Perineural invasion is an infiltrative process of peripheral nerves by the primary neoplasm within the immediate vicinity. Aggressive forms of keratinocyte carcinomas, such as basal cell and squamous cell carcinomas, may feature perineural invasion, which is often associated with tumor recurrence and poorer prognosis. Diagnosis requires a high clinical suspicion. Imaging and histopathology are used to assess for extent of disease while surgical excision with complete circumferential peripheral and margin assessment is the treatment goal. However, there is still significant uncertainty about adjuvant chemotherapy and definitive management guidelines. Here, we summarize the current understanding of this complex pathogenic process, the clinical presentation, and the significance of perineural inflammation. We also discuss the recommendations about staging, prognosis, adjuvant radiotherapy, and general guidelines for managing keratinocyte carcinomas with perineural invasion. A better understanding of perineural invasion is essential to improve diagnosis, tailor interventions, and mitigate patient morbidity and mortality.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer. Cancer. 2009;115:3379–91.
Feasel AM, Brown TJ, Bogle MA, Tschen JA, Nelson BR. Perineural invasion of cutaneous malignancies. Dermatol Surg. 2001;27:531–42.
Goepfert H, Dichtel WJ, Medina JE, Lindberg RD, Luna MD. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am J Surg. 1984;148:542–7.
Gupta A, Veness M, De’Ambrosis B, Selva D, Huilgol SC. Management of squamous cell and basal cell carcinomas of the head and neck with perineural invasion. Australas J Dermatol. 2016;57:3–13.
Karia PS, Morgan FC, Califano JA, Schmults CD. Comparison of tumor classifications for cutaneous squamous cell carcinoma of the head and neck in the 7th vs 8th edition of the AJCC cancer staging manual. JAMA Dermatol. 2018;154:175–81.
Alam M. Uncertainty and variance in the management of high-risk cutaneous squamous cell carcinoma: comment on “Uncertainty in the Perioperative Management of High-Risk Cutaneous Squamous Cell Carcinoma Among Mohs Surgeons.” Arch Dermatol. 2010;146. http://archderm.jamanetwork.com/article.aspx?doi=10.1001/archdermatol.2010.1231. Accessed 29 Dec 2020.
Miller SJ. Defining, treating, and studying very high-risk cutaneous squamous cell carcinomas. Arch Dermatol. 2010;146. http://archderm.jamanetwork.com/article.aspx?doi=10.1001/archdermatol.2010.309. Accessed 31 Dec 2020.
NCCN. NCCN clinical practice guidelines in oncology. https://www.nccn.org/professionals/physician_gls/. Accessed 8 Nov 2020.
Jambusaria-Pahlajani A, Hess SD, Katz KA, Berg D, Schmults CD. Uncertainty in the perioperative management of high-risk cutaneous squamous cell carcinoma among Mohs surgeons. Arch Dermatol. 2010;146:1225–31.
Larson DL, Rodin AE, Roberts DK, O’Steen WK, Rapperport AS, Lewis SR. Perineural lymphatics: myth or fact. Am J Surg. 1966;112:488–92.
Brown IS. Pathology of perineural spread. J Neurol Surg B Skull Base. 2016;77:124–30.
Bakst RL, Wong RJ. Mechanisms of perineural invasion. J Neurol Surg B Skull Base. 2016;77:96–106.
Fagan JJ, Collins B, Barnes L, D’Amico F, Myers EN, Johnson JT. Perineural invasion in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1998;124:637–40.
Carter RL, Foster CS, Dinsdale EA, Pittam MR. Perineural spread by squamous carcinomas of the head and neck: a morphological study using antiaxonal and antimyelin monoclonal antibodies. J Clin Pathol. 1983;36:269–75.
Dunn M, Morgan MB, Beer TW. Perineural invasion: identification, significance, and a standardized definition. Dermatol Surg. 2009;35:214–21.
Geist DE, Garcia-Moliner M, Fitzek MM, Cho H, Rogers GS. Perineural invasion of cutaneous squamous cell carcinoma and basal cell carcinoma: raising awareness and optimizing management: perineural invasion. Dermatol Surg. 2008;34:1642–51.
Bauer EA, Gordon JM, Reddick ME, Eisen AZ. Quantitation and immunocytochemical localization of human skin collagenase in basal cell carcinoma. J Invest Dermatol. 1977;69:363–7.
Leibovitch I, Huilgol SC, Selva D, Richards S, Paver R. Basal cell carcinoma treated with Mohs surgery in Australia III. Perineural invasion. J Am Acad Dermatol. 2005;53:458–63.
