EUS in submucosal tumors

Submucosal tumors

A Chak

EUS in submucosal tumors Amitabh Chak, MD

DEFINITION OF SUBMUCOSAL TUMORS The term submucosal tumor (SMT) is really a misnomer because lesions in this category do not necessarily arise or confine themselves to the submucosa. Any growth underneath the mucosa of the GI tract whose etiology cannot readily be determined by lumenal diagnostic endoscopy or barium radiography is called an SMT (Fig. 1). Experienced endoscopists often make an educated guess about the etiology of an SMT on the basis of size, shape, firmness, color, and overall appearance of the “tumor” but are histologically limited to normal biopsies of the overlying mucosa. As will be discussed in subsequent paragraphs, EUS helps to define SMTs by imaging these lesions in greater detail, which eliminates the guesswork.1-5 During the past decade EUS has become an invaluable modality for determining the etiology, obtaining a cytologic diagnosis (on occasion), and for clinical Current affiliation: Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio. Reprint requests: Amitabh Chak, MD, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106-1736. Copyright © 2002 by the American Society for Gastrointestinal Endoscopy 0016-5107/2002/$35.00 + 0 37/0/127700 doi:10.1067/mge.2002.127700 VOLUME 56, NO. 4 (SUPPL), 2002

Figure 1. Endoscopic picture of a duodenal SMT showing smooth overlying normal mucosa.

management when a symptomatic or asymptomatic SMT is encountered at endoscopy. SYMPTOMS The majority of SMTs do not cause symptoms and are discovered incidentally during endoscopic or radiologic examinations. They occur in equal frequency in men and women, generally after the fifth decade. The overlying mucosa usually appears smooth and normal at endoscopy. On occasion, large submucosal neoplasms may outgrow their blood supply, ulcerate through the mucosa, and present with GASTROINTESTINAL ENDOSCOPY

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Submucosal tumors

Table 1. EUS characteristics of various submucosal tumors that are intrinsic to the GI wall Etiology

EUS layer(s)

GI stromal tumors

Lipomas Varices Cysts

Carcinoids Pancreatic rests

Granular cell tumors Metastatic deposits

Figure 2. EUS image shows a mixed echogenicity rectal carcinoid at about the 6 o’clock position involving the first 3 wall layers. The presence of an adjacent hypoechoic lymph node (outlined by cursor marks) is suggestive of malignancy.

GI bleeding. Firm SMTs may also present with obstructive symptoms, especially if they are located near the cardia, the pylorus, or the ileocecal valve. SMTs obstructing the major or minor papilla may cause jaundice or pancreatitis. Pain and weight loss, often associated with very large submucosal GI stromal tumors, are symptoms that suggest malignancy. EUS IMAGING OF SMTs Optimal EUS imaging of an SMT requires submersion of the tumor under water.1-5 Depending on the SMT location, the patient may need to be repositioned after the GI lumen has been filled with water. “Submucosal tumors” related to extrinsic organs are usually easy to delineate.1,2,6 They cause extrinsic compression of the normal 5 EUS layers. For SMTs that are intrinsic to the GI wall (Table 1), it is important to characterize the layer(s) of origin or involvement, the echogenicity of the “tumor,” the smoothness of the border, and any internal features (e.g., echogenic foci, or septae). Adjacent adenopathy might suggest a malignant etiology (Fig. 2) but can also be found with benign neoplasms. Catheter US (miniprobes), if available, may be particularly useful for evaluating SMTs because it permits sonographic examination of the tumor while the patient is having a diagnostic endoscopy.7,8 In addition to being convenient, catheter-type US probes are particularly useful for imaging small SMTs that are difficult to identify with dedicated echoendoscopes. They are also S44

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Appearance

4th

Hypoechoic mass (irregular borders, echogenic foci, anechoic spaces suggest malignancy) 3rd Hyperechoic, often polypoid 3rd Anechoic, serpiginous structures 3rd Anechoic, compressible, round or oval (3- or 5layer walls suggestive of duplication cyst) 1st, 2nd, Homogeneous, mildly and/or 3rd hypoechoic mass 2nd, 3rd, Hypoechoic or mixed echoor 4th genicity (ductal structures may be present) 3rd Heterogeneous mass with smooth borders Any or all Hypoechoic, heterogeneous mass

useful in imaging SMTs in the right colon (intermediate length colonoscopes are often required for this latter indication). EXTRINSIC COMPRESSIONS An enlarged (or sometimes normal) left atrium, left hepatic lobe, spleen (Fig. 3), prostate, or uterus may commonly masquerade as an SMT of the esophagus, stomach, or rectum during endoscopy. The EUS characterization of these organs is well described.1,2,6 Engorged or tortuous vessels in association with these organs, for example, tortuous aorta or dilated vessels at the splenic hilum, may also cause an extrinsic, often pulsatile, compression of the GI wall.9 On rare occasions, a pancreatic cyst or incidental pancreatic neoplasm may be identified when evaluating an SMT by EUS. Endometriosis, which may involve the distal colon, can also cause extrinsic compression of the gastrointestinal tract, and is imaged as a hypoechoic irregular mass that is externally adherent to the serosa (fifth sonographic layer). GI STROMAL TUMORS The most common SMTs encountered during GI endoscopy are GI stromal tumors (GISTs). They comprise about 1% of all GI tumors.10-12 These tumors were originally referred to as leiomyomas, leiomyoblastomas, and leiomyosarcomas10-14 because they bore a histologic resemblance to smooth muscle cells, and this incorrect terminology continues to be commonly used. The cell of origin of these neoplasms is mesenchymal, possibly the interstitial cell of Cajal.15-20 Therefore, the preferred and correct terVOLUME 56, NO. 4 (SUPPL), 2002

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Figure 3. Gastric EUS demonstrates liver on the left side of the image and spleen on the right. Compression on the stomach by the enlarged spleen gave the appearance of an SMT.

minology is now GIST. At EUS