY. Address reprint requests to Hilda E. Stambuk, MD, 1275 York Ave, Suite C-278, New York, NY 10065. E-mail: [email protected]
0887-2171/$-see front matter & 2013 Published by Elsevier Inc. http://dx.doi.org/10.1053/j.sult.2013.09.002
nerves and vidian nerves. Malignancies with perineural tumor spread to the central skull base region include mucosal squamous cell carcinoma (including nasopharyngeal carcinoma), adenoid cystic carcinoma, and cutaneous malignancies including squamous cell carcinoma and melanoma.1,3 Adenoid cystic carcinoma and desmoplastic melanoma are particularly notorious for their neurotropic growth and PNS, although squamous cell carcinoma, with its much higher prevalence, would account for most cases in a typical neuroradiologic practice. The anatomical complexity of the orbital apex, orbital fissures, pterygopalatine fossa (PPF), multiple foramina, and the cavernous sinuses makes recognition of perineural tumor spread in the central skull base region challenging. The soft tissue contrast and multiplanar capabilities of magnetic resonance imaging (MRI) are superior in their capacity to identify perineural tumor spread, although computed tomography (CT) can be complementary in certain situations. The sensitivity of MRI in detecting perineural tumor spread has been reported as high as 95%.4 As the presence and extent of tumor spread influence selection of treatment and prognosis, radiologic detection of perineural tumor spread in the central skull base region is crucial. Contrary to popular belief, up to one-half of patients with radiographic findings of perineural tumor spread are asymptomatic and would go undiagnosed based on clinical presentation alone. Furthermore, surgeons are reluctant to resect or biopsy tissue in the central skull base region, placing more reliance on imaging interpretation for therapeutic decision making. Appropriate imaging and interpretation, therefore, play a crucial role in detection and management of perineural tumor spread in the central skull base region. 445
446 Early recognition of PNS is important but often difficult because its radiographic signs can be very subtle. Therefore, the radiologist needs to be aware of situations where there is an elevated risk for PNS. Familiarity with associated tumor types and radiologic indicators of PNS is an important precursor to be able to identify its presence early in the course of the disease.
Etiology and Pathogenesis The etiopathologic mechanisms of PNS are beginning to be elucidated but remain poorly understood. However, the adverse implications of PNS on oncologic outcomes have been recognized for decades. There is a general agreement that most patients with clinically or radiographically demonstrable PNS will have poor outcomes in spite of aggressive treatment. By the time patients have PNS symptoms or signs, most have radiographically evident PNS; however, up to one-half of patients with radiographic evidence of PNS may be asymptomatic. The traditional concept that PNS is a form of tumor spread along lymphatic channels within the epineurium is no longer accepted, as we now know that lymphatic channels do not penetrate the epineurium of nerves.5 It has also been postulated that a tumor may grow along nerves, as they offer tumor cells a path of least resistance. Thus, tumors in certain organs, such as the pancreas and prostate, having rich innervations, were once thought to be at higher risk for PNS. However, we now know that PNS is a dynamic process involving active cross talk between the tumor and nerve cells.6 Cytokines such as neurotrophins (NTs) and laminin-5 are upregulated during the initial process of interaction between a tumor cell and an adjacent nerve cell.7,8 Proteins that participate in neural homeostasis, dendritic growth, and axonal sprouting have the potential for initiating and promoting cancer cell invasion. An example is glial-derived neurotrophic factor, which promotes differentiation of neurons. However, in many cancers with poor prognosis, upregulation and overexpression of several glial-derived neurotrophic factor family receptors and ligands has been observed.9-11 Immune cells in the perineural environment also secrete growth factors that may promote tumor cell proliferation and invasion.12 Nerves, in turn, are attracted to tumor cells through a family of proteins including semaphorins and their receptors plexins, which play a role in nerve cell adhesion, axon migration, and central nervous system development.13 Once a tumor cell interacts with a nerve cell, migration of cancer cells along the axon toward the dorsal root ganglion is necessary for the phenomenon of PNS to occur. The precise mechanism by which this happens is unclear, but it is believed that NTs such as nerve growth factor, brain-derived neurotrophic factor, NT-3, and NT 4/5 may be responsible.5 Cytoskeletal actin remodeling regulatory proteins, such as destrin, which governs actin dynamics, may also play a role in tumor cell migration.14 The term PNS is often used interchangeably with perineural invasion (PNI) in the literature. It is important to recognize and emphasize, however, that PNI is a histopathologic tumor feature that indicates direct involvement of microscopic or small nerves engulfed by the primary tumor itself, but it cannot
H.E. Stambuk be seen radiologically. PNI is defined by the presence of tumor invasion into, around, and through any of the 3 layers of the nerve sheath.15 Involvement of at least one-third of the circumference of the nerve by tumor cells is used as a surrogate if there is no obvious invasion of the nerve.16 The incidence of PNI has been reported to vary with the primary site and histologic type of the tumor: 20%-25% of patients with prostatic adenocarcinoma,17 up to 50%-70% of patients with head and neck cutaneous squamous cell cancer,18,19 more than 80%-90% of patients with pancreatic adenocarcinoma,20 and 30%-95% of patients with adenoid cystic carcinoma21 have been reported to have PNI. PNS, on the contrary, denotes extension of a tumor along a nerve that is distant to the primary tumor. Although microscopy can potentially detect PNS, these distant nerve sites are seldom biopsied as part of an initial surgical excision of head and neck cancer. Generally, PNS refers to the recognition of macroscopic disease on MRI or CT. Although the histologic presence of PNI in some tumors does increase the risk of metastatic disease and recurrence, it does not in and of itself indicate spread beyond the primary tumor site or macroscopic PNS.22
Anatomical Pathways of PNS Tumors can invade and spread along virtually any CN as well as various cervical rami that provide cutaneous innervation to the neck and scalp. CN V, which provides extensive sensory and motor innervations, is one of the largest nerves in the central skull base region—and the most common CN to be affected by PNS (Table 1).23,24 Distal to the gasserian ganglion, within Meckel’s cave, CN V divides into 3 major divisions: ophthalmic division (V1), maxillary division (V2), and the mandibular division (V3). These divisions provide cutaneous sensory innervation to the face and scalp in reliable dermatomal distributions. Skin malignancies represent a major source of PNS and the location of a primary cutaneous lesion can be important in predicting potential PNS. Malignant cutaneous lesions of the face and anterior scalp can gain access to the distal trigeminal nerve branches and then extend in retrograde fashion to the central skull base. Figure 1 illustrates the typical dermatomal distribution of the CN V branches of the face and anterior forehead as well as additional cutaneous innervations. CN V also provides sensory innervations to the lacrimal gland, the globe, the sinonasal region, and the oral cavity including the maxilla, the mandible, and anterior two-thirds of the tongue. The V3 division also provides motor innervation to the masticator space. Noncutaneous soft tissue malignancies including mucosal squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, and sarcoma can gain access to the trigeminal network and result in PNS. Figure 2 illustrates the pathways of PNS along the branches of CN V. Perineural tumor spread of CN V as well as other CNs generally results in retrograde spread toward the brainstem. Cutaneous and noncutaneous lesions involving the forehead and superior orbit can track posteriorly along V1 branches (frontal, lacrimal, and nasociliary nerves) through the superior orbital fissure and into the cavernous sinus (Fig. 3). Tumors of
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Table 1 Common Anatomical Sites and Neural Pathways Associated With Perineural Spread in the Head and Neck* Anatomical Site
Initial Pathway
Cranial Nerve
Skin: Melanoma and squamous cell carcinoma Forehead, dorsum of nose, and upper eyelid Cheek, lateral nose, lower eyelid, and upper lip Temple and malar eminence Pretragal area Lower lip and lower cheek Pinna and retromandibular area Retroauricular area Occipital scalp Nape of neck and upper back Anterior triangle of neck Supraclavicular triangle of neck
Supratrochlear, supraorbital Infraorbital Zygomaticotemporal Auriculotemporal Mental (inferior alveolar) Greater auricular nerve (ventral rami C2 and C3) Lesser occipital nerve (ventral ramus C2) Greater occipital nerve (dorsal rami C2 and C3) Dorsal rami of C3-5 Transverse cutaneous nerve of neck (ventral rami of C2 and C3) Supraclavicular nerves (ventral rami of C3 and C4)
V1 V2 V2 V3 V3 NA NA NA NA NA NA
Mucosa: Adenoid cystic carcinoma and squamous cell carcinoma Hard palate Greater and lesser palatine nerves Upper alveolus Superior alveolar nerve Tongue, floor of mouth, and, retromolar trigone Lingual nerve Lower alveolus Inferior alveolar nerve
V2 V2 V3 V3
Salivary glands: Adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, and metastatic squamous cell carcinoma Parotid Facial nerve branches VII Submandibular Lingual nerve V3 Hypoglossal nerve XII Sublingual Lingual nerve V3 NA, not applicable. *More detailed anatomical descriptions of these pathways are available in Maroldi et al23 and Moonis et al.24
the cheek, inferior orbit, or maxillary sinus can invade the infraorbital nerve (V2) and track posteriorly through the inferior orbital fissure and into the PPF (Fig. 4). From the PPF,
Figure 1 The sensory dermatomes of the head and neck.
tumor can extend posteriorly through the foramen rotundum along V2 to reach the cavernous sinus and Meckel’s cave or through the vidian canal to reach the petrous apex. Tumors of the hard palate can gain access to the greater and lesser palatine nerves within the palatine canals and spread superiorly into the PPF and ultimately to V2 (Fig. 5). Lip, oral cavity, or oropharyngeal malignancies
Figure 2 CN V is a large cranial nerve that traverses the central skull base region and divides into 3 major trunks, providing sensory innervations of the face and motor innervations to the masticator space. Given its multiple communications, it is a major pathway of PNS to the central skull base.
