Despite their similar endoscopic appearances, submucosal tumors (SMTs) may differ substantially as to their nature and malignant potential. Overtly malignant tumors are relatively rare; potentially malignant ones are a much more common problem. The spectrum of malignancies is dominated by gastrointestinal stromal tumors (GISTs); however, other less common malignant conditions presenting as SMTs are also described, including malignant lymphoma, metastases to the wall of the gastrointestinal tract, and, surprisingly enough, primary adenocarcinoma [ 1 ]. Because endoscopic forceps biopsies usually fail to provide specimens adequate for diagnosis [ 2 ] [ 3 ] [ 4 ] [ 5 ], there is a persistent interest in endoscopic ultrasound (EUS)-guided needle biopsy, performed either with a standard aspiration needle (fine-needle aspiration, FNA) or a special cutting device (trucut biopsy, TCB). Recently, several publications on this topic have appeared [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ], and this issue of Endoscopy contains two more. Philipper et al. present EUS-FNA results obtained in a group of 47 patients, 12 with esophageal, 32 with gastric, and 3 with duodenal SMTs [ 11 ], and Fernández-Esparrach et al. report on a study conducted in 40 patients with gastric hypoechoic tumors 2 cm or more in size [ 12 ]. Both studies stand out because of their prospective design; an additional advantage of the latter study is that it was the first to directly compare the diagnostic yield of EUS-FNA and EUS-TCB in the setting of SMTs. Despite the different methods used to ensure specimen adequacy – an immediate microscopic assessment by a cytologist present on site [ 12 ], or simply a macroscopic visual inspection by the endoscopist performing EUS-FNA [ 11 ] – the proportion of patients from whom EUS-FNA provided tumor cells for cytological evaluation was similar in both studies. The results obtained, 70 % and 74 %, respectively, were also similar to those reported by other authors ([ Table 1 ]) [ 5 ] [ 8 ] [ 10 ]. Table 1 Diagnostic yield of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in patients with submucosal tumors*. Author, year (design) n EUS-FNA specimen adequate for: Cytological diagnosis, % Cytological diagnosis and immunostaining, % Philipper et al. 11, 2010 (prospective) 47 74 34 Fernández-Esparrach et al. 12, 2010 (prospective) 40 70 53 Hoda et al. 5, 2009 (retrospective) 112 84 62 Sepe et al. 10, 2009 (retrospective) 37 78 n. d. Akahoshi et al. 8, 2007 (prospective) 53 79 79 n, number of evaluated patients; n. d., no data. * Studies including more than 25 patients that were published after 2000. Most tumors evaluated in these studies were gastrointestinal stromal tumors of the stomach. Of note, all but two tumors in which EUS-FNA provided an adequate specimen were of mesenchymal origin. The underrepresentation of nonmesenchymal tumors among the SMTs being sampled (and even more so among those being successfully sampled) is common to all studies on this subject [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ]. As a result, knowledge of the capabilities of EUS-FNA in this particular group remains rudimentary. On the other hand, the huge predominance of mesenchymal tumors requires us to shift the focus of the cytological assessment from cytomorphological features, which cannot differentiate GISTs from other types of mesenchymal tumors, to immunocytochemical assays, which are key in establishing a specific diagnosis. Unfortunately, both studies discussed indicate that immunostaining of EUS-FNA samples from SMTs frequently fails, which has a negative effect on the diagnostic yield of this technique: when samples with unsatisfactory immunostaining are considered nondiagnostic, the diagnostic yield drops from 70 % – 74 % to 53 % [ 12 ] or even 34 % [ 11 ]. It may be hypothesized that the unusually high failure rate of immunostaining in the latter study might have been the result of performing the assays on de-stained Papanicolaou smears rather than the cell blocks preferred at most centers [ 5 ] [ 7 ] [ 8 ] [ 12 ]. The good news among the bad is that, in cases where immunostaining was successful, the EUS-FNA diagnosis was in all cases consistent with the final diagnosis based on surgical pathology [ 11 ] [ 12 ]. There is also evidence to suggest that the problems with immunostaining encountered by most investigators [ 5 ] [ 7 ] [ 11 ] [ 12 ] are not inevitable and can be minimized [ 8 ]. The problems with immunostaining along with another important limitation of the cytological specimens – the lack of capability to determine the mitotic index and hence the malignant potential of GISTs – were the reasons why the introduction of the trucut needle a few years ago was seen as an important advancement [ 9 ]. It seems, however, that the initial optimism must be tempered with the rather disappointing results of recent studies ([ Table 2 ]) [ 5 ] [ 9 ] [ 12 ]. The diagnostic yield of EUS-TCB reported from these studies was moderate (ranging from 47 % to 63 %) and, as shown in the head-to-head comparison by Fernández-Esparrach et al. published in this issue of Endoscopy, no better than that of EUS-FNA (55 % vs. 53 %, P > 0.05) [ 12 ]. Although problems with immunostaining were less common with EUS-TCB samples than with EUS-FNA samples, the technical failures, which were very rare with EUS-FNA, occurred frequently with trucut (in 40 % of cases) [ 12 ]. The trucut device is relatively stiff and very sensitive to bending; as a result, it is likely to fail to obtain tissue whenever the tumor location requires scope angulation and/or elevator use during the puncture. Combining EUS-TCB and EUS-FNA significantly improves the diagnostic yield when compared with either technique alone (77 % vs. 55 % and 53 %, respectively; P < 0.05 for both comparisons) [ 12 ], but also...