ORIGINAL ARTICLE: Clinical Endoscopy
Compliance with surveillance recommendations for foregut subepithelial tumors is poor: results of a prospective multicenter study Vladimir M. Kushnir, MD,1 Rajesh N. Keswani, MD,2 Thomas G. Hollander, BS,1 Cara Kohlmeier, BS,1 Daniel K. Mullady, MD,1 Riad R. Azar, MD,1 Faris M. Murad, MD,1 Srinadh Komanduri, MD,2 Steven A. Edmundowicz, MD,1 Dayna S. Early, MD1 St Louis, Missouri; Chicago, Illinois, USA
Background: American Gastroenterological Association guidelines recommend performing EUS to characterize subepithelial lesions (SELs) discovered on upper endoscopy (EGD), followed by surveillance if no high-risk features are identified. However, limited data are available on the impact of and compliance with surveillance recommendations. Objective: To determine the natural history of SELs ! 30 mm in size evaluated by EUS and to determine the degree of patient compliance with surveillance recommendations. Design: Prospective registry. Setting: Two tertiary centers. Patients: We studied 187 consecutive adult patients referred for EUS evaluation of foregut SELs. Main Outcome Measurements: Proportion of patients in whom SELs change in size or echo-features and compliance with follow-up recommendations. Results: Surveillance was recommended in 65 patients with hypoechoic SELs (44.6% women, age 59.5 13.2 years); of these, 29 (44.6%) underwent surveillance EUS as recommended and were followed for a median of 30 months (range, 12-105). During follow-up, 16 SELs (25%) increased in size, with a mean increase of 3.4 3.9 mm (range, 1-15). No changes in echo-texture of the SELs were observed. One patient was referred to surgery during follow-up (because of SEL growth O 30 mm). Limitations: Short follow-up duration; compliance was a secondary aim. Conclusions: During a median follow-up of 30 months, growth in size was observed in 25% of small foregut SELs. However, change in size was minimal, and only 1 patient was referred for surgery based on surveillance EUS findings. Compliance with surveillance recommendations is poor, with fewer than 50% of patients undergoing surveillance EUS as recommended. (Gastrointest Endosc 2015;81:1378-84.)
Subepithelial lesions (SELs) in the lumen of the GI tract are incidentally identified in approximately 1 in every 300 upper endoscopies.1 When discovered during endoscopy,
SELs pose a diagnostic challenge because optical endoscopy only visualizes the mucosa, and tissue acquisition by mucosal biopsy is of limited value.2 SELs
Abbreviations: GIST, GI stromal tumor; IQR, interquartile range; SEL, subepithelial lesion.
Current affiliations: Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA (1), Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA (2).
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. See CME section; p. 1439. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2014.11.013 Received June 9, 2014. Accepted November 5, 2014.
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Presented at Digestive Disease Week, May 18-21, 2013, Orlando, Florida. (Gastrointest Endosc 2013;77:5:AB363-4). Reprint requests: Dayna S. Early, MD, Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8124, St Louis, MO 63110. If you would like to chat with an author of this article, you may contact Dr Early at [email protected].
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range from benign lesions (lipoma, duplication cyst) to tumors of variable malignant potential, such as GI stromal tumors (GISTs) and neuroendocrine tumors.3,4 Cross-sectional imaging, specifically CT, can be used to evaluate SELs; however, evaluation of SELs on crosssectional imaging is limited by the spatial resolution of the scanner, particularly for smaller lesions. EUS is the preferred modality for evaluation of SELs discovered on endoscopy because it allows for the evaluation of lesion size, layer of origin, and morphologic features; moreover, EUS allows for tissue acquisition from SELs by FNA or tru-cut biopsy sampling.5,6 Current National Comprehensive Cancer Center guidelines recommend performing EUS to characterize and sample SELs.7 Most SELs are mesenchymal tumors of the GI tract, such as leiomyoma and GIST.3,8 These lesions typically present as a hypoechoic SEL in the second (muscularis mucosa) or fourth (muscularis propria) echo-layers of the GI tract.6,9 Surgical resection is recommended for lesions with features associated with high malignant potential, such as size O 3 cm and positive staining for CD117/c-kit on immunohistochemistry, irregular outer margins, echogenic foci, presence of cystic spaces, inhomogeneous echo-texture, or pathologic lymphadenopathy on EUS. Surveillance is recommended for smaller lesions (!2-3 cm) without high-risk features.7,10-12 However, this recommendation is based largely on expert opinion, because the natural history of incidentally discovered SELs is poorly understood.4 Long-term data with regard to EUS-based surveillance of small, incidentally discovered SELs are limited and based largely on retrospective case series.13-15 As such, the optimal approach to the EUS evaluation and surveillance of small SELs is unknown. Furthermore, the impact of and compliance with recommended follow-up for SELs is unclear. Our primary aim in this study was to determine the natural history of small SELs discovered incidentally during upper endoscopy and evaluated by EUS. The secondary aims were to determine the degree of patient compliance with surveillance recommendations, describe the diagnostic yield of EUS FNA/tru-cut biopsy sampling in evaluating SELs, and compare SEL size estimation based on EUS, EGD, and CT.
METHODS Consecutive adult patients (O18 years old) referred for EUS evaluation of foregut SELs at 2 tertiary care centers between August 2008 and August 2012 were invited to participate in this prospective cohort study. Patients were excluded if they were unable to provide written informed consent. Demographic characteristics were recorded before endoscopy. When available, pre-endoscopy CT studies were reviewed and SEL size and radiographic features were recorded. EUS findings and follow-up recomwww.giejournal.org
Poor compliance with surveillance recommendations for SELs
mendations were recorded by the attending gastroenterologist at the completion of the procedure on a study data form. Follow-up data were collected by manual review of the institutional electronic medical record. The study was approved by the Institutional Review Board of Washington University School of Medicine/Barnes Jewish Hospital (IRB no. 201104076) and Northwestern University Feinberg School of Medicine.
Endoscopic and endosonographic examination All endoscopic procedures were performed by 1 of 6 experienced endosonographers. At the time of EUS examination, all patients first underwent upper endoscopy using an adult gastroscope (GIF-H180; Olympus Medical Systems, Center Valley, Pa). Lesion location was noted and the lesion measured to the nearest millimeter using an Olympus measuring device. EUS examinations were then performed using a radial and/or linear echoendoscope (GF UE 160; Olympus Medical Systems) or with an ultrasonographic mini-probe (12-20 MHz; Olympus Medical Systems), at the discretion of the attending endoscopist. During endosonographic evaluation, the following SEL characteristics were recorded: layer of origin, maximum diameter, regularity of extraluminal border, echo-pattern, and presence of echogenic foci or cystic spaces. While measuring the SEL during EUS, the endosonographer was blinded to the measurement display on the monitor until the measurement was completed.
