Recurrent Mutations within the Amino-Terminal Region of β-Catenin Are Probable Key Molecular Driver Events in Sinonasal Hemangiopericytoma

Abstract

Sinonasal hemangiopericytoma (SN-HPC) is an uncommon, site-specific, low-grade mesenchymal neoplasm of probable perivascular myoid cell origin. In contrast to solitary fibrous tumors of soft tissue and sinonasal tract origin, SN-HPCs were recently shown to lack recurrent NAB2-STAT6 fusion variants. Other molecular alterations known to occur in some of soft tissue perivascular myoid cell neoplasms were also absent in SN-HPC; thus, the molecular pathogenesis of SN-HPCs remained unknown. Guided by whole-genome sequencing combined with RNA sequencing of an index case, we analyzed a total of six SN-HPCs for mutations within the amino-terminal region of the gene CTNNB1 (cadherin-associated protein), β 1, 88 kDa, encoding β-catenin. All six cases showed missense mutations, with amino acid substitutions clustering at positions 33 to 45, corresponding to the recognition site of the β-catenin destruction complex. Similar CTNNB1 mutations have been described in a variety of epithelial and mesenchymal neoplasms. These mutations prevent β-catenin phosphorylation and proteasomal degradation but promote its nuclear accumulation and subsequent increased transcription of Wingless-related integration site target genes. Consistent with these molecular findings, β-catenin IHC showed consistent diffuse and strong nuclear staining of the tumor cells in all six SN-HPCs. Our results highlight, for the first time, CTNNB1 mutations as the likely initiating molecular events driving SN-HPC tumorigenesis, which places SN-HPC among the growing family of β-catenin-driven mesenchymal neoplasms.

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].…”

“…The spindled cells tend to be much more elongated, with tapering elongated nuclei [30][31][32][33]. By immunohistochemistry, SFTs reveal diffuse reactivity with CD34, bcl-2, STAT6, and CD99, but are negative with actins and bcatenin [7,32,34], although a subset of SFT may express bcatenin [35]. SFT is further characterized by NAB2-STAT6 gene fusion and over expression of the fusion protein [36], a finding not found in GPC [8,23].…”

“…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].…”