{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T01:14:13Z","timestamp":1793236453244,"version":"4.5.0"},"reference-count":51,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Localized cutaneous squamous cell carcinoma (cSCC) has a favorable prognosis, unlike advanced disease, especially with clinical perineural invasion (PNI), which poses substantial management challenges due to aggressivity and higher recurrence, metastasis, and mortality risks. PNI, a high-risk staging feature, has worse outcomes, particularly when clinically evident rather than incidental. Clinical PNI (cPNI) is evident by clinical symptoms (such as pain, paresthesia, or motor deficits) or radiologic findings, whereas incidental PNI (iPNI) is identified only histologically without associated symptoms or radiologic evidence. PNI remains a novel area with varying practice patterns across institutions. Improving risk stratification and tailoring multidisciplinary approaches are critical for optimizing outcomes. Our review outlines clinical practice patterns at our institution, providing insights into managing cSCC with PNI, focusing on diagnosis, imaging, staging, and emerging immunotherapies. A structured search was conducted using the terms \u201cperineural invasion,\u201d \u201ccutaneous squamous cell carcinoma,\u201d and \u201cimmunotherapy.\u201d cPNI has a poor prognosis and requires nuanced clinical decision-making. Surgery and radiation remain central to management. Adjuvant therapy offers substantial survival benefit in cSCC with PNI, with improved disease-free and overall survival compared with surgery alone, supporting its use in appropriately selected high-risk patients. Traditional systemic therapies, including cisplatin and cetuximab, remain foundational but have shown only moderate response rates and limited durability in advanced or neurotropic cSCC. In contrast, immunotherapy\u2014now preferred for advanced or unresectable cases\u2014has transformed management, with programmed cell death protein-1 (PD-1) inhibitors showing promising results (up to 69% response rate) and disease stabilization. Neoadjuvant immunotherapy may enable tumor downstaging, improve radiation planning, and reduce surgical morbidity. Imaging for squamous cell carcinoma (SCC) with PNI aids staging and surveillance, but symptoms remain key for detecting recurrence. Our multidisciplinary approach emphasizes personalized care. Larger trials are needed to define the optimal role and sequencing of immunotherapy in this high-risk patient population.<\/jats:p>","DOI":"10.3390\/cancers17243921","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T10:35:51Z","timestamp":1765190151000},"page":"3921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Immunotherapy and Radiation for Clinical Perineural Invasion in Cutaneous Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9333-1123","authenticated-orcid":false,"given":"Renee A.","family":"Morecroft","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, HCA Florida Orange Park Hospital, Orange Park, FL 32073, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan S.","family":"Phillipps","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lang","family":"Gou","sequence":"additional","affiliation":[{"name":"College of Chemistry, UC Berkeley, Berkeley, CA 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3400-7123","authenticated-orcid":false,"given":"Alok A.","family":"Bhatt","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungjune","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7471-643X","authenticated-orcid":false,"given":"Homan","family":"Mohammadi","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxana S.","family":"Dronca","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bently","family":"Doonan","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruqin","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3214-2658","authenticated-orcid":false,"given":"Yujie","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Seon","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Pulmonology, Department of Internal Medicine, Bucheon St. Mary\u2019s Hospital College of Medicine, Seoul 14647, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenduo","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Janus","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\/Audiology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8268-3623","authenticated-orcid":false,"given":"Phillip","family":"Pirgousis","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\/Audiology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1575-4043","authenticated-orcid":false,"given":"Samip","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\/Audiology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluwafunmilola T.","family":"Okuyemi","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\/Audiology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisha M.","family":"Singer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila M.","family":"Tolaymat","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Mayo 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