Nuclear expression and gain-of-function β-catenin mutation in glomangiopericytoma (sinonasal-type hemangiopericytoma): insight into pathogenesis and a diagnostic marker

Abstract

Glomangiopericytoma (sinonasal-type hemangiopericytoma) is a rare mesenchymal neoplasm with myoid phenotype (smooth muscle actin-positive), which distinguishes this tumor from soft tissue hemangiopericytoma/solitary fibrous tumor. Molecular genetic changes underlying the pathogenesis of glomangiopericytoma are not known. In this study, 13 well-characterized glomangiopericytomas were immunohistochemically evaluated for β-catenin expression. All analyzed tumors showed strong expression and nuclear accumulation of β-catenin. Following this observation, β-catenin glycogen serine kinase-3 beta phosphorylation region, encoded by exon 3, was PCR amplified in all cases and evaluated for mutations using Sanger sequencing. Heterozygous mutations were identified in 12 of 13 tumors. All mutations consisted of single-nucleotide substitutions: three in codon 32 (c.94G>C (n=2) and c.95A>T), four in codon 33 (two each c.98C>G and c.98C>T), two in codon 37 (c.109T>G), one in codon 41 (c.121A>G), and two in codon 45 (c.133T>C). At the protein level, these substitutions would lead to p.D32H, p.D32V, p.S33C, p.S33F, p.S37A, p.T41A, and p.S45L mutations, respectively. Previously, similar mutations have been reported in different types of cancers and shown to trigger activation of β-catenin signaling. All analyzed glomangiopericytomas showed prominent nuclear expression of cyclin D1, as previously shown for tumors with nuclear expression of β-catenin as a sign of oncogenic activation. These results demonstrate that mutational activation of β-catenin and associated cyclin D1 overexpression may be central events in the pathogenesis of glomangiopericytoma. In additon, nuclear accumulation of β-catenin is a diagnostic marker for glomangiopericytoma.

Figure 1

Histological features of glomangiopericytoma. (a–c) The tumor is composed of epithelioid cells set in a perivascular pattern around prominent blood vessels with prominent perivascular hyalinization. (d) One example contained multinucleated giant cells.

Figure 2

All glomangiopericytomas were strongly positive for β-catenin with both nuclear and cytoplasmic staining. There is a purely nuclear labeling for cyclin D1. The tumors typically express SMA. CD34 expression, typically focal, is also a common feature for these tumors.

Figure 3

Examples of Sanger sequencing of CTNNB1 exon 3 from glomangiopericytomas analyzed in this study. Arrows indicate single-nucleotide substitutions: c.98C>G in codon 33 (a), c.109T>G in codon 37 (b), c.121A>G in codon 41 (c), and c.133T>C in codon 45 (d).