Defining High-Risk NMSC: Integrating Staging Systems and Tumor Biology to Guide Management

At the 2026 American Academy of Dermatology (AAD) Annual Meeting in Denver, Colorado, Todd Schlesinger, MD, presented, “Defining High-Risk NMSC: Clinical and Pathologic Predictors That Guide Treatment Decisions.”¹ While discussing the key points of his session, Schlesinger, a dermatologist, Mohs surgeon, and clinical trialist at Epiphany Dermatology in South Carolina, and director of Clinical Research Center of the Carolinas, emphasized that accurate identification of high-risk nonmelanoma skin cancer (NMSC) hinges on understanding both established staging systems and individual tumor characteristics. “You need to understand what the risk factors are,” he said, noting that clinicians should be familiar with both the AJCC 8th edition and the Brigham and Women’s Hospital (BWH) staging systems.

Schlesinger explained that these systems offer complementary insights. The AJCC framework is largely depth-driven, whereas the BWH model is risk-based, incorporating factors such as tumor characteristics and patient features. “Taking those together…can help us understand what the risk factors are for our patients,” he noted. While these models are most robust for cutaneous squamous cell carcinoma (cSCC), clinicians often extrapolate them for basal cell carcinoma (BCC), where formal staging remains limited.

Patient and Tumor-Specific Risk Factors

Beyond staging, Schlesinger stressed the importance of global patient assessment, particularly immunosuppression. “Immunosuppression is a big one that could increase the risk of spread,” he said, especially in cSCC.

He also highlighted key histopathologic features that elevate risk. Among these, perineural invasion (PNI) remains a critical but sometimes misunderstood factor. “There’s a difference between incidental perineural invasion… and large caliber nerve invasion,” he explained, defining high-risk PNI as involvement of nerves ≥0.1 mm in diameter or named nerves. These findings are associated with deeper invasion and increased metastatic potential.

Integrating Molecular Tools Into Clinical Practice

Emerging tools such as gene expression profiling may further refine risk assessment. Schlesinger noted that combining staging systems with molecular diagnostics “can help us be much more accurate” in identifying patients at higher risk of recurrence or metastasis.

This integrated approach has practical implications for management decisions, including the use of adjuvant radiation therapy and consideration of sentinel lymph node biopsy in advanced cSCC. “This really helps us decide if they need sentinel lymph node biopsies,” he said.

Expanding Options

Schlesinger also pointed to ongoing innovations in NMSC treatment. Investigational approaches include intralesional immunotherapy, such as cemiplimab, being studied for lower-risk cSCC in outpatient dermatology settings. “Lots of companies are looking at subcutaneous injections…for basal cell carcinoma and squamous cell carcinoma,” he said.

Additionally, advances in photodynamic therapy—such as topical aminolevulinic acid with red light for superficial BCC—highlight the continued evolution of noninvasive treatment strategies.

Ongoing Research in NMSC and Beyond

Schlesinger highlighted several active areas of investigation within his research program. Recent work includes a study published in the Journal of the American Academy of Dermatology evaluating topical 10% aminolevulinic acid gel with red light photodynamic therapy for superficial BCC.² “This medication is now at the FDA, hopefully to get approval soon,” he said.

He also pointed to ongoing clinical trials exploring intralesional immunotherapy. The CLEAR SCC study (NCT06585410) is evaluating subcutaneous cemiplimab for lower-risk cSCC in the dermatology clinic setting. “We’re seeing if we can actually treat lower-risk squamous cell carcinoma with a subcutaneous injection,” Schlesinger noted, adding that this approach reflects broader industry interest in localized immunotherapeutic strategies.

Key Data Trends at AAD 2026

Beyond NMSC, Schlesinger emphasized several areas of interest at the meeting. He noted growing attention to novel antibacterial mechanisms of action aimed at improving specificity and durability of microbial targeting. “Can we be more specific to the pathogenic bacteria…or do a better job of killing all the bacteria longer?” he said.

In aesthetics, he highlighted emerging neuromodulators and fillers, including short-acting toxin formulations and expanded indications for structural fillers. Additionally, he pointed to recent approvals in medical dermatology, including new therapies for psoriasis (icotrokinra) and chronic spontaneous urticaria (remibrutinib), as examples of the rapidly evolving therapeutic landscape.

References

1. Schlesinger T. Defining high-risk NMSC: clinical and pathologic predictors that guide treatment decisions. Presented at: 2026 American Academy of Dermatology Annual Meeting; March 27-31, 2026; Denver, CO.
2. Schlesinger T, Chapman MS, Tu JH, et al. Red light photodynamic therapy with 10% aminolevulinic acid gel showed efficacy for treatment of superficial basal cell carcinoma in a randomized, vehicle controlled, double-blind, multicenter phase III study. J Am Acad Dermatol. 2025;93(6):1489-1498. doi:10.1016/j.jaad.2025.08.031