Tissue acquisition Sampling of the SEL was performed at the discretion of the endoscopist, using FNA or tru-cut biopsy or cold “tunnel” biopsy sampling. The diagnostic yield of individual sampling modalities and overall diagnostic yield for tissue acquisition were calculated. During the time of the study, it was our practice to obtain tissue from all SELs R 10 mm in size, unless they demonstrated classic EUS features of a lipoma (hyperechoic third-wall-layer SELs) or cyst.
Treatment algorithm Patients with SELs O 30 mm or with other high-risk features (irregular outer margins, echogenic foci, presence of cystic spaces, inhomogeneous echo-texture, pathologic lymphadenopathy) were referred for consideration of surgical resection. No surveillance was recommended for clearly benign SELs (hyperechoic third-wall-layer SELs, duplication cysts, biopsy specimen–proven pancreatic rest, or esophageal leiomyoma). The management of gastric leiomyoma O 30 mm in size was not standardized. Annual surveillance was recommended for patients with indeterminate SELs (those not meeting the above-listed criteria).
Postprocedure surveillance Follow-up recommendations were discussed with patients immediately after the procedure and when Volume 81, No. 6 : 2015 GASTROINTESTINAL ENDOSCOPY 1379
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pathology data became available, and patients and their referring physicians were provided with written copies of endoscopy and pathology reports. Patients for whom surveillance was recommended were contacted by phone to schedule a repeat EUS, approximately 11 months after initial examination. In cases in which patients could not be contacted by telephone, a reminder letter was sent to the patient’s home address. Patients were considered to be compliant with surveillance recommendations if they underwent a follow-up EUS 12 to 36 months after the initial examination. During surveillance examinations, EUS lesion size and endosonographic characteristics were recorded. Tissue was obtained at the time of repeat examination if change was noted in SEL echo-features or growth in size was noted and the lesion had not been previously sampled or if initial cytology was nondiagnostic or inconclusive (ie, inadequate tissue or spindle cells seen on cytology but c-kit stain could not be performed). Patients were referred for consideration of surgery if the SEL developed features suggestive of progression (increase in size by R10 mm or to O30 mm or development of highrisk EUS features).
Statistical analysis Data are reported as means standard deviation for normally distributed data and median and range for skewed data. Grouped continuous variable data were compared by using the 2-tailed Student t test and MannWhitney U test where appropriate. Intergroup and categorical comparisons were made using the c2 and Fisher exact tests. P ! .05 was required for statistical significance. All statistical analyses were performed using PASW 19.0 (SPSS, Inc, Chicago, Ill.).
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Compliance with surveillance recommendations Endosonographic surveillance was recommended in 65 patients with hypoechoic SELs (44.6% women; mean age 59.5 13.2 years); of these, 29 (44.6%) underwent surveillance EUS as recommended. Patients underwent initial surveillance EUS a median of 13 months (range, 12-29) after the initial examination.
Findings on surveillance EUS The median duration of follow-up was 30.3 months (range, 12-105); patients underwent a median of 1 surveillance EUS examination (range, 1-3). During follow-up, 16 SELs increased in size; the mean increase was 3.4 3.9 mm (range, 1-15 mm) (Table 1). No changes in echotexture of the SELs were observed. Twelve lesions were sampled during follow-up examinations, which led to a change in management in 2 cases (tissue diagnosis was that of lipoma in both cases and patients were exited from surveillance). Three patients were referred to surgery during follow-up, 2 because of SEL growth (1 increased in size from 29 to 35 mm in 23 months and 1 increased in size from 18 to 29 mm in 12 months; surgical pathology was consistent with a GIST in both) and 1 because of patient preference.
SEL size estimation: EUS versus EGD versus CT
There were 187 patients enrolled in the study, of which 99 were women (52.9%), and the average age was 59.9 13.3 years. No intramural lesion was identified on endoscopic and endosonographic examination in 36 patients (19.3%); 28 lesions were located in the esophagus, 114 in the stomach, and 9 in the duodenum. SEL locations in the wall of the GI tract were as follows: 69 in the muscularis propria, 44 in the submucosa, 29 in the deep mucosa, and 2 in the superficial mucosa; the wall layer of origin could not be clearly determined in 7 cases. One hundred ten SELs were hypoechoic, 33 hyperechoic, and the remaining 8 SEL were cysts within the wall of the GI tract. The outer margins of the SEL were irregular in 28, and cystic spaces were seen in 16. Pathologic lymphadenopathy was not identified in any patient.
When measured on white-light endoscopy, the mean SEL size was 14.0 mm (interquartile range [IQR], 820 mm) and on EUS measurement the mean SEL size was 13.0 mm (IQR, 8.5-22 mm), a median difference of 2 mm (IQR, 1-4.5 mm). A clinically significant difference in size was only identified in 3 cases, in which EUS measured the SEL at O30 mm versus !30 mm on endoscopy. There was good correlation between crosssectional size estimates made using the sizing tool during direct endoscopy and EUS (r Z .90, P ! .001; Fig. 1). CT results were available for review in 24 patients (15.8%); SELs were visualized both endoscopically and endosonographically in all cases. In 4 patients the SEL was not visualized on CT; these lesions measured 9, 10, 11, and 22 mm, respectively, on EUS. The mean size of the SELs visualized on CT was 26 mm (IQR, 16-39 mm) and 27 mm (IQR, 17.333.5 mm) on EUS, a median difference of 6.4 mm (IQR, 2.0-8.2 mm). Again, there was good correlation between cross-sectional size estimates between CT and EUS (r Z .82, P ! .001; Fig. 2). Surgical follow-up was available in 14 cases. The mean size of the SELs on surgical pathology was 34.4 17.3 mm, whereas on EUS the mean size of the lesion was 32.3 12.2 mm. There was no significant difference in SEL size as measured by EUS and the criterion standard (surgical pathology) (r Z .95, P ! .001).
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RESULTS Baseline EUS findings
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TABLE 1. Characteristics of SELs that increased in size during surveillance
Wall layer
Initial size (mm)
Follow-up size (mm)
Change in size (mm)
Tissue diagnosis
Method of tissue diagnosis
Follow-up (mo)
Stomach
4
13
14
1
GIST
EUS
35
2
Esophagus
4
8
15
7
N/A
EUS
105
3
Stomach
4
18
20
2
Pancreatic rest
Surgery*
13
4
Stomach
4
21
22
1
GIST
EUS
80
5
Esophagus
2
5
6
1
N/A
EUS
12
6
Stomach
4
14
15
1
N/A
EUS
36
7
Stomach
4
9
10
1
N/A
EUS
29
8
Stomach
4
29
35
6
GIST
Surgeryy
23
9
Stomach
4
16
17
1
GIST
EUS
12
10
Stomach
4
10
12
2
N/A
EUS
36
11
Esophagus
4
15
16
1
Leiomyoma
EUS
36
12
Stomach
2
18
22
4
GIST
EUS
13
13
Stomach
4
9
11
2
N/A
EUS
28
14
Esophagus
4
14
23
9
Leiomyoma
EUS
42
15
Esophagus
2
10
25
15
N/A
EUS
25
16
Stomach
4
18
29
11
GIST
Surgeryz
12
17
Stomach
4
7
8
1
N/A
EUS
17
Patient
SEL location
1
SEL, subepithelial lesion; GIST, GI stromal tumor; N/A, insufficient tissue to establish diagnosis. *Underwent surgery based on patient preference; pre- and postoperative tissue diagnosis were concordant. yEUS-FNA revealed spindle cells; however, tissue was not sufficient to perform c-kit staining; surgical pathology was consistent with a GIST. zEUS-FNA and surgical pathology were consistent with a GIST.
