Conjunctival epithelial tumors are a general term for tumors arising from the conjunctival epithelium. They are broadly classified into benign tumors (papilloma, epithelial cyst, etc.), precancerous lesions (conjunctival intraepithelial neoplasia, CIN), and malignant tumors (invasive squamous cell carcinoma, SCC).
The concept of ocular surface squamous neoplasia is also widely used. It is a general term for the spectrum of epithelial tumors ranging from epithelial dysplasia to conjunctival intraepithelial neoplasia and invasive squamous cell carcinoma.
Conjunctival intraepithelial neoplasia is further classified by severity.
The incidence of conjunctival squamous cell carcinoma varies greatly by geographic region. It is reported to range from 0.02 to 3.5 per 100,000 people (depending on latitude and UV exposure)1). 75% of patients are male, 75% are aged 60 years or older, and 75% arise from the corneal limbus1).
In a study of 771 non-melanocytic conjunctival tumors by Shields et al., ocular surface squamous neoplasia accounted for 23% (179 cases), making it the most common non-pigmented tumor1). The worldwide age-standardized incidence rate of ocular surface squamous neoplasia is 0.26 per 100,000 per year, with the highest rate in Africa (3.4 per 100,000 per year)1).
The classification of conjunctival epithelial tumors is shown below.
| Classification | Children | Adults |
|---|---|---|
| Benign | Papilloma (HPV types 6/11), epithelial cyst | Papilloma (HPV-related), hereditary benign intraepithelial dyskeratosis, epithelial cyst |
| Premalignant lesions | Conjunctival intraepithelial neoplasia (rare) | Conjunctival intraepithelial neoplasia (mild to severe) |
| Malignant | Squamous cell carcinoma (rare) | Invasive squamous cell carcinoma, mucoepidermoid carcinoma |
The incidence of squamous cell carcinoma varies greatly by region, ranging from 0.02 to 3.5 per 100,000 people1). The age-standardized rate of ocular surface squamous neoplasia worldwide is 0.26 per 100,000 per year, but in Africa it is as high as 3.4 per 100,000 per year1).
Conjunctival intraepithelial neoplasia is observed as a sessile, slightly opaque, flat elevated lesion. It appears white to pale red, with characteristic abnormal vascular patterns described as “firework-like”.
Invasive squamous cell carcinoma takes various forms.
The morphological variations of the lesion and their clinical significance are shown below.
Elevated lesions tend to have higher malignancy than flat lesions1). Common sites are the interpalpebral fissure and limbus, while the palpebral conjunctiva is less frequently involved1).
Clinical features of benign tumors are as follows:
HPV types 16/18, immunodeficiency (HIV/AIDS), xeroderma pigmentosum, smoking, chemical exposure (petroleum products, beryllium, arsenic, etc.), and vitamin A deficiency are listed 1). HIV infection and positive surgical margins are strongly associated with tumor recurrence 1).
Clinical differentiation between conjunctival intraepithelial neoplasia and invasive squamous cell carcinoma is difficult, and histopathological examination is always required for definitive diagnosis1).
Histopathological diagnosis is based on 10–20% formalin fixation, paraffin embedding, and HE staining.
The stages according to the TNM classification are shown below1).
| Stage | Definition |
|---|---|
| Stage 0 | Tis, N0, M0 (carcinoma in situ) |
| Stage I | T1, N0, M0 (no invasion into adjacent structures) |
| Stage II | T2, N0, M0 (invasion into cornea, fornix, caruncle, sclera, or globe) |
| Stage III | T3, N0, M0 or any T, N1, M0 (invasion into orbit, paranasal sinuses, or eyelid; or regional lymph node metastasis) |
| Stage IV | any T, any N, M1 (distant metastasis) |
Pterygium, pinguecula, Salzmann nodular degeneration, pyogenic granuloma, papilloma, nevus, sebaceous gland carcinoma, amelanotic melanoma, conjunctival lymphoma, keratoacanthoma1).
Clinical differentiation between conjunctival intraepithelial neoplasia and squamous cell carcinoma is difficult, and histopathological examination is essential for definitive diagnosis. High-resolution optical coherence tomography is useful for distinguishing invasive from non-invasive types1), but the final diagnosis is based on histological examination.
Complete tumor resection is the first choice.
