Clinical manifestations and differential diagnosis

Clinically, SC of the eyelid may manifest as a painless solitary nodule or diffuse pseudo inflammation. The more common painless solitary nodule presents as a firm subcutaneous lesion that arises in and is fixed to the tarsus, or it appears in the eyelid margin when it arises from the gland of Zeis. In such cases, SC may mimic chalazion. However, SC eventually causes loss of cilia, which can be differentiated from chalazion.5 Special care should be paid to elderly individuals. Their increased eyelid skin laxity may disguise an ocular SC mass as a chalazion, and this patient group is less likely to contact a doctor for apparently benign eyelid swelling.9 The second most common presentation of SC is diffuse thickening of the eyelid, which may involve the fornical and bulbar conjunctiva. In these cases, the patient may be misdiagnosed with persistent unilateral blepharitis or conjunctivitis at onset because of the pagetoid spread.5

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Pagetoid spread refers to intraepithelial (in situ) disease in the conjunctiva, even to the cornea26 in a noncontiguous fashion. The rates of pagetoid spread have been reported as 26%–51%.9,12,27 The most common symptom and sign of SC with pagetoid invasion is ocular irritation and diffuse eyelid thickening. Pagetoid invasion generally carries a higher risk of orbital exenteration, recurrence, or tumor-related metastases,4,28 but contradictory opinions also exist.16,29,30

Furthermore, ocular SC may be clinically indistinguishable from SCC, BCC, intratarsal keratinous cyst, or other rare eyelid lesions.10,12,31 In conclusion, clinicians must consider the diagnosis of SC when a patient has a recurrent, atypical, and/or treatment-resistant lesion that is originally presumed to be benign.9,17

Histology and pathology

The diagnosis of SC largely relies on primary excisional biopsy during the management.

When the lesion is small and circumscribed, complete excision is strongly suggested before histopathologic verification, whereas relatively more extensive lesions require incisional biopsy.5 It has been reported that the majority of UK centers perform full-thickness eyelid biopsy.9 If diffuse involvement of palpebral and bulbar conjunctiva is suspected, multiple conjunctival map biopsies are recommended.5 Map biopsies scheduled at the time of wide excision with permanent section control rather than frozen sections may improve the reliability of complete excisions.16 Some have advocated that conjunctival map biopsy should be the primary procedure in all suspected cases.9 Unfortunately, SC is often misdiagnosed on initial biopsy and may require multiple biopsies or special stains before a definitive diagnosis can be made.10,17

Histopathologically, SC can be recognized by the following 4 patterns: lobular, comedocarcinoma, papillary, and mixed.5 An extended evaluation of hematoxylin and eosin stains remains essential, but immunohistochemistry has shown an unequivocal profile in ocular SC. Immunostaining has largely replaced lipid and fat staining on fresh frozen sections and is widely applied to differentiate SC from other malignant neoplasms.16 Tumor cells stain with epithelial membrane antigen, cytokeratin, Ber-EP4, cyclooxygenase 2, peroxisome proliferator-activated receptor γ and androgen receptor. And SCs are negative for carcinoembryonic antigen, S100 protein, or gross cystic disease fluid protein.32,33Compared to benign sebaceous proliferations, SC expresses increased p53 and Ki-67 levels (proliferation markers) and decreased bcl-2 and p21 levels (antiapoptotic markers).34 Adipophilin shows an annular staining of lipid granules in immature sebaceous cells in contrast to a more granular staining pattern in BCC and SCC.33 In addition, a provisional classification of SC based on hormone receptor expression and HER2 status has been recently proposed. Expression of HER2 protein was found in 33.8% of cases and was associated with better outcomes with borderline significance (P=0.060).35

However, the high rate of interobserver variability cannot be neglected. Incorrect histopathological interpretations have been reported in 23%–77% of cases, and these misinterpretations may be due to tumor rarity, low clinical suspicion, and pathologists’ lack of familiarity with the histological features of SC.9,36


The management of SC is largely dependent on its histopathologic type and disease stage according to the American Joint Committee on Cancer seventh edition TNM guidelines for eyelid carcinomas after complete clinical evaluation. A brief summary of major treatment options is provided (Table 1).

Therefore, treatment needs to be tailored in each case based on the extent of the tumor and the specific demands of the patient. Moreover, combination therapy is currently being promoted, especially in advanced cases. Radiotherapy, cryotherapy, topical chemotherapy, amniotic membrane grafting, flap reconstruction, and other techniques are followed by surgical excision to achieve the best treatment effect.5,13,16,37,38

Patient evaluation

Patients with suspected eyelid malignancies should undergo a thorough medical history inquiry with special care about a history of prior skin cancer, sun exposure, radiation exposure, and immune status. Meanwhile, a complete ocular adnexal examination is indispensable. Baseline external photographs or slit-lamp photographs are useful for documentation and future comparison.30

Considering that no standardized imaging or staging guidelines currently exist, imaging studies and additional work up for regional or distant disease should be symptom driven. Based on the suspicion of orbital invasion or a risk of lymph node metastasis, examinations, including orbital computed tomography or MRI, ultrasonography of the parotid, submandibular, and cervical nodes, and fine-needle aspiration biopsy of suspicious lymph nodes, should be considered. For cases associated with a risk of distant metastasis, baseline chest radiography or computed tomography should be performed.30

The identification of high- and low-risk features in ocular SC based on clinical evaluations enables a stratified approach to treatment.