New Insights into Pathogenesis and Management of Keratoacanthoma: A Narrative Review

Abstract

Keratoacanthoma (KA) is a rapidly growing epithelial neoplasm characterized by clinical and histopathological features that often overlap with well-differentiated squamous cell carcinoma (SCC), posing diagnostic challenges. This review provides a comprehensive overview of KA, emphasizing advances in non-invasive diagnostic techniques such as dermoscopy, reflectance confocal microscopy (RCM), and line-field confocal optical coherence tomography (LC-OCT), which improve lesion characterization and differentiation from SCC. We discuss the histopathological phases of KA and highlight key features aiding in diagnosis. Furthermore, we explore the emerging role of human papillomavirus (HPV), particularly β-genus types, as a cofactor in KA carcinogenesis through modulation of apoptosis and DNA damage response pathways, especially under ultraviolet (UV) radiation exposure. Therapeutic strategies remain centered on complete surgical excision; however, alternative treatments, including radiotherapy, cryotherapy, topical agents, and systemic retinoids, are discussed with their respective benefits and limitations. Finally, we review current HPV vaccines and novel vaccine candidates targeting a broad spectrum of mucosal and cutaneous HPV types. This review underscores the importance of integrated diagnostic and therapeutic approaches to optimize KA management and highlights future directions in understanding its pathogenesis and treatment.

Keywords: carcinogenesis; dermoscopy; human papillomavirus; keratoacanthoma; line-field confocal optical coherence tomography; non-melanoma skin cancer; reflectance confocal microscopy; therapies; vaccines.

Figure 1

Clinical presentation of three keratoacanthomas. (a) Dome-shaped nodule with a central keratin-filled crater located on the right tragus of an elderly man. (b) Large exophytic lesion on the right cheek of an elderly man. (c) Keratoacanthoma of the right zygomatic-temporal region in an elderly male patient. All three lesions share the classical clinical features of keratoacanthoma: a rapidly growing, skin-colored to erythematous nodule with a characteristic central crater filled with keratin.

Figure 2

Rapidly growing keratoacanthoma on the left zygomatic-temporal region of an 86-year-old woman. (a) Clinical presentation showing a dome-shaped lesion with a central keratin-filled crater. (b) Dermoscopic image revealing a central amorphous keratin mass surrounded by a thin erythematous rim.

Figure 3

Rapidly growing keratoacanthoma on the dorsum of the right hand in a 78-year-old woman. (a) Clinical presentation showing an erythematous nodule with a central keratinous core. (b) Dermoscopic image highlighting a central keratin mass, surrounded by white structureless areas and peripheral dotted or hairpin vessels. (c) 3D reconstruction of the lesion using line-field optical coherence tomography (LC-OCT). (d) Vertical mode LC-OCT image showing marked hyperkeratosis and parakeratosis (yellow stars), atypical keratinocytes (yellow bracket), a central keratinous core (red bracket), and a preserved dermo-epidermal junction (yellow arrows).

Figure 4

Best-characterized molecular mechanisms involved in carcinogenesis occurring in HPV-infected skin cell. UV radiation induces damage on DNA, which is normally repaired by the Nucleotide Excision Repair (NER) pathway. If NER fails and the DNA damaged is maintained, in the healthy skin cells (a) p53 undergoes some post-translational modifications leading to the assembly of a tetramer, resulting in induction of its transcriptional activity, allowing the expression of the cell-cycle inhibitor p21^waf1, which mediates the cell cycle block in G1 phase, and proapoptotic BAX and BAK proteins. When the NER pathway fails in the skin cell infected by β-HPV (b), the presence of E6 interferes with the assembly of p53 monomer into tetramer, finally resulting in loss of apoptotic pathway activation and cell cycle progression. E6 also interferes in a not fully understood way with BAX and, by recruiting E6AP ubiquitin-ligase induces BAX proteasome-mediated degradation.

Figure 4

Best-characterized molecular mechanisms involved in carcinogenesis occurring in HPV-infected skin cell. UV radiation induces damage on DNA, which is normally repaired by the Nucleotide Excision Repair (NER) pathway. If NER fails and the DNA damaged is maintained, in the healthy skin cells (a) p53 undergoes some post-translational modifications leading to the assembly of a tetramer, resulting in induction of its transcriptional activity, allowing the expression of the cell-cycle inhibitor p21^waf1, which mediates the cell cycle block in G1 phase, and proapoptotic BAX and BAK proteins. When the NER pathway fails in the skin cell infected by β-HPV (b), the presence of E6 interferes with the assembly of p53 monomer into tetramer, finally resulting in loss of apoptotic pathway activation and cell cycle progression. E6 also interferes in a not fully understood way with BAX and, by recruiting E6AP ubiquitin-ligase induces BAX proteasome-mediated degradation.

Figure 5

Schematic representation of new promising vaccine candidates, containing the L2 polytope of the cutaneous HPV types, fused to the thioredoxin scaffold.