A Clinical and Biological Review of Keratoacanthoma

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


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

In This Article

Tumour Biology

Cell Cycle and Regulation

The triphasic nature of the KA life cycle has drawn parallels to follicular morphogenesis, with anagen, catagen and telogen cycles. This has led to the hypothesis that KAs have a follicular origin and undergo apoptosis akin to catagen involution of the hair follicle. Expanding upon this, a murine model of chemically induced KAs demonstrated that follicle signalling pathways, namely the Wnt and retinoic acid pathways, are important regulators of regression observed in KAs.[57] Wnt signalling was selectively active in the KA growth phase relative to the regression phase, and retinoic acid-mediated inhibition of Wnt was sufficient to induce KA regression. Furthermore, retinoic acid was able to induce regression of a proportion of cSCC-like nonspontaneously regressing tumours via Wnt downregulation. These findings reinforce the use of retinoids in the treatment of KAs, especially in patients with multiple lesions.[51] They also provides further rationale for the use of retinoids, such as acitretin, as a prophylactic agent for patients at increased risk of keratinocytic carcinomas. Table 3 further expands upon key cell-cycle regulators whose role in KA and cSCC has been elucidated in clinical studies.[13,18,49,51,56,107–127]

BRAF inhibitor therapy for melanoma has elucidated the role of RAS in development of both cSCC and KA.[128,129] Recent studies have demonstrated an increased frequency of gain-of-function RAS mutations (35–60%) in BRAF inhibitor-induced cSCC vs. sporadic cSCC (12–20%).[130] BRAF inhibitor-induced KAs and cSCCs appear almost exclusively on sun-exposed skin, suggesting that BRAF inhibition in keratinocytes expressing wildtype BRAF acts as a 'second hit' in sun-damaged skin. It has been postulated that in ultraviolet-damaged keratinocytes harbouring RAS mutations, BRAF inhibition leads to activation of the mitogen-activated protein kinase pathway, precipitating tumorigenesis.[129] Use of the BRAF inhibitor vemurafenib led to the development of cSCC in 16% of patients and KA in 10%.[129,131] Multikinase inhibitors, such as sorafenib, have similarly triggered growth of KAs and cSCCs; however, the mechanism has yet to be fully characterized.[132]


KA possesses the ability to regress due to an upregulation of the apoptosis pathway compared with normal skin.[111] Alternatively, cSCC expresses fewer pro-apoptotic factors, with concurrent expression of anti-apoptotic factors supporting dysregulated growth (Figure 2).[133–135]

Figure 2.

Comparison of keratoacanthoma (KA) and cutaneous squamous cell carcinoma (cSCC). Features of KA, left, and well-differentiated cSCC, right. Gross images and low- and high-power histopathology exemplify the similar but varied presentation of these entities. Prominent nuclear changes, intracellular factors and tumour microenvironment features of both lesions are listed. cSCC has greater expression of the anti-apoptotic factors Bcl-2, Bcl-xL and Bcl-X and proapoptotic factors AIF and M30.14,133,135,153,154 Keratoacanthoma demonstrates greater expression of proapoptotic factors P2X7 and Bak.120,134,135 Overall, proapoptotic markers have been found to be more prominent in KA than in cSCC. cSCC tend to exhibit a proliferative phenotype with concurrent expression of anti-apoptotic markers supporting dysregulated growth.133 Created with BioRender.com.


KA and cSCC have distinct genetic signatures. Transcript levels of more than 1400 genes were found to be greater than fivefold differentially expressed between KA and SCC, indicating disparate tumorigenesis pathways.[136] Furthermore, comparative genomic hybridization of 132 KAs and 37 cSCCs showed significant differences in chromosome aberration between the groups.[121,137] Li et al. used comparative genomic hybridization to detect gross DNA copy number aberrations, which allowed for the discrimination of KA and cSCC in 85% of cases, as defined by histopathological criteria.[138,139] A higher degree of chromosomal instability was demonstrated in SCCs relative to KAs, with recurrent aberrations on chromosomes 7, 8 and 10.[138] Aberrations were less frequently found in KAs, and when found involved chromosomes 19, 20 and X.[137] Additionally, loss of heterozygosity appears to be high in SCC and low in KA.[137,140,141]

Several genetic syndromes predispose individuals to KA development: Muir–Torre syndrome, Ferguson–Smith disease, and generalized eruptive KAs of Grzybowski (Table 1).[41,52–55,58,60,64] Generalized eruptive KAs of Grzybowski is considered a serious condition because the eruptions are diffuse, persistent and recurrent.[53] The KAs associated with Muir–Torre syndrome demonstrate sebaceous differentiation and a loss of DNA mismatch repair gene products.[59,60] However, the microsatellite instability and loss of heterozygosity that are present in Muir–Torre syndrome do not appear to play a role in general KA development.[4] Despite similar clinical presentations, the interdisease relationship of genetic drivers, and between the broader category of solitary KA, remains unclear.