Seborrheic keratosis is a common benign epidermal proliferation typically occurring in middle age. Clinically, it is a well-circumscribed round to oval, dome-shaped verrucoid “stuck-on” papule, appearing tan pink to dark brown. Histologically, although several architectural patterns are possible, all lesions demonstrate hyperkeratosis, acanthosis, and some degree of papillomatosis. The acanthosis is a result of the proliferation of either polygonal or basaloid squamous cells without dysplasia. In more pigmented lesions, the basal epidermal layer contains an increased amount of melanin. Pseudohorn cysts, concentrically laminated collections of surface keratin within an epidermal crypt, are a characteristic histologic finding in most types of seborrheic keratosis (Fig 13-12).
Figure 13-11 Apocrine hidrocystoma. A, Low-power photomicrograph shows a partially collapsed cyst that is lined by a double layer of epithelium (ie, an inner, low cuboidal layer and an outer, flattened myoepithelial layer). The lumen appears empty as the clear liquid contents are not visible on routine histologic examination. B, High magnification shows apocrine differentiation with cytoplasmic projections (snouts) on the inner surface (arrowheads) that are typical of decapitation secretion.
(Courtesy of Nasreen A. Syed, MD.)
Figure 13-12 Seborrheic keratosis. A, The epidermis is acanthotic with a papillary configuration. Note the keratin-filled pseudohorn cysts (asterisks).B, When serial histologic sections are studied, pseudohorn cysts (asterisk) within the epidermis are found to represent crevices or infoldings of epidermis (arrow) rather than true cysts.
(Courtesy of Hans E. Grossniklaus, MD.)
Irritated seborrheic keratosis, also termed inverted follicular keratosis, shows nonkeratinized squamous epithelial whorling, or squamous “eddies,” within the proliferating epidermis (Fig 13-13). Sudden onset of multiple seborrheic keratoses is known as the Leser-Trélat sign and is associated with visceral malignancy, usually a gastrointestinal adenocarcinoma; these keratoses may in fact represent evolving acanthosis nigricans. Table 13-2 lists other systemic neoplastic syndromes with possible eyelid manifestations.
Figure 13-13 Irritated seborrheic keratosis (also known as inverted follicular keratosis). A, Low-magnification photomicrograph shows a papillary epidermal proliferation with hyperkeratosis on the surface. Clinically, this lesion appeared as a cutaneous horn. B, High-magnification photomicrograph of a different lesion. The epidermis often shows whorls of cells, known as squamous “eddies” (arrows), and mild disorganization.
(Part B courtesy of Nasreen A. Syed, MD.)
Table 13-2 Eyelid Neoplasms Associated With Systemic Neoplastic Syndromes
Actinic keratoses are precancerous squamous lesions that typically occur starting in middle age. They appear clinically as erythematous, scaly macules or papules on sun-exposed skin, particularly the face and the dorsal surfaces of the hands. Actinic keratoses range from a few millimeters to 1 cm in diameter. Hyperkeratotic types of these lesions may form a cutaneous horn, and hyperpigmented types may clinically simulate lentigo maligna. Squamous cell carcinoma may develop from preexisting actinic keratosis, although most studies indicate that the risk is less than 15%. When squamous cell carcinoma arises in actinic keratosis, the risk of subsequent metastatic dissemination is very low (0.5%–3.0%).
Histologically, there are multiple variants, including a pigmented type. All types demonstrate changes in the epidermis with hyperkeratosis and parakeratosis. Cellular atypia (nuclear hyperchromatism and/or pleomorphism and an increased nuclear-to-cytoplasmic ratio) is present and ranges from mild (involving only the basal epithelial layers) to frank carcinoma in situ (full-thickness involvement of the epidermis). Loss of the granular cell layer, dyskeratosis (premature keratinization of individual cells), and mitotic figures above the basal epithelial layer are often found (Fig 13-14). The underlying dermis often shows solar elastosis (elastotic degeneration of collagen) (Fig 13-15), which manifests as fragmentation, clumping, and basophilic discoloration of the dermal collagen. A chronic inflammatory cell infiltrate is usually observed at the base of the lesion in the superficial dermis. Histologic examination of the base of the lesion is necessary to determine whether invasion through the epidermal basement membrane, indicative of squamous cell carcinoma, is present.
Figure 13-14 Actinic keratosis. A, Note the epidermal acanthosis (bracket), disorganization within the epidermis (dysplasia), parakeratosis (asterisk), and inflammation within the dermis. B, Higher magnification of part A; note the epidermal dysplasia and mitotic figures (arrows).
Figure 13-15 Solar elastosis of the dermis. The collagen of the dermis appears bluish (asterisks) instead of pink in this hematoxylin-eosin–stained section. This is a histologic indicator of ultraviolet light–induced tissue damage.
Basal cell carcinoma Basal cell carcinoma (BCC), the most common malignant neoplasm of the eyelids, accounts for more than 90% of all malignant eyelid tumors. Although exposure to sunlight is the main risk factor, genetic factors can play a role in familial syndromes. The lower eyelid and medial canthus are the most common sites of involvement. Tumors in the medial canthal area are more likely to be deeply invasive and to involve the orbit.
