- Email: [email protected]
Use of Endoscopic Ultrasound to Evaluate Large Gastric Folds: Features Predictive of Malignancy
Ultrasound in Med. & Biol., Vol. 41, No. 10, pp. 2614–2620, 2015 Copyright Ó 2015 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2015.05.017
d
Original Contribution USE OF ENDOSCOPIC ULTRASOUND TO EVALUATE LARGE GASTRIC FOLDS: FEATURES PREDICTIVE OF MALIGNANCY HYUN LIM,* GIN HYUG LEE,* HEE KYONG NA,* JI YONG AHN,* JEONG HOON LEE,* KWI-SOOK CHOI,* DO HOON KIM,* KEE DON CHOI,* HO JUNE SONG,* HWOON-YONG JUNG,* JIN-HO KIM,* DOWHAN KIM,y and YOUNG SOO PARKy * Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, South Korea; and y Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, South Korea (Received 4 July 2014; revised 20 May 2015; in final form 22 May 2015)
Abstract—The aim of this study was to investigate with endoscopic ultrasound (EUS) the features of the gastric wall that can be used to predict malignant disease in patients with large gastric folds. We retrospectively reviewed the EUS findings of 65 patients (26 with benign and 39 with malignant disease) with large gastric folds on endoscopy and EUS and analyzed the predictors of malignant disease (e.g., gastric wall thickness, preservation of fivelayered structure, thickened layers). Gastric wall thickness ($9.8 mm), thickened deep layer, thickened muscularis propria and non-preserved wall layer structures were significantly more prevalent in patients with malignant disease on EUS. Among them, gastric wall thickness ($9.8 mm) (odds ratio 5 6.72, 95% confidence interval 5 1.23–36.73, p 5 0.028) and thickened muscularis propria (odds ratio 5 37.14, 95% confidence interval 5 7.02–196.49, p , 0.001) were significantly associated with malignant disease. Our data indicate that EUS is a useful tool for assessing large gastric folds and that gastric wall thickness ($9.8 mm) and thickened muscularis propria are significant features predictive of malignant disease on EUS. (E-mail: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Large gastric folds, Endoscopic ultrasonography, Gastric neoplasms.
highly accurate for diagnosing malignant diseases that reveal large gastric folds (Chen et al. 2010; Park et al. 2004). However, false-negative findings can occur in up to 50% of cases and require additional analysis methods for confirmation, such as endoscopy and endoscopic ultrasound (EUS) (Dooley et al. 1984). Endoscopy can also identify large gastric folds and obtain specimens for histologic diagnosis. However, the role of endoscopy is limited by the similarities between various benign and malignant diseases. Moreover, standard endoscopic biopsies are often unrevealing and provide low diagnostic yield because they usually only assess superficial mucosa (Andriulli et al. 1990; An-Foraker and Vise 1981; Winawer et al. 1975). Positron emission tomography was recently used to diagnose malignant diseases with high specificity; however, it has low sensitivity for gastric cancer, especially diffuse-type gastric cancers (e.g., signet ring carcinomas) (De Potter et al. 2002). For these reasons, exploratory laparotomy and fullthickness gastric biopsy are frequently required to rule out malignancy (Bjork et al. 1977).
INTRODUCTION Large gastric folds are defined according to several criteria: folds .10 mm on barium upper gastrointestinal series; thickening on abdominal computed tomography (CT); and folds that do not flatten with insufflation during endoscopy (Bjork et al. 1977; Mendis et al. 1994). Large gastric folds are seen in malignant (e.g., adenocarcinoma, lymphoma) and benign (e.g., hypertrophic gastritis, Menetrier’s disease, lymphoid hyperplasia, Zollinger– Ellison syndrome) diseases (Blaser et al. 1991; Levine et al. 1990; Reeder et al. 1974). Therefore, accurate diagnosis is pivotal to predicting prognosis and making treatment plans, but this is a clinical challenge because of the diverse etiology. Barium upper gastrointestinal series and abdominal CT scans are widely available, non-invasive methods for assessment. Recent studies report that these methods are Address correspondence to: Gin Hyug Lee, Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. E-mail: [email protected] 2614
Endoscopic US of large gastric folds d H. LIM et al.
Endoscopic ultrasound can accurately visualize the gastric wall structure, including thickened layers, degree of wall layer preservation and internal echo patterns (Akahoshi et al. 1991; Botet et al. 1991a, 1991b; Nickl and Cotton 1990). Different diseases exhibit different levels of EUS infiltration in the gastric wall and characteristic echo patterns. Thus, EUS aids in the differential diagnosis of large gastric folds. Although EUS is more commonly used to differentiate the causes of large gastric folds, data are still insufficient (Caletti et al. 2000; Gines et al. 2006; Mendis et al. 1994; Songur et al. 1995; Tio 1995). Previous studies indicate that deep-layer thickening on EUS is associated with malignant disease, but further studies are needed. The aim of this study was to investigate the features of the gastric wall on EUS that can be used to predict malignant disease in patients with large gastric folds. METHODS Patient selection and clinical characteristics Between January 2003 and January 2011, 70 patients underwent EUS to evaluate large gastric folds found on endoscopy at our institution. We retrospectively reviewed 65 of the 70 patients who met the following inclusion criteria: (i) thickened gastric wall confirmed on EUS (gastric wall thickness .4 mm); (ii) gold standard evaluation, such as histologically proven malignant disease or clinical follow-up .2 y in patients without histologic diagnosis; (iii) no history of previous gastric surgery or neoplasia. Five patients were excluded because thickened layers were not found on EUS. This observational study was approved by the institutional review board of Asan Medical Center (2013-0025-0002) and required neither patient approval nor informed consent for review of patient images and records; however, informed consent was obtained from all patients for macrobiopsy with snare, EUS-guided fine-needle aspiration (EUS-FNA), and surgery before each procedure. Of 65 patients, 39 (60.0%) were diagnosed with malignant disease (34 adenocarcinomas, four mucosaassociated lymphatic tissue lymphomas and one plasmacytoma) and 26 patients (40.0%) were diagnosed with benign disease (three with gastritis cystica profunda, two with hypertrophic gastritis, two with Menetrier’s disease, one with inflammatory pseudo-tumor and 18 patients with no specific histologic diagnosis) (Table 1). Among patients with malignant disease, the median age was 51 y (range: 32–78) and 7 patients (17.9%) were male. Twenty-four patients (61.5%) presented with the alarm symptoms (age .55 y with new-onset dyspepsia, recent [,3 mo before upper endoscopy/EUS] weight loss of at least 5 pounds, any evidence [clinical or laboratory] of gastrointestinal bleeding, progressive dysphagia,
2615
Table 1. Baseline characteristics of the study patients with large gastric folds
Age (y), median (range) Sex, male/female Duration of follow-up (mo) Alarm symptoms Time from symptom onset to hospital visit (mo) Initial endoscopic diagnosis Malignant disease Benign disease Number of endoscopic biopsy Methods of final diagnosis Histopathologic findings Endoscopic biopsy Endoscopic ultrasound fine-needle aspiration Macrobiopsy with snare Surgery Clinical follow-up
Malignant disease (n 5 39)
Benign disease (n 5 26)
51 (32–78)* 7/32 20 (5–144) 24 2 (0–10)
47 (18–73) 20/6 67 (17–144) 3 0 (0–6)
34 5 2 (1–6)
8 18 2 (1–5)
39 31 1
8 2 1
1 6 0
4 1 18
* Median (range).
