Endosonography of large gastric folds

Endosonography of Large Gastric Folds Leonardo De Luca, MD, and Paul Fockens, MD, PhD

Several different pathological processes, such as neoplastic, vascular, infectious, inflammatory, and infiltrative disorders involving a part of or the entire gastric wall, may result in thickening of the gastric folds. Large gastric folds (LGF) can present a difficult diagnostic problem when biopsies are negative, but a suspicion of malignancy persists. Endoscopic ultrasonography (EUS), a combination of endoscopy and ultrasound, has been developed to improve the diagnostic accuracy of ultrasound by direct imaging of the target lesions via the gastrointestinal lumen This technique, providing a detailed display of the gastric wall, has been reported to be accurate in the diagnosis and staging of benign and malignant gastric abnormalities. Therefore, it should be used early i~ evaluation of differential diagnosis of LGF of unknown origin detected by endoscopy, barium x-ray, or computed tomography (CT) scan. EUS may determine whether the process is superficial (layers 1 and 2), or whether the process involves the deeper layers. EUS also can detect the presence of intramural vessels that would contraindicate performing endoscopic biopsies. For this purpose, the color Doppler capability of some EUS systems may be useful. Differential diagnosis of LGF and the technical details are discussed. Copyright 9 2000 by W.B. Saunders Company

arge gastric folds (LGF) may be defined as folds wider than

L 10 mm on standard barium upper gastrointestinal radiogra-

phy, or that appear thickened on abdominal computed tomography scan, or that do not flatten with insufflation at the time of endoscopy. LGF can present a difficult diagnostic problem, especially when there is a clinical or endoscopic suspicion of malignancy, but no proof can be obtained with endoscopic biopsies. The differential diagnosis of a thickened stomach wall is complex and comprises both benign and malignant diseases. The spectrum includes malignancy (adenocarcinoma, linitis plastica, and tymphoma) as well as benign conditions (hyperrugosity and gastritis). Less common causes include Menetrier's disease, anisakiasis, gastritis cystica profunda, and amyloidosis. Rarely, metastatic cancer from a distant primary site may present as LGF (Table 1). 1 Standard endoscopic biopsy specimens may not always be helpful because they contain only superficial mucosa. In infiltrative malignancies of the stomach, traditional biopsies have been positive in only 50% of the cases. 2,3 Large-particle biopsies, which are performed with a polypectomy diathermic From the Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, The Netherlands. Address reprint requests to Paul Fockens, MD, PhD, Department of Gastroenterology, Academic Medical Center, PO Box 22700, 1100 DE Amsterdam, The Netherlands. Copyright 9 2000 by W.B. Saunders Company 1096-2883/00/0202-0006510.00/0 doi:10.1053/TG.2000.5434

snare, may be used to obtain deeper specimens in an effort to increase the diagnostic yield. However, this technique has not been widely accepted because of the risk of major complications (hemorrhage or perforation). For these reasons, taparotomy with full-thickness gastric biopsy has been the standard approach in the past to patients with this diagnostic problem. Endoscopic ultrasonography (EUS), a combination of endoscopy and ultrasound, has been increasingly used for the diagnosis and staging of malignancies of the upper gastrointestinal tract. High-resolution imaging of the gastric wall with endosonography measures the gastric wall thickness and therefore could be helpful in these difficult cases. EUS noninvasively determines which layers are involved in the thickening, whether the abnormality infiltrates in adjacent structures, and whether enlarged lymph nodes or ascites are present. In addition, EUS has been shown to be highly accurate in preoperative TNM staging of gastric malignancies. 4

Instruments Ultrasound imaging systems consist of an ultrasonic transducer, and electronic processor, and an imaging device. The ultrasonic transducer contains piezoelectric crystals that, when activated, permit the transmission and reception of ultrasound waves. The electronic processor, which activates the piezoelectric crystals, processes the echo signals received from the transducer. The imaging device displays the processed signals on to a screen. Because of the fact that the transducer lies very close to the wall of the gastrointestinal (GI) tract, it provides a high-resolution image of the layers. Currently, the available instruments for EUS in the upper GI tract can be divided into dedicated echoendoscopes and miniprobes.