Nodular BCC (the most common subtype) is a slow-growing, slightly elevated lesion, often with ulceration and pearly, raised, rolled edges (Fig 13-16A). The morpheaform, or sclerosing, variant of BCC is a flat or slightly elevated pale-yellow indurated plaque; this type is often infiltrative, and its extent is difficult to determine clinically. A small percentage of BCCs are pigmented or multicentric.
As the name implies, BCCs originate from the stratum basale, or stratum germinativum, of the epidermis and the outer root sheath of the hair follicle and occur only in hair-bearing tissue. Tumor cells are characterized by relatively bland oval nuclei and a high nuclear-to-cytoplasmic ratio. BCC forms cohesive islands with nuclear palisading of the peripheral cell layer, mimicking the hair matrix (Fig 13-16B). In the morpheaform type, thin cords and strands of tumor cells are set in a fibrotic stroma (Fig 13-17).
The treatment of choice is complete excision, and surgical margin evaluation is required. Typically, margin control is achieved with frozen sections or Mohs micrographic surgery. Morbidity in BCCs is almost always the result of local spread; metastasis is extremely unusual.
Squamous cell carcinoma Although squamous cell carcinoma (SCC) may occur in the eyelids, it is far less common than BCC of the eyelid. Like BCCs, most SCCs arise in solar-damaged skin, so the lower eyelid is more frequently involved than the upper eyelid. However, SCC is more likely to involve the upper eyelid than is BCC. The clinical appearance of SCC is diverse, ranging from ulcers to plaques to fungate or nodular growths. Accordingly, the clinical differential diagnosis is long; an accurate diagnosis requires pathologic examination of excised tissue.
Figure 13-16 Basal cell carcinoma, nodular type. A, Clinical appearance with elevated, rolled edges and central ulceration. B, Histologic appearance. Note the characteristic palisading of the cells around the outer edges of the tumor islands (arrows) and the artifactitious separation (due to tissue processing) between the nests of tumor cells and the dermis (retraction artifact, arrowheads).
(Part B courtesy of Nasreen A. Syed, MD.)
Figure 13-17 Basal cell carcinoma, morpheaform (sclerosing) type. Thin cords and strands of tumor cells infiltrating the dermis are surrounded by fibrotic (desmoplastic) dermal tissue.
Figure 13-18 Squamous cell carcinoma. A, Clinical appearance. Note the focal loss of eyelashes (madarosis) and scaly appearance of the lower eyelid. B, Histologic appearance. Note the tumor cells (T) invading the dermis. C, A keratin pearl (asterisk), a keratinized structure present within the epidermis rather than on the surface, is demonstrated in this well-differentiated squamous cell carcinoma.
(Part A courtesy of Keith D. Car ter, MD.)
Histologic examination shows atypical squamous cells that form nests and strands, extend beyond the epidermal basement membrane, infiltrate the dermis, and incite a fibrotic tissue reaction (Fig 13-18). Tumor cells may be well differentiated (forming keratin and easily recognizable as squamous), moderately differentiated, or poorly differentiated (requiring ancillary studies to confirm the nature of the neoplasm). When the diagnosis is in question, the pathologist should look for the presence of intercellular bridges. Perineural and lymphatic invasion may be present and is important to include in the pathology report when identified microscopically, as this finding may be associated with a less favorable prognosis. To treat this tumor adequately, frozen section (conventional or Mohs technique) or permanent section margin control is required. Regional lymph node metastasis may occur in patients with SCC of the eyelid.
Keratoacanthoma is a rapidly growing epithelial proliferation with the potential for spontaneous involution. Strong evidence supports the idea that keratoacanthomas are a variant of a well-differentiated SCC. These dome-shaped nodules, which have keratin-filled central craters, may attain considerable size, up to 2.5 cm in diameter, within a matter of weeks to a few months (Fig 13-19). The natural history is typically spontaneous involution over several months, resulting in a slightly depressed scar. The incidence of keratoacanthoma is higher in immunosuppressed individuals because the health of the epidermis and epithelium of mucous membranes is supported by the immune system.
Histologically, keratoacanthomas show a cup-shaped invagination of well-differentiated squamous cells that proliferate in nests (squamous eddies) and acanthotic projections and incite a chronic inflammatory host response. The proliferating epithelial cells undermine the adjacent normal epidermis with a downward growth pattern. In the deeper portions of the proliferating nodule, mitotic activity, dykeratosis, and nuclear atypia may occur, similar to that seen in typical SCC. Many dermatopathologists and ophthalmic pathologists prefer to call this lesion well-differentiated squamous cell carcinoma withkeratoacanthoma-like differentiation because of the possibility of perineural invasion and metastasis.
Figure 13-19 Keratoacanthoma. A, Clinical photograph. Note the elevated lesion with a central ulcerated crater and focal loss of eyelashes. In this case, the central crater was originally filled with keratin. B, Low-magnification histologic section illustrates the central keratin-filled crater and the downward (invasive) growth pattern.
(Part B courtesy of Nasreen A. Syed, MD.)
If the lesion does not involute spontaneously, the lesion should be completely excised to permit optimal histologic examination of the lateral and deep margins of the tumor–host interface.
Excerpted from BCSC 2020-2021 series: Section 4 - Ophthalmic Pathology and Intraocular Tumors. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.