Sebaceous Carcinoma

Sebaceous carcinoma is a rare, aggressive malignant tumor of the sebaceous glands. Ocular sebaceous carcinoma (about 75% of cases) arises in the meibomian glands, the glands of Zeis or the caruncle, mainly in the upper eyelid, and extraocular tumors occur on the head and neck, trunk and genitals. Mean age is 60 to 70 years, with higher incidence in women for periocular disease and in Asian populations.

Risk factors: age, radiotherapy, immunosuppression and Muir-Torre syndrome (a variant of Lynch syndrome with sebaceous neoplasms and visceral cancers, caused by germline mismatch repair gene mutations, most often MSH2 and MLH1). Sebaceous carcinoma may be the first manifestation of the syndrome, so every patient needs mismatch repair testing.

Pathology: lobules of atypical sebocytes with foamy, vacuolated cytoplasm, and pagetoid spread through the conjunctival and eyelid epithelium in about 25 to 40% of ocular tumors. Immunohistochemistry: epithelial membrane antigen, androgen receptor and adipophilin positive. It is notorious for misdiagnosis as chalazion or chronic blepharoconjunctivitis, with delay of 1 to 3 years in many patients.

Nodal metastasis (preauricular, submandibular and cervical) occurs in about 20 to 25%, distant metastasis in 5 to 15%, and mortality is about 5 to 10%. Complications: orbital extension, local recurrence (up to 30%), and visual loss.

• A firm, painless eyelid nodule that mimics a chalazion and recurs after incision and curettage
• Diffuse eyelid thickening, lash loss (madarosis), loss of lid margin architecture, and unilateral chronic blepharoconjunctivitis that does not respond to treatment
• A yellowish nodule with a telangiectatic surface
• Extraocular: a firm pink or yellow nodule or ulcer on the scalp, face or trunk
• Features of Muir-Torre syndrome: multiple sebaceous adenomas, keratoacanthomas, and a history of colorectal, endometrial, urinary tract or other Lynch-spectrum cancers
• Red flags: a recurrent chalazion in an older patient, unilateral blepharitis, lash loss, nodal enlargement and proptosis

1. Full-thickness eyelid biopsy of any recurrent or atypical chalazion, sent for histology (fresh tissue allows oil red O staining for lipids).
2. Map biopsies of the conjunctiva (4 quadrants and the lid margin) to detect pagetoid spread.
3. Immunohistochemistry: epithelial membrane antigen, androgen receptor, adipophilin (positive), and BerEP4 (negative or weak), to distinguish from basal and squamous cell carcinoma.
4. Mismatch repair protein immunostaining (MLH1, MSH2, MSH6, PMS2) with genetic counseling, and germline testing when abnormal.
5. Staging imaging: MRI of the orbit, ultrasound of preauricular and cervical nodes, and CT of the chest, abdomen and pelvis for advanced tumors.

Differentials: chalazion, blepharitis, basal cell carcinoma, squamous cell carcinoma, ocular surface squamous neoplasia, cicatricial pemphigoid, conjunctival melanoma.

1. Surgery: wide local excision with 5 to 6 mm margins, controlled by frozen section or Mohs micrographic surgery, followed by eyelid reconstruction (direct closure, tarsoconjunctival flap or graft). Anesthesia with lidocaine 1% with adrenaline 1:100,000. Cefazolin 2 g IV before incision for large reconstructions.
2. Conjunctival pagetoid spread: topical mitomycin C 0.04% four times daily for 1 week followed by 1 week off, for 2 to 3 cycles, together with cryotherapy, or excision of the conjunctiva. Protect the cornea and punctum, and monitor for punctal stenosis and limbal stem cell injury.
3. Orbital invasion: orbital exenteration with eyelid-sparing technique when possible.
4. Sentinel lymph node biopsy for tumors over 10 mm (T2b and higher) or with high-risk features, and therapeutic neck and parotid dissection for positive nodes.
5. Radiotherapy 50 to 66 Gy in 25 to 33 fractions as an adjunct for positive margins, perineural invasion, nodal disease or in patients who cannot have surgery. Complications: dry eye, cataract and radiation keratopathy.
6. Metastatic disease: cisplatin 75 mg/m2 IV with 5-fluorouracil or doxorubicin-based regimens, and pembrolizumab 200 mg IV every 3 weeks for mismatch repair deficient tumors. Monitor thyroid function and liver tests.
7. Muir-Torre syndrome surveillance: colonoscopy every 1 to 2 years from age 20 to 25, annual skin examination, endometrial sampling in women from age 30 to 35, and urinary tract surveillance, with counseling for relatives and testing at risk.

Follow-up: every 3 months for the first year, every 6 months for 3 years, then yearly, with palpation of the nodes and conjunctival examination. Counsel on recurrence and on vigilance for new lesions.