Contrast-enhanced harmonic EUS (CH-EUS) has achieved large interest in the detection and characterization of pancreatic neoplasms. We read the manuscript by Ishikawa et al. about CH-EUS in the evaluation of pancreatic neuroendocrine neoplasms (PanNENs). 1 They enrolled 47 patients with newly-diagnosed PanNENs, comparing CH-EUS to computed tomography (CT) and histology. The tumors were classified as either aggressive or non-aggressive according to pathological or biological features. CH-EUS proved to be superior to CT in the diagnosis of aggressive PanNENs in terms of sensitivity and accuracy (94.7% vs 17.6% and 97.9% vs 66.7%, respectively) with the same specificity (100%).Conservative management of small (<2 cm), non-functional G1-G2 PanNENs is currently advised. 2 However, Ishikawa et al. showed that even small low-grade PanNENs can develop aggressive behavior. Surprisingly, 7/47 (14.9%) low-grade and 11/47 (23.4%) small neoplasms had a malignant course. Of note, 18/19 (94.7%) aggressive PanNENs showed a hypo-enhancement pattern in the late phase at CH-EUS.Hypo-enhancement of a pancreatic lesion at CH-EUS should always raise the suspicion of malignancy. 3 On the other hand, hyper-enhancement is a strong predictor of a diagnosis different from adenocarcinoma and is often related to PanNENs. Other hyper-enhanced lesions are massforming pancreatitis and metastases from kidney cancer and from hematologic malignancies. 4 In Ishikawa et al. study, histopathological examination revealed that aggressive PanNENs had higher percentage of fibrosis indicators and smaller vessel area than non-aggressive ones, explaining their hypo-enhancement.Tissue acquisition, together with patients' medical history, is still pivotal for the diagnosis of pancreatic tumors. However, since histological grading of PanNENs is not strongly predictive of their favorable course, we usually rely on suboptimal parameters such as Ki67 and size. The present study corroborates previous findings to maintain that CH-EUS should always be combined to EUS-tissue sampling and CT to obtain as much information as possible in PanNENs patients. 5 Authors declare no conflict of interest for this article.