Accuracy of EUS in the evaluation of small gastric subepithelial lesions

ORIGINAL ARTICLE: Clinical Endoscopy

Accuracy of EUS in the evaluation of small gastric subepithelial lesions Cetin Karaca, MD,* Brian G. Turner, MD,* Sevdenur Cizginer, MD, David Forcione, MD, William Brugge, MD Boston, Massachusetts, USA

Background: EUS combined with endoluminal resection techniques is increasingly used to provide a definitive diagnosis of small gastric subepithelial lesions seen on standard upper endoscopy. Objective: To evaluate the accuracy of EUS in diagnosing small gastric subepithelial lesions by using histology as the criterion standard. Design: A retrospective study. Setting: Academic tertiary care center. Patients: A total of 22 patients (15 women, mean age 62.2 years) with an endoscopically resected gastric subepithelial lesion were included in this 3-year retrospective study. Main Outcome Measurements: The size, echogenicity, the layer of origin, and presumptive diagnosis were determined by EUS. The diagnostic accuracy of EUS was determined by using histology as the criterion standard. Results: The mean size of the 22 lesions was 13.6 mm (range 8-20 mm). An endoscopic cap band mucosectomy device was used to resect 16 (72.7%) lesions, whereas 6 (27.3%) were resected with a saline solution–assisted and snare technique. Using histology as a criterion standard, we found that the accuracy of the EUS diagnosis was 10 of 22 (45.5%). EUS alone had an accuracy rate of 30.8% and 66.7%, respectively, in the diagnosis of neoplastic and non-neoplastic lesions. Limitations: A single-center, retrospective analysis. Conclusion: EUS imaging had a low accuracy rate in the diagnosis of gastric subepithelial lesions, and endoscopic submucosal resection should be performed to provide a histologic diagnosis. Resection of small subepithelial lesions of 20 mm or less can be accomplished en bloc with an endoscopic cap band mucosectomy device. (Gastrointest Endosc 2010;71:722-7.)

The term subepithelial lesion is applied to a mass or bulge covered by normal-appearing mucosa identified during standard endoscopy. These lesions are usually

Copyright ª 2010 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.10.019

found incidentally during GI endoscopy. In a study of 15,104 patients undergoing routine upper endoscopy, the incidence of gastric subepithelial lesions (GSLs) was reported as 0.36%.1 Differentiation between benign and malignant lesions is of great clinical consequence; however, the accurate diagnosis of GSLs can be challenging because of the low diagnostic yield of conventional biopsies during gastroscopy.1,2 Alternative imaging methods to characterize GSLs such as transabdominal US, CT, and magnetic resonance imaging have been used, but are often insufficient.3-5 EUS is increasingly being used to assess these lesions because of its ability to differentiate GSLs from extraluminal structures, identify the layers of origin, and establish the echo pattern and size of intraluminal lesions.6,7 EUS alone has been shown to have a sensitivity and a specificity

722 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 4 : 2010

www.giejournal.org

Abbreviations: ESMR, endoscopic submucosal-mucosal resection; GIST, GI stromal tumor; GSL, gastric subepithelial lesion; MALT, mucosa-associated lymphoid tissue. DISCLOSURE: The following author disclosed a financial relationship relevant to this publication: W. Brugge: Consultant to Boston Scientific. All other authors disclosed no financial relationships relevant to this publication. * These authors contributed equally to the concept, design, and writing of this article and share first authorship.

Karaca et al

of 64% and 80%, respectively, in the differentiation of malignant and benign subepithelial lesions.8 The combination of EUS and FNA allows cytologic evaluation of GSLs, particularly GI stromal tumors (GISTs), with studies reporting accuracies of 80% to 91%.9-11 In general, surgical resection has been recommended as the criterion standard treatment of GSLs. The relatively recent introduction of an endoscopic submucosal-mucosal resection (ESMR) technique permits pathologic diagnosis and offers the opportunity for a complete resection. One study demonstrated that ESMR had a significantly better diagnostic yield (89%) compared with the use of jumbo biopsy forceps (42%).12 A more recent prospective head-to-head comparison of ESMR and jumbo forceps also found a significant difference in the use of ESMR and jumbo forceps with respective diagnostic yields of 87% and 17%.13 Characterizing small, early-stage subepithelial lesions can be challenging because of a lack of well-defined echosonographic features. To our knowledge, few studies have examined the accuracy of EUS alone in establishing a diagnosis of small GSLs. Hwang et al14 reviewed the histology of 23 cases of GSLs obtained by EUS with FNA, snare resection, or EMR and found the EUS diagnosis correct in only 48% of cases.14 The objective of this study was to determine the accuracy of EUS imaging alone in the diagnosis of GSLs with confirmed histologic samples (en bloc) acquired with the use of an endscopic cap band mucosectomy device or saline solution lift technique.

PATIENTS AND METHODS Study design All patients referred to Massachusetts General Hospital between November 2005 and November 2008 undergoing EUS evaluation and concomitant resection of a subepithelial lesion were identified from the Provation Medical (Minneapolis, Minn) electronic procedure database by an attending gastroenterologist. Procedure reports and pathology reports obtained from the patient’s online medical record were reviewed and entered into an Excel database. The study was approved by the Partners Human Research Committee Institutional Review Board.

Endoscopic resection Informed consent was obtained from each patient for all procedures described. All procedures were performed with the patients under monitored anesthesia care in a hospital-based endoscopy suite. Two experienced endosonographers performed the procedures by using linear echoendoscopes (5-7.5 MHz; Pentax Medical Co, Montvale, NJ) to characterize the subepithelial lesion. The size of the lesion was determined by recording the largest cross-sectional measurement as determined by EUS. After evaluation of the size and confines of the lesions, ESMR was performed. The method of resection was left to the www.giejournal.org

EUS accuracy in gastric subepithelial lesions

Capsule Summary What is already known on this topic d

Accurate diagnosis of gastric subepithelial lesions can be challenging because of the low diagnostic yield of conventional biopsy specimens obtained during gastroscopy.

What this study adds to our knowledge d

In a retrospective study of 22 patients who underwent endoscopic resection of a gastric subepithelial lesion, the accuracy of the EUS diagnosis was 45.5% compared with histologic results.

discretion of the endoscopist. A snare technique after the injection of saline solution and epinephrine was used to remove the lesion from the submucosa. An endoscopic cap band mucosectomy device (Cook Medical Inc, Bloomington, Ind) was used without saline solution or epinephrine injection. In both techniques, after snare closure, the entrapped tissue was resected by applying blended current cautery (ICC 200 Endocut; Erbe USA Inc, Marietta, Ga) at a setting of 30-W and 60-W output. Patients were observed in the recovery room for at least 2 hours after the procedure. A postprocedure oral proton pump inhibitor (twice daily) was administered to all patients.

Histopathologic assessment Immediately after resection, the retrieved ESMR specimens were flattened and pinned at their periphery with thin needles into a backing before immersion in formalin. Serial sections at 2-mm intervals were then obtained for histopathologic examination. The sections were sequentially submitted in either 1 or a few cassettes, routinely processed, and stained with hematoxylin and eosin.

Statistical analysis Patient demographics and subepithelial tumor characteristics were analyzed. Summary statistics including mean size and range as well as accuracy were determined for the lesions. The diagnostic accuracy of EUS was determined by comparing the endoscopist’s impression on the electronic procedure report with histologic findings.

RESULTS During the study period, 22 patients undergoing standard endoscopy, EUS, and endoscopic resection of a subepithelial tumor were identified. Two experienced endosonographers performed all EUS-ESMR procedures. The patients ranged in age from 28 to 84 years, with a mean age of 60.2 years. There were 15 women (68.2%) Volume 71, No. 4 : 2010 GASTROINTESTINAL ENDOSCOPY 723

EUS accuracy in gastric subepithelial lesions

Karaca et al

Figure 1. A, Linear EUS image of a small GSL. B, Standard endoscopic view of a pancreatic rest. C, A GSL after banding with the endoscopic cap band mucosectomy device. D, Appearance of mucosa after resection of the lesion with an electrocautery snare. E, Explanted specimen after ESMR.

included in the analysis. GSLs were diagnosed incidentally in 17 (77%) patients undergoing evaluation for symptoms of dyspepsia or reflux. Five (23%) patients were evaluated for a history of carcinoid tumor (2 patients), anemia, mucosa-associated lymphoid tissue (MALT), or GIST. The mean tumor size determined by EUS was 13.6 mm (range 8-20 mm). The mucosectomy device was used to resect 16

(73%) GSLs (Fig. 1), whereas 6 (27%) were resected with the saline solution–assisted technique. All lesions were removed en bloc, except in 1 patient in whom the saline solution–assisted technique was used. An intraoperative bleeding complication occurred in 1 (17%) of 6 patients when ESMR was performed with the saline solution–assisted technique. No intraoperative bleeding complications

724 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 4 : 2010

www.giejournal.org

Karaca et al

EUS accuracy in gastric subepithelial lesions

TABLE 1. Presumptive diagnosis by EUS in gastric subepithelial lesions No. histologic diagnoses

No. presumptive EUS diagnoses

EUS and pathology findings in agreement (no.)

