An 82-year-old man developed a right abduction deficit and horizontal double vision. He was diagnosed with ocular myasthenia based on positive acetylcholine receptor blocking and binding antibodies. His double vision resolved with azathioprine and prednisone. Four years later, he experienced a central retinal vein occlusion in the right eye. He was treated with intravenous tissue plasminogen activator without improvement and his vision stabilized at 20/50 in that eye, with a 0.6 log unit right relative afferent pupillary defect (RAPD). Seven years later, he developed right brow numbness that progressed to dysesthesia and allodynia within a year. Four years after the onset of right brow numbness, the patient had resection of basal and squamous cell skin cancers of the head and neck. Because of concerns of increasing skin cancer, thrombocytopenia, and elevated liver enzymes, azathioprine was reduced. Prednisone was continued. Seven months later, he reported stabbing pain in his right cheek and right facial weakness. This prompted brain magnetic resonance imaging (MRI).
The contrast-enhanced, fat-suppressed MRI shows well-delineated right intraconal mass adjacent to the optic nerve sheath (Fig. 1). No other abnormalities are present. Specifically, the right trigeminal and facial nerves appeared normal.
The patient was evaluated in the neuro-ophthalmology clinic because of recurrence of horizontal diplopia and worsening right facial weakness. Visual acuity was 20/50, right eye and 20/20, left eye with a 0.6 log unit right RAPD. Visual field testing of the right eye revealed a central scotoma; the field of the left eye was full. Color vision was impaired on the right and stereovision was reduced. Extraocular motility showed a significantly limited (−3) abduction of the right eye and mild (−1) adduction and supraduction deficits of the left eye. The anterior and posterior segments were normal. There was no proptosis. The patient's neurologic examination was normal except for decreased sensation to light touch over the distribution of the maxillary and mandibular divisions of the right trigeminal nerve. In addition, the patient could not raise his right eyebrow and had flattening of his right nasolabial fold.
Because of the recent dose reduction of azathioprine, the patient was thought to have worsening myasthenia, and his prednisone was increased without any improvement. Although the facial weakness and diplopia could be explained by worsening myasthenia, the decreased sensation in his right face could not. With his constellation of findings and the presence of an enhancing intraconal mass, there was concern for metastatic disease, perineural invasion (PNI), or leptomeningeal carcinomatosis.
The patient underwent Mohs surgery of his scalp for squamous cell skin cancer. There was poor wound healing. Because of worsening right facial weakness, pain, and numbness, MRI was repeated 8 months after his previous study.
This study shows that the right intraconal mass adjacent to the optic nerve sheath has slightly increased in size (Fig. 2) compared with the study carried out 8 months earlier (Fig. 1). There is no thickening or contrast enhancement of the trigeminal or facial nerves (not shown).
A number of diagnoses had been considered in this patient, including metastatic squamous or basal cell carcinoma, lymphoma, leptomeningeal carcinomatosis, chronic central nervous system infection, and neoplastic PNI. The diagnosis of cranial nerve and leptomeningeal disease can be difficult to establish when imaging does not reveal enhancement of affected nerves or leptomeninges. Although cerebrospinal fluid samples are only positive for malignant cells in 54% of first lumbar puncture in patients with leptomeningeal metastasis (1), we recommended a lumbar puncture. Our patient declined this procedure, preferring to be followed without further intervention. At 3-month follow-up, his vision remained stable, with a persistent right abduction deficit, but the subtle elevation and adduction deficit of the left eye resolved. Although the orbital mass did not explain the patient's initial clinical findings and was not accompanied by worsening optic nerve function, when the second MRI showed enlargement of the lesion, a biopsy was performed.
The biopsy of the right intraconal orbital mass shows multiple fingers of tumor cells with round basophilic staining nuclei and cytoplasm, typical of metastatic squamous cell carcinoma (SCC) (Fig. 3A). The mass stains diffusely with p63 (Fig. 3B), cytokeratins 5/6 (Fig. 3C), and AE 1/3 (Fig. 3D) and E-cadherin (Fig. 3E), indicating squamous cell differentiation. Staining for estrogen receptors was negative (Fig. 3F), arguing against a breast origin of the lesion. Stains for CD3 and CD20 also were negative (Fig. 3G, H), excluding lymphoma and other lymphoid tumors.
At 17-month follow-up, the patient died. An MRI done 1 month previous to his death showed normal trigeminal and facial nerves on the right. However, there was new enhancement of the left facial nerve along the internal auditory canal (Fig. 4).
