SEBACEOUS CARCINOMA

Sebaceous carcinoma accounts for 1–6% of all eyelid malignancies, making it the second most common malignancy of the eyelids after basal cell carcinoma.2 It most commonly arises on the upper lid, followed by the lower lid, caruncle, and brow in descending order of frequency.

Sebaceous carcinoma can arise from any sebaceous gland but is by far most common on the eyelid, arising from the meibomian glands or the sebaceous glands associated with the eyelashes (glands of Zeis). Rarely, sebaceous carcinoma can arise from the lacrimal gland, parotid gland, or accessory salivary glands. It should be stressed that the vast majority of sebaceous carcinoma is on the eyelid, underscoring the importance of the ophthalmologist’s familiarity with this tumor. Inexperienced general pathologists can mistake this tumor for squamous carcinoma, a much less aggressive tumor. If the ophthalmologist has any suspicion of sebaceous carcinoma the opinion of an experienced eye pathologist or dermatopathologist is vital.

Histologically this tumor consists of tightly packed bizarre appearing basophilic cells. Clusters of cells with frothy cytoplasm are seen. The amount of sebaceous differentiation varies, occasionally causing these tumors to be mistaken for aggressive squamous cell carcinoma. Mitotic figures are necessary for diagnosis, and tend to be frequent (159). This tumor usually does not respect the basal lamina of the epithelium, showing direct extension into the dermis. Areas of pagetoid spread through strictly epithelial layers are often seen, a feature that makes this tumor highly aggressive.

Four histologic patterns are recognized: lobular, comedocarcinoma, papillary, and mixed. The lobular pattern is most typical, reminiscent of a nodular basal cell carcinoma. The comedo pattern focuses around an area of central necrosis (160). The papillary pattern is composed of fronds of malignancy. The mixed pattern is most common, and is a combination of the above.

Special stains are sometimes helpful in the diagnosis of sebaceous carcinoma. Fat stains can identify the presence of sebaceous differentiation. Tissue must be fixed fresh/frozen, although tissue placed in formalin for short periods of time prior to receipt in the histology laboratory can often be used for frozen section with good results. Most often fat stains are not necessary for making a diagnosis.

Squamous cell carcinoma represents less than 5% of all neoplasms of the eyelid. It is the second or third most common epidermal cancer of the eyelid, being far outweighed by basal cell carcinoma, and outweighed in some series by sebaceous carcinoma.3, 4 Squamous carcinoma may arise de novo or from a pre-existing actinic keratosis or intraepithelial neoplasia. Early recognition and treatment is important since early lesions have a very low metastatic potential.

Squamous cell carcinoma arises from the acanthocytes, or prickle-cell layer of the epidermis. This tumor is usually an eosinophilic (pink-staining) cluster of atypical hyperchromatic squamous cells with abundant mitotic figures, acanthosis (thickening of the prickly layers), parakeratosis (retention of nuclei within the keratin layers), and dyskeratosis (keratin found in deep layers) (161). The hallmark of invasive squamous cell carcinoma is that it does not respect the basement membrane of the epidermis and invades the dermis (162). In more differentiated tumors, intracellular bridges can be identified, with a high degree of keratinization and numerous keratin pearls. Less differentiated tumors may lack keratinization and intracellular bridges, and appear as masses of spindle-shaped cells. Immunohistochemical stains to identify keratin and its precursors can often aid in diagnosis of poorly differentiated squamous carcinomas. Perineural infiltration is occasionally seen in more aggressive tumors. This feature has negative prognostic implications.

A variant of squamous cell carcinoma called adenoid squamous cell carcinoma is occasionally found on the head or neck of older individuals. Histologically it exhibits pseudoglandular proliferation with marked acantholysis. This variant carries a good prognosis.

Histologic examination of the thickness of squamous cell carcinomas helps to predict the chance of metastasis. Thin lesions (<2 mm [0.1 in] thick) almost never metastasize. Lesions 2–6 mm (0.1–0.2 in) thick have an approximately 5% chance of metastasis. Lesions >6 mm (0.2 in) thick carry a 15% chance of metastasis.

159 Sebaceous carcinoma.The arrowhead indicates a mitotic figure. The arrows point to cells with frothy sebaceous cytoplasm. (Original magnification x 400.)

160 Sebaceous carcinoma in a comedo pattern. Malignant sebaceous cells are organized around a central area of necrosis (circled). (Original magnification x 300.)

