A multicenter study validates the WHO 2022 classification for conjunctival melanocytic intraepithelial lesions with clinical and prognostic relevance

Several nomenclature and grading systems have been proposed for Conjunctival Melanocytic Intraepithelial Lesions (C-MIL). The 4th 'WHO Classification of Eye Tumours' (WHO-EYE04) proposed a C-MIL classification, capturing the progression of non-invasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS) and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin-and-eosin (H&E) and immunohistochemistry. C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with H&E, Melan-A, SOX10 and PReferentially expressed Antigen in Melanoma (PRAME). Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists, to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were: 28 benign conjunctival melanoses; 13 low-grade C-MIL; 37 high-grade C-MIL; and 27 conjunctival melanoma in-situ. Utilizing this system resulted in 93% of pathologists showing only fair-to-moderate agreement (Kappa-statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of non-invasive lesions developed in 8% low-grade- and in 34% high-grade cases. Invasive melanoma only occurred in 47% cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility.