How Molecular Tools Are Reshaping Risk Stratification in Cutaneous SCC

"I've been borderline traumatized by the number of patients who come in with extraordinarily large squamous cell carcinoma," Shadi Khalil, MD, PhD, said in a recent Dermatology Times DermView custom video series.

Khalil, a physician-scientist, dermatologist, and dermatopathologist at Scripps Health in San Diego, California, joined Gaurav Singh, MD, MPH, a Mohs surgeon at City of Hope Cancer Center in Chicago, Illinois, and moderator of the program titled "Integrating Gene Expression Profiling to Improve Cutaneous Squamous Cell Carcinoma Management.” The panel covered risk stratification, diagnostic workup, and how molecular tools are reshaping management decisions in cutaneous squamous cell carcinoma (cSCC).

Risk Factors and Diagnostic Challenges in cSCC

Both clinicians described high daily patient volumes driven largely by ultraviolet exposure and immunosuppression, whether disease-related, such as chronic lymphocytic leukemia, or induced by treatments physicians themselves prescribe. Khalil said presentation varies widely and singled out sun exposure history and immunosuppression as the 2 factors most likely to raise suspicion for cSCC from the moment a patient walks in. Singh added variability in presentation, from an obvious crateriform nodule to a subtle scar-like lesion, complicates efforts to define low-risk disease consistently across physicians and patients. Delayed diagnosis also emerged as a persistent problem tied to access to dermatology, rather than to clinical uncertainty alone.

"Wait lists can be as long as 6 months or even longer to actually get in and see a provider," Khalil said. "Access to dermatology is extraordinarily limited. There's a shortage of dermatologists, and more patients need to be seen."

For staging, Khalil said he relies primarily on Brigham and Women's Hospital criteria rather than the American Joint Committee on Cancer staging to flag patients needing closer attention and to identify those who can be definitively treated with straightforward excision. Singh said he layers multiple staging systems, including tumor size over 2 cm and depth of invasion, to inform his Mohs surgery decision-making, noting that the 2 staging frameworks do not always agree on which patients are considered high risk.

The Role of Gene Expression Profiling in Risk Stratification

Singh characterized molecular profiling as instrumental to Mohs surgery planning, noting that subjectivity in traditional risk factors drives interest in more objective tools. Gene expression profiling (GEP), tumor mutational burden, and PD-L1 expression were discussed as complementary molecular approaches, with GEP tests such as DecisionDx-SCC drawing the most attention from the panel. Singh explained that the test is RNA-based, extracting genetic material directly from the original biopsy specimen to generate an individualized risk score for recurrence and metastasis.

Singh pointed to roughly 70 published studies supporting GEP's ability to identify patients at elevated metastatic risk, with new data emerging monthly. He also outlined current limitations: Radiation-response data remain limited for higher-risk class 2A patients, and GEP does not currently predict the need for imaging or sentinel lymph node biopsy, an unresolved question he noted is discussed more actively in otolaryngology literature than in dermatology.

Practical Barriers and Treatment Selection Across Disease Stages

Timing was the most immediate practical barrier Singh identified. He said the biggest challenge is not having the GEP result available before a patient reaches him as a Mohs surgeon, since imaging, radiation, immunotherapy, and surgical decisions are typically weighed together during the same visit. Cost and insurance coverage were noted as additional barriers to the broad integration of GEP into practice, particularly outside academic or cancer-center settings.

On treatment selection, Khalil said shared decision-making carries significant weight for localized, low-risk cSCC, where options include curettage and electrodesiccation, photodynamic therapy, and topical therapy. High-risk localized disease typically escalates to excision, Mohs surgery, or adjuvant radiation, whereas advanced or metastatic disease moves into chemotherapy, targeted therapy, or immunotherapy. Khalil described his follow-up strategy for high-risk and advanced disease as split between clinical interventions he directs and patient-directed lifestyle guidance aimed at preventing recurrence over time.

Guidelines and the Future of Personalized cSCC Management

Singh compared following current guidelines to doing the minimum required, describing GEP use as an "extra credit" addition beyond baseline standards of care. Both clinicians acknowledged that gaps remain between what guidelines formally recommend and what is feasible in everyday practice, particularly around access and cost for patients outside major metropolitan centers. Singh closed by framing GEP as an adjunct, rather than a replacement, for clinical judgment.

"This does not replace clinical decision-making," Singh said. "It's another tool, it's a valid tool, it adds a lot of information." He added that physicians who see high volumes of small head and neck tumors are likely underestimating their true metastasis rate, absent systematic tracking, and encouraged colleagues to consider using GEP where they see fit in practice.

Watch the full video series here.