Pathogenesis and Etiology.
The etiology of squamous cell papilloma is poorly understood. It is rarely associated with high-risk human papillomavirus (HPV) types 6 and 11. UV radiation has also been proposed to play a role in some cases.10 In addition, chronic irritation from repeated tactile stimulation is hypothesized to have a role in its development.
Investigations.
Biopsy is required for definitive diagnosis and to exclude malignancy. Excisional biopsy is recommended for smaller lesions and incisional biopsy for larger lesions. Shave biopsy is chosen for lid margin lesions for cosmesis and to avoid notch formation, but has a higher chance or recurrence. Radiofrequency ablation has also been used for excisional biopsy.11 Microscopically, squamous cell papillomas demonstrate fingerlike projections of vascularized connective tissue (Fig. 22.1B). The overlying stratified squamous epithelium is acanthotic with hyperkeratosis and parakeratosis.
Management.
Asymptomatic papillomas do not require intervention, as they tend to progress slowly, have an excellent prognosis, and do not exhibit malignant transformation. If they become symptomatic or are cosmetically bothersome, options for removal include surgical excision, laser ablation, or cryotherapy. The latter two approaches may cause destructive changes near the lid margins.12 Photodynamic therapy has been used for the treatment of papilloma on the eyelid margin, with good functional and cosmetic results. One case report described successful use of intralesional interferon-α2B to reduce the size of the tumor before excision.13
Seborrheic Keratosis
Clinical Features.
Seborrheic keratosis (SK) presents as a well-circumscribed, greasy “stuck on” papule (Fig. 22.2A). On thin eyelid skin, it may appear lobulated, papillary, or pedunculated. It ranges in color from pink to brown and has a crusty surface because of hyperkeratosis. SK is characterized by pseudohorn cysts, or concentrically laminated collections of keratin within the epithelium. Using dermoscopy, hairpin looped vessels can be visualized.14 These vessels may be seen in other keratinizing tumors as well but have a higher positive predictive value for SK.
The sudden onset of multiple seborrheic keratoses is known as the Leser-Trélat sign. It is a type of acanthosis nigricans and is associated with malignancy, especially gastrointestinal adenocarcinoma.
Investigations.
Definitive diagnosis can be made only with biopsy and histopathologic examination, but typically, the history and clinical examination are adequate to diagnose and manage SK. Histologically, SKs demonstrate hyperkeratosis, acanthosis, and papillomatosis and often have keratin-filled cysts (Fig. 22.2B). In irritated SK, or inverted follicular keratosis, there is nonkeratinizing squamous epithelial whorling instead of pseudohorn cysts.
Management.
SKs are benign and pose minimal risk of malignant transformation, and so typically they do not require intervention. Excision may be performed if they cause undesired symptoms such as itching or bleeding, or if they obstruct vision. SKs can be managed with shave excision at the dermal–epidermal junction, as they tend to remain superficial. Suspicion of Leser-Trélat sign should prompt a referral for workup of gastrointestinal malignancy.
Keratoacanthoma
Clinical Features.
Keratoacanthoma (KA) occurs as a single crater-like nodule with a central keratin plug (Fig. 22.3A). The lower eyelid is more commonly affected than the upper eyelid. Although KAs often have a characteristic appearance, a percentage of clinically diagnosed KAs are actually SCCs. Muir-Torre syndrome presents with visceral malignancy associated with sebaceous gland neoplasms (discussed in the following sections) or multiple KAs. Individuals affected by Ferguson-Smith syndrome, also known as multiple self-healing squamous epithelioma, develop numerous KA-like lesions that spontaneously regress. This rare autosomal dominant disorder is caused by a loss-of-function mutation in TGFBR1.
Investigations.
