Pathology of Sebaceous Carcinoma

Sebaceous carcinoma is an aggressive, malignant tumor arising from sebaceous glands of the skin adnexa (see the following image).

Sebaceous gland carcinoma is an uncommon tumor, with approximately 75% occurring in the periocular region. ^[1] In the United States, sebaceous gland carcinoma is the fourth most common eyelid tumor after basal cell carcinoma, squamous cell carcinoma, and melanoma, and it represents 1-5% of eyelid malignancies. ^{[2, 3]} This tumor is more common in Asian countries, reportedly comprising 33% of eyelid tumors and second behind basal cell carcinoma. ^[4] The upper eyelid is involved 2 to 3 times more commonly than the lower eyelid. ^{[1, 2, 5, 6]}

Sebaceous carcinoma typically occurs in the sixth or seventh decade of life, with a wide age range from early childhood through the 90s. ^{[7, 8, 9]} Women are affected more than men, comprising between 55% and 77% of cases. ^{[2, 7, 10]}

See Sebaceous Carcinoma and Sebaceous Gland Carcinoma for more information.

Sebaceous carcinoma has been separated into two anatomic groups: ocular and extraocular.

The ocular tumors most commonly originate from the meibomian glands (51%) and glands of Zeiss (10%) on the eyelid. ^{[1, 11]} Less commonly, these tumors may arise from sebaceous glands of the eyebrows (< 10%), the caruncle (< 10%), or the fine hair follicles of the eyelid surface. ^[2] The upper eyelid is involved 2 to 3 times more commonly than the lower eyelids. ^{[1, 2, 5, 6]}

The extraocular lesions account for 20% of sebaceous carcinomas and are most commonly found in the head and neck region of elderly patients, including the scalp and face. More rarely, sebaceous carcinoma may be found on the trunk, genital region, extremities, and oral cavity. ^{[12, 13, 14]} The most common extracutaneous location is the parotid gland. ^[15]

The etiology of sebaceous carcinoma is not entirely known. No association with ultraviolet (UV) radiation has been documented, although this condition has been reported to follow ionizing radiation therapy for retinoblastoma, cavernous hemangioma, and barber's itch (folliculitis barbae). ^{[2, 8, 16, 17]}

Sebaceous carcinoma may rarely occur in patients with the familial disorder Muir-Torre syndrome (MTS) (now known to be part of Lynch syndrome). ^[18] The more typical sebaceous tumors in MTS are sebaceous adenoma, sebaceoma, and basal cell carcinoma with sebaceous differentiation. ^[19] Sebaceous carcinoma has also been reported to arise in association with nevus sebaceus. ^[20]

Genetic factors

One study detected human papilloma virus (HPV) in a high percentage of cases of sebaceous carcinoma in Japan by in situ hybridization (ISH), as well as increased expression of TP53 in advanced cases. ^{[21, 22]} Mutations in the TP53 gene have been seen in invasive but not in-situ sebaceous carcinoma. ^{[23, 24]}

Ocular sebaceous carcinomas present as slowly enlarging, painless nodules of the eyelid margins or conjunctiva that may be clinically mistaken for benign inflammatory lesions, such as chalazions, blepharitis, and conjunctivitis. ^{[5, 25, 26, 27]} The extraocular lesions often present as larger, ulcerated, yellow-tan nodules and measure 1–4 cm or more in diameter. ^{[1, 28]}

The following are considered part of the differential diagnosis of sebaceous carcinoma:

• Bacterial Conjunctivitis

• Viral Conjunctivitis

• Basal Cell Carcinoma

• Blepharitis

• Chalazion

• Conjunctival Melanoma

• Ocular Sarcoidosis

• Sebaceous Gland Carcinoma

• Pathology of Cutaneous Squamous Cell Carcinoma and Bowen Disease

• Conjunctival Squamous Cell Carcinoma

• Cutaneous Squamous Cell Carcinoma

• Orbital Tumors

Sebaceous carcinoma commonly forms a firm nodule that is yellow-tan, often ulcerated, and hemorrhagic. ^[1] The tumor may also mimic conjunctivitis lacking a discreet tumor mass. The tumor consists of irregular lobules and sheets of cells, as seen in the first three images below, with varying degrees of sebaceous differentiation, including scalloped, centrally located nuclei with foamy, multivacuolated cytoplasm, secondary to intracytoplasmic lipid (see the 4th and 5th images). ^[29]

