The occurrence of this tumor varies significantly among different ethnic groups. Among populations from China, Japan, Hong Kong, and Singapore, SbC represents as much as 30% to 40% of all periocular malignancies.¹⁰,¹¹,¹²,¹³,¹⁴ Among Caucasians, SbC accounts for less than 5% of eyelid malignancies.⁷,¹⁵ No specific causes for these ethnic differences have yet been determined.

While the pathogenesis is unclear, cases of SbC have been associated with the Muir-Torre syndrome (MTS),¹⁶,¹⁷ previous radiation in the area of the tumor,¹⁸ or diuretic use.¹⁹ MTS is an autosomal dominant disorder associated with multiple internal malignancies including head and neck, small bowel, and hematologic cancers. As many as 25% to 30% of MTS patients may develop sebaceous tumors, mostly in the periorbital region.²⁰,²¹,²²,²³,²⁴

Radiation-associated periocular SbC has been described following radiation treatment for retinoblastoma and cavernous hemangioma.²⁵,²⁶,²⁷ This can be very long term following radiotherapy and in one case was reported 17 years after treatment for retinoblastoma²⁸ and after more than 40 years affecting all four eyelids following radiotherapy for juvenile facial eczema.²⁹

Sung et al³⁰ described a case of early-onset SbC in a 32-year-old patient who used a UV tanning bed for 9 years, suggesting that UV exposure could be an additional risk factor, but there is little published evidence to support this conclusion. Several recent studies have identified mutations in tumor suppressor genes, including TP53, RB1, and the p16 gene in SbC patients.³¹ The p53 gene has been well studied in several malignancies. This gene promotes either cell cycle arrest, therefore allowing time for DNA repair, or apoptosis.³¹ Harris et al³² found that 67% of SbCs of the eyelid from Asian patients had p53 mutations. These were point mutations, rather than tandem mutations, suggesting that they may not be related to UV exposure. The p53 mutations in eyelid SbC may be caused by UV-independent processes, in contrast to other skin cancers that are associated with UV exposure.³³

SbC is well known in the literature as a “great masquerader,” clinically mimicking other benign and malignant eyelid lesions, such as chalazion and blepharitis, which are frequently the initial misdiagnoses. This raises an interesting question as to the relationship between these lesions and the development of SbC. The relationship between cancer and inflammation has been recognized since the 17th century.³⁴ There is a small but intriguing literature regarding the relationship between chronic inflammation and the subsequent development of cutaneous malignancies.³⁵,³⁶,³⁷ There is much evidence that the inflammatory microenvironment can contribute to the development and progression of epithelial skin cancers by contributing to the physical processes of wound
healing and infection,³⁵ and it has been estimated that as many as 20% of cancers may be initiated by chronic inflammation or persistent infection.³⁸ Inflammatory-mediated release of various growth factors as well as cytokines and chemokines help to orchestrate tissue repair, but may also serve as promotors of oncogenesis acting on initiators such as accumulated somatic mutations.³⁶,³⁷,³⁹ Many of the so-called masqueraders of SbC, such as chalazion and blepharitis, are chronic inflammatory lesions. Although there are no reports documenting the evolution of a chalazion or blepharitis to SbC or other malignancies, the relationship between inflammation and cutaneous tumors should be kept in mind.

Eyelid and periocular SbC typically presents in the sixth to eight decades of life, with a mean age of about 65 to 70 years³,⁴⁰; however, studies from Asia have repeatedly shown that SbC occurs a decade earlier in Asians than in Caucasian populations.¹⁰ A recent study has shown that the median age at diagnosis in Asian Indians was 57 years.¹⁰ Rarely, cases in younger age groups have also been described in Caucasians.³⁰,⁴¹ The tumor involves extraocular sites in about 25% of cases, predominantly on the head, trunk, and genitalia. Ocular SbC arises from the meibomian glands of the upper eyelid in 40% to 60% of cases. It can also arise from accessory glands of Zeis along the eyelid margin, in the caruncle, or on the eyebrow. In a series of 60 cases of eyelid SbC, females were involved in 73%, and Caucasians in 95%.³ In another large series of 1333 cases, Desiato et al reported a female predominance of 60%, with 62% involving the upper eyelid, 32% the lower eyelid, and 5% both.⁴²

The clinical appearance is very diverse, mimicking a variety of benign eyelid inflammations and lesions such as chalazion, blepharitis, sarcoidosis, and ocular pemphigoid (Figures 144.1 and 144.2).⁴³,⁴⁴ Two-thirds of cases are initially misdiagnosed as benign lesions.³ In cases of unilateral blepharitis or conjunctivitis unresponsive to appropriate treatment, it is essential to rule out SbC. This tumor can also be confused with other malignancies including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), lymphoma, or Merkel cell carcinoma (Figure 144.3). When SbC arises in the glands of Zeis, it can present as an ulcerated nodule or even a cutaneous horn.⁴⁵

Clinically, SbC appears as a unilateral, firm, indurated, yellow, flesh-colored, or pink mass on the tarsal conjunctiva, caruncle, or eyelid margin, often associated with madarosis and ulceration. The upper eyelid is involved in 75% of eyelid cases. Pagetoid spread is seen in 30% to 80% of cases resulting in diffuse eyelid thickening that can mimic blepharoconjunctivitis.⁴⁶ When the conjunctiva is involved, forniceal contraction is often seen, along with invasion of the cornea. SbC can spread to the lacrimal drainage system, and rare orbital invasion has been reported in more advanced cases.⁴⁷

As with other eyelid malignancies, tumor staging is assessed using the TNM definitions in the 8th edition of the American Joint Committee on Cancer (AJCC) recommendations where T1 = ≤10 mm, T2 = >10 mm, T3 = >20 mm but not greater than 30 mm, and T4 is any stage with invasion of adjacent ocular, orbital, or facial structures.⁴⁸ Metastasis to regional lymph nodes is common and seen in 10% to 30% of cases.³,⁴⁹

The differential diagnosis is extensive and includes other malignant tumors such as BCC, SCC, and a variety of benign lesions and inflammations including papilloma, chalazion, blepharitis, ocular cicatricial pemphigoid, cutaneous horns, discoid lupus, and pyogenic granuloma.

A definitive diagnosis requires a high level of suspicion and is best made with a full-thickness eyelid biopsy. Because of the common occurrence of skip lesions and the multicentric nature of this tumor, an adequate wide biopsy is necessary.³ Pagetoid spread has been reported in 8% to 51% of cases,⁵⁰,⁵¹ but may not be apparent clinically. Shields et al reported an accurate clinical judgment of conjunctival involvement in only 57.5% of nodular tumor cases.³ Map biopsies have been advocated to evaluate the conjunctiva for suspected cases of pagetoid spread.⁵² However, the accuracy of routine map biopsies has been questioned, and Koreen et al found that 15% of specimens from 144 conjunctival map
biopsies were nondiagnostic due to artifactual epithelial loss, and nondiagnostic specimens were more frequent in patients with extensive pagetoid spread.⁵³ Immunohistochemical evaluation is important in distinguishing sebaceous carcinoma from other neoplasms.

Periocular Sbcs are generally more aggressive than Sbcs in extraocular sites, and this is generally attributed to pagetoid spread.³¹ Local recurrence rates of 0% to 43% have been reported,⁵¹ often seen within 5 years. The most common risk factors for local recurrence are higher AJCC T stage category, tumor size, tumor location, pagetoid spread, diffuse growth pattern, multicentric origin, and delayed diagnosis. Recently, it has been demonstrated in Asian Indians that age may play a key prognostic factor in SbC.¹⁰ In the older age group, the incidence of tumor recurrence is higher possibly due to immune senescence, while death due to disease, locoregional metastasis, and systemic metastasis is more common in the younger age group, possibly because younger patients have a longer number of years to live which hypothetically causes some micrometastasis to become apparent over the years.¹⁰

Based on the AJCC 8th Edition classification,⁴⁸ nodal metastases are significantly more frequent with advanced T3/T4 stages and associated more with poor tumor differentiation.⁶³,⁶⁴ The most common sites for systemic metastases include the lungs, regional lymph nodes, liver, brain, and bone. Important risk factors for recurrence and metastasis include medial canthal involvement, occurrence on both upper and lower eyelids, orbital invasion, longer duration of symptoms >6 months, and tumor size >10 mm.⁶³ Pagetoid spread, lymphatic invasion, and poor histologic differentiation are also associated with a worse prognosis.³,⁶¹ Tumors originating from the glands of Zeis and those associated with MTS are reported to have a better prognosis.⁶⁵,⁶⁶