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Advances in cutaneous squamous cell carcinoma

Nature Reviews Cancer volume 23, pages 430–449 (2023)Cite this article

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Abstract

Human malignancies arise predominantly in tissues of epithelial origin, where the stepwise transformation from healthy epithelium to premalignant dysplasia to invasive neoplasia involves sequential dysregulation of biological networks that govern essential functions of epithelial homeostasis. Cutaneous squamous cell carcinoma (cSCC) is a prototype epithelial malignancy, often with a high tumour mutational burden. A plethora of risk genes, dominated by UV-induced sun damage, drive disease progression in conjunction with stromal interactions and local immunomodulation, enabling continuous tumour growth. Recent studies have identified subpopulations of SCC cells that specifically interact with the tumour microenvironment. These advances, along with increased knowledge of the impact of germline genetics and somatic mutations on cSCC development, have led to a greater appreciation of the complexity of skin cancer pathogenesis and have enabled progress in neoadjuvant immunotherapy, which has improved pathological complete response rates. Although measures for the prevention and therapeutic management of cSCC are associated with clinical benefit, the prognosis remains poor for advanced disease. Elucidating how the genetic mechanisms that drive cSCC interact with the tumour microenvironment is a current focus in efforts to understand, prevent and treat cSCC.

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Fig. 1: Progression from normal skin to cutaneous squamous cell carcinoma.
Fig. 2: Cutaneous squamous cell carcinoma architecture.

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Acknowledgements

The authors thank members of the Khavari laboratory for helpful discussions. This work was supported by the US Veterans Affairs Office of Research and Development I01BX00140908, NIH, National Cancer Institute (NIH/NCI) CA142635, and by NIH, National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS) AR43799 and AR49737 (P.A.K.).

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Authors and Affiliations

  1. Program in Epithelial Biology, Stanford University, Stanford, CA, USA

    Mårten C. G. Winge, Laura N. Kellman, Konnie Guo & Paul A. Khavari

  2. Department of Dermatology, Stanford University, Redwood City, CA, USA

    Mårten C. G. Winge, Jean Y. Tang, Susan M. Swetter, Sumaira Z. Aasi, Kavita Y. Sarin, Anne Lynn S. Chang & Paul A. Khavari

  3. Stanford Cancer Institute, Stanford University, Stanford, CA, USA

    Laura N. Kellman, Susan M. Swetter & Paul A. Khavari

  4. Stanford Program in Cancer Biology, Stanford University, Stanford, CA, USA

    Laura N. Kellman & Paul A. Khavari

  5. Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA

    Susan M. Swetter & Paul A. Khavari

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Contributions

M.C.G.W. wrote the article and designed and executed the primary literature search. L.N.K. wrote a section of the manuscript, and L.N.K., K.G., K.Y.S., S.Z.A., J.Y.T. and S.M.S. contributed substantially to discussions of the content, assisted with the literature search, and edited the manuscript. A.L.S.C. co-wrote a section of the manuscript, assisted with the literature search, edited, critically reviewed and revised the manuscript. P.A.K. conceptualized the article and edited the manuscript.

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Correspondence to Paul A. Khavari.

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Competing interests

A.L.S.C. has been a clinical investigator and advisory board member for Regeneron and Merck, an advisory board member for Castle Biosciences and a consultant for Feldan Therapeutics. M.C.G.W. is a cofounder of PSOMRI Holding AB. The other authors declare no competing interests.

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Glossary

Acantholytic SCC

A type of cutaneous squamous cell carcinoma that involves the breakdown of connections between skin cells.

Actinic keratosis

(AK). A premalignant lesion and common cutaneous squamous cell carcinoma precursor characterized by in situ epidermal dysplasia. It forms on skin damaged by chronic exposure to UV radiation from the sun and/or indoor tanning.

Bulge

A region of the hair follicle in which hair stem cells are located.

Cauterization

The process of heating tissue with an instrument or chemical to stop bleeding or to remove tissue.

cSCC in situ

Cutaneous squamous cell carcinoma in situ, also known as Bowen’s disease, is an intra-epidermal malignancy of the skin with a 3–5% risk of progression to invasive carcinoma when left untreated.

Cutaneous graft versus host disease

An immune-mediated condition after transplantation, in which grafted immune cells recognize host skin antigens as foreign, resulting in a complex interaction between donor and recipient adaptive immunity.

Ferguson–Smith syndrome

A rare genetic disorder characterized by the development of multiple skin tumours, including keratoacanthomas and trichoepitheliomas.

Field cancerization

The concept of how large areas of skin are affected by tumorigenic changes. This arises from prolonged DNA-damaging exposure over time, such as chronic UV exposure.

Foramen

An anatomical opening or passage in a bone that allows nerves and blood vessels to pass through.

Hair follicle stem cells

A type of epidermal stem cell found in hair follicles that can differentiate into various cell types, including hair cells.

Interfollicular epidermis

The stratified squamous epithelium located between hair follicles that regenerates from the pool of stem cell progenitors in the basal layer.

Intralesional therapies

Delivery of a therapeutic directly into the tumour or lesion, commonly by injection.

Jadassohn variant

In the context of cutaneous squamous cell carcinoma a rare variant, often classified as of intermediate risk, morphologically characterized by the presence of well-defined islands of monomorphic epithelial cells, typical or atypical, within a thickened epidermis.

Lamina-associated domains

(LADs). Genomic regions that are in close contact with the nuclear lamina, a fibrous layer that lines the inner nuclear membrane. LADs help to establish interphase chromosome topology and may have a role in gene repression.

Langerhans cells

A type of immune cell found in the skin that has a key role in antigen detection and responses.

Lymphoepithelioma-like subtype

A rare variant of squamous cell carcinoma that involves lymphoid tissue.

Mohs micrographic surgery

A surgery technique named after Frederick Mohs that is a tissue-sparing method of skin cancer removal that involves microscopic, intra-operative examination of all tissue margins.

Muir–Torre syndrome

A rare genetic condition caused by germline mutations in DNA mismatch repair genes, characterized by the development of sebaceous tumours and certain types of cancer, particularly in the gastrointestinal tract.

Non-Mendelian polygenic inheritance pattern

An inheritance pattern with a complex genetic basis involving more genomic loci than single loci patterns normally observed in classical autosomal dominant and recessive inheritance.

Oncolytic virus

A genetically engineered or naturally existing virus that can selectively replicate in cancer cells and kill them without damaging healthy cells.

Perineural invasion

The spread of cancer cells along nerves.

Pigmentation

The process of deposition of the pigment melanin in pigment granules of keratinocytes.

Pilar tumours

A type of cutaneous tumour that arises from hair follicles.

Recessive dystrophic epidermolysis bullosa

(RDEB). An incurable, often fatal, condition characterized by severe skin blistering, chronic wounding and inflammation that is caused by lack of functional type VII collagen protein in the skin.

Spatial transcriptomics

Technology that enables spatial mapping of particular mRNA transcripts to specific locations in a tissue.

Transit-amplifying cells

Progenitor cells that, after stem cell division, undergo several rounds of cell division to produce a large number of specialized cells.

Ungual cSCC

Cutaneous squamous cell carcinoma of the nail unit that often invades more quickly and has higher association with human papillomavirus (HPV), especially HPV16.

UV signature

The pattern of specific UV-induced DNA mutations produced by sunlight, commonly leading to a C>T transversion.

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Winge, M.C.G., Kellman, L.N., Guo, K. et al. Advances in cutaneous squamous cell carcinoma. Nat Rev Cancer 23, 430–449 (2023). https://doi.org/10.1038/s41568-023-00583-5

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