SCC and other malignancies must be ruled out whenever there is clinical suspicion of KA. Complete excision, including the base of the lesion, is essential for histologic confirmation of the diagnosis. In one large series, the development of SCC was observed in 5.7% of KAs and the incidence increased with age.15 Microscopically, KA demonstrates a cup-shaped invagination of squamous cells, forming irregular nests and strands that extend into the dermis (Fig. 22.3B). The cells are large and pale pink with a hyaline appearance. There may be a lymphoplasmacytic host response.
Management.
Single lesions can be treated with surgical excision, which also provides tissue for histopathologic examination. In select patients, multiple lesions may be treated with systemic chemotherapy or oral retinoids.16 Early treatment of periocular KA helps maintain normal eyelid function and prevents local tissue invasion.
Complications and Prognosis.
Although they may cause local complications, KAs have been shown to have a largely benign course.16 They tend to grow rapidly over weeks, remain stationary for weeks, and spontaneously involute over months, leaving an atrophic scar. Most KAs exhibit some degree of spontaneous regression.17 Those that are excised or treated have a 4% rate of recurrence. The risk of malignant transformation is low, and reports of metastases are rare. Uncommonly, KAs may exhibit perineural or perivascular invasion.
Controversy: Some authors and pathology laboratories have suggested that KA is a variant of SCC based on their similar histopathologic appearances,18,19 whereas others believe that KA is a benign lesion distinct from SCC with a unique natural history.15–17
Actinic Keratosis
Clinical Features.
Actinic keratosis (AK) is a premalignant, erythematous, scaly, flat lesion that occurs more frequently on the lower eyelid compared with the upper eyelid (Fig. 22.4A). It classically has a sandpaper texture on palpation. AKs are considered to occur on a disease spectrum with SCC. They are common in older individuals and are often multiple. Patients with eyelid AK typically have additional AKs elsewhere on the face and on the upper extremities.
Investigations.
Incisional or excisional biopsy, with permanent or frozen section, allows for the histopathologic diagnosis of AK. The epithelium shows varying degrees of dysplasia, with hyperkeratosis and parakeratosis on histologic examination (Fig. 22.4B). There are atypical squamous cells exhibiting increased nuclear-to-cytoplasmic ratio and solar elastosis with breakdown of collagen fibers in the dermis.
Management.
The management of AK may depend on the patient’s age and the presence of comorbid conditions. Because AK is premalignant, excision is typically recommended for tumors in the high-risk periocular region. Most oculoplastic surgeons surveyed treat AK at the eyelid margin by excision with permanent pathology, followed by referral for Mohs surgery or excision with frozen section control.20 The cure rate is over 90%, although AKs have a small risk of recurrence after excision.21 Risk factors for recurrence include older age, larger tumor size, and longer evolution time.
Various nonsurgical alternatives have also been used, with either a lesion-directed or field-directed approach. Ablative treatments include cryotherapy, laser therapy, and photodynamic therapy. Topical therapies include imiquimod cream (Aldera), 5-fluorouracil (5-FU) cream, and diclofenac gel.22–24 These treatments should be used with care for lesions near the eye, since they can cause local irritation. They may be more suitable for lesions greater than 2 mm from the eyelid margin. In addition, multiple courses of therapy may be required because of residual lesion or recurrence.
Complications and Prognosis.
AKs transform into invasive SCC at a rate of 0.25% to 10% per year.21 These lesions rarely metastasize. Up to 25% of individual AKs spontaneously resolve over a year; however, new lesions also tend to develop. All patients should be advised to utilize sun protection to prevent malignant transformation of existing lesions, as well as the development of additional AKs.
Squamous Cell Carcinoma in situ
Clinical Features.
SCC in situ (Bowen disease) is a premalignant lesion, presenting as an erythematous plaque with overlying scaling or crusting (Fig. 22.5A). It is considered to be a more advanced form of AK, with cellular atypia involving the entire epidermis.
Investigations.
