A small interventional case series from Northwestern University's Feinberg School of Medicine suggests that compounded imiquimod 5% ointment may offer a potential therapeutic option for patients with diffuse conjunctival melanoma in situ (MIS) or ocular surface squamous neoplasia (OSSN) who are not ideal candidates for standard treatments.

Traditional management of ocular surface malignancies relies on wide-margin surgical excision and topical chemotherapies, such as 5-fluorouracil and mitomycin C, which are associated with ocular surface toxicity. Because interferon alfa-2b is no longer available, interest has grown in immunomodulatory treatments such as imiquimod, a Toll-like receptor 7/8 agonist that is approved for dermatologic indications.

“The package insert for imiquimod cream indicates that it is not for ophthalmic use, as it contains benzyl, cetyl, and stearyl alcohols,” wrote ophthalmologist R. Christopher Bowen, MD, MS, lead author of a JAMA Ophthalmology article about the case series. “Although the product has been used on the eye, in an effort to make imiquimod more tolerable, a 503A compounding pharmacy compounded imiquimod 5% in an ophthalmic petrolatum-based ointment to eliminate the irritants.”

This retrospective case series included 5 adults who were treated from June 2024 to March 2025 at a tertiary referral center. Each patient had a histologic diagnosis of conjunctival intraepithelial neoplasia, conjunctival squamous cell carcinoma, conjunctival MIS, or conjunctival melanoma with primary acquired melanosis (PAM). Patients applied the compounded imiquimod 5% ointment to the conjunctival surface 5 days per week for at least 12 weeks, along with topical antibiotics.

The mean patient age was 77.4 years, and 4 of the 5 patients were female. Three patients had OSSN, 1 had diffuse MIS, and 1 had PAM adjacent to excised conjunctival melanoma. Two patients also received cryotherapy and one patient received systemic cemiplimab alongside imiquimod. Across the group, 4 of 5 patients (80%) achieved complete histologic response during a mean treatment duration of 12.6 weeks, though one patient received 15 weeks of treatment. One patient demonstrated partial response. Mean follow-up occurred after 21 weeks, and visual acuity remained largely stable: the mean logMAR change was +0.04.

In the patient with diffuse MIS, persistent epithelial pigmentation was seen clinically, but biopsy showed complete histologic clearance within treated areas. A patient with squamous cell carcinoma and positive surgical margins experienced no recurrence after 12 weeks of therapy.

All 5 patients experienced ocular surface or eyelid adverse events, including conjunctival injection (100%), blepharitis (80%), poliosis (40%), transient lash loss (20%), and eyelid excoriation (20%). These events resolved within 1 to 14 days after a treatment break or at completion of therapy. No cases of keratitis, limbal stem cell deficiency, uveitis, infection, or posterior segment complications were observed.

Because of the small sample size and lack of controls, safety and efficacy cannot be determined by this case series alone, Dr. Bowen and colleagues noted, though they referenced the rule of 3 and suggested a true rate of serious adverse events would be no more than 60% with reasonable confidence. Still, they wrote, “[R]andomly assigned comparisons against 5FU and MCC are needed to better understand efficacy and safety.” Further limitations include selection bias, information bias, and bias from limited follow-up, as well as limited evaluation of uninvolved tissue and variable presentations of disease. However, the authors wrote, the study design can be influential in rare diseases or new treatments.

“Further studies with prospective follow-up, controls, and larger numbers are needed to assess longer-term risks and benefits of this therapy,” they concluded.