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Figure 3 Perineural tumor spread from cutaneous SCCA. (A) Illustration depicts PNS from lesion in forehead along the frontal nerve branch of V1 in the superior orbit. (B) Sagittal T1-weighted image through the orbit shows soft tissue density along the frontal nerve. This might be difficult to discriminate from the levator palpebra and superior rectus muscles. (C) Coronal postcontrast with fat saturation demonstrates marked enhancing tissue along V1. (D) Axial postcontrast, T1-weighted image demonstrates nodular enhancing tissue within the superior orbital fissure and foramen rotundum. SCCA, squamous cell carcinoma.
can gain access to the mandibular nerve (V3) and ascend through the masticator space to the foramen ovale, reaching Meckel’s cave (Fig. 6).
Antegrade extension can occur as well. In fact, multidirectional PNS of the CNs can occur at branch points or points of communication with other nerves, especially at the
Figure 4 PNS along V2 from recurrent nasolabial fold SCCA. (A) Illustration depicts PNS along the infraorbital nerve from cutaneous malignancy of the cheek. (B) Sagittal postcontrast T1-weighted image through the cheek reveals solidly enhancing lesion in the subcutaneous soft tissues of the right cheek (M). Tumor extends in retrograde fashion to the infraorbital nerve (arrow). (C) Coronal MRI with gadolinium demonstrates marked nodular enhancing tissue along the infraorbital nerve. SCCA, squamous cell carcinoma.
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Figure 5 PNS from adenoid cystic carcinoma of the hard palate. (A) Illustration though the deep face demonstrates the path of PNS from the hard palate, along the palatine nerves (black arrows), up to the pterygpopalatine ganglion (PPG), and then along the vidian nerve (double red arrow) and V2 (single red arrow). (B) Axial, enhanced T1-weighted image through the oral cavity demonstrates peripherally enhancing lesion in the posterior hard palate on the left (arrow). (C) Axial, enhanced T1-weighted image (slightly higher) demonstrates nodular enhancing tissue along the palatine nerves within the palatine canal (arrow). (D) Axial, enhanced T1-weighted image shows enhancing tissue within the pterygopalatine fossa at expected location of PPG (arrow).
Figure 6 PNS from adenoid cystic carcinoma of the oral cavity. (A) Illustration depicts retrograde perineural tumor spread from oral cavity along V3 (black arrows).Tumor extends through the foramen ovale (red arrow). Note the secondary atrophic changes in the ipsilateral muscles of mastication. (B) Coronal, enhanced T1-weighted image with fat saturation demonstrates marked enhancement (arrows) along V3 extending from the left masticator space through the foramen ovale. (C) Coronal, unenhanced T1-weighted image through the deep face demonstrates atrophic changes in the left masticator space (arrows). This is generally a late finding in PNS.
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Figure 7 Advanced PNS to cavernous sinus along V1 from forehead SCCA with jump lesions to adjacent cranial nerves. (A) Axial, postcontrast fat-saturated image through the skull base demonstrates bulky enhancing tumor in the left cavernous sinus and extending retrograde along CN V to the pons. (B) Slightly higher axial, postcontrast fat-saturated image demonstrates retrograde spread of tumor along CN III to the midbrain. SCCA, squamous cell carcinoma. (Figures and case study courtesy of Joel Cure, MD, who kindly provided both.)
pterygopalaitne ganglion within the PPF or the gasserian ganglion within Meckel’s cave. Additionally, there are important conduits of tumor spread between CN V and CN VII including the vidian nerve, the greater superficial petrosal nerve,25 and the auriculotemporal nerve, which is a branch of V3.26 Finally, tumor that reaches the orbital apex or cavernous sinus along one CN can be of sufficient bulk to parasitize nearby CNs and result in multiple cranial neuropathies (Fig. 7).27
Clinical Presentation and Prognostic Implications In many cases, PNS can be insidious. Up to 40% of patients with PNS are asymptomatic, or have nonspecific symptoms.1 When they do occur, symptoms are determined by the specific CN or nerve branch involved. As most cases in the head and neck involve CN V, the primary symptoms are usually related
to pain, formication (feeling of something crawling under the skin), paresthesias, or anesthesia in the distribution of the involved nerve segment. Weakness of mastication muscles is generally a late symptom related to involvement of V3, the mandibular nerve. The sensory symptoms may be subtle and initially be attributed to the primary tumor itself or the local effects of biopsy, excision, or radiation at the primary site. The pain associated with PNS of CN V can be misdiagnosed as trigeminal neuralgia. The sensory deficit in trigeminal neuralgia is accompanied by pain and is diagnosed only after excluding all other causes. PNS of CN VII (facial nerve) branches is less frequent and results in peripheral facial palsy. PNS of CN VII generally occurs in the setting of primary parotid neoplasm or tumor that has metastasized to the parotid. Facial paralysis of PNS can be confused with Bell palsy. Bell palsy affects all branches of CN VII, is of sudden onset, and is self-limiting with recovery in 3 weeks to 6 months. Atypical features including gradual
Figure 8 CT demonstration of foraminal or canal enlargement in PNS. (A) Axial CT skull base bone window shows nondestructive widening of left foramen ovale (closed arrow) from PNS along V3 from cutaneous melanoma. Note the normal-sized right foramen ovale (open arrow). (B) Different patient with nasopharyngeal carcinoma with PNS along the vidian nerve demonstrates diffuse enlargement of the vidian canal (arrow).
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Figure 9 (A) Postcontrast, coronal T1-weighted MRI in a patient with nasopharyngeal carcinoma (T) with no obvious pathology at the skull base. The right V2 (open arrow) is nicely seen in foramen rotundum; however, left V2 is obscured by blooming artifact (closed arrow) produced by the fat-saturation technique. (B) Postcontrast, coronal, T1-weighted MRI without fat suppression again demonstrates the primary tumor (T) of the left nasopharynx. However, it also clearly shows enlargement and enhancement within the foramen rotundum consistent with PNS along left V2 (arrow). Note that the right V2 is also better seen on this sequence compared with the previous image that used fat suppression.
onset, partial facial paralysis, or hemifacial spasm that precedes the palsy should be viewed with suspicion. PNS can result in extension of tumor to the osseous skull base and dura producing severe headache. Bulky PNS in the orbital apex or cavernous sinus can result in multiple cranial neuropathies including orbital apex syndrome or cavernous sinus syndrome, respectively. A history of head and neck cancer, especially that of the skin, oral cavity, salivary gland, or lymphoma, should be sought in the presence of any of these symptoms. PNS along the CNs, especially CN V, is common in older males with a history of sun exposure, and these patients often have cryotherapy or shave excision of cutaneous lesions without histopathologic examination and recorded history of skin cancer. Moreover, treatment of the primary cutaneous lesion often predates PNS by a number of years; patients with chronically sun-damaged skin do not always recall the nature of every skin lesion that required treatment. A primary cutaneous lesion responsible for PNS may, therefore, not always be identifiable in spite of directed questioning and detailed physical examination. The presence of PNS may drastically influence treatment selection and is a harbinger for a poor prognosis. Most patients with gross PNS extending to the skull base are not amenable to curative surgical resection. Multidisciplinary treatment involving external beam radiation therapy is an important adjuvant, and the role of accurate radiographic identification of the extent of PNS in these patients cannot be overemphasized, as there is no standard, systemic treatment available.
Imaging Features CT and MRI are complementary in assessing patients for PNS, but each has its advantages. Positron emission tomography scans are generally insensitive for detection of PNS but can
occasionally show positive results. Radiologic evaluation of PNS requires knowledge of the normal location, course, associated foramina, and potential connections of the CNs as
Figure 10 Postcontrast, axial, T1-weighted MRI showing abnormal enlargement and enhancement of right V2. The perineural tumor (arrows) tracks along the nerve through foramen rotundum into the cavernous sinus, Meckel’s cave, and main trunk of CN V within the basilar cistern and involves the nucleus of CN V in the brainstem. Note that the normally fluid-filled hypointense Meckel’s cave is filled with enhancing tumor.
