Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations

Abstract

Craniopharyngioma is a rare tumor occurring in the sellar region comprising 3% of all intracranial tumors. To elucidate the contribution of beta-catenin gene mutation to tumorigenesis, we examined genetic alterations and expression of beta-catenin in 10 cases of adamantinomatous and 6 cases of papillary craniopharyngiomas. Beta-catenin gene mutations were found in all of the adamantinomatous and none of the papillary craniopharyngiomas. Immunohistochemically, all cases of adamantinomatous craniopharyngioma showed cytoplasmic and nuclear expression of beta-catenin. In contrast, papillary craniopharyngiomas showed exclusively membranous expression. The results suggest that adamantinomatous- and papillary-type craniopharyngiomas are not only clinicopathologically, but also genetically, distinctive variants. Mutation of the beta-catenin gene therefore seems to play an important role in the tumorigenesis of adamantinomatous craniopharyngioma. Among the adamantinomatous-type tumors, beta-catenin-positive mesenchymal cells were observed in two cases. Microdissection-based mutational analysis revealed that these mesenchymal cells also harbor the same beta-catenin gene mutations as those of epithelial cells, suggesting their tumorous nature. Thus, at least a subset of adamantinomatous craniopharyngioma is considered to be biphasic.

Figure 1.

Representative histology of cases (A, B) and immunohistochemistry for β-catenin (C, D). A: Adamantinomatous craniopharyngioma. Loosely cohesive squamous cells surrounded by peripherally palisading cells. A squamous nodule (wet keratin) (arrowheads) is observed (case 7-1). B: Papillary craniopharyngioma. Well-differentiated squamous epithelium lining loose connective tissue (case 16). C: Adamantinomatous craniopharyngioma. Membranous and cytoplasmic staining for β-catenin. Peripherally palisading cells show stronger expression. Clusters of cells along the epithelial cell whorls show strong nuclear accumulation (case 7-1). D: Papillary craniopharyngioma. Membranous staining pattern (case 11). H&E (A, B) and immunohistochemistry for β-catenin (C, D). Original magnifications: ×100 (A, B); ×200 (C, D).

Figure 2.

Adamantinomatous craniopharyngioma with a mesenchymal component (A, C: case 8; B, D: case 1). A and B: Whorling and streaming spindle-cell fascicles are observed around the epithelial cell nests. A highly cellular area is seen in case 8 (A). C and D: Immunohistochemistry for β-catenin. Spindle cells around the epithelial cell nests show moderate to strong cytoplasmic and nuclear expression and lack membranous staining observed in epithelial cells. H&E (A, B) and immunohistochemistry for β-catenin (C, D). Original magnifications, ×200.

Figure 3.

Microdissection-based analysis (case 8). A and B: Sections after microdissection for epithelial (A) and mesenchymal (B) components. Microdissection was performed using peripherally palisading cells as a hallmark of borders between the epithelial and mesenchymal cells. Microdissected areas were marked by arrowheads. C: Direct sequencing of the β-catenin gene. Both components harbor missense mutations affecting a threonine residue at GSK-3β phosphorylation sites. H&E (A, B). Original magnifications, ×200 (A, B).