In day-to-day clinical practice, oncologists often face the problem of how to manage patients whose mediastinal lymph nodes have increased in size. The diagnostic accuracy of lymph nodes is a general problem given that lymph nodes larger than 0.5–1 cm are not essentially affected by cancer and, in contrast, smaller lymph nodes may contain micrometastatic disease. In practice, preoperative treatment staging with endoscopic ultrasound (EUS), computed tomography, and positron emission tomography is associated with modest predictive accuracy, and pretreatment staging without histopathological examination of surgical specimen is inappropriate. In specialized hospitals with a high volume of endoscopic ultrasound-guided fine-needle aspiration (EUSFNA) performed, positive results in assessing mediastinal lymphadenopathy have been reported. Whether this approach can be a valuable diagnostic tool in low-volume EUS-FNA hospital is still unclear. To assess the safety, diagnostic accuracy, and costs of EUS-FNA in low-volume EUS centers (\50 mediastinal EUS-FNA/endoscopist/ year), Hirdes et al. [1] performed a study that was reported in the September issue of Surgical Endoscopy. The authors report the results of 213 consecutive patients who were referred to two Dutch endoscopy centers for mediastinal lymphadenopathy and who underwent EUS-FNA between 2002 and 2008. Sensitivity and specificity were 89 and 100%, respectively. Overall, EUS-FNA had a positive impact on the clinical management of 84% of cases by either influencing the surgical decision made or excluding malignant lymphadenopathy. In two patients a nonfatal perforation was occurred (0.9%). The authors concluded that mediastinal EUS-FNA can be performed safely and effectively in low-volume EUS centers. Although this was a retrospective study whose results were not compared with those of a high-volume EUS-FNA center and it did not include a control group whose members did not undergo EUS-FNA, sensitivity and specificity rates, the impact on treatment decisions for patients with mediastinal lymphadenopathy, and the risk associated with EUS-FNA were very positive. How could sensitivity and specificity be improved and how realistic is it to achieve accurate diagnostics without using an invasive method such as EUS-FNA? Could biomarkers be used to accurately distinguish between inflammatory and malignant disease?