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Figure 11 (A) Precontrast, axial, T1-weighted MRI shows an isointense tumor in the premaxillary soft tissues (arrow) that is well delineated against the normal high-signal fat. (B) Precontrast, axial, T1-weighted MRI shows tumor continuing along the infraorbital nerve into the pterygopalatine fossa (arrow) enlarging the canal. Note that the nerve is abnormally enlarged with obvious replacement of the normal fat in comparison to the normal right-hand side. (C) Postcontrast, axial, T1-weighted MRI shows abnormally enhancing and grossly enlarged intracranial tumor extension along V2 (arrow) into the cavernous sinus and Meckel’s cave. (D) Postcontrast, coronal, T1-weighted MRI shows an abnormally enlarged and enhancing left infraorbital nerve (arrow) in close proximity to the air-filled maxillary sinus. Subtle involvement of the infraorbital nerve may be missed if there is sufficient blooming artifact from the air-tissue interface when fat suppression is applied to this sequence. (E) Postcontrast, coronal, T1-weighted MRI shows enhancing and enlarged V2 (white arrow) markedly expanding the foramen rotundum. Note the normal-sized relatively nonenhancing right V2 (black arrow).
well as the normal appearance of the nerves themselves. Imaging criteria used to diagnose PNS along a nerve include the following28: (1) (2) (3) (4)
asymmetric enlargement, asymmetric enhancement, obliteration of perineural fat planes, denervation changes in end organs, for example, muscles of facial expression and mastication, and (5) widening of foramina transmitting the nerve. MRI is generally more sensitive than CT in detecting all features of PNS except for enlargement and destruction of bony foramina. Widening of a foramen or fissure that an
involved nerve normally traverses is an indirect sign of PNS, and this is best appreciated on CT scan using bone algorithm (Fig. 8). Features such as obliteration of juxtaforaminal fat pads and fat planes along the path of a CN are seen well on both modalities. Expansion of the cavernous sinus and soft tissue enhancement of Meckel’s cave, which is normally fluid filled, are other indicators of PNS on CT and MRI. Contrast-enhanced high-resolution MRI techniques including field of view (18 cm); thin slice (3 mm), and highresolution matrix (320 192)3 are preferable when evaluating the CNs and the skull base. PNS is typically a unilateral process so that comparison of the suspected abnormal nerve with the contralateral normal nerve is of primary importance. The
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Figure 12 Postcontrast, axial, T1-weighted, fat-saturated MRI. (A) This patient had a cutaneous melanoma with PNS along V2 into the left Meckel cave. Note abnormally enhancing and enlarged left CN VII (arrow) within the temporal bone involving the geniculate ganglion, labyrinthine segment and internal auditory canal, and the horizontal segment of CN VII. This pattern of PNS illustrates the communication of CN V and CN VII via the greater superficial petrosal nerve. (B) With passage of time, the tumor extended into the cerebellopontine angle cistern toward the brainstem. Postcontrast, fatsaturated image shows persistent disease in Meckel’s cave (long arrow) on the left as well as nodular enhancement along the tympanic and intracanalicular segments (short arrows) of the facial nerve. (C) Axial postcontrast T1-weighted image at later stage of disease demonstrates extensive PNS of tumor with nodular enhancement in the left pterygopalatine fossa, Meckel’s cave, and internal auditory canal. There is now invasion of the brainstem (large arrow) as well as intracochlear invasion (small arrow) along CN VIII.
intracranial cisternal portions of the normal CNs show no significant contrast enhancement, owing to minimal perineural venous plexus and intact blood nerve barrier. Obvious enhancement along these segments should be viewed with suspicion. However, nerve ganglia including the gasserian of V and geniculate ganglion of VII demonstrate conspicuous enhancement normally and should not be considered pathologic based on enhancement alone. As CNs penetrate the dura and travel extracranially, normal CNs can demonstrate variable peripheral enhancement related to the perineural venous
plexus. This perineural enhancement can be pronounced within the skull base canals and foramina as well as within the immediate extracranial soft tissues and can produce a targetlike or tram track–like enhancement normally. This is particularly true of V3 at the foramen ovale and proximal masticator space. Such venous plexus enhancement could be difficult to separate from early or subtle PNS. With PNS pattern of tumor spread, the tumor tissue is generally contiguous along the nerve. That is, histologically, it is uncommon to identify normal nerve or skip areas separated
Figure 13 This patient had a squamous cell carcinoma of the left preauricular skin, which was treated with excision. including left partial parotidectomy (A) He developed recurrent tumor, which is visible in this postcontrast, axial, T1-weighted, fat-saturated MRI as an enlarged and enhancing left auriculotemporal nerve (arrow) posterior to the left mandibular condyle tracking in the left parapharyngeal space toward left V3. (B) Postcontrast, axial, fat-saturated, T1-weighted MRI shows PNS along left CN V3 (closed arrow) in foramen ovale. Note the normal contralateral right relatively nonenhancing CN V3 (open arrow).
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Figure 14 (A) Precontrast, sagittal T1-weighted MRI of a patient with a locally advanced base of tongue tumor (T) involving the root of the tongue. (B) Precontrast, axial, T1-weighted MRI shows the expected T1 bright fatty marrow signal within the mandible. Abnormal enlargement of the right inferior alveolar nerve (arrow) in its entire course within the mandibular canal to the mental foramen is nicely contrasted against the normal fatty marrow. This oropharyngeal tumor (T) gained access to the lingual nerve in the floor of mouth and traveled antegrade along the inferior alveolar nerve into the mandible.
by segments of tumor involvement. However, perineural tumor growth along the nerve is not often uniform, so that on imaging, more conspicuous (thick, nodular, or masslike) areas of PNS tumor may appear to be isolated from adjacent radiologically negative segments of involvement. Given the possibility of such radiologic skip areas, it is important for the radiologist to examine the path of the entire CN from end organ to its nucleus when PNS is suspected. In addition to asymmetric enhancement and enlargement of the nerve, MRI findings of PNS include obliteration of perineural or juxtaforaminal fat and denervation atrophy of the end organs innervated by the affected CN. Evaluation of perineural and juxtaforaminal fat is best done on 3-mm axial and coronal precontrast T1-weighted sequences without fat
suppression. The fat-suppression sequence results in artifacts at the skull base that may obscure accurate assessment of PNS. Denervation changes appear in the muscles innervated by the respective CN acutely (within 1 month). These changes include enhancing, hyperintense muscles on T2-weighted sequence. Subacute denervation changes persist for up to 12-20 months and include T1 hyperintensity without volume loss. Chronic denervation changes beyond 12-20 months include loss of muscle volume, enhancement, and eventually fatty atrophy (Fig. 6C). Denervation of the muscles of mastication should not be confused with a mass in the masticator space. Other indirect signs of denervation atrophy include middle ear effusion from eustachian tube dysfunction that results from denervation of the tensor veli palatini muscle.
Figure 15 (A) Postcontrast, fat-saturated, axial, T1-weighted MRI showing enhancing soft tissue mass in the right-posterior maxillary sinus extending into the right pterygopalatine fossa (arrow). Histologic examination of tumor showed adenoid cystic carcinoma. Note normal left pterygopalatine fossa (*). (B) Postcontrast, fat-saturated, axial, T1-weighted MRI showing PNS along right V2 (arrow) in foramen rotundum and cavernous sinus. (C) Postcontrast, fat-saturated, coronal, T1-weighted MRI showing PNS along enlarged right V2 (closed arrow) and vidian nerve (open arrow).
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Figure 16 (A) Axial, postcontrast CT scan showing abnormal thickened soft tissue (arrows) in the right pterygopalatine fossa, sphenopalatine foramen, foramen rotundum, and Meckel’s cave. (B) Axial CT scan bone window showing relatively smooth widening of the right pterygopalatine fossa (PPF) and foramen rotundum (R) without bony destruction, which is typical of perineural spread. (C) Coronal, CT scan bone window showing marked enlargement of both the right foramen rotundum (closed arrow) and vidian canal (open arrow). (D) Following treatment of lymphoma, coronal, CT scan bone window shows normalization of foramen rotundum (closed arrow) and restored cortical margin of vidian canal (open arrow) indicative of treatment response. The bony foramina and canals often remain radiographically widened after treatment.
