Cutaneous Squamous Cell Carcinoma With Perineural Invasion: A Case Report and Review of the Literature

Author and Disclosure Information

Perineural invasion (PNI) is an uncommon manifestation of cutaneous squamous cell carcinoma (SCC). We report a case of recurrent cutaneous SCC with PNI diagnosed both clinically and histologically. We also provide a review the literature. Clinicians should be aware of this uncommon finding, as PNI has been associated with increased local recurrence, local and distant metastasis, and poor prognosis. Patients with clinical findings associated with perineural involvement have a poorer prognosis than those incidentally discovered on histologic examination, which emphasizes the importance of a thorough history and neurologic examination in patients with cutaneous SCC to identify those who will require more aggressive therapy.

Practice Points

• Patients with suspected cutaneous squamous cell carcinoma should be asked about neurological symptoms including pain, loss of motor skills, anesthesia, dysesthesia, and/or paresthesia, which may indicate perineural invasion.

• Patients with perineural invasion carry a much higher risk for local and distant recurrence and may require more aggressive treatment including Mohs micrographic surgery and adjuvant radiation.



Case Report

A 74-year-old man with a history of squamous cell carcinoma (SCC) on the right side of the temple that was treated with Mohs micrographic surgery (MMS) 3 years prior presented with a burning and tingling sensation of 3 months’ duration in the medial border of the repair scar. The patient denied prior anesthesia or muscle weakness of the face as well as any loss or change in vision.

Physical examination revealed a well-healed advancement flap scar with induration at the medial border (Figure 1). Biopsy results were positive for recurrent SCC. Based on anatomic location, clinical symptoms, and tumor recurrence, treatment with MMS was initiated. Mohs sections demonstrated perineural invasion (PNI) (Figures 2 and 3). Multiple treatment stages were required for tumor clearance following the retrograde course of a nerve, which resulted in a substantial defect (Figure 4). The defect was allowed to heal by second intention followed by radiation therapy.


Incidence and Pathogenesis—Perineural invasion was first described by Cruveilhier1 in a report of invasion of the facial nerve in a patient with mammary carcinoma. Neumann2 reported the first case of a primary cutaneous lesion exhibiting PNI in a patient with a primary carcinoma of the lower lip with invasion and spread along the mental nerve. Perineural invasion is seen in approximately 5% of 200,000 total cases of cutaneous SCC reported annually in the United States.3,4 Other malignancies exhibit PNI more frequently, such as microcystic adnexal carcinoma of the skin, which has been reported to have an 80% rate of perineural growth.5

Perineural invasion can involve nerves of variable thickness, but invasion of larger nerves typically portends a poorer prognosis.6 Characteristics of cutaneous SCC that predispose the lesion to PNI include size greater than 2 cm, male gender, location on the face, and prior treatment of the lesion.6,7 In a study of cutaneous SCC, Leibovitch et al7 found PNI in 4.7% (36/772) of primary lesions and 6.9% (34/491) of recurrent lesions. In another study of 180 SCC tumors of the head and neck with PNI, Carter et al8 found that PNI was most commonly seen in tumors that were greater than 2.5 cm, suggesting that larger lesions have an increased predisposition for PNI.

The mechanism(s) by which PNI develops from these malignancies has not been fully elucidated, but some clues have been found. Vural et al9 showed a statistically significant difference (P<.01) in expression of neural cell adhesion molecules with 93% (38/41) of SCCs with PNI showing evidence of expression versus 36% (9/25) of SCCs without PNI. Chen-Tsai et al10 also suggested that levels of neural cell adhesion molecules may be a factor in determining the metastatic potential of cutaneous SCCs and that levels of neurotrophic tyrosine kinase receptor type 1 (TrkA) may predict PNI, but their study results lacked statistical power to form a firm conclusion.

Diagnosis and Prognosis—Perineural invasion can be diagnosed clinically, radiologically, or microscopically. On clinical examination, PNI is suggested by findings of neuropathy most frequently in cranial nerves V and/or VII, likely due to their extensive subcutaneous distribution.11 Common symptoms include pain, loss of motor skills, anesthesia, dysesthesia, and/or paresthesia (ie, tingling, burning, pricking, numbness).12,13 In a study of 72 cases, Goepfert et al14 found that only 40% (29/72) of patients with pathologically confirmed PNI presented with clinical symptoms and these patients had a poorer prognosis.

Radiologically, PNI can be identified via computed tomography or magnetic resonance imaging through findings of enlargement or abnormal enhancement of the nerve, obliteration of the normal fat plane surrounding the nerve, or erosion or enlargement of its related foramen.15 Magnetic resonance imaging is the preferred method for assessing enhancement of the nerve, while computed tomography is preferred to assess involvement of bone.16,17 Microscopically, there is some debate as to what defines PNI. Suggested findings include the presence of cells inside the epineurium, involvement of nerves outside the main bulk of the tumor, or presence of tumor cells surrounding a nerve.18

These definitions have prognostic significance. Mendenhall et al16 found that patients with radiologic evidence of PNI without clinical symptoms had a higher cure rate using surgery and postoperative irradiation compared to patients with clinical symptoms (80% vs 45%). Although prognosis generally is good in patients with cutaneous SCC without PNI, prognosis is notably poorer when PNI is present due to the association of this finding with increased tumor recurrence and both local and distant metastasis.13 Most frequently, cutaneous SCC with PNI spreads proximally, which can lead to invasion into the base of the brain, but also can extend distally, leading to increased local burden.12,19 In a study of 64 patients with mucosal SCC, Soo et al20 found that patients with lesions that exhibited PNI had a 5-year survival of 16% versus 44% in those without PNI. In their study of SCC of the head and neck, Goepfert et al14 reported that 46% (33/72) of patients with PNI had died or were alive with recurrence at 2 years’ follow-up versus 9.1% (41/448) of patients without PNI. In a systematic review of outcomes, Jambusaria-Pahlajani et al21 reported a disease-specific death rate of 16% for cutaneous SCC with PNI compared to 4% for SCC without PNI.


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