Study of β-catenin and BRAF alterations in adamantinomatous and papillary craniopharyngiomas: mutation analysis with immunohistochemical correlation in 54 cases

Abstract

Craniopharyngiomas (CP) are rare benign epithelial tumors, with two histological variants, namely the adamantinomatous variant (ACP) and the rarer papillary variant (PCP). They are locally infiltrative and surgically challenging tumors with severe long term morbidity. CTNNB1 mutations with β-catenin immunopositivity and BRAFV600E mutations with anti-VE immunopositivity have been recently described in ACPs and PCPs respectively. We aimed to study BRAF and CTNNB1 gene mutations in CPs operated at our institute, and correlate it with clinicopathological parameters including histopathology and immunohistochemistry (IHC) for proteins VE-1 and β-catenin. A total of 54 CPs diagnosed over 3-year duration were included. IHC for β-catenin and VE-1 proteins, and Sanger sequencing for CTNNB1 (exon 3) and BRAF (exon 15) genes were performed. CTNNB1 mutations were identified in 63% (27/43) of ACPs while nuclear immunopositivity for β-catenin was observed in 79% (34/43) of them. Seven ACPs showed β-catenin immunopositivity in the absence of mutations. BRAFV600E (p.Val600Glu) mutations were observed in 57% of PCPs (4/7), while cytoplasmic immunopositivity for anti-VE1 antibody was observed only in 43% of PCPs (3/7), all of which also harboured BRAFV600E mutations. The mutations and IHC staining patterns of ACPs and PCPs were non-overlapping. Four cases with uncertain histological pattern could be subcategorised into specific variants only following mutation analysis/IHC. The identification of hallmark molecular signatures in the two CP variants holds promise for alternate improved treatment modalities, emphasizing the need for sub-categorization in routine histopathology reporting. IHC for β-catenin and targeted sequencing for BRAFV600E serve as useful adjuncts.