odynophagia, persistent vomiting, palpable mass or lymphadenopathy, jaundice) (Talley et al. 2005). All patients were diagnosed on the basis of their histopathologic findings. Of 39 patients, 6 (15.3%) were diagnosed with malignant disease only by explorative laparotomy. Among patients with benign disease, the median age was 47 y (range: 18–73) and 20 patients (76.9%) were male. Eight (30.1%) patients were diagnosed by histopathologic findings, whereas the remaining patients were diagnosed on clinical follow-up using the available gold standard. The median follow-up duration of the latter was 67 mo (range: 24–144), and no patients developed clinical or radiologic aggravation. Of 26 patients, one (3.8%) underwent explorative laparotomy because malignant disease could not be ruled out and inflammatory pseudo-tumor was diagnosed. METHODS The reviewed data include the final diagnosis according to the available gold standard, EUS features of the gastric wall (e.g., thickness of the gastric wall, preservation or non-preservation of the five-layered structure, thickened layers [mucosa and/or submucosal and/or muscularis propria]), presence of ascites and presence of lymph node enlargement with EUS features suggestive of malignant disease (e.g., round or sharp borders, size .1 cm, hypo-echogenicity) (Bhutani et al. 1997; Catalano et al. 1994). The gold standard evaluations used to diagnose malignant or benign diseases include pathologic diagnosis (e.g., biopsy, EUS-FNA, macrobiopsy obtained by diathermic snare or surgery) and
2616
Ultrasound in Medicine and Biology
clinical follow-up examination (Gines et al. 2006). In the latter group, patients were diagnosed with benign disease if they were alive without clinical signs of progression after .2 y of follow-up examinations. Patients were diagnosed with malignant disease when there was evidence of disease progression on CT or ultrasonography. Endoscopic ultrasound was performed by experienced endosonographers using a radial echo-endoscope (GF UM250 or GF UE260; Olympus Medical Systems, Center Valley, PA, USA) provided with switchable ultrasound frequencies of 5, 7.5, 12 and 20 MHz, respectively. The gastric lumen was filled with 300–600 mL of water. Gastric wall thickness was quantitatively assessed, and the measurements were made on the thickest part of the gastric wall. Enlargement of the endosonographic layer was determined by comparison with normal gastric wall layer structure in the neighboring non-thickened gastric wall, and the gastric wall layer was considered thickened if it is more than 1.5 times the normal wall layer thickness. Compared with normal gastric wall structure in the neighboring non-thickened gastric wall, the fivelayered structure was considered preserved if each layer could be clearly identified on EUS (Fig. 1a), and nonpreserved if the thickened layer could be recognized, but distinction between the layers was not clear (Fig. 1b) or the layers were indistinct (Fig. 1c). Layers 1 (superficial mucosa) and 2 (deep mucosa) on EUS were considered superficial, and layers 3 (submucosa and interface), 4 (muscularis propria) and 5 (serosa and subserosal fat) were considered deep (Kimmey et al. 1989; Mendis et al. 1994). EUS-FNA was performed in the standard fashion using a curvilinear array echo-endoscope (GF-UC140 P or GF-UCT140, Olympus Medical Systems). Under EUS guidance, thickened layers were aspirated with a 22gauge EUS-FNA needle (EUS N-3; Cook Medical, Winston Salem, NC, USA). The procedure was repeated until a core of tissue was obtained. Macrobiopsy obtained by diathermic snare was carried out using the strip-off biopsy methods (Komorowski et al. 1986). Under endoscopic observation, saline–epinephrine solution was injected into the submucosa. Then, the elevated mucosa and superficial submucosa were resected by electrocautery snare. After the resected specimen was taken up, addition endoscopic forceps biopsy targeting the exposed submucosal layer was performed. Review of EUS imaging Two independent experienced endosonographers (J.Y.A. and D.H.K.), who were unaware of the final diagnoses, retrospectively reviewed the EUS images to determine their features. In the case of disagreement, these endosonographers met later to review the EUS images and reach consensus.
Volume 41, Number 10, 2015
Statistical analysis Differences were determined using the Fisher exact test, c2-test or Student t-test, as appropriate. Additional multiple logistic regression analyses were performed to identify predictive factors associated with malignant disease. All potential predictive factors with p # 0.05 on univariate analysis were entered into the forward stepwise logistic regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relative risk of malignant disease. In this study, p , 0.05 is considered as indicating statistical significance. All data were analyzed using the Statistical Package for the Social Sciences software (Version 18.0 for Windows, SPSS, Chicago, IL, USA). RESULTS EUS findings indicative of benign and malignant disease Table 2 compares the EUS findings for benign and malignant disease. All EUS findings, except the presence of ascites (p 5 0.078), differed significantly between groups. Among patients with benign disease, median wall thickness was 7.8 mm (range: 4.5–25.7), and the superficial layer was thickened (53.8% of patients). All but one patient had a preserved wall layer structure. No patients presented with ascites or lymph node enlargement. Among patients with malignant disease, median wall thickness was 13.7 mm (range: 6.2–26.0), and the deep layer was mostly thickened (94.9% of patients). Twenty patients (51.3%) had a non-preserved wall layer structure. Five (12.8%) and 11 (28.2%) patients presented with ascites and lymph node enlargement, respectively. Cutoff level of gastric wall thickness predictive of malignant disease The receiver operating characteristic (ROC) curve determining the cutoff value for gastric wall thickness that predicts malignant disease is illustrated in Figure 2. The cutoff value for gastric wall thickness was 9.8 mm, with a sensitivity and specificity of 87.2% and 73.1%, respectively (p , 0.001). The area under the ROC curve was 0.806. EUS gastric wall features predictive of malignant disease Tables 3 and 4 summarize the EUS features of the gastric wall that are predictive of malignant disease. According to the univariate analysis, gastric wall thickness ($9.8 mm), thickened deep layers, thickened muscularis propria and non-preserved wall layer structure are associated with malignant disease (Table 3). On the other hand, a thickened superficial layer is
Endoscopic US of large gastric folds d H. LIM et al.
