Recent advances in field cancerization and management of multiple cutaneous squamous cell carcinomas

Abstract

Cutaneous squamous cell carcinoma (SCC) is among the most common cancers in humans, and many patients with SCC will develop multiple tumors within their lifetime. The field cancerization concept, originally proposed over 60 years ago, hypothesized that multiple primary cancers may arise simultaneously and coexist with subclinical precursor lesions within a defined field. Genetic sequencing of SCC and precursor lesions has identified what may be the earliest clonal proliferations in SCC development and confirmed that field cancerization in the skin is mediated by ultraviolet radiation. For patients with multiple SCCs and severe actinic damage, treatment of precursor lesions within a cancerized field can decrease the risk of subsequent cancer development. Sunblock is an effective intervention for field cancerization, even in patients with established disease. There is now direct evidence that field therapy with topical 5-fluorouracil is effective in reducing the incidence of subsequent SCC, and there is indirect evidence suggesting that topical imiquimod, topical ingenol mebutate, and photodynamic therapy are similarly effective. There is limited direct evidence to show that systemic acitretin or nicotinamide can decrease incident SCC in patients with field cancerization. In this review, an approach to the management of patients with multiple SCCs and field cancerization is presented along with the rationale to support field-directed therapy.

Keywords: cutaneous squamous cell carcinoma; field cancerization; lesion-directed therapy.

Figure 1.. Clinical presentation of squamous cell carcinoma (SCC) and SCC in situ.

( a) Invasive SCC presenting as a firm ulcerated lesion with central core of keratinaceous and hemorrhagic debris on the preauricular cheek. ( b) SCC in situ presenting as multi-focal and poorly demarcated pink scaly plaques on the dorsal forearm.

Figure 2.. Clinical presentation of field cancerization.

( a) Squamous cell carcinoma (SCC) in situ (circled lesion) presenting on the scalp with chronic actinic damage and innumerable small, gritty actinic keratoses. It is not clear which lesions are precursors and which may have progressed to SCC. ( b) SCC (circled lesion) presenting on the forehead in close proximity to three additional lesions. Two of the satellite lesions were SCC in situ that was discontiguous with the primary SCC, suggesting simultaneous but independent development of the lesions.

Figure 3.. Pathogenesis of field cancerization.

Ultraviolet (UV) radiation directly induces mutation in a single keratinocyte. If this mutation provides a selective growth advantage, such as with loss of functional TP53, ongoing UV exposure will facilitate expansion of the clone as well as inhibit immune-mediated surveillance. Chronic UV exposure results in development and expansion of additional clones that evolve and compete with normal cells and each other in a field of actinically damaged skin. Accumulation of additional mutations over time and ongoing UV exposure will allow progression of a microscopic subclone into a visible actinic keratosis and eventually invasive squamous cell carcinoma.

Figure 4.. Approach to the patient with field cancerization.

Field cancer treatment is based on risk of subsequent squamous cell carcinoma (SCC), as determined by clinical factors. All patients require ultraviolet (UV) protection and lesion-directed therapy as indicated. AK, actinic keratosis; PDT, photodynamic therapy.