Kim and Abramson PAM with atypia may progress to malignant melanoma in up to 46% of cases (Folberg et al 1984). Cases of PAM with atypia demonstrating certain histopathologic features, such as epithelioid cells or pagetoid extension, carry a 75%–90% chance of transforming into invasive melanoma (Jakobiec et al 1989). The median time for PAM with atypia to progress to melanoma is approximately 2.5 years, but it may take as long as 10 years (Folberg et al 1985b). Malignant melanoma of the conjunctiva is commonly associated with PAM with atypia, although it can also arise de novo or from conjunctival nevi (Folberg et al 1985a). The incidence of conjunctival melanoma is only 0.2–0.8 per million in Caucasian popula- tions (Seregard and Kock 1992; Seregard 1998), but it is a potentially lethal ocular malignancy with an overall 10 year mortality as high as 26%–30% (De Potter et al 1993; Seregard 1998). Currently, surgical resection with cryotherapy applied to the conjunctival margins is the most commonly employed method for treating PAM with atypia. However, using the pigmented margins to deﬁne the extent of resection is often problematic due to the diffuse or amelanotic features of these tumors. Local recurrence rates for PAM with atypia after local excision and cryotherapy range between 24%–79% with long-term follow-up (Paridaens et al 1994; Shields et al 2001). Recurrences are typically associated with incomplete excision, corneal involvement, and/or multifocal disease. The established management approach for invasive conjunctival melanoma is wide surgical excision, although with long-term follow-up nearly 50%–60% of patients manifest local recur- rence (Liesegang and Campbell 1980; Paridaens et al 1994; Demirci et al 2000). Despite orbital exenteration, 33%–50% of patients with conjunctival melanomas develop metastatic disease when the thickness of the primary tumor exceeds 1.0 mm (Paridaens et al 1994). Melanocytic lesions and MMC Over the past decade, there have been numerous papers describing the use of topical MMC for both PAM with atypia and conjunctival melanoma (Finger et al 1993; Frucht-Pery and Pe’er 1996; Demirci et al 2000; Shields et al 2001; Rodriguez-Ares et al 2003; Yuen et al 2003; Kurli and Finger 2005). Finger and colleagues (1993) described the use of topical MMC as a treatment modality for conjuncti- val melanomas. Since then, his group has published several papers describing their clinical experience with this treatment approach (Demirci et al 2000; Kurli and Finger 2005). In 2005 they published the long-term results of 16 patients with biopsy-proven PAM with atypia (8 patients) or conjunctival 506 MM (8 patients) treated with topical MMC (Kurli and Finger 2005). When MMC was used as primary therapy, the regimen used in their protocol was one drop of 0.04% MMC instilled into the superior conjunctival fornix four times a day for 14 days, discontinuing treatment for 14 days, and then restarting MMC for a second 14 day course of treatment. When given as an adjuvant to surgical excision and cryotherapy, MMC was given for 7 days starting within 2 weeks of surgery. In this study, topical MMC was used as primary therapy in 8 patients with PAM with atypia, in 2 patients with invasive melanoma, and in 6 patients as adjunctive therapy following surgical excision for conjunctival melanoma. Interestingly, all 16 patients in his case series demonstrated a clinical response to topical MMC, deﬁned as regression of the areas of pigmentation. With long-term follow-up, however, ﬁve of the ten patients in the primary treatment group developed tumor recurrence: 3/8 patients with PAM with atypia and 2/2 patients with melanoma. For the 6 patients in the adjuvant group, 2 developed tumor recurrences during the follow-up period. Overall, surgical excision was performed in 8 of the 16 cases for tumor recurrence, and 3 cases required orbital exenteration. One of the patients with invasive melanoma treated with MMC as primary therapy had subepithelial nests of melanoma which were resistant to repeated courses of topical treatment. Despite orbital exenteration, this patient ultimately developed metastatic disease 42 months after the initial course of topical MMC. Because of this patient, the authors commented that they were reluctant to use topical MMC as primary treatment for any patient with nodules of invasive melanoma. Another advocate of topical MMC for conjunctival melanocytic lesions is the group at the Hadassah University Hospital in Jerusalem, Israel (Frucht-Pery and Ilsar 1994; Frucht-Pery and Pe’er 1996; Frucht-Pery et al 2002; Pe’er and Frucht-Pery 2005). Frucht-Pery and Pe’er (1996) suc- cessfully treated a 63 year old woman with diffuse PAM with atypia. They treated the patient with two 14 day courses of treatment, the ﬁrst with 0.2 mg/ml concentration and the sec- ond with 0.4 mg/ml concentration. The diffuse pigmentation cleared and a repeat biopsy showed no evidence of atypia. A follow-up paper in 2005 described a series of 12 consecutive patients treated by their group with topical MMC for melano- cytic lesions of the conjunctiva (Pe’er and Frucht-Pery 2005). Among the 12 patients, 9 had PAM with atypia and 3 had invasive melanoma. The patients in their protocol (except the ﬁrst patient) used 0.04% MMC 4 times per day for 2 weeks, with pauses of 2 weeks between courses, until “disappear- ance or stabilization of the remnants of the pigmentation” Clinical Ophthalmology 2008:2(3)