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BMJ Case Rep. 2009; 2009: bcr12.2008.1409.
Published online 2009 June 1. doi:  10.1136/bcr.12.2008.1409
PMCID: PMC3029157
Novel treatment (new drug/intervention; established drug/procedure in new situation)

Efficacy of low-dose topical mitomycin C treatment for primary acquired melanosis


Primary acquired melanosis (PAM) with atypical cytological features has nearly a 50% chance of progressing to malignant melanoma. Surgical excision with cryotherapy has been the mainstay of treatment, but topical treatment with mitomycin C (MMC) is an increasingly common alternative treatment. Since PAM is relatively rare and MMC is a new treatment option, publications are limited to case reports and a few small series. Optimum doses, duration and timing of treatment cycles have not been established. Two patients were diagnosed with PAM with atypia and were treated with either primary or adjuvant treatment of 0.02% MMC for approximately 10 days for three cycles, which is the lowest dose protocol published to date for the treatment of PAM. Both patients showed stable partial response and only experienced temporary ocular drug toxicity.


Primary acquired melanosis (PAM) is most often characterised by flat, superficial, brown pigmentation on bulbar conjunctiva, but it can have variegated pigmentation and involve the fornix, palpebral conjunctiva or cornea. Histologically, PAM is a predominantly melanocytic proliferation limited to the conjunctival epithelium that is classified into two groups—those having melanocytes with atypical cytological features (PAM with atypia) and those that lack melanocytes with cytological atypia (PAM without atypia).1 The distinction between PAM with and without atypia is critical because few, if any, cases of PAM without atypia progress to malignancy, but PAM with atypia progresses to malignant melanoma nearly 50% of the time.1

When conjunctival melanoma is present, surgical excision with cryotherapy has been the mainstay of treatment.2,3 Occasionally, complete resection of conjunctival melanoma arising from PAM results in residual PAM with atypia at the excisional margin. These areas are treated by cryotherapy, but complete eradication of PAM with atypia may not occur. Recurrences of melanoma may be due to residual marginal disease, amelanotic lesions, multifocal involvement or diffuse disease. Treatments for PAM alone include observation, excisional biopsy, alcohol epitheliectomy and cryotherapy.36

Recently, extrapolating from successes in treating squamous ocular surface neoplasia, topical mitomycin C (MMC) has been used in the treatment of pigmented conjunctival malignancies with encouraging results.5,711 Topical chemotherapy has the advantage of treating the entire ocular surface, simplifying treatment for diffuse or multifocal PAM. Additionally, when used as an adjunct to resection and cryotherapy for conjunctival melanoma, topical chemotherapy may minimise melanoma recurrence from residual areas of PAM.5,711

Since PAM is relatively rare and MMC is a relatively new treatment option, publications are limited to case reports and a few small series.5 Optimum doses, duration and timing of treatment cycles have not been established. Most published regimens for treating PAM use MMC at a concentration of 0.04% with 14-day cycles of four times daily dosing.711 Few reports have experimented with lower dose regimens using 0.02% MMC.9,11 Naturally, the lowest effective dose should be used to minimise the ocular surface toxicity that is often the dose-limiting side effect for MMC. We report our experience using MMC, either as primary or adjuvant treatment, at a concentration of 0.02% at four times daily for 10 days with a 3-week holiday separating three cycles—the lowest dose protocol published to date for the treatment of PAM.


Patient characteristics, treatment and response data are summarised in table 1. Both patients had biopsy confirmed PAM with atypia (fig 1).

Figure 1
Pathologic diagnosis (200×). The fornix of patient 1 displays numerous melanocytes, some with atypia, that lie in the deeper layers of the epithelium with a few extending into the more superficial layers (panel A). The limbus of patient 2 shows ...
Table 1
Summary of results by patient setting

Case 1

A 93-year-old woman was diagnosed with PAM with atypia in the left eye that involved bulbar conjunctiva and extended into the palpebral conjunctiva. Her other concurrent ocular diagnoses were macular degeneration and pseudophakia. At onset, her left visual acuity was 20/400.

