Submucosal lesions

Gastrointest Endoscopy Clin N Am 15 (2005) 33 – 54

Submucosal lesions Marcin Polkowski, MD, PhD*, Eugeniusz Butruk, MD, PhD Department of Gastroenterology, Medical Center for Postgraduate Education, Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland

The term ‘‘submucosal lesion’’ (SML) encompasses a variety of neoplastic and non-neoplastic conditions arising from deeper layers of the wall of the gastrointestinal (GI) tract, (ie, from the muscularis propria, submucosa, or muscularis mucosae). The overlaying mucosa is not involved; however, it may be ulcerated or inflamed. Terms such as submucosal, subepithelial, or intramural tumors, lesions, or masses are used interchangeably. SMLs are usually asymptomatic and detected incidentally on endoscopic or radiologic examinations performed for unrelated reasons; symptoms attributable to lesions, including bleeding, dysphagia, or obstruction, are present in the minority of cases [1,2]. The prevalence of SMLs has not been thoroughly studied. According to a retrospective study addressing this issue, abnormalities suggesting gastric SMLs are encountered in 0.36% of routine endoscopies [3]. The mean case volume at seven endoscopic ultrasonography (EUS) centers in various countries ranged from 4.5 to 23 gastric SMLs per year, with a weighted average of eight cases [4–10]. Esophageal and duodenal SMLs were less common (an average of 4 and 2.8 cases per center per year, respectively) [6,8,11].

Differentiation of submucosal lesions and extraluminal compressions The protrusion of the GI wall covered by normal mucosa, a picture characteristic for submucosal lesion, can also be caused by organs or structures compressing the wall from outside the (extraluminal or extrinsic compression [EC]). The relative frequencies of ECs and SMLs in 11 endosonographic series, in-

* Corresponding author. E-mail address: [email protected] (M. Polkowski). 1052-5157/05/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.giec.2004.07.005

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cluding a total of 1181 predominantly gastric lesions, were 29% and 71%, respectively [1,4,5,7,9,12–17]. The differentiation between an SML and an EC is important for patient management. Although a variety of pathologic conditions have been identified as a cause of EC, it is a normal or nearly normal organ that compresses the wall in the majority of cases (Table 1) [1,5,7,9,12,14–16]. In such a situation, the diagnostic process can be finished and the patient reassured. By contrast, a ‘‘true’’ SML usually necessitates surveillance or treatment. It is generally accepted that EUS is nearly 100% accurate in differentiating between ECs and SMLs and that this method offers advantages over endoscopy, CT, transabdominal ultrasound, or upper GI series [7,14,18]. The accuracy reported for endoscopy in this setting is low (39% to 69%), and the most common error consists in the misclassification of ECs as SMLs [1,12,18]. In the prospective multicenter study by Rfsch et al [1], endoscopic examination led to a correct diagnosis in only 14 of 48 (29%) patients with EC. The evidence to support EUS superiority comes from studies using EUS as the reference standard for EC diagnosis, and this may have biased the results toward EUS accuracy. Because the EUS diagnoses of compression caused by a normal organ were not verified surgically, some false results (innocent EC on EUS, which is a SML or other clinically significant pathology) cannot be excluded. Cases of submucosal tumors misdiagnosed as extramural structures were described [17,19]. The errors were attributed to the nonvisualization of the thin stalk-like connection of the tumor to the wall on EUS. Nevertheless, because similar cases seem to be rare, it can be assumed that EUS diagnosis of EC is accurate.

Table 1 Causes of extraluminal compression of the wall of the upper GI tract Cause of compression Liver Spleen Blood vessels Gallbladder Pancreas Bowel Retroperitoneum, omentum Enlarged lymph nodes Kidney Others Total

Normal organ or structure 34 48 28 30 10 8 0 0 2 4 164 (69%)

Benign conditionsa 16 6 6 2 7 0 1 0 2 3 43 (18%)

Malignant conditions 6 1 0 0 8 1 5 5 0 6 32 (13%)

Total 56 55 34 32 25 9 6 5 4 13

(23%) (23%) (14%) (13%) (10%) (4%) (3%) (2%) (2%) (5%)

239 (100%)

Figures denote numbers of patients. a Liver cyst (12), liver hemangioma (4), splenic cyst (5), splenomegaly (1), aneurysm of the left renal artery (2) or splenic artery (1), collateral vessels (3), enlarged gallbladder (2), pancreatic pseudocyst (6), pancreatic cystadenoma (1), benign tumor of the retroperitoneum (1), renal cyst (2), bronchogenic cyst (1), adrenal cyst (1), pericardial effusion (1). Data from [1,5,7,9,12–16].

