AK is an epidermal proliferation of atypical keratinocytes that is induced by excessive exposure to nonionizing radiation, especially within the ultraviolet (UV) spectrum of sunlight, which generates a cascade of structural damage to a cell’s DNA and membrane lipids.²,¹¹ UV-A radiation (320-400 nm) is responsible for 95% of the solar radiation that reaches the Earth and can penetrate deeply into the dermis having devastating effects.¹¹ Among other mechanisms, UV-A primarily induces indirect photooxidative damage via the generation of reactive oxygen species (ROS). Once these are generated, ROS damages cellular nuclei as well as cell membrane lipids. A secondary effect of UV-A is that it promotes guanine (G) to thymine (T) replacement mutations in DNA. Consequently, signal transduction and cellular interaction pathways are affected, and abnormal cellular proliferation ensues.³,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵ UV-B radiation (290-320 nm) constitutes just 5% of the solar radiation reaching the Earth’s surface, but it penetrates the basal layer of the epidermis, so that its effect on keratinocytes is more devastating as it is directly absorbed by cellular DNA.¹¹ UV-B radiation causes replacement of the thymine and cytosine bases (C-T DNA substitutions) and promotes errors in the repair of cyclobutane thymidine dimers, with subsequent DNA damage.¹¹ The DNA mutations in these sun-damaged areas predominantly affect the p⁵³ gene (TP53).³,¹²,¹³,¹⁴,¹⁵ TP53 is a tumor suppressor gene that interrupts the cell cycle to allow the repair of damaged DNA. The abnormal expression of TP53 and its protein p⁵³ are considered markers of premalignant conditions and play pivotal roles in the development of AK/SCC. Chromosomal mutations in this gene are found in 16% to 100% of AK lesions, but p53 mutations in AK are different from those associated with SCC.⁵,¹⁰,¹⁶ Other oncogenes, particularly those along the mitogen-activated protein kinase pathway, may not be instrumental in AK per se but may play a pivotal role in the transition from AK to SCC.¹⁶

Other risk factors for the development of AK, besides solar radiation, include light skin, old age, male sex, and immunosuppression.¹¹,¹⁷ Patients with a light complexion (Fitzpatrick types I and II skin), light hair, or light iris color are more susceptible to develop AK. This light complexion is why the condition is more common among people of European ancestry.¹¹,¹⁷ Patients older than 80 years are six times more likely to develop AK than patients in the sixth decade.¹¹ Increased prevalence in men may simply reflect their occupational exposure to solar radiation since men work outdoors more often than women. Immunosuppressed patients, such as organ transplant recipients, are also more susceptible to develop AK.¹¹,¹⁷ Other risk factors for AK include episodes of painful sunburn before the age of 20 years, never using sunscreen, and a positive family history of cutaneous neoplasms.¹⁰ Multiple bouts of painful sunburn before the age of 20 years may initiate the carcinogenic cascade, which is an indication that acute recurrent exposure to UV radiation can also lead to p⁵³ mutations and not just a chronic form of exposure.¹⁰

The exact nature of AK is contested. Whether it is a premalignant condition (intraepithelial keratinocytic dysplasia), a malignant superficial SCC (in situ SCC), or merely a photoaging epiphenomenon resulting from chronic sun damage is uncertain.³,⁵,⁶,⁹,¹⁵ Whether considered premalignant or malignant, the argument is rather semantic, because both conditions can potentially break through the basement membrane causing frank SCC.¹⁵ Because all AK lesions show signs of cytologic atypia, the widely held view is that AK probably represents a premalignant condition that may progress to Bowen disease or SCC.¹,² Proponents of the hypothesis that AKs are merely by-products of photodamage argue that AKs are fairly stable lesions that are neither malignant nor premalignant, as evidenced by the fact that most of the lesions do not routinely progress to SCC.¹⁵ They contend that even when AKs progress to malignancy, the process follows a two-step model of carcinogenesis. An initial mutation in a tumor suppressor gene results in the development of AK, which in this scenario is merely an initiated or a precursor lesion insufficiently promoted to become malignant. In a second step, an additional or second carcinogenic hit leads to the acquisition of invasive properties and progression to SCC.¹⁰,¹⁵ Whether the time factor (lesion duration) contributes to this second hit or not is controversial.¹⁰