She started primary treatment of MMC following complete excision of PAM. Her MMC regimen was 0.02% four times daily for 10 days, with 21 days rest in between each of the three cycles. She was able to fully complete her regimen as planned. The patient was followed for 32 months afterwards and was evaluated for evidence of ocular surface toxicity and response to treatment.

She tolerated the treatment well, with dry eye symptoms as her sole side effect. After completion of MMC, the patient demonstrated nearly a complete resolution with stabilisation, showing a mild, flat residual pigmentation after treatment (fig 2). Post-treatment, her visual acuity was decreased to counting fingers at 5 ft.

Figure 2
Diffuse primary acquired melanosis with atypia on the bulbar and palpebral conjunctiva of patient 1 before treatment with topical mitomycin C (panels A and B) and after three cycles of mitomycin C 0.02%, four times daily for 10 days separated by 21 days ...

Case 2

An 81-year-old woman was initially diagnosed with conjunctival malignant melanoma arising from PAM in the left eye. She was treated with cryotherapy and resection. One year later, she had repeat cryotherapy and resection and amniotic membrane graft reconstruction. After her procedures, the biopsy showed residual PAM with atypia on the bulbar conjunctiva with corneal extension without any evidence of recurrent melanoma. Her concurrent ocular diagnoses were glaucoma, keratoconus, blepharitis and pseudophakia. Left visual acuity at this time was 20/30.

She received adjuvant treatment of MMC with a planned regimen of 0.02% four times daily for 10 days with 21 days rest in between each cycle. However, the regimen was modified due to side effects of keratoconjunctivitis, lid erythema and chemical corneal epitheliopathy. Her second and third cycles were reduced to 8 and 7 days, respectively, maintaining a 21-day rest period between each cycle.

She was followed for 30 months after completion of MMC. She demonstrated a partial resolution with stabilisation and had full recovery from her ocular surface toxicity (fig 3). Post-treatment, visual acuity decreased to 20/60.

Figure 3
Primary acquired melanosis with atypia on the bulbar conjunctiva of patient 2 before treatment with topical mitomycin C (panels A and B) and after three cycles of mitomycin C 0.02%, four times daily for 10, 8 and 7 days separated by 21 days between courses ...


Topical chemotherapy with MMC for PAM has several advantages over repeated resections with cryotherapy. First, MMC has the advantage of treating the entire conjunctiva without the need to define tumour margins, which can be difficult to define clinically. Second, in cases with diffuse conjunctival involvement, where complete resection would result in significant ocular morbidity, topical treatment may reduce or obviate the need for resection. Third, the toxicity of MMC is typically temporary and resolves with cessation of treatment unlike the symblepharon, ptosis, scarring, extraocular motility restriction and eyelash loss that can be associated with resection and cryotherapy.4 Finally, MMC can be used to reduce the overall tumour burden in order to facilitate definitive resection.

Our low dose MMC regimen was effective in achieving lasting partial resolution and stabilisation of PAM with atypia when used as primary or adjuvant treatment. We have not attempted, nor would we advocate, the use of MMC as primary treatment for conjunctival melanoma. Previous reports using higher dose regimens show MMC produces lower recurrence rates when treating PAM alone than when used as adjuvant treatment after treatment for conjunctival melanoma.8 Because of the higher risk of recurrence associated with melanoma, we routinely resect to negative margins and treat with cryotherapy as primary treatment as was done for patient 2. MMC treatment was instituted as adjuvant treatment for her residual PAM with atypia.

Visual acuity decreased during follow-up for both patients, but the changes are unlikely to be attributable to MMC treatment. Patient 1 had progression of age-related macular degeneration over the 32 months of follow-up and patient 2 had progression of her previously diagnosed keratoconus. One case has been reported in which an intumescent cataract developed after treating conjunctival melanoma originating from PAM with atypia with topical MMC at a dose of 0.04%,13 but most reports using topical MMC do not describe lasting changes in vision.