Patients who have a well-aerated sphenoid sinus are susceptible to MRI blooming artifact if fat suppression is used.29 Fat suppression mildly enlarges the signal void of the aerated sphenoid sinus and obscures visualization of the adjacent foramen rotundum, foramen ovale, and the vidian canal. This artifact is even more pronounced in a 3-T magnet and therefore the 1.5-T is currently preferred. A similar susceptibility artifact can also occur in the temporal bone because the aerated mastoid air cells are in close proximity to the course of CN VII. The way to overcome the loss of signal around the skull base foramina and temporal bone is to add an additional postcontrast coronal T1-weighted sequence without fat saturation (Fig. 9). Evaluation of the postsurgical patient for PNS can be difficult because of distortion of V2 or V3 after maxillectomy or infratemporal fossa resection where these nerves can enhance and appear enlarged. In these instances, the key is to evaluate the preoperative scan for nerve involvement. If negative for PNS, postoperative enhancement and enlargement is likely related to postoperative change, which can persist long term. Close surveillance and stability on interval imaging
studies is an indicator of postoperative change rather than PNS in these patients. Similarly, evaluation of response of PNS to radiation therapy is also difficult to monitor because soft tissue changes in the involved nerve can persist indefinitely. Progression of the radiographic appearance of PNS or development of new symptoms is generally the only definite indicator of progression of disease in these patients. Elderly patients with skin cancer often present with symptoms or clinical signs of PNS involving CN V or CN VII or both. The patient shown in Figure 10 had a long history of removal of skin lesions from the scalp and face that were reportedly benign. Over time, he developed facial numbness and then diplopia for which he was referred to a neurologist for a presumed cavernous sinus primary tumor. Postcontrast axial T1-weighted MRI shows the classic appearance of PNS along the infraorbital nerve retrograde to V2, through foramen rotundum into the cavernous sinus and Meckel’s cave to the main trunk of CN V and into the CN V nucleus in the brainstem. The importance of precontrast T1-weighted MRI in assessment of PNS is illustrated in Figure 11. This patient had a
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Figure 17 Schwannoma of the right cavernous sinus. (A) Axial, postcontrast, T1-weighted MRI showing a fusiform lesion within the right cavernous sinus (arrow). (B) Coronal, T2-weighted MRI with fat saturation showing a hyperintense lesion (arrow) displacing but not narrowing the right internal carotid artery.
malignant melanoma of the skin of the left infraorbital skin. Note how easily the T1 isointense tumor in the premaxillary soft tissues contrasts against the adjacent normal T1 hyperintense fat (Fig. 11A). This finding could be missed on postcontrast T1-weighted sequence, as the enhancing tumor could blend in with the fat signal on a non–fat suppressed sequence, or if there is inadequate fat suppression. The tumor tracks along the infraorbital nerve into the PPF, where the nerve is abnormally enlarged with obvious replacement of the normal fat in comparison with the normal, right-hand side (Fig. 11B). Although widening of the PPF is easily seen in this patient, lesser degrees of bony canal abnormalities are better appreciated on CT. Once the tumor extends intracranially, it is best imaged with the postcontrast T1-weighted sequence
(Fig. 11C). Coronal imaging is useful for demonstrating the infraorbital nerve within the infraorbital canal in the floor of the orbit (Fig. 11D) and also nicely shows the abnormally enlarged V2 in the cavernous sinus (Fig. 11E) when compared with the opposite right-hand side. Tumors can spread between CN V and CN VII from one of many connections either centrally or peripherally. PNS along the greater superficial petrosal nerve is an example of central spread of tumor from CN V to CN VII (Fig. 12). The greater superficial petrosal nerve is a branch of CN VII that emanates from the geniculate ganglion, courses anteromedially just inferior to Meckel’s cave, and joins the deep petrosal nerve to form the vidian nerve which travels through the vidian canal into the PPF
Figure 18 Meningioma of the left cavernous sinus. (A) Axial, postcontrast, T1-weighted MRI with fat saturation showing a homogenously enhancing dural-based lesion extending into the left cavernous sinus (arrow). The lesion has dural tails anteriorly and posteriorly. (B) Coronal, postcontrast, T1-weighted MRI with fat saturation again demonstrates enhancing lesion of the cavernous sinus (arrow) with luminal narrowing of the left internal carotid artery, a classic feature of cavernous meningioma.
Perineural tumor spread where its preganglionic fibers synapse with the pterygopalatine ganglion. Therefore, tumor involving the PPF can track retrograde toward Meckel’s cave or vice versa. Tumor can also track directly from Meckel’s cave to the greater superficial petrosal nerve because of anatomical proximity. The auriculotemporal nerve is a peripheral pathway of tumor spread between CN V and CN VII (Fig. 13). It is the first branch off V3 below foramen rotundum. It exits as 2 rootlets that go around the middle meningeal artery, fuse into a short trunk, and split into multiple branches with anterior and posterior rami that connect to branches of CN VII within the parotid gland. Squamous cell carcinomas of the oral cavity and oropharynx have a lower propensity for PNS compared with cutaneous squamous cell carcinoma. However, involvement of the inferior alveolar nerve can result in PNS along V3 and is generally retrograde in direction. Antegrade PNS along the inferior alveolar nerve is rare but can have significant implications in treatment planning because of the intraosseous course of the nerve within the mandibular canal (Fig. 14). Adenoid cystic carcinoma has a particular affinity for nerves and is a common cause of PNS in tumors of the maxillary sinus and hard palate (Fig. 15). These tumors are generally treated with primary surgical resection, and accurate assessment for PNS is of practical value in management. Among other tumors that are associated with PNS, lymphoma is an often-ignored cause. In the absence of other primary tumors that are known to cause PNS, lymphoma should be considered in the differential diagnosis (Fig. 16) because of the obvious implications in terms of treatment. Lymphoma is not treated surgically and CT-guided biopsy is an excellent modality to obtain tissue for diagnosis so that the patient can expeditiously proceed to appropriate treatment. There are certain benign conditions that can mimic the appearance of PNS on radiographic imaging. One example of such a condition is schwannoma of the CNs. Unlike PNS, schwannomas are more fusiform in configuration, are T2 hyperintense, and can have a heterogeneous appearance (Fig. 17). Meningiomas are frequently seen in the cavernous sinus and should not be confused with PNS. These tumors are dural based, can extend into the cavernous sinus, and should have a dural tail. They enhance homogenously and when they extend into the cavernous sinus, they classically cause luminal narrowing of the internal carotid artery (Fig. 18).
Summary PNS of tumor is an underrecognized feature of many head and neck tumors. CN V is the most commonly involved CN and serves as conduit for extracranial tumors to the central skull base region. Given the density of CNs and the complexity of the anatomical structures in the central skull base region, radiologic detection of PNS along CN V and other nerves can be challenging. Ultimately, the presence and extent of PNS influence the selection of treatment and determine prognosis. Appropriate imaging and interpretation, therefore, play a crucial role in management of these patients.
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References 1. Nemec SF, Herneth AM, Czerny C: Perineural tumor spread in malignant head and neck tumors. Top Magn Reson Imaging 18(6):467-471, 2007 2. Boerman RH, Maassen EM, Joosten J, et al: Trigeminal neuropathy secondary to perineural invasion of head and neck carcinomas. Neurology 53(1):213-216, 1999 3. Gandhi MR, Panizza B, Kennedy D: Detecting and defining the anatomic extent of large nerve perineural spread of malignancy: Comparing “targeted” MRI with the histologic findings following surgery. Head Neck 33(4):469-475, 2011 4. Caldemeyer KS, Mathews VP, Righi PD, et al: Imaging features and clinical significance of perineural spread or extension of head and neck tumors. Radiographics 18(1):97-110, 1998; [quiz 147] 5. Liebig C, Ayala G, Wilks JA, et al: Perineural invasion in cancer: A review of the literature. Cancer 115(15):3379-3391, 2009 6. Marchesi F, Piemonti L, Mantovani A, et al: Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor Rev 21(1):77-82, 2010 7. Ketterer K, Rao S, Friess H, et al: Reverse transcription-PCR analysis of laser-captured cells points to potential paracrine and autocrine actions of neurotrophins in pancreatic cancer. Clin Cancer Res 9(14):5127-5136, 2003 8. Anderson TD, Feldman M, Weber RS, et al: Tumor deposition of laminin5 and the relationship with perineural invasion. Laryngoscope 111 (12):2140-2143, 2001 9. Gil Z, Cavel O, Kelly K, et al: Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst 102(2):107-118, 2010 10. Veit C, Genze F, Menke A, et al: Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells. Cancer Res 64(15):5291-5300, 2004 11. Esseghir S, Todd SK, Hunt T, et al: A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer. Cancer Res 67 (24):11732-11741, 2007 12. Esposito I, Menicagli M, Funel N, et al: Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 57(6):630-636, 2004 13. Binmadi NO, Yang YH, Zhou H, et al: Plexin-B1 and semaphorin 4D cooperate to promote perineural invasion in a RhoA/ROK-dependent manner. Am J Pathol 180(3):1232-1242, 2012 14. Klose T, Abiatari I, Samkharadze T, et al: The actin binding protein destrin is associated with growth and perineural invasion of pancreatic cancer. Pancreatology 12(4):350-357, 2012 15. Batsakis JG: Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol 94(4 Pt 1):426-427, 1985 16. Fagan JJ, Collins B, Barnes L, et al: Perineural invasion in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 124 (6):637-640, 1998 17. Delancey JO, Wood DP Jr, He C, et al: Evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. Urology 81(2):354-357, 2013 18. Soo KC, Carter RL, O'Brien CJ, et al: Prognostic implications of perineural spread in squamous carcinomas of the head and neck. Laryngoscope 96 (10):1145-1148, 1986 19. Panizza B, Warren T: Perineural invasion of head and neck skin cancer: Diagnostic and therapeutic implications. Curr Oncol Rep 2012 20. Conlon KC, Klimstra DS, Brennan MF: Long-term survival after curative resection for pancreatic ductal adenocarcinoma. clinicopathologic analysis of 5-year survivors. Ann Surg 223(3):273-279, 1996 21. Barrett AW, Speight PM: Perineural invasion in adenoid cystic carcinoma of the salivary glands: A valid prognostic indicator? Oral Oncol 45 (11):936-940, 2009 22. Brandwein-Gensler M, Smith RV, Wang B, et al: Validation of the histologic risk model in a new cohort of patients with head and neck squamous cell carcinoma. Am J Surg Pathol 34(5):676-688, 2010 23. Maroldi R, Farina D, Borghesi A, et al: Perineural tumor spread. Neuroimaging Clin N Am 18(2):413-429, 2008; [xi]