Reconstruction options include primary conjunctival closure, amniotic membrane transplantation, or autologous conjunctival transplantation.
Surgical Treatment
First choice: Complete excision using the no-touch technique. Margin of at least 4 mm.
Cryotherapy: Apply double freeze-slow thaw technique to the excision margin.
Reconstruction: Choose from primary conjunctival closure, amniotic membrane transplantation, or autologous conjunctival transplantation.
Extended surgery: Enucleation for intraocular invasion, orbital exenteration for orbital invasion.
Medical Therapy (Topical Chemotherapy)
Interferon alfa-2b: Eye drops or subconjunctival injection. Low toxicity and good tolerability.
Mitomycin C: 0.04% eye drops. Used as preoperative or postoperative adjuvant therapy.
5-Fluorouracil: Topical chemotherapy. Used as primary or adjuvant therapy.
Cidofovir: One of the options for topical chemotherapy.
Topical chemotherapy is used as primary or adjuvant therapy. A cycle of “1 week on, 1 week off” is typical.
In Japan, there are reports of tumor cure with low-dose mitomycin C or 5-fluorouracil eye drops. However, some reports indicate that it is only effective for intraepithelial lesions, and long-term recurrence rates and complications have not been fully elucidated.
Interferon alpha-2b is used as eye drops or subconjunctival injection. It has lower toxicity and better tolerability compared to mitomycin C and 5-fluorouracil, but is more costly.
Metastasis is rare and the prognosis for life is good. The local recurrence rate of invasive squamous cell carcinoma is reported as 5%, and the regional lymph node metastasis rate as 2% 1). On the other hand, the mortality rate of untreated squamous cell carcinoma is 8–24%, and orbital invasion occurs in about 10% of cases 1).
Topical chemotherapy such as mitomycin C, 5-fluorouracil, and interferon alpha-2b is used as primary or adjuvant therapy. However, there are reports of efficacy only for intraepithelial lesions 1), and long-term outcomes and complications are not well established. Radiation therapy is used adjuvantly for unresectable cases or those with eyelid invasion.
The conjunctiva consists of three parts: bulbar conjunctiva, fornix, and palpebral conjunctiva. Special areas include the plica semilunaris (remnant of the nictitating membrane) and the caruncle (conjunctival and skin structures).
The main mechanism is UV exposure → p53 gene mutation → mutation of regulatory protein complex → carcinogenesis 1).
The molecular abnormalities involved are as follows 1):
Squamous cell carcinoma is thought to originate from limbal stem cells1).
Conjunctival Intraepithelial Neoplasia (Precancerous Lesion)
Mild conjunctival intraepithelial neoplasia: Part of the surface epithelium is replaced by abnormal cells lacking normal maturation.
Severe conjunctival intraepithelial neoplasia: The full thickness of the epithelium is replaced by abnormal cells lacking maturation. Epithelial cells show loss of polarity and atypia throughout the full thickness.
The basement membrane remains intact: This is a key difference from invasive squamous cell carcinoma.
Invasive Squamous Cell Carcinoma
Basement membrane breach: Malignant squamous epithelial cells proliferate beyond the basement membrane into the stroma1).
Histological features: Thickened cells with atypia and mitotic figures infiltrate the lamina propria.
Mucoepidermoid carcinoma: An aggressive subtype of squamous cell carcinoma. It occurs more often in older individuals and contains yellow cystic components from mucus-secreting cells1).
Histopathology of benign tumors is as follows:
The application of bevacizumab and ranibizumab to conjunctival lesions has been reported1).
According to a review by Tsatros et al., studies using ranibizumab (1.25–2.5 mg, subconjunctival injection 1–2 times per month) showed complete regression in 34% and partial regression in 66%, with no recurrence during 6 months of follow-up1). Bevacizumab is promising for conjunctival lesions, but its efficacy for corneal lesions is unclear, and a risk of delayed corneal epithelial healing has been noted. Large-scale studies are needed for both.
According to a review by Tsatros et al., a pilot study combining verteporfin and laser reported 100% tumor regression and no recurrence in conjunctival squamous cell carcinoma1). High cost, need for specialized training, and limited availability are challenges for widespread use.
A case report has shown a remarkable effect of the HPV vaccine on HPV type 16-positive conjunctival intraepithelial neoplasia. Large-scale studies are needed for validation.
