Many aging changes in the skin, including the eyelid, are secondary to gradual damage from lifelong exposure to ultraviolet light. Such damage is particularly prone to occur in light-skinned individuals (1,2,3,4,5,6,7,8,9,10,11,12). Actinic keratosis (solar keratosis) is a common precancerous cutaneous lesion that affects face, dorsa of the hands, bald areas on the head in men, and commonly the eyelids (1). Excessive exposure to sunlight is clearly a predisposing factor. A report from Japan found a mean patient age at diagnosis of 62 years and a slight predilection for females (3). If untreated, approximately 20% are believed to progress to squamous cell carcinoma (SCC) (2).

Actinic keratosis has several clinical variations, but is usually characterized by multiple, erythematous, excoriated, sessile plaques that may eventually assume a nodular, horny, or warty configuration (8). The lesions range from 1 to 10 mm in diameter and have a pink color. As mentioned, they generally occur on sun-exposed areas of older Caucasians who have had excessive sunlight exposure over a prolonged period of time (7).

The differential diagnosis includes most of the benign and malignant epidermal lesions mentioned in this atlas. It differs from seborrheic keratosis in that it has less distinct margins. Some actinic keratoses are pigmented, making the clinical differentiation from lentigo maligna and early melanoma difficult. The presence of multiple actinic lesions in the adjacent skin can facilitate the diagnosis.

Histopathologically, actinic keratosis is composed of acanthosis, focal hyperkeratosis, dyskeratosis, and mildly atypical keratinocytes with epithelial buds that extend into the papillary dermis (1,2,3,4). Clefts often form as a result of dyskeratosis and disruption of intercellular bridges. A characteristic feature is orthokeratosis in the area of the ostea of the pilosebaceous structures. Such sparing of the ostea of these units is unlike true SCC. The dermis shows moderate to severe basophilic collagen degeneration and a moderate lymphoplasmacytic infiltration (1). Several histopathologic variants are described in the literature (2). Histopathologic study of eyelid SCC generally reveals evidence of actinic keratosis.

There are several ways to manage actinic keratosis; treatment must be individualized. Small, asymptomatic lesions can be observed only. Larger lesions can be selectively resected with a shaving or elliptical approach, or curettage. Liquid nitrogen spray is often helpful for more indurated lesions (1). Multiple lesions or those that cannot be completely excised can be treated with topical chemotherapeutic agents or cryotherapy (1). Topical chemotherapy using 5-fluorouracil cream has been applied twice daily for 2 to 3 weeks (1).

There has been recent interest in treatment of actinic keratosis of the face and bald areas of the head with topical imiquimod (Aldara; Graceway Pharmaceuticals, Bristol, TN) cream administered 3 times weekly (11,12). In a randomized, double-blind, parallel-group, vehicle-controlled trial of 492 patients, complete and partial clearance rates for imiquimod-treated patients (48.3% and 64.0%, respectively) were clinically and statistically significantly higher than for vehicle-treated patients (7.2% and 13.6%, respectively). The median percentage reduction of baseline lesions was 86.6% for the imiquimod-treated group and 14.3% for the vehicle-treated group. It was concluded that 5% imiquimod cream applied 3 times weekly for 16 weeks is safe and effective for the treatment of actinic keratosis (11).

SCC that arises from actinic keratosis is low grade and offers an excellent prognosis because local invasiveness is minimal and metastasis occurs in only 1% to 3% of cases (10). In assessing SCC histopathologically, it is important to look for actinic keratosis near the margins. Such a finding imparts a better prognosis and compared with SCC that arises de novo, a condition that is somewhat more likely to metastasize.

In addition to excessive sunlight exposure, there are miscellaneous other insults that can predispose the eyelid to malignant neoplasms. Selected examples include radiation blepharopathy, xeroderma pigmentosum, and the nevus sebaceous of Jadassohn, each of which are discussed. In addition, patients who are immunosuppressed for any reason have an increased risk of developing a number of benign and malignant eyelid lesions (1,2,3,4,5,6).

Radiation blepharopathy occurs secondary to therapeutic irradiation to the ocular region for a variety of conditions (1,2,3,4,5). A number of years ago, facial radiation was often used for acne and other benign conditions. This led to acute and chronic changes that predisposed the facial skin to the long-term development of several “radiation-induced” epithelial and glandular neoplasms, as well as soft tissue sarcomas. Ocular irradiation for retinoblastoma, particularly in patients with the germline mutation for that disease, can contribute to a variety of neoplasms, including eyelid tumors (1,2,3,4,5,6). In addition, irradiation for malignancies of the paranasal sinuses or nasopharynx can predispose to radiation blepharopathy and subsequent eyelid malignancies. Sebaceous carcinoma of the eyelid, normally a disease of older individuals, can occur at a young age in children who have undergone irradiation for retinoblastoma (5,6). Many of these neoplasms were more common many years ago when .80 Gy was used in some cases of retinoblastoma. Most radiation today employs a dose of 25 to 40 Gy, depending on the disease being treated.

The acute stage of radiation blepharopathy develops about a week after initiation of irradiation. It is characterized by eyelid erythema, loss of cilia, and occasional excoriation or ulcer. Chronic radiation blepharopathy can show only minimal abnormalities, with skin atrophy and loss of cilia.