Accuracy of EUS imaging no./no. (%)

10

7

5

5/10 (50.0)

Leiomyoma

2

0

1

1/2 (50.0)

GIST

0

5

0

0/0 undefined*

Carcinoid

2

7

2

2/2 (100.0)

MALT

2

1

1

1/2 (50.0)

Lipoma

1

1

1

1/1 (100)

Parietal cell hyperplasia

1

0

0

0/1 (0)

Fibroid polyp

1

0

0

0/1 (0)

Gastritis cystica profunda

2

0

0

0/2 (0)

Foveolar hyperplasia

1

0

0

0/1 (0)

Inflammatory

0

1

0

22

22

10

GSL Pancreatic rest

Total

0/0 undefined*

GSL, Gastric subepithelial lesion; GIST, GI stromal tumor; MALT, mucosa-associated lymphoid tissue. *The term undefined denotes division by 0 because of the absence of a histologic diagnosis of GIST or an inflammatory lesion.

TABLE 2. Gastric subepithelial lesions and EUS layer of origin by histology GSL

Muscularis mucosa (layer 1) Lamina propria (layer 2) Submucosa (layer 3) Muscularis propria (layer 4)

Pancreatic rest

1

1

8

0

Leiomyoma

1

0

0

1

MALT

2

0

0

0

Carcinoid

1

1

0

0

Fibroid polyp

0

1

0

0

Lipoma

0

0

1

0

Gastritis cystica profunda

0

0

2

0

Parietal cell hyperplasia

0

0

1

0

Foveolar hyperplasia

1

0

0

0

GSL, Gastric subepithelial lesion; MALT, mucosa-associated lymphoid tissue.

were seen with the mucosectomy device. No patients required a return visit for additional resection.

Accuracy of diagnosis

Histopathology was performed for all 22 patients. The diagnoses included pancreatic rest in 10 patients, carcinoid tumor in 2 patients, MALT in 2 patients, leiomyoma in 2 patients, gastritis cystica profunda in 2 patients, and 1 each of parietal cell hyperplasia, foveolar hyperplasia, lipoma, and fibroid polyp in the remaining patients.

The presumptive imaged-based diagnosis by EUS agreed with the histopathologic results in 10 (45.5%) of 22 cases. The results for each case are outlined in Table 1. The majority (58.3%) of incorrectly diagnosed lesions by EUS originated from the third layer. The origins of all lesions are outlined in Table 2. On histology, these incorrectly diagnosed lesions were determined to be pancreatic rests (n Z 5), gastritis cystica profunda (n Z 2), and 1 each of a fibroid polyp, MALT, leiomyoma, parietal cell hyperplasia, and foveolar hyperplasia.

www.giejournal.org

Volume 71, No. 4 : 2010 GASTROINTESTINAL ENDOSCOPY 725

Histologic outcomes

EUS accuracy in gastric subepithelial lesions

EUS imaging alone predicted non-neoplastic lesions (pancreatic rest, lipoma, inflammatory) in 6 (66.7%) of 9 cases and neoplastic lesions (carcinoid or MALT) in 4 (30.8%) of 13 cases. The most commonly misdiagnosed lesions on EUS were neoplastic lesions, especially presumed GISTs and carcinoid tumors.

Karaca et al

EUS is a relatively new endoscopic technology, and recent studies showed that it seems to be of great value in the evaluation of GSLs.10,15 When a GSL is identified, EUS is the diagnostic test of choice to assess the size, margins, layer of origin, echotexture of the lesion, presence of adjacent lymph nodes and to differentiate between intramural and extramural lesions. The most common GSLs encountered during gastroscopy are GISTs. GISTs are characterized by a hypoechoic appearance and originate from the fourth hypoechoic endosonographic layer at EUS. Irregular extraluminal border, cystic areas, echogenic foci, and size greater than 30 mm are associated with invasive GISTs. However, the behavior of a GIST that is 3 or 4 cm and contains only 1 or 2 distinguishing EUS features is difficult to predict.16,17 Lipomas are the second most common GSLs encountered during gastroscopy. Lipomas are typically identified as hyperechoic neoplasms in the third layer.15 Carcinoid tumors are generally homogeneous, well demarcated, and hyperechoic. They are usually present in the first, second, and third endosonographic layers. The behavior of carcinoid tumors can be predicted by the tumor size. Carcinoid tumors larger than 2 cm in maximal cross-sectional dimension on EUS are more likely to be malignant.18 Pancreatic rests may appear as hypoechoic or mixed echogenicity lesions in the second, third, or fourth layer.6 Cysts appear as anechoic, rounded or ovoid, compressible structures in the third layer of the GI tract.19,20 Although these EUS findings are helpful in categorizing a lesion, they cannot absolutely determine the type of lesion or whether a lesion is benign or malignant. In the current study, EUS was better for diagnosing non-neoplastic GSLs than for neoplastic lesions with respective accuracies of 66.7% and 30.8%. The EUS accuracy was only fair in predicting the ultimate histology of non-neoplastic lesions and quite poor in the case of neoplastic lesions. Many investigators have used EUS guidance with FNA to obtain diagnostic histologic material from GSLs, but this technique has had limited success. This limitation is mainly because of the firm nature of GSLs, poor cytologic yield, and the large amount of force required to penetrate the neoplasm with small-gauge needles.21,22 GSLs pose a diagnostic challenge, often requiring resection to establish a definitive diagnosis. EUS-guided FNA or trucut biopsy of GSLs can help to establish a tissue diagnosis and potentially characterize malignant risk. Fu et al9