Tissue acquisition Tissue was obtained from 88 lesions (58.3%) during the initial examination. Sampled SELs were significantly larger than unsampled SELs, with a mean diameter of 21.8 mm versus 10.8 mm (P ! .001), respectively. FNA was performed in 52 cases (34%), and sufficient tissue for cytopathologic examination was obtained in 41 (78.8%). Core needle biopsy specimens were obtained in 15 cases, and sufficient tissue for histopathologic examination was obtained in 10 cases (66.7%). Cold “tunnel” biopsy specimens were obtained in 48 cases, and sufficient tissue for histopathologic examination was obtained in 41 (85.4%). Based on cytology and histology results, a tissue diagnosis was obtained from 67 SELs (76.1%) (Table 2). Surgical follow-up was available in 12 cases in which sufficient tissue was obtained during endoscopy. The preoperative diagnosis was spindle cell neoplasm in all cases, c-kit positive (GIST) in 10 cases and c-kit negative (leiomyoma) in 2. Histopathologic examination of surgical resection specimens revealed spindle cell neoplasm in 11 cases. There was 1 false positive, in which the cytology www.giejournal.org
demonstrated spindle cells; however, on surgical resection the lesion proved to be a pancreatic rest. In spindle cell lesions, c-kit staining was discordant in 1 case; with falsepositive results, surgical pathology served as a criterion standard (Fig. 3).
DISCUSSION Most hypoechoic SELs discovered during upper endoscopy are mesenchymal tumors of the GI tract, such as leiomyoma and GIST. It is widely accepted that surgical resection is the treatment of choice for lesions with highrisk features (size O 3 cm and positive staining for CD117 on immunohistochemistry, irregular margins, or presence of cystic spaces on EUS).7 However, the optimal management strategy for incidentally discovered smaller SELs (!2-3 cm) without high-risk features is unknown. The American Society for Gastrointestinal Endoscopy recommends annual EUS surveillance for such patients to monitor for changes in SEL size and Volume 81, No. 6 : 2015 GASTROINTESTINAL ENDOSCOPY 1381
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TABLE 2. Diagnostic yield of endoscopic tissue acquisition
60
EGD Size (mm)
Tissue diagnosis (n [ 88) Sufficient tissue obtained
40
20
r=0.90, p< .001
0 0
20
40
60
80
100
EUS Size (mm)
GIST
28
Spindle cell neoplasm (c-kit negative)
23
Lipoma
7
Pancreatic rest
5
Heterotopic liver
1
Metastatic renal cell carcinoma
1
Duplication cyst
2
Nondiagnostic Figure 1. Comparison between SEL size as measured by upper endoscopy and EUS.
Value 67 (76.1%)
21 (23.9%)
GIST, GI stromal tumor.
echo-texture that may indicate malignant progression. However, this recommendation is based largely on expert opinion and small retrospective studies.4,6,15-17 The main purpose of the current study was to chart the natural history of small incidentally identified SELs, driven by our anecdotal impression that surveillance rarely identified a clinically significant lesion, and that the American Society for Gastrointestinal Endoscopy surveillance guidelines are based primarily on expert opinion. In this prospective observational study, we found that most hypoechoic SELs ! 3 cm in size do not exhibit a clinically significant change in size or echo-features during a median 30-month follow-up period. During surveillance, 2 of 29 patients were referred for surgery because of an increase in SEL size to O3 cm, and no lesions developed other
high-risk EUS features. These findings are in agreement with the available medical literature on the natural history of hypoechoic SELs ! 3 cm in size. In the only other prospective study on the subject, Nickl et al18 reported in abstract form that 3 of 92 hypoechoic SELs ! 3 cm in size demonstrated change in EUS size or appearance, meeting criteria for surgical referral during a 36-month follow-up. Similarly, retrospective studies demonstrated that fewer than 15% of patients with hypoechoic SELs ! 3 cm in size have clinically significant changes detected on EUS-based surveillance during intermediate term follow-up (24-36 months).13,14,16,17,19 Because the c-kit mutation appears to be an early event in the evolution of GISTs (and may not be a reliable biomarker for identifying clinically significant tumors),20 it appears reasonable to perform serial surveillance at intervals of at least 24 to 36 months instead of yearly in patients with hypoechoic SELs ! 3 cm in size and without high-risk EUS features. A second finding of our study is that fewer than 50% of patients completed at least 1 surveillance EUS. The poor rate of patient compliance seen in our study mirrors the results of the Hypoechoic Intramural Tumor Study in which only 50% of patients underwent the first surveillance EUS.18 In that study, patients were contacted by a study coordinator for follow-up; in our study, patients were contacted by phone to schedule a repeat EUS, and if telephone contact could not be made, a reminder letter was sent by an endoscopy nurse as part of our usual clinical practice. The reasons behind the poor compliance with surveillance in this patient population are unknown, but the lack of compliance suggests that recommending surveillance of SELs ! 3 cm in size is a poor management strategy if compliance is low. This low rate of compliance with follow-up recommendations suggests that when technically feasible, tissue acquisition should be pursued,
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60
CT size (mm)
50
40
30
20
r=0.82, p< .001
10 10.00
20.00
30.00
40.00
50.00
60.00
EUS size (mm)
Figure 2. Comparison between SEL size as measured by CT and EUS.
