Eyelid sebaceous carcinoma (SGC) is a highly malignant tumor arising from the sebaceous glands of the eyelid—the meibomian glands, Zeis glands, and glands of the caruncle. It is considered one of the most important malignant tumors of the eyelid. The distribution of origin is 92% from meibomian glands, 6% from Zeis glands, and 2% from the caruncle2). Since the upper eyelid has about 50 meibomian glands and the lower eyelid about 25, it commonly occurs in the upper eyelid. It mainly occurs after the age of 50, slightly more often in women, and metastasis or recurrence occurs in 10–20% of cases. It is a poor-prognosis disease that can sometimes be fatal.
The disease is positioned very differently in Western countries and East Asia. In Western countries, basal cell carcinoma accounts for 80–95% of all malignant eyelid tumors, while sebaceous carcinoma accounts for only 1–3% 1). In contrast, the proportion of sebaceous carcinoma is significantly higher in Asian populations.
| Region/Population | Proportion of sebaceous carcinoma |
|---|---|
| Western countries | 1–3% 1) |
| India (536 cases) | 53% 1) |
| China (1,086 cases) | 32% 1) |
| Japan (38 cases) | 29% 1) |
In Asians with malignant eyelid tumors, the probability that it is sebaceous carcinoma is 6.21 times higher (range 3.8–10.1) than in non-Asians 1). However, the incidence rate of sebaceous carcinoma itself is higher in Caucasians (2.03 per million) than in Asians/Pacific Islanders (1.07 per million). Because basal cell carcinoma is relatively less common in Asians, the proportion of sebaceous carcinoma among all malignant tumors appears higher.
The average age of onset is reported as 58 years in Indian populations and 57–72 years overall 1). In addition to the eyelid, 25% of cases may occur in the head and neck, other skin sites, or the genital region.
Muir–Torre syndrome is an autosomal dominant genetic disorder characterized by the combination of sebaceous tumors and internal malignancies (gastrointestinal, endometrial, and urological). It is caused by mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6). Sebaceous carcinoma occurs in 24% of patients with Muir–Torre syndrome. When diagnosing sebaceous carcinoma, it is advisable to also inquire about family history and gastrointestinal symptoms.
The possibility of Muir-Torre syndrome should be considered. Muir-Torre syndrome is a genetic disorder in which sebaceous tumors and internal malignancies such as colorectal cancer coexist. If loss of expression is observed on immunostaining for MLH1, MSH2, and MSH6, referral to a gastroenterologist or other specialist is recommended. When sebaceous carcinoma or sebaceous adenoma is found, family history and gastrointestinal symptoms should also be elicited.
Nodular type (56%)
Yellowish nodular mass: Characteristic yellow appearance due to lipids within tumor cells. Commonly occurs on the upper eyelid margin, with irregular surface and fragile tumor vessels.
Observation by eyelid eversion: It is important to evert the eyelid and also examine the conjunctival side.
Diffuse type (7%)
Intraepithelial infiltration without mass formation: A type that spreads thinly from the meibomian gland openings to the eyelid margin skin and palpebral conjunctiva. Diagnosis is most often delayed.
Eyelash loss (madarosis): One of the characteristic findings of the diffuse type. Always check as a sign of malignancy or severe inflammation.
The tumor occurs in the upper eyelid in 59% of cases, lower eyelid 29%, medial canthus 3%, and lateral canthus 2%1).
Importance of eyelash loss: When malignant tumors such as sebaceous carcinoma or severe inflammation are present at the eyelid margin, eyelashes fall out. If eyelash loss is observed, carefully examine the surrounding area for causative lesions, and consider biopsy or consultation with a tumor specialist for lesions suspicious for malignancy.
Pagetoid spread: A characteristic pattern in which tumor cells proliferate and spread in a sheet-like manner within the bulbar and palpebral conjunctival epithelium away from the main lesion. It presents with fireworks-like tumor vessels and tumor cell proliferation covering the entire palpebral conjunctiva, and may form skip lesions.
Great masquerader: Resembles chalazion, chronic blepharitis, basal cell carcinoma, squamous cell carcinoma, superior limbic keratoconjunctivitis, and ocular cicatricial pemphigoid. Nodular lesions are easily mistaken for chalazion, and after incision they repeatedly recur and enlarge. In some cases, the presence or absence of improvement with antibiotic eye ointment can help differentiate pagetoid spread from blepharitis.
