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Why did this 68-year-old man develop persistent headache and numbness on the right side of his face, which gradually worsened over the past 5 years? That's what David S. Buchberger, MD, MSc, of Taussig Cancer Institute at the Cleveland Clinic, and colleagues needed to determine when the man presented with slurred speech, atrophy of his right temple, and a drooping right eyelid.

The patient said that his vision had gradually deteriorated over the last few years as he developed muscle weakness and loss of sensation affecting the right side of his face. This resulted in a facial droop and slurred speech, as well as the eyelid ptosis. Finally, the patient developed "binocular vertical and horizontal diplopia and periorbital headaches," Buchberger and team recounted in .

While the patient had tried several treatments, including gabapentin and steroids, he found no relief. His medical history included complete excision of a melanoma on his left cheek years ago, and successful removal of several cutaneous squamous and basal cell carcinomas of the bilateral head and neck. He also had type 2 diabetes and hyperlipidemia. He was receiving treatment with metformin and simvastatin, and had no history of smoking or drinking.

On clinical assessment, the patient had "right-sided ptosis and severe right facial weakness in a lower motor neuron pattern with temporal wasting. The right pupil was fixed and dilated. There was no afferent pupillary defect," the authors noted. The left pupil was of normal size, and appropriately reactive.

Ophthalmologic assessment revealed blurry vision in his right eye, with impairment (20/250), and vertical and horizontal diplopia affecting his left and right eye. "Right extraocular movements were significantly limited in all directions and painful, and right-sided facial sensation was diminished to pinprick in all cranial nerve (CN) V distributions," the authors wrote.

The patient underwent MRI, with unremarkable findings. Buchberger and team said that biopsy of CN VII was nondiagnostic, and HbA1c was 6.8%. There was no evidence of infection and autoimmune disease on blood test results, although cerebrospinal fluid studies identified minor elevation in protein values.

The researchers determined that the patient's symptoms were due to perineural spread of cutaneous malignancy.

Discussion

MRI of the patient's brain and orbital cavity "showed asymmetric enhancement of right cranial nerves V and VII on the right side, with evidence of denervation atrophy of the masticator space," the authors wrote. They biopsied the infraorbital nerve, which revealed squamous cell carcinoma (SCC). Based on the patient's history, this was likely from a cutaneous source. He was initiated on immunotherapy with cemiplimab (Libtayo).

"MRI findings have remained stable over the past 2 years with no progression of disease or worsening symptoms," the authors noted. "The onset of multiple cranial neuropathies presents a diagnostic dilemma."

A cancer diagnosis can be challenging without presentation of an obvious lesion and normal or equivocal imaging, they explained, with the risk of delayed diagnosis and worse outcomes.

This patient's malignancy was only diagnosed after 5 years of contact with 20 different physicians, including general, autonomic, and neuromuscular neurologists and neuro-ophthalmologists, Buchberger and co-authors wrote. "It can take time for perineural invasion (PNI) to become radiographically apparent, and a high index of suspicion for underlying malignancy must be maintained even with initially negative imaging."

This patient's symptoms, history, and imaging results were most likely to reflect PNI of cutaneous SCC, a presumptive diagnosis that the team confirmed by biopsy.

This common cancer tends to present on the head and neck, secondary to sun exposure. An estimated 2% to 6% of patients with cutaneous SCC of the head and neck develop PNI, in which the tumor spreads into nerves and surrounding space.

"Cranial nerves V and VII are most commonly involved given their extensive anatomical distributions," the authors wrote. "Clinically or radiographically apparent PNI confers a poor prognosis with a reported 5-year absolute survival rate of 50%."

Cutaneous SCC of the head and neck may be treated with surgery (if resectable); high-dose radiotherapy and systemic therapy may also be used in appropriate cases. In addition, immunotherapy with checkpoint inhibition is being used with increasing frequency and notable effectiveness, the authors noted, citing several early-phase studies that have shown "impressive response rates near 50% for advanced, unresectable, and metastatic cutaneous SCC of the head and neck."

The positive findings have resulted in FDA approval of two checkpoint inhibitors in this setting -- cemiplimab and (Keytruda).

Indeed, Buchberger and colleagues pointed to recent findings from a of neoadjuvant cemiplimab for stage II through IV (M0) cutaneous SCC, with "51% complete pathological response rates and 68% objective response rates on imaging."

Another recent analysis of checkpoint inhibitor treatment in 11 patients with clinical PNI secondary to cutaneous SCC of the head and neck showed in nine patients at extended follow-up. "Many of these responses are durable and curative," the authors wrote.

"The presence of both CN V and VII symptoms in a patient with a history of head and neck cutaneous SCC should raise suspicion for perineural recurrence of disease," notwithstanding negative findings on initial MRI studies, they noted. Over time, imaging may reveal evidence of PNI as the disease advances and symptoms worsen, they added, advising that a neuroradiologist's review may lead to earlier identification of such findings.

"Mounting evidence suggests that immunotherapy is a promising treatment option for this population and should be considered as first-line therapy," the team concluded.

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