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submucosal lesions

Conditions presenting as submucosal lesions The list of conditions that present as SML is long (Table 2); however, one category predominates: 53% of lesions encountered in 13 EUS series were tumors referred to as GI smooth muscle neoplasms and, more specifically, as leiomyomas, leiomyoblastomas, or leiomyosarcomas [4–6,8,11–13,15,20–24]. In the esophagus and stomach, they made up 77% and 54% of all SMLs, respectively, and far outnumbered other types: granular cell tumors and lymph- or hemangiomas in the esophagus, and heterotopic pancreas, cystic lesions, and lipomas in the stomach (Table 2). In the duodenum, the smooth muscle neoplasms were less common and constituted only 17% of SMLs, a frequency similar to cystic lesions, Brunner’s gland hyperplasia, carcinoids, and lipomas. The most common SMLs of the large bowel were carcinoids, followed by lipomas and lymph- or hemangiomas; smooth muscle neoplasms were relatively rare in this location (14%) [4–6,8,11–13,15,20–24]. The studies that provided data for this analysis antedated recent changes in the classification of GI mesenchymal tumors and did not include the category of gastrointestinal stromal tumor (GIST). Table 2 Relative frequency of various types of GI submucosal lesions (only lesions with pathologic verification were included) Esophagus

Stomach

Smooth muscle neoplasma Heterotopic pancreas Carcinoid Lipoma Cystic lesionb Granular cell tumor Lymph-, hemangioma Brunner’s gland hyperplasia Malignant lymphoma Other lesionsc

109 (77%)

176 (54%)

1 (1%) 3 (2%)

5 (2%) 32 (10%)

1 (2%) 3 (7%)

1 (2%) 9 (14%)

8 (1%) 47 (8%)

Total

141 (100%)

325 (100%)

42 (100%)

63 (100%)

571 (100%)

0 0 1 2 18 7 0

(1%) (1%) (13%) (5%)

52 9 17 28 2 4 0

(16%) (3%) (5%) (9%) (1%) (1%)

Duodenum 7 (17%) 1 7 6 8 0 1 8

(2%) (17%) (14%) (19%) (2%) (19%)

Colon, rectum 9 (14%) 0 27 (43%) 9 (14%) 0 0 8 (13%) 0

Total 301 (53%) 53 43 33 38 20 20 8

(9%) (8%) (6%) (7%) (4%) (4%) (1%)

Figures denote numbers of patients. a Predominantly leiomyomas, rare cases of leiomyoblastomas, and leiomyosarcomas. Studies that provided data for this table antedated recent changes in the classification of GI mesenchymal tumors and did not include the category of gastrointestinal stromal tumor (GIST). According to current criteria, the majority of tumors formerly diagnosed as smooth muscle neoplasms are GISTs, whereas true smooth muscle neoplasms are rare. Only in the esophagus are true leiomyomas the most common type. b Twelve of 28 cystic lesions in the stomach were not verified pathologically. c In the esophagus: fibroma, fibrovascular polyp. In the stomach: carcinoma, fibroma, fibrovascular polyp, granuloma, inflammatory fibroid polyp, intramural metastasis, schwannoma, varix. In the doudenum: adenoma, early carnicoma, fibrovascular polyp, epithelial polyp, malignant lymphoma. In the colon: endometriosis, suture granuloma, unclassified. Data from [4–6,8,11–13,15,20–24].

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According to current criteria, the majority of tumors formerly diagnosed as smooth muscle neoplasms are GISTs, whereas true smooth muscle neoplasms are rare (see below). Although various types of SMLs listed in Table 2 differ in EUS characteristics, a definite diagnosis cannot be made on the basis of EUS image alone. In two series including a total of 123 SMLs, the EUS and pathologic diagnosis matched only in 77% of cases [17,21]. Nevertheless, describing EUS features of a lesion, such as its size, layer or origin, echopattern, and borders, may narrow down the list of conditions taken into account in the differential diagnosis. The most comprehensive description of EUS features of various SMLs in a series of 109 consecutive cases with pathologic verification was published by Kawamoto et al [8]. Many case series devoted to specific types of SMLs provide detailed descriptions of EUS characteristic of Brunner’s gland hamartomas [25], carcinoids [26], cystic lesions [27,28], endometriosis [29], gastric varices [30], granular cell tumors [31], heterotopic pancreas [32,33], inflammatory fibroid polyps [34], lymphangiomas [35], and stromal tumors [36–38].

Differentiation between benign and malignant submucosal lesions One of the most important reasons for performing EUS in patients with SMLs is to assess the risk of malignancy and to guide management. Most of the SMLs encountered on endoscopy or endosonography are benign; however, the fact that some of them may be malignant influences the attitude toward the whole group. The proportion of malignant lesions reported in 18 EUS or endoscopic studies varied between 0% and 27%, with a weighted average of 12% in a collective material of 829 lesions (Table 3) [1,4–6,8,11–13,15,20–24,36,37,39,40]. A further 10% of the tumors were classified as borderline or of indeterminate malignant potential; the remaining 78% were benign. Because these results concern only lesions verified pathologically, they probably overestimate the real Table 3 Relative frequency of benign and malignant submucosal lesions in the upper GI tract and in the large bowel (only lesions with pathologic verification were included) Benign lesions

Lesions of indeterminate malignant potentiala

Malignant lesions

Total

Esophagus Stomach Duodenum Colon, rectum GIb

151 296 33 33 132

0 22 7 27 31

2 57 2 5 31

153 375 42 65 194

Total

645 (78%)

a

(99%) (79%) (79%) (51%) (68%)

(6%) (17%) (42%) (16%)

87 (10%)

(1%) (15%) (5%) (8%) (16%)

97 (12%)

(100%) (100%) (100%) (100%) (100%)

829 (100%)

Forty-four stromal tumors of indeterminate malignant potential and 43 carcinoids (all carcinoids were arbitrarily included in this group). b Precise location not specified. Data from [1,4–6,8,11–13,15,20–24,36,37,39,40].

