Cutaneous Squamous Cell Carcinoma: Risk Stratification, Staging, and the Immunotherapy Revolution

Conclusions

• Cutaneous squamous cell carcinoma is an increasingly common and clinically important cancer, especially in older and immunosuppressed patients, so accurate risk stratification is essential.
• Among current staging approaches, BWH staging appears more specific for identifying high-risk disease than AJCC staging, and higher-risk subsets such as BWH T2b/T3 and AJCC-8 T3 are most associated with poor outcomes.
• Risk stratification may improve by refining how perineural invasion is defined, since extensive or symptomatic perineural spread seems more prognostically important than incidental nerve caliber alone.
• AI-based and gene-expression-based tools may outperform traditional staging systems in predicting aggressive cSCC and could become useful adjuncts for treatment planning.
• High-risk cSCC should generally prompt more intensive workup, including consideration of imaging and sentinel lymph node biopsy, because clinical exam alone can miss occult nodal disease.
• Imaging is helpful for detecting nodal, bony, and perineural spread, with modality choice depending on the suspected pattern of invasion, and abnormal imaging findings should be confirmed with biopsy.
• Management of high-risk cSCC is best handled with a multidisciplinary approach that combines complete surgical clearance with selective adjuvant radiation, systemic therapy, and close follow-up.
• Routine adjuvant radiation after negative margins remains uncertain, and the decision should be individualized based on tumor features and patient factors.
• Checkpoint immunotherapy has transformed advanced cSCC treatment, with cemiplimab, pembrolizumab, and cosibelimab now providing meaningful response rates.
• The C-POST trial established adjuvant cemiplimab after surgery and radiation as a standard option for very high-risk cSCC by substantially reducing recurrence or death.
• Neoadjuvant immunotherapy is an emerging strategy that can shrink tumors before surgery, improve pathologic response, and may allow less morbid or even organ-preserving surgery in selected patients.
• Immunotherapy in solid-organ transplant recipients remains challenging because of graft-rejection risk, but carefully selected patients may still benefit from treatment.
• Field cancerization control and chemoprevention remain important, with topical field therapy, nicotinamide, and acitretin helping reduce future skin cancer burden in high-risk patients.
• Future progress is likely to come from biomarkers, circulating tumor DNA, intralesional therapy, and combination immunotherapy strategies that better tailor treatment to tumor biology.