ACTINIC KERATOSIS

This is the most common precancerous cutaneous lesion. It occurs most frequently on the face (including the eyelids), back of the hands, and scalp, areas with a high degree of sun exposure. It is estimated that up to 25% of these lesions spontaneously regress, and between 12% and 20% undergo malignant transformation, most commonly into squamous carcinoma.5, 6

Histologically, actinic keratosis shows parakeratosis, hyperkeratosis, dyskeratosis and acanthosis of varying thickness. Normal rete pegs are usually enlarged, invading deeper into the dermis. However, this tumor respects its underlying basement membrane. An inflammatory response underneath the basement membrane is commonly observed (163).

BOWEN’S DISEASE

It is commonly accepted that Bowen’s disease is a marker for the development of other skin cancers and internal malignancies. Clinically, Bowen’s disease appears on sunexposed areas of the skin as scaly, crusty, well-demarcated, keratotic plaques.

Histologically Bowen’s disease shares many of the features of squamous carcinoma and actinic keratosis. The epithelium displays hyperkeratosis, parakeratosis, dyskeratosis, and acanthosis. The difference between Bowen’s disease and actinic keratosis is that in Bowen’s disease the epithelium is completely replaced by full thickness atypia. Bowen’s disease is said by some to be histopathologically indistinct from squamous carcinoma in situ (there is no invasion beyond the basement membrane) (164).4

RADIATION DERMATOSIS

Epidermal changes related to radiation damage occur in two stages: early and late. Early changes include erythema with intraand extracellular edema, occasionally progressing to formation of bullae and vesiculation. These changes usually begin within two days of exposure. Late changes include atrophy of the epidermis and dermal appendages (occasionally leading to loss of eyelashes), telangiectasis, and irregular hyperpigmentation. The incidence of radiation dermatosis was much greater in the past when radiation was used to treat benign skin conditions such as acne, psoriasis, and eczema.

The most common malignancies to arise from radiation dermatosis are basal cell carcinoma, followed by squamous carcinoma, and, much more rarely, mesenchymal sarcoma.

The Merkel cell is a specialized cell found within the epidermis and dermis that is of neural crest origin, and probably acts as a touch receptor. Tumors arising from these cells occur primarily on the head and neck, trunk, arms, and legs. These tumors occur most commonly in older individuals.

Histopathologically Merkel cell tumors resemble lymphoma with tightly packed round or oval cells displaying numerous nucleoli, usually found in sheets or clusters underlying the epidermis. Mitotic figures are frequent. Immunohistochemistry is most useful in establishing a diagnosis.

METASTATIC EYELID CARCINOMA

Metastases to the eyelid are uncommon. The most frequent primary sites are breast, lung, cutaneous melanoma, and stomach.7 The histopathology of these lesions varies according to the primary tumor. Immunohistochemistry and electron microscopy are often helpful in establishing the diagnosis in cases where the primary tumor is not known.

MELANOCYTIC TUMORS

MELANOCYTIC NEVUS

A melanocytic nevus is a congenital hamartomatous lesion resulting from hyperproliferation of benign epidermal melanocytes within the dermis or epidermis. For the purposes of this chapter only melanocytic nevi will be discussed. Nevi arising from dermal dendritic nevi such as the nevus of Ota, the Mongolian spot, and the blue nevus will not be covered.

Nevi are described by their depth within the skin. Nevi can be intradermal, junctional, or compound. A commonly accepted theory describing the evolution of nevi holds that nevi are present at birth or at a very young age in the epidermis. They obtain pigmentation before or during puberty and begin to move deeper towards the dermis. Junctional nevi (at the junction between epidermis and dermis) are said to be present during teenage years or young adulthood, after which nevi become purely dermal. A compound nevus is found in both the dermis and epidermis.

Histologically nevi appear as medium-sized round basophilic cells arranged in nests, often with prominent nucleoli and no other visible organelles. The amount of melanin varies within and around the melanocytes of a nevus. Occasionally these cells can be mistaken for lymphocytes because of their bland appearance. The location of the nests varies by tumor type (intradermal, junctional, or subdermal). As nevi age they induce fibroplasia, such that deeper nevi tend to be surrounded by a dense collagenous stroma. Cellular atypia is often present to mild degrees, but mitotic figures are not commonly seen (165).