Cutaneous Squamous Cell Carcinoma

Epidemiology & Impact

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with an estimated 1.8 million cases diagnosed annually in the United States. Incidence has been increasing 3-10% per year over recent decades. Like basal cell carcinoma, cSCC is driven primarily by cumulative ultraviolet radiation exposure and occurs predominantly in fair-skinned individuals, with the highest rates in Australia. However, cSCC carries a more significant metastatic risk than BCC: approximately 2-5% of cases metastasize, resulting in an estimated 15,000 deaths annually in the United States — exceeding melanoma deaths in some analyses. Risk factors include chronic sun exposure, immunosuppression (organ transplant recipients have a 65-250 fold increased risk), human papillomavirus infection, chronic wounds or scarring, and previous radiation therapy. The risk of cSCC in solid organ transplant recipients is so high that dermatologic screening is a standard component of post-transplant care.

Molecular Biology & Biomarkers

Cutaneous SCC is characterized by one of the highest tumor mutational burdens of any cancer, averaging 50 mutations per megabase, driven by chronic UV-induced mutagenesis. TP53 mutations are nearly universal and occur early in pathogenesis, even in precursor actinic keratoses. Additional frequent alterations include CDKN2A inactivation, NOTCH1/2 mutations (40-75%), HRAS mutations, and amplification of EGFR. The NOTCH pathway appears to function as a tumor suppressor in the skin, and its loss drives squamous differentiation abnormalities. PD-L1 expression is found in approximately 30-50% of cSCCs, and the high tumor mutational burden generates abundant neoantigens, providing the biological rationale for the remarkable activity of checkpoint immunotherapy. Immunosuppressed patients, particularly transplant recipients, may have impaired anti-tumor immune responses that explain their dramatically elevated cSCC risk, and the use of checkpoint inhibitors in this population requires careful balancing of rejection risk.

Evolving Treatment Landscape

Surgical excision, including Mohs micrographic surgery for high-risk lesions, cures the vast majority of cSCCs. For locally advanced or metastatic disease, cemiplimab (Libtayo) was the first systemic therapy specifically approved for cSCC based on phase 2 studies demonstrating response rates of approximately 44-50%. Pembrolizumab subsequently received approval based on the KEYNOTE-629 trial. These checkpoint inhibitors have transformed the management of advanced cSCC, which previously relied on platinum-based chemotherapy with poor response rates and significant toxicity. Cemiplimab has also shown promising activity in the neoadjuvant setting, with the phase 2 study demonstrating pathological complete response rates exceeding 50%, suggesting that preoperative immunotherapy may reduce the extent of surgery needed. For the challenging population of transplant recipients with cSCC, where checkpoint inhibitors carry rejection risk, EGFR inhibitors (cetuximab) and clinical trials investigating modified immunotherapy approaches represent active areas of investigation.

EMA-Approved Therapies for Cutaneous Squamous Cell Carcinoma

The European Medicines Agency (EMA) regulates drug approvals across the European Union. Below are key therapies with comparative information to FDA approvals.

For complete European drug information, visit ema.europa.eu ↗