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prevalence of malignancy expected in the unselected SML population (larger, symptomatic, or otherwise suspicious tumors are more likely to undergo resection and verification, and this selection may bias the results toward a higher malignancy rate). Lesions verified pathologically made up 73% of all SMLs included in the discussed studies. Assuming that the vast majority of the remaining 27% were benign, the malignancy rate in the whole group would be about 8.5% (plus a further 7.5% of tumors of indeterminate malignant potential).

Gastrointestinal stromal tumor revolution The robustness of these data is challenged by recent changes in the pathologic classification of GI mesenchymal tumors. The changes focused on tumors traditionally called ‘‘smooth muscle neoplasms,’’ a category into which about a half of all SMLs fall. The majority of these tumors are currently classified as GISTs, and this group comprises most of the lesions that were formerly diagnosed as leiomyomas and virtually all leiomyoblastomas and leiomyosarcomas. The true smooth muscle neoplasms are considered rare. Only in the esophagus are true leiomyomas the most common type, whereas GISTs predominate in the stomach and intestine [41–43]. The definition and differential diagnosis of GISTs and their clinical and histologic features have been reviewed elsewhere [41–43] and are beyond the scope of this article. However, some fundamental facts about GISTs have to be emphasized because they potentially affect the role of EUS in the management of patients with SMLs. The following points are based mainly on recent state-of-the art reviews [42,43] and on the ‘‘Consensus Approach’’ developed at a GIST workshop convened by NIH in April 2001 [41]. 1. GISTs are defined as cellular spindle cell, epithelioid, or occasionally pleomorphic mesenchymal tumors of the GI tract that express receptor tyrosine kinease (KIT) as detected using immunohistochemistry (CD117) [41,43]. 2. The clinical spectrum of GIST spans from small, benign nodules, discovered incidentally on surgery or endoscopy, to overt sarcomas. It remains unclear whether the small GISTs are precursors to sarcomas or represent a biologically indolent subset of GISTs [41,43]. 3. The behavior of a given GIST is difficult to predict unless the tumor metastasizes or recurs after resection. Definite terms such as benign or malignant are avoided and replaced by ‘‘the risk of aggressive behavior.’’ The criteria for low, intermediate, or high risk are based on the combination of tumor size and mitotic activity [41]. 4. The risk determined using this approach is a relative risk. For unknown reasons there is a subset of GISTs that shows unpredictable behavior: Even a tumor labeled as low risk may occasionally metastasize, sometimes with a delay of many years. There are no precise data on how big this un-

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predictable group is; hopefully, no more than 10% behave in this way [41]. This is a rather small proportion; however, pathologists are increasingly reluctant to use the term benign for any GIST [41]. The knowledge about GISTs will probably continue to develop rapidly, and this development is likely to influence the future role of EUS in the management of SMLs. The most important questions in this setting are the following: Can GISTs be diagnosed reliably using EUS and EUS-guided needle biopsy? If so, are these methods capable of assessing the risk of malignant behavior? Should every GIST be resected, regardless of its size and other features? On the other hand, the changing classifications and definitions pose difficulties with the interpretation of older data. Only a few EUS studies postdated the GIST revolution and adopted the current terminology.

Endosonographic features predictive of malignancy Several endosonographic features of SMLs associated with an increased risk for malignancy have been identified retrospectively [17,36,37] and evaluated in prospective studies [1,40,44]. Among them, tumor size exceeding 30 mm or 40 mm (depending on the study) and tumor irregular margins seem to be the most important. Their prognostic significance was confirmed in the majority of studies in univariate [17,37] or multivariate analysis [36,40]. There is less agreement on the value of other features that were found to be associated with the risk of malignancy in some studies, whereas others did not confirm or did not evaluated their significance. This group includes echogenic foci [36], cystic spaces [36,37], heterogeneous echotexture [17], lymph nodes with malignant pattern [37], exophytic development [37], ulcerated mucosa [40], and nonround or non-oval shape [40]. The prospective multicenter study by Rfsch et al [1] failed to confirm any significant relationship between the presence or absence of a single feature and the risk of malignancy. The discrepant results may be due to the relatively small sample sizes evaluated or to different inclusion criteria and statistical methods; however, the most significant confounding factor is probably the interobserver variation in the interpretation of EUS image. Chak et al [36] showed that the agreement for the presence or absence of a given EUS feature between different pairs of experts varies widely. The agreement for a panel of five experts, measured by a mean kappa value for all possible expert pairs, was poor for echogenicity (k = 0.12), irregular luminal border (k = 0.16), presence of cystic spaces (k = 0.28), and echogenic foci (k = 0.39); it was fair for irregular extraluminal border (k = 0.43) and for heterogeneity (k = 0.47). Another study evaluating interobserver agreement for the EUS diagnosis of various SMLs indicated that the agreement was excellent for extraluminal compression (k = 0.94) and cystic lesions (k = 0.8), good for lipoma (k = 0.65), and fair or poor for other types of lesions (k = 0.34–0.54). In addition, the endosonographer’s experience seemed to play an important role in the accuracy of the method [45].