Because it resembles multiple diseases such as chalazion, blepharitis, and basal cell carcinoma, making clinical diagnosis extremely difficult. Nodular lesions are easily mistaken for chalazion, and the diffuse type with pagetoid spread resembles blepharitis. For recurrent chalazion requiring repeated incisions, sebaceous carcinoma should always be considered, and curettage material must be sent for pathological examination.
In Asians with eyelid malignancy, the probability of sebaceous carcinoma is 6.21 times that of non-Asians 1). However, this is a relative proportion; the incidence rate (per population) of sebaceous carcinoma is higher in Caucasians (2.03 per million) than in Asians/Pacific Islanders (1.07 per million). Because basal cell carcinoma is less common in Asians, the proportion of sebaceous carcinoma appears relatively higher.
Having a high index of suspicion is most important. Actively suspect sebaceous carcinoma in the following cases:
Even if it appears to be a chalazion, always submit the curettage material for pathological examination. In some cases, response to antibiotic eye ointment can help differentiate pagetoid spread from blepharitis.
If sebaceous carcinoma is suspected, the following imaging tests are performed to evaluate metastasis and invasion.
Tumors are classified as T1 to T4 based on tumor size and eyelid/orbital invasion2).
| T Category | Definition |
|---|---|
| T1 | Greatest tumor diameter ≤10 mm |
| T2 | Greatest tumor diameter >10 to 20 mm |
| T3 | Greatest tumor diameter >20 mm |
| T4 | Invasion of orbit, paranasal sinuses, etc. |
In the 8th edition, compared to the 7th edition, the definition of T1 has been expanded (from ≤5 mm to ≤10 mm), and it has been shown that downstaging occurs 2).
Histologically, basophilic tumor cells proliferate in nests, with marked atypia and pleomorphism, and intracytoplasmic lipid droplets (appearing as clear vacuoles on H&E staining) are characteristic. In poorly differentiated tumors, lipid droplets may be inconspicuous, and a pathological diagnosis of squamous cell carcinoma may be made. If the tumor arises from within the tarsal plate, even a few intracytoplasmic lipid droplets should lead to a diagnosis of sebaceous carcinoma.
Current standard immunohistochemical markers are shown below.
| Marker | Characteristic |
|---|---|
| Adipophilin | Intracellular lipid droplet-associated protein. Highly sensitive for sebaceous differentiation and practical 3) |
| Androgen receptor | Generally positive in sebaceous carcinoma of the eyelid |
| Epithelial membrane antigen (EMA) | Positive |
Muir-Torre syndrome screening: Check for loss of expression of MLH1, MSH2, and MSH6 by immunohistochemistry.
Muir-Torre syndrome is suspected when sebaceous gland tumors (sebaceous carcinoma, sebaceous adenoma, etc.) are combined with internal malignancies (especially colorectal cancer). If loss of expression of MLH1, MSH2, or MSH6 is confirmed by immunostaining of pathological tissue specimens, referral to gastroenterology or gynecology for further examination is recommended. When sebaceous carcinoma is found, family history should also be taken, keeping in mind that it is an autosomal dominant genetic disease.
Surgical excision is the mainstay of treatment.
For localized eyelid cases, excise with a safety margin of 3 mm or more. Intraoperative margin assessment using frozen sections is desirable.
Reconstruction strategy based on tarsal defect size:
Mohs micrographic surgery or complete peripheral and deep margin assessment (CCPDMA) in Western countries is a method of excising while evaluating all margins, and is expected to reduce the positive margin rate.
If Pagetoid spread is confined to the epithelium, antitumor eye drops may preserve the eye. If the lesion invades beyond the basement membrane, eye drop treatment is ineffective.
Mitomycin C (MMC) eye drops:
5-Fluorouracil (5-FU) eye drops:
This is performed for cases with orbital invasion, large deeply infiltrating lesions, or extensive bulbar conjunctival involvement. The reported rates of exenteration by AJCC stage are T1 3%, T2 3%, T3 8%, and T4 63%2).
This is considered for periorbital tumors of stage T2c or higher.
Sebaceous carcinoma is radiosensitive and is used for cases where complete resection is difficult or as adjuvant therapy after surgery.
