In addition, within the BRAF inhibitor-associated group, the lesions designated as KAs and BRAF inhibitor-associated verrucous keratoses had a similar mutational profile (mutations in PIK3CA, APC, and HRAS), which was distinct to that seen in squamous cell carcinomas (FGFR3, CDKN2A, and STK11).
The degree and pattern of staining suggest a loss of bcl-2 expression with tumor maturity in keratoacanthoma and a possible role in their ultimate involution.
RAF inhibitors are effective against melanomas with BRAFV600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs).
However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors.
We have previously noted histological overlap between KAs and BRAF inhibitor-associated verrucous keratoses, and this finding supports the notion that they may represent morphological or temporal variants of a single lesion type.
In clinical trials trametinib, a MEK inhibitor (MEKi) increases BRAFi therapy efficacy in BRAF(V600E) melanomas and reduces BRAFi-induced KA and cuSCC frequency.
This phenomenon manifests clinically in the development of squamous cell carcinomas (SCCs) and keratoacanthomas (KAs) in patients treated with BRAF inhibitors.
Interestingly, overexpression of cyclin D1 - observed in 80% of KAs and SCCs, respectively - showed a cell cycle-independent function in HaCaT cell transplants on nude mice.
Thus, our results identify 11q13 gain/cyclin D1 overexpression as an important step in KA formation and point to a function that exceeds its known role in proliferation by disrupting tissue organization and thereby allowing abnormal growth.
We observed a very strong positive correlation between the PD-L1 protein expression of tumour cells of KA and the PD-L1 protein expression of TILs (r = 0.97; P < 0.0001).
These findings suggest that CD44 and beta-catenin expression may have an important role in the development of malignancy and in the determination of biological features of keratoacanthoma and squamous cell carcinoma of the skin.
A series of 120 biopsies from benign (verruca vulgaris and keratoacanthoma), premalignant (actinic keratosis and extragenital Bowen's disease) and malignant (squamous cell carcinoma) skin lesions were studied immunohistochemically for the expression of cell-cycle proteins p53, p21 (WAF-1), PCNA and Ki-67.
In addition, within the BRAF inhibitor-associated group, the lesions designated as KAs and BRAF inhibitor-associated verrucous keratoses had a similar mutational profile (mutations in PIK3CA, APC, and HRAS), which was distinct to that seen in squamous cell carcinomas (FGFR3, CDKN2A, and STK11).
By comparing the expression of p53, cyclin D1, p16, hTERT, and TSP-1 in spontaneously regressing keratoacanthoma (KA) as a paradigm of early neoplasia, with malignant invasive cutaneous squamous cell carcinoma (SCC) as a paradigm of advanced tumour development, we are now able to assign the changes in the expression of these proteins to specific stages and allocate them to defined roles in the multi-step process of skin carcinogenesis.
These findings suggest that CD44 and beta-catenin expression may have an important role in the development of malignancy and in the determination of biological features of keratoacanthoma and squamous cell carcinoma of the skin.
The karyotype of the keratoacanthoma was more complex: 46,XX,der(2)(2pter----2p13::2p11----cen----2q37: :5q33----5qter),der(2) (:2p13----cen----2q37::6q23----6qter),der(5)t(2; 7;5)(q37;q11;q33),der(6) (6pter----cen----6q23::2p13----2pter),der(7)t(2; 7;5)(q37;q11;q33), del(13)(q11q14).