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Figure 3. Lesion arising from the muscularis mucosa on (A) white-light endoscopy and (B) EUS. C, c-kit staining on core biopsy was weakly positive. D, c-kit staining on the surgically resected specimen was negative.
because a tissue diagnosis may help to reassure the patient, guide surveillance recommendations, and in some cases eliminate the need for follow-up EUS examinations. This study and other recent reports demonstrate that an accurate tissue diagnosis can be obtained for a large majority of SELs using the currently available endoscopic tissue acquisition modalities and will likely increase further with the introduction of new fine-needle biopsy sampling platforms.21,22 An alternative to surveillance is removal of these lesions, particularly with the emergence of minimally invasive and endoscopic methods of en-bloc SEL removal.23-25 When surveillance is recommended, this may be performed with EGD rather than EUS or CT based on the finding of our study that EGD estimates of SEL size correlate well with EUS measurement. This requires further study, however. Before the present study only 1 report had evaluated the comparison between SEL size with different diagnostic modalities. In a prospective study, Hwang et al2 found good correlation between SEL size measurements made on endoscopy and EUS. Similarly, we found a very strong correlation between endoscopic and EUS size measurement of SELs. Moreover, we found SELs visualized on both EUS and CT showed a good correlation between size measurements; however, SELs ! 15 mm in size were not reliably visualized on CT scan, so that CT imaging may not be an appropriate surveillance modality for small SELs. There are several limitations to the present study. Foremost was the O50% loss to follow-up observed in our cohort, despite recommendations for a 12-month www.giejournal.org
follow-up in all patients with hypoechoic SELs. This limits our ability to draw definitive conclusion regarding the natural history of incidental SELs. However, our findings are consistent with the existing medical literature showing a low risk of progression in small hyopechoic SELs. A second limitation is that a precise histopathologic diagnosis was not available in a number of patients in the surveillance cohort, because of the known limitations of the currently available endoscopic tissue acquisition methods. Additionally, we did not prospectively collect data pertaining to the reason(s) for patient noncompliance with post-EUS surveillance recommendations and can only speculate on the factors leading to poor compliance with post-EUS recommendations. Finally, it is important to acknowledge that the median surveillance period in our cohort was less than 3 years. It remains possible that the incidence of SEL progression in this cohort would have been higher during longer-term follow-up. In conclusion, the results of this study indicate that most hypoechoic SELs! 3 cm in size do not exhibit a clinically significant change in size or EUS features during a median 30-month follow-up. Based on this finding, we believe it is reasonable to perform surveillance examinations at intervals of at least 24 to 36 months. However, compliance with serial surveillance in this patient population is poor, suggesting that surveillance of small asymptomatic SELs is not an effective management strategy unless compliance with surveillance can be increased. Finally, we observed excellent correlation between small SEL size measured by EUS and EGD, suggesting that upper Volume 81, No. 6 : 2015 GASTROINTESTINAL ENDOSCOPY 1383
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1. Hedenbro JL, Ekelund M, Wetterberg P. Endoscopic diagnosis of submucosal gastric lesions. The results after routine endoscopy. Surg Endosc 1991;5:20-3. 2. Hwang JH, Saunders MD, Rulyak SJ, et al. A prospective study comparing endoscopy and EUS in the evaluation of GI subepithelial masses. Gastrointest Endosc 2005;62:202-8. 3. Humphris JL, Jones DB. Subepithelial mass lesions in the upper gastrointestinal tract. J Gastroenterol Hepatol 2008;23:556-66. 4. Hwang JH, Rulyak SD, Kimmey MB, et al. American Gastroenterological Association Institute technical review on the management of gastric subepithelial masses. Gastroenterology 2006;130: 2217-28. 5. Alkhatib AA, Faigel DO. Endoscopic ultrasonography-guided diagnosis of subepithelial tumors. Gastrointest Endosc Clin North Am 2012;22: 187-205, vii. 6. Mullady DK, Tan BR. A multidisciplinary approach to the diagnosis and treatment of gastrointestinal stromal tumor. J Clin Gastroenterol 2013;47:578-85. 7. Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw 2010;8(Suppl 2):S1-41; quiz S42-4. 8. Brand B, Oesterhelweg L, Binmoeller KF, et al. Impact of endoscopic ultrasound for evaluation of submucosal lesions in gastrointestinal tract. Dig Liver Dis 2002;34:290-7. 9. Chak A. EUS in submucosal tumors. Gastrointest Endosc 2002;56:S43-8. 10. Palazzo L, Landi B, Cellier C, et al. Endosonographic features predictive of benign and malignant gastrointestinal stromal cell tumours. Gut 2000;46:88-92.
11. Ha CY, Shah R, Chen J, et al. Diagnosis and management of GI stromal tumors by EUS-FNA: a survey of opinions and practices of endosonographers. Gastrointest Endosc 2009;69:1039-44. 12. Shah P, Gao F, Edmundowicz SA, et al. Predicting malignant potential of gastrointestinal stromal tumors using endoscopic ultrasound. Dig Dis Sci 2009;54:1265-9. 13. Bruno M, Carucci P, Repici A, et al. The natural history of gastrointestinal subepithelial tumors arising from muscularis propria: an endoscopic ultrasound survey. J Clin Gastroenterol 2009;43:821-5. 14. Lok KH, Lai L, Yiu HL, et al. Endosonographic surveillance of small gastrointestinal tumors originating from muscularis propria. J Gastrointestin Liver Dis 2009;18:177-80. 15. Kim MY, Jung HY, Choi KD, et al. Natural history of asymptomatic small gastric subepithelial tumors. J Clin Gastroenterol 2011;45:330-6. 16. Lim YJ, Son HJ, Lee JS, et al. Clinical course of subepithelial lesions detected on upper gastrointestinal endoscopy. World J Gastroenterol 2010;16:439-44. 17. Gill KR, Camellini L, Conigliaro R, et al. The natural history of upper gastrointestinal subepithelial tumors: a multicenter endoscopic ultrasound survey. J Clin Gastroenterol 2009;43:723-6. 18. Nickl N, Gress F, McClave S, et al. Hypoechoic Intramural Tumor Study: final report. Gastrointest Endosc 2002;55:AB98. 19. Lachter J, Bishara N, Rahimi E, et al. EUS clarifies the natural history and ideal management of GISTs. Hepatogastroenterology 2008;55:1653-6. 20. Muenst S, Thies S, Went P, et al. Frequency, phenotype, and genotype of minute gastrointestinal stromal tumors in the stomach: an autopsy study. Hum Pathol 2011;42:1849-54. 21. Komanduri S, Keefer L, Jakate S. Diagnostic yield of a novel jumbo biopsy “unroofing” technique for tissue acquisition of gastric submucosal masses. Endoscopy 2011;43:849-55. 22. Ahmed AM, Bass M, Goodman AJ, et al. A prospective single center comparison of EUS-guided core biopsy and EUS-guided fine needle aspiration for suspected upper GI lesions. Gastrointest Endosc 2013;77:AB397. 23. Catalano F, Rodella L, Lombardo F, et al. Endoscopic submucosal dissection in the treatment of gastric submucosal tumors: results from a retrospective cohort study. Gastric Cancer 2013;16:563-70. 24. Binmoeller KF, Shah JN, Bhat YM, et al. Suck-ligate-unroof-biopsy by using a detachable 20-mm loop for the diagnosis and therapy of small subepithelial tumors (with video). Gastrointest Endosc 2014;79:750-5. 25. Arezzo A, Verra M, Miegge A, et al. Loop-and-let-go technique for a bleeding, large sessile gastric gastrointestinal stromal tumor (GIST). Endoscopy 2011;43(Suppl 2 UCTN):E18-9.
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endoscopy could be used for surveillance when access to EUS is limited, which could increase compliance with surveillance recommendations. Areas for future research include improving minimally invasive means to remove SELs that do not meet criteria for surgical resection so that surveillance is unnecessary and developing means to improve risk stratification for patents who would benefit from surveillance.
