LEF1, TFE3, and AR are putative diagnostic markers of solid pseudopapillary neoplasms.

Eun Kyung Kim,Mi Jang,Hoguen Kim,Minhee Park

doi:10.18632/oncotarget.21854

Abstract

The diagnosis of solid pseudopapillary neoplasms (SPNs) is challenging because some SPNs share many similar morphological and immunohistochemical features with other pancreatic neoplasms. In this study, we investigated potential diagnostic markers of SPN.Based on the SPN-specific upregulated genes from a previous DNA microarray and proteome study, we selected six immunohistochemical markers [beta-catenin, androgen receptor (AR), lymphoid enhancer-binding factor 1 (LEF1), transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3), fused in sarcoma (FUS), and WNT inhibitory factor 1 (WIF-1)]. We also evaluated the Ki-67 proliferative index to investigate its associations with prognosis. To validate these markers, we studied 91 SPNs as well as 51 pancreatic ductal carcinomas (PDC) and 48 neuroendocrine tumors (NET) as controls.We found frequent and diffuse nuclear expressions of β-catenin (98.9%), AR (81.3%), LEF1 (93.4%), TFE3 (74.7%), FUS (84.6%), and cytoplasmic expression of WIF-1 (96.7%) in SPNs. In contrast, PDCs and NETs showed no expression. (P < 0.001). When beta-catenin, LEF1, and TFE3 staining were combined, the sensitivity and specificity were 100% and 91.9%, respectively. Four (4.4%) SPNs showed distant metastasis and these tumors were associated with a relatively high Ki-67 proliferative index (≥ 5%; P = 0.013).We identified LEF1, TFE3, and AR as putative diagnostic markers of SPN, auxiliary to β-catenin. Incorporated into an immunohistochemical panel, these markers could be beneficial to distinguish SPN from PDC and NET. In addition, we suggest that the Ki-67 proliferative index can be a predictive marker of metastasis in SPNs.

Highlights

Among pancreatic tumors, solid pseudopapillary neoplasm (SPN) is very rare and comprises only 1–3% of primary pancreatic tumors
SPN is composed of small monomorphic cells with clear or eosinophilic cytoplasm that form solid or pseudopapillary structures with poor cohesion
Mutations in exon 3 of the β-catenin gene have been identified in the majority of SPNs [2, 3] and diffuse nuclear expression of β-catenin is www.impactjournals.com/oncotarget known to be a characteristic feature used in the diagnosis of SPN

Summary

Introduction

Solid pseudopapillary neoplasm (SPN) is very rare and comprises only 1–3% of primary pancreatic tumors. SPN is composed of poorly cohesive monomorphic epithelial cells that form solid, pseudopapillary structures, and it occurs predominantly in young women [1]. SPNs are genetically characterized by somatic mutations in exon 3 of CTNNB1, which encodes β-catenin [2, 3]. The molecular regulatory networks of SPN have recently been well-characterized [4,5,6,7]. Through an integrative analysis of mRNA, microRNA, and proteome expression profiles, we have identified many (> 1,000) SPN-specific upregulated genes, activated Wnt/β-catenin, Hedgehog, and androgen receptor (AR) signaling pathways [6, 8]

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