2617
Fig. 1. Typical endoscopic ultrasound (EUS) and histologic findings of three endosonographic subtypes of large gastric folds. (a) EUS image revealing the preserved five-layered structure (1 5 superficial mucosa, 2 5 deep mucosa, 3 5 submucosa, 4 5 muscularis propria). Each layer is clearly distinguishable (white arrowheads). Histologic examination reveals clear distinction between all layers (black arrowheads). The final diagnosis was hypertrophied gastritis (hematoxylin and eosin [H&E], original magnification 310). (b) EUS image revealing non-preserved five-layered structure. Distinctions between all layers are unclear (white arrowheads); however, thickened muscularis propria is recognizable (white arrow). Histologic examination reveals indistinct layers (black arrowheads) and thickened muscularis propria (black arrow). The final diagnosis was gastric adenocarcinoma, with transmural involvement and its epicenter located primarily in the submucosa (H&E, original magnification 310). (c) EUS image revealing non-preserved five-layered structure. Each layer is undistinguishable. Histologic examination reveals destroyed layers, and it is impossible to distinguish layers. The final diagnosis was gastric adenocarcinoma with transmural involvement (H&E, original magnification 310).
associated with benign disease. Among the significant factors identified by the univariate analysis, gastric wall thickness ($9.8 mm) and thickened muscularis
are significant predictive features associated with malignant disease according to the multivariate analysis (Table 4).
2618
Ultrasound in Medicine and Biology
Table 2. Comparison of endoscopic ultrasound findings in benign and malignant disease Malignant disease (n 5 39)
Volume 41, Number 10, 2015
Table 3. EUS characteristics of the gastric wall according to univariate analysis Odds ratio
Benign disease (n 5 26)
Wall thickness (mm) 13.7 (6.2–26.0)* 7.8 (4.5–25.7) Thickened superficial layer 2 14 Thickened deep layer 37 12 Thickened muscularis propria 35 3 Non-preserved wall layer structure 20 1 Presence of lymph node enlargement 11 0 Presence of ascites 5 0
Gastric wall thickness ($9.8 mm) Thickened superficial layer (1) Thickened deep layer (1) Thickened muscularis propria (1) Non-preserved wall layer structure (1)
95% CI
18.46 5.14–66.22 0.05 0.01–0.23 21.58 4.28–108.89 67.08 13.73–327.88 35.00 4.33–282.82
p ,0.001 ,0.001 ,0.001 ,0.001 0.001
CI 5 confidence interval.
* Median (range).
DISCUSSION Although EUS is very useful for visualizing the architecture of the gastric wall layer, the usefulness of EUS for assessing patients with large gastric folds remains unclear (Caletti et al. 2000; Gines et al. 2006; Mendis et al. 1994; Songur et al. 1995; Tio 1995). Therefore, here we analyzed the EUS features that helped make a differential diagnosis in 65 patients. We report that gastric wall thickness ($9.8 mm) and thickened muscularis propria are the EUS features of the gastric wall that are associated with malignant disease in patients with large gastric folds. Various diseases show different levels of EUS infiltration in the gastric wall, hence clinicians can narrow the possible differential diagnoses using EUS (Caletti et al. 2000). Thickened deep or muscularis propria layers are common EUS findings in patients with large gastric folds
and malignant diseases, whereas a thickened superficial layer is a common finding in benign diseases (Caletti et al. 2000; Gines et al. 2006; Mendis et al. 1994; Songur et al. 1995; Tio 1995). Likewise, a study on patients with large gastric folds and negative biopsy results reports that a thickened deep layer on EUS is associated with malignant disease (Gines et al. 2006). In this study, a thickened superficial layer was significantly more common in patients with benign disease, and thickened deep or muscularis propria layers were more common in patients with malignant disease. In addition, thickened muscularis propria was a significant EUS feature predictive of malignant disease. Our results are consistent with previous studies, thus reinforcing the finding that thickened muscularis propria is a significant predictive feature associated with malignant disease in patients with large gastric folds (Caletti et al. 2000; Gines et al. 2006; Mendis et al. 1994; Songur et al. 1995; Tio 1995). Although EUS is very useful for assessing the architecture of the gastric wall layer, operator dependency is a big demerit of EUS. However, measurement of gastric wall thickness might be a semi-objective method because it may be a quantitative metric. In this study, we found the cutoff value for gastric wall thickness that predicted malignant disease using the ROC curve analysis. The best cutoff value for gastric wall thickness was 9.8 mm, and the area under the ROC curve was 0.806. In addition, gastric wall thickness ($9.8 mm) was significantly associated with malignant disease. To the best of our knowledge, this is the first study to report a cutoff value for gastric wall thickness that predicts malignant disease.
Table 4. Endoscopic ultrasound characteristics of the gastric wall according to multivariate analysis
Fig. 2. Receiver operating characteristic curve determining the cutoff value of gastric wall thickness that predicts malignant disease.
Gastric wall thickness ($9.8 mm) Thickened muscularis propria (1) CI 5 confidence interval.
Odds ratio
95% CI
p
6.72 37.14
1.23–36.73 7.02–196.49
0.028 ,0.001
Endoscopic US of large gastric folds d H. LIM et al.
A non-preserved wall layer structure is regarded as an important EUS finding predictive of malignant disease (Caletti et al. 2000). However, to date, there are no studies that associate non-preserved wall layer structure with malignant disease in patients with large gastric folds. Several studies report an association between nonpreserved wall layer structure and malignant disease, but these do not report statistical associations because of the small numbers of patients included (Gines et al. 2006). In this study, all cases of non-preserved wall layer structure except one were observed in patients with malignant disease, and this was found to be statistically significant in univariate analysis. However, contrary to our expectations, it did not reach statistical significance in multivariate analysis. As in the previous study, this discrepancy might have resulted from the small sample size, although our study included a relatively larger number of patients and non-preserved wall layers in patients with malignant diseases. Further studies are needed. Although this study analyzed only the EUS features of the gastric wall that are predictive of malignant disease, ascites and lymph node enlargement are important extraluminal EUS features that can be used to predict malignant disease (Gines et al. 2006). In this study, no patient with benign disease manifested ascites or lymph node enlargement with EUS features of malignant disease. This finding is consistent with previous studies (Gines et al. 2006) and provides high-value information that could be used to predict malignant disease in patients with large gastric folds, although we did not include the EUS features predictive of malignant disease in this analysis. Interestingly, one female patient whose diagnosis could not be ruled out as malignant disease by many methods, including EUS, was finally diagnosed with inflammatory pseudo-tumor after explorative laparotomy. This case exemplifies the difficulty in clinically distinguishing malignant from benign disease. A case of immunoglobulin G-related pseudo-tumor in the pancreas mimicking pancreatic cancer was reported by Kim et al. (Park et al. 2008). We think this case may be an example of immunoglobulin G-related pseudo-tumor involving the stomach, which is undistinguishable from benign and malignant diseases. Thus, there are subgroups that are undistinguishable from benign and malignant diseases on EUS. Further studies of these subgroups are needed, and additional workup is needed to avoid unnecessary laparotomy. Our study has some potential limitations. First, we could not use standard EUS protocols because our study was retrospective. Second, although our study contained more diverse disease categories compared with previous studies, we could not include all diseases in which there are large gastric folds. However, this is difficult limitation
2619
to overcome because patients with large gastric folds are relatively rare. Third, we included patients without definite histologic diagnoses and used clinical follow-up examinations to make our diagnoses; however, previous studies have also used this method (Gines et al. 2006). CONCLUSIONS Endoscopic ultrasound is a useful tool for assessing patients with large gastric folds. Gastric wall thickness ($9.8 mm) and thickened muscularis propria on EUS are significant features predictive of malignant disease in patients with large gastric folds. Acknowledgments—This article was not supported by grants and funds.
