Methylation Assessment for the Prediction of Malignancy in Mediastinal Adenopathies Obtained by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Patients with Lung Cancer.

Virginia Leiro-Fernandez,Loretta De Chiara,Diana Valverde,Manuel Núñez-Delgado,Mar Rodríguez-Girondo,Alberto Fernández-Villar,Maribel Botana-Rial

doi:10.3390/cancers11101408

Abstract

The evaluation of mediastinal lymph nodes is critical for the correct staging of patients with lung cancer (LC). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique for mediastinal staging, though unfortunately lymph node micrometastasis is often missed by cytological analysis. The aim of this study was to evaluate the predictive capacity of methylation biomarkers and provide a classification rule for predicting malignancy in false negative EBUS-TBNA samples. The study included 112 patients with a new or suspected diagnosis of LC that were referred to EBUS-TBNA. Methylation of p16/INK4a, MGMT, SHOX2, E-cadherin, DLEC1, and RASSF1A was quantified by nested methylation-specific qPCR in 218 EBUS-TBNA lymph node samples. Cross-validated linear regression models were evaluated to predict malignancy. According to EBUS-TBNA and final diagnosis, 90 samples were true positives for malignancy, 110 were true negatives, and 18 were false negatives. MGMT, SHOX2, and E-cadherin were the methylation markers that better predicted malignancy. The model including sex, age, short axis diameter and standard uptake value of adenopathy, and SHOX2 showed 82.7% cross-validated sensitivity and 82.4% specificity for the detection of malignant lymphadenopathies among negative cytology samples. Our results suggest that the predictive model approach proposed can complement EBUS-TBNA for mediastinal staging.

Highlights

Lung cancer (LC) is the leading cause of cancer death worldwide [1]
Sampling of mediastinal lymph nodes with these procedures associates with reduced morbidity compared to surgical biopsy, which is the current gold-standard for mediastinal lymph node staging [6]
It has been demonstrated that samples obtained with EBUS-TBNA are adequate for accurate characterization of cytopathology and molecular testing, including methylation biomarkers, and can have a role in diagnosis, prognosis, and response to chemotherapy [7,8,9,10,11,12]

Summary

Introduction

Lung cancer (LC) is the leading cause of cancer death worldwide [1]. Approximately 80% of the cases are non-small cell lung cancer (NSCLC), with lung adenocarcinoma being the most prevalent type. Correct mediastinal and hilar staging is critical for choosing the best option for management. Cancers 2019, 11, 1408 and treatment of patients with NSCLC who are potential candidates of curative therapeutic strategies that include surgery, radiotherapy, chemotherapy and multimodal treatments [2,3]. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) are minimally invasive techniques that have shown high diagnostic value for mediastinal staging in patients with LC [4,5]. It has been demonstrated that samples obtained with EBUS-TBNA are adequate for accurate characterization of cytopathology and molecular testing, including methylation biomarkers, and can have a role in diagnosis, prognosis, and response to chemotherapy [7,8,9,10,11,12]

Objectives

Methods

Results