REFERENCES
Compliance with surveillance recommendations for foregut subepithelial tumors is poor: results of a prospective multicenter study Vladimir M. Kushnir, MD,1 Rajesh N. Keswani, MD,2 Thomas G. Hollander, BS,1 Cara Kohlmeier, BS,1 Daniel K. Mullady, MD,1 Riad R. Azar, MD,1 Faris M. Murad, MD,1 Srinadh Komanduri, MD,2 Steven A. Edmundowicz, MD,1 Dayna S. Early, MD1 St Louis, Missouri; Chicago, Illinois, USA
Background: American Gastroenterological Association guidelines recommend performing EUS to characterize subepithelial lesions (SELs) discovered on upper endoscopy (EGD), followed by surveillance if no high-risk features are identified. However, limited data are available on the impact of and compliance with surveillance recommendations. Objective: To determine the natural history of SELs ! 30 mm in size evaluated by EUS and to determine the degree of patient compliance with surveillance recommendations. Design: Prospective registry. Setting: Two tertiary centers. Patients: We studied 187 consecutive adult patients referred for EUS evaluation of foregut SELs. Main Outcome Measurements: Proportion of patients in whom SELs change in size or echo-features and compliance with follow-up recommendations. Results: Surveillance was recommended in 65 patients with hypoechoic SELs (44.6% women, age 59.5 13.2 years); of these, 29 (44.6%) underwent surveillance EUS as recommended and were followed for a median of 30 months (range, 12-105). During follow-up, 16 SELs (25%) increased in size, with a mean increase of 3.4 3.9 mm (range, 1-15). No changes in echo-texture of the SELs were observed. One patient was referred to surgery during follow-up (because of SEL growth O 30 mm). Limitations: Short follow-up duration; compliance was a secondary aim. Conclusions: During a median follow-up of 30 months, growth in size was observed in 25% of small foregut SELs. However, change in size was minimal, and only 1 patient was referred for surgery based on surveillance EUS findings. Compliance with surveillance recommendations is poor, with fewer than 50% of patients undergoing surveillance EUS as recommended. (Gastrointest Endosc 2015;81:1378-84.)
Subepithelial lesions (SELs) in the lumen of the GI tract are incidentally identified in approximately 1 in every 300 upper endoscopies.1 When discovered during endoscopy,
SELs pose a diagnostic challenge because optical endoscopy only visualizes the mucosa, and tissue acquisition by mucosal biopsy is of limited value.2 SELs
Abbreviations: GIST, GI stromal tumor; IQR, interquartile range; SEL, subepithelial lesion.
Current affiliations: Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA (1), Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA (2).
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. See CME section; p. 1439. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2014.11.013 Received June 9, 2014. Accepted November 5, 2014.
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Presented at Digestive Disease Week, May 18-21, 2013, Orlando, Florida. (Gastrointest Endosc 2013;77:5:AB363-4). Reprint requests: Dayna S. Early, MD, Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8124, St Louis, MO 63110. If you would like to chat with an author of this article, you may contact Dr Early at [email protected].
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range from benign lesions (lipoma, duplication cyst) to tumors of variable malignant potential, such as GI stromal tumors (GISTs) and neuroendocrine tumors.3,4 Cross-sectional imaging, specifically CT, can be used to evaluate SELs; however, evaluation of SELs on crosssectional imaging is limited by the spatial resolution of the scanner, particularly for smaller lesions. EUS is the preferred modality for evaluation of SELs discovered on endoscopy because it allows for the evaluation of lesion size, layer of origin, and morphologic features; moreover, EUS allows for tissue acquisition from SELs by FNA or tru-cut biopsy sampling.5,6 Current National Comprehensive Cancer Center guidelines recommend performing EUS to characterize and sample SELs.7 Most SELs are mesenchymal tumors of the GI tract, such as leiomyoma and GIST.3,8 These lesions typically present as a hypoechoic SEL in the second (muscularis mucosa) or fourth (muscularis propria) echo-layers of the GI tract.6,9 Surgical resection is recommended for lesions with features associated with high malignant potential, such as size O 3 cm and positive staining for CD117/c-kit on immunohistochemistry, irregular outer margins, echogenic foci, presence of cystic spaces, inhomogeneous echo-texture, or pathologic lymphadenopathy on EUS. Surveillance is recommended for smaller lesions (!2-3 cm) without high-risk features.7,10-12 However, this recommendation is based largely on expert opinion, because the natural history of incidentally discovered SELs is poorly understood.4 Long-term data with regard to EUS-based surveillance of small, incidentally discovered SELs are limited and based largely on retrospective case series.13-15 As such, the optimal approach to the EUS evaluation and surveillance of small SELs is unknown. Furthermore, the impact of and compliance with recommended follow-up for SELs is unclear. Our primary aim in this study was to determine the natural history of small SELs discovered incidentally during upper endoscopy and evaluated by EUS. The secondary aims were to determine the degree of patient compliance with surveillance recommendations, describe the diagnostic yield of EUS FNA/tru-cut biopsy sampling in evaluating SELs, and compare SEL size estimation based on EUS, EGD, and CT.
METHODS Consecutive adult patients (O18 years old) referred for EUS evaluation of foregut SELs at 2 tertiary care centers between August 2008 and August 2012 were invited to participate in this prospective cohort study. Patients were excluded if they were unable to provide written informed consent. Demographic characteristics were recorded before endoscopy. When available, pre-endoscopy CT studies were reviewed and SEL size and radiographic features were recorded. EUS findings and follow-up recomwww.giejournal.org
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mendations were recorded by the attending gastroenterologist at the completion of the procedure on a study data form. Follow-up data were collected by manual review of the institutional electronic medical record. The study was approved by the Institutional Review Board of Washington University School of Medicine/Barnes Jewish Hospital (IRB no. 201104076) and Northwestern University Feinberg School of Medicine.
Endoscopic and endosonographic examination All endoscopic procedures were performed by 1 of 6 experienced endosonographers. At the time of EUS examination, all patients first underwent upper endoscopy using an adult gastroscope (GIF-H180; Olympus Medical Systems, Center Valley, Pa). Lesion location was noted and the lesion measured to the nearest millimeter using an Olympus measuring device. EUS examinations were then performed using a radial and/or linear echoendoscope (GF UE 160; Olympus Medical Systems) or with an ultrasonographic mini-probe (12-20 MHz; Olympus Medical Systems), at the discretion of the attending endoscopist. During endosonographic evaluation, the following SEL characteristics were recorded: layer of origin, maximum diameter, regularity of extraluminal border, echo-pattern, and presence of echogenic foci or cystic spaces. While measuring the SEL during EUS, the endosonographer was blinded to the measurement display on the monitor until the measurement was completed.