Biopsy and histopathologic evaluation are necessary to confirm the diagnosis of SCC in situ. It is histologically similar to AK but demonstrates a greater degree of dysplasia (Fig. 22.5B). SCC in situ is defined by full-thickness atypia of the epidermis, including intraepidermal adnexal structures, without invasion of the basement membrane. Keratinocytes appear with numerous mitotic figures and loss of polarity. Parakeratosis (retention of nuclei in the stratum corneum), hyperkeratosis (thickening of the stratum corneum), and acanthosis (thickening of the stratum spinosum and stratum basale) are often seen.
Management.
Excision or Mohs micrographic surgery are the preferred methods for treatment of SCC in situ. There is a small chance of recurrence after surgical excision. However, management should be guided by the size and location of the lesion, as well as by individual patient characteristics. Other treatment options include cryotherapy, topical creams, and ablative therapies. Topical 5-FU has been used to treat early SCC in situ and can be preferable for lesions that affect the eyelid margin or would be otherwise difficult to resect.23,24 However, topical therapies may be associated with a higher risk of tumor recurrence because of involvement of the eyelash follicles.
Complications and Prognosis.
Between 3% and 5% of cases of SCC in situ progress to invasive carcinoma.9 Individuals with SCC in situ and those who are immunosuppressed are at high risk for developing subsequent nonmelanoma skin cancers and should be followed up closely.25 In addition, patients should be referred to Dermatology for a complete skin examination, since they often have concurrent lesions elsewhere on the body. Recurrent SCC in situ is associated with a greater likelihood of skip lesions within the tumor.26 Clinicians may consider multiple map biopsies to rule out involvement of adjacent areas, as is performed for sebaceous carcinoma affecting the conjunctiva.27
The Dermis
Benign tumors arising from the dermis are less common than those originating in other eyelid structures because the eyelid dermis is so thin. They include melanocytic and vascular tumors, and most are congenital or arise early in childhood. Congenital nevi are found in 1% of newborns and tend to be larger than lesions first presenting in adolescence or adulthood.28 Acquired nevi frequently occur as a result of sun exposure in early life. Nevi represent approximately 20% of benign eyelid lesions.6 Divided nevus is a rare congenital lesion that arises in the developing embryo before separation of the eyelids. Infantile hemangioma occurs in roughly 4% to 12% of infants, with a higher incidence in females.29 It may originate in the embryo as early as 6 to 8 weeks, during rapid angiogenesis associated with eyelid development.
Many dermal tumors are caused by abnormal cellular proliferation in the developing embryo. Nevi arise from the proliferation of melanocytes at the dermal–epidermal junction, whereas blue nevi and oculodermal melanocytosis originate from deeper melanocytes in the dermis that have failed to migrate into the epidermis during development. Infantile hemangioma and port-wine stain are discussed extensively in Chapters 24 and 25.
Melanocytic Skin Lesions
Nevus
Clinical Features.
Nevi represent benign proliferations of melanocytes, which are melanin-containing cells derived from the neural crest. Melanocytes are normally distributed throughout the skin and may undergo abnormal cellular proliferation to form nevi. Nevi are extremely common and can be found almost anywhere on the body. In the periocular region, these lesions are often found on the eyelid margin. Nevi evolve over time and may be classified histologically as junctional, compound, and intradermal. Junctional nevi are small, tan macules that typically first present in childhood. They evolve into compound nevi and then intradermal nevi, which are common in adults. Nevi become increasingly elevated and gradually lose the ability to produce melanin. Junctional and compound nevi are pigmented (Fig. 22.6A), whereas intradermal nevi may be hypomelanotic or amelanotic (Fig. 22.6B).
Investigations.
