Accurate Classification of Non-small Cell Lung Cancer (NSCLC) Pathology and Mapping of EGFR Mutation Spatial Distribution by Ambient Mass Spectrometry Imaging.

Min Zhang,Fan Yang,Xiaofei Li,Chuanhao Tang,Qunfeng Ma,Xiaoqing Liu,Hao Xing,Tiegang Li,Jun Wang,Zeper Abliz,Haixu Hu,Jiuming He,Bing Liu

doi:10.3389/fonc.2019.00804

Abstract

Objectives: Tumor pathology examination especially epidermal growth factor receptor (EGFR) mutations molecular testing has been integral part of lung cancer clinical practices. However, the EGFR mutations spatial distribution characteristics remains poorly investigated, which is critical to tumor heterogeneity analysis and precision diagnosis. Here, we conducted an exploratory study for label-free lung cancer pathology diagnosis and mapping of EGFR mutation spatial distribution using ambient mass spectrometry imaging (MSI).Materials and Methods: MSI analysis were performed in 55 post-operative non-small cell lung cancer (NSCLC) tumor and paired normal tissues to distinguish tumor from normal and classify pathology. We then compared diagnostic sensitivity of MSI and ADx-amplification refractory mutation system (ARMS) for the detection of EGFR mutation in pathological confirmed lung adenocarcinoma (AC) and explored EGFR mutations associated biomarkers to depict EGFR spatial distribution base on ambient MSI.Results: Of 55 pathological confirmed NSCLC, MSI achieved a diagnostic sensitivity of 85.2% (23/27) and 82.1% (23/28) for AC and squamous cell carcinoma (SCC), respectively. Among 27 AC, there were 17 EGFR-wild-type and 10 EGFR-mutated-positive samples detected by ARMS, and MSI achieved a diagnostic sensitivity of 82.3% (14/17) and 80% (8/10) for these two groups. Several phospholipids were specially enriched in AC compared with SCC tissues, with the higher ions intensity of phospholipids in EGFR-mutated-positive compared with EGFR-wild-type AC tissues. We also found EGFR mutations distribution was heterogeneous in different regions of same tumor by multi-regions ARMS detection, and only the regions with higher ions intensity of phospholipids were EGFR-mutated-positive.Conclusion: MSI method could accurately distinguish tumor pathology and subtypes, and phospholipids were reliable EGFR mutations associated biomarkers, phospholipids imaging could intuitively visualize EGFR mutations spatial distribution, may facilitate our understanding of tumor heterogeneity.

Highlights

Lung cancer is a highly heterogeneous malignant epithelial tumor with distinct pathological features and clinical behavior [1]
Of 55 pathological confirmed non-small cell lung cancer (NSCLC), mass spectrometry imaging (MSI) achieved a diagnostic sensitivity of 85.2% (23/27) and 82.1% (23/28) for AC and squamous cell carcinoma (SCC), respectively
Among 27 AC, there were 17 Epidermal growth factor receptor (EGFR)-wild-type and 10 EGFR-mutated-positive samples detected by amplification refractory mutation system (ARMS), and MSI achieved a diagnostic sensitivity of 82.3% (14/17) and 80% (8/10) for these two groups

Summary

Introduction

Lung cancer is a highly heterogeneous malignant epithelial tumor with distinct pathological features and clinical behavior [1]. It can be routinely classified into non-small cell lung cancer (NSCLC) and small cell lung cancer according to histopathology, with NSCLC accounts for 85% of cases. The clinical treatment program decisions in lung cancer always depended largely on accurate classification of tumor types and subtypes. Advance in molecular diagnostic technology and deep study of tumor biology, NSCLC are found to have diverse molecular subtypes according to lung cancer-specific driver oncogenes [2,3,4,5]. Accurate molecular pathology testing especially EGFR mutations detection has been an expert consensus in lung cancer clinical practice [11]

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