Actinic keratosis

(Ref. Pathology of the skin, PH McKee, 3rd Ed. Elsevier-Mosby)

Clinical features

Actinic (solar, senile) keratoses are common, usually presenting as multiple, erythematous or yellow-brown, dry, scaly lesions in the middle aged or elderly. Heavily pigmented variants that may be clinically mistaken for lentigo maligna are occasionally encountered. Actinic keratoses may also coexist with lentigo maligna, thereby adding to problems in the differential diagnosis. They are more common in males than in females and especially in those with fair complexions who burn rather than tan following sun exposure." They usually measure 1 cm in diameter or less.' The surrounding skin frequently shows additional features of sun damage including atrophy, pigmentary changes and telangiectasia. Actinic keratoses are of particular importance because they are a sensitive indicator of exposure to UV light and strongly predict the likelihood of developing cutaneous squamous cell carcinoma.

Despite the publication of many large series (mostly from Australia ), the prevalence of actinic keratosis is uncertain. Histological confirmation has been uniformly absent in these reports and variation in the popu­lations studied and lack of consistency of clinical criteria make accurate assessment and comparison difficult. Nevertheless actinic keratoses are markedly influenced by latitude, quoted prevalence ranging from approximately 10% of the adult population in Galway , Ireland , to 40% in Queensland , and in excess of 60% in Victoria , Australia ."

Because these hyperkeratotic skin lesions occur on sun-damaged skin, the sites of involvement are usually the face and neck and the dorsal aspects of the hands and forearms. Oral lesions (chronic actinic cheilitis) tend to affect the middle of the lower lip and present as burning or painful scaly lesions. Conjunctival involvement has also been described. Hyperkeratosis is sometimes marked and the lesion may present as a cutaneous horn. Actinic keratoses may rarely be associated with Kindler syndrome, and an eruptive presentation has been reported after heart transplantation. Sun-exposed lesions of vitiligo may also be affected.

Although only a small proportion of actinic keratoses appear to develop into an invasive squamous cell carcinoma, patients usually have multiple and often numerous lesions for many years and so have a much higher risk of ultimately developing squamous carcinoma. In that sense, even though only an estimated 0.1-10% of actinic keratoses are thought to progress to invasive squamous cell carcinoma, the presence of these keratoses reflects the total actinic damage to the skin and serves as an indicator to identify a high-risk population for the development of sun damage-related disease such as squamous cell carcinoma, basal cell carcinoma and to a lesser extent melanoma at other sites. The cumu­lative probability of development of invasive squamous cell carcinoma in patients with 10 or more actinic keratoses has been estimated at 14% in a 5-year period. Actinic keratoses may be contiguous with an invasive squamous cell carcinoma in 44% of cases with metastasis. Metastases, however, are rare except for those arising on the ear and lip, which are often associated with more aggressive behavior. A higher rate of malignant transformation is also observed in hyperkeratotic lesions located on the dorsum of hands, wrists or forearm. Sometimes actinic keratoses appear to regress, presumably as a consequence of immune mechanisms. Radiation keratoses may resemble solar­induced lesions.

 

Pathogenesis and histological features

Actinic keratoses develop in white-skinned populations as a consequence of the effects of excessive exposure to UV radiation, particularly UVB. Owing to the protective effects of a higher epidermal melanin concentration, they are much less common in dark-skinned races. In addition to the total dosage and possibly the rate of exposure, inherent susceptibility is probably important in determining the extent of skin damage. Actinic keratoses are common in individuals with an increased sensitivity to the effects of LTV radiation such as occurs in albinism and xeroderma pigmentosum. Outdoor workers or those who devote a considerable proportion of their leisure time to sunbathing have a much higher risk. It has recently been suggested that sun exposure in childhood is particularly important. Treatment with hydroxyurea has been implicated in the development of multiple actinic keratoses. Although the keratosis is objective evidence of skin damage, it should be noted that perilesional skin frequently shows evidence of minor cellular damage such as nuclear hyperchromatism, cytoplasmic and nuclear pleomorphism, slight architectural disarray and increased uptake of [3 H] thymidine.

Adjacent morphologically normal epidermis overexpresses p53 protein. Spontaneous regression of actinic keratoses has been reported.

Genetically, actinic keratoses show a high rate of aneuploidy in addition to clonal karyotypic abnormalities and frequent loss of hetero­zygosity of 17p, 17q, 9p and 9q as well as p53 mutations. P53 mutations are observed in most actinic keratoses in Caucasians (75-80%) but are present to a significantly lesser extent in Asians (30-40%). Expression of CD95 (Fas) appears to be reduced in actinic keratoses compared to sun-damaged non-dysplastic skin, and patients with a glutathione S-transferase M1 null phenotype are at increased risk of developing actinic keratoses. The direct link of UV light to the development of actinic keratosis has been established in an animal model. Actinic keratoses have been induced in human skin maintained in severe combined immunodeficient (SCID) mice exposed to UVB, and specific UV signature mutations identified in the p53 gene.

Squamous cell carcinoma frequently develops in a background and in association with actinic keratoses (more than 80%). Certain events may play a role in the progression of actinic keratoses to squamous cell carcinoma including deletion of chromosome 9p2l encoding the p16 tumor suppressor gene, activation of ras genes and loss of the inflammatory cell infiltrate when invasion occurs.

UV-induced immunosuppression is also probably of importance, but the precise mechanisms are uncertain. Immunosuppressed renal transplant patients have an increased risk of developing actinic keratoses in addition to squamous cell carcinomas. There is no evidence of a pathogenetic role for either Epstein-Barr virus or herpesvirus-8.

Although a variety of quite distinct histopathological variants of actinic keratoses may be recognized, many examples display a spectrum of patterns, manifesting epithelial dysplasia from mild changes through to carcinoma in situ and commonly accompanied by parakeratosis.

A frequently seen subtype is the hyperkeratotic/hyperplastic actinic keratosis. This lesion is characterized by alternating bands of hyperkeratosis and parakeratosis. The latter covers areas of dysplastic epithelium, whereas the former overlies the uninvolved epithelia of the follicular ostia and sweat gland orifices (Freudenthal funnel). Actinic keratoses are typified by varying degrees of epidermal dysplasia involving the interadnexal epidermis. Sometimes this is limited to the basal layers only; in other examples the lesion appears as budding of atypical epithelium into the papillary dermis (proliferative actinic keratosis). In occasional keratoses the atypical cells form a mantle around the outer aspects of the cutaneous adnexae.

Characteristically, the edges of these lesions are angulated with their broader aspects occupying the base. Sometimes actinic keratoses are atrophic and occasionally, due to marked acantholysis, an acantholytic or pseudoglandular pattern results, which may show a marked resemblance to lesions of Darier's disease (acantholytic actinic keratoses). Some actinic keratoses are typified by full-thickness dysplasia (squamous cell carcinoma in situ Bowenoid actinic keratoses). Bowenoid actinic keratosis is associated with a loss of desmosomes as well as hemidesmosomes, and it has been postulated that this correlates with more aggressive behavior compared to acantholytic actinic keratoses. Clear cell change due to an excess of cytoplasmic glycogen is sometimes evident and occasionally the features of epidermolytic hyperkeratosis or a keratin horn may be superimposed. The dermis underlying and adjacent to the keratosis often shows solar elastosis and vascular ectasia. A lymphohistiocytic infiltrate is commonly evident and sometimes this is associated with the features of an interface dermatitis including basal cell liquefactive degeneration and apoptosis (lichenoid actinic keratosis). This variant is reminiscent of lichenoid keratoses but may be distinguished from it by the presence of nuclear atypia.

Actinic keratoses may be pigmented, showing increased melanin pigment in the lower epidermis within keratinocytes as well as in melanocytes and dermal macrophages. This variant has been referred to as spreading pigmented actinic keratosiS. On occasion, difficulty may be experienced in distinguishing this lesion from in situ melanoma (lentigo maligna). In such cases the use of immunohistochemistry to exclude a melanocytic lesion is often helpful. Actinic keratoses arising in immunosuppressed patients are more often hyperkeratotic with confluent parakeratosis and more prominent mitotic figures. They occur in younger and predominantly male patients.

 

Differential diagnosis

A common problem is the histological differentiation between proli­ferating actinic keratosis and early squamous cell carcinoma. Although this is a somewhat artificial distinction because both conditions form part of a continuum, the presence of atypical keratinocytes, either singly or in groups, detached from the main lesion or often associated with a stromal reaction, are features that imply dermal invasion. Thickness of the keratosis is irrelevant and whether the tumor cells are present in the reticular as well as the papillary dermis has little bearing in distinguishing between the two lesions. At some sites where the prognosis of squamous carcinoma is known to be poor, it is wise to err on the side of the hawks rather than the doves. In general, however, the distinction between a proliferating solar keratosis and a 'microinvasive' squamous carcinoma is of little clinical significance because both lesions will have an identical outcome provided excision is complete. The distinction of actinic keratoses from superficial basal cell carcinoma may sometimes be problematic. In these circumstances, immunohistochemistry for bcl-2 and Ber-EP4, both of which stain positively in basal cell carcinoma and negatively in actinic keratoses, can be helpful.