REFERENCES Akahoshi K, Misawa T, Fujishima H, Chijiiwa Y, Maruoka A, Ohkubo A, Nawata H. Preoperative evaluation of gastric cancer by endoscopic ultrasound. Gut 1991;32:479–482. An-Foraker SH, Vise D. Cytodiagnosis of gastric carcinoma, linitis plastica type (diffuse, infiltrating, poorly differentiated adenocarcinoma). Acta Cytol 1981;25:361–366. Andriulli A, Recchia S, De Angelis C, Mazzucco D, Berti E, Arrigoni A, Verme G. Endoscopic ultrasonographic evaluation of patients with biopsy negative gastric linitis plastica. Gastrointest Endosc 1990; 36:611–615. Bhutani MS, Hawes RH, Hoffman BJ. A comparison of the accuracy of echo features during endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration for diagnosis of malignant lymph node invasion. Gastrointest Endosc 1997;45:474–479. Bjork JT, Geenen JE, Soergel KH, Parker HW, Leinicke JA, Komorowski RA. Endoscopic evaluation of large gastric folds: A comparison of biopsy techniques. Gastrointest Endosc 1977;24: 22–23. Blaser MJ, Perez-Perez GI, Lindenbaum J, Schneidman D, Van Deventer G, Marin-Sorensen M, Weinstein WM. Association of infection due to Helicobacter pylori with specific upper gastrointestinal pathology. Rev Infect Dis 1991;13(Suppl 8):S704–S708. Botet JF, Lightdale CJ, Zauber AG, Gerdes H, Urmacher C, Brennan MF. Preoperative staging of esophageal cancer: Comparison of endoscopic US and dynamic CT. Radiology 1991a;181: 419–425. Botet JF, Lightdale CJ, Zauber AG, Gerdes H, Winawer SJ, Urmacher C, Brennan MF. Preoperative staging of gastric cancer: Comparison of endoscopic US and dynamic CT. Radiology 1991b;181:426–432. Caletti G, Fusaroli P, Togliani T, Bocus P, Roda E. Endosonography in gastric lymphoma and large gastric folds. Eur J Ultrasound 2000;11: 31–40. Catalano MF, Sivak MV Jr, Rice T, Gragg LA, Van Dam J. Endosonographic features predictive of lymph node metastasis. Gastrointest Endosc 1994;40:442–446. Chen CY, Jaw TS, Wu DC, Kuo YT, Lee CH, Huang WT, Liu GC. MDCT of giant gastric folds: Differential diagnosis. AJR Am J Roentgenol 2010;195:1124–1130. De Potter T, Flamen P, Van Cutsem E, Penninckx F, Filez L, Bormans G, Maes A, Mortelmans L. Whole-body PET with FDG for the diagnosis of recurrent gastric cancer. Eur J Nucl Med Mol Imaging 2002;29:525–529. Dooley CP, Larson AW, Stace NH, Renner IG, Valenzuela JE, Eliasoph J, Colletti PM, Halls JM, Weiner JM. Double-contrast barium meal and upper gastrointestinal endoscopy: A comparative study. Ann Intern Med 1984;101:538–545. Gines A, Pellise M, Fernandez-Esparrach G, Soria MT, Mata A, Membrillo A, Martinez-Palli G, Sole MM, Llach J, Bordas JM, Pique JM. Endoscopic ultrasonography in patients with large gastric folds at endoscopy and biopsies negative for malignancy: Predictors
2620
Ultrasound in Medicine and Biology
of malignant disease and clinical impact. Am J Gastroenterol 2006; 101:64–69. Kimmey MB, Martin RW, Haggitt RC, Wang KY, Franklin DW, Silverstein FE. Histologic correlates of gastrointestinal ultrasound images. Gastroenterology 1989;96:433–441. Komorowski RA, Caya JG, Geenen JE. The morphologic spectrum of large gastric folds: Utility of the snare biopsy. Gastrointest Endosc 1986;32:190–192. Levine MS, Kong V, Rubesin SE, Laufer I, Herlinger H. Scirrhous carcinoma of the stomach: Radiologic and endoscopic diagnosis. Radiology 1990;175:151–154. Mendis RE, Gerdes H, Lightdale CJ, Botet JF. Large gastric folds—A diagnostic-approach using endoscopic ultrasonography. Gastrointest Endosc 1994;40:437–441. Nickl NJ, Cotton PB. Clinical application of endoscopic ultrasonography. Am J Gastroenterol 1990;85:675–682. Park MS, Ha HK, Choi BS, Kim KW, Myung SJ, Kim AY, Kim TK, Kim PN, Lee NJ, Lee JK, Lee MG, Kim JH. Scirrhous gastric carci-
Volume 41, Number 10, 2015 noma: Endoscopy versus upper gastrointestinal radiography. Radiology 2004;231:421–426. Park SJ, Kim MH, Moon SH, Han JH, Park do H, Lee SS, Seo DW, Lee SK. Clinical characteristics, recurrence features, and treatment outcomes of 55 patients with autoimmune pancreatitis. Korean J Gastroenterol 2008;52:230–246. Reeder MM, Olmsted WW, Cooper PH. Large gastric folds, local or widespread. JAMA 1974;230:273–274. Songur Y, Okai T, Watanabe H, Motoo Y, Sawabu N. Endosonographic evaluation of giant gastric folds. Gastrointest Endosc 1995;41:468–474. Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756–1780. Tio TL. Large gastric folds evaluated by endoscopic ultrasonography. Gastrointest Endosc Clin N Am 1995;5:683–691. Winawer SJ, Posner G, Lightdale CJ, Sherlock P, Melamed M, Fortner JG. Endoscopic diagnosis of advanced gastric cancer: Factors influencing yield. Gastroenterology 1975;69:1183–1187.
