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

Hardeep Singh Mudhar, Yamini Krishna, Simon Cross, Claudia Auw-Haedrich, Raymond Barnhill, Svetlana Cherepanoff, Ralph Eagle, James Farmer, Robert Folberg, Hans Grossniklaus, Martina C Herwig-Carl, Martin Hyrcza, Sandra Lassalle, Karin U Loeffler, Alexandre Moulin, Tatyana Milman, Robert M Verdijk, Steffen Heegaard, Sarah E Coupland*

*Corresponding author af dette arbejde


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.

TidsskriftLaboratory investigation; a journal of technical methods and pathology
Sider (fra-til)100281
StatusE-pub ahead of print - 2 nov. 2023


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