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Because none of the single EUS features is characterized by both high sensitivity and specificity [1,37,44], more complex criteria involving combinations of features have been developed to predict malignancy more accurately (Table 4). These models, created using stepwise ROC analysis [40] or other (unspecified) methods [1,17, 36,37,44], were rarely evaluated in a prospective data set [1,44]. Nevertheless, one may assume that if they were used as a guide for management, it would result in removing 64% to 100% of malignant tumors with an acceptable rate of unnecessary surgery for benign lesions (12% to 23%) (Table 4) [1,17,37,40,44]. Nickl et al [40] estimated that 45% of all hypoechoic intramural tumors would undergo surgery if their model were applied. Some of the studies dealt exclusively [36,37,44] or predominantly [40] with mesenchymal tumors originating from the muscle layer, whereas others included SMLs of all kinds [1,17].

Table 4 Endosonography for the prediction of malignancy in patients with submucosal lesions of the upper GI tract Author, year, type of analysis, [reference] Chak et al, 1997, retro [36]a

Palazzo et al, 2000, retro [37]a Brand et al, 2002, retro [17] Rfsch et al, 2002, prosp [1]

Nickl et al, 2002, retro [40]b

Ando et al, 2003, prosp [44]a

EUS features predictive of malignancy Irregular extraluminal border Cystic spaces N 4 mm Echogenic foci N 3 mm Irregular margins Cystic spaces LN with malignant pattern Tumor size N 30 mm Irregular margins Heterogeneous echotexture Tumor size N 30 mm Inhomogeneous echopattern Irregular outer border Presence of LN N 10 mm Tumor size N 30 mm Irregular margins Ulcerated mucosa Shape not oval/round Abnormal regional LN Tumor size N 50 mm Irregular borders Cystic spaces

Criteria for diagnosis of malignancy

Sensitivity for detecting malignancy

Specificity for detecting malignancy

 2 features present

80 –90% (8–9/10)c

No data

 1 feature present

91% (20/22)d

88% (30/34)d

2 features present

80% (16/20)

77% (51/66)

 2 features present

64% (7/11)

80% (24/30)

 1 feature present

100% (11/11)

No data

Size N 50 mm plus one or both other features

83% (5/6)

76% (13/17)

Abbreviations: LN, lymph nodes; prosp, prospective; retro, retrospective. a Only mesenchymal tumors originating from the muscle layer were included. b Only hypoechoic tumors were included. c Results for five different EUS experts. d Malignant and borderline tumors were pooled together as potentially malignant.

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Recently, Hunt et al [38] compared retrospectively EUS features of CD117positive and CD117-negative mesenchymal tumors and found that tumors displaying size N 40 mm, mucosal ulceration, or cystic spaces were more likely to be GISTs than CD117-negative spindle cell tumors [38]. Although the specificity of these criteria for GIST diagnosis was high (92%), the model had a rather low sensitivity (65%). Similar results (sensitivity of 95% and specificity of 72%) were achieved by Brand et al [17]; however, the criteria applied in their prospective series were less complex: Every hypoechoic lesion that did not originate from submucosa was diagnosed as GIST (it is unclear if pathologic assessment in this study included immunostaining).

Endosonography–guided (–assisted) tissue acquisition EUS is an improvement on the imaging of SMLs; nevertheless, tissue is required for definite diagnosis. However precise EUS is, it cannot replace histology. Unfortunately, material adequate for histologic assessment cannot be easily obtained from SMLs. Standard endoscopic forceps biopsies taken from the surface of the lesion are too superficial and usually fail to provide material other than normal mucosa [23,46]. This is why special methods have been developed, such as bite-on-bite jumbo biopsy [46] or biopsy after exposure of the tumor surface by ethanol injection into overlaying mucosa or by mucosectomy [21]. These techniques, however, have never become popular. By contrast, their EUS-based alternatives, including EUS-guided needle biopsy and EUS-assisted endoscopic removal of the entire lesion, are used increasingly often. Endosonography–guided needle biopsy Before EUS-guided fine needle aspiration (EUS-FNA) became available, Caletti et al [39] reported a series of 21 gastric submucosal tumors sampled with a guillotine needle under endoscopic control. EUS was performed in this series before the puncture to confirm that the lesion targeted was a solid intramural tumor. Although this technique proved to be effective (correct diagnosis in 19 of 21 tumors, including three malignant lesions) and safe (no serious complications), the needle used was a prototype that has never become commercially available. As a result, no subsequent study reported on its use. Wiersema et al [47] used similar technique (EUS assessment followed by puncture under endoscopic control) to obtain cytologic specimens from 25 SMLs with a transbronchial needle. The diagnostic yield of FNA in this series was 64%. Because the diagnosis was verified histologically in only seven cases, no conclusions can be drawn as to the accuracy of the method for detection of malignancy. No complications were observed. A natural consequence of introducing real-time, EUS-guided FNA in the early 1990s was the use of this technique to sample submucosal lesions. The results were reported in articles dealing exclusively with the puncture of SMLs