Mohs FE, Lathrop TG. Modes of spread of cancer of skin. AMA Arch Derm Syphilol. 1952;66:427–39.
Ratner D, Lowe L, Johnson TM, Fader DJ. Perineural spread of basal cell carcinomas treated with Mohs micrographic surgery. Cancer. 2000;88:1605–13.
Brown CI, Perry AE. Incidence of perineural invasion in histologically aggressive types of basal cell carcinoma. Am J Dermatopathol. 2000;22:123–5.
Walling HW, Fosko SW, Geraminejad PA, Whitaker DC, Arpey CJ. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev. 2004;23:389–402.
Leibovitch I, Huilgol SC, Selva D, Hill D, Richards S, Paver R. Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia II. Perineural invasion. J Am Acad Dermatol. 2005;53:261–6.
Karia PS, Morgan FC, Ruiz ES, Schmults CD. Clinical and incidental perineural invasion of cutaneous squamous cell carcinoma: a systematic review and pooled analysis of outcomes data. JAMA Dermatol. 2017;153:781–8.
Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip: implications for treatment modality selection. J Am Acad Dermatol. 1992;26:976–90.
Mendenhall WM, Parsons JT, Mendenhall NP, Brant TA, Stringer SP, Cassisi NJ, et al. Carcinoma of the skin of the head and neck with perineural invasion. Head Neck. 1989;11:301–8.
Weimar VM, Ceilley RI, Babin RW. Squamous-cell carcinoma with invasion of the facial nerve and underlying bone and muscle: report of a case. J Dermatol Surg Oncol. 1979;5:526–30.
Kerkelä E, Saarialho-Kere U. Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer. Exp Dermatol. 2003;12:109–25.
Chen-Tsai CP, Colome-Grimmer M, Wagner RF. Correlations among neural cell adhesion molecule, nerve growth factor, and its receptors, TrkA, TrkB, TrkC, and p75, in perineural invasion by basal cell and cutaneous squamous cell carcinomas. Dermatol Surg. 2004;30:1009–16.
Jungehuelsing M, Sittel C, Fischbach R, Wagner M, Stennert E. Limitations of magnetic resonance imaging in the evaluation of perineural tumor spread causing facial nerve paralysis. Arch Otolaryngol Head Neck Surg. 2000;126:506–10.
Rumboldt Z, Gordon L, Gordon L, Bonsall R, Ackermann S. Imaging in head and neck cancer. Curr Treat Opt Oncol. 2006;7:23–34.
Nemzek WR, Hecht S, Gandour-Edwards R, Donald P, McKennan K. Perineural spread of head and neck tumors: how accurate is MR imaging? AJNR Am J Neuroradiol. 1998;19:701–6.
Williams LS, Mancuso AA, Mendenhall WM. Perineural spread of cutaneous squamous and basal cell carcinoma: CT and MR detection and its impact on patient management and prognosis. Int J Radiat Oncol Biol Phys. 2001;49:1061–9.
Law WP, Pereira N, Vaska K. Perineural spread of recurrent cutaneous melanoma along cervical nerves into the spinal cord. BJR Case Rep. 2017;3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159240/. Accessed 8 Nov 2020.
Lee TJ, Glastonbury CM, Buckley AF, Eisele DW, Hawkins RA. Perineural spread of melanoma demonstrated by F-18 FDG PET With MRI and pathologic correlation. Clin Nucl Med. 2008;33:106–8.
Hannah A, Feigen M, Quong G, Akhurst T, Berlangieri SU, Zimet A, et al. Use of [F]-fluorodeoxyglucose positron emission tomography in monitoring response of recurrent neurotropic desmoplastic melanoma to radiotherapy. Otolaryngol Head Neck Surg. 2000;122:304–6.
Jimenez FJ, Grichnik JM, Buchanan MD, Clark RE. Immunohistochemical techniques in Mohs micrographic surgery: their potential use in the detection of neoplastic cells masked by inflammation. J Am Acad Dermatol. 1995;32:89–94.
Schmitd LB, Beesley LJ, Russo N, Bellile EL, Inglehart RC, Liu M, et al. Redefining perineural invasion: integration of biology with clinical outcome. Neoplasia. 2018;20:657–67.
Dunn M, Morgan MB, Beer TW, Chen KTK, Acker SM. Histologic mimics of perineural invasion. J Cutan Pathol. 2009;36:937–42.
Hassanein AM, Proper SA, Depcik-Smith ND, Flowers FP. Peritumoral fibrosis in basal cell and squamous cell carcinoma mimicking perineural invasion: potential pitfall in Mohs micrographic surgery. Dermatol Surg. 2005;31:1101–6.