examined 10 patients with GISTs undergoing preoperative evaluation by EUS-FNA. Cytologic results were compared with surgical specimens. The study by Fu et al showed that EUS-FNA effectively diagnosed GISTs preoperatively in 80% of cases, when the EUS-FNA cytology specimen was combined with immunocytochemical studies. A prospective study evaluating the accuracy of EUS in characterizing 100 consecutive patients with submucosal lesions found that standard endoscopy had a sensitivity of 98% and a specificity of 64% in identifying intramural lesions. Histologic confirmation was obtained by EUS-FNA, snare resection, or EMR in 23 cases, with presumptive EUS diagnosis correct in only 48% of cases. Most misdiagnoses occurred with hypoechoic lesions in the third and fourth layers.14 In the current study, 22 GSLs were evaluated and the EUS diagnosis was compared with histologic findings in each patient. Unlike the study by Hwang et al,14 all lesions in our series were completely resected and sent for histology. Similarities of our study and Hwang et al include an accuracy rate of 45% in the EUS prediction of histologic diagnosis and the observation that most misdiagnosed lesions occurred in the third echosonographic layer. Our study suggests that EUS alone is insufficient for characterizing small GSLs. In a separate study, the interobserver agreement among experienced endosonographers was poor in the diagnosis of neoplastic lesions such as carcinoids, metastases, and granular cell tumors.23 In our study, the accuracy of EUS in the evaluation of GSL was low, but the mean size of lesions in our study population was quite small, with an average size of 13.6 mm. All patients were examined by the lower frequency standard EUS. For small (!1 cm) lesions, imaging with high-frequency catheter probes may be technically easier than using low-frequency standard EUS. High-frequency catheter probes (12, 20, and 30 MHz) permit more detailed imaging of the GI wall compared with the lower frequency standard EUS.24 The use of low-frequency catheter probes in our study could have contributed to a lower accuracy rate. EUS guides patient management and can help determine whether a lesion should be followed clinically or removed (endoscopically or surgically). The introduction of EUS and ESMR has changed the management of small subepithelial lesions (!3 cm) by allowing many lesions to be removed en bloc in 1 endoscopic session. In this study, GSLs were removed en bloc in 21 (95%) of 22 patients. Postresection bleeding occurred in 1 (4.5%) of 22 patients undergoing resection (the 1 complication was seen with the saline solution–assisted technique). Our results suggest that an endoscopic cap band mucosectomy device successfully accomplishes en bloc resection of small GSLs and has a low rate of intraoperative complications. The limitations of this study are that it was based at a single center and the results may not reflect EUS technologies used at other institutions. The study was also retrospective in nature. The strengths of the study include

726 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 4 : 2010

www.giejournal.org

DISCUSSION

Karaca et al

examination of all patients by 2 endosonographers, a good number of patients, and available histologic results. Although at first the patient number seems small, it represents a sizable number considering the low incidence of GSLs (0.36%) in patients undergoing routine endoscopy.

CONCLUSION EUS imaging alone has a low accuracy rate in the diagnosis of GSLs. EUS technology should be combined with endoluminal resection techniques to obtain pathologic confirmation. In experienced hands, ESMR with an endoscopic cap band mucosectomy device allows en bloc resection of small GSLs with low complication rates.