submucosal lesions

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[38,44,48–51] or in studies summarizing large, heterogeneous materials in which SMLs made up only a small subset of lesions punctured [52–55]. Various types of needles, 21 to 25 Gauge (G) in diameter, were used to perform aspiration biopsies yielding cytologic or histologic (core tissue) specimens (Table 5). The number of needle passes ranged from one to seven, with reported averages of three to four passes. No serious complications were described. The adequacy of the specimen was ensured by immediate on-site cytologic examination [38,49,51,54] or by performing repeated punctures until a core specimen was obtained [44]. It remains unclear why one group from Japan [44,48] was able to collect exclusively core tissue samples, whereas others, using apparently similar equipment and aspiration technique, obtained ‘‘only’’ cytologic material [47,49–55]. Recently, a 19 G cutting needle has been commercialized (Quick-Core, Wilson-Cook Medical, Inc., Winston-Salem, NC) and used to obtain histologic samples from perigastric organs in a swine model [56] and from various mass lesions, including five SMLs in humans [57]. Levy et al [57] proposed that this technique be described as EUS-guided trucut biopsy to avoid confusion with EUS-FNA. The vast majority of SMLs in the discussed series were spindle cell tumors (SCTs), which would probably fall into GIST or true esophageal leiomyoma category. Data on EUS-FNA of SMLs other than GISTs/SCTs are sparse: single cases of successful FNA diagnosis of aberrant pancreas, lipoma, granular cell tumor, metastases to GI tract wall, or cancer recurrence were reported [47,48,55]. Although GISTs constitute the largest group of SMLs punctured, only the most recent EUS studies adopted the current criteria for GIST diagnosis and included immunostaining analysis [38,44,49–51]. Nevertheless, at least a part of data, especially on biopsy technical success rate and diagnostic yield, may be extrapolated from articles using older terminology. In addition, many up-to-date studies focusing on percutaneous (CT- or US-guided) puncture of GISTs are available in cytologic literature. Conclusions from all these studies are summarized below. There is accumulating evidence from studies on EUS-guided [49–51] and percutaneous [58–61] FNA biopsy of GISTs that highly or at least moderately cellular material adequate for cytologic analysis can be obtained using these techniques. In addition, core tissue specimens that enable histologic evaluation have been collected using standard EUS-aspiration [44,48] or EUS-trucut needles [57]. The rate at which an adequate specimen was obtained by EUS-guided FNA varies widely depending on the study. In six studies that included at least five GISTs/SCTs and provided data sufficient for analysis, the diagnostic yield of EUS-FNA biopsy ranged from 20% to 92%, with a weighted average of 81% in a collective material of 119 cases (Table 5) [38,44,47,48,53,55]. More recent studies [38,44] and studies using the biopsy technique providing core tissue specimens [44,48] tend to report better results than the older ones and those dealing with cytologic material. The only prospective study reported a rather low diagnostic yield of 57% [53]. Technical tips on how to improve biopsy yield have been suggested. The material should be collected from various parts of the tumor.

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Table 5 Summary of the experience on EUS-guided fine needle biopsy of submucosal lesions (studies reporting at least 5 cases were included)

GIST/SCT

Other SMLs

Sensitivity for malignancy detection

Histologic (core specimens)

89% (17/19)

100% (2/2)

100% (3/3)

Cytologic (smears, cell blocks)

58% (7/12)

69% (9/13)

n.d.

Cytologic (smears) Microbiopsy in some cases Cytologic (smears)

n.d.

n.d.

n.d.

Cytologic (smears, cell blocks)

57% (4/7)

40% (2/5)

n.a.

Manufact. unk, 22 G (3–4, n.d.)

Histologic (core tissue specimens)

82% (18/22)

n.a.

75% (3/4)

WC 23G or GIP 22G (n.d.)

Cytologic

20% (1/5)

100% (2/2)

50% (1/2)

21 gastric (16 LM, 1 LMB, 2 LMS, 2 LIP)

Wiersema et al, 1994 [47]a

Retro, CC, var. path.

Giovannini et al, 1995 [52]

Retro, CC, var. path.

25 GI (12 LM, 4 REC, 3 LIP, 3 CRD, 1 LAC, 2 UNK) 7 GI (4 LM, 1 SCHW, 2 meta)

Flexi-Temno guillotine needle (1–4, 3.0) Microvasive 21 G transbronchial needle (n.d.) Various types 22–25 G (n.d.)

Gress et al, 1997 [54] Wiersema et al, 1997 [53]

Retro, CC, var. path. Prosp, CC, var. path.

Matsui et al, 1998 [48]

Retro, CC, SML only

Williams et al, 1999 [55]

Retro, CC, var. path.

27 GI (types not specified) 12 gastric and esophageal (types not specified) 20 gastric and 2 duodenal (11 LM, 3 LMS, 3 AP, 1 NFB, 1 meta, 3 UNK) 7 GI (4 LM, 1 LMS, 1 GCT, 1 meta)

WC 23G or GIP 22 G (n.d.) WC, GIP, Pentax, 21–25 G (n.d.)

84% (n.d.)

n.d.

butruk

Study design Retro, CC, SML only

Caletti et al, 1991 [39]a

&

Adequate material obtained

Needle type used (# of passes: range, mean)

polkowski

Type of specimen obtained

Number and type of submucosal lesions sampled

Author, year, [reference]

Gu et al, 2001 [49] Rader et al, 2001 [50] Fu et al, 2002 [51] Ando et al, 2002 [44] Hunt et al, 2003 [38]

Retro, SC, SML only Retro, SC, SML only Retro, CC, SML only Retro, CC, SML only Retro, SC, SML only

12 gastric GISTs 5 gastric GISTs 5 gastric, 5 duodenal GISTs 49 GI GISTs 24 GI (15 GIST, 8 LM, 1 SCHW)

WC or GIP 22G (1–5, 3.0) WC 22G Echotip (3–6, n.d.) WC 22G (n.d.) Manufact. unk, 22G (1–5, 2.8) WC 22G Echotip, Core biopsy device in 1 case (2–7, n.d.)

