Expression of EGFR in Pituitary Corticotroph Adenomas and Its Relationship With Tumor Behavior.

Xiaohai Liu,Congxin Dai,Renzhi Wang,Xinjie Bao,Ming Feng,Kan Deng,Yong Yao

doi:10.3389/fendo.2019.00785

Abstract

Objective: Epidermal growth factor receptor (EGFR) has been found to localize in several human neoplasms and has been shown to have a significant correlation with adenomaigenesis and patient prognosis. EGFR is also overexpressed in pituitary corticotroph adenomas. However, its clinical significance and relationship with tumor behavior, especially tumor recurrence status, remain obscure. The purpose of the present study was to identify the expression patterns of EGFR and its downstream signaling pathway molecules in pituitary corticotroph adenomas and to investigate the association of EGFR with clinicopathological characteristics and tumor recurrence.Methods: Fifty-two sporadic pituitary adenoma specimens and six normal pituitary glands were collected. The expression levels of EGFR and its downstream signaling molecules in each sample were evaluated and quantified using immunohistochemistry and Western blot. The relationships of EGFR expression with clinicopathological characteristics and tumor recurrence status were analyzed.Results: EGFR was overexpressed in 55.8% of the pituitary corticotroph adenomas and in 1 of 6 of the normal adenohypophysial tissues. The expression degree was significantly higher in pituitary corticotroph adenomas than in normal adenohypophysial tissues. In EGFR-overexpressing adenomas, the downstream pathway phosphorylated Erk (p-Erk) was also significantly activated. Moreover, the expression levels of EGFR were positively correlated with the adrenocorticotropic hormone (ACTH) and cortisol levels but were not correlated with age, sex or symptom duration. The expression levels of EGFR, phosphorylated EGFR (p-EGFR) and p-Erk were significantly up-regulated in the recurrent adenoma group compared with those in the non-recurrent adenoma group (all p < 0.05). The expression levels of EGFR were strongly correlated with the recurrence-free interval (p = 0.005, CC = −0.31).Conclusion: The expression levels of EGFR and its downstream pathway components were significantly increased in pituitary corticotroph adenomas compared to the levels in normal adenohypophysial tissues. EGFR expression levels were positively associated with the ACTH and cortisol levels and with tumor recurrence status. Pituitary corticotroph adenomas with high EGFR expression levels were correlated with an increased recurrence rate and a decreased recurrence-free interval. EGFR could be used as a promising biomarker for predicting pituitary corticotroph tumor recurrence.

Highlights

Pituitary corticotroph adenomas arising from pituitary corticotroph cells account for 70% of endogenous Cushing disease (CD) cases [1, 2]
We identified the expression patterns of Epidermal growth factor receptor (EGFR) and its downstream pathway in pituitary corticotroph adenomas and investigated its association with clinicopathological characteristics and tumor recurrence
Due to the unavailability of human pituitary adenoma cell lines and reproducible animal models, the pace of translational research underlying the pathogenesis and progression was very slow until several studies showed that ubiquitin specific peptidase 8 (USP8), USP48, and BRAF are frequently mutated in pituitary corticotroph adenomas, causing CD by enhancing the promoter activity and transcription of the gene encoding POMC, which is the precursor of adrenocorticotropic hormone (ACTH) [8,9,10]

Summary

Introduction

Pituitary corticotroph adenomas arising from pituitary corticotroph cells account for 70% of endogenous Cushing disease (CD) cases [1, 2]. CD is associated with increased morbidity and mortality mainly due to metabolic and cardiovascular complications, osteoporosis, psychiatric changes, and cognitive impairment as a result of the excessive production of adrenocorticotropic hormone (ACTH), which induces adrenal hypercortisolemia [3]. Curative surgery is challenging, as postoperative recurrence rates at 10 years are as high as 12–45%, even though most CD patients (90%) have adenomas smaller than 1 centimeters in diameter [4]. For those recurrent adenomas, medical therapy to inhibit adrenal function, radiotherapy, and bilateral adrenalectomy has been used with limited efficacy [5]. Early prediction of tumor recurrence is of great importance

Methods

Results

Discussion

Conclusion