http://dx.doi.org/10.1016/j.ultrasmedbio.2015.05.017
d
Original Contribution USE OF ENDOSCOPIC ULTRASOUND TO EVALUATE LARGE GASTRIC FOLDS: FEATURES PREDICTIVE OF MALIGNANCY HYUN LIM,* GIN HYUG LEE,* HEE KYONG NA,* JI YONG AHN,* JEONG HOON LEE,* KWI-SOOK CHOI,* DO HOON KIM,* KEE DON CHOI,* HO JUNE SONG,* HWOON-YONG JUNG,* JIN-HO KIM,* DOWHAN KIM,y and YOUNG SOO PARKy * Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, South Korea; and y Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, South Korea (Received 4 July 2014; revised 20 May 2015; in final form 22 May 2015)
Abstract—The aim of this study was to investigate with endoscopic ultrasound (EUS) the features of the gastric wall that can be used to predict malignant disease in patients with large gastric folds. We retrospectively reviewed the EUS findings of 65 patients (26 with benign and 39 with malignant disease) with large gastric folds on endoscopy and EUS and analyzed the predictors of malignant disease (e.g., gastric wall thickness, preservation of fivelayered structure, thickened layers). Gastric wall thickness ($9.8 mm), thickened deep layer, thickened muscularis propria and non-preserved wall layer structures were significantly more prevalent in patients with malignant disease on EUS. Among them, gastric wall thickness ($9.8 mm) (odds ratio 5 6.72, 95% confidence interval 5 1.23–36.73, p 5 0.028) and thickened muscularis propria (odds ratio 5 37.14, 95% confidence interval 5 7.02–196.49, p , 0.001) were significantly associated with malignant disease. Our data indicate that EUS is a useful tool for assessing large gastric folds and that gastric wall thickness ($9.8 mm) and thickened muscularis propria are significant features predictive of malignant disease on EUS. (E-mail: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Large gastric folds, Endoscopic ultrasonography, Gastric neoplasms.
highly accurate for diagnosing malignant diseases that reveal large gastric folds (Chen et al. 2010; Park et al. 2004). However, false-negative findings can occur in up to 50% of cases and require additional analysis methods for confirmation, such as endoscopy and endoscopic ultrasound (EUS) (Dooley et al. 1984). Endoscopy can also identify large gastric folds and obtain specimens for histologic diagnosis. However, the role of endoscopy is limited by the similarities between various benign and malignant diseases. Moreover, standard endoscopic biopsies are often unrevealing and provide low diagnostic yield because they usually only assess superficial mucosa (Andriulli et al. 1990; An-Foraker and Vise 1981; Winawer et al. 1975). Positron emission tomography was recently used to diagnose malignant diseases with high specificity; however, it has low sensitivity for gastric cancer, especially diffuse-type gastric cancers (e.g., signet ring carcinomas) (De Potter et al. 2002). For these reasons, exploratory laparotomy and fullthickness gastric biopsy are frequently required to rule out malignancy (Bjork et al. 1977).
INTRODUCTION Large gastric folds are defined according to several criteria: folds .10 mm on barium upper gastrointestinal series; thickening on abdominal computed tomography (CT); and folds that do not flatten with insufflation during endoscopy (Bjork et al. 1977; Mendis et al. 1994). Large gastric folds are seen in malignant (e.g., adenocarcinoma, lymphoma) and benign (e.g., hypertrophic gastritis, Menetrier’s disease, lymphoid hyperplasia, Zollinger– Ellison syndrome) diseases (Blaser et al. 1991; Levine et al. 1990; Reeder et al. 1974). Therefore, accurate diagnosis is pivotal to predicting prognosis and making treatment plans, but this is a clinical challenge because of the diverse etiology. Barium upper gastrointestinal series and abdominal CT scans are widely available, non-invasive methods for assessment. Recent studies report that these methods are Address correspondence to: Gin Hyug Lee, Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. E-mail: [email protected] 2614
Endoscopic US of large gastric folds d H. LIM et al.
Endoscopic ultrasound can accurately visualize the gastric wall structure, including thickened layers, degree of wall layer preservation and internal echo patterns (Akahoshi et al. 1991; Botet et al. 1991a, 1991b; Nickl and Cotton 1990). Different diseases exhibit different levels of EUS infiltration in the gastric wall and characteristic echo patterns. Thus, EUS aids in the differential diagnosis of large gastric folds. Although EUS is more commonly used to differentiate the causes of large gastric folds, data are still insufficient (Caletti et al. 2000; Gines et al. 2006; Mendis et al. 1994; Songur et al. 1995; Tio 1995). Previous studies indicate that deep-layer thickening on EUS is associated with malignant disease, but further studies are needed. The aim of this study was to investigate the features of the gastric wall on EUS that can be used to predict malignant disease in patients with large gastric folds. METHODS Patient selection and clinical characteristics Between January 2003 and January 2011, 70 patients underwent EUS to evaluate large gastric folds found on endoscopy at our institution. We retrospectively reviewed 65 of the 70 patients who met the following inclusion criteria: (i) thickened gastric wall confirmed on EUS (gastric wall thickness .4 mm); (ii) gold standard evaluation, such as histologically proven malignant disease or clinical follow-up .2 y in patients without histologic diagnosis; (iii) no history of previous gastric surgery or neoplasia. Five patients were excluded because thickened layers were not found on EUS. This observational study was approved by the institutional review board of Asan Medical Center (2013-0025-0002) and required neither patient approval nor informed consent for review of patient images and records; however, informed consent was obtained from all patients for macrobiopsy with snare, EUS-guided fine-needle aspiration (EUS-FNA), and surgery before each procedure. Of 65 patients, 39 (60.0%) were diagnosed with malignant disease (34 adenocarcinomas, four mucosaassociated lymphatic tissue lymphomas and one plasmacytoma) and 26 patients (40.0%) were diagnosed with benign disease (three with gastritis cystica profunda, two with hypertrophic gastritis, two with Menetrier’s disease, one with inflammatory pseudo-tumor and 18 patients with no specific histologic diagnosis) (Table 1). Among patients with malignant disease, the median age was 51 y (range: 32–78) and 7 patients (17.9%) were male. Twenty-four patients (61.5%) presented with the alarm symptoms (age .55 y with new-onset dyspepsia, recent [,3 mo before upper endoscopy/EUS] weight loss of at least 5 pounds, any evidence [clinical or laboratory] of gastrointestinal bleeding, progressive dysphagia,
2615
Table 1. Baseline characteristics of the study patients with large gastric folds
Age (y), median (range) Sex, male/female Duration of follow-up (mo) Alarm symptoms Time from symptom onset to hospital visit (mo) Initial endoscopic diagnosis Malignant disease Benign disease Number of endoscopic biopsy Methods of final diagnosis Histopathologic findings Endoscopic biopsy Endoscopic ultrasound fine-needle aspiration Macrobiopsy with snare Surgery Clinical follow-up
Malignant disease (n 5 39)
Benign disease (n 5 26)
51 (32–78)* 7/32 20 (5–144) 24 2 (0–10)
47 (18–73) 20/6 67 (17–144) 3 0 (0–6)
34 5 2 (1–6)
8 18 2 (1–5)
39 31 1
8 2 1
1 6 0
4 1 18
* Median (range).