Resection with a safety margin of 3 mm or more is standard. Perform intraoperative margin assessment with frozen sections; if margins are positive, perform additional resection. If the tarsal defect is one-third or less, reconstruction with simple closure or local flap is possible; if larger, reconstruct the anterior and posterior lamellae separately. For T4 tumors or orbital invasion, orbital exenteration is considered.
Sebaceous carcinoma is a malignant tumor arising from the glandular epithelium of sebaceous glands. The distribution of primary sites is reported as 92% from Meibomian glands, 6% from Zeis glands, and 2% from the caruncle 2).
Histologically, sebaceous cells (lipid-rich cells with vacuolated cytoplasm) and undifferentiated basaloid cells are mixed, with differentiation ranging from well-differentiated to poorly differentiated. The lipid within tumor cells gives a yellowish macroscopic appearance. When poorly differentiated, histological differentiation from squamous cell carcinoma can be difficult, but if the tumor arises within the tarsus, even a few intracytoplasmic lipid droplets should lead to a diagnosis of sebaceous carcinoma.
Mechanism of pagetoid spread: Malignant cells individually migrate and proliferate in the epithelium—palpebral conjunctiva, bulbar conjunctiva, and skin—at sites distant from the main tumor. This forms skip lesions, and tumor cells may be present in areas that appear grossly normal. Therefore, understanding the extent of spread via conjunctival mapping biopsy is essential for treatment.
Molecular mechanism of Muir-Torre syndrome: An autosomal dominant genetic disorder caused by mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2). The mutations lead to loss of repair function for DNA replication errors, causing accumulation of mutations in tumor suppressor genes, resulting in sebaceous neoplasms.
Prognostic factors: Tumor size >15 mm increases the risk of regional lymph node metastasis. Cases with pagetoid spread or orbital invasion tend to have a poor prognosis, and metastasis-related death can occur.
Morawala (2023) evaluated the AJCC 8th edition T classification in 119 cases of sebaceous carcinoma and demonstrated its usefulness in predicting prognosis 2). The hazard ratios for T4 tumors were 2.38 for lymph node metastasis, 4.30 for distant metastasis, and 6.62 for metastasis-related death. Additionally, the 8th edition changed the definition of T1 from ≤5 mm in the 7th edition to ≤10 mm, resulting in downstaging.
Li & Finger (2021) treated T2bN0M0 orbital sebaceous carcinoma with resection, cryotherapy, and ultra-thick amniotic membrane transplantation followed by high-dose-rate brachytherapy (2,000 cGy/5 fractions) plus electron beam external beam radiotherapy (36 Gy/20 fractions), totaling 56 Gy 5). At 1 year, visual acuity was 20/20 with no radiation retinopathy or optic neuropathy. However, cervical lymph node metastasis occurred.
Adachi (2022) treated a 97-year-old patient with inoperable preauricular sebaceous carcinoma using 60 Gy/30 fractions of electron beam therapy plus hydrogen peroxide-impregnated gauze 4). At 8 months, macroscopic complete remission was achieved. The only adverse event was Grade 2 radiation dermatitis. A radiosensitizing effect of hydrogen peroxide is suggested, but this is a report of a small number of cases and further validation is needed.
Kaliki S, Bothra N, Bejjanki KM, et al. Malignant eyelid tumors in India: a study of 536 Asian Indian patients. Ocul Oncol Pathol. 2019;5(3):210-219.
Morawala A, Mohamed A, Krishnamurthy A, Jajapuram SD, Kaliki S. Sebaceous gland carcinoma: analysis based on the 8th edition of American Joint Committee on Cancer classification. Eye (Lond). 2023;37(4):714-719.
Ramachandran V, Tumyan G, Loya A, Treat K, Vrcek I. Sebaceous carcinoma masquerading as orbital cellulitis. Cureus. 2022;14(2):e22288.
Adachi A, Oike T, Tamura M, Ota N, Ohno T. Radiotherapy with hydrogen peroxide-soaked gauze for preauricular sebaceous carcinoma. Cureus. 2022;14(7):e27464.
Li F, Stewart RD, Finger PT. Interstitial brachytherapy for orbital sebaceous carcinoma. Ophthalmic Plast Reconstr Surg. 2021;37(6):e215-e217.
