Cutaneous Squamous With Perineural : 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 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 CUTIS a 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). 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 , 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 . 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 exhibit PNI more frequently, such as microcystic adnexal carcinoma of the , which has Dr. Adams is from Uniformed Services University of the 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

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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 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 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

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(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. In a systematic review of out- excision had a 47% (34/72) local recurrence rate; how- comes, Jambusaria-Pahlajani et al21 reported a disease- ever, it bears noting that the varying follow-up periods specific death rate of 16% for cutaneous SCC with PNI in the Cottel4 study may underestimate recurrence rate. compared to 4% for SCC without PNI. Leibovitch et al7 had similar findings in their prospec- Perineural invasion can be further classified as tive case series study of 70 patients, which revealed an clinical or microscopic (incidental) for prognostic 8% recurrence rate within 5 years in patients treated purposes. A study by Garcia-Serra et al13 found that with MMS, a rate lower than other non-MMS modali- patients with clinical PNI had a notably poorer prog- ties. In this same study, the authors noted that some nosis than those with microscopic (incidental) PNI. researchers believe an additional level should be taken The clinical group achieved a local control rate of 55% with MMS beyond the appearance of free margins in at 5 years’ follow-up versus 87% in the microscopic cases with PNI.7 group. McCord et al22 found a 5-year local control rate Jambusaria-Pahlajani et al21 reported that PNI of 78% for microscopic (incidental) PNI versus 50% is one of the most common reasons cited for using for clinical PNI; they also found that patients with adjuvant radiation therapy for cases of cutaneous SCC radiologic evidence of PNI had a worse prognosis, not- because of the known propensity of local recurrence; ing that patients with radiologic evidence of PNI were however, in 74 reviewed cases, there was no statisti- nearly all clinically symptomatic. cally significant difference in outcomes in cases of