Consistent with reports using higher dose regimens of MMC for ocular surface neoplasia,14 side effects in this report were mild and manageable. Patient 1 experienced dry eye symptoms that responded to topical ocular lubrication. Patient 2, who had the pre-treatment diagnosis of blepharitis, had more significant ocular surface toxicity requiring modification of her MMC regimen. Her second and third MMC courses were shortened in duration and topical steroids were used as rescue treatment between cycles. All side effects in both patients were tolerated and fully recovered after completion of treatment.

We report that a low dose 0.02% MMC protocol for 10 days is effective in treating PAM and can produce responses similar to reports using higher doses, which suggests that lower doses may be used to reduce treatment toxicity without sacrificing treatment efficacy. Further study with longer follow-up and greater numbers of patients is required.


  • It is important to distinguish between primary acquired melanosis (PAM) with and without atypia because PAM with atypia progresses to malignant melanoma nearly 50% of the time.
  • Topical mitomycin C (MMC) treatment for PAM with atypia is a viable alternative to repeated resections with cryotherapy and can spare a patient the ocular morbidity of more invasive surgical treatment.
  • Low dose 0.02% MMC for 10 days for three cycles with 21 day rest period is as efficacious as previously reported higher dose regimens, producing similar responses and reduction in drug adverse effects, when used as either primary or adjuvant treatment.


Competing interests: none.

Patient consent: Patient/guardian consent was obtained for publication.


1. Folberg R, McLean IW, Zimmerman LE. Primary acquired melanosis of the conjunctiva. Hum Pathol 1985; 16: 129–35 [PubMed]
2. Shields CL, Shields JA, Gunduz K, et al. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Arch Ophthalmol 2000; 118: 1497–507 [PubMed]
3. Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol 1997; 115: 808–15 [PubMed]
4. Jakobiec FA, Rini FJ, Fraunfelder FT, et al. Cryotherapy for conjunctival primary acquired melanosis and malignant melanoma. Experience with 62 cases. Ophthalmology 1988; 95: 1058–70 [PubMed]
5. Chalasani R, Giblin M, Conway RM. Role of topical chemotherapy for primary acquired melanosis and malignant melanoma of the conjunctiva and cornea: review of the evidence and recommendations for treatment. Clin Experiment Ophthalmol 2006; 34: 708–14 [PubMed]
6. Liesegang TJ. Pigmented conjunctival and scleral lesions. Mayo Clin Proc 1994; 69: 151–61 [PubMed]
7. Kemp EG, Harnett AN, Chatterjee S. Preoperative topical and intraoperative local mitomycin C adjuvant therapy in the management of ocular surface neoplasias. Br J Ophthalmol 2002; 86: 31–4 [PMC free article] [PubMed]
8. Kurli M, Finger PT. Topical mitomycin chemotherapy for conjunctival malignant melanoma and primary acquired melanosis with atypia: 12 years’ experience. Graefes Arch Clin Exp Ophthalmol 2005; 243: 1108–14 [PubMed]
9. Pe’er J, Frucht-Pery J. The treatment of primary acquired melanosis (PAM) with atypia by topical Mitomycin C. Am J Ophthalmol 2005; 139: 229–34 [PubMed]
10. Rodriguez-Ares T, Tourino R, De Rojas V, et al. Topical mitomycin C in the treatment of pigmented conjunctival lesions. Cornea 2003; 22: 114–17 [PubMed]
11. Yuen VH, Jordan DR, Brownstein S, et al. Topical mitomycin treatment for primary acquired melanosis of the conjunctiva. Ophthal Plast Reconstr Surg 2003; 19: 149–51 [PubMed]
12. Finger PT. Do you speak ocular tumor? Ophthalmol 2003; 110: 13–4 [PubMed]
13. Sacu S, Segur-Eltz N, Horvat R, et al. Intumescent cataract after topical mitomycin-C for conjunctival malignant melanoma. Am J Ophthalmol 2003; 136: 375–7 [PubMed]
14. Khong JJ, Muecke J. Complications of mitomycin C therapy in 100 eyes with ocular surface neoplasia. Br J Ophthalmol 2006; 90: 819–22 [PMC free article] [PubMed]

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