The majority of SCCs arise from preexisting lesions such as actinic keratosis, Bowen disease, radiation dermatoses, burn scars, and chronic inflammatory lesions.⁷ Tumors with no clinical or histologic evidence of a precursor lesion or cutaneous insult are referred to as arising de novo.⁸ This is considered a distinct variant of SCC, primarily occurring in Caucasians in both sun-exposed and sun-protected skin areas.

More than 60% to 90% of all SCCs contain mutations in the p53 cell cycle regulator gene located on chromosome 17p13 that supports repair of DNA injury and induces apoptosis if the damage is lethal.¹ With p53 loss by UVB damage, cell proliferation can lead to carcinogenic progression. Other abnormalities of genes regulating tumor suppression and keratinocyte proliferation and differentiation on chromosomes 3, 9, 13, and 17 have been reported.¹

SCC can present with diverse clinical manifestations ranging from small erythematous scaly patches to very large, ulcerated lesions. It is more common in males where it represents 65% to 75% of cases.¹,⁹ The age at presentation can be from 30 to 90+ years, with a median of about 65 years. The most common site of eyelid involvement is the lower eyelid, followed by the medial canthus, which together accounts for about 80% of all SCC eyelid tumors.⁹ Compared with basal cell carcinoma, squamous cell tumors have a higher tendency toward ulceration and tend to affect the eyelid margin. They often begin as a premalignant lesion, such as actinic keratosis.⁶ Early in the course of SCC, lesions can appear erythematous, thickened, and may be associated with loss of lashes (Figure 145.1). As the lesion advances, it can appear as an infiltrative, ulcerated lesion that bleeds easily and may be covered with scales or a thick crust (Figure 145.2). Occasionally, SCC can

appear nodular with a central ulceration simulating a basal cell carcinoma, or papillomatous, cystic, pigmented, or even hyperkeratotic (Figure 145.3), and may be masked by an overlying cutaneous horn. Advanced tumors can become more aggressive and can invade the orbit by perineural spread or direct soft tissue extension (Figures 145.3 and 145.4).¹⁰,¹¹,¹²

Intraepithelial squamous neoplasia, also known as Bowen disease, is a form of SCC that often arises in areas of chronic infection, inflammation, or burns.⁶,¹³ It is confined to the epithelium, but with time it may break through the basement membrane to become invasive SCC. These lesions typically present as slowly enlarging, well-demarcated, vascularized, erythematous plaques with surface crusting or scaling, and they may occur anywhere on a skin surface or on mucosal surfaces. It may become ulcerated with a heaped-up rim. It often spares the basal epidermal layer and typically involves the follicular epithelium. Bowen disease commonly develops on sun-exposed areas of the body and may occur at any age in adults, mostly in patients over 60 years, and rarely before age 30. Although the literature frequently states that females are affected more commonly than males, among 94 cases, Foo et al¹⁴ recorded a slight predominance for males in a ratio of about 1.5:1. When it involves the conjunctiva, it is referred to as conjunctival intraepithelial neoplasia and may present as flat to minimally elevated fleshy, sessile, gelatinous, or papillomatous masses that mostly involve the interpalpebral conjunctiva but may also involve the palpebral conjunctiva (Figure 145.4).¹⁵ Suggested etiologies are similar to SCC and include irradiation, ultraviolet irradiation, radiotherapy, carcinogens such as arsenic, immunosuppression, chronic injury, or dermatoses such as chronic lupus erythematosus. Bowen disease may become invasive in 5% to 19% of cases, and 13% to 20% of those patients may develop distant metastases.¹³

Treatment options for Bowen disease include photodynamic therapy, cryotherapy, topical 5-fluorouracil or imiquimod, and surgical excision.¹⁶,¹⁷,¹⁸,¹⁹

The differential diagnosis of SCC includes basal cell carcinoma, sebaceous cell carcinoma, Merkel cell carcinoma, Bowen disease, actinic keratosis, keratoacanthoma, inverted follicular keratosis, papilloma, pseudoepitheliomatous hyperplasia, seborrheic keratosis, trichilemmoma, fungal infection, and verruca vulgaris.