odynophagia, persistent vomiting, palpable mass or lymphadenopathy, jaundice) (Talley et al. 2005). All patients were diagnosed on the basis of their histopathologic findings. Of 39 patients, 6 (15.3%) were diagnosed with malignant disease only by explorative laparotomy. Among patients with benign disease, the median age was 47 y (range: 18–73) and 20 patients (76.9%) were male. Eight (30.1%) patients were diagnosed by histopathologic findings, whereas the remaining patients were diagnosed on clinical follow-up using the available gold standard. The median follow-up duration of the latter was 67 mo (range: 24–144), and no patients developed clinical or radiologic aggravation. Of 26 patients, one (3.8%) underwent explorative laparotomy because malignant disease could not be ruled out and inflammatory pseudo-tumor was diagnosed. METHODS The reviewed data include the final diagnosis according to the available gold standard, EUS features of the gastric wall (e.g., thickness of the gastric wall, preservation or non-preservation of the five-layered structure, thickened layers [mucosa and/or submucosal and/or muscularis propria]), presence of ascites and presence of lymph node enlargement with EUS features suggestive of malignant disease (e.g., round or sharp borders, size .1 cm, hypo-echogenicity) (Bhutani et al. 1997; Catalano et al. 1994). The gold standard evaluations used to diagnose malignant or benign diseases include pathologic diagnosis (e.g., biopsy, EUS-FNA, macrobiopsy obtained by diathermic snare or surgery) and
2616
Ultrasound in Medicine and Biology
clinical follow-up examination (Gines et al. 2006). In the latter group, patients were diagnosed with benign disease if they were alive without clinical signs of progression after .2 y of follow-up examinations. Patients were diagnosed with malignant disease when there was evidence of disease progression on CT or ultrasonography. Endoscopic ultrasound was performed by experienced endosonographers using a radial echo-endoscope (GF UM250 or GF UE260; Olympus Medical Systems, Center Valley, PA, USA) provided with switchable ultrasound frequencies of 5, 7.5, 12 and 20 MHz, respectively. The gastric lumen was filled with 300–600 mL of water. Gastric wall thickness was quantitatively assessed, and the measurements were made on the thickest part of the gastric wall. Enlargement of the endosonographic layer was determined by comparison with normal gastric wall layer structure in the neighboring non-thickened gastric wall, and the gastric wall layer was considered thickened if it is more than 1.5 times the normal wall layer thickness. Compared with normal gastric wall structure in the neighboring non-thickened gastric wall, the fivelayered structure was considered preserved if each layer could be clearly identified on EUS (Fig. 1a), and nonpreserved if the thickened layer could be recognized, but distinction between the layers was not clear (Fig. 1b) or the layers were indistinct (Fig. 1c). Layers 1 (superficial mucosa) and 2 (deep mucosa) on EUS were considered superficial, and layers 3 (submucosa and interface), 4 (muscularis propria) and 5 (serosa and subserosal fat) were considered deep (Kimmey et al. 1989; Mendis et al. 1994). EUS-FNA was performed in the standard fashion using a curvilinear array echo-endoscope (GF-UC140 P or GF-UCT140, Olympus Medical Systems). Under EUS guidance, thickened layers were aspirated with a 22gauge EUS-FNA needle (EUS N-3; Cook Medical, Winston Salem, NC, USA). The procedure was repeated until a core of tissue was obtained. Macrobiopsy obtained by diathermic snare was carried out using the strip-off biopsy methods (Komorowski et al. 1986). Under endoscopic observation, saline–epinephrine solution was injected into the submucosa. Then, the elevated mucosa and superficial submucosa were resected by electrocautery snare. After the resected specimen was taken up, addition endoscopic forceps biopsy targeting the exposed submucosal layer was performed. Review of EUS imaging Two independent experienced endosonographers (J.Y.A. and D.H.K.), who were unaware of the final diagnoses, retrospectively reviewed the EUS images to determine their features. In the case of disagreement, these endosonographers met later to review the EUS images and reach consensus.
Volume 41, Number 10, 2015
Statistical analysis Differences were determined using the Fisher exact test, c2-test or Student t-test, as appropriate. Additional multiple logistic regression analyses were performed to identify predictive factors associated with malignant disease. All potential predictive factors with p # 0.05 on univariate analysis were entered into the forward stepwise logistic regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relative risk of malignant disease. In this study, p , 0.05 is considered as indicating statistical significance. All data were analyzed using the Statistical Package for the Social Sciences software (Version 18.0 for Windows, SPSS, Chicago, IL, USA). RESULTS EUS findings indicative of benign and malignant disease Table 2 compares the EUS findings for benign and malignant disease. All EUS findings, except the presence of ascites (p 5 0.078), differed significantly between groups. Among patients with benign disease, median wall thickness was 7.8 mm (range: 4.5–25.7), and the superficial layer was thickened (53.8% of patients). All but one patient had a preserved wall layer structure. No patients presented with ascites or lymph node enlargement. Among patients with malignant disease, median wall thickness was 13.7 mm (range: 6.2–26.0), and the deep layer was mostly thickened (94.9% of patients). Twenty patients (51.3%) had a non-preserved wall layer structure. Five (12.8%) and 11 (28.2%) patients presented with ascites and lymph node enlargement, respectively. Cutoff level of gastric wall thickness predictive of malignant disease The receiver operating characteristic (ROC) curve determining the cutoff value for gastric wall thickness that predicts malignant disease is illustrated in Figure 2. The cutoff value for gastric wall thickness was 9.8 mm, with a sensitivity and specificity of 87.2% and 73.1%, respectively (p , 0.001). The area under the ROC curve was 0.806. EUS gastric wall features predictive of malignant disease Tables 3 and 4 summarize the EUS features of the gastric wall that are predictive of malignant disease. According to the univariate analysis, gastric wall thickness ($9.8 mm), thickened deep layers, thickened muscularis propria and non-preserved wall layer structure are associated with malignant disease (Table 3). On the other hand, a thickened superficial layer is
Endoscopic US of large gastric folds d H. LIM et al.