Cytologic (smears, cell blocks) Cytologic (smears, cell blocks) Cytologic (smears, cell blocks) Histologic (core specimens) n.d.

100%b (12/12)

n.a.

n.d.

100%b (5/5)

n.a.

n.d.

80% (8/10)

n.a.

n.d.

90% (44/49)

n.a.

67% (4/6)

92% (22/24)

n.a.

n.d.

submucosal lesions

Abbreviations: n.a., not applicable; n.d., no sufficient data provided. Column 2: CC, consecutive cases undergoing puncture included; prosp, prospective (studies were classified as prospective only if there was an explicit statement ‘‘prospective study’’); retro, retrospective; SC, selected cases included; SML only, study focused on the puncture of submucosal lesions; var. path., biopsy of various pathology reported, including a subgroup of submucosal lesions. Column 3: AP, aberrant pancreas; BGH, Brunner’s gland hamartoma; CRD, carcinoid; GCT, granular cell tumor; GIST, gastrointestinal stromal tumor; LAC, lymphangiocele; LIP, lipoma; LM, leiomyoma; LMB, leiomyoblastoma; LMS, leiomyosarcoma; NFB, neurofibroma; REC, cancer recurrence; SCHW, schwannoma; UNK, unknown. Column 4: GIP, GIP, Medi-Globe Inc., Tempe, Arizona; Manufact. unk, manufacturer unknown; WC, Wilson-Cook Medical Inc. Winston-Salem, North Carolina. Column 6: GIST, gastrointestinal stromal tumor; SCT, spindle cell tumor. a EUS-assisted endoscopic biopsy. Puncture performed under endoscopic control after EUS assessment of the target lesion. b Only cases successfully diagnosed by EUS-FNA were included.

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Changing the needle tract with an elevator was deemed useful for that purpose [44,48]. Because GISTs are usually hard, the needle should be thrust abruptly into the tumor to prevent it from moving back during the puncture [44]. Cytomorphologic features of GISTs, reviewed in detail elsewhere, have recently been characterized. As a result, these tumors can be diagnosed reliably on FNA specimens [49,51,59–61]. The same holds true for leiomyosarcomas [59]. In addition, it has been shown that spindle cell and epithelioid types of GISTs can be distinguished in cytologic material [60]. Care must be taken not to confuse epithelioid type GISTs with adenocarcinoma [19,60]. Despite all this optimism, one needs to keep in mind that the studies that provided these promising data were designed solely to characterize the cytologic features of GISTs or leiomyosarcomas and not to evaluate the ability of cytology to make a diagnosis in a prospective, blinded fashion. Immunochemical staining, which is essential for GIST diagnosis, is feasible and reliable on material from EUS- and non-EUS–guided FNA. This holds true for core tissue specimens [44] and for cytologic material (in the latter case cell blocks—formalin-fixed, paraffin-embedded cell pellets obtained by the centrifugation of fresh needle rinses—are preferred) [49,50,59–62]. The typical panel of assays performed consists of CD117 and CD34, markers that are essential for the positive identification of GIST, along with smooth muscle actin, desmin, and S-100 protein that are used to differentiate those tumors from true smooth muscle tumors and schwannomas [51,59–61]. Ando et al [44] showed that immunohistochemical profiles of 23 GISTs determined on EUS-FNA core tissue specimens and surgical sections from the same tumors were concordant in 91% of cases, with false-negative results in only 3 of 92 assays performed. The accuracy for the assessment of CD117, CD34, muscle actin, and S-100 status in FNA specimen was 96%, 100%, 100%, 91%, respectively [44]. An excellent correlation of immunostaining between cytologic (cell blocks) and tissue specimens has also been shown in material obtained by percutaneous FNA of GISTs and leiomyosarcomas [49,59,61]. Although GISTs can be diagnosed with confidence on FNA specimens, the assessment of their malignant potential based on cytomorphologic and immunochemical characteristics alone is difficult or impossible [50,60,61]. The major problem is false-negative diagnoses, which may result not only from sampling errors and interpretation errors, as in case of cytologic diagnosis of other tumors, but also from difficulties in applying GIST-specific criteria of malignancy to cytologic examination. As concluded by Li et al [58] and other experts, mitoses are seldom seen in FNA smears, and therefore mitotic count, which is essential for the assessment of GIST malignant potential on histology, cannot be used on cytology. Other malignant features, such as nuclear pleomorphism, hyperchromasia, irregular nuclear contours, or increased nuclear/cytoplasmatic ratio, may be present in some samples but are neither persistent nor prominent in most cases of malignant GISTs. Immunostaining for CD117 and other markers, though helpful in confirming the GIST diagnosis, does not facilitate the assessment of their malignant potential [49–51,60,61].