Batsakis JG. Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol. 1985;94:426–7.
Abbas O, Bhawan J. Cutaneous perineural inflammation: a review. J Cutan Pathol. 2010;37:1200–11.
Frierson HF, Deutsch BD, Levine PA. Clinicopathologic features of cutaneous squamous cell carcinomas of the head and neck in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Hum Pathol. 1988;19:1397–402.
Albregts T, Orengo I, Salasche S, Duncan L, Sillman J, Hassoun H. Squamous cell carcinoma in a patient with chronic lymphocytic leukemia: an intraoperative diagnostic challenge for the Mohs surgeon. Dermatol Surg. 1998;24:269–72.
Dhandha MM, Kozel JA, Erickson QL, Vidal CI. Perineural granulomatous inflammation: a potential harbinger of perineural invasion in cutaneous squamous cell carcinoma: correspondence. Br J Dermatol. 2013;168:899–901.
Leow LJ. High-risk squamous cell carcinoma masquerading as dense inflammation on Mohs frozen sections. Australas J Dermatol. 2018;59:214–6.
Macdonald J, Sneath JR, Cowan B, Zloty D. Tumor detection after inflammation or fibrosis on Mohs levels. Dermatol Surg. 2013;39:64–6.
Green JS, Tournas JA, Allen EJ, Youker SR, Fosko SW. Mohs frozen tissue sections in comparison to similar paraffin-embedded tissue sections in identifying perineural tumor invasion in cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2012;67:113–21.
Alam M, Khan M, Veledar E, Pongprutthipan M, Flores A, Dubina M, et al. Correlation of inflammation in frozen sections with site of nonmelanoma skin cancer. JAMA Dermatol. 2016;152:173–6.
Cottel WI. Perineural invasion by squamous-cell carcinoma. J Dermatol Surg Oncol. 1982;8:589–600.
Hanke CW, Wolf RL, Hochman SA, O’Brian JJ. Chemosurgical reports: perineural spread of basal-cell carcinoma. J Dermatol Surg Oncol. 1983;9:742–7.
Kist D, Perkins W, Christ S, Zachary CB. Anti-human epithelial antigen (Ber-EP4) helps define basal cell carcinoma masked by inflammation. Dermatol Surg. 1997;23:1067–70.
Katz KH, Helm KF, Billingsley EM, Maloney ME. Dense inflammation does not mask residual primary basal cell carcinoma during Mohs micrographic surgery. J Am Acad Dermatol. 2001;45:231–8.
Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al., editors. AJCC cancer staging manual. 8th ed. Springer International Publishing; 2017. https://www.springer.com/gp/book/9783319406176. Accessed 1 Jan 2021.
Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al. Head and neck cancers: major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:122–37.
Roscher I, Falk RS, Vos L, Clausen OPF, Helsing P, Gjersvik P, et al. Validating 4 staging systems for cutaneous squamous cell carcinoma using population-based data: a nested case-control study. JAMA Dermatol. 2018;154:428–34.
Ruiz ES, Karia PS, Besaw R, Schmults CD. Performance of the American Joint Committee on Cancer staging manual, 8th Edition vs the Brigham and Women’s Hospital tumor classification system for cutaneous squamous cell carcinoma. JAMA Dermatol. 2019;155:819.
Breuninger H, Brantsch K, Eigentler T, Häfner H-M. Comparison and evaluation of the current staging of cutaneous carcinomas. J Dtsch Dermatol Ges. 2012;10:579–86.
Berlingeri-Ramos AC, Detweiler CJ, Wagner RF, Kelly BC. Dual S-100-AE1/3 immunohistochemistry to detect perineural invasion in monmelanoma skin cancers. J Skin Cancer. 2015;2015:
Han A, Ratner D. What is the role of adjuvant radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion? Cancer. 2007;109:1053–9.
Keohane SG, Proby CM, Newlands C, Motley RJ, Nasr I, Mustapa MFM, et al. The new 8th edition of TNM staging and its implications for skin cancer: a review by the British Association of Dermatologists and the Royal College of Pathologists, U.K. Br J Dermatol. 2018;179:824–8.
Wysong A, Newman JG, Covington KR, Kurley SJ, Ibrahim SF, Farberg AS, et al. Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2021;84:361–9.
Carter JB, Johnson MM, Chua TL, Karia PS, Schmults CD. Outcomes of primary cutaneous squamous cell carcinoma with perineural invasion: an 11-year cohort study. JAMA Dermatol. 2013;149:35–41.
