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It is not uncommon in clinical practice for an ophthalmologist to identify, during routine examination, unilateral or bilateral areas of flat stippled pigmentation in the bulbar or palpebral conjunctiva in middle aged or elderly patients. The pigmentation can have been unrecognised for many years and be static but in a minority of cases the process may progress to malignant melanoma. Thus, any pigmented lesion which is increasing in size should be given serious consideration and tissues should be submitted to an experienced pathologist in the form of an excision biopsy.
The simplest form of conjunctival pigmentation is the result of hypertrophy and hyperplasia of the basal cell layer of the epithelium which becomes packed with melanosomes. In this histological pattern, the nuclei of the melanocytes do not show variations in size and shape and do not possess obvious nucleoli: this pathology is classified as primary acquired melanosis without atypia (or benign acquired melanosis).1-3 Primary acquired melanosis without atypia does not carry the risk of progression to malignancy.2
A more sinister type of melanocytic proliferation (within the basal and wing cell layers of the epithelium) is characterised by variation in size and shape of the nuclei, the presence of prominent nucleoli, and migration of these cells towards the surface of the epithelium. This histological pattern is graded as mild/moderate or severe primary acquired melanosis with atypia.2 The problem for the pathologist is that assessment of the degree of “atypia” is subjective and atypia does not necessarily signify neoplasia because, as a reactionary process, it is seen after cryotherapy4 or irradiation. An added pathobiological complication is that melanocytic proliferation in areas of primary acquired melanosis with atypia can be very variable within a large area of pigmentation: this could be regarded as a field change with multistep neoplasia or alternatively as superficial spreading of neoplastic melanocytes within the epithelium. In some individuals primary acquired melanosis with severe atypia progresses to full thickness infiltration of the epithelium by neoplastic melanocytic cells (melanocarcinoma in situ) and there is no doubt that this carries an increased risk of invasion of the basement membrane and frank malignant melanoma.1-3 In attempts to simplify and strengthen the subclassifications of melanocytic proliferation pathologists have used immunohistochemistry to identify melanocytic cells.
Initially reports were optimistic that the immunohistochemical marker HMB-45 would differentiate malignant melanocytes from reactionary benign cells5 but subsequent studies showed that this marker simply identifies active melanocytes. The antibody NK1C3 was regarded as more reliable as a marker for malignancy but again the distinction between benign reactionary proliferations is not made clear by this marker. Neither is S100 a useful marker except in the situation where the proliferating melanocytes do not contain melanosomes as in primary acquired melanosis sine pigmento.6 These markers are advantageous in one regard in that they clearly demonstrate the extent of melanocytic infiltration within a conjunctival biopsy and as time goes by there is cause for optimism that the specificity of immunohistochemical markers for malignant melanocytes will improve.
The study of cell proliferation has advanced considerably owing to identification of non-histone nuclear proteins such as Ki 67 and proliferating cell nuclear antigen (PCNA) within the nuclei of dividing cells. In paraffin sections Ki 67 can be labelled with MIB-1 antibody and PCNA by PC10 antibody using conventional immunohistochemical techniques. The proliferating cells are identified by a red label which immunostains the nuclei. In the current issue of the BJOChowers et al (p 1316) have shown the value of this approach and have stressed the lack of interobserver variation, thus substantiating an earlier study by Seregard.7 By these techniques it is possible to identify those melanocytic proliferations which carry a high risk of progression to malignant melanoma.
These advances in histopathology are relevant to changes in protocols for the treatment of precancerous melanosis which has traditionally been based on excision and cryotherapy.4 Recent reports8 9 indicate that topical mitomycin C chemotherapy may be an appropriate treatment for primary acquired melanosis with atypia so that accurate pretreatment diagnosis is essential for correct management.