458 24. Moonis G, Cunnane MB, Emerick K, et al: Patterns of perineural tumor spread in head and neck cancer. Magn Reson Imaging Clin N Am 20(3): 435-446, 2012 25. Ginsberg LE, De Monte F, Gillenwater AM: Greater superficial petrosal nerve: Anatomy and MR findings in perineural tumor spread. Am J Neuroradiol 17(2):389-393, 1996 26. Schmalfuss IM, Tart RP, Mukherji S, et al: Perineural tumor spread along the auriculotemporal nerve. Am J Neuroradiol 23(2):303-311, 2002
H.E. Stambuk 27. Catalano PJ, Sen C, Biller HF: Cranial neuropathy secondary to perineural spread of cutaneous malignancies. Am J Otol 16(6):772-777, 1995 28. Williams LS, Mancuso AA, Mendenhall WM: Perineural spread of cutaneous squamous and basal cell carcinoma: CT and MR detection and its impact on patient management and prognosis. Int J Radiat Oncol Biol Phys 49(4):1061-1069, 2001 29. Curtin HD: Detection of perineural spread: Fat suppression versus no fat suppression. Am J Neuroradiol 25(1):1-3, 2004
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erineural spread (PNS) of tumor is a distinct growth pattern in which a malignant neoplasm spreads from a primary tumor site to a secondary site via the scaffolding of a nerve or nerve plexus. Although histologic evaluation can demonstrate microscopic tumor invasion of the central aspects of the nerve—the endoneurium, PNS is generally limited to the outer layers of the nerve sheath—the epineurium and the perineurium.1 As tumor spreads in this pattern, it extends from one anatomical compartment or space to another and escapes local treatment effects, culminating in disease persistence and progression. Given the density of the cranial nerves (CNs) in the central skull base region and their intricate communications with extracranial sites, malignancies can extend to the central skull base region from a variety of distant sites and via a number of perineural pathways. Tumors can reach the central skull base from the oral cavity, oropharynx, nasopharynx, sinonasal region, orbits, and cutaneous structures of the face and scalp. CN V, owing to its large size and extent, is the most commonly involved nerve of the central skull base region, and V2, its maxillary division, is the most commonly involved branch.2 However, perineural tumor spread can also affect V1, V3, CN III, CN IV, CN VI, and smaller nerves like the palatine Project Editor: Suzanne Byan-Parker. Tel.: þ1-205-934-4274; þ1-205-4823229 (mobile). E-mail: [email protected]. The author thank medical illustrator David Fisher for providing the conceptual, anatomic illustrations. *Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY. †Weill Cornell Medical College, New York, NY. Address reprint requests to Hilda E. Stambuk, MD, 1275 York Ave, Suite C-278, New York, NY 10065. E-mail: [email protected]
0887-2171/$-see front matter & 2013 Published by Elsevier Inc. http://dx.doi.org/10.1053/j.sult.2013.09.002
nerves and vidian nerves. Malignancies with perineural tumor spread to the central skull base region include mucosal squamous cell carcinoma (including nasopharyngeal carcinoma), adenoid cystic carcinoma, and cutaneous malignancies including squamous cell carcinoma and melanoma.1,3 Adenoid cystic carcinoma and desmoplastic melanoma are particularly notorious for their neurotropic growth and PNS, although squamous cell carcinoma, with its much higher prevalence, would account for most cases in a typical neuroradiologic practice. The anatomical complexity of the orbital apex, orbital fissures, pterygopalatine fossa (PPF), multiple foramina, and the cavernous sinuses makes recognition of perineural tumor spread in the central skull base region challenging. The soft tissue contrast and multiplanar capabilities of magnetic resonance imaging (MRI) are superior in their capacity to identify perineural tumor spread, although computed tomography (CT) can be complementary in certain situations. The sensitivity of MRI in detecting perineural tumor spread has been reported as high as 95%.4 As the presence and extent of tumor spread influence selection of treatment and prognosis, radiologic detection of perineural tumor spread in the central skull base region is crucial. Contrary to popular belief, up to one-half of patients with radiographic findings of perineural tumor spread are asymptomatic and would go undiagnosed based on clinical presentation alone. Furthermore, surgeons are reluctant to resect or biopsy tissue in the central skull base region, placing more reliance on imaging interpretation for therapeutic decision making. Appropriate imaging and interpretation, therefore, play a crucial role in detection and management of perineural tumor spread in the central skull base region. 445
446 Early recognition of PNS is important but often difficult because its radiographic signs can be very subtle. Therefore, the radiologist needs to be aware of situations where there is an elevated risk for PNS. Familiarity with associated tumor types and radiologic indicators of PNS is an important precursor to be able to identify its presence early in the course of the disease.
Etiology and Pathogenesis The etiopathologic mechanisms of PNS are beginning to be elucidated but remain poorly understood. However, the adverse implications of PNS on oncologic outcomes have been recognized for decades. There is a general agreement that most patients with clinically or radiographically demonstrable PNS will have poor outcomes in spite of aggressive treatment. By the time patients have PNS symptoms or signs, most have radiographically evident PNS; however, up to one-half of patients with radiographic evidence of PNS may be asymptomatic. The traditional concept that PNS is a form of tumor spread along lymphatic channels within the epineurium is no longer accepted, as we now know that lymphatic channels do not penetrate the epineurium of nerves.5 It has also been postulated that a tumor may grow along nerves, as they offer tumor cells a path of least resistance. Thus, tumors in certain organs, such as the pancreas and prostate, having rich innervations, were once thought to be at higher risk for PNS. However, we now know that PNS is a dynamic process involving active cross talk between the tumor and nerve cells.6 Cytokines such as neurotrophins (NTs) and laminin-5 are upregulated during the initial process of interaction between a tumor cell and an adjacent nerve cell.7,8 Proteins that participate in neural homeostasis, dendritic growth, and axonal sprouting have the potential for initiating and promoting cancer cell invasion. An example is glial-derived neurotrophic factor, which promotes differentiation of neurons. However, in many cancers with poor prognosis, upregulation and overexpression of several glial-derived neurotrophic factor family receptors and ligands has been observed.9-11 Immune cells in the perineural environment also secrete growth factors that may promote tumor cell proliferation and invasion.12 Nerves, in turn, are attracted to tumor cells through a family of proteins including semaphorins and their receptors plexins, which play a role in nerve cell adhesion, axon migration, and central nervous system development.13 Once a tumor cell interacts with a nerve cell, migration of cancer cells along the axon toward the dorsal root ganglion is necessary for the phenomenon of PNS to occur. The precise mechanism by which this happens is unclear, but it is believed that NTs such as nerve growth factor, brain-derived neurotrophic factor, NT-3, and NT 4/5 may be responsible.5 Cytoskeletal actin remodeling regulatory proteins, such as destrin, which governs actin dynamics, may also play a role in tumor cell migration.14 The term PNS is often used interchangeably with perineural invasion (PNI) in the literature. It is important to recognize and emphasize, however, that PNI is a histopathologic tumor feature that indicates direct involvement of microscopic or small nerves engulfed by the primary tumor itself, but it cannot
H.E. Stambuk be seen radiologically. PNI is defined by the presence of tumor invasion into, around, and through any of the 3 layers of the nerve sheath.15 Involvement of at least one-third of the circumference of the nerve by tumor cells is used as a surrogate if there is no obvious invasion of the nerve.16 The incidence of PNI has been reported to vary with the primary site and histologic type of the tumor: 20%-25% of patients with prostatic adenocarcinoma,17 up to 50%-70% of patients with head and neck cutaneous squamous cell cancer,18,19 more than 80%-90% of patients with pancreatic adenocarcinoma,20 and 30%-95% of patients with adenoid cystic carcinoma21 have been reported to have PNI. PNS, on the contrary, denotes extension of a tumor along a nerve that is distant to the primary tumor. Although microscopy can potentially detect PNS, these distant nerve sites are seldom biopsied as part of an initial surgical excision of head and neck cancer. Generally, PNS refers to the recognition of macroscopic disease on MRI or CT. Although the histologic presence of PNI in some tumors does increase the risk of metastatic disease and recurrence, it does not in and of itself indicate spread beyond the primary tumor site or macroscopic PNS.22
Anatomical Pathways of PNS Tumors can invade and spread along virtually any CN as well as various cervical rami that provide cutaneous innervation to the neck and scalp. CN V, which provides extensive sensory and motor innervations, is one of the largest nerves in the central skull base region—and the most common CN to be affected by PNS (Table 1).23,24 Distal to the gasserian ganglion, within Meckel’s cave, CN V divides into 3 major divisions: ophthalmic division (V1), maxillary division (V2), and the mandibular division (V3). These divisions provide cutaneous sensory innervation to the face and scalp in reliable dermatomal distributions. Skin malignancies represent a major source of PNS and the location of a primary cutaneous lesion can be important in predicting potential PNS. Malignant cutaneous lesions of the face and anterior scalp can gain access to the distal trigeminal nerve branches and then extend in retrograde fashion to the central skull base. Figure 1 illustrates the typical dermatomal distribution of the CN V branches of the face and anterior forehead as well as additional cutaneous innervations. CN V also provides sensory innervations to the lacrimal gland, the globe, the sinonasal region, and the oral cavity including the maxilla, the mandible, and anterior two-thirds of the tongue. The V3 division also provides motor innervation to the masticator space. Noncutaneous soft tissue malignancies including mucosal squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, and sarcoma can gain access to the trigeminal network and result in PNS. Figure 2 illustrates the pathways of PNS along the branches of CN V. Perineural tumor spread of CN V as well as other CNs generally results in retrograde spread toward the brainstem. Cutaneous and noncutaneous lesions involving the forehead and superior orbit can track posteriorly along V1 branches (frontal, lacrimal, and nasociliary nerves) through the superior orbital fissure and into the cavernous sinus (Fig. 3). Tumors of
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Table 1 Common Anatomical Sites and Neural Pathways Associated With Perineural Spread in the Head and Neck* Anatomical Site
Initial Pathway
Cranial Nerve
Skin: Melanoma and squamous cell carcinoma Forehead, dorsum of nose, and upper eyelid Cheek, lateral nose, lower eyelid, and upper lip Temple and malar eminence Pretragal area Lower lip and lower cheek Pinna and retromandibular area Retroauricular area Occipital scalp Nape of neck and upper back Anterior triangle of neck Supraclavicular triangle of neck
Supratrochlear, supraorbital Infraorbital Zygomaticotemporal Auriculotemporal Mental (inferior alveolar) Greater auricular nerve (ventral rami C2 and C3) Lesser occipital nerve (ventral ramus C2) Greater occipital nerve (dorsal rami C2 and C3) Dorsal rami of C3-5 Transverse cutaneous nerve of neck (ventral rami of C2 and C3) Supraclavicular nerves (ventral rami of C3 and C4)
V1 V2 V2 V3 V3 NA NA NA NA NA NA
Mucosa: Adenoid cystic carcinoma and squamous cell carcinoma Hard palate Greater and lesser palatine nerves Upper alveolus Superior alveolar nerve Tongue, floor of mouth, and, retromolar trigone Lingual nerve Lower alveolus Inferior alveolar nerve
V2 V2 V3 V3
Salivary glands: Adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, and metastatic squamous cell carcinoma Parotid Facial nerve branches VII Submandibular Lingual nerve V3 Hypoglossal nerve XII Sublingual Lingual nerve V3 NA, not applicable. *More detailed anatomical descriptions of these pathways are available in Maroldi et al23 and Moonis et al.24
the cheek, inferior orbit, or maxillary sinus can invade the infraorbital nerve (V2) and track posteriorly through the inferior orbital fissure and into the PPF (Fig. 4). From the PPF,
Figure 1 The sensory dermatomes of the head and neck.
tumor can extend posteriorly through the foramen rotundum along V2 to reach the cavernous sinus and Meckel’s cave or through the vidian canal to reach the petrous apex. Tumors of the hard palate can gain access to the greater and lesser palatine nerves within the palatine canals and spread superiorly into the PPF and ultimately to V2 (Fig. 5). Lip, oral cavity, or oropharyngeal malignancies
Figure 2 CN V is a large cranial nerve that traverses the central skull base region and divides into 3 major trunks, providing sensory innervations of the face and motor innervations to the masticator space. Given its multiple communications, it is a major pathway of PNS to the central skull base.
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Figure 3 Perineural tumor spread from cutaneous SCCA. (A) Illustration depicts PNS from lesion in forehead along the frontal nerve branch of V1 in the superior orbit. (B) Sagittal T1-weighted image through the orbit shows soft tissue density along the frontal nerve. This might be difficult to discriminate from the levator palpebra and superior rectus muscles. (C) Coronal postcontrast with fat saturation demonstrates marked enhancing tissue along V1. (D) Axial postcontrast, T1-weighted image demonstrates nodular enhancing tissue within the superior orbital fissure and foramen rotundum. SCCA, squamous cell carcinoma.
can gain access to the mandibular nerve (V3) and ascend through the masticator space to the foramen ovale, reaching Meckel’s cave (Fig. 6).
Antegrade extension can occur as well. In fact, multidirectional PNS of the CNs can occur at branch points or points of communication with other nerves, especially at the
Figure 4 PNS along V2 from recurrent nasolabial fold SCCA. (A) Illustration depicts PNS along the infraorbital nerve from cutaneous malignancy of the cheek. (B) Sagittal postcontrast T1-weighted image through the cheek reveals solidly enhancing lesion in the subcutaneous soft tissues of the right cheek (M). Tumor extends in retrograde fashion to the infraorbital nerve (arrow). (C) Coronal MRI with gadolinium demonstrates marked nodular enhancing tissue along the infraorbital nerve. SCCA, squamous cell carcinoma.
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Figure 5 PNS from adenoid cystic carcinoma of the hard palate. (A) Illustration though the deep face demonstrates the path of PNS from the hard palate, along the palatine nerves (black arrows), up to the pterygpopalatine ganglion (PPG), and then along the vidian nerve (double red arrow) and V2 (single red arrow). (B) Axial, enhanced T1-weighted image through the oral cavity demonstrates peripherally enhancing lesion in the posterior hard palate on the left (arrow). (C) Axial, enhanced T1-weighted image (slightly higher) demonstrates nodular enhancing tissue along the palatine nerves within the palatine canal (arrow). (D) Axial, enhanced T1-weighted image shows enhancing tissue within the pterygopalatine fossa at expected location of PPG (arrow).
Figure 6 PNS from adenoid cystic carcinoma of the oral cavity. (A) Illustration depicts retrograde perineural tumor spread from oral cavity along V3 (black arrows).Tumor extends through the foramen ovale (red arrow). Note the secondary atrophic changes in the ipsilateral muscles of mastication. (B) Coronal, enhanced T1-weighted image with fat saturation demonstrates marked enhancement (arrows) along V3 extending from the left masticator space through the foramen ovale. (C) Coronal, unenhanced T1-weighted image through the deep face demonstrates atrophic changes in the left masticator space (arrows). This is generally a late finding in PNS.
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Figure 7 Advanced PNS to cavernous sinus along V1 from forehead SCCA with jump lesions to adjacent cranial nerves. (A) Axial, postcontrast fat-saturated image through the skull base demonstrates bulky enhancing tumor in the left cavernous sinus and extending retrograde along CN V to the pons. (B) Slightly higher axial, postcontrast fat-saturated image demonstrates retrograde spread of tumor along CN III to the midbrain. SCCA, squamous cell carcinoma. (Figures and case study courtesy of Joel Cure, MD, who kindly provided both.)
pterygopalaitne ganglion within the PPF or the gasserian ganglion within Meckel’s cave. Additionally, there are important conduits of tumor spread between CN V and CN VII including the vidian nerve, the greater superficial petrosal nerve,25 and the auriculotemporal nerve, which is a branch of V3.26 Finally, tumor that reaches the orbital apex or cavernous sinus along one CN can be of sufficient bulk to parasitize nearby CNs and result in multiple cranial neuropathies (Fig. 7).27
Clinical Presentation and Prognostic Implications In many cases, PNS can be insidious. Up to 40% of patients with PNS are asymptomatic, or have nonspecific symptoms.1 When they do occur, symptoms are determined by the specific CN or nerve branch involved. As most cases in the head and neck involve CN V, the primary symptoms are usually related
to pain, formication (feeling of something crawling under the skin), paresthesias, or anesthesia in the distribution of the involved nerve segment. Weakness of mastication muscles is generally a late symptom related to involvement of V3, the mandibular nerve. The sensory symptoms may be subtle and initially be attributed to the primary tumor itself or the local effects of biopsy, excision, or radiation at the primary site. The pain associated with PNS of CN V can be misdiagnosed as trigeminal neuralgia. The sensory deficit in trigeminal neuralgia is accompanied by pain and is diagnosed only after excluding all other causes. PNS of CN VII (facial nerve) branches is less frequent and results in peripheral facial palsy. PNS of CN VII generally occurs in the setting of primary parotid neoplasm or tumor that has metastasized to the parotid. Facial paralysis of PNS can be confused with Bell palsy. Bell palsy affects all branches of CN VII, is of sudden onset, and is self-limiting with recovery in 3 weeks to 6 months. Atypical features including gradual
Figure 8 CT demonstration of foraminal or canal enlargement in PNS. (A) Axial CT skull base bone window shows nondestructive widening of left foramen ovale (closed arrow) from PNS along V3 from cutaneous melanoma. Note the normal-sized right foramen ovale (open arrow). (B) Different patient with nasopharyngeal carcinoma with PNS along the vidian nerve demonstrates diffuse enlargement of the vidian canal (arrow).
