Identifying Biomarkers in Lymph Node Metastases of Esophageal Adenocarcinoma for Tumor-Targeted Imaging

Abstract

Introduction Tumor-targeted imaging is a promising technique for the detection of lymph node metastases (LNM) and primary tumors. It remains unclear which biomarker is the most suitable target to distinguish malignant from healthy tissue in esophageal adenocarcinoma (EAC).Objective We performed an immunohistochemistry study to identify viable tumor markers for tumor-targeted imaging of EAC. Methods We used samples from 72 patients with EAC to determine the immunohistochemical expression of ten potential tumor biomarkers for EAC (carbonic anhydrase IX [CA-IX], carcinoembryonic antigen [CEA], hepatic growth factor receptor, epidermal growth factor receptor, epithelial membrane antigen [EMA], epithelial cell adhesion molecule [EpCAM], human epidermal growth factor receptor 2 [HER-2], urokinase plasminogen activator receptor, vascular endothelial growth factor-A [VEGF-A], and VEGF receptor 2). Immunohistochemistry was performed on tissue microarrays of LNM (n = 48), primary EACs (n = 62), fibrotic tissues (n = 11), nonmalignant lymph nodes (n = 24), and normal esophageal and gastric tissues (n = 40). Tumor marker staining was scored on intensity and percentage of positive cells. Results EMA and EpCAM showed strong expression in LNM (> 95%) and primary EACs (> 95%). Significant expression was also observed for LNM and EAC using VEGF-A (85 and 92%), CEA (68 and 54%), and CA-IX (4 and 34%). The other tumor biomarkers showed expression of 0-15% for LNM and primary EAC. Except for VEGF-A, nonmalignant lymph node staining was scored as slight or absent. Conclusions High expression rates and correlation between LNM in EAC combined with low expression rates in healthy lymph nodes and esophagus tissues were observed for EpCAM and CEA, meaning these are promising targets for tumortargeted imaging approaches for lymph nodes in patients with EAC. Key PointsThe use of intraoperative targeted imaging to detect lymph node metastases is promising and will be an important step forward in personalizing the surgical treatment of patients with esophageal cancer.The most suitable biomarker for targeted imaging techniques in lymph node metastases of esophageal adenocarcinoma remains unclear.Histological evaluation shows that epithelial cell adhesion molecule and carcinoembryonic antigen are suitable targets for image-guided esophageal surgery, both before and after neoadjuvant chemoradiotherapy.

Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma: New opportunities towards molecularly targeted therapy

“…In consistency with the high frequency of amplification, significant increase in VEGFA expression was found in tumor and peritumoral adipose tissue during the progression of normal squamous epithelium to EAC 76 , 77 . Elevated expression of VEGFA was also observed in lymph node metastases of EAC, indicating an important role in tumor metastasis 78 . Furthermore, VEGFA expression was significantly associated with poor prognosis, which supports the targeted-VEGFR therapy for EAC patients 79 .…”

NIR-II Navigation with an EGFR-Targeted Probe Improves Imaging Resolution and Sensitivity of Detecting Micrometastases in Esophageal Squamous Cell Carcinoma Xenograft Models

“…Among multiple IR800-labeled antibodies, bevacizumab-IR800 targeting VEGF-A is the first antibody probe used for imaging-guided endoscopic resection of esophageal adenocarcinoma . However, VEGF-A was also expressed in normal lymph nodes of esophageal cancer patients, which may reduce the specificity in imaging-guided lymphadenectomy . Herein, we consider that cetuximab-IR800 may have superiority over the VEGF probe for ESCC patients.…”

“…Bevacizumab-IR800, targeted to vascular endothelial growth factor-A (VEGF-A), for instance, has been used in endoscopic surgical resection of esophageal adenocarcinoma to determine the positive margin . However, the expression of VEGF-A in benign lymph nodes was almost on par with that of metastases, which may inhibit the differential diagnosis . Increasing evidence has shown that the expression rate of epidermal growth factor receptor (EGFR) is up to 60–80.9%, , indicating that probes targeting EGFR would be beneficial in the detection of ESCC.…”

Preoperative Clinical Characteristics Predict Recurrent Laryngeal Nerve Lymph Node Metastasis and Overall Survival in Esophageal Squamous Cell Carcinoma: A Retrospective Study With External Validation

“…The reason why it has differed from our result may be that they set CEA as categorical data with a cut-off of 5 ng/ml. Although no specialized literature has confirmed the relationship between CEA and RLN LNM, CEA was shown to be correlated with LNM ( 34 ). Tetsuro et al.…”