A Clinical and Biological Review of Keratoacanthoma

A. Tisack; A. Fotouhi; C. Fidai; B.J. Friedman; D. Ozog; J. Veenstra

Disclosures

The British Journal of Dermatology. 2021;185(3):487-498. 

In This Article

Tumour Microenvironment

Divergent immune reactivity further differentiates KA and cSCC (Figure 2). Both have a tendency to harbour elevated populations of immunosuppressive cells, with KAs having a higher proportion of activated lymphocytes.[5,7,121] This includes greater infiltration of CD4+ T cells, with an increased percentage expressing interleukin-2 receptor (CD25), a marker of activation.[7] However, this may be confounded by the population of CD4+ regulatory T cells that express high levels of CD25 constitutively. Nonetheless, a greater number of interleukin-27-producing cells, which favours T helper type 1 differentiation and activation, in the KA tumour microenvironment is suggestive of an inflammatory milieu favouring an antitumour response as compared with cSCC.[121] Moreover, recent multimodal analysis of human cSCC found greater populations of regulatory T cells, exhausted T cells and tolerogenic dendritic cells relative to normal skin.[142] However, a similar multiomics approach has not yet directly compared cSCC and KA.

Both KA and well-differentiated cSCC can express elevated levels of the immune checkpoint molecule programmed cell death-1 (PD-1) and its ligand PD-L1. In a study examining tumour membrane staining for PD-L1, 33·3% of KAs and 26·9% of cSCC were positive, whereas actinic keratosis and Bowen disease were negative.[143] Additionally, tumour-infiltrating lymphocytes expressing PD-L1 were found in 33% of KAs and 35% of cSCCs. Thus, both KA and cSCC may have a variably immunosuppressive environment relative to precursor lesions. Tumour-associated macrophages have been found to secrete elevated levels of matrix metalloproteinase 9, which plays a key role in remodelling the extracellular matrix and has been widely implicated in carcinogenesis and metastasis.[144–146] Significantly increased matrix metalloproteinase 9-expressing tumour-associated macrophages have been observed in cSCC vs. KA (266·7 ± 23·7 vs. 105·7 ± 25), reflecting their difference in malignant potential.[121]

Despite similarities in PD-L1 expression, KA and cSCC behave disparately in response to PD-1 checkpoint blockade: PD-1 inhibition is an efficacious treatment for advanced cSCC, whereas the same therapy may precipitate eruptive KAs.[27] The lesions preferentially appear on sun-exposed skin, similarly to the presentation seen with inhibitors of BRAF, transforming growth factor-β and Janus kinase.[27,117,131,147] A recent report of three patients suggested that PD-1 inhibition leads to formation of KAs via upregulation of an inflammatory pathway and represents reactive hyperplasia, not neoplasia as observed in sporadic KAs; however, the mechanism has yet to be defined. Anti-inflammatory treatments, including hydroxychloroquine and topical steroids, led to resolution of both the underlying dermatitis and KAs in these patients.[148]

Prolonged immunosuppression greatly increases the risk of developing cSCC, but the risk is not as clear with KA.[17] T-cell immune surveillance against commensal beta HPV suppresses cSCC in immunocompetent individuals, which is substantially blunted in immunosuppressed patients. Importantly, it was found that the increased risk of cSCC in immunosuppressed patients was caused by dampened immunosurveillance rather than the oncogenic effect of unchecked HPV.[149] In KAs, HPV DNA has been identified in about half of cases and is more common among those from immunosuppressed individuals; however, it has yet to be identified as a driver of tumorigenesis in KA.[150–152]

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