Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-
MIL). The fourth "WHO Classification of Eye
Tumors" (WHO-EYE04) proposed a C-
MIL classification, capturing the progression of noninvasive 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 and immunohistochemistry. However, C-
MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with
hematoxylin and
eosin,
Melan-A, SOX10, and PReferentially expressed
Antigen in
Melanoma. 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 as follows: 28 benign conjunctival
melanoses, 13 low-grade C-
MIL, 37 high-grade C-
MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the 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 noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive
melanoma only occurred in 47% of the 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.