The patient had survived 6 years from the onset of his facial numbness. An autopsy was not performed.
Metastatic, poorly differentiated SCC with presumed PNI of the trigeminal and facial nerves.
The terms PNI and perineural spread (PNS) are used to describe involvement of nerves by certain tumors. PNI is microscopic infiltration of the nerve by tumor cells, whereas PNS describes gross tumor spread along a nerve that is, at least in part, distinct from the main tumor mass. The right facial pain, weakness, and dysesthesias in our patient could be explained by PNI of the trigeminal and facial nerves from metastatic, poorly differentiated SCC. His diplopia with bilateral motility deficits could have been due to undertreatment of his preexisting ocular myasthenia, although all cranial nerve deficits also could have been due to leptomeningeal carcinomatosis. Although we cannot exclude carcinomatous meningitis as a cause for our patient's neurological and visual deficits, repeated normal brain imaging, the length of time of his clinical course, and his overall well-being over this time, make this diagnosis unlikely.
PNI is an insidious form of tumor growth and is more often a feature of malignant than benign lesions. The prevalence of PNI in cases of SCC is 2.5%–5%. The following factors increase the risk of PNI: tumor size >2 cm, male gender, forehead location, recurrences, and previous treatment (2).
PNI most often involves the maxillary, mandibular, and facial nerves. The pterygopalatine fossa plays an important role in the involvement of these nerves. This fossa is a small space just behind the maxillary sinus and in front of the pterygoid plates of the sphenoid bone. An important feature of the pterygopalatine fossa is the many connections that it affords to other areas of the cranium. The fossa communicates with the orbit, nasal cavity, and infratemporal fossa through the inferior orbital fissure, sphenopalatine foramen, and pterygomaxillary fissure. Once the tumor reaches the pterygopalatine fossa or the foramen rotundum, it can spread into the cavernous sinus, Meckel cave and, eventually, along the cisternal portion of the trigeminal ganglion into the lateral aspect of the pons. Likewise, from the pterygopalatine fossa through the Vidian canal, tumor can spread to the petrous bone to involve the facial nerve.
Other cranial nerves that can be affected by PNI include the oculomotor, abducens, and hypoglossal. Typically, these patients present with facial pain, paresthesias, ptosis, diplopia, facial weakness, ophthalmoparesis, or a combination of these manifestations (3). Nevertheless, Nemzek et al (4) reported that 30%–60% of patients remain asymptomatic.
There are 3 current theories regarding the pathophysiology of PNI. First, nerve cell adhesion molecule (NCAM), an immunoglobulin with several functions including adhesion, proliferation, and migration of neural cells, is expressed in a large percentage of adenoid cystic carcinomas (ACCs). Although its role in PNI of SCC is not as well defined, Vural et al (5) showed that 93% of specimens from patients with PNS stained positive for NCAM. Second, tyrosine kinase A, one of a family of cell surface receptors with high affinity for polypeptide growth factors, cytokines, and hormones, is expressed along with nerve growth factor in 95% of cases of PNI from SCC of the tongue (6). Finally, Toll-like receptor 3 (TLR3), a protein encoded by the TLR3 gene, plays a key role in pathogen recognition by producing Type I interferons, and TLR3 expression is significantly correlated with poor differentiation and PNI of SCC of the head and neck (7).
In 1998, Nemzek et al (4) conducted a retrospective review of imaging findings in 19 patients with evidence of PNI. Among these patients, 10 had SCC, 4 ACC, 1 poorly differentiated carcinoma of unknown origin, 1 salivary duct carcinoma, 1 mucoepidermoid carcinoma, 1 had a chordoma, and 1 meningioma. The trigeminal nerve and its branches were involved in 85% of these patients. The authors concluded that MRI sensitivity in determining PNI was 95%. Bowyer et al (8) reported a 24% false-negative rate with MRI but concluded that MRI is better than computed tomography in detecting PNI.
Although a consensus on treatment guidelines for patients with PNI has not been established, most patients undergo surgery followed by radiation therapy. This regimen results in a local control rate of 50%–85%, with the ultimate prognosis depending, in part, on pretreatment imaging findings. The absolute 5-year survival rate is 50% in patients with MRI funding of PNI compared with 86% in patients whose imaging studies are unremarkable (P = 0.048) (9).
In summary, PNI is a known complication of SCC of the head and neck, and most commonly affects the trigeminal and facial nerves. Biopsy of asymptomatic lesions may help to confirm diagnosis. The imaging findings in PNI can be subtle, variable, and even normal despite clear-cut clinical findings.
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