Beyond the Stain: BAP1 -Inactivated Melanocytic Tumors With Retained BAP1 Nuclear Expression due to Missense Mutations in the Catalytic Domain. J Cutan Pathol 2026 Jun;53(6):511-517
Date
03/12/2026Pubmed ID
41813058DOI
10.1111/cup.70086Scopus ID
2-s2.0-105032421802 (requires institutional sign-in at Scopus site)Abstract
BAP1-inactivated melanocytic tumors (BIMTs) demonstrate loss of BAP1 nuclear expression by immunohistochemistry (IHC), which serves as a key diagnostic marker. Here, we present four cases of BIMTs with retained BAP1 nuclear expression. All cases demonstrated dual cytomorphology, low mitotic activity, and either absence of PRAME expression or only weak focal expression. Three cases demonstrated BAP1 p.H169Y missense mutations alongside BRAF V600E mutations. In one case, a BAP1 p.G185R missense mutation and a BRAF V600_S602delinsDT mutation were identified. Both BAP1 missense variants were located in the functional ubiquitin carboxyl hydrolase (UCH) domain at the N-terminus. Although most BAP1 mutations are missense, the majority lead to loss of nuclear expression by IHC due to misfolding or impaired nuclear localization. Therefore, IHC directed against the C-terminus of BAP1 protein remains a sensitive diagnostic tool. In contrast, the p.H169Y and p.G185R variants appear to uniquely preserve both protein folding and nuclear localization, allowing retained nuclear expression despite functional inactivation. Therefore, in tumors with morphologic features suggestive of BIMT, retained BAP1 nuclear expression should not preclude diagnosis or additional molecular testing to confirm BAP1 inactivation.
Author List
Milanovic S, Sun C, Gunnell L, Wilk V, Shinohara MM, Chang O, Admassu N, Chiu Y, Wanat KA, Young KE, Xu Y, Flaman AN, Nohr E, Motaparthi KAuthors
Yvonne E. Chiu MD Vice Chair, Professor in the Dermatology department at Medical College of WisconsinKarolyn A. Wanat MD Chair, Professor in the Dermatology department at Medical College of Wisconsin
Kara E. Young MD Associate Professor in the Dermatology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultBiomarkers, Tumor
Catalytic Domain
Cell Nucleus
Child
Female
Humans
Immunohistochemistry
Male
Melanoma
Middle Aged
Mutation, Missense
Proto-Oncogene Proteins B-raf
Skin Neoplasms
Tumor Suppressor Proteins
Ubiquitin Thiolesterase