Dedicated Echoendoscopes Radial Scanner There are 2 types of dedicated echoendoscopes. The most commonly used echoendoscope is equipped with a mechanical rotating sector scanner and manufactured by the Olympus Optical Company (Tokyo, Japan). The GF-UM130 instrument has a 45 ~ oblique viewing angle and a conically shaped nose with a maximal outer diameter of 12.7 mm. The transducer rotates at approximately 10 cycles per second, creating a 360 ~ image perpendicular to the long axis of the endoscope. The instrument has long rigid nose of 4.2 cm, which makes its introduction into the esophagus somewhat more difficult than that of a regular endoscope. Furthermore, it has 2 switchable frequencies of 7.5 and 12 (or 20) MHz. Generally, the 7.5-MHz is used for orientation and imaging of organs or abnormalities outside the GI tract, whereas the higher frequency is used for the abnormalities in the GI wall. This type of instrument has

Techniques in Gastrointestinal Endoscopy, Vol 2, No 2 (April), 2000: pp 79-83

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TABLE 1. Etiology of Large Gastric Folds Malignancies Infections Infiltrating diseases Vascular diseases Benign conditions

Adenocarcinoma, linitis plastica, lymphoma, metastases Secondary syphilis, tubercolosis, CMV, HSV, histoplasmosis, cryptococcosis, aspergillosis, H pylori infection, anisakiasis Crohn's diseases, sarcoidosis, amyloidosis, eosinophilic, granulomatous and lymphocytic gastritis Portal hypertensive gastropathy, gastric varices Menetrier's disease, Zollinger-Ellison syndrome, gastritis, hyperrugosity, gastritis cystica profunda

been used in almost all of the published studies that fornl the basis of our current knowledge of endosonography.

Curved Array Two curve-array echoendoscopes are available. Linear convex array endoscope FG-34UA made by Pentax Precision Instruments (Tokyo, Japan) is a 60 ~ oblique-viewing endoscope, with a maximum outer diameter of 11.5 mm, providing a 100 ~ ultrasound image parallel to the long axis of the endoscope. It is a switchable 5- and 7.5-MHz liner electronic array transducer and is used in connection with a Hitachi EUB-515 or similar scanner. Since 1997, the Olympus GF-UC30P linear echoendoscope has been available. Its direction of view is 45 ~ oblique viewing. It provides a 180 ~ ultrasound image. The outer diameter is of 12.8 mm. This type of echoendoscope has the advantage of color Doppler signal detection, with or without color, attached to the tip. It can permit accurate visualization of neighboring blood vessels. Moreover, the position of the ultrasonographic scanning plane allows fine-needle aspiration biopsy (EUS-guided FNAB) of target lesions, such as bowel wall and lesions beyond the bowel wall, and enlarged lymph nodes to be performed under direct EUS control, because only these allow monitoring the course of the needle. Sufficient data are available to show that EUS-guided FNAB is an accurate and safe technique. Although EUS-guided FNAB is a very accurate technique for lesions outside the GI tract (sensitivity and specificity >90%), the sensitivity and specificity for bowel wall lesions has been shown to be much lower (61% to 79%, respectively). 5

of intramural lesions. However, the use of high frequency limits the depth of penetration, making the assessment of large tumors and extramural lesions difficult.

Technique After introduction, the echoendoscope is advanced into the distal antrum. Air is aspirated as completely as possible from the lumen of the stomach. To distend the stomach and produce clear EUS images, the endosonographist should fill the gastric lumen with 200 to 400 mL de-aerated water through the accessory channel of the echoendoscope. Satisfactory imaging can be technically difficult in certain areas of the stomach, such as the prepyloric antrum and the fundus, because of insufficient transducer contact and difficulty in obtaining adequate water filling of these areas. Changing the patient's position may be helpful, but this should be done with caution to avoid regurgitation and aspiration. A standard endosonographic examination carefully notes gastric wall architecture, presence of lymph nodes, and status of adjacent organs and surrounding vasculature.

Normal Bowel Wall Anatomy Echos are produced from interfaces between components of the bowel wall, which present different acoustic impedance to ultrasound. The thickness of the ultrasound layers does not correspond exactly to the thickness of the individual histological layers, but there is a good ultrasound correlation with histology. A normal GI wall measures between 3 and 5 mm and shows a 5-layer pattern at a frequency of 7.5 MHz, with alternating bright and dark bands. 6 In this pattern, 5 distinct uhrasound layers can be identified in the normal gastric wall: the first 2 layers represent superficial and deep mucosa. The third ultrasonic layer is the most echogenic and represents the submucosa. The fourth ultrasonic layer, hypoechoic, represents the muscularis propria. In the stomach, the fifth layer represents the serosa (Table 2; Fig 1).

