Keratinocyte Carcinomas: Current Concepts and Future Research Priorities

Abstract

Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are keratinocyte carcinomas, the most frequently diagnosed cancers in fair-skinned populations. Ultraviolet radiation (UVR) is the main driving carcinogen for these tumors, but immunosuppression, pigmentary factors, and aging are also risk factors. Scientific discoveries have improved the understanding of the role of human papillomaviruses (HPV) in cSCC as well as the skin microbiome and a compromised immune system in the development of both cSCC and BCC. Genomic analyses have uncovered genetic risk variants, high-risk susceptibility genes, and somatic events that underlie common pathways important in keratinocyte carcinoma tumorigenesis and tumor characteristics that have enabled development of prediction models for early identification of high-risk individuals. Advances in chemoprevention in high-risk individuals and progress in targeted and immune-based treatment approaches have the potential to decrease the morbidity and mortality associated with these tumors. As the incidence and prevalence of keratinocyte carcinoma continue to increase, strategies for prevention, including effective sun-protective behavior, educational interventions, and reduction of tanning bed access and usage, are essential. Gaps in our knowledge requiring additional research to reduce the high morbidity and costs associated with keratinocyte carcinoma include better understanding of factors leading to more aggressive tumors, the roles of microbiome and HPV infection, prediction of response to therapies including immune checkpoint blockade, and how to tailor both prevention and treatment to individual risk factors and needs.

European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 1. epidemiology, diagnostics and prevention

“…Cutaneous SCC is a common skin cancer characterised by the malignant proliferation of epidermal keratinocytes and it is classified as a keratinocyte carcinoma together with basal cell carcinoma. [7]. It is distinguished in in situ (Bowen's disease) and invasive form.…”

Mechanical Force and Actin Dynamics during Cutaneous Squamous Cell Carcinoma (cSCC) Progression: Opportunities for Novel Treatment Modalities

“…Recent trials using cytotoxic chemotherapy have, however, shown limited advances for the treatment of cSCC, and trials investigating combined immune checkpoint inhibitor and radiation therapies, which may have synergistic effects in treatment of cSCC, are still pending [13]. This highlights the need for increased research to close the gaps in our knowledge of cSCC biology, including better understanding of the factors that lead to aggressive cSCC, the role of microbiomes and HPV infection, the role that mechanical force and actin dynamics plays in this process, prediction of clinical response to therapies including immune checkpoint blockade, and how to tailor better prevention and treatment strategies to individual risk factors and needs [6]. Emerging evidence on the crosstalk between different components of the cytoskeleton in metastatic progression combined with clinical data illustrating strong relationships between cytoskeletal alterations and metastasis in various cancers pinpoints important opportunities for potential therapeutic targets [11].…”

“…The incidence of cSCC is higher in individuals who are fair-skinned and have a sun-sensitive phenotype; however, the aggressive forms of cSCC are more common in men and the elderly [3]. Despite its prevalence, the relatively low fatality rate of cSCC means that its health and economic burden is often substantially underestimated [3], albeit latest data showing that in addition to significant morbidity cSCC accounts for up to 8000 deaths per year and costs approximately $4.8 billion annually in USA alone [6].cSCC generally presents as a scaly, red or bleeding abnormal lesion on sunexposed areas, and is associated with relatively benign outcomes and a low risk of metastasis. However, cSCC can demonstrate dramatic histopathological heterogeneity, resulting in a wide range of clinical outcomes [7].…”

“…The incidence of cSCC is higher in individuals who are fair-skinned and have a sun-sensitive phenotype; however, the aggressive forms of cSCC are more common in men and the elderly [3]. Despite its prevalence, the relatively low fatality rate of cSCC means that its health and economic burden is often substantially underestimated [3], albeit latest data showing that in addition to significant morbidity cSCC accounts for up to 8000 deaths per year and costs approximately $4.8 billion annually in USA alone [6].…”

Differentiating keratoacanthoma from squamous cell carcinoma—In quest of the holy grail

“…Based on some of the histopathologic features and immunohistochemical detection of follicular markers, some suggest that the well‐developed and regressing stages of keratoacanthoma may display features of isthmic and infundibular/epidermal keratinization/differentiation, respectively . The clinicopathologic features of KAs are variable through the proliferative to regressing phases, and there is significant clinical overlap of all phases with squamous cell carcinoma (SCC), with the well‐developed stage of KA being most similar to SCC histopathologically (Figure ) …”