Dim-Jamora KC, Perone JB. Management of cutaneous tumors with Mohs micrographic surgery. Semin Plast Surg. 2008;22:247–56.
Shriner DL, McCoy DK, Goldberg DJ, Wagner RF. Mohs micrographic surgery. J Am Acad Dermatol. 1998;39:79–97.
DuBay D, Cimmino V, Lowe L, Johnson TM, Sondak VK. Low recurrence rate after surgery for dermatofibrosarcoma protuberans: a multidisciplinary approach from a single institution. Cancer. 2004;100:1008–16.
Pugliano-Mauro M, Goldman G. Mohs surgery is effective for high-risk cutaneous squamous cell carcinoma. Dermatol Surg. 2010;36:1544–53.
Ballantyne AJ, Mccarten AB, Ibanez ML. The extension of cancer of the head and neck through peripheral nerves. Am J Surg. 1963;106:651–67.
Cartee TV, Monheit GD. How many sections are required to clear a tumor? Results from a web-based survey of margin thresholds in Mohs micrographic surgery. Dermatol Surg. 2013;39:179–86.
Eliezri YD, Cohen PR. Cancer recurrence following Mohs micrographic surgery: a mechanism of tumor persistence. Plast Reconstr Surg. 1992;90:121–5.
Matorin PA, Wagner RF. Mohs micrographic surgery: technical difficulties posed by perineural invasion. Int J Dermatol. 1992;31:83–6.
Mendenhall WM, Amdur RJ, Williams LS, Mancuso AA, Stringer SP, Mendenhall NP. Carcinoma of the skin of the head and neck with perineural invasion. Head Neck. 2002;24:78–83.
Garcia-Serra A, Hinerman RW, Mendenhall WM, Amdur RJ, Morris CG, Williams LS, et al. Carcinoma of the skin with perineural invasion. Head Neck. 2003;25:1027–33.
McCord MW, Mendenhall WM, Parsons JT, Flowers FP. Skin cancer of the head and neck with incidental microscopic perineural invasion. Int J Radiat Oncol Biol Phys. 1999;43:591–5.
Jambusaria-Pahlajani A, Miller CJ, Quon H, Smith N, Klein RQ, Schmults CD. Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: a systematic review of outcomes. Dermatol Surg. 2009;35:574–84.
Stevenson ML, Criscito MC, Wilken R, Doudican NA, Bain EE, Parashar B, et al. Use of adjuvant radiotherapy in the treatment of high-risk cutaneous squamous cell carcinoma with perineural invasion. JAMA Dermatol. 2020;156:918.
Lai SY, Weinstein GS, Chalian AA, Rosenthal DI, Weber RS. Parotidectomy in the treatment of aggressive cutaneous malignancies. Arch Otolaryngol Head Neck Surg. 2002;128:521–6.
Jackson JE, Dickie GJ, Wiltshire KL, Keller J, Tripcony L, Poulsen MG, et al. Radiotherapy for perineural invasion in cutaneous head and neck carcinomas: toward a risk-adapted treatment approach. Head Neck. 2009;31:604–10.
Kropp L, Balamucki CJ, Morris CG, Kirwan J, Cognetta AB, Stoer CB, et al. Mohs resection and postoperative radiotherapy for head and neck cancers with incidental perineural invasion. Am J Otolaryngol. 2013;34:373–7.
Ruiz ES, Koyfman SA, Kass J, Schmults CD. Surgery and salvage limited-field irradiation for control of cutaneous squamous cell carcinoma with microscopic residual disease. JAMA Dermatol. 2019;155:1193–5.
Massey PR, Morgan FC, Ruiz ES, Schmults CD. Histologic perineural invasion of unnamed nerves does not affect basal cell carcinoma outcomes. J Am Acad Dermatol. 2020;82:1528–30.
Leus AJG, Perrels EFD, Halmos GB, Terra JB, Steenbakkers RJHM, van Kester MS, et al. Postoperative radiotherapy for cutaneous squamous cell carcinoma in patients with microscopic residual disease. JAMA Dermatol. 2021;157(3):349–52.
Waxweiler W, Sigmon JR, Sheehan DJ. Adjunctive radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion: ART in the treatment of CSCC with PNI. J Surg Oncol. 2011;104:104–5.
Shetti M. Parallel uncertainty for adjuvant radiotherapy indications in cutaneous squamous cell carcinoma (CSCC) with perineural invasion (PNI) among radiation oncologists and Mohs surgeons. J Am Acad Dermatol. 2012;66:AB155.
Catalano PJ, Sen C, Biller HF. Cranial neuropathy secondary to perineural spread of cutaneous malignancies. Am J Otol. 1995;16:772–7.