Miniprobes Miniprobes, with a diameter small enough to fit through the instrumentation channel of an endoscope, have been developed by several companies (Fujinon, Olympus, etc.). Most of these probes, which use frequencies in the range of 12 to 30 MHz, use the principle of a rotating sector scanner. High-frequency miniprobes allow the visualization of mural GI structures with much higher resolution. Therefore, these might be useful for the diagnostic evaluation of relatively small and fiat lesions, such as early cancers or other superficial types

TABLE 2. Gastric Five Layers at Endosonography Layer

Pattern

Structures

1 2 3 4 5

Hyperchoic Hypoechoic Hyperchoic Hypoechoic Hyperchoic

Superficial mucosa Deep mucosa Submucosa Muscularis propria Serosa

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Fig 1. Normal bowel wall at 7.5 MHz with 5 layers. Serosa is well visible because of some ascites, DE LUCA AND FOCKENS

Large Gastric Folds Enlarging of the normal gastric folds is seen in a large number of benign and malignant conditions. The great similarity of the endoscopic and radiographic appearance of LGF in various conditions makes this feature a diagnostic challenge for the gastroenterologist. From the clinical point of view, the differentiation of benign diseases from malignant giant folds is most important.

Benign Disease On EUS, gastritis and simple hyperrugosity are the most frequent causes of hypoechoic enlargement of layer 2. Menetrier's disease may be one of the possible pathological entities causing large folds of the gastric body. On EUS, the second layer alone (deep mucosa) is thickened, with small anechoic areas inside, suggestive of cysts (Fig 2).7 The diagnosis can be supported by the presence of hypoalbuminemia; low gastric secretion after stimulation; and histological findings of glandular atrophy and foveolar hyperplasia. These findings can be related to the serum protein loss through the mucosa and low acid output. Anisakiasis of the digestive tract has been reported to affect the stomach in 75% of cases. This disease might be suspected when the third (submucosal) layer alone is abnormally enlarged and homogenous h~'poechoic, s The pathogenesis of gastritis cystica profunda has been described as an interruption of the muscularis mucosae caused by erosion of the gastric mucosa in chronic gastritis and ischemia, or by the effects of surgery and presence of suture material, which allow epithelial elements to migrate to the submucosa. On EUS, a thickness of the third layer with multiple anechoic areas can be observed, which indicates the presence of submucosal cysts.9 EUS has been shown to be superior to endoscopy in the diagnosis of gastric varices. In portal hypertension, intramural vessels ([undic and gastric varices, portal hypertensive gastropathy) can cause thickening of gastric folds. On EUS, gastric

Fig 2. Menetrier's disease with marked thickening of second layer. ENDOSONOGRAPHY OF LARGE GASTRIC FOLDS

Fig 3. Multiple gastric varices in a patient with portal hypertension and ascites.

varices are detected as curved, serpiginous, and dilated anechoic structures in the thickening of the submucosa (layer 3) (Fig 3).lo Helicobacter wlori gastritis also may cause gastric wall thickening. Avunduk et a111 reported the use of EUS to investigate LGF caused by H pylori, before and after bacterial eradication. They showed a diffuse thickening of the inner 3 layers. After antimicrobial therapy, EUS showed normalization of the layers and resolution of the thickening. They concluded that H pylori is a common cause for gastric wall thickening, which can be attributed to increased luminal-mucosal mucus interface and edema, and inflammatory cellular infiltration of the deep mucosa and submucosa. Watermelon stomach is a rare cause of recurrent upper GI bleeding. It is characterized by visible column of vessels in the gastric antrum, and typical histological features, which include

Fig 4. Typical EUS image of linitis plastica with swelling of second, third, and fourth layers.

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T A B L E 3. L a y e r s I n v o l v e d in t h e L a r g e G a s t r i c F o l d s and Their Endosonography Characteristics Disease

Infiltrated Layer

Gastritis, hyperrugosity Menetrier's disease Anisakiasis Gastritis cystica profunda