2617
Fig. 1. Typical endoscopic ultrasound (EUS) and histologic findings of three endosonographic subtypes of large gastric folds. (a) EUS image revealing the preserved five-layered structure (1 5 superficial mucosa, 2 5 deep mucosa, 3 5 submucosa, 4 5 muscularis propria). Each layer is clearly distinguishable (white arrowheads). Histologic examination reveals clear distinction between all layers (black arrowheads). The final diagnosis was hypertrophied gastritis (hematoxylin and eosin [H&E], original magnification 310). (b) EUS image revealing non-preserved five-layered structure. Distinctions between all layers are unclear (white arrowheads); however, thickened muscularis propria is recognizable (white arrow). Histologic examination reveals indistinct layers (black arrowheads) and thickened muscularis propria (black arrow). The final diagnosis was gastric adenocarcinoma, with transmural involvement and its epicenter located primarily in the submucosa (H&E, original magnification 310). (c) EUS image revealing non-preserved five-layered structure. Each layer is undistinguishable. Histologic examination reveals destroyed layers, and it is impossible to distinguish layers. The final diagnosis was gastric adenocarcinoma with transmural involvement (H&E, original magnification 310).
associated with benign disease. Among the significant factors identified by the univariate analysis, gastric wall thickness ($9.8 mm) and thickened muscularis
are significant predictive features associated with malignant disease according to the multivariate analysis (Table 4).
2618
Ultrasound in Medicine and Biology
Table 2. Comparison of endoscopic ultrasound findings in benign and malignant disease Malignant disease (n 5 39)
Volume 41, Number 10, 2015
Table 3. EUS characteristics of the gastric wall according to univariate analysis Odds ratio
Benign disease (n 5 26)
Wall thickness (mm) 13.7 (6.2–26.0)* 7.8 (4.5–25.7) Thickened superficial layer 2 14 Thickened deep layer 37 12 Thickened muscularis propria 35 3 Non-preserved wall layer structure 20 1 Presence of lymph node enlargement 11 0 Presence of ascites 5 0
Gastric wall thickness ($9.8 mm) Thickened superficial layer (1) Thickened deep layer (1) Thickened muscularis propria (1) Non-preserved wall layer structure (1)
95% CI
18.46 5.14–66.22 0.05 0.01–0.23 21.58 4.28–108.89 67.08 13.73–327.88 35.00 4.33–282.82
p ,0.001 ,0.001 ,0.001 ,0.001 0.001
CI 5 confidence interval.
* Median (range).
DISCUSSION Although EUS is very useful for visualizing the architecture of the gastric wall layer, the usefulness of EUS for assessing patients with large gastric folds remains unclear (Caletti et al. 2000; Gines et al. 2006; Mendis et al. 1994; Songur et al. 1995; Tio 1995). Therefore, here we analyzed the EUS features that helped make a differential diagnosis in 65 patients. We report that gastric wall thickness ($9.8 mm) and thickened muscularis propria are the EUS features of the gastric wall that are associated with malignant disease in patients with large gastric folds. Various diseases show different levels of EUS infiltration in the gastric wall, hence clinicians can narrow the possible differential diagnoses using EUS (Caletti et al. 2000). Thickened deep or muscularis propria layers are common EUS findings in patients with large gastric folds
and malignant diseases, whereas a thickened superficial layer is a common finding in benign diseases (Caletti et al. 2000; Gines et al. 2006; Mendis et al. 1994; Songur et al. 1995; Tio 1995). Likewise, a study on patients with large gastric folds and negative biopsy results reports that a thickened deep layer on EUS is associated with malignant disease (Gines et al. 2006). In this study, a thickened superficial layer was significantly more common in patients with benign disease, and thickened deep or muscularis propria layers were more common in patients with malignant disease. In addition, thickened muscularis propria was a significant EUS feature predictive of malignant disease. Our results are consistent with previous studies, thus reinforcing the finding that thickened muscularis propria is a significant predictive feature associated with malignant disease in patients with large gastric folds (Caletti et al. 2000; Gines et al. 2006; Mendis et al. 1994; Songur et al. 1995; Tio 1995). Although EUS is very useful for assessing the architecture of the gastric wall layer, operator dependency is a big demerit of EUS. However, measurement of gastric wall thickness might be a semi-objective method because it may be a quantitative metric. In this study, we found the cutoff value for gastric wall thickness that predicted malignant disease using the ROC curve analysis. The best cutoff value for gastric wall thickness was 9.8 mm, and the area under the ROC curve was 0.806. In addition, gastric wall thickness ($9.8 mm) was significantly associated with malignant disease. To the best of our knowledge, this is the first study to report a cutoff value for gastric wall thickness that predicts malignant disease.
Table 4. Endoscopic ultrasound characteristics of the gastric wall according to multivariate analysis
Fig. 2. Receiver operating characteristic curve determining the cutoff value of gastric wall thickness that predicts malignant disease.
Gastric wall thickness ($9.8 mm) Thickened muscularis propria (1) CI 5 confidence interval.
Odds ratio
95% CI
p
6.72 37.14
1.23–36.73 7.02–196.49
0.028 ,0.001
Endoscopic US of large gastric folds d H. LIM et al.
A non-preserved wall layer structure is regarded as an important EUS finding predictive of malignant disease (Caletti et al. 2000). However, to date, there are no studies that associate non-preserved wall layer structure with malignant disease in patients with large gastric folds. Several studies report an association between nonpreserved wall layer structure and malignant disease, but these do not report statistical associations because of the small numbers of patients included (Gines et al. 2006). In this study, all cases of non-preserved wall layer structure except one were observed in patients with malignant disease, and this was found to be statistically significant in univariate analysis. However, contrary to our expectations, it did not reach statistical significance in multivariate analysis. As in the previous study, this discrepancy might have resulted from the small sample size, although our study included a relatively larger number of patients and non-preserved wall layers in patients with malignant diseases. Further studies are needed. Although this study analyzed only the EUS features of the gastric wall that are predictive of malignant disease, ascites and lymph node enlargement are important extraluminal EUS features that can be used to predict malignant disease (Gines et al. 2006). In this study, no patient with benign disease manifested ascites or lymph node enlargement with EUS features of malignant disease. This finding is consistent with previous studies (Gines et al. 2006) and provides high-value information that could be used to predict malignant disease in patients with large gastric folds, although we did not include the EUS features predictive of malignant disease in this analysis. Interestingly, one female patient whose diagnosis could not be ruled out as malignant disease by many methods, including EUS, was finally diagnosed with inflammatory pseudo-tumor after explorative laparotomy. This case exemplifies the difficulty in clinically distinguishing malignant from benign disease. A case of immunoglobulin G-related pseudo-tumor in the pancreas mimicking pancreatic cancer was reported by Kim et al. (Park et al. 2008). We think this case may be an example of immunoglobulin G-related pseudo-tumor involving the stomach, which is undistinguishable from benign and malignant diseases. Thus, there are subgroups that are undistinguishable from benign and malignant diseases on EUS. Further studies of these subgroups are needed, and additional workup is needed to avoid unnecessary laparotomy. Our study has some potential limitations. First, we could not use standard EUS protocols because our study was retrospective. Second, although our study contained more diverse disease categories compared with previous studies, we could not include all diseases in which there are large gastric folds. However, this is difficult limitation
2619
to overcome because patients with large gastric folds are relatively rare. Third, we included patients without definite histologic diagnoses and used clinical follow-up examinations to make our diagnoses; however, previous studies have also used this method (Gines et al. 2006). CONCLUSIONS Endoscopic ultrasound is a useful tool for assessing patients with large gastric folds. Gastric wall thickness ($9.8 mm) and thickened muscularis propria on EUS are significant features predictive of malignant disease in patients with large gastric folds. Acknowledgments—This article was not supported by grants and funds.