The diagnosis of radiation blepharopathy lies mainly in taking a patient history for prior irradiation, combined with the clinical findings mentioned. We have found that some patients who develop eyelid malignancies in middle age may not immediately recall having had irradiation for acne or other reasons when they were young.

Acute radiation blepharopathy shows edema and early degenerative changes in the epidermis, and epithelium of sebaceous glands and hair follicles. Late radiation blepharopathy is similar histopathologically to actinic keratosis, with nuclear atypia in the epidermal cells and individual cell keratinization. There may be scattered macrophages in the papillary dermis, fibrosis in the dermis, and atrophy of adnexal structures. The blood vessels become telangiectatic and may show individual cell swelling and thrombosis and recanalization. Squamous cell carcinoma that arises from these changes is generally of spindle cell type with a higher degree of malignancy and a greater tendency to metastasize than ordinary SCC. Atrophy of sebaceous gland is often profound (3).

Management is directed toward prevention of cutaneous erosion, infection, and long-term cancers. Topical lubrication with antibiotics tends to soothe the site and prevent infection. Avoidance of steroid preparations is advised. The patient should avoid excess exposure to sunlight because actinic stimulation can further increase the chance of malignant transformation. Advanced cases with excoriation or ulceration may require more aggressive management with surgical intervention to restore vascular supply to the site. It is most important to check the patient yearly and to advise the patient to return earlier should there be any suspicious symptoms or signs.

Radiation blepharopathy can cause acute and chronic changes in the eyelids that can predispose to the development of squamous and sebaceous neoplasms later in life.

Xeroderma pigmentosum (XP) is an autosomal-recessive disorder that is not a specific eyelid lesion like other conditions discussed in this atlas. However, it is appropriate to discuss this disease because affected patients have a marked sensitivity to ultraviolet light that can predispose them to a variety of skin cancers, many of which involve the eyelid and conjunctiva (1,2,3,4,5,6,7). Cultures of skin fibroblasts and blood lymphocytes have demonstrated a deficiency in repair of damaged DNA. Death often occurs by the age of 20 years and, occasionally, by the age of 10 years, usually owing to metastasis from cutaneous squamous cell carcinoma or malignant melanoma.

Six progressive stages of XP are identified, the details of which are beyond the scope of this atlas. In the earlier stages, the exposed skin shows numerous freckles, erythema, and scaling (4). Later, there is mottled pigmentation with telangiectasia that resembles radiation dermatopathy. The final stage is characterized by the development of a variety of malignant neoplasms often in the second or third decade of life, including squamous cell carcinoma, basal cell carcinoma, malignant melanoma, and some sarcomas (1). These multiple benign and malignant tumors can cause bothersome cosmetic problems.

The diagnosis of XP can generally be made by the classic cutaneous features described, a positive family history, or both. Some patients have associated noncutaneous abnormalities, including mental deficiency, retarded growth, and delayed sexual development. The de Sanctis-Cacchione syndrome is characterized by XP, mental deficiency, microcephaly, dwarfism, hypogonadism, deafness, and ataxia (4).

Histopathologically, the earlier stages are characterized by nonspecific changes, such as hyperkeratosis and hyperpigmentation of the basal layer of the epidermis. Later, there are irregular patches of hyperpigmentation with acanthosis and atypical downward proliferation of epidermis similar to actinic keratosis. The final stages are characterized by eruption of the various neoplasms mentioned (1).

Management mainly includes avoidance of sunlight, topical sunscreens, protective clothing, ultraviolet blocking spectacles, and early removal of premalignant and malignant skin lesions. Some workers have published extensively on treatment of the lesions in the early stages, using a variety of oral and topical agents (6,7). The specific treatments are complex and beyond the scope of this atlas.

Like radiation blepharopathy, XP can also predispose the eyelids and conjunctiva to squamous cell carcinoma, basal cell carcinoma, malignant melanoma and other skin malignancies.

Nevus sebaceous of Jadassohn (epidermal nevus syndrome) is an intriguing syndrome that has received attention in the recent literature (1,2,3,4,5,6,7,8,9,10,11,12,13). Sebaceous nevus can be an isolated lesion in the eyelid area, or a part of the organoid nevus syndrome. The neurologic aspects of the organoid nevus syndrome include seizures and mental retardation secondary to arachnoid cysts and cerebral atrophy. The best known ocular finding is the epibulbar complex choristoma (discussed in the section on conjunctival choristomas). The most frequent cutaneous feature of the organoid nevus syndrome is the sebaceous nevus of Jadassohn. This congenital cutaneous lesion can frequently give rise later in life to BCC and other benign and malignant cutaneous neoplasms.

Sebaceous nevus can occur on the eyelid or eyebrow as a solitary lesion or as a component of a larger geographic lesion that affects the skin of the face, retroauricular area, and scalp, with contiguous involvement of the eyebrow and eyelid. It usually has a pink to brown color and well-defined irregular margins. The component that involves the scalp is usually associated with localized alopecia. The lesions are initially flat but become more elevated about the time of puberty, perhaps owing to sebaceous gland hyperplasia (1,2,3,4,5,6,7,8,9,10,11,12,13).

The diagnosis can be easily made based on the typical clinical features mentioned. The patient should have a thorough ocular, dermatologic, and neurologic survey to exclude some of the mentioned systemic findings.