2 2 3 3

Gastric varices

3

H pyloriinfection

2, 2 + 3

Watermelon stomach Gastric amyloidosis Adenocarcinoma, linitis plastica

2+ 3 2+ 3 2, 2 + 3, 2+ 3+ 4

Gastric lymphoma

2, 2 + 3, 2+3+4

Metastasis

2, 2 + 3, 2+3+4

Endosonography Characteristics Small anechoic areas (cysts) Homogenous echo Multiple anechoic areas (submucosal cysts) Anechoic Antral hyperechogenity Rough hyperechoic swelling Diffuse thickening with some hypoechoic changes mainly in third layer Hypoechoic, homogeneous, localized mucosal ulcerations, longitudinal growth Hypoechoic

hyperplasia of the antral mucosa, dilated mucosal and submucosal vessels, focal thrombosis, and fibromuscolar hypertrophy of the lamina propria. On EUS, Parente et a112 observed in the patients with this disease a thickened antral wall with hyperechoic areas in the second (deep mucosa) and third (submucosa) layer. Amyloidosis is a disease process characterized by extracellular deposition of the fibrous protein amyloid in 1 or more sites of the body Yanai et aP 3 observed amyloid deposit on EUS as a rough hyperechoic swelling in the gastric mucosa and submucosa (second and third layer). The diagnosis was confirmed by strip biopsy.

Malignant Lesions The term Iinitis plastica refers to a scirrhous form of carcinoma, most commonly gastric in origin, that tends to infiltrate and not be circumscribed. This carcinoma, which constitutes 5% to 15% of all gastric malignancies, incites a marked desmoplastic response in the gastric wall. EUS characteristic of linitis

plastica is the localized irregular nonhomogenous hypoechoic thickness of the second (deep mucosa), third (submucosal) and fourth (muscolaris propria) layer involving longitudinally, sometimes circularly, the entire gastric wall of gastric antrum and body. The fifth (serosa) layer is normal (Fig 4). 3 The possible therapeutic approaches are different in patients with gastric malignant lymphoma as compared with gastric cancer, so it is important to establish a correct preoperative diagnosis of primary gastric lymphoma. At an early stage, lymphoma may be at EUS as a thickening of the second layer alone, or the second and third layers, with preservation of these layers as distinctive structures. In advanced cases, thickening is diffuse (layers 2, 3, and 4) with a typical hypoechoic pattern, and the individual sonographic layers are not distinguishable. It is well known, especially in the patients with a lobulartype breast carcinoma, that these tumors can metastasize diffusely to the digestive tract and closely mimic a linitis plastica type growth pattern. 14 Gastric metastases are seen in 6% to 10% of patients with breast cancer. An overview of the layers involved in the LGF and their endosonographic characteristics is given in Table 3. Mendis et al 1~ examined the usefulness of EUS in 28 patients with endoscopically or radiographically diagnosed LGE in most of whom endoscopic biopsies had been inconclusive for malignancy . EUS showed gastric varices in 4 patients in whom biopsy specimens had not been taken. In 3 patients, the biopsy results were negative for malignancy, although because of ultrasonographic findings of wall thickening involving third and fourth layer, they underwent laparotomy, which showed primary gastric carcinoma. In the remaining patients, largeforceps endoscopic biopsy showed acute or chronic inflammation in 16 (67%), malignancy in 4 (16%), and Menetrier's disease in one (4%). Malignancy did not develop in any of the patients with gastric wall thickening limited to second layer and negative biopsy results during a mean follow-up period of 35 months. Only 7 of 28 consecutive patients (25%) turned out to have a malignancy. The authors concluded that, when EUS

Large Gastric Folds

I

Endoscopy, BariumX-ray,US, CTscan not diagnostic

L EU$

Thickening only Layer2 (deep mucosa)

I (deep Layers Thickening 2 and 3 mucosaand submucosa)

Thickening Layer 4 (muscularispropria)

I

I

Endoscopicbiopsies

Jumbo forceps biopsyI

Fig 5. A l g o r i t h m of d i a g n o s t i c e v a l u a t i o n of large g a s t r i c folds.

I

Jumboforcepsbiopsy

/ Positive: treat malignancy

82

Negative: medicalfollow-up

Positive: treat malignancy

1 Negative: medicalfollow-up

I Positive: treat malignancy

Negative: considerexploration or EUS-guidedFNAB

DE LUCA AND FOCKENS

abnormalities involve only the mucosal layer, endoscopic biopsies are diagnostic. Abnormalities involving the muscularis propria in the absence of ulceration suggest malignancy, and should be investigated further if the endoscopic biopsy findings are negative. Furthermore, potentially dangerous biopsies of gastric varices can be avoided. In a retrospective study, Songur et al, ~6 analyzing the EUS features in 35 patients with LGE described findings that might be useful to characterize each type of lesion. According to the investigators, the second layer alone was thickened in Menetrier's disease, and the third layer alone was enlarged in anisakiasis. Most of the patients with linitis plastica showed abnormally enlarged third and fourth layers. The second and third layers were thickened in healthy subjects with simple hyperrugosity, but also in patients with gastric lymphoma. The fourth layer was significantly thickened only in malignant conditions. The only caveat in these studies is that in the presence of ulceration, the finding of a thickened layer 4 is not as specific as in the absence of ulceration.

