High-risk cutaneous squamous cell carcinoma: our contributions to the current understanding and research priorities
Javier Cañueto Álvarez
Hospital Universitario de Salamanca, IBSAL
CSCC is the second most common tumour in humans, after basal cell carcinoma (BCC). Its incidence is increasing but is underestimated because it is excluded from the Surveillance, Epidemiology, and End Results (SEER) Program and other national cancer registries. Although it is usually easily resolved with surgery, it can progress locally, metastasize, and cause death in a subset of patients. There are an estimated 15,000 deaths per year from CSCC in the United States, which surpasses the number of deaths from melanoma (www.skincancer.org). The increase in life expectancy will mean an increase in the health impact of the CSCC (in 2050, 15.3% of the population will be over 80 years, almost 3 times more than in 2011 [http://envejecimientoenred. es]).
Defining the prognosis of HRCSCC remains a challenge. Based on the limitations that we identified in the current AJCC8 staging system, our group has identified prognostic subgroups of HRCSCC and proposed alternatives to the current AJCC8 system. However, when comparing it with other alternative systems, we have seen that the prognostic precision of alternative staging systems is not good for HRCSCC, making improvements essential. Therefore, improving these staging systems is essential to improving clinical practice. The recognition of new prognostic factors in CSCC is a priority, as it would allow a better identification of patients with the highest risk of relapse and would improve current staging systems. Therefore, to discriminate the groups at higher risk, we examined the usefulness of some already known prognostic factors in greater depth. Thus, we better defined perineural invasion (PNI) and its relationship with the prognosis of the disease and identified groups of tumours with PNI that would benefit from postoperative radiotherapy, something that would not be useful in all CSCCs presenting this trait. Also, we explored the impact of growth rate. There are other clinicopathological variables whose prognostic relevance has yet to be adequately defined and in which we are focusing. The study of the tumour microenvironment, consisting of the stroma and its associated inflammatory infiltrate has become increasingly important. Beyond clinical and histopathologic features, a more translational approach has let us recognize the prognostic impact of certain miRNAs, of the overexpression of EGFR and of D2-40. Currently, we are trying to more precisely stratify HR-CSCC based on a genomic and multi-omic approaches.
Until just over two years ago, there had been very few advances in the pharmacological treatment of CSCC. In 2018 and 2020, respectively, the FDA approved cemiplimab and pembrolizumab for the treatment of locally advanced and metastatic CSCCs. However, around half of the patients do not respond to anti-PD1 drugs and there are no approved alternatives for the treatment of advanced forms of CSCC. Therefore, identifying patients who will respond to these new therapies and potential new therapeutic targets is a priority, as we highlighted in a recent review. This will be another research priority of our group.