Dr Gross on Features That Predict for Nodal Involvement in CSCC

“[Patients with] advanced cutaneous squamous cell carcinoma can develop nodal metastasis. There’s also a separate group of patients who seem to behave very different biologically, so instead of nodal metastasis they can have very advanced local disease without regional or distant metastasis. There’s also a group [of patients] that can have significant perineural disease without regional or distant metastasis and still [have their disease considered] advanced stage.”

Neil D. Gross, MD, FACS, director of Clinical Research in the Department of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, discussed the heterogeneous nature of advanced cutaneous squamous cell carcinoma (CSCC).

Gross began by noting that some patients with CSCC will develop regional nodal metastases, while others present with biologically distinct forms of disease, including extensive locally advanced tumors or significant perineural invasion without evidence of regional or distant spread. According to Gross, these varied clinical presentations underscore why advanced CSCC has historically remained underrepresented in large oncology databases as well as research efforts.

Despite CSCC being one of the most common malignancies worldwide, only a subset of patients will develop an aggressive disease phenotype. Identifying which patients are at greatest risk remains a critical focus in the field, Gross said. Larger tumors, recurrent lesions, and locally advanced disease are all associated with an increased likelihood of metastasis. Additionally, immunosuppressed patients represent a particularly vulnerable population, as they face significantly higher risks of recurrence, metastatic spread, and disease-related mortality.

Perineural spread and lymphovascular invasion have also emerged as key predictors of poor outcomes, including recurrence and metastasis, Gross explained. These high-risk pathologic features may indicate more aggressive tumor biology, even in the absence of detectable nodal or distant disease. The complexity and variability of advanced CSCC presentations have contributed to a longstanding “blind spot” in both clinical research and industry investment.

As understanding of advanced CSCC continues to evolve, the melanoma field is increasingly recognizing the importance of risk stratification and early identification of aggressive disease characteristics. Although the patient population with advanced disease represents only a fraction of all CSCC cases, the unmet need remains substantial. Ongoing efforts to better define high-risk features and improve patient selection for treatment strategies may ultimately help address gaps in care and improve outcomes for this historically underserved population, Gross concluded.