Conclusion The examination of patients with LGF, in whom endoscopic biopsies fail to show the malignant character of the disease in 50%, is an established indication for EUS. Endoscopic biopsies are frequently not diagnostic, because the biopsy forceps do not penetrate deeper than the mucosal layer. EUS is the only technology in clinical practice that can accurately and noninvasively image the wall layers of the gastrointestinal tract. From the studies in the literature, we know that it is possible to use EUS in large gastric folds to select some patients for exploration and others for a more conservative approach. If only the second layer is thickened, endoscopic biopsies are preferred. In the absence of ulceration, if clearly thickened second and third layers are seen, careful follow-up with jumbo forceps biopsy seems to be warranted. When the fourth layer is thickened, the likelihood of malignancy is so high that surgical exploration seems to be indicated (Fig 5). The role of FNAB under EUS guidance still has to be determined.

ENDOSONOGRAPHY OF LARGE GASTRIC FOLDS

References 1. Caletti G, Fusaroli P, Bocus P: Endoscopic ultrasonography in large gastric folds. Endoscopy 30:A72-A75, 1998 (suppl) 2. Winawer SJ, Posner G, Lightdate CJ, et al: Endoscopic diagnosis of advanced gastric cancer: Factors influencing yield. Gastroenterology 69:1183-1187, 1975 3. Andriulli A, Recchia A, De Angelis C, et al: Endoscopic ultrasonographic evaluation of the patients with biopsy negative gastric linitis plastica. Gastrointest Endosc 36:611-615, 1990 4. Caletti G, Ferrari A, Bronchi E, et al: Accuracy of endoscopic ultrasonography in the diagnosis and staging of gastric cancer and lymphoma. Surgery 113:14-27, 1993 5. Wiersema MJ, Vilmann P, Giovannini M, et al: Endosonographyguided fine needle aspiration biopsy: Diagnostic accuracy and complication assessment. Gastroenterology 112:1087-1095, 1997 6. Kimmey MB, Martin RW, Haggitt RC, et al: Histologic correlates of gastrointestinal ultrasound images. Gastroenterology 96:433-441, 1989 7. Fujishima H, Misawa T, Chijiiwa Y, et al: Scirrhous carcinoma of the stomach versus hypertrophic gastritis: Findings at endoscopic US. Radiology 181:197-200, 1991 8. Okai T, Mouri I, Yamaguchi Y, et al: Acute gastric anisakiasis: observations with endoscopic ultrasonography. Gastrointest Endosc 39:450-452, 1993 9. Okada M, Lizuka Y, Oh K, et al: Gastritis cystica profunda presenting as giant gastric mucosal folds: The role of endoscopic ultrasonography and mucosectomy in the diagnosis work-up. Gastrointest Endosc 40:640-644, 1994 10. Caletti GC, Brocchi E, Ferrari A, et al: Value of endoscopic ultrasonography in the management of portal hypertension. Endoscopy 24:342346, 1992 (suppl) 11. Avunduk C, Navab F, Hampf F, et al: Prevalence of Helicobacter pylori infection in patients with large gastric folds: evaluation and follow-up with endoscopic ultrasound before and after antimicrobial therapy. Am J Gastroentero190:1969-1973, 1995 12. Parente F, Petrillo M, Vago L, et al: The watermelon stomach: clinical, endoscopic, endosonographic, and therapeutic aspects in three cases. Endoscopy 27:203-206, 1995 13. Yanai H, Fuji T, Tada M, et al: Localized amyloidosis of the stomach. Gastrointest Endosc 37:408-409, i991 14. Taal BG, den Hartog Jager FCA, Steinmertz R, et al: The spectrum of gastrointestinal metastases of breast carcinoma. Gastrointest Endosc 38:130-135, 1992 15. Mendis RE, Gerdes H, Lightdale C, et al: Large gastric folds: A diagnostic approach using endoscopic ultrasonography. Gastrointest Endosc 40:437-441,1994 16. Songur Y, Okai T, Watanabe H, et al: Endosonographic evaluation of giant gastric folds. Gastrointest Endosc 41:468-474, 1995

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