The process of skin carcinogenesis involves a series of transitional events, which can be initiated and promoted by many events such as exposure to physical or chemical carcinogens, chronic inflammation and viral infection. The primary factor contributing to the molecular pathogenesis of non-melanoma skin cancers (NMSC) is unprotected skin exposure to ultraviolet (UV) radiation. While UV-A (320-400 nm) induced photo-oxidative stress indirectly induces characteristic DNA mutations, the spectrum of UV-B (290-320 nm) irradiation directly results in the formation of cyclobutane (thymin) dimer formation in DNA and RNA (1). Many tumour suppressor genes and oncogenes have been studied and implicated in photocarcinogenesis, particularly p53, PTCH1, BRM and RAS (2). Persistent HPV infection is confirmed necessary factor for development of cervical cancer and anogenital neoplasia. The most common high-risk HPV types observed in anogenital intraepithelial neoplasia or anogenital cancer are HPV 16, 18 and 45 (3). Rates of anal HPV infection are extremely high in HIV-positive patients, particularly in men who have sex with men (MSM) (4). HPVs infect stratified epithelia and link productive replication with differentiation. The viral oncoproteins E6, E7 and E5 play a key role in the (pre)malignant transformation (5). Occupational skin cancers have particularly been due to industrial exposure to chemical carcinogens such as polycyclic hydrocarbons (e.g. from coal tar products) or to arsenic (6). Ionizing radiation such as X-rays can also cause skin cancer (5).

This article provides an update on precancerous lesions and carcinomas in situ of the skin and anogenital region with special emphasis on the diagnosis and management.

Actinic keratosis (AK) is the most common precancerous lesion of the epidermis. Clinically, they can vary from small erythematous scaly macules to pigmented rough patches in sun-exposed areas. The field cancerization can contain multiple clinically visible AKs, subclinical AKs (only visible under a microscope), and groups of keratinocytes with genetic mutations detectable only with molecular biology methods (7). AKs are characterized by keratinocytic atypia and considered carcinomas in situ. Three histologic grades of AK can be distinguished on the basis of degree of intraepidermal involvement of keratinocytic atypia: AK-I, in the lower third of the epidermis; AK-II, in the lower two-thirds of the epidermis; and AK-III, affecting the full thickness of the epidermis (8). Chronic exposure to ultraviolet radiation in fair-skinned patients is the most important risk factor for the development of AK. In the absence of appropriate repair mechanisms, these DNA changes represent the initiation of keratinocyte mutations which can progress into the development of AKs (9). Associated factors include advanced age, male sex, outdoor occupations (e.g., farming or seagoing occupations) and recreational activities (e.g., tennis, golf), place of residence (high altitude, latitudes closer to the equator), and exposure to artificial UV radiation (10). Skin phototype (I and II), chronic iatrogenic immunodeficiency (e.g., in organ transplant patients), genetic syndromes that undermine DNA repair mechanisms or chromosome stability, photosensitivity and exposure to certain toxins or drugs that affect the cell cycle (e.g., hydroxyurea or arsenic, and various biologic agents used in oncology are also probably implicated) (10). The relative risk of AK is 250-fold higher in transplanted patients than in immunocompetent individuals (11). Sunscreen has shown to be an effective AK prevention method reducing up to 24% AK lesions over time (12). Research also has shown the benefits of oral Nicotinamide use (500 mg daily or twice daily for 4 months) that caused 29-35% relative reduction in AK count (13). Products that combine sun screens with DNA reparative agents are currently being tested (14). Diagnosis of AK is mainly clinical. Hypertrophic or hyperkeratotic, pigmented, lichenoid and atrophic variants are recognized. Dermoscopy can help distinguish AK from superficial basal cell carcinoma, lentigo maligna or pigmented basal cell carcinoma. Confocal scanning laser microscopy and photodynamic diagnosis is currently used more for research than routine clinical care. AK lesions may regress spontaneously, remain AKs, or progress to invasive SCC (11). The risk of progression to invasive SCC over 10 years is between 6.1 and 10.2% and rises to 40% in immunodeficient patients (15). The progression to invasive disease should be suspected when a lesion appears inflamed, indurated, ulcerated or large (> 2 cm). Other signs of possible progression are bleeding, rapid growth, lack of response to appropriate treatment, or recurrence after successful treatment.