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Figure 9 (A) Postcontrast, coronal T1-weighted MRI in a patient with nasopharyngeal carcinoma (T) with no obvious pathology at the skull base. The right V2 (open arrow) is nicely seen in foramen rotundum; however, left V2 is obscured by blooming artifact (closed arrow) produced by the fat-saturation technique. (B) Postcontrast, coronal, T1-weighted MRI without fat suppression again demonstrates the primary tumor (T) of the left nasopharynx. However, it also clearly shows enlargement and enhancement within the foramen rotundum consistent with PNS along left V2 (arrow). Note that the right V2 is also better seen on this sequence compared with the previous image that used fat suppression.
onset, partial facial paralysis, or hemifacial spasm that precedes the palsy should be viewed with suspicion. PNS can result in extension of tumor to the osseous skull base and dura producing severe headache. Bulky PNS in the orbital apex or cavernous sinus can result in multiple cranial neuropathies including orbital apex syndrome or cavernous sinus syndrome, respectively. A history of head and neck cancer, especially that of the skin, oral cavity, salivary gland, or lymphoma, should be sought in the presence of any of these symptoms. PNS along the CNs, especially CN V, is common in older males with a history of sun exposure, and these patients often have cryotherapy or shave excision of cutaneous lesions without histopathologic examination and recorded history of skin cancer. Moreover, treatment of the primary cutaneous lesion often predates PNS by a number of years; patients with chronically sun-damaged skin do not always recall the nature of every skin lesion that required treatment. A primary cutaneous lesion responsible for PNS may, therefore, not always be identifiable in spite of directed questioning and detailed physical examination. The presence of PNS may drastically influence treatment selection and is a harbinger for a poor prognosis. Most patients with gross PNS extending to the skull base are not amenable to curative surgical resection. Multidisciplinary treatment involving external beam radiation therapy is an important adjuvant, and the role of accurate radiographic identification of the extent of PNS in these patients cannot be overemphasized, as there is no standard, systemic treatment available.
Imaging Features CT and MRI are complementary in assessing patients for PNS, but each has its advantages. Positron emission tomography scans are generally insensitive for detection of PNS but can
occasionally show positive results. Radiologic evaluation of PNS requires knowledge of the normal location, course, associated foramina, and potential connections of the CNs as
Figure 10 Postcontrast, axial, T1-weighted MRI showing abnormal enlargement and enhancement of right V2. The perineural tumor (arrows) tracks along the nerve through foramen rotundum into the cavernous sinus, Meckel’s cave, and main trunk of CN V within the basilar cistern and involves the nucleus of CN V in the brainstem. Note that the normally fluid-filled hypointense Meckel’s cave is filled with enhancing tumor.
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Figure 11 (A) Precontrast, axial, T1-weighted MRI shows an isointense tumor in the premaxillary soft tissues (arrow) that is well delineated against the normal high-signal fat. (B) Precontrast, axial, T1-weighted MRI shows tumor continuing along the infraorbital nerve into the pterygopalatine fossa (arrow) enlarging the canal. Note that the nerve is abnormally enlarged with obvious replacement of the normal fat in comparison to the normal right-hand side. (C) Postcontrast, axial, T1-weighted MRI shows abnormally enhancing and grossly enlarged intracranial tumor extension along V2 (arrow) into the cavernous sinus and Meckel’s cave. (D) Postcontrast, coronal, T1-weighted MRI shows an abnormally enlarged and enhancing left infraorbital nerve (arrow) in close proximity to the air-filled maxillary sinus. Subtle involvement of the infraorbital nerve may be missed if there is sufficient blooming artifact from the air-tissue interface when fat suppression is applied to this sequence. (E) Postcontrast, coronal, T1-weighted MRI shows enhancing and enlarged V2 (white arrow) markedly expanding the foramen rotundum. Note the normal-sized relatively nonenhancing right V2 (black arrow).
well as the normal appearance of the nerves themselves. Imaging criteria used to diagnose PNS along a nerve include the following28: (1) (2) (3) (4)
asymmetric enlargement, asymmetric enhancement, obliteration of perineural fat planes, denervation changes in end organs, for example, muscles of facial expression and mastication, and (5) widening of foramina transmitting the nerve. MRI is generally more sensitive than CT in detecting all features of PNS except for enlargement and destruction of bony foramina. Widening of a foramen or fissure that an
involved nerve normally traverses is an indirect sign of PNS, and this is best appreciated on CT scan using bone algorithm (Fig. 8). Features such as obliteration of juxtaforaminal fat pads and fat planes along the path of a CN are seen well on both modalities. Expansion of the cavernous sinus and soft tissue enhancement of Meckel’s cave, which is normally fluid filled, are other indicators of PNS on CT and MRI. Contrast-enhanced high-resolution MRI techniques including field of view (18 cm); thin slice (3 mm), and highresolution matrix (320 192)3 are preferable when evaluating the CNs and the skull base. PNS is typically a unilateral process so that comparison of the suspected abnormal nerve with the contralateral normal nerve is of primary importance. The
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Figure 12 Postcontrast, axial, T1-weighted, fat-saturated MRI. (A) This patient had a cutaneous melanoma with PNS along V2 into the left Meckel cave. Note abnormally enhancing and enlarged left CN VII (arrow) within the temporal bone involving the geniculate ganglion, labyrinthine segment and internal auditory canal, and the horizontal segment of CN VII. This pattern of PNS illustrates the communication of CN V and CN VII via the greater superficial petrosal nerve. (B) With passage of time, the tumor extended into the cerebellopontine angle cistern toward the brainstem. Postcontrast, fatsaturated image shows persistent disease in Meckel’s cave (long arrow) on the left as well as nodular enhancement along the tympanic and intracanalicular segments (short arrows) of the facial nerve. (C) Axial postcontrast T1-weighted image at later stage of disease demonstrates extensive PNS of tumor with nodular enhancement in the left pterygopalatine fossa, Meckel’s cave, and internal auditory canal. There is now invasion of the brainstem (large arrow) as well as intracochlear invasion (small arrow) along CN VIII.
intracranial cisternal portions of the normal CNs show no significant contrast enhancement, owing to minimal perineural venous plexus and intact blood nerve barrier. Obvious enhancement along these segments should be viewed with suspicion. However, nerve ganglia including the gasserian of V and geniculate ganglion of VII demonstrate conspicuous enhancement normally and should not be considered pathologic based on enhancement alone. As CNs penetrate the dura and travel extracranially, normal CNs can demonstrate variable peripheral enhancement related to the perineural venous
plexus. This perineural enhancement can be pronounced within the skull base canals and foramina as well as within the immediate extracranial soft tissues and can produce a targetlike or tram track–like enhancement normally. This is particularly true of V3 at the foramen ovale and proximal masticator space. Such venous plexus enhancement could be difficult to separate from early or subtle PNS. With PNS pattern of tumor spread, the tumor tissue is generally contiguous along the nerve. That is, histologically, it is uncommon to identify normal nerve or skip areas separated
Figure 13 This patient had a squamous cell carcinoma of the left preauricular skin, which was treated with excision. including left partial parotidectomy (A) He developed recurrent tumor, which is visible in this postcontrast, axial, T1-weighted, fat-saturated MRI as an enlarged and enhancing left auriculotemporal nerve (arrow) posterior to the left mandibular condyle tracking in the left parapharyngeal space toward left V3. (B) Postcontrast, axial, fat-saturated, T1-weighted MRI shows PNS along left CN V3 (closed arrow) in foramen ovale. Note the normal contralateral right relatively nonenhancing CN V3 (open arrow).
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Figure 14 (A) Precontrast, sagittal T1-weighted MRI of a patient with a locally advanced base of tongue tumor (T) involving the root of the tongue. (B) Precontrast, axial, T1-weighted MRI shows the expected T1 bright fatty marrow signal within the mandible. Abnormal enlargement of the right inferior alveolar nerve (arrow) in its entire course within the mandibular canal to the mental foramen is nicely contrasted against the normal fatty marrow. This oropharyngeal tumor (T) gained access to the lingual nerve in the floor of mouth and traveled antegrade along the inferior alveolar nerve into the mandible.
by segments of tumor involvement. However, perineural tumor growth along the nerve is not often uniform, so that on imaging, more conspicuous (thick, nodular, or masslike) areas of PNS tumor may appear to be isolated from adjacent radiologically negative segments of involvement. Given the possibility of such radiologic skip areas, it is important for the radiologist to examine the path of the entire CN from end organ to its nucleus when PNS is suspected. In addition to asymmetric enhancement and enlargement of the nerve, MRI findings of PNS include obliteration of perineural or juxtaforaminal fat and denervation atrophy of the end organs innervated by the affected CN. Evaluation of perineural and juxtaforaminal fat is best done on 3-mm axial and coronal precontrast T1-weighted sequences without fat
suppression. The fat-suppression sequence results in artifacts at the skull base that may obscure accurate assessment of PNS. Denervation changes appear in the muscles innervated by the respective CN acutely (within 1 month). These changes include enhancing, hyperintense muscles on T2-weighted sequence. Subacute denervation changes persist for up to 12-20 months and include T1 hyperintensity without volume loss. Chronic denervation changes beyond 12-20 months include loss of muscle volume, enhancement, and eventually fatty atrophy (Fig. 6C). Denervation of the muscles of mastication should not be confused with a mass in the masticator space. Other indirect signs of denervation atrophy include middle ear effusion from eustachian tube dysfunction that results from denervation of the tensor veli palatini muscle.
