Primary Acquired Melanosis
PAM is considered the benign counterpart of CM and is the precursor lesion in 25-75% of CMs, while nearly 50% of PAM with atypia progress to CM.17 PAM usually presents as unilateral patchy or diffuse superficial pigmentation of the epibulbar conjunctiva with or without waxing and waning (Figure 2). The rest of CM cases not associated with PAM arise from preexisting nevi or de novo, with only 1% of conjunctival nevi found to progress to CM after 7 years of follow-up.2,15 Additionally, dysplastic nevus syndrome is another possible predisposing condition for CM, although a risk prediction or prognostication for CM or a direct link between the two diseases has yet to be determined. Studies of time trends in CM incidence have revealed that CM lesions have been detected at lower thicknesses and diameters over time, which suggests earlier diagnosis, but tumors as large as 40 mm in largest basal diameter and 15 mm in thickness are still reported in large series.6
In general, CM presents nearly a decade later than PAM, which correlates with the process of transformation into melanoma. Similarly, patients with PAM without atypia were found to be younger than those having PAM with atypia, though a similar pattern of progression among the latter two has yet to be determined in humans.17 The differentiation of PAM with atypia and without atypia is based on histopathology only; however, clinical clues favoring CM versus PAM have been defined as: thickness more than 1 mm, lack of pigment, presence of feeder or intrinsic vessels, cysts, hemorrhage, older age, and tarsal location.6
The terminology for what is called PAM today has shifted over time, initially from precancerous melanosis to benign acquired melanosis, then to melanoma in situ,18 and today PAM represents acquired melanosis with or without atypia.16,17 Some centers have replaced the term PAM with conjunctival melanocytic intraepithelial neoplasm (C-MIN) with an additional histological grading system based on horizontal epithelial involvement, vertical depth of melanocytic infiltration, and degree of cellular atypia, where the lowest C-MIN score of 0 corresponds to melanosis, 1 corresponds to “PAM with mild atypia”, 2 or 3 corresponds to “PAM with moderate atypia”, 4 corresponds to “PAM with severe atypia”, and a score of 5 or more corresponds to CM in situ.19 In both cases, either PAM or C-MIN, the lesions are described clinically as flat, usually unilateral, patchy or diffuse, unifocal or multifocal, noncystic melanocytic lesions of the conjunctiva generally seen in Caucasians.
Based on current knowledge, it is now considered overtreatment to perform orbital exenteration, whereas this was once considered the main approach for these lesions.18 The contemporary approach to PAM treatment lacks standardization and consists of close observation, excision alone or combined with cryotherapy, and topical chemotherapy with mitomycin C, 5-fluorouracil, or interferon-alpha-2-beta.19 Additional mapping biopsies before commencing treatment may aid in determining the need for brachytherapy in tumors with a high C-MIN score, the extent of the disease (particularly in amelanotic disease),19 and the degree of atypia at different locations, as the lesion may be multifocal. However, incisional or needle biopsies for CM should be avoided because these procedures are associated with tumor recurrence and iatrogenic seeding.1 Impression cytology (IC) is also not recommended in melanocytic proliferations of the conjunctiva.20 Our approach to PAM/C-MIN consists of total excision where possible and several incisional biopsies combined with topical 0.04% mitomycin C drops 4 times a day for 2 weeks followed by a 2-week drop-free period, for at least 2 cycles, targeting residual or resistant areas in more extensive cases. Extensive PAM or PAM with atypia should be approached with vigilance, as PAM with atypia has a 13% risk of conversion to CM as opposed to 0% in PAM without atypia, and each clock hour increase in the extent of the lesion increases the likelihood of CM 1.7 times.21 Histologically, PAM with atypia is considered to pose a higher risk of progression to melanoma with increasing number of epithelioid melanocytes and when there is intraepithelial pagetoid spread.16 Additionally, the risk of progression to CM increases with increasing clinical extent of PAM.21