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 b-catenin expression. All analyzed tumors showed strong expression and nuclear accumulation of b-catenin. Following this observation, b-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.94G4C (n ¼ 2) and c.95A4T), four in codon 33 (two each c.98C4G and c.98C4T), two in codon 37 (c.109T4G), one in codon 41 (c.121A4G), and two in codon 45 (c.133T4C). 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 b-catenin signaling. All analyzed glomangiopericytomas showed prominent nuclear expression of cyclin D1, as previously shown for tumors with nuclear expression of b-catenin as a sign of oncogenic activation. These results demonstrate that mutational activation of b-catenin and associated cyclin D1 overexpression may be central events in the pathogenesis of glomangiopericytoma. In additon, nuclear accumulation of b-catenin is a diagnostic marker for glomangiopericytoma. Modern Pathology (2015) 28, 715-720; doi:10.1038/modpathol.2014.161; published online 28 November 2014Glomangiopericytoma (sinonasal-type hemangiopericytoma) is a rare mesenchymal neoplasm of the nasal cavity and sinuses of low biologic potential. [1][2][3][4] It shows a myoid phenotype with consistent expression of smooth muscle actin. 3 b-Catenin, a cadherin-associated membrane protein, participates in the regulation of cell-to-cell adhesion and in some circumstances, also gene transcription as a nuclear protein, a terminal component of the canonical Wnt-signaling pathway. Aberrant expression of b-catenin encoded by CTNNB1 gene is a well-known event in tumorigenesis and tumor progression. 5,6 Among soft tissue tumors, somatic mutations in CTNNB1 are well known in the pathogenesis of sporadic desmoid-type fibromatosis. 7,8 These mutations cluster in CTNNB1 glycogen serine kinase-3 beta (GSK3b) phosphorylation region and constitutionally activate b-catenin signal by upholding cellular b-catenin levels. This happens via interference of ubiquitin-mediated proteolytic degradation by elimination of the phosphorylation sites necessary for ubiquitin action. 7,8 Accumulation of b-catenin in turn results in nuclear translocation, which is a telltale sign of a mutation, typically seen in sporadic de...

Update on Select Benign Mesenchymal and Meningothelial Sinonasal Tract Lesions

“…Strong nuclear b-catenin and cyclin D1 immunoexpression is observed in nearly all cases of GPC. Somatic, single nucleotide substitution mutations in CTNNB1 gene encoding b-catenin, specifically in the glycogen serine kinase-3 beta (GSK3b) phosphorylation region (encoded by exon 3) have been identified in GPC (using Sanger sequencing) [7,8]. These heterozygous mutations involved codons 32, 33, 37, 41 and 45, findings similar to those in other tumor types demonstrated to constitutionally activate b-catenin signaling by upholding cellular b-catenin levels [29].…”

“…Individual cells are highlighted with laminin, similar to argyrophilic stains that envelop individual pericytes by a silver impregnated matrix representing basal laminar material [25]. Rare cases have demonstrated focal bcl-2, S100 protein, CD34, GFAP and CD68 [6,8,11,17,18,26]. The intensity of immunoreactivity may vary both within and between cases, ranging from diffuse and strong to focal and weak, but in general, the SMA, b-catenin and cyclin-D1 are strong and diffuse reactions.…”

“…The histologic features of the sinonasal type HPC appear unique, combined with a myoid phenotype (a sitespecific myofibroma), as a part of the myopericytic family of tumors [2][3][4][5]. Although there are morphologic similarities to other myopericytic entities, ''GPC'' of the sinonasal tract is a relatively distinct tumor, defined as a tumor demonstrating composite features of perivascular modified smooth muscle (myoid phenotype of glomus tumor) arranged in a characteristic syncytium of ovoid to spindle-shaped cells in a variably fibrotic stroma with distinctive branching vessels (HPC) [6][7][8][9][10].…”

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

“…Mutations in b-catenin result in its intranuclear accumulation, thereby evading ubiquitination and degradation which leads to increased transcription of Wnt pathway target genes, which are involved in cellular proliferation [6]. CTNNB1 alterations in sinonasal HPC have been consistently reported in exon 3, with missense mutations [4,5]; mutations affecting positions 32-45 of the amino-terminal region disrupt phosphorylation-dependent degradation of b-catenin [6]. Numerous other tumor types harbor CTNNB1 mutations, most frequently desmoid-type fibromatosis [7,8] as well as salivary basal cell adenoma [9], pilomatricoma and pilomatrix carcinoma [10], hepatocellular carcinoma [11], colorectal carcinoma [12], medulloblastoma [13], endometrial adenocarcinoma [14], Wilms tumor [15], and adrenocortical carcinoma [16].…”

“…Perivascular myoid differentiation is evident by immunohistochemistry, as sinonasal HPC expresses SMA and HHF-35, and is typically negative for desmin, CD34, and keratin. CTNNB1 gene mutations and nuclear expression of b-catenin have recently been identified in sinonasal HPC [4,5].…”