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Limitations inherent in the assessment of cytologic material from stromal tumors may be obviated by the use of needles providing core tissue specimen for histologic evaluation. Whether such a biopsy, aspiration or cutting, may aid in the diagnosis of malignant GISTs remains to be determined. The unequivocal separation of malignant from benign lesions is difficult (or impossible) to achieve even if the whole resected tumor is available. Despite this skepticism, initial attempts to determine GISTs’ malignant potential on core tissue samples have been made. Ando et al [44] used predefined criteria (eg, high mitotic count, high cellularity, and severe nuclear atypia) to evaluate core tissue samples aspirated from 23 GISTs and achieved 67% sensitivity, 100% specificity, and 91% accuracy for detection of malignancy. In two of six malignant GISTs in this series, the EUS-FNA result was false negative. However, when an ancillary test, quantitative immunostaining for Ki-67 (Ki-67 labeling index), was performed, the sensitivity and the accuracy rose to 100%, and specificity remained at 100%. Levy et al [57] sampled four smooth muscle tumors, including one leiomyosarcoma, with conventional 22 G aspiration needles and novel 19 G trucut needles. All the tumors were correctly diagnosed by EUS trucut biopsy, whereas EUS-FNA was nondiagnostic in each instance [57]. The mutational analysis of the c-kit gene is feasible and may aid in the diagnosis of GISTs on EUS- and non-EUS–guided FN aspirates [50,58]. Li et al [58] performed an analysis of KIT mutation in fine needle aspirates (15 cell blocks and one smear) and detected in-frame deletions of KIT gene exon 11 in 6 of 10 malignant and in three of four borderline GISTs, whereas no mutation was found in two benign tumors. The authors concluded that although the detection of a KIT mutation was strongly predictive of malignant behavior, the absence of the mutation did not preclude malignancy. Further research in the field of EUS-guided needle biopsy should focus on the role of core tissue specimens and on ancillary techniques, especially genetic markers. Endosonography–assisted endoscopic removal of submucosal lesions The endoscopic removal of an SML offers diagnostic and therapeutic advantages over biopsy: the whole specimen can be evaluated histologically, and the patient is cured of the tumor. Although post-procedure complications have been described (16 cases [7%] of bleeding, including one requiring surgery, in 223 procedures), the risk is low as compared with surgical resection [11,21–24,63]. Not every SML is suitable for endoscopic removal. Typical criteria include (1) diameter b 2 cm [22] or 3 cm [24,63], (2) overlying mucosa without ulceration [22,23], (3) lack of tumor extension into the muscularis propria [21–23,46,63], and (4) no sign of malignancy on EUS [23,63]. Excluding varices as a cause of wall protrusion is also mandatory. Attempting the removal of tumors originating from the muscularis propria may lead to perforation and should be avoided [21–23,46,63]. Nevertheless, the safe endoscopic resection of tumors up to 7.5 cm in diameter, involving the muscle layer, has been reported [11,24].

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Although SMLs have been removed endoscopically without prior EUS assessment [11,64], it is the majority view that endosonography should be prerequisite for such treatment [21–24,46,63]. The role of EUS consists in selecting tumors suitable for removal; in addition, the method has been used to guide [24] or assess the effect [22] of saline injection performed to detach the lesion from deeper wall layers. Dedicated echoendoscopes and high-frequency miniprobes have been successfully used for that purpose [21–24,46,63]. The most important information from EUS in the setting of endoscopic therapy of SMLs is determining the wall layer the lesion originates from. However, EUS accuracy in this regard is not perfect: Kojima et al [21] found that only 43 of 54 lesions (80%) were correctly assigned to the layer they originated from; six lesions were located deeper in the GI wall than estimated with EUS, and five lesions were located more superficially.

Catheter-based endoscopic ultrasonography (miniprobes) Catheter-based EUS (C-EUS) is potentially an attractive alternative to standard endosonography (S-EUS) in the setting of SMLs. One may assume that performing C-EUS during endoscopy that just revealed suspected bulging of the wall may obviate the need for subsequent S-EUS, especially if extrinsic compression caused by a normal organ is found. This assumption is supported by evidence from recent studies [15,21,22,65–67] that showed that: 1. C-EUS is easy to perform [21,65] and adds only 5 to 15 minutes to the time required for standard endoscopic examination [67]. 2. As compared with endoscopy, C-EUS yielded conclusive or important supplementary information in 80% of cases investigated [66]. 3. C-EUS is as good as or better than S-EUS at evaluating SMLs, particularly small lesions [15,65]. C-EUS image interpretation concurs with that of standard EUS in 84% of cases (95% confidence interval, 71–94) [67]. The ability to distinguish extrinsic compression from SMLs is less well established; nevertheless, in one study C-EUS correctly identified the cause of EC in seven cases and excluded an abnormality in two cases [15]. Because C-EUS and S-EUS in the discussed studies were performed by experienced endosonographers, it remains unclear whether the results can be reproduced by an endoscopist who is not a EUS expert but has received training in C-EUS. 4. Technical problems specific to C-EUS include difficulties in obtaining good acoustic contact, especially in the esophagus, and limited penetration depth impeding the assessment of larger (N 2 cm) lesions [21,22,65,67]. The former problem may be obviated by using balloon-tipped EUS probes [67] or a water-filled condom surrounding the probe and providing an acoustic window [68]. Low-frequency probes may help to overcome the problem of limited penetration depth [22].

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5. Miniprobes have been successfully applied for EUS-assisted endoscopic removal of SMLs [21–23].