The undifferentiated cells are atypical and show considerable nuclear and nucleolar pleomorphism with eosinophilic cytoplasm, as seen in the final image above. ^[30] Some atypical keratinizing cells, as seen in squamous cell carcinoma, are seen in larger lobules (also depicted in the final image above). ^[28]

Sebaceous carcinoma commonly shows zones of necrosis, marked nuclear atypia, and abnormal mitotic figures, and an infiltrative growth pattern. Pagetoid or intraepithelial spread is a classic histologic feature. ^{[31, 32]}

Classically, special stains have been used to confirm the presence of intracytoplasmic lipids. ^[2] If performed on frozen section slides, Oil Red O and Sudan Black demonstrate intracytoplasmic lipid in the vacuolated cells. These stains cannot be performed on formalin-fixed paraffin embedded tissue. However, immunohistochemical stains (adipophilin, perilipin, and TIP47) that can be performed on formalin-fixed paraffin embedded tissue have been found to be able to recognize proteins present on the surface of intracellular lipid droplets. ^{[33, 34]}

A study by Plaza et al aimed to determine the efficacy of immunohistochemistry in the diagnosis of sebaceous carcinoma. The study indicated that adipophilin represents a sensitive and reliable marker for diagnosis and can be of help in differentiating this tumor from others. ^[35]

Sebaceous carcinoma is positive for epithelial membrane antigen (EMA), Ber-EP4, androgen receptor (AR), cytokeratin 7 (CK7), CAM 5.2, and BRST-1. The tumor is negative for carcinoembryonic antigen (CEA), S100 protein, or gross cystic disease fluid protein-15 (GCDFP). ^[36] According to one study, androgen receptor is more sensitive than EMA in poorly differentiated sebaceous carcinoma. ^[37] However, focal expression of androgen receptor was seen in 60% of basal cell carcinoma. Ocular sebaceous carcinomas express CK7, but basal and squamous cell carcinomas are negative for this marker. ^{[38, 39]}

If immunohistochemistry is necessary, a panel of stains may be helpful. One immunohistochemical review of a 3-antibody panel including EMA, BRST-1, and CAM 5.2 showed that positivity for all 3 antibodies suggests sebaceous carcinoma over both basal cell and squamous carcinomas. ^[40] Another immunohistochemical review demonstrated that a small panel of EMA and Ber-EP4 can differentiate sebaceous, basal, and squamous carcinomas. ^[41] An EMA-positive, Ber-EP4–positive immunophenotype supports sebaceous carcinoma; an EMA-positive, Ber-EP4–negative result supports squamous cell carcinoma; and an EMA-negative, Ber-EP4–positive result supports basal cell carcinoma. ^[41]

Ocular sebaceous gland carcinoma is an aggressive tumor, with a tendency for both local recurrence and distant metastasis. Approximately 10% of the tumors are multicentric, ^[42] and they often have direct extension or intraepithelial (pagetoid) spread to adjacent organs (lacrimal drainage system and nasopharynx). ^[31] There is local tumor recurrence in 40% of the affected patients, lymph node metastasis (preauricular and cervical nodes) in 25-33% of cases, and a 5-year tumor-related mortality rate of 22%. ^{[2, 15]}

Although extraocular sebaceous carcinoma was originally considered to be less aggressive, studies have found this tumor to have a similar occurrence of regional and visceral metastases as well as resultant mortality as ocular sebaceous carcinoma. ^{[15, 43, 44]}

Sebaceous gland carcinoma is an aggressive tumor, with a tendency for both local recurrence and distant metastasis. Complete excision remains the mainstay of treatment with radiation reserved as adjuvant therapy or for poor surgical candidates. Targeted therapies are evolving. ^{[45, 46, 47, 48]}

The following are the various clinicopathologic features predictive of poor prognosis ^[2] :

• Vascular, lymphatic, and orbital invasion

• Involvement of both upper and lower eyelids

• Poor differentiation

• Multicentric origin

• Duration of symptoms longer than 6 months

• Tumor diameter exceeding 10 mm

• A highly infiltrative pattern

• Pagetoid invasion of the overlying epithelia of the eyelids