A clinical and biological review of keratoacanthoma*

Abstract

Keratoacanthoma (KA) is a common skin tumour that remains controversial regarding classification, epidemiology, diagnosis, prognosis and management. Classically, a KA manifests as a rapidly growing, well-differentiated, squamoid lesion with a predilection for sun-exposed sites in elderly people and a tendency to spontaneously regress. Historically, KAs have been considered a variant of cutaneous squamous cell carcinoma (cSCC) and are often reported as KA-type cSCC. However, the penchant for regression has led many to categorize KAs as biologically benign tumours with distinct pathophysiological mechanisms from malignant cSCC. The clinical and histopathological similarities between KA and cSCC, particularly the well-differentiated variant of cSCC, have made definitive differentiation difficult or impossible in many cases. The ambiguity between entities has led to the general recommendation for surgical excision of KAs to ensure a potentially malignant cSCC is not left untreated. This current standard creates unnecessary surgical morbidity and financial strain for patients, especially the atrisk elderly population. There have been no reports of death from a definitive KA to date, while cSCC has an approximate mortality rate of 1Á5%. Reliably distinguishing cSCC from KA would shift management strategies for KAs towards lessinvasive treatment modalities, prevent unnecessary surgical morbidity, and likely reduce associated healthcare costs. Herein, we review the pathophysiology and clinical characteristics of KA, and conclude on the balance of current evidence that KA is a benign lesion and distinct from cSCC.Defective mismatch repair genes (MLH1, MSH2, MSH6) leading to microsatellite instability 59,60 HPV, human papillomavirus.

Computer Image Analysis Reveals C-Myc as a Potential Biomarker for Discriminating between Keratoacanthoma and Cutaneous Squamous Cell Carcinoma

“…In specific, the morphological and histopathological characteristics of KA are very similar to those of cSCC, making it difficult to distinguish between these two conditions. In fact, some clinicians consider KA to be a variant of cSCC [2], which contributes to the controversy regarding the definition and diagnosis of KA. However, genomic differences, prognosis, and metastasis rates that exist between KA and cSCC suggest that these two conditions do not belong to the same category [3][4][5].…”

Multiple eruptive squamoproliferative lesions during anti‐PD1 immunotherapy for metastatic melanoma: Pathogenesis, immunohistochemical analysis and treatment

“…- Follicle signaling pathways, Wnt and retinoic acid pathways, are involved in tumor growth and tumor regression of KAs, respectively. 23 The prominent infundibulocystic features of our KA could suggest a link with the follicular hair cycle. Other PD1 related IRAE-have been hypothesized to be due to loss of immunosuppressive follicular milieu, which in the case of eruptive KA may favor proliferation of keratinocytes of the follicular infundibulum and explain why regression occurred with retinoic-acid mediated inhibition by acitretin in our patients.…”

“…Follicle signaling pathways, Wnt and retinoic acid pathways, are involved in tumor growth and tumor regression of KAs, respectively 23 . The prominent infundibulocystic features of our KA could suggest a link with the follicular hair cycle.…”

“…Such local immunosuppressive conditions may provide a fertile microenvironment for the "unmasking" of previously silent, ultraviolet (UV)induced activating mutations in growth stimulating oncogenes (such as H-RAS) in epidermal keratinocytes leading to the development of KAs and other squamoproliferative lesions. PD-1/PD-L1 blockade may also activate alternative intracellular signaling networks and enhance squamoproliferative growth in a mechanism similar to the mechanism of multiple KA induced by BRAF inhibition 3,23. In this setting, BRAF inhibition leads to paradoxical activation of the mitogen activated protein kinase (MAPK) pathway via CRAF dimerization in BRAF wild type keratinocytes that contained mutations in KRAS or HRAS, stimulating growth in RAS mutated cells.…”

Considerations in the management of keratoacanthoma

“…DEAR EDITOR, We read with interest the review article on keratoacanthoma (KA) by Tisack et al 1 The authors assert that diagnosis of KA is based on a characteristic clinical presentation, a triphasic evolution of proliferation, stabilization and regression, and histopathology. They state that 'Distinguishing a KA from welldifferentiated [cutaneous] squamous cell carcinoma (SCC) relies on often subtle architectural and cytological differences.…”