Cutaneous Squamous Cell Carcinoma With Perineural Invasion: A Case Report and Review of the Literature Chad C. Adams, MD; Brian Thomas, MD; Jonathan L. Bingham, MD Practice Points Patients with suspected cutaneous squamous cell carcinoma should be asked about neurological symp- toms 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. Perineural invasion (PNI) is an uncommon man- or muscle weakness of the face as well as any loss or ifestation of cutaneous squamous cell carci- change in vision. noma (SCC). We report CUTISa case of recurrent Physical examination revealed a well-healed cutaneous SCC with PNI diagnosed both clini- advancement flap scar with induration at the medial cally and histologically. We also provide a review border (Figure 1). Biopsy results were positive for recur- of the literature. Clinicians should be aware of rent SCC. Based on anatomic location, clinical symp- this uncommon finding, as PNI has been associ- toms, and tumor recurrence, treatment with MMS ated with increased local recurrence, local and was initiated. Mohs sections demonstrated perineural distant metastasis, and poor prognosis. Patients invasion (PNI)(Figures 2 and 3). Multiple treatment withDo clinical findings associated Not with perineural stages wereCopy required for tumor clearance following the involvement have a poorer prognosis than those retrograde course of a nerve, which resulted in a sub- incidentally discovered on histologic examination, stantial defect (Figure 4). The defect was allowed to which emphasizes the importance of a thorough heal by second intention followed by radiation therapy. history and neurologic examination in patients with cutaneous SCC to identify those who will Comment require more aggressive therapy. Incidence and Pathogenesis—Perineural invasion was Cutis. 2014;93:141-144. first described by Cruveilhier1 in a report of invasion of the facial nerve in a patient with mammary carcinoma. Case Report Neumann2 reported the first case of a primary cutane- A 74-year-old man with a history of squamous cell ous lesion exhibiting PNI in a patient with a primary carcinoma (SCC) on the right side of the temple that carcinoma of the lower lip with invasion and spread was treated with Mohs micrographic surgery (MMS) along the mental nerve. Perineural invasion is seen in 3 years prior presented with a burning and tingling approximately 5% of 200,000 total cases of cutaneous sensation of 3 months’ duration in the medial border SCC reported annually in the United States.3,4 Other of the repair scar. The patient denied prior anesthesia malignancies exhibit PNI more frequently, such as microcystic adnexal carcinoma of the skin, which has Dr. Adams is from Uniformed Services University of the Health been reported to have an 80% rate of perineural growth.5 Sciences, Bethesda, Maryland. Drs. Thomas and Bingham are from Perineural invasion can involve nerves of vari- Walter Reed National Military Medical Center, Bethesda. The authors report no conflict of interest. able thickness, but invasion of larger nerves typically 6 Correspondence: Chad C. Adams, MD, 2903 Ivydale St, Silver Spring, portends a poorer prognosis. Characteristics of cuta- MD 20902 ([email protected]). neous SCC that predispose the lesion to PNI include WWW.CUTIS.COM VOLUME 93, MARCH 2014 141 Copyright Cutis 2014. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. SCC With Perineural Invasion Figure 1. Recurrent cutaneous squamous cell carcinoma on the right side of the temple that was treated with Mohs micrographic surgery 3 years prior to presenta- tion, which resulted in a scar. Figure 3. A large peripheral nerve (diameter, 0.1 mm) in cross-section with perineural and intraneural carci- noma was evident. An associated lymphocytic inflam- matory infiltrate was present around the nerve bundle (H&E, original magnification 10). CUTIS Figure 2. A large peripheral nerve (diameter, 0.1 mm) demonstrated an intraneural island of enlarged,Do atypical keratinocytes Notthat formed keratin Copy eddies. A lymphocytic infiltrate surrounded the peri- neurium (H&E, original magnification 10). size greater than 2 cm, male gender, location on the face, and prior treatment of the lesion.6,7 In a study Figure 4. Multiple stages of Mohs micrographic sur- gery resulted in a substantial defect. 