A study of 237 Japanese skin cancer patients showed that squamous cell carcinoma (SCC) arising from hidradenitis suppurativa (HS) on the buttocks is far more likely to recur or spread. The peptide LL‑37, which is higher in HS‑affected skin, seems to help the tumor grow, and a gene called ACTA1 was also found to be increased in these cancers.

<b>Background/Objectives</b>: Cutaneous squamous cell carcinoma (cSCC) is a common cutaneous malignancy with diverse etiologies, including actinic keratosis, burns, and hidradenitis suppurativa (HS). <b>Methods</b>: We reviewed 237 cases diagnosed as cSCC in our department between 2013 and 2023. In addition, we focused on HS as an aggravating factor for cSCC. The mechanism of cSCC progression was investigated with a focus on LL-37, a peptide implicated in the pathogenesis of HS. Relevant gene expression was analyzed comprehensively via RNA sequencing in vitro. <b>Results</b>: The median age of the patients was 82 years (range: 33-101), with 139 males and 98 females. The primary sites were as follows: head and neck (125 cases), trunk (10 cases), vulva (11 cases), extremities (81 cases), and buttocks (10 cases). Among the five cases (2.1%) of buttocks cSSc associated with HS, all cases (100%) had local recurrence or lymph node metastasis at the time of diagnosis, and one case (20%) developed multi-organ metastasis. The incidence of disease progression in cSCC originating from HS-affected buttocks was significantly higher than in other sites (<i>p</i> &lt; 0.05). RNA sequencing revealed the significant amplification of <i>ACTA1</i>, which was confirmed by Western blotting and immunohistochemical staining. <b>Conclusions</b>: These results suggest that HS is a prognostic factor in cSCC and that LL-37 stimulation contributes to tumor progression, partly by enhancing multiple tumor growth factors.