BAP1 protein loss by immunohistochemistry: a potentially useful tool for prognostic prediction in patients with uveal melanoma

Background:Uveal melanoma is the most common primary malignant intraocular tumour in adults. Recently, biallelic inactivation of the BAP1 gene was shown to be associated with increased risk of metastasis in patients with uveal melanoma. Immunohistochemical (IHC) assessment of BAP1 protein loss has been shown to be an excellent surrogate for biallelic inactivation of BAP1. In this pilot study, we investigated whether loss of BAP1 expression by IHC is associated with prognosis in uveal melanoma patients.Methods:We retrieved clinical data, reviewed pathological slides, and performed IHC for BAP1 in 40 primary uveal melanomas. Tumour cell type was classified as: spindle (>90% spindle cells); epithelioid (>90% epithelioid cells); or mixed. BAP1 expression was scored as diffuse (nuclear staining in >90% of tumour cells), heterogenous (nuclear staining in <90% of tumour cells), or absent (no nuclear staining). We analysed associations of BAP1 expression with clinical and pathological parameters, and with overall survival.Results:Tumours were obtained from 20 males and 20 females, with a median age of 60 years (range 31-81 years). Tumour cell types were: epithelioid (n=7, 18%), mixed (n=20, 50%), and spindled (n=13, 33%). BAP1 expression was absent in 23 (58%) tumours, heterogenous in seven (18%) tumours, and diffuse in 10 (25%) tumours. Absent BAP1 expression was more frequently seen in epithelioid/mixed cell tumours (19/27, 70%) than was heterogenous (3/27, 11%) or diffuse (5/27, 19%) expression; the corresponding figures for spindle cell tumours were 4/13 (31%), 4/13 (31%) and 5/13 (38%), respectively (p=0.057). Factors associated with improved survival were diffuse or heterogenous BAP1 expression (compared with absent expression, p=0.03) and age less than 60 years (p=0.049).Conclusion:Analysis of BAP1 protein expression using immunohistochemistry may serve as a rapid and cost-effective means of identifying uveal melanoma patients with aggressive disease, who can then be managed appropriately.