Squamous cell carcinoma and keratoacanthomas are biologically distinct and can be diagnosed by light microscopy: a review

Abstract

Keratoacanthomas (KAs) are self-limiting squamoproliferative lesions usually seen on sun damaged skin. These tumours are in many ways enigmatic, and the relation between KAs and squamous cell carcinoma is still a contested topic. In this review the biology and histology of KAs will be discussed, and based on morphology, clinical outcome and recent genetic analysis of the tumour types, we conclude that KAs and SCCs are two distinct biological entities which can usually be distinguished by conventional microscopy. The sentinel observation of rapid and frequent appearance of KAs after BRAF treatment of malignant melanoma patients has paved the way for a more general understanding of the pathogenesis leading to the appearance of KAs in patients with inflammation in the skin. In BRAF treated patients, the KAs are a consequence of paradoxical activation of the MAP kinase pathway. Similarly, any external trauma or pharmaceutical interventions resulting in inflammation in the skin will activate the MAP kinase pathway. Such inflammation-mediated MAP kinase activation in the skin will result in the development of KAs through the same pathway as demonstrated for BRAF treated patients. It is characteristic that skin tumours following short acting inflammatory stimulation of severely sun damaged skin develop almost exclusively into KAs, whereas it is exceedingly rare that such inflammatory conditions lead to formation of SCCs. The understanding that inflammatory reactions in sun-damaged skin may activate pathways specifically leading to the formation of KAs may spare the patient the discomfort and disfigurement of needless overtreatment.

Keratoacanthoma management: results of a survey of U.K. dermatologists and surgeons

“…Of note, in two phase II vemurafenib trials, central review of SCC histology specimens led to reclassification as KA in up to 94Á4% of cases. 4 Our survey demonstrates significant clinical equipoise in the management of KA-like lesions among U.K. clinicians and confirms a willingness to enrol patients in a clinical trial, while highlighting the need to mitigate against undertreatment of any potential SCC within the trial design.…”

“…And yet, the benign natural history of KA is supported by various studies, including a systematic review of 455 cases with no metastasis or death and observational studies confirming spontaneous resolution . Unlike in SCC, perineural or venous invasion in KA is not associated with an adverse outcome . Comparative genomic hybridization and DNA microarray studies indicate that KA and SCC are genetically distinct .…”

“…In a clinical trial, centralized expert histopathologist review could overcome this issue. Of note, in two phase II vemurafenib trials, central review of SCC histology specimens led to reclassification as KA in up to 94·4% of cases …”

“…1 Unlike in SCC, perineural or venous invasion in KA is not associated with an adverse outcome. 3,4 Comparative genomic hybridization and DNA microarray studies indicate that KA and SCC are genetically distinct. 5,6 Some have suggested that the rare reports of metastatic KA may have arisen from SCC development within KA.…”

Ingenol Mebutate 0.06% Gel for Field Treatment of Actinic Keratosis on 250 cm2 of Skin on Trunk and Extremities: A Randomized Dose-Finding Trial

“…[22][23][24] This treatmentassociated development of KA may be due to inflammation-mediated mitogenactivated protein (MAP) kinase stimulation in the presence of UVinduced activating Ras mutations in keratinocytes in sun-damaged skin. 25 As the frequency of KA increases with increased sun exposure, 6,25 this may partially explain why KAs were observed exclusively in Australian patients.…”