Tissue acquisition Sampling of the SEL was performed at the discretion of the endoscopist, using FNA or tru-cut biopsy or cold “tunnel” biopsy sampling. The diagnostic yield of individual sampling modalities and overall diagnostic yield for tissue acquisition were calculated. During the time of the study, it was our practice to obtain tissue from all SELs R 10 mm in size, unless they demonstrated classic EUS features of a lipoma (hyperechoic third-wall-layer SELs) or cyst.
Treatment algorithm Patients with SELs O 30 mm or with other high-risk features (irregular outer margins, echogenic foci, presence of cystic spaces, inhomogeneous echo-texture, pathologic lymphadenopathy) were referred for consideration of surgical resection. No surveillance was recommended for clearly benign SELs (hyperechoic third-wall-layer SELs, duplication cysts, biopsy specimen–proven pancreatic rest, or esophageal leiomyoma). The management of gastric leiomyoma O 30 mm in size was not standardized. Annual surveillance was recommended for patients with indeterminate SELs (those not meeting the above-listed criteria).
Postprocedure surveillance Follow-up recommendations were discussed with patients immediately after the procedure and when Volume 81, No. 6 : 2015 GASTROINTESTINAL ENDOSCOPY 1379
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pathology data became available, and patients and their referring physicians were provided with written copies of endoscopy and pathology reports. Patients for whom surveillance was recommended were contacted by phone to schedule a repeat EUS, approximately 11 months after initial examination. In cases in which patients could not be contacted by telephone, a reminder letter was sent to the patient’s home address. Patients were considered to be compliant with surveillance recommendations if they underwent a follow-up EUS 12 to 36 months after the initial examination. During surveillance examinations, EUS lesion size and endosonographic characteristics were recorded. Tissue was obtained at the time of repeat examination if change was noted in SEL echo-features or growth in size was noted and the lesion had not been previously sampled or if initial cytology was nondiagnostic or inconclusive (ie, inadequate tissue or spindle cells seen on cytology but c-kit stain could not be performed). Patients were referred for consideration of surgery if the SEL developed features suggestive of progression (increase in size by R10 mm or to O30 mm or development of highrisk EUS features).
Statistical analysis Data are reported as means standard deviation for normally distributed data and median and range for skewed data. Grouped continuous variable data were compared by using the 2-tailed Student t test and MannWhitney U test where appropriate. Intergroup and categorical comparisons were made using the c2 and Fisher exact tests. P ! .05 was required for statistical significance. All statistical analyses were performed using PASW 19.0 (SPSS, Inc, Chicago, Ill.).
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Compliance with surveillance recommendations Endosonographic surveillance was recommended in 65 patients with hypoechoic SELs (44.6% women; mean age 59.5 13.2 years); of these, 29 (44.6%) underwent surveillance EUS as recommended. Patients underwent initial surveillance EUS a median of 13 months (range, 12-29) after the initial examination.
Findings on surveillance EUS The median duration of follow-up was 30.3 months (range, 12-105); patients underwent a median of 1 surveillance EUS examination (range, 1-3). During follow-up, 16 SELs increased in size; the mean increase was 3.4 3.9 mm (range, 1-15 mm) (Table 1). No changes in echotexture of the SELs were observed. Twelve lesions were sampled during follow-up examinations, which led to a change in management in 2 cases (tissue diagnosis was that of lipoma in both cases and patients were exited from surveillance). Three patients were referred to surgery during follow-up, 2 because of SEL growth (1 increased in size from 29 to 35 mm in 23 months and 1 increased in size from 18 to 29 mm in 12 months; surgical pathology was consistent with a GIST in both) and 1 because of patient preference.
SEL size estimation: EUS versus EGD versus CT
There were 187 patients enrolled in the study, of which 99 were women (52.9%), and the average age was 59.9 13.3 years. No intramural lesion was identified on endoscopic and endosonographic examination in 36 patients (19.3%); 28 lesions were located in the esophagus, 114 in the stomach, and 9 in the duodenum. SEL locations in the wall of the GI tract were as follows: 69 in the muscularis propria, 44 in the submucosa, 29 in the deep mucosa, and 2 in the superficial mucosa; the wall layer of origin could not be clearly determined in 7 cases. One hundred ten SELs were hypoechoic, 33 hyperechoic, and the remaining 8 SEL were cysts within the wall of the GI tract. The outer margins of the SEL were irregular in 28, and cystic spaces were seen in 16. Pathologic lymphadenopathy was not identified in any patient.
When measured on white-light endoscopy, the mean SEL size was 14.0 mm (interquartile range [IQR], 820 mm) and on EUS measurement the mean SEL size was 13.0 mm (IQR, 8.5-22 mm), a median difference of 2 mm (IQR, 1-4.5 mm). A clinically significant difference in size was only identified in 3 cases, in which EUS measured the SEL at O30 mm versus !30 mm on endoscopy. There was good correlation between crosssectional size estimates made using the sizing tool during direct endoscopy and EUS (r Z .90, P ! .001; Fig. 1). CT results were available for review in 24 patients (15.8%); SELs were visualized both endoscopically and endosonographically in all cases. In 4 patients the SEL was not visualized on CT; these lesions measured 9, 10, 11, and 22 mm, respectively, on EUS. The mean size of the SELs visualized on CT was 26 mm (IQR, 16-39 mm) and 27 mm (IQR, 17.333.5 mm) on EUS, a median difference of 6.4 mm (IQR, 2.0-8.2 mm). Again, there was good correlation between cross-sectional size estimates between CT and EUS (r Z .82, P ! .001; Fig. 2). Surgical follow-up was available in 14 cases. The mean size of the SELs on surgical pathology was 34.4 17.3 mm, whereas on EUS the mean size of the lesion was 32.3 12.2 mm. There was no significant difference in SEL size as measured by EUS and the criterion standard (surgical pathology) (r Z .95, P ! .001).
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RESULTS Baseline EUS findings
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TABLE 1. Characteristics of SELs that increased in size during surveillance
Wall layer
Initial size (mm)
Follow-up size (mm)
Change in size (mm)
Tissue diagnosis
Method of tissue diagnosis
Follow-up (mo)
Stomach
4
13
14
1
GIST
EUS
35
2
Esophagus
4
8
15
7
N/A
EUS
105
3
Stomach
4
18
20
2
Pancreatic rest
Surgery*
13
4
Stomach
4
21
22
1
GIST
EUS
80
5
Esophagus
2
5
6
1
N/A
EUS
12
6
Stomach
4
14
15
1
N/A
EUS
36
7
Stomach
4
9
10
1
N/A
EUS
29
8
Stomach
4
29
35
6
GIST
Surgeryy
23
9
Stomach
4
16
17
1
GIST
EUS
12
10
Stomach
4
10
12
2
N/A
EUS
36
11
Esophagus
4
15
16
1
Leiomyoma
EUS
36
12
Stomach
2
18
22
4
GIST
EUS
13
13
Stomach
4
9
11
2
N/A
EUS
28
14
Esophagus
4
14
23
9
Leiomyoma
EUS
42
15
Esophagus
2
10
25
15
N/A
EUS
25
16
Stomach
4
18
29
11
GIST
Surgeryz
12
17
Stomach
4
7
8
1
N/A
EUS
17
Patient
SEL location
1
SEL, subepithelial lesion; GIST, GI stromal tumor; N/A, insufficient tissue to establish diagnosis. *Underwent surgery based on patient preference; pre- and postoperative tissue diagnosis were concordant. yEUS-FNA revealed spindle cells; however, tissue was not sufficient to perform c-kit staining; surgical pathology was consistent with a GIST. zEUS-FNA and surgical pathology were consistent with a GIST.
