Clinical Perineural Invasion of Cutaneous SCC May Warrant Adjuvant Treatment Interview with:
Dr. Chrysalyne D. Schmults, MD, MSCE
Associate Professor of Dermatology, Harvard Medical School
Director, Mohs and Dermatologic Surgery Center and
Mr. Pritesh S. Karia, MPH
Department of Epidemiology
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

Department of Dermatology
Brigham and Women’s Faulkner Hospital
Harvard Medical School, Boston, Massachusetts
Jamaica Plain, MA 02130-3446 What is the background for this study?

Response: Perineural nerve invasion (PNI) is a well-recognized risk factor for poor prognosis in patients with cutaneous squamous cell carcinoma (CSCC). Most cases of CSCC with PNI are identified on histologic examination at the time of surgery and the patient has no clinical symptoms or radiologic evidence of PNI. These cases are classified as incidental PNI (IPNI). However, some patients with PNI present with clinical symptoms and/or radiologic evidence of PNI. These cases are classified as clinical PNI (CPNI). A few studies have shown differences in disease-related outcomes between CSCC patients with IPNI and CPNI but consensus regarding adjuvant treatment and detailed guidelines on follow-up schedules have not yet materialized. What are the main findings?

Response: This systematic review included 12 studies of CSCC with PNI which reported patient outcomes. Patients with CPNI (n=241) were significantly more likely to develop local recurrence and die of CSCC compared with the 381 patients with IPNI (local recurrence, 37% vs. 17%, p<0.001; CSCC death, 27% vs. 6%, p<0.001). Additionally, patients with CPNI had poorer 5-year recurrence-free survival (61% vs. 76%, p=0.009) and disease-specific survival (70% vs. 88%, p=0.002) compared with patients with IPNI. What should clinicians and patients take away from your report?

Response: Based on the pooled analysis of outcomes data, patients with CPNI have a 27% risk of death from CSCC and therefore may warrant adjuvant treatment (radiation) and close surveillance for recurrence following treatment though the benefits of these have not yet been well-quantified. Surveillance via MRI every 6 months for 2 to 4 years after treatment may be considered after taking patient preference, age, and comorbidities into account.

Adjuvant therapy and MRI surveillance may also benefit patients with IPNI who have large-caliber PNI (≥0.1 mm) as they have an elevated risk of recurrence as compared to CSCC in general, though again, benefits are unproven.

Previous studies have shown that patients with IPNI of small-caliber PNI (<0.1 mm) have a low risk of poor outcomes in the absence of other prognostic risk factors and therefore do not require treatment beyond the NCCN recommendation of clear-margin excision via complete circumferential and deep margin assessment. What recommendations do you have for future research as a result of this study?

Response: Further studies are needed to determine the efficacy of adjuvant therapy and post-treatment surveillance in patients with CSCC and PNI. A phase 2 trial is currently ongoing of anti PD-1 therapy in patients with advanced CSCC. If immunotherapy is shown to be efficacious for advanced CSCC, future studies could be conducted to examine its role in the adjuvant setting in patients with CPNI or IPNI of large-caliber nerves. Thank you for your contribution to the community.


Karia PS, Morgan FC, Ruiz ES, Schmults CD. Clinical and Incidental Perineural Invasion of Cutaneous Squamous Cell CarcinomaA Systematic Review and Pooled Analysis of Outcomes Data. JAMA Dermatol. Published online July 05, 2017. doi:10.1001/jamadermatol.2017.1680

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