Surveillance of patients with submucosal lesions In a substantial proportion of patients with SMLs, the lesion does not cause clinically significant symptoms, is less than 3 to 4 cm in size, and does not display endosonographic features suggesting malignancy. In addition, some patients are not fit for or do not accept surgical treatment. Precise data on how big this group is are not available; however, at a rough estimate approximately 50% of all SMLs meet these criteria. The estimate is based on the data from two prospective multicenter trials including a total of 296 patients of whom only 48% underwent resection [1,40]. The options for patients not referred for surgery include endoscopic removal, which is possible only at specialized centers and only in a subset of lesions, or surveillance programs aimed at detecting changes in tumor size. Although the latter approach is common practice, it has not been validated in formal trials. No guidelines for surveillance have been developed, and the data on the natural course of SMLs are sparse. Rapidly growing tumors, from 3.5 to 25 cm over 2 years, have been reported [69]; nevertheless, such cases are exceptional, and the majority of SMLs do not enlarge, at least in the mediumterm follow-up. Tio et al [70] found no significant changes in the size and echofeatures of 18 small, asymptomatic SMLs followed for 1 to 3 years. Melzer and Fidder [71] followed endosonographically 25 patients with submucosal tumors b 40 mm in size for a mean period of 19 months. Changes in size and appearance were noted in only one tumor, which was found to be a GIST with high malignant potential. Because GIST behavior is difficult to predict, more long-term follow-up data are necessary to assess the risk associated with not removing small, asymptomatic, benign-appearing lesions. A study by Ueyama et al [72] that included seven gastric smooth muscle tumors suggested that short tumor doubling time (of 16 months or less) may be a potentially useful indicator of malignant potential. Nickl et al [40] attempted to validate this parameter prospectively; however, rapid tumor enlargement was a rare occurrence in their large multicenter material, and all three tumors that were resected due to changes in their size or appearance were benign. In addition, patient compliance with the surveillance program was poor: Only 50% of patients completed even one surveillance examination despite persistent effort from the study endoscopists. An analysis using a decision model suggested that if a mean of 1.6 surveillance examinations are needed for the follow-up of initially benign-appearing lesions, then EUS-directed management is more expensive than surgical management [73]. If surveillance is chosen despite all these uncertainties, it involves the repeated use of endoscopy or endosonography, which are invasive and expensive techniques. A noninvasive method potentially useful for the surveillance of patients

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with gastric SMLs is transabdominal ultrasound of the water-filled stomach (Figs. 1 and 2). We showed that 69% of 51 tumors (median size of 25 mm) could be visualized and measured using this method. The visualization rate for lesions 30 mm was 61% [10]. Groups from Taiwan [20] and Japan [74] achieved visualization rates of 82.5% and 93%, respectively. Whether this noninvasive surveillance method may improve patients’ compliance remains an open

Fig. 1. Gastric submucosal tumor (arrows) originating in the muscle layer, 23  17 mm in size. (A) Endosonographic image. (B) Image on transabdominal ultrasound of the water-filled stomach.

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Fig. 2. Gastric submucosal tumor (arrows) originating in the muscle layer, 43  38 mm in size: (A) Endosonographic image. (B) Image on transabdominal ultrasound of the water-filled stomach.

question. No prospective surveillance studies using transabdominal ultrasound of the water-filled stomach have been conducted.

Endosonography–guided therapy of submucosal tumors EUS-guided anti-tumor therapy is an emerging concept that has been evaluated in a handful of pilot studies focused on pancreatic and hepatic lesions

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[75]. Recently, a case of a gastric stromal tumor treated with EUS-guided ethanol injection was reported by a group from Germany [76]. A total of 1.5 mL of 95% ethanol was injected in a single session into a 40-mm GIST. No adverse experiences occurred except for upper abdominal pain, which developed one week after the procedure and continued for a few days. Mucosal ulceration and slight thickening of the muscle layer was observed on endoscopy and EUS seven weeks after the procedure. No evidence of residual tumor was found on follow-up examinations at six and 24 months. Although this method is an interesting alternative to endoscopic or surgical treatment, more data on its safety and efficacy are needed before it can be recommended.

Summary If endoscopy reveals abnormalities suggesting a SML, then EUS should be performed as the next diagnostic step to confirm that the lesion is present; to assess its size, margins, layer of origin, and echostructure; and to differentiate between a true SML and extraluminal compression. The information obtained on EUS can be used to narrow down the differential diagnosis and to assess the risk of malignancy; however, neither definite diagnosis nor definite exclusion of malignancy is possible on the basis of the endosonographic image alone. Standard-EUS and catheter based- EUS seem to be equivalent in terms of diagnostic capabilities, at least if smaller lesions are considered. The EUS-guided fine needle biopsy of SMLs is feasible and safe. Material adequate for diagnosis can be obtained in the majority of cases, although less encouraging results have been reported. The major limitation of cytologic evaluation in the setting of SML is that the malignant potential can only rarely be determined unequivocally. EUS is helpful, if not mandatory, for selecting lesions suitable for endoscopic removal. Another challenge EUS has to face is to adapt to rapid changes in the understanding of the biology of GISTs, a category into which a substantial proportion of SMLs fall. There is accumulating evidence that cytomorphologic diagnosis of GISTs and immunostaining essential for a differential diagnosis of these tumors are feasible on fine needle aspirates. In addition, core tissue specimens enabling a histologic evaluation may be obtained using aspiration and trucut biopsy. Ancillary tests such as Ki67 labeling index or mutational analysis may aid the diagnosis of malignancy. The endosonographic (or endoscopic) surveillance of patients with asymptomatic, small tumors without signs of malignancy is a common approach, although it has not been formally validated. Questions as to safety, cost-effectiveness, yield, and patients’ compliance with surveillance programs have been raised. Transabdominal ultrasound of the water-filled stomach is a noninvasive method that is potentially useful for the visualization and surveillance of EUS-confirmed gastric SMLs.

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