Tissue acquisition Tissue was obtained from 88 lesions (58.3%) during the initial examination. Sampled SELs were significantly larger than unsampled SELs, with a mean diameter of 21.8 mm versus 10.8 mm (P ! .001), respectively. FNA was performed in 52 cases (34%), and sufficient tissue for cytopathologic examination was obtained in 41 (78.8%). Core needle biopsy specimens were obtained in 15 cases, and sufficient tissue for histopathologic examination was obtained in 10 cases (66.7%). Cold “tunnel” biopsy specimens were obtained in 48 cases, and sufficient tissue for histopathologic examination was obtained in 41 (85.4%). Based on cytology and histology results, a tissue diagnosis was obtained from 67 SELs (76.1%) (Table 2). Surgical follow-up was available in 12 cases in which sufficient tissue was obtained during endoscopy. The preoperative diagnosis was spindle cell neoplasm in all cases, c-kit positive (GIST) in 10 cases and c-kit negative (leiomyoma) in 2. Histopathologic examination of surgical resection specimens revealed spindle cell neoplasm in 11 cases. There was 1 false positive, in which the cytology www.giejournal.org
demonstrated spindle cells; however, on surgical resection the lesion proved to be a pancreatic rest. In spindle cell lesions, c-kit staining was discordant in 1 case; with falsepositive results, surgical pathology served as a criterion standard (Fig. 3).
DISCUSSION Most hypoechoic SELs discovered during upper endoscopy are mesenchymal tumors of the GI tract, such as leiomyoma and GIST. It is widely accepted that surgical resection is the treatment of choice for lesions with highrisk features (size O 3 cm and positive staining for CD117 on immunohistochemistry, irregular margins, or presence of cystic spaces on EUS).7 However, the optimal management strategy for incidentally discovered smaller SELs (!2-3 cm) without high-risk features is unknown. The American Society for Gastrointestinal Endoscopy recommends annual EUS surveillance for such patients to monitor for changes in SEL size and Volume 81, No. 6 : 2015 GASTROINTESTINAL ENDOSCOPY 1381
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TABLE 2. Diagnostic yield of endoscopic tissue acquisition
60
EGD Size (mm)
Tissue diagnosis (n [ 88) Sufficient tissue obtained
40
20
r=0.90, p< .001
0 0
20
40
60
80
100
EUS Size (mm)
GIST
28
Spindle cell neoplasm (c-kit negative)
23
Lipoma
7
Pancreatic rest
5
Heterotopic liver
1
Metastatic renal cell carcinoma
1
Duplication cyst
2
Nondiagnostic Figure 1. Comparison between SEL size as measured by upper endoscopy and EUS.
Value 67 (76.1%)
21 (23.9%)
GIST, GI stromal tumor.
echo-texture that may indicate malignant progression. However, this recommendation is based largely on expert opinion and small retrospective studies.4,6,15-17 The main purpose of the current study was to chart the natural history of small incidentally identified SELs, driven by our anecdotal impression that surveillance rarely identified a clinically significant lesion, and that the American Society for Gastrointestinal Endoscopy surveillance guidelines are based primarily on expert opinion. In this prospective observational study, we found that most hypoechoic SELs ! 3 cm in size do not exhibit a clinically significant change in size or echo-features during a median 30-month follow-up period. During surveillance, 2 of 29 patients were referred for surgery because of an increase in SEL size to O3 cm, and no lesions developed other
high-risk EUS features. These findings are in agreement with the available medical literature on the natural history of hypoechoic SELs ! 3 cm in size. In the only other prospective study on the subject, Nickl et al18 reported in abstract form that 3 of 92 hypoechoic SELs ! 3 cm in size demonstrated change in EUS size or appearance, meeting criteria for surgical referral during a 36-month follow-up. Similarly, retrospective studies demonstrated that fewer than 15% of patients with hypoechoic SELs ! 3 cm in size have clinically significant changes detected on EUS-based surveillance during intermediate term follow-up (24-36 months).13,14,16,17,19 Because the c-kit mutation appears to be an early event in the evolution of GISTs (and may not be a reliable biomarker for identifying clinically significant tumors),20 it appears reasonable to perform serial surveillance at intervals of at least 24 to 36 months instead of yearly in patients with hypoechoic SELs ! 3 cm in size and without high-risk EUS features. A second finding of our study is that fewer than 50% of patients completed at least 1 surveillance EUS. The poor rate of patient compliance seen in our study mirrors the results of the Hypoechoic Intramural Tumor Study in which only 50% of patients underwent the first surveillance EUS.18 In that study, patients were contacted by a study coordinator for follow-up; in our study, patients were contacted by phone to schedule a repeat EUS, and if telephone contact could not be made, a reminder letter was sent by an endoscopy nurse as part of our usual clinical practice. The reasons behind the poor compliance with surveillance in this patient population are unknown, but the lack of compliance suggests that recommending surveillance of SELs ! 3 cm in size is a poor management strategy if compliance is low. This low rate of compliance with follow-up recommendations suggests that when technically feasible, tissue acquisition should be pursued,
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60
CT size (mm)
50
40
30
20
r=0.82, p< .001
10 10.00
20.00
30.00
40.00
50.00
60.00
EUS size (mm)
Figure 2. Comparison between SEL size as measured by CT and EUS.
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Figure 3. Lesion arising from the muscularis mucosa on (A) white-light endoscopy and (B) EUS. C, c-kit staining on core biopsy was weakly positive. D, c-kit staining on the surgically resected specimen was negative.