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 molecules may be a factor in determining the meta- that PNI was most commonly seen in tumors that were static potential of cutaneous SCCs and that levels of greater than 2.5 cm, suggesting that larger lesions have neurotrophic tyrosine kinase receptor type 1 (TrkA) an increased predisposition for PNI. may predict PNI, but their study results lacked statisti- The mechanism(s) by which PNI develops from cal power to form a firm conclusion. these malignancies has not been fully elucidated, but Diagnosis and Prognosis—Perineural invasion can be some clues have been found. Vural et al9 showed a sta- diagnosed clinically, radiologically, or microscopically. tistically significant difference (P.01) in expression On clinical examination, PNI is suggested by findings of neural cell adhesion molecules with 93% (38/41) of neuropathy most frequently in cranial nerves V of SCCs with PNI showing evidence of expression and/or VII, likely due to their extensive subcutaneous versus 36% (9/25) of SCCs without PNI. Chen-Tsai distribution.11 Common symptoms include pain, loss of et al10 also suggested that levels of neural cell adhesion motor skills, anesthesia, dysesthesia, and/or paresthesia 142 CUTIS® WWW.CUTIS.COM Copyright Cutis 2014. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. SCC With Perineural Invasion (ie, tingling, burning, pricking, numbness).12,13 In a Prognosis also is altered by the diameter of the study of 72 cases, Goepfert et al14 found that only nerve involved. In a study of 48 patients, Ross et al23 40% (29/72) of patients with pathologically confirmed found that patients with cutaneous SCC involv- PNI presented with clinical symptoms and these ing small-caliber nerves (diameter, ≤0.1 mm) had a patients had a poorer prognosis. 0% disease-specific death rate versus 32% in those with Radiologically, PNI can be identified via computed large-caliber nerves (0.1 mm). Perineural involve- tomography or magnetic resonance imaging through ment of small-caliber nerves (0.1 mm) was a posi- findings of enlargement or abnormal enhancement tive prognostic indicator in that it was associated with of the nerve, obliteration of the normal fat plane sur- smaller tumor diameter, more shallow invasion, and rounding the nerve, or erosion or enlargement of its increased likelihood to be primary tumors.23 In a recent related foramen.15 Magnetic resonance imaging is the study, Jambusaria-Pahlajani et al24 investigated tumor preferred method for assessing enhancement of the staging for cutaneous SCC and reported that PNI is nerve, while computed tomography is preferred to a statistically independent prognostic risk factor for assess involvement of bone.16,17 Microscopically, there nodal metastasis (subhazard ratio, 2.2 [95% confidence is some debate as to what defines PNI. Suggested find- interval, 0.9-5.1]) and disease-specific death (subhaz- ings include the presence of cells inside the epineurium, ard ratio, 3.4 [95% confidence interval, 0.9-13.3]). involvement of nerves outside the main bulk of the Of interest, this increased risk applied only to PNI in tumor, or presence of tumor cells surrounding a nerve.18 nerves that were greater than 0.1 mm.24 These definitions have prognostic significance. Treatment Options—Management of confirmed Mendenhall et al16 found that patients with radiologic cases of cutaneous SCC with PNI is difficult because evidence of PNI without clinical symptoms had a of the nature of the lesions, including their increased higher cure rate using surgery and postoperative irra- propensity for metastasis, increased frequency of poorly diation compared to patients with clinical symptoms differentiated cell types, highly aggressive nature, and (80% vs 45%). Although prognosis generally is good the unique challenge of skip lesions.4,16 Skip lesions are in patients with cutaneous SCC without PNI, prog- found microscopically and show (or appear to show) nosis is notably poorer when PNI is present due to the neoplastic cells invading a nerve in a discontinuous association of this finding withCUTIS increased tumor recur- fashion. This phenomenon has been suggested as rence and both local and distant metastasis.13 Most fre- one explanation for the relatively higher postsurgical quently, cutaneous SCC with PNI spreads proximally, recurrence rate of SCC with PNI compared to lesions which can lead to invasion into the base of the brain, without PNI.7 They are of particular interest when but also can extend distally, leading to increased local removing cutaneous SCC with PNI using MMS and burden.12,19 In a study of 64 patients with mucosal SCC, attempting to define clear margins. Despite this limita- Soo et al20 found that patients with lesions that exhib- tion, MMS generally is accepted as the primary mode ited DoPNI had a 5-year survival Notof 16% versus 44% in of excisionCopy of cutaneous SCCs with PNI, as it has those without PNI. In their study of SCC of the head the highest known cure rate.7 Cottel4 did not report and neck, Goepfert et al14 reported that 46% (33/72) any cases of local recurrence over 1 to 42 months in of patients with PNI had died or were alive with recur- 17 patients who were treated with MMS, in contrast to rence at 2 years’ follow-up versus 9.1% (41/448) of Rowe et al25 who demonstrated that traditional surgical patients without PNI.