Peters LJ, Goepfert H, Ang KK, Byers RM, Maor MH, Guillamondegui O, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys. 1993;26:3–11.
Locke J, Karimpour S, Young G, Lockett MA, Perez CA. Radiotherapy for epithelial skin cancer. Int J Radiat Oncol Biol Phys. 2001;51:748–55.
Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350:1937–44.
Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre J-L, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945–52.
Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet. 2000;355:949–55.
Loeffler JS, Larson DA, Clark JR, Weichselbaum RR, Norris CM, Ervin TJ. Treatment of perineural metastasis from squamous carcinoma of the skin with aggressive combination chemotherapy and irradiation. J Surg Oncol. 1985;29:181–3.
Balamucki CJ, Mancuso AA, Amdur RJ, Kirwan JM, Morris CG, Flowers FP, et al. Skin carcinoma of the head and neck with perineural invasion. Am J Otolaryngol. 2012;33:447–54.
Homma A, Shirato H, Furuta Y, Nishioka T, Oridate N, Tsuchiya K, et al. Randomized phase II trial of concomitant chemoradiotherapy using weekly carboplatin or daily low-dose cisplatin for squamous cell carcinoma of the head and neck. Cancer J. 2004;10:326–32.
Porceddu SV, Bressel M, Poulsen MG, Stoneley A, Veness MJ, Kenny LM, et al. Postoperative concurrent chemoradiotherapy versus postoperative radiotherapy in high-risk cutaneous squamous cell carcinoma of the head and neck: the randomized phase III TROG 05.01 trial. J Clin Oncol. 2018;36:1275–83.
Zabielinski M, Leithauser L, Godsey T, Gloster HM. Laboratory errors leading to nonmelanoma skin cancer recurrence after Mohs micrographic surgery. Dermatol Surg. 2015;41:913–6.
Ampil FL, Hardin JC, Peskind SP, Stucker FJ. Perineural invasion in skin cancer of the head and neck: a review of nine cases. J Oral Maxillofac Surg. 1995;53:34–8.
Wang JT, Palme CE, Morgan GJ, Gebski V, Wang AY, Veness MJ. Predictors of outcome in patients with metastatic cutaneous head and neck squamous cell carcinoma involving cervical lymph nodes: improved survival with the addition of adjuvant radiotherapy. Head Neck. 2012;34:1524–8.
Lin C, Tripcony L, Keller J, Poulsen M, Martin J, Jackson J, et al. Perineural infiltration of cutaneous squamous cell carcinoma and basal cell carcinoma without clinical features. Int J Radiat Oncol Biol Phys. 2012;82:334–40.
Terra JB, Gaster MB, Halmos GB, Roodenburg JL, van der Vegt B, Romeijn TR, et al. Local control of 151 head and neck cutaneous squamous cell carcinoma after radiotherapy: a retrospective study on efficacy and prognostic factors. Clin Otolaryngol. 2017;42:851–5.
Malhotra R, Huilgol SC, Huynh NT, Selva D. The Australian Mohs database, part II: periocular basal cell carcinoma outcome at 5-year follow-up. Ophthalmology. 2004;111:631–6.
Lawrence N, Cottel WI. Squamous cell carcinoma of skin with perineural invasion. J Am Acad Dermatol. 1994;31:30–3.
Miller J, Chang T, Schwartz D, Peters M, Baum C. Outcomes of adjuvant radiotherapy following negative surgical margins for cutaneous squamous cell carcinoma. Dermatol Surg. 2019;45:1111–6.
Osguthorpe JD, Abel CG, Lang P, Hochman M. Neurotropic cutaneous tumors of the head and neck. Arch Otolaryngol Head Neck Surg. 1997;123:871–6.
O’Bryan K, Sherman W, Niedt GW, Taback B, Manolidis S, Wang A, et al. An evolving paradigm for the workup and management of high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2013;69:595–602.
No external funding was used in the preparation of this article.
Conflicts of Interest/Competing Interests
Albert E. Zhou, Karl M. Hoegler, and Amor Khachemoune have no conflicts of interest that are directly relevant to the content of this article.
Consent to participate
Consent for publication
Availability of data and material
KMH and AK conceived the idea for the manuscript. AEZ and KMH analyzed the literature and drafted the manuscript. All authors edited the manuscript.
About this article
Cite this article
Zhou, A.E., Hoegler, K.M. & Khachemoune, A. Review of Perineural Invasion in Keratinocyte Carcinomas. Am J Clin Dermatol (2021). https://doi.org/10.1007/s40257-021-00615-6