Non-melanoma skin cancers are the most common form of skin cancer worldwide, with cutaneous squamous cell carcinoma (cSCC) being the second most prevalent type.1,2 Affecting over 2 million people globally, the incidence of cSCC has seen a dramatic increase of 310% between 1990 and 2017.1,3 Despite this rise, comprehensive epidemiological data on advanced cSCC are limited, often due to underreporting or exclusion from national cancer registries.4
While metastatic cSCC represents a small percentage of overall cSCC cases, it is the most serious form of keratinocyte cancer. Metastasis occurs in 3% to 5% of patients, leading to significant morbidity and higher mortality rates. These severe cases often necessitate systemic treatments to manage the disease effectively.4
Ultra-violet (UV) light exposure is the primary risk factor for cutaneous squamous cell carcinoma (cSCC), leading these tumors to harbor high mutational burdens. In treating other malignancies, a high mutation burden has been associated with clinical benefits from antibodies targeting the programmed death-1 (PD-1) immune checkpoint receptor.5 Highly mutated tumors are more likely to express immunogenic tumor neoantigens that attract effector T cells, which can be unleashed by blocking the PD-1 immune checkpoint.6 When T cells infiltrate tumors, they produce signals that cause cells in the tumor microenvironment to express PD-L1, which inhibits T cell activity through the engagement of the PD-1 receptor, allowing for immune invasion. This understanding has driven numerous case reports on using immune checkpoint inhibitors (ICIs) in advanced cSCC.7,8
Adaptive immunity plays a significant role in the tumorigenesis of cSCC, with up to 10% of tumor-infiltrating cells being T cells. The differentiation of naïve T cells into specialized subpopulations allows for coordinating specific immune responses to diverse threats, including cancer cells (Figure 1).9 Here is an overview of key immune agents involved in tumorigenesis; notably, immunosuppressive cytokines TGF-β and IL-10 are overexpressed in high-grade cSCC.10-12
In patients with cancer, immune dysfunction can result in tumor antigens not being detected. Dendritic cells and T cells may treat these antigens as self rather than foreign, creating regulatory T cell responses rather than effector responses. T cells might not properly seek out tumors or may be inhibited from infiltrating them. Moreover, factors in the tumor microenvironment might suppress the effector cells that are produced.9
Research has established that exposure to sunlight significantly increases the risk of cutaneous squamous cell carcinoma (cSCC).13 cSCC typically appears on sun-exposed areas of the body, such as the face, ears, neck, lips, and backs of the hands, but can also develop in scars or chronic skin sores. Individuals with fair hair, skin, and eye color who have experienced excessive sun exposure are at the highest risk of developing cSCC.14 A strong correlation exists between chronic sun exposure, the number of site-specific sunburns, total site-specific exposure, and the development of cSCC. Consequently, cSCC rates are higher among individuals with outdoor occupations, with the risk increasing with age.
Actinic keratoses (AKs) on sun-damaged skin are among the strongest predictors of cSCC in unaffected individuals. Although only a small proportion of AKs are cSCC precursors, the true rate of malignant transformation of AKs remains unknown. While benign, numerous AKs increase the risk of developing basal cell carcinoma (BCC), cSCC, and melanoma.15 Estimates of progression rates from AK to cSCC vary widely, ranging from 0.025% to 20% per AK lesion per year to 0% to 0.075% per lesion per year.16
Certain medications can increase the risk of cutaneous squamous cell carcinoma (cSCC). These include17:
The risk of cSCC recurrence depends on the tumor’s location and size.18 Lesions on the head and neck, particularly in the “mask area” of the face, are more likely to recur than those on the trunk or extremities. Tumors larger than 2 cm in diameter double the risk of recurrence and triple the rate of metastasis compared to smaller lesions.19 A tumor diameter greater than 2 cm is the risk factor most highly associated with disease-specific death, conferring a 19-fold higher risk compared with tumors less than 2 cm.20
A patient with at least one cSCC is at risk for additional cSCC and other skin cancers, including basal cell carcinoma and melanoma.21
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