REFERENCES 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. Crosta C, Meroni E, Alloni R, et al. Gastric submucosal neoplasms: new diagnostic and therapeutic procedures. Ital J Surg Sci 1987;17:131-4. 3. Catalano MF. Endoscopic ultrasonography for esophageal and gastric mass lesions. Gastroenterologist 1997;5:3-9. 4. Tanaka M, Akahoshi K, Chijiiwa Y, et al. Diagnostic value of endoscopic ultrasonography in an unusual case of gastric cyst. Am J Gastroenterol 1995;90:662-3. 5. Sahai AV, Siess M, Kapfer B, et al. Endoscopic ultrasonography for upper gastrointestinal submucosal lesions: a cost minimization analysis with an international perspective. Am J Gastroenterol 2003;98:1989-95. 6. Boyce GA, Sivak MV Jr, Ro¨sch T, et al. Evaluation of submucosal upper gastrointestinal tract lesions by endoscopic ultrasound. Gastrointest Endosc 1991;37:449-54. 7. Nesje LB, Laerum OD, Svanes K, et al. Subepithelial masses of the gastrointestinal tract evaluated by endoscopic ultrasonography. Eur J Ultrasound 2002;15:45-54. 8. Ro¨sch T, Kapfer B, Will U, et al. Accuracy of endoscopic ultrasonography in upper gastrointestinal submucosal lesions: a prospective multicenter study. Scand J Gastroenterol 2002;37:856-62. 9. Fu K, Eloubeidi MA, Jhala NC, et al. Diagnosis of gastrointestinal stromal tumor by endoscopic ultrasound-guided fine needle aspiration biopsyda potential pitfall. Ann Diagn Pathol 2002;6:294-301.

www.giejournal.org

EUS accuracy in gastric subepithelial lesions

10. Ando N, Goto H, Niwa Y, et al. The diagnosis of GI stromal tumors with EUS-guided fine needle aspiration with immunohistochemical analysis. Gastrointest Endosc 2002;55:37-43. 11. Sepe PS, Moparty B, Pitman MB, et al. EUS-guided FNA for the diagnosis of GI stromal cell tumors: sensitivity and cytologic yield. Gastrointest Endosc 2009;70:254-61. 12. Hunt GC, Smith PP, Faigel DO. Yield of tissue sampling for submucosal lesions evaluated by EUS. Gastrointest Endosc 2003;57:68-72. 13. Cantor MJ, Davila RE, Faigel DO. Yield of tissue sampling for subepithelial lesions evaluated by EUS: a comparison between forceps biopsies and endoscopic submucosal resection. Gastrointest Endosc 2006;64:29-34. 14. 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. 15. Chak A. EUS in submucosal tumors. Gastrointest Endosc 2002;56:S43-8. 16. Franquemont DW. Differentiation and risk assessment of gastrointestinal stromal tumors. Am J Clin Pathol 1995;103:41-7. 17. Tio TL, Tytgat GN, den Hartog Jager FC. Endoscopic ultrasonography for the evaluation of smooth muscle tumors in the upper gastrointestinal tract: an experience with 42 cases. Gastrointest Endosc 1990;36:342-50. 18. Yoshikane H, Suzuki T, Yoshioka N, et al. Duodenal carcinoid tumor: endosonographic imaging and endoscopic resection. Am J Gastroenterol 1995;90:642-4. 19. Van Dam J, Zuccaro G Jr, Sivak MV Jr. Endosonographic diagnosis of a submucosal gastric cyst. J Ultrasound Med 1992;11:61-3. 20. Geller A, Wang KK, DiMagno EP. Diagnosis of foregut duplication cysts by endoscopic ultrasonography. Gastroenterology 1995;109:838-42. 21. Wiersema MJ, Wiersema LM, Khusro Q, et al. Combined endosonography and fine-needle aspiration cytology in the evaluation of gastrointestinal lesions. Gastrointest Endosc 1994;40:199-206. 22. Caletti GC, Brocchi E, Ferrari A, et al. Guillotine needle biopsy as a supplement to endosonography in the diagnosis of gastric submucosal tumors. Endoscopy 1991;23:251-4. 23. Gress F, Schmitt C, Savides T, et al. Interobserver agreement for EUS in the evaluation and diagnosis of submucosal masses. Gastrointest Endosc 2001;53:71-6. 24. Waxman I, Saitoh Y, Raju GS, et al. High-frequency probe EUS-assisted endoscopic mucosal resection: a therapeutic strategy for submucosal tumors of the GI tract. Gastrointest Endosc 2002;55:44-9.

Received September 8, 2009. Accepted October 8, 2009. Current affiliations: Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. Reprint requests: William R. Brugge, MD, 55 Fruit Street, Blake 4, Boston, MA 02114.

Volume 71, No. 4 : 2010 GASTROINTESTINAL ENDOSCOPY 727