Figure 13-11 An apocrine hidrocystoma is typically lined with a double layer of cuboidal epithelium. Epithelial cells may demonstrate decapitation secretion. (Courtesy of Nasreen A. Syed, MD.)

Neoplasia

Epidermal Neoplasms

Seborrheic keratosis

Seborrheic keratosis, a common benign epithelial proliferation, occurs in middle age. Clinically, it is a well-circumscribed, oval, dome-shaped to verrucoid “stuck-on” papule, varying from pink to brown in color. Histologically, several architectural patterns are possible, although all 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.

A characteristic finding in most types of seborrheic keratoses is the formation of pseudohorn cysts, which are concentrically laminated collections of surface keratin within the acanthotic epithelium (Fig 13-12). Irritated seborrheic keratosis, also termed inverted follicular keratosis, shows nonkeratinizing squamous epithelial whorling, or squamous “eddies,” instead of pseudohorn cysts

(Fig 13-13). Heavy melanin phagocytosis by keratinocytes may impart a dark brown color to an otherwise typical seborrheic keratosis, which may then be confused clinically with melanoma.

Figure 13-12 Seborrheic keratosis. A, The epidermis is acanthotic with a papillary configuration. Note the keratin-filled cysts (asterisks). B, When serial histologic sections are studied, pseudohorn cysts (asterisk) within the epidermis are seen to represent crevices or infoldings of epidermis (arrow). (Courtesy of Hans E. Grossniklaus, MD.)

Figure 13-13 Irritated seborrheic keratosis, also known as inverted follicular keratosis. Clinically, this lesion appeared as a cutaneous horn.

Sudden onset of multiple seborrheic keratoses is known as the Leser-Trélat sign and is associated with a malignancy, usually a gastrointestinal adenocarcinoma; these keratoses may in fact represent evolving acanthosis nigricans. Table 13-3 lists other systemic malignancies with cutaneous manifestations.

Table 13-3

Keratoacanthoma

Keratoacanthoma is a rapidly growing epithelial proliferation with a potential for spontaneous involution. There is strong evidence supporting the idea that keratoacanthomas are a variant of a well-differentiated squamous cell carcinoma. These studies are based on expression of proliferation markers (cyclins and cyclin-dependent kinases) and oncoproteins (mutated p53) that are expressed similarly by both entities. Dome-shaped nodules with a keratin-filled central crater may attain a considerable size, up to 2.5 cm in diameter, within a matter of weeks to months (Fig 13-14). The natural history is typically spontaneous involution over several months, resulting in a slightly depressed scar.

Histologically, keratoacanthomas show a cup-shaped invagination of well-differentiated squamous cells forming irregularly configured nests and strands and inciting a chronic inflammatory host response. The proliferating epithelial cells undermine the adjacent normal epidermis. At the deep aspect of the proliferating nodules, mitotic activity and nuclear atypia may occur, making the distinction between keratoacanthoma and invasive squamous cell carcinoma problematic. If unequivocal invasion is present, the lesion should be considered a well-differentiated squamous cell carcinoma. Many dermatopathologists and ophthalmic pathologists have ceased to use the term keratoacanthoma altogether and prefer to call this lesion well-differentiated keratinizing squamous cell carcinoma because of the possibility of perineural invasion and metastasis. When the clinical differential diagnosis is keratoacanthoma versus squamous cell carcinoma, the lesion should be completely excised to permit optimal histologic examination of the lateral and deep margins of the tumor–host interface.

Actinic keratosis

Actinic keratoses are precancerous squamous lesions that appear, clinically, as erythematous, scaly macules or papules in middle age on sun-exposed skin, particularly on the face and the dorsal surfaces of the hands. Actinic keratoses range from a few millimeters up to 1 cm in greatest dimension. Hyperkeratotic types may form a cutaneous horn, and hyperpigmented types may clinically simulate lentigo maligna. Squamous cell carcinoma may develop from preexisting actinic keratosis; thus, biopsy of suspicious lesions and long-term follow-up are necessary in patients with this condition. However, when squamous cell carcinoma arises in actinic keratosis, the risk of subsequent metastatic dissemination is very low (0.5%–3.0%).

Figure 13-14 A, Patient with keratoacanthoma. Note the cuplike configuration. In this case, the central crater was originally filled with keratin. B, Low-power histologic section illustrating the central keratin crater and the downward (invasive) growth

pattern. (Part B courtesy of Nasreen A. Syed, MD.)

Histologically, there are 5 subtypes, ranging from hypertrophic to atrophic; all types demonstrate changes in the epidermis with hyperkeratosis and parakeratosis. Cellular atypia such as nuclear hyperchromasia and enlargement, nuclear membrane irregularities, and increased nuclear-to- cytoplasmic ratio is present and ranges from mild (involving only the basal epithelial layers) to frank carcinoma in situ, or full-thickness involvement of the epidermis. Dyskeratosis (premature individual cell keratinization) and mitotic figures above the basal epithelial layer are often present (Fig 13-15). The underlying dermis shows solar elastosis (elastotic degeneration of collagen) (Fig 13-16), which manifests as fragmentation, clumping, and loss of eosinophilia of dermal collagen. A chronic inflammatory cell infiltrate is usually present in the superficial dermis. The base of the lesion must be examined histologically to determine whether invasive squamous cell carcinoma is present; for this reason, shave biopsy not including the base of the lesion is contraindicated.

Carcinoma

Basal cell carcinoma (BCC) is the most common malignant neoplasm of the eyelids, accounting for more than 90% of all eyelid malignancies. Exposure to sunlight is the main risk factor, although genetic factors can play a role in familial syndromes. The lower eyelid is more commonly involved than the upper eyelid, with the medial canthus being the second most common site of involvement. Tumors in the medial canthal area are more likely to be deeply invasive and to involve the orbit. The most common type, nodular BCC (Fig 13-17A) is a slowly enlarging, slightly elevated lesion with ulceration and pearly, raised, rolled edges. The morpheaform, or sclerosing, variant of BCC is a flat or slightly depressed pale yellow indurated plaque; this type is often infiltrative, and its extent is difficult to determine clinically. A small percentage of BCCs are pigmented.

Figure 13-15 Actinic keratosis. A, Note the epidermal thickening (acanthosis [I]), disorganization within the epidermis (dysplasia), parakeratosis (asterisk), and inflammation within the dermis. B, Note the epidermal disorganization and mitotic figures (arrows).

Figure 13-16 Solar elastosis. The collagen of the dermis appears bluish (asterisks) in this H&E stain, instead of pink. This is a histopathologic sign of ultraviolet light–induced damage.

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, monomorphous nuclei and a high nuclear-to-cytoplasmic ratio. BCC forms cohesive islands with nuclear palisading of the peripheral cell layer. Frequently, a clear space surrounds the islands of tumor cells, presumably an artifact of tissue processing (Fig 1317B). BCCs may exhibit a variety of histologic patterns, including keratotic (hair follicle), squamous (metatypical), sebaceous, adenoid, and eccrine (syringoid) differentiation. The morphea (sclerosing) variant shows thin cords and strands of tumor cells set in a fibrotic stroma (Fig 13-18).

Figure 13-17 Basal cell carcinoma. A, Clinical appearance of the nodular type. B, Histologic appearance. Note the characteristic palisading of the cells around the outer edge of the tumor (arrow) and the artifactitious separation between the nest of tumor cells and the dermis (retraction artifact, arrowhead).

Figure 13-18 Basal cell carcinoma, morpheaform (sclerosing) type. Thin strands and cords of tumor cells are seen in a fibrotic (desmoplastic) dermis.

Complete excision is the treatment of choice, and surgical margin control is required. Typically, margin control is achieved with frozen sections or Mohs micrographic excision. Morbidity in BCCs is almost always the result of local spread; metastasis is extremely unusual.

Although squamous cell carcinoma (SCC) may occur in the eyelids, it is at least 10 and perhaps up to 40 times less common than BCC. Because most SCCs arise in solar-damaged skin, the lower eyelid is more frequently involved than the upper. However, the proportion of SCCs occurring in the upper eyelid is larger than the proportion of BCCs occurring in the upper eyelid. The clinical appearance of SCC is diverse, ranging from ulcers to plaques to fungating or nodular growths. Accordingly, the clinical differential diagnosis is a long list, and pathologic examination of excised tissue is necessary for accurate diagnosis.

Histologic examination shows atypical squamous cells forming nests and strands, extending beyond the epidermal basement membrane, infiltrating the dermis, and inciting a fibrotic tissue reaction (Fig 13-19). 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). The presence of intercellular bridges between tumor cells should be sought when the diagnosis is in question. Perineural and lymphatic invasion may be present and should be reported when identified microscopically. The use of frozen section (conventional or Mohs microsurgery) or permanent section margin control is indicated to treat this tumor adequately. Regional lymph node metastasis is reported to occur in up to 20% of patients with SCC of the eyelid.