High-Risk Cutaneous Squamous Cell Carcinoma: Refining Risk Stratification and Management

In this episode of Topical Conversations, Laura Ferris, MD, and Désirée Ratner, MD, discuss approaches to identifying and managing high-risk cutaneous squamous cell carcinoma (cSCC), with a focus on integrating traditional staging systems and molecular testing to guide treatment decisions.

Defining high-risk cSCC 

Historically, high-risk cSCC was defined by a combination of clinical and histologic features, such as tumor location on the head or neck, ill-defined borders, aggressive growth patterns, immunosuppression, or perineural invasion. The NCCN has since formalized a list of high-risk features, and staging systems such as AJCC and BWH now provide structured frameworks for evaluation. While these systems differ (for example, BWH includes poor differentiation as a criterion while AJCC does not) both have improved risk prediction compared to earlier approaches. 

Molecular testing with the 40-GEP assay 

Molecular assays such as the 40-GEP test offer additional prognostic refinement by evaluating gene expression within an individual tumor. The test categorizes patients as Class 1 (low risk), Class 2A (intermediate but clinically comparable to high risk in AJCC/BWH), or Class 2B (very high risk). Both physicians note the value of this tool in identifying patients who may benefit from closer surveillance or more aggressive therapy, as well as in de-escalating treatment for patients with low-risk results. 

Implications for treatment decisions 

Data suggest that patients with Class 2B tumors have significantly lower metastasis-free survival compared with Class 1 tumors, particularly in high-risk NCCN groups. Retrospective evidence indicates that Class 2B patients may derive the greatest benefit from adjuvant radiation therapy. Conversely, a Class 1 result may support omitting radiation in favor of close monitoring. The test also informs decisions regarding alternative systemic treatments such as immunotherapy for patients who are not candidates for radiation. 

Multidisciplinary integration and clinical pearls 

Dr Ratner emphasizes the benefit of sharing 40-GEP results with multidisciplinary oncology teams to individualize treatment plans and emphasizes ensuring adequate tissue sampling to allow molecular testing. The clinicians emphasize that results can be unexpected, even for experienced clinicians; thus, incorporating both staging systems and molecular tools can help optimize outcomes through more precise risk stratification and tailored management strategies. 

Key takeaways 

• High-risk cSCC classification is evolving, with AJCC and BWH staging systems providing structured frameworks for clinical and histologic risk assessment
• The 40-GEP molecular assay refines prognosis by evaluating gene expression, categorizing patients into low, intermediate, or very high-risk groups
• Class 2B tumors as defined by the 40-GEP test carry a significantly higher risk of recurrence and metastasis and may benefit most from adjuvant radiation
• Class 1 results can support de-escalation of therapy in patients who may otherwise be overtreated
• Molecular results can inform multidisciplinary discussions and guide individualized treatment strategies