EADV Congress plenary sessions

Tumor-related characteristics remain the cornerstone of risk stratification. Larger tumor diameter, specific anatomical locations such as the ear, lip, temple, and scalp, increasing depth of invasion beyond the subcutaneous tissue, poor histological differentiation, lymphovascular invasion, and especially perineural invasion are consistently associated with a significantly higher risk of recurrence and metastatic spread. Host-related factors also contribute substantially to prognosis. Immunosuppressed patients, including solid-organ transplant recipients, individuals with hematologic malignancies, and those receiving long-term immunosuppressive therapy, develop more aggressive tumors with higher recurrence rates and poorer survival. Nevertheless, currently available staging systems have several limitations, and there is still no consensus regarding the optimal risk stratification model for routine clinical practice.

Although the 8th edition of the American Joint Committee on Cancer (AJCC-8) staging system remains the international standard for many cutaneous malignancies, it was developed exclusively for CSCC of the head and neck and does not incorporate several important pathological and patient-related variables, including tumor differentiation and immune status. Alternative staging systems, such as the Brigham and Women’s Hospital (BWH), improve prognostic accuracy by incorporating additional pathological variables associated with metastatic potential. In particular, BWH T2b and T3 tumors account for the majority of nodal metastases and disease-specific deaths despite representing only a minority of all primary tumors. Nevertheless, no single classification fully captures the biological heterogeneity of high-risk CSCC. More recently, multidimensional prognostic models integrating clinicopathological variables, molecular biomarkers, and artificial intelligence-assisted image analysis have shown considerable promise in providing more refined risk estimates and improved prognostic discrimination, particularly for clinically relevant outcomes such as metastasis and disease-specific mortality, while enabling individualized risk assessment based on key clinical and histopathological variables.

Therapeutic strategies have also evolved substantially over the last years. The management of high-risk CSCC increasingly relies on a multidisciplinary approach involving dermatologists, dermatologic surgeons, surgical oncologists, plastic surgeons, radiation oncologists, medical oncologists, pathologists, radiologists, and, when appropriate, head and neck surgeons. Such multidisciplinary evaluation allows optimal integration of surgery, radiotherapy, and systemic treatment according to tumor stage and patient characteristics.

Surgical excision remains the first-line treatment for most patients. Complete histological margin assessment is critical, as inadequate excision significantly increases the risk of local recurrence and may compromise subsequent therapeutic options. Whenever feasible, Mohs micrographic surgery is considered the treatment of choice for recurrent tumors, lesions with poorly defined clinical margins, tumors located in anatomically critical areas, and lesions exhibiting aggressive histopathological characteristics.

Radiotherapy continues to play an important role in selected patients, particularly those who are poor surgical candidates or present with positive margins, extensive perineural invasion, or regional nodal involvement. Adjuvant radiotherapy may improve local control in selected high-risk cases, although its impact on overall survival remains less clearly established.

A remarkable therapeutic advance in recent years has been the introduction of immune checkpoint inhibitors targeting the PD-1 pathway. CSCC is characterized by one of the highest tumor mutational burdens among human malignancies as a consequence of chronic ultraviolet radiation exposure, making it particularly immunogenic and therefore highly responsive to immune checkpoint blockade.

Cemiplimab was the first PD-1 inhibitor approved for patients with advanced CSCC who are not candidates for curative surgery or radiotherapy. In the pivotal EMPOWER-CSCC-1 trial, cemiplimab achieved objective response rates of approximately 44–50%, with complete responses observed in nearly 17% of patients following longer follow-up. Importantly, clinical benefit was maintained beyond two years in the the majority of responding patients. Furthermore, long-term analyses demonstrated encouraging overall survival outcomes together with an acceptable safety profile, establishing PD-1 blockade as the standard first-line systemic treatment for unresectable locally advanced and metastatic CSCC. Pembrolizumab has subsequently expanded the therapeutic armamentarium, showing comparable efficacy and durable responses in patients with recurrent or metastatic disease, thereby providing an additional therapeutic option in selected clinical settings.

The role of immunotherapy has progressively expanded from advanced disease to the perioperative setting. Adjuvant immunotherapy is emerging as a new standard of care for patients with high-risk resected CSCC. In the randomized phase III C-POST trial, adjuvant cemiplimab reduced the risk of disease recurrence or death by approximately 68% compared with placebo (HR 0.32), resulting in a clinically meaningful improvement in disease-free survival. These findings represent the first robust evidence supporting adjuvant systemic therapy in resected high-risk CSCC and are expected to substantially modify future treatment algorithms for selected patients.

Even more remarkable are the results obtained with neoadjuvant immunotherapy, which represents a paradigm shift in the management of resectable, locally advanced CSCC. In the phase II study evaluating neoadjuvant cemiplimab, 51% of patients achieved a pathological complete response (pCR), while an additional 13% achieved a major pathological response (MPR), resulting in an overall pathological response rate of 64%. Interestingly, pathological responses substantially exceeded radiological complete responses, highlighting the limitations of imaging in accurately assessing residual viable tumor after immunotherapy. These impressive pathological response rates suggest that neoadjuvant PD-1 blockade can effectively downstage tumors, facilitate less extensive surgical procedures, reduce surgical morbidity, and potentially improve long-term oncological outcomes. Ongoing randomized studies with longer follow-up will determine whether these early pathological responses ultimately translate into improved disease-free and overall survival while also identifying predictive biomarkers capable of selecting patients most likely to benefit from perioperative immunotherapy.

Alongside systemic treatment, intralesional therapy represents an attractive therapeutic option for selected patients with CSCC, particularly elderly or frail individuals for whom surgery or systemic immunotherapy may not be feasible. Intralesional immunotherapy aims not only to induce direct tumor regression but also to stimulate systemic antitumor immune responses capable of controlling both injected and non-injected lesions through activation of adaptive immunity. Several innovative strategies are currently under clinical investigation, including talimogene laherparepvec (T-VEC), RP1, Daromun (L19IL2/L19TNF), STING agonists, RNA-based immune stimulators, and other locally delivered immunomodulatory agents. Although available evidence is still largely derived from early-phase clinical trials, these approaches have demonstrated encouraging local response rates together with favorable safety profiles, raising the possibility that intralesional immunotherapy may become an important component of multimodal treatment strategies for selected patients with localized or oligometastatic disease.

In conclusion, the management of high-risk CSCC has evolved from a predominantly stage-based approach to a dynamic, individualized strategy that integrates clinicopathological characteristics, multidisciplinary evaluation, and increasingly effective systemic therapies to guide clinical decision-making. The introduction of immune checkpoint inhibitors has fundamentally transformed the therapeutic landscape, not only improving survival in advanced disease but also opening new opportunities in both the neoadjuvant and adjuvant settings. At the same time, advances in molecular pathology, digital imaging, artificial intelligence, and precision oncology are expected to further refine prognostic assessment and therapeutic selection. Future risk stratification algorithms will likely combine traditional histopathological parameters with molecular biomarkers and computational prediction models, enabling earlier identification of patients at highest risk, more personalized treatment selection, avoidance of unnecessary interventions, and ultimately improved survival, functional outcomes, and quality of life.

Learning objectives:

• Risk stratification of patients with high-risk basal cell carcinoma and squamous cell carcinoma  
• Evidence-based management algorithms according to the latest international guidelines
• Emerging therapeutic strategies and future perspectives