Sebaceous carcinoma (SC) is a rare, often aggressive form of skin cancer originating from the sebaceous glands, the microscopic oil-producing glands found throughout the skin. While it most commonly appears in the periocular region, specifically the eyelids, it can occur elsewhere. Because its clinical presentation sometimes mimics common, benign conditions like a stye or chronic eyelid inflammation, diagnosis relies almost entirely on histology—the microscopic examination of tissue—to confirm the presence of cancerous sebaceous cells and distinguish them from other skin tumors.
Defining Characteristics of Sebaceous Differentiation
The diagnosis of sebaceous carcinoma rests on identifying specific cellular features indicating sebaceous differentiation. The tumor is composed of two main cell populations: small, dark, undifferentiated basaloid cells and larger, more mature sebocytes, which are the differentiated tumor cells.
The most distinctive microscopic feature is the presence of foamy or vacuolated cytoplasm within the sebocytes. This appearance results from the accumulation of intracellular lipids (fats) that dissolve during standard tissue processing, leaving clear, bubbly spaces within the cell. These differentiated sebocytes are typically found toward the center of the tumor nests.
Malignant cells often show significant variation in size and shape, a feature known as pleomorphism. The high volume of lipid vacuoles can physically push against the nucleus, causing it to appear scalloped or indented. Additionally, sebaceous carcinoma exhibits a high mitotic rate, indicating aggressive, uncontrolled growth.
Specialized fat stains like Oil Red O can be applied to frozen tissue sections to visually confirm the presence of lipids, which stain bright red or orange. A well-differentiated sebaceous carcinoma shows a higher proportion of vacuolated sebocytes. Conversely, poorly differentiated tumors are dominated by the more aggressive, non-vacuolated basaloid cells.
Architectural Growth Patterns
The microscopic arrangement of sebaceous carcinoma cells provides important clues about the tumor’s identity. The tumor cells typically grow in large, irregular aggregates or nests, often described as lobules. These lobules usually display an asymmetrical and infiltrative growth pattern, pushing deeply into the surrounding dermis and subcutaneous fat.
A characteristic feature of SC is “reverse differentiation” seen within these lobules. The periphery, or outer edge, is often lined by smaller, darker, less-differentiated basaloid cells. Moving inward, the cells gradually mature and differentiate into the lipid-filled sebocytes toward the center. This arrangement is the opposite of a benign sebaceous lesion, where mature cells are typically found closer to the center.
Pagetoid spread is another key architectural finding, particularly in eyelid tumors. This phenomenon involves the upward migration of malignant sebaceous cells from the main tumor mass into the overlying epidermis or conjunctival epithelium. These single, scattered malignant cells or small clusters within the epithelium can lead to a misdiagnosis of a benign inflammatory condition, making this pattern a diagnostic marker for ocular sebaceous carcinoma.
Immunohistochemical Confirmation
When sebaceous differentiation is subtle or poorly formed, pathologists rely on immunohistochemistry (IHC), a technique using antibodies to stain specific proteins within the tumor cells. IHC confirms the sebaceous origin of the cells and helps rule out other types of skin cancer.
Positive Markers
Several markers are used in a diagnostic panel. Adipophilin is sensitive and reliable for sebaceous differentiation, as this protein surrounds lipid droplets, allowing visualization of intracellular fat even in formalin-fixed tissue. Epithelial Membrane Antigen (EMA) is another frequently positive marker, staining the cell membranes of the sebaceous tumor cells.
Negative Markers
The use of negative markers is equally important for diagnosis. Sebaceous carcinoma is typically negative for Melan-A and S-100, which helps to exclude melanoma. Furthermore, these negative results, along with other specific markers, aid in differentiating SC from other common skin carcinomas.
Systemic Implications
The diagnosis of sebaceous carcinoma often triggers additional IHC testing for mismatch repair (MMR) proteins, such as MLH1 and MSH2. Loss of expression of these MMR proteins can indicate Muir-Torre syndrome, a genetic predisposition that increases the patient’s risk for internal malignancies, particularly colorectal cancer.
Distinguishing Sebaceous Carcinoma from Mimics
Sebaceous carcinoma can histologically resemble several other common skin tumors, making accurate distinction crucial for appropriate treatment.
Basal Cell Carcinoma (BCC)
BCC is a common mimic. Unlike SC, BCC typically exhibits classic features such as peripheral palisading, where the nuclei of the outermost cells align in a fence-like pattern, and clefting, an artificial space that forms between the tumor nest and the surrounding tissue. IHC staining helps differentiate them, as BCC is strongly positive for Ber-EP4, while sebaceous carcinoma is generally negative.
Squamous Cell Carcinoma (SCC)
SC must also be distinguished from SCC, especially the clear cell variant, which can have a pale, clear cytoplasm. SCC is characterized by the formation of keratin pearls and the presence of intercellular bridges between cells. Sebaceous carcinoma lacks these features and is generally negative for CK7, a marker often expressed in SCC.
Benign Sebaceous Lesions
Distinguishing SC from benign sebaceous lesions, such as Sebaceous Adenoma or Sebaceous Hyperplasia, can be the most challenging. Benign lesions are well-circumscribed, non-infiltrative, and show an orderly maturation of sebocytes from periphery to center. In contrast, SC exhibits cellular atypia, an elevated number of mitotic figures, and an aggressive, infiltrative growth pattern.