Figure 15 (A) Postcontrast, fat-saturated, axial, T1-weighted MRI showing enhancing soft tissue mass in the right-posterior maxillary sinus extending into the right pterygopalatine fossa (arrow). Histologic examination of tumor showed adenoid cystic carcinoma. Note normal left pterygopalatine fossa (*). (B) Postcontrast, fat-saturated, axial, T1-weighted MRI showing PNS along right V2 (arrow) in foramen rotundum and cavernous sinus. (C) Postcontrast, fat-saturated, coronal, T1-weighted MRI showing PNS along enlarged right V2 (closed arrow) and vidian nerve (open arrow).
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Figure 16 (A) Axial, postcontrast CT scan showing abnormal thickened soft tissue (arrows) in the right pterygopalatine fossa, sphenopalatine foramen, foramen rotundum, and Meckel’s cave. (B) Axial CT scan bone window showing relatively smooth widening of the right pterygopalatine fossa (PPF) and foramen rotundum (R) without bony destruction, which is typical of perineural spread. (C) Coronal, CT scan bone window showing marked enlargement of both the right foramen rotundum (closed arrow) and vidian canal (open arrow). (D) Following treatment of lymphoma, coronal, CT scan bone window shows normalization of foramen rotundum (closed arrow) and restored cortical margin of vidian canal (open arrow) indicative of treatment response. The bony foramina and canals often remain radiographically widened after treatment.
Patients who have a well-aerated sphenoid sinus are susceptible to MRI blooming artifact if fat suppression is used.29 Fat suppression mildly enlarges the signal void of the aerated sphenoid sinus and obscures visualization of the adjacent foramen rotundum, foramen ovale, and the vidian canal. This artifact is even more pronounced in a 3-T magnet and therefore the 1.5-T is currently preferred. A similar susceptibility artifact can also occur in the temporal bone because the aerated mastoid air cells are in close proximity to the course of CN VII. The way to overcome the loss of signal around the skull base foramina and temporal bone is to add an additional postcontrast coronal T1-weighted sequence without fat saturation (Fig. 9). Evaluation of the postsurgical patient for PNS can be difficult because of distortion of V2 or V3 after maxillectomy or infratemporal fossa resection where these nerves can enhance and appear enlarged. In these instances, the key is to evaluate the preoperative scan for nerve involvement. If negative for PNS, postoperative enhancement and enlargement is likely related to postoperative change, which can persist long term. Close surveillance and stability on interval imaging
studies is an indicator of postoperative change rather than PNS in these patients. Similarly, evaluation of response of PNS to radiation therapy is also difficult to monitor because soft tissue changes in the involved nerve can persist indefinitely. Progression of the radiographic appearance of PNS or development of new symptoms is generally the only definite indicator of progression of disease in these patients. Elderly patients with skin cancer often present with symptoms or clinical signs of PNS involving CN V or CN VII or both. The patient shown in Figure 10 had a long history of removal of skin lesions from the scalp and face that were reportedly benign. Over time, he developed facial numbness and then diplopia for which he was referred to a neurologist for a presumed cavernous sinus primary tumor. Postcontrast axial T1-weighted MRI shows the classic appearance of PNS along the infraorbital nerve retrograde to V2, through foramen rotundum into the cavernous sinus and Meckel’s cave to the main trunk of CN V and into the CN V nucleus in the brainstem. The importance of precontrast T1-weighted MRI in assessment of PNS is illustrated in Figure 11. This patient had a
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Figure 17 Schwannoma of the right cavernous sinus. (A) Axial, postcontrast, T1-weighted MRI showing a fusiform lesion within the right cavernous sinus (arrow). (B) Coronal, T2-weighted MRI with fat saturation showing a hyperintense lesion (arrow) displacing but not narrowing the right internal carotid artery.
malignant melanoma of the skin of the left infraorbital skin. Note how easily the T1 isointense tumor in the premaxillary soft tissues contrasts against the adjacent normal T1 hyperintense fat (Fig. 11A). This finding could be missed on postcontrast T1-weighted sequence, as the enhancing tumor could blend in with the fat signal on a non–fat suppressed sequence, or if there is inadequate fat suppression. The tumor tracks along the infraorbital nerve into the PPF, where the nerve is abnormally enlarged with obvious replacement of the normal fat in comparison with the normal, right-hand side (Fig. 11B). Although widening of the PPF is easily seen in this patient, lesser degrees of bony canal abnormalities are better appreciated on CT. Once the tumor extends intracranially, it is best imaged with the postcontrast T1-weighted sequence
(Fig. 11C). Coronal imaging is useful for demonstrating the infraorbital nerve within the infraorbital canal in the floor of the orbit (Fig. 11D) and also nicely shows the abnormally enlarged V2 in the cavernous sinus (Fig. 11E) when compared with the opposite right-hand side. Tumors can spread between CN V and CN VII from one of many connections either centrally or peripherally. PNS along the greater superficial petrosal nerve is an example of central spread of tumor from CN V to CN VII (Fig. 12). The greater superficial petrosal nerve is a branch of CN VII that emanates from the geniculate ganglion, courses anteromedially just inferior to Meckel’s cave, and joins the deep petrosal nerve to form the vidian nerve which travels through the vidian canal into the PPF
Figure 18 Meningioma of the left cavernous sinus. (A) Axial, postcontrast, T1-weighted MRI with fat saturation showing a homogenously enhancing dural-based lesion extending into the left cavernous sinus (arrow). The lesion has dural tails anteriorly and posteriorly. (B) Coronal, postcontrast, T1-weighted MRI with fat saturation again demonstrates enhancing lesion of the cavernous sinus (arrow) with luminal narrowing of the left internal carotid artery, a classic feature of cavernous meningioma.
Perineural tumor spread where its preganglionic fibers synapse with the pterygopalatine ganglion. Therefore, tumor involving the PPF can track retrograde toward Meckel’s cave or vice versa. Tumor can also track directly from Meckel’s cave to the greater superficial petrosal nerve because of anatomical proximity. The auriculotemporal nerve is a peripheral pathway of tumor spread between CN V and CN VII (Fig. 13). It is the first branch off V3 below foramen rotundum. It exits as 2 rootlets that go around the middle meningeal artery, fuse into a short trunk, and split into multiple branches with anterior and posterior rami that connect to branches of CN VII within the parotid gland. Squamous cell carcinomas of the oral cavity and oropharynx have a lower propensity for PNS compared with cutaneous squamous cell carcinoma. However, involvement of the inferior alveolar nerve can result in PNS along V3 and is generally retrograde in direction. Antegrade PNS along the inferior alveolar nerve is rare but can have significant implications in treatment planning because of the intraosseous course of the nerve within the mandibular canal (Fig. 14). Adenoid cystic carcinoma has a particular affinity for nerves and is a common cause of PNS in tumors of the maxillary sinus and hard palate (Fig. 15). These tumors are generally treated with primary surgical resection, and accurate assessment for PNS is of practical value in management. Among other tumors that are associated with PNS, lymphoma is an often-ignored cause. In the absence of other primary tumors that are known to cause PNS, lymphoma should be considered in the differential diagnosis (Fig. 16) because of the obvious implications in terms of treatment. Lymphoma is not treated surgically and CT-guided biopsy is an excellent modality to obtain tissue for diagnosis so that the patient can expeditiously proceed to appropriate treatment. There are certain benign conditions that can mimic the appearance of PNS on radiographic imaging. One example of such a condition is schwannoma of the CNs. Unlike PNS, schwannomas are more fusiform in configuration, are T2 hyperintense, and can have a heterogeneous appearance (Fig. 17). Meningiomas are frequently seen in the cavernous sinus and should not be confused with PNS. These tumors are dural based, can extend into the cavernous sinus, and should have a dural tail. They enhance homogenously and when they extend into the cavernous sinus, they classically cause luminal narrowing of the internal carotid artery (Fig. 18).
Summary PNS of tumor is an underrecognized feature of many head and neck tumors. CN V is the most commonly involved CN and serves as conduit for extracranial tumors to the central skull base region. Given the density of CNs and the complexity of the anatomical structures in the central skull base region, radiologic detection of PNS along CN V and other nerves can be challenging. Ultimately, the presence and extent of PNS influence the selection of treatment and determine prognosis. Appropriate imaging and interpretation, therefore, play a crucial role in management of these patients.
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