REFERENCES Akahoshi K, Misawa T, Fujishima H, Chijiiwa Y, Maruoka A, Ohkubo A, Nawata H. Preoperative evaluation of gastric cancer by endoscopic ultrasound. Gut 1991;32:479–482. An-Foraker SH, Vise D. Cytodiagnosis of gastric carcinoma, linitis plastica type (diffuse, infiltrating, poorly differentiated adenocarcinoma). Acta Cytol 1981;25:361–366. Andriulli A, Recchia S, De Angelis C, Mazzucco D, Berti E, Arrigoni A, Verme G. Endoscopic ultrasonographic evaluation of patients with biopsy negative gastric linitis plastica. Gastrointest Endosc 1990; 36:611–615. Bhutani MS, Hawes RH, Hoffman BJ. A comparison of the accuracy of echo features during endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration for diagnosis of malignant lymph node invasion. Gastrointest Endosc 1997;45:474–479. Bjork JT, Geenen JE, Soergel KH, Parker HW, Leinicke JA, Komorowski RA. Endoscopic evaluation of large gastric folds: A comparison of biopsy techniques. Gastrointest Endosc 1977;24: 22–23. Blaser MJ, Perez-Perez GI, Lindenbaum J, Schneidman D, Van Deventer G, Marin-Sorensen M, Weinstein WM. Association of infection due to Helicobacter pylori with specific upper gastrointestinal pathology. Rev Infect Dis 1991;13(Suppl 8):S704–S708. Botet JF, Lightdale CJ, Zauber AG, Gerdes H, Urmacher C, Brennan MF. Preoperative staging of esophageal cancer: Comparison of endoscopic US and dynamic CT. Radiology 1991a;181: 419–425. Botet JF, Lightdale CJ, Zauber AG, Gerdes H, Winawer SJ, Urmacher C, Brennan MF. Preoperative staging of gastric cancer: Comparison of endoscopic US and dynamic CT. Radiology 1991b;181:426–432. Caletti G, Fusaroli P, Togliani T, Bocus P, Roda E. Endosonography in gastric lymphoma and large gastric folds. Eur J Ultrasound 2000;11: 31–40. Catalano MF, Sivak MV Jr, Rice T, Gragg LA, Van Dam J. Endosonographic features predictive of lymph node metastasis. Gastrointest Endosc 1994;40:442–446. Chen CY, Jaw TS, Wu DC, Kuo YT, Lee CH, Huang WT, Liu GC. MDCT of giant gastric folds: Differential diagnosis. AJR Am J Roentgenol 2010;195:1124–1130. De Potter T, Flamen P, Van Cutsem E, Penninckx F, Filez L, Bormans G, Maes A, Mortelmans L. Whole-body PET with FDG for the diagnosis of recurrent gastric cancer. Eur J Nucl Med Mol Imaging 2002;29:525–529. Dooley CP, Larson AW, Stace NH, Renner IG, Valenzuela JE, Eliasoph J, Colletti PM, Halls JM, Weiner JM. Double-contrast barium meal and upper gastrointestinal endoscopy: A comparative study. Ann Intern Med 1984;101:538–545. Gines A, Pellise M, Fernandez-Esparrach G, Soria MT, Mata A, Membrillo A, Martinez-Palli G, Sole MM, Llach J, Bordas JM, Pique JM. Endoscopic ultrasonography in patients with large gastric folds at endoscopy and biopsies negative for malignancy: Predictors
2620
Ultrasound in Medicine and Biology
of malignant disease and clinical impact. Am J Gastroenterol 2006; 101:64–69. Kimmey MB, Martin RW, Haggitt RC, Wang KY, Franklin DW, Silverstein FE. Histologic correlates of gastrointestinal ultrasound images. Gastroenterology 1989;96:433–441. Komorowski RA, Caya JG, Geenen JE. The morphologic spectrum of large gastric folds: Utility of the snare biopsy. Gastrointest Endosc 1986;32:190–192. Levine MS, Kong V, Rubesin SE, Laufer I, Herlinger H. Scirrhous carcinoma of the stomach: Radiologic and endoscopic diagnosis. Radiology 1990;175:151–154. Mendis RE, Gerdes H, Lightdale CJ, Botet JF. Large gastric folds—A diagnostic-approach using endoscopic ultrasonography. Gastrointest Endosc 1994;40:437–441. Nickl NJ, Cotton PB. Clinical application of endoscopic ultrasonography. Am J Gastroenterol 1990;85:675–682. Park MS, Ha HK, Choi BS, Kim KW, Myung SJ, Kim AY, Kim TK, Kim PN, Lee NJ, Lee JK, Lee MG, Kim JH. Scirrhous gastric carci-
Volume 41, Number 10, 2015 noma: Endoscopy versus upper gastrointestinal radiography. Radiology 2004;231:421–426. Park SJ, Kim MH, Moon SH, Han JH, Park do H, Lee SS, Seo DW, Lee SK. Clinical characteristics, recurrence features, and treatment outcomes of 55 patients with autoimmune pancreatitis. Korean J Gastroenterol 2008;52:230–246. Reeder MM, Olmsted WW, Cooper PH. Large gastric folds, local or widespread. JAMA 1974;230:273–274. Songur Y, Okai T, Watanabe H, Motoo Y, Sawabu N. Endosonographic evaluation of giant gastric folds. Gastrointest Endosc 1995;41:468–474. Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756–1780. Tio TL. Large gastric folds evaluated by endoscopic ultrasonography. Gastrointest Endosc Clin N Am 1995;5:683–691. Winawer SJ, Posner G, Lightdale CJ, Sherlock P, Melamed M, Fortner JG. Endoscopic diagnosis of advanced gastric cancer: Factors influencing yield. Gastroenterology 1975;69:1183–1187.