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surgery alone versus surgery and adjuvant irradiation. in perineural invasion by basal cell and cutaneous squamous Radiation therapy is a possible alternative primary cell . Dermatol Surg. 2004;30:1009-1016. treatment of cutaneous SCC with PNI, especially 11. McCord M, Mendenhall WM, Parsons JT, et al. Skin in cases of perineural involvement that is extensive of the head and neck with clinical perineural invasion. Int J or affects proximal portions of cranial nerves when Radiat Oncol Biol Phys. 2000;47:89-93. surgery is a less viable option.17 Mendenhall et al16 12. Ampil FL, Hardin JC, Peskind SP, et al. Perineural invasion suggested that patients with positive margins after exci- in skin cancer of the head and neck: a review of nine cases. sion who display extensive PNI should be treated with J Oral Maxillofac Surg. 1995;53:34-38. adjuvant irradiation locally and along the course of the 13. Garcia-Serra A, Hinerman RW, Mendenhall WM, et al. involved nerve to the skull base. Carcinoma of the skin with perineural invasion. Head Neck. 2003;25:1027-1033. Conclusion 14. Goepfert H, Dichtel WJ, Medina JE, et al. Perineural inva- Physicians should recognize the importance of early sion in squamous cell skin carcinoma of the head and neck. detection of PNI in cases of cutaneous SCC. A thor- Am J Surg. 1984;148:542-547. ough history with good neurologic examination of 15. Galloway TJ, Morris CG, Mancuso AA, et al. Impact of the head and neck in patients with cutaneous SCC radiographic findings on prognosis for skin carcinoma with is imperative so patients can be treated earlier in the clinical perineural invasion. Cancer. 2005;103:1254-1257. course of the lesion, increasing the likelihood of local 16. Mendenhall WM, Amdur RJ, Williams LS, et al. Carcinoma control, minimizing the risk for future recurrence, and of the skin of the head and neck with perineural invasion. decreasing mortality. Head Neck. 2002;24:78-83. 17. Williams LS, Mancuso AA, Mendenhall WM. Perineural REFERENCES spread of cutaneous squamous and basal cell carcinoma: 1. Cruveilhier J. Maladies des nerfs. In: Cruveilhier J, ed. CT and MR detection and its impact on patient man- Anatomie Pathologique du Corps Humain. 2nd ed. Paris, agement and prognosis. Int J Radiat Oncol Biol Phys. France: JB Bailliere; 1835:1-3. 2001;49:1061-1069. 2. Neumann E. Secondare cancroid infiltration des nervus 18. Veness MJ, Biankin S. Perineural spread leading to mentalis bei einem fall von lippincroid.CUTIS Arch Pathol Anat. orbital invasion from skin cancer. Australasian Radiol. 1862;24:201-205. 2000;44:296-302. 3. Salasche S. Epidemiology of actinic keratoses and squamous 19. Feasel AM, Brown TJ, Bogle MA, et al. Perineural inva- cell carcinoma. J Am Acad Dermatol. 2000;42(1, pt 2):4-7. sion of cutaneous malignancies. Dermatol Surg. 2001; 4. Cottel WI. Perineural invasion by squamous-cell carcinoma. 27:531-542. J Dermatol Surg Oncol. 1982;8:589-600. 20. Soo K, Carter RL, O’Brien CJ, et al. Prognostic implications 5. Cooper PH, Mills SE, Leonard DD, et al. Sclerosing of perineural spread in squamous carcinomas of the head Dosweat duct (syringomatous) carcinoma.Not Am J Surg Pathol. and Copyneck. Laryngoscope. 1986;96:1145-1148. 1985;9:422-433. 21. Jambusaria-Pahlajani A, Miller CJ, Quon H, et al. Surgical 6. Ross AS, Whalen FM, Elenitsas R, et al. Diameter of monotherapy versus surgery plus adjuvant radiotherapy in involved nerves predicts outcomes in cutaneous squa- high-risk cutaneous squamous cell carcinoma: a systematic mous cell carcinoma with perineural invasion: an investi- review of outcomes. Dermatol Surg. 2009;35:574-584. gator-blinded retrospective cohort study. Dermatol Surg. 22. McCord MW, Mendenhall WM, Parsons JT, et al. Skin 2009;35:1859-1866. cancer of the head and neck with incidental micro- 7. Leibovitch I, Huilgol SC, Selva D, et al. Cutaneous squa- scopic perineural invasion. Int J Radiat Oncol Biol Phys. mous cell carcinoma treated with Mohs micrographic 1999;43:591-595. surgery in II. perineural invasion. J Am Acad 23. Ross AS, Whalen FM, Elenitsas R, et al. Diameter of Dermatol. 2005;53:261-266. involved nerves predicts outcomes in cutaneous squa- 8. Carter RL, Foster CS, Dinsdale EA, et al. Perineural spread mous cell carcinoma with perineural invasion: an investi- by squamous carcinomas of the head and neck: a morpho- gator-blinded retrospective cohort study. Dermatol Surg. logical study using antiaxonal and antimyelin monoclonal 2009;35:1859-1866. antibodies. J Clin Pathol. 1983;36:269-275. 24. Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. 9. Vural E, Hutcheson J, Korourian S, et al. Correlation of neu- Evaluation of AJCC tumor staging for cutaneous squamous ral cell adhesion molecules with perineural spread of squa- cell carcinoma and a proposed alternative tumor staging sys- mous cell carcinoma of the head and neck. Otolaryngol Head tem. JAMA Dermatol. 2013;149:402-410. Neck Surg. 2000;122:717-720. 25. Rowe DE, Carroll RJ, Day CL. Prognostic factors for local 10. Chen-Tsai CP, Colome-Grimmer M, Wagner RF Jr. recurrence, metastasis, and survival rates in squamous cell Correlations among neural cell adhesion molecule, nerve carcinoma of the skin, , and lip. J Am Acad Dermatol. growth factor, and its receptors, TrkA, TrkB, TrkC, and p75, 1992;26:976-990.

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