The clinical significance of AKs stems from the fact that they are closely related to nonmelanoma skin cancers (NMSCs) or keratinocyte carcinomas (KCs).¹⁰ Although both terms (NMSC and KC) are loosely used interchangeably in the literature, they are not identical, and the term KC is preferred over NMSC because AKs and other KCs universally arise from epidermal keratinocytes.⁵,⁷ Furthermore, the ambiguous term NMSC also includes other nonkeratinocyte malignancies like basal cell, squamous cell, and Merkel cell carcinoma, cutaneous lymphoma, or sebaceous carcinoma. Therefore, the term KC rather than NMSC will be used throughout this chapter.⁷

AK may progress to SCC in one of the two ways. The classic pathway requires a stepwise development of full-thickness epidermal neoplasia, which should precede the development of invasive SCC. The alternative mechanism, termed the differentiated pathway, entails the direct invasion of proliferating atypical keratinocytes that are originally limited to the epidermal basal layer along the shafts of hair follicles and sweat ducts.¹⁰,¹⁸ This adnexal invasion mode is far more aggressive than the classic or direct pathway.¹⁰ However, there is an ongoing controversy regarding the possibility of progression of solar keratosis to BCC, and the mechanism of this alleged progression is not precisely known.⁵,⁸ It could be argued that some early lesions, which were presumably diagnosed initially as AK, were BCCs from the start, previously mistaken for AKs.⁵,⁸ Alternatively, an AK may be masking an underlying infiltrative or nodular BCC.¹⁹ Adding to the confusion is that several other reports documented that solar keratosis may have histologic features suggestive of both SCC and BCC.⁸,²⁰

The epidemiology of AK is simply a reflection of the different nomenclatures it bears in the literature (actinic, solar, or senile).¹⁷ AK is quite common and is the third most frequent cause for dermatologic consultations.²¹ On an international level, the prevalence of AK is highest in subtropical and hot sunny regions like Australia. The condition affects approximately one in six North Americans during their lifetime, as well as 40% to 60% of Australians older than 40 years, and it has been calculated that up to 34% of males in the United Kingdom older than 70 years have at least one AK lesion.⁴,¹⁰

As was mentioned earlier, studies in Europe, Australia, and the United States have consistently shown that the disease is more common in males. Whether this has a prognostic significance or impacts on the progression of AK to SCC is debatable.²²,²³,²⁴,²⁵,²⁶,²⁷ Because AK results from cumulative exposure to the sun, it is mainly a disease of individuals older than 45 years, and the incidence rises with advancing age.¹,²,³,⁴,⁵

The body areas most affected include the forehead, balding scalp, ears, the vermilion of the lower lip (actinic cheilitis), forearms, and dorsal aspect of the hands.⁴,⁵ AK is rarely reported in the periorbital region, though it accounts for 2% to 5% of eyelid tumors. Unfortunately, because of the rarity of the condition, and the subsequent lack of epidemiological studies about eyelid AK, it is not clear whether periorbital AK is more frequent in the upper or the lower eyelids. One clinicopathological study showed that 81% of periorbital AKs occur in the upper eyelid.²⁷ This finding is counterintuitive because the upper eyelids are considered a more sun-protected site in the face, compared with the lower eyelids.²⁸ Moreover, other KCs like SCC and BCC are more common in the lower eyelid and medial canthal region. In our experience, approximately 70% of eyelid AKs involve the lower eyelids, a proportion similar to periocular BCC and SCC. The 30% of AKs in the upper eyelids may be due, at least in part, to the upper eyelid skin being the thinnest skin in the body, making it highly vulnerable to actinic damage despite its privileged location.²⁹