Ordinary benign nevi can often be diagnosed clinically. However, large congenital nevi are associated with a higher risk of malignant transformation into melanoma and should be biopsied. Microscopically, most nevi are composed of clusters of nevus cells, which are incompletely differentiated melanocytes that appear larger than typical melanocytes. Nevus cells tend to grow within and around adnexal structures and may extend into the deep reticular dermis or subcutaneous tissue. Junctional nevi are composed of nests of nevus cells at the dermal–epidermal junction. Over time, the cells stop growing and start migrating into the superficial dermis, forming compound nevi. These lesions are classified as intradermal nevi when the nevus cells are confined to the dermis (Fig. 22.6C). Nevus cells also show a classic progression from epithelioid morphology in the superficial portions to spindle-shaped in the deep portions.
Management.
Most nevi can be safely observed. Junctional or compound nevi rarely transform into malignant lesions. If nevi become large enough, they may cause astigmatism or obstruction of vision. Lesions that are symptomatic or cause undesired cosmetic effects can be managed with shave excision or wedge resection of the eyelid margin.30 Nevi with rapid growth and suspicious appearance should also be excised. Various methods of excision and reconstruction have been described for large congenital nevi of the eyelid.31
Divided Nevus
Clinical Features.
Divided (“kissing”) nevus of the eyelid, which was first described by Fuchs in 1919, is a rare congenital lesion, with relatively few cases reported in the literature since then.32 It is seen more frequently in white persons and less frequently in Asians. Divided nevus has a distinct appearance because of its involvement of the opposing portions of the upper and lower eyelids (Fig. 22.7A). It may affect the medial and lateral canthi, as well as the cheek.
Divided nevus is thought to develop in utero as a single lesion between the ninth and 24th weeks of gestation, when the eyelids are fused.33 On histology, the vast majority of these lesions are found to be intradermal.
Management.
If divided nevus is symptomatic or cosmetically bothersome, both surgical and nonsurgical treatment options are available. Some experts recommend removal of divided nevus before school age, when peer pressure may lead to negative psychological consequences (Fig. 22.7B). Reports have described successful one-stage and two-stage reconstruction methods, most commonly using local tissue transfer and skin grafts.34,35 However, treatment is highly individualized, depending on the size of the lesion and the structures affected. Conservative management may be appropriate for smaller lesions.36 Nonsurgical options include dermabrasion, cryotherapy, and laser therapy; however, their use has remained limited.
Complications and Prognosis.
Divided nevi are nearly always benign, with only two cases of malignant transformation reported in the literature.33,37,38 They grow slowly over time, becoming more darkly pigmented and elevated.39 Enlarging lesions may cause local complications, including ptosis, ectropion, entropion, and corneal irritation.
Controversy: Primary orbital melanoma has been reported arising from congenital oculodermal melanocytosis and hypercellular blue nevus, but rarely from divided nevus.40 To date, only one large series has reported no malignant transformation in 73 patients followed up.39 However, there are two recent case reports of divided nevus associated with malignant melanoma.37,38
Blue Nevus
Clinical Features.
Blue nevus is a dark blue to black, flat or slightly elevated papule that is thought to be congenital. The lesion may appear for the first time during childhood, with gradually increasing size and pigmentation. Compared with ordinary nevi (see above), blue nevi are relatively rare. Even fewer cases have been documented in the periocular region.
Epidemiology.
Blue nevi were first characterized in 1906 by the Swiss dermatologist Jadassohn.41 They usually occur sporadically. Rarely, blue nevus is associated with Carney complex, a syndrome characterized by spotty skin pigmentation and multiple tumors, including cardiac myxomas, endocrine tumors, and schwannomas.
Investigations.
Blue nevi are associated with a low malignant potential and therefore require biopsy to rule out malignant transformation. Under microscopy, blue nevi demonstrate epithelioid melanocytes in the dermis. The majority of cells are globular and heavily pigmented, whereas others are polygonal and more lightly pigmented. There may be varying degrees of atypia.
Management.
Blue nevi should be observed closely or removed surgically, given their risk of malignant transformation. They encompass a spectrum of lesions ranging from the cellular blue nevus, to the atypical cellular blue nevus, and finally to the malignant cellular blue nevus.42
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