because a tissue diagnosis may help to reassure the patient, guide surveillance recommendations, and in some cases eliminate the need for follow-up EUS examinations. This study and other recent reports demonstrate that an accurate tissue diagnosis can be obtained for a large majority of SELs using the currently available endoscopic tissue acquisition modalities and will likely increase further with the introduction of new fine-needle biopsy sampling platforms.21,22 An alternative to surveillance is removal of these lesions, particularly with the emergence of minimally invasive and endoscopic methods of en-bloc SEL removal.23-25 When surveillance is recommended, this may be performed with EGD rather than EUS or CT based on the finding of our study that EGD estimates of SEL size correlate well with EUS measurement. This requires further study, however. Before the present study only 1 report had evaluated the comparison between SEL size with different diagnostic modalities. In a prospective study, Hwang et al2 found good correlation between SEL size measurements made on endoscopy and EUS. Similarly, we found a very strong correlation between endoscopic and EUS size measurement of SELs. Moreover, we found SELs visualized on both EUS and CT showed a good correlation between size measurements; however, SELs ! 15 mm in size were not reliably visualized on CT scan, so that CT imaging may not be an appropriate surveillance modality for small SELs. There are several limitations to the present study. Foremost was the O50% loss to follow-up observed in our cohort, despite recommendations for a 12-month www.giejournal.org
follow-up in all patients with hypoechoic SELs. This limits our ability to draw definitive conclusion regarding the natural history of incidental SELs. However, our findings are consistent with the existing medical literature showing a low risk of progression in small hyopechoic SELs. A second limitation is that a precise histopathologic diagnosis was not available in a number of patients in the surveillance cohort, because of the known limitations of the currently available endoscopic tissue acquisition methods. Additionally, we did not prospectively collect data pertaining to the reason(s) for patient noncompliance with post-EUS surveillance recommendations and can only speculate on the factors leading to poor compliance with post-EUS recommendations. Finally, it is important to acknowledge that the median surveillance period in our cohort was less than 3 years. It remains possible that the incidence of SEL progression in this cohort would have been higher during longer-term follow-up. In conclusion, the results of this study indicate that most hypoechoic SELs! 3 cm in size do not exhibit a clinically significant change in size or EUS features during a median 30-month follow-up. Based on this finding, we believe it is reasonable to perform surveillance examinations at intervals of at least 24 to 36 months. However, compliance with serial surveillance in this patient population is poor, suggesting that surveillance of small asymptomatic SELs is not an effective management strategy unless compliance with surveillance can be increased. Finally, we observed excellent correlation between small SEL size measured by EUS and EGD, suggesting that upper Volume 81, No. 6 : 2015 GASTROINTESTINAL ENDOSCOPY 1383
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1. Hedenbro JL, Ekelund M, Wetterberg P. Endoscopic diagnosis of submucosal gastric lesions. The results after routine endoscopy. Surg Endosc 1991;5:20-3. 2. Hwang JH, Saunders MD, Rulyak SJ, et al. A prospective study comparing endoscopy and EUS in the evaluation of GI subepithelial masses. Gastrointest Endosc 2005;62:202-8. 3. Humphris JL, Jones DB. Subepithelial mass lesions in the upper gastrointestinal tract. J Gastroenterol Hepatol 2008;23:556-66. 4. Hwang JH, Rulyak SD, Kimmey MB, et al. American Gastroenterological Association Institute technical review on the management of gastric subepithelial masses. Gastroenterology 2006;130: 2217-28. 5. Alkhatib AA, Faigel DO. Endoscopic ultrasonography-guided diagnosis of subepithelial tumors. Gastrointest Endosc Clin North Am 2012;22: 187-205, vii. 6. Mullady DK, Tan BR. A multidisciplinary approach to the diagnosis and treatment of gastrointestinal stromal tumor. J Clin Gastroenterol 2013;47:578-85. 7. Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw 2010;8(Suppl 2):S1-41; quiz S42-4. 8. Brand B, Oesterhelweg L, Binmoeller KF, et al. Impact of endoscopic ultrasound for evaluation of submucosal lesions in gastrointestinal tract. Dig Liver Dis 2002;34:290-7. 9. Chak A. EUS in submucosal tumors. Gastrointest Endosc 2002;56:S43-8. 10. Palazzo L, Landi B, Cellier C, et al. Endosonographic features predictive of benign and malignant gastrointestinal stromal cell tumours. Gut 2000;46:88-92.
11. Ha CY, Shah R, Chen J, et al. Diagnosis and management of GI stromal tumors by EUS-FNA: a survey of opinions and practices of endosonographers. Gastrointest Endosc 2009;69:1039-44. 12. Shah P, Gao F, Edmundowicz SA, et al. Predicting malignant potential of gastrointestinal stromal tumors using endoscopic ultrasound. Dig Dis Sci 2009;54:1265-9. 13. Bruno M, Carucci P, Repici A, et al. The natural history of gastrointestinal subepithelial tumors arising from muscularis propria: an endoscopic ultrasound survey. J Clin Gastroenterol 2009;43:821-5. 14. Lok KH, Lai L, Yiu HL, et al. Endosonographic surveillance of small gastrointestinal tumors originating from muscularis propria. J Gastrointestin Liver Dis 2009;18:177-80. 15. Kim MY, Jung HY, Choi KD, et al. Natural history of asymptomatic small gastric subepithelial tumors. J Clin Gastroenterol 2011;45:330-6. 16. Lim YJ, Son HJ, Lee JS, et al. Clinical course of subepithelial lesions detected on upper gastrointestinal endoscopy. World J Gastroenterol 2010;16:439-44. 17. Gill KR, Camellini L, Conigliaro R, et al. The natural history of upper gastrointestinal subepithelial tumors: a multicenter endoscopic ultrasound survey. J Clin Gastroenterol 2009;43:723-6. 18. Nickl N, Gress F, McClave S, et al. Hypoechoic Intramural Tumor Study: final report. Gastrointest Endosc 2002;55:AB98. 19. Lachter J, Bishara N, Rahimi E, et al. EUS clarifies the natural history and ideal management of GISTs. Hepatogastroenterology 2008;55:1653-6. 20. Muenst S, Thies S, Went P, et al. Frequency, phenotype, and genotype of minute gastrointestinal stromal tumors in the stomach: an autopsy study. Hum Pathol 2011;42:1849-54. 21. Komanduri S, Keefer L, Jakate S. Diagnostic yield of a novel jumbo biopsy “unroofing” technique for tissue acquisition of gastric submucosal masses. Endoscopy 2011;43:849-55. 22. Ahmed AM, Bass M, Goodman AJ, et al. A prospective single center comparison of EUS-guided core biopsy and EUS-guided fine needle aspiration for suspected upper GI lesions. Gastrointest Endosc 2013;77:AB397. 23. Catalano F, Rodella L, Lombardo F, et al. Endoscopic submucosal dissection in the treatment of gastric submucosal tumors: results from a retrospective cohort study. Gastric Cancer 2013;16:563-70. 24. Binmoeller KF, Shah JN, Bhat YM, et al. Suck-ligate-unroof-biopsy by using a detachable 20-mm loop for the diagnosis and therapy of small subepithelial tumors (with video). Gastrointest Endosc 2014;79:750-5. 25. Arezzo A, Verra M, Miegge A, et al. Loop-and-let-go technique for a bleeding, large sessile gastric gastrointestinal stromal tumor (GIST). Endoscopy 2011;43(Suppl 2 UCTN):E18-9.
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endoscopy could be used for surveillance when access to EUS is limited, which could increase compliance with surveillance recommendations. Areas for future research include improving minimally invasive means to remove SELs that do not meet criteria for surgical resection so that surveillance is unnecessary and developing means to improve risk stratification for patents who would benefit from surveillance.
REFERENCES
