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DOI: 10.1055/s-0029-1244070
© Georg Thieme Verlag KG Stuttgart · New York
Endoscopic ultrasonography-guided biopsy for submucosal tumors: needless needling?
Publikationsverlauf
Publikationsdatum:
30. März 2010 (online)
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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 increases the cost.
Table 2 Diagnostic yield of endoscopic ultrasound-guided trucut biopsy (EUS-TCB) in patients with submucosal tumors*. Author, year (design) n EUS-TCB specimen adequate for: Histological diagnosis, % Histological diagnosis and immunostaining, % Fernández-Esparrach et al. 12, 2010 (prospective) 40 60 55 Polkowski et al. 9, 2009 (prospective) 49 78 63 Hoda et al. 5, 2009 (retrospective) 15 60 47 n, number of evaluated patients. *Most tumors evaluated in these studies were gastrointestinal stromal tumors of the stomach.
Another big disappointment is that specimens obtained with the trucut needle are too small to be used to determine the mitotic index reliably. This limitation precludes assessment of the malignant potential of GIST, which is one of the important factors guiding management decisions, together with unequivocally related symptoms such as bleeding [9] [12].
The study by Fernández-Esparrach et al. did not confirm the safety concerns raised in an earlier study that reported two septic complications among 52 EUS-TCB procedures performed for gastric SMTs [9]. Of note, however, is that in the current study, patients were monitored for only 24 hours after the procedure, and this period may not be long enough to allow detection of delayed complications [12]. The risk of tumor rupture and peritoneal spillage of GIST cells – a factor known to adversely affect survival after surgery [13] – has not been studied in the setting of EUS-guided biopsy.
To answer the question of the role of EUS-guided needle biopsy in the management of SMTs, several matters other than the limitations of the technique discussed above must be considered. It is essential to realize that the risk of malignancy associated with SMTs depends on tumor location, and is much higher for gastric tumors than for those involving the esophagus or duodenum [1]. The distinction between gastric and nongastric tumors is also important for another reason. Most of the data available on EUS-guided needle biopsy of SMTs is, in fact, on biopsies of gastric tumors, whereas data pertaining to other locations are scant (esophagus) or entirely lacking (duodenum, large bowel) [1]. Obviously, the focus is on tumors that appear hypoechoic on EUS, because those that are hyperechoic or cystic are generally believed to represent benign conditions – lipomas and duplication cysts, respectively. Finally, there is an accumulating body of evidence that the risk associated with small SMTs up to 2 cm in size is very low, although some of these (especially the gastric and hypoechoic ones) may represent small GISTs. The natural history of small GISTs has not been adequately studied; however, there is evidence to suggest that such lesions are more prevalent than previously thought, but that they only infrequently progress to clinically evident tumors [14] [15] [16]. The recognition of the very low risk associated with small GISTs recently led oncologists to accept guidelines where surveillance is a valid option for incidental tumors less than 2 cm in size [17] [18]. The very low chance that these lesions are malignant makes it unlikely that EUS-guided sampling will impact their management.
In view of the above data, it seems reasonable to focus the discussion on tumors that are located in the stomach, are hypoechoic, and are larger than 2 cm. Studies consistently show that when a SMT has these characteristics, there is about a 70 % – 75 % chance that it is a GIST [9] [11] [12]. Although most of these tumors have low mitotic activity, and thus very low malignant potential, some are mitotically active and pose a greater risk [9] [11] [17]. Ideally, the biopsy should be able to (i) establish the diagnosis (i. e., GIST vs. non-GIST), and (ii) identify the relatively rare GISTs with high mitotic activity. Because, as discussed earlier, the mitotic index cannot be determined on either EUS-FNA or EUS-TCB samples, the latter goal remains elusive. As far as the diagnosis is concerned, the biopsy results are quite predictable, even before the needle is thrust into the tumor, and have limited potential to impact patient management. In the majority of cases, the biopsy would either diagnose a tumor that requires surgical resection, or fail to provide a specimen adequate for diagnosis, which would be a reasonable indication for surgery as well. In the pooled data from three prospective studies including a total of 121 gastric tumors, the EUS-FNA- or EUS-TCB-based diagnosis was GIST in 59 % of cases, a suspected GIST (a mesenchymal tumor without further subclassification due to failed immunostaining) in 17 % of cases, and no diagnosis in 18 % of cases. In only 7 cases (6 %) did the biopsy diagnose a benign condition that could be left untreated (true leiomyoma or schwannoma) or a condition that required a treatment other than a wedge resection indicated for GIST (metastases to the stomach wall, an extragastric tumor invading the stomach from the outside) [9] [11] [12]. Whether these rare cases justify puncturing all gastric hypoechoic SMTs of 2 cm or larger remains questionable. It may be argued that the biopsy could be omitted in most cases and the patient be directly referred for wedge resection of the tumor – a relatively minor operation, safe for most patients, and which can be performed laparoscopically [19]. Following this line of reasoning, EUS-guided needle biopsy should be reserved for (i) poor surgical candidates, (ii) patients with tumors in surgically difficult areas such as the cardia, and (iii) patients with tumors that are deemed unresectable, for whom tissue diagnosis is required before commencing treatment with tyrosine kinase inhibitors [20]. Needle biopsy should also be considered whenever the endoscopic, endosonographic, or clinical presentation is not typical of a mesenchymal tumor and raises suspicion that the SMTs in question may be a metastasis, carcinoma, lymphoma, or tumor invading the stomach from the outside. Endoscopic forceps biopsies, although generally believed to be of little help, may provide a specimen adequate for diagnosis in some cases and should not be abandoned a priori.
As already mentioned, data on EUS-guided needle biopsy of nongastric SMTs are scant. Extrapolation to other sites of the results obtained in the stomach, although tempting, is not possible because of the site-specific dissimilarities in the pathological spectrum of SMTs and in the risk of malignancy. For instance, the risk of malignancy associated with esophageal SMTs is very low, about 1 %. Potentially malignant tumors such as GIST rarely involve the esophagus, and most hypoechoic esophageal SMTs are true leiomyomas with no malignant potential [1]. Thus, the indications for biopsy of esophageal tumors also seem to be limited to selected patients with large or otherwise suspicious tumors. Conclusions on duodenal and colorectal lesions are precluded by the paucity of data on these lesions in the EUS literature.
In summary, the available data do not support routine use of EUS-guided needle biopsy in most patients with SMTs, although the technique may be useful in selected cases, especially in patients with unresectable tumors or those at high operative risk. Factors that limit its usefulness include its moderate diagnostic yield, its inability to allow determination of the mitotic index, and its limited impact on management. The trucut needle does not seem to offer a significant advantage over standard FNA needles. Efforts should be aimed at better specimen processing and handling to minimize problems with immunostaining, improvements in trucut needle design, and, last but not least, defining molecular markers of GISTs with high malignant potential that could be applied to samples from needle biopsy.
Competing interests: None
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M. PolkowskiMD
Department of Gastroenterology
M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Roentgena 5
02-781 Warsaw
Poland
Fax: +48-22-5463035
eMail: m.polkowski@coi.waw.pl