Eyelid papilloma is a benign epithelial tumor in which tumor cells proliferate like leaves on a branch of tumor blood vessels. It is also called squamous cell papilloma or simple papilloma. Human papillomavirus (HPV) is involved in its development, and it can occur in multiple lesions.
Lesions on the eyelid skin are non-ulcerated and may be pedunculated. They grow in a leafy pattern, with a keratinized surface and vascular fibrous tissue. Those near the eyelid margin have less keratinization and appear reddish.
Among benign eyelid tumors by pathological diagnosis, papilloma accounts for 6 out of 64 eyes (9%), making it the fourth most common tumor. HPV may be involved in its development, and some cases show a tendency for multiple lesions. It occurs in both children and adults, and immunocompromised patients have a higher risk of multiple lesions and recurrence 1).
Regarding HPV involvement, studies of conjunctival papilloma have shown that HPV types 6 and 11 are mainly involved as low-risk types 1). HPV types 16 and 18 are high-risk types and have been associated with malignant transformation 2).
Eyelid papillomas are classified into the following two types based on growth pattern.
HPV may be involved in the development, and theoretically, contact transmission is possible. However, the risk of transmission between eyelids through normal daily contact is low. In immunocompromised states (e.g., after organ transplantation, HIV infection), the risk of multiple occurrences and recurrence is reported to be higher. It is recommended to see an ophthalmologist for multiple or rapidly growing lesions on the eyelid.
The clinical findings of eyelid papilloma differ depending on whether it is pedunculated or sessile.
Pedunculated papilloma
Pink cauliflower-like mass: Forms a pink, finely lobulated cauliflower-like mass.
Attachment by a thin vascular stalk: Because it is pedunculated, the area of attachment to the palpebral conjunctival surface is smaller than it appears. It grows in a frond-like pattern, and the surface is composed of keratinized, vascular-rich fibrous tissue. Lesions near the eyelid margin are less keratinized and appear reddish.
Sessile papilloma
Broad-based growth: The base of the tumor is wide and attaches to the palpebral conjunctival surface. Clinically, it may be difficult to distinguish from squamous cell carcinoma.
Sessile lesions: Sessile papillomas can resemble giant papillary conjunctivitis, making diagnosis challenging3).
Rarely, malignant transformation can occur; rapid enlargement, bleeding, or ulceration of the lesion warrants further investigation.
Rarely, malignant transformation (squamous cell carcinoma) is known to occur. Broad-based growth pattern, rapid enlargement, surface bleeding or ulceration, and the appearance of corkscrew tumor vessels are findings suspicious for malignancy. Pathological examination after excision is essential for definitive diagnosis, and regular follow-up is also important.
The main cause of eyelid papilloma is HPV infection.
The most important aspect in diagnosing eyelid papilloma is evaluating whether it is pedunculated or sessile.
Sessile papilloma may resemble giant papillary conjunctivitis in appearance, making accurate clinical diagnosis difficult in some cases 3). A combination of detailed slit-lamp microscopy and histopathological examination is key to diagnosis.
| Differential Disease | Key Differentiating Features |
|---|---|
| Verruca vulgaris | Tendency for multiple lesions, small nodules on the eyelid margin |
| Seborrheic keratosis | Brown to black, keratotic surface tumor |
| Squamous cell carcinoma | Sessile growth, firework-like tumor vessels, ulceration |
| Giant papillary conjunctivitis | Similar to sessile papilloma; history of allergies or contact lens use |
After excision, the specimen must always be submitted for histopathological examination. Particularly for broad-based, rapidly growing lesions, malignancy should be considered.
As a rule, excised specimens must always be submitted for histopathological examination. Excisional biopsy provides a definitive diagnosis and helps avoid missing rare malignant components (malignant transformation to squamous cell carcinoma). Especially for lesions with broad-based growth, rapid enlargement, bleeding, or ulceration, malignancy should be strongly suspected, and early excisional biopsy is recommended.
Surgical excision is the first-line treatment for eyelid papilloma. Since simple excision alone tends to result in recurrence, the following steps are standard.
Simple excision alone tends to result in recurrence. Adding cryotherapy can reduce the recurrence rate.
| Treatment | Indications | Remarks |
|---|---|---|
| Resection + hemostasis by cautery + cryocoagulation | All cases (standard) | 2 sets of freeze and thaw after tumor base resection |
| CO2 laser vaporization | Multiple or recurrent cases | Preservation of surrounding normal tissue possible2) |
| Oral cimetidine | Adjuvant therapy | Utilizes immunomodulatory effects of H2 receptor antagonists3) |
| Interferon alpha-2b | Recurrent papilloma | Subconjunctival injection reported effective4) |
Subconjunctival interferon alpha-2b injection has been reported effective for recurrent and refractory conjunctival papilloma4). It is thought to reduce HPV-related lesions through local antiviral and immunostimulatory effects.
Oral cimetidine (H2 receptor antagonist) has been reported to have therapeutic effects on HPV-related skin lesions via immunomodulatory mechanisms and is sometimes used as an adjuvant therapy3).
The preventive effect of HPV vaccine (quadrivalent vaccine, Gardasil, etc.) against HPV types 6, 11, 16, and 18 is being investigated for the prevention of ocular surface papilloma 5).
Simple excision alone is known to have a high recurrence rate. To prevent recurrence, it is standard to add two sets of cryotherapy (freeze and thaw) to the excision margins. Patients who are immunocompromised have a particularly high risk of recurrence. For recurrent cases, additional treatments such as subconjunctival interferon alpha-2b injection may be considered.
Eyelid papilloma has a structural characteristic where tumor cells proliferate in a leaf-like pattern, branching from tumor blood vessels. The frond-like growth pattern results from cell proliferation around blood vessels. Histological features include surface keratinization and vascular-rich fibrous tissue.
Pedunculated papilloma results from exophytic growth of conjunctival epithelium, whereas sessile papilloma tends to show endophytic growth. This difference in growth pattern correlates with clinical prognosis (benign vs. malignant potential).
HPV types 6 and 11 are low-risk types involved in the majority of eyelid and conjunctival papillomas 1). The E6 and E7 proteins expressed by these viruses are involved in host cell growth regulation and promote neoplastic proliferation through persistent infection 2).
On the other hand, HPV types 16 and 18 are high-risk types that promote malignant transformation of cells through degradation of p53 by E6 protein and inactivation of Rb protein by E7 protein 2). The involvement of these high-risk HPV types is suspected in the rare malignant transformation of eyelid papilloma to squamous cell carcinoma.
Host cell-mediated immunity plays an important role in controlling HPV infection. In immunocompromised states such as after organ transplantation, HIV infection, or hematologic malignancies, the immune response to HPV is reduced, leading to increased occurrence, recurrence, and enlargement of papillomas 2). Management of eyelid papilloma in immunocompromised patients requires regular ophthalmologic evaluation alongside treatment of the underlying disease.
The possibility of applying HPV vaccines (especially the quadrivalent and 9-valent vaccines) to prevent eyelid and conjunctival papillomas caused by HPV types 6 and 11 is being investigated 5). Vaccines developed for cervical cancer prevention may also be effective in preventing papilloma development in the ophthalmic field, but large-scale clinical trials in ophthalmology have not yet been established.
Cidofovir is an antiviral drug being considered for application to HPV-related lesions. It is not a standard treatment for ocular surface papilloma and remains an investigational option for cases that are difficult to control with existing treatments 6).
Photodynamic therapy has been reported in a small number of cases for refractory papilloma 6). Research on the efficacy of PDT for HPV-related epithelial tumors is still ongoing.
