NF1 and SPRED1 loss in acral melanoma. A) NF1 immunohistochemistry in an acral melanoma without NF1 mutation (top) shows robust expression of NF1 within neoplastic melanocytes, whereas as expression is lost in a melanoma with a truncating mutation in NF1 and loss of the wild-type allele (bottom, residual staining is in endothelial cells). B) NF1 and SPRED1 loss are mutually exclusive. All cases with bi-allelic loss of NF1 or SPRED1 (deep deletion or loss of function mutation with loss of the wild-type allele) and/or absence of NF1 protein expression by immunohistochemistry are shown, one sample per column. Additional MAPK pathway activating alterations are present in a majority of cases.