Actinic keratoses (AKs) are likely the most common keratinocyte-derived precancerous lesion in humans; they are found predominantly in fair-skinned individuals on sun-exposed surfaces (1
). The primary risk factor for AKs is cumulative UV exposure from sunlight and/or tanning salons, and it is expected that the incidence of AKs will rise given an aging US population (3
). AKs are frequently found in skin harboring fully developed cutaneous squamous cell carcinomas (cSCCs) (6
). AKs progress to cSCC at a rate estimated between 0.025% and 16% for an individual lesion per year (7
). The typical patient has 6 to 8 lesions; therefore, a patient with multiple AKs has a annual risk of developing invasive squamous cell carcinoma (SCC) ranging from 0.15% to 80% (2
). This wide range in risk reflects a lack of precision in our knowledge of the progression of carcinoma in the epidermis. It is estimated that approximately 26% of AKs will undergo regression over a year’s span (8
). The probability of an AK or a patient with multiple AKs developing a cSCC or metastatic lesion is shown in Figure (9
Probability that human cutaneous neoplastic lesions will progress to invasive carcinoma.
AKs are defined at the histologic level by dysplasia and consist of keratinocytes manifesting atypical nuclei that are enlarged, irregular, and hyperchromatic. AKs also display disorganized growth, which disrupts differentiation and results in a thickened stratum corneum with retained nuclei. To stratify degrees of epidermal dysplasia, a three-tiered grading scale has been proposed for AKs that parallels that used for evaluation of cervical dysplasia (11
). The histological features of keratinocytic intraepidermal neoplasia I (KIN I) are cellular atypia of basal keratinocytes confined to the lower third of the epidermis. KIN II shows atypical keratinocytes occupying the lower two-thirds of the epidermis, and KIN III shows atypical keratinocytes throughout the epidermis; this latter stage is equivalent to carcinoma in situ (11
). The localized epidermal atypia in AKs reflects a partial disruption of the differentiation program, whereas a more complete disruption of differentiation is associated with SCC in situ (SCCIS). The regression rate of AKs may be inversely related to their degree of dysplasia, as has been seen in vaginal epithelium (12
). While the KIN grading criteria evaluate the macroscopic and microscopic features of AKs, identification of genetic and molecular abnormalities associated with these lesions has provided mechanistic insight into their pathogenesis (Figure ).
A clinical, histologic, and molecular comparison of AKs, cSCC, and metastatic cSCC.
The classic multistep model of carcinogenesis is useful for understanding the progression from AK to cSCC (13
). According to this model, mutations in one gene, often a tumor suppressor, may lead to the development of a precursor lesion with increased genetic instability or loss of cell cycle control. Additional mutations in other driver oncogenes permit the emergence of more neoplastic properties, leading to invasive carcinoma; the number of genetic changes required to transition from benign epithelium to metastatic carcinoma internal malignancies is thought to range from four to six (13
). However, 3D models of human epidermis have shown that as few as two proto-oncogene mutations changes are sufficient to drive SCC (14
). An improved understanding of epigenetic regulation of oncogene and anti-oncogene expression will add layers of regulatory complexity to the multistep model of carcinogenesis.
As with other cancers, cSCC exhibits impaired genomic maintenance that facilitates acquisition of new mutations (16
). The mechanism leading to genomic instability in keratinocytes likely results from UVB-induced inactivation of p53, since approximately 58% of cSCCs harbor UVB signature mutations such as CC→TT and C→T transitions (17
). The role of p53 in UVB-induced carcinogenesis has been confirmed in p53–/–
mice which have an increased propensity for developing AK-like lesions and cSCCs secondary to UVB exposure (18
). Since the initial observations of ultraviolet-induced mutations in p53
, other groups have confirmed the presence of p53 mutations in significant percentages of cSCCs (19
is mutated commonly in AKs, demonstrating that dysplastic lesions have acquired the initial genetic mutations prior to becoming cSCC (20
). Additional studies have shown a high prevalence (74%) of p53
mutations in unremarkable sun-exposed skin compared to non–sun-exposed skin (5%) (23
), setting the stage for acquisition of mutations in driver oncogenes. Consistent with these findings, 40% of SCCIS harbors p53 mutations, indicating that p53 loss occurred prior to tumor invasion (24
). In contrast, several internal malignancies demonstrate mutation of the p53
gene as a late event in neoplastic evolution after formation of an invasive lesion (25
Aberrant activation of EGFR and Fyn, a Src-family tyrosine kinase (SFK), are seen in human cSCCs, and these kinases downregulate p53 mRNA and protein levels through a c-Jun–dependent mechanism (28
), revealing another mechanism for controlling p53 function. Additional molecular events associated with AK formation include increased activation or levels of SFKs, EGFR, Myc, and ATF-3 (30
). In addition, decreased levels of inositol polyphosphate 5′-phosphatase have also been reported in AKs, which could result in increased PI3K/Akt signaling (34
Immunohistochemical studies of AKs to assess p53 levels have shown variable results, but many studies show increased p53 levels in lesional cells that are likely due to the enhanced stability of the mutant p53 proteins (35
). However, more mechanistic studies are needed to link specific p53 mutations found in human AKs with altered functional status and protein stability.
Loss-of-heterozygosity studies of AKs have shown genetic alterations at the following loci: 3p, 9p, 9q, 13q, 17p, and 17q; these data indicate that substantial genomic instability is already present at the preneoplastic AK stage (36
). However, the genes, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) affected by these genetic alterations have not yet been linked to mechanisms driving neoplasia.
Loss of heterozygosity has also been observed in cSCCs at chromosome 9p in 13 of 16 primary tumors (37
). Loss of heterozygosity of p16, a cell cycle regulator that lies in this region, is hypothesized to be associated with progression from AKs to cSCCs (38
), and loss of function of p16 is more frequent in cSCCs than in precancerous lesions (39
). Additional loss-of-heterozygosity loci in cSCCs include 3p, 2q, 8p, and 13 and allelic gains on 3q and 8q (37
Amplification and activating mutations of the Ras oncogene have been found in SCCs and AKs (42
). Of the three Ras genes, Harvey rat sarcoma virus oncogene (Hras
) is preferentially mutated in the general population (44
). Ras molecules are a family of GTP-binding proteins that are among the most frequently mutated genes in humans cancers (45
). Ras is an upstream activator of the Raf/Mek/Erk1/Erk2 kinase pathway, and activating mutations in Ras can promote cSCC formation (45
). The latest data from the catalog of somatic mutations in cancer (COSMIC; Sanger Institute) indicate that 21% of cSCCs harbor activating Ras mutations (9% Hras, 7% Nras, 5% Kras) (46
). The characteristic mutations at codons 12, 13, and 61 of H-Ras are all localized opposite pyrimidine dimer sites (C-C) and likely result from UVB exposure (42