The choice of treatment should depend on patient profile, lesion characteristics, what options are locally available, and other constraints at the time of treatment. When lesions are few and isolated, treatment should target individual lesions. The most commonly used therapy for AK treatment is cryotherapy with liquid nitrogen. Side effects include blistering, hypopigmentation, hyperpigmentation, scarring, and infection as well as discomfort during the freezing cycle. Targeting options of AK treatment include also electrodessication and curettage. Curettage harvests tissue for pathology, although it is impossible to confirm whether there is tumor invasion of the margins. Surgical removal of an AK is not routine and is undertaken only when there is suspicion of invasive SCC or lesions are recurrent (10, 15). In the management of multiple actinic keratoses, field therapies should be preferred to more destructive and/or invasive treatments, which allows treatment of both visible and subclinical lesions (16). Field therapies can be divided into patient-administered options such as topical therapies and physician-administered options such as photodynamic therapy (PDT), laser resurfacing, dermabrasion, and medium – to deep-depth chemical peels. Current approved topical therapies include 5-fluorouracil (5-FU) 0.5-5% cream, imiquimod 5% and 3.75%, diclofenac sodium gel 3%, and ingenol 0.015% and 0.05% gel (17). All of the topical agents are associated with common side effects that include localized erythema, flaking, scaling, and crusting; however, dyspigmentation and scarring occur infrequently (18). It is noteworthy that the uniquely brief regimen for ingenol mebutate, 2 to 3 days, produced clearance rates similar to those with the other agents, which have treatment regimens of several weeks (18). Combining destructive treatments and topical ones may be advisable when there is progression to invasive SCC. Topical treatment with PDT and imiquimod may also be a beneficial combination (10). Oral systemic retinoids, dermabrasion, chemical peeling, and laser therapy are considered second-line or coadjuvant treatments and they should be considered for possible use in special circumstances (10).

Actinic cheilitis (AC) is basically AK of the lower lip (in 95% of the cases), and it is caused by chronic and excessive exposure of the lips to the ultraviolet radiation in sunlight. AC clinically presents as loss of the usually sharp border of the lip, atrophy of the vermilion border and darkening of the lip at the border between the lip and the skin of the face, as well as ulcers of the lip. Prevalences of AC range from 0.45 to 2.4% of the population (19). The most important risk factors for AC are outdoor activity and skin type (19). Histopathologically, AC is characterized by hyperplasia, acanthosis or atrophy of the epithelium, thickening of the keratin layer, and/or dysplasia, which may range from mild to severe. In connective tissue, basophilic degeneration of collagen fibers, called solar elastosis, is usually detected (19). Dermoscopy is a useful tool for evaluating AC. Dermoscopic characteristics of AC are ill-demarcated borders and vascular telangiectasia, white-coloured projections and island-like structures around the ulcerous areas (20). AC deserves special attention because of its malignant potential to develop into invasive SCC of the lip. The frequency of malignant transformation of these lesions ranges from 10 to 30% (19). Once SCC develops on the lip, the risk of invasion and metastasis to the cervical lymph nodes is higher than that for SCC of the skin.

The cutaneous horn (CH) is defined as a tumour, usually of conical appearance which prevails over the length of its diameter, with large hyperkeratosis in its extreme. Various skin diseases may present with cutaneous horns including viral warts, AK, keratoacanthoma, seborrhoeic keratosis, pyogenic granuloma, discoid lupus erythematosus, verruca vulgaris, Bowen’s disease, basal cell carcinoma and squamous cell carcinoma (21). Over 60% of the lesions are benign, 23% of the cases premalignant and 16% of the cases malignant (21). Majority of the cases occur on areas that are exposed to sunlight. Forearm, cartilaginous portion of the ear, leg, and back of the hands may also be involved (22). The incidence of penile CH is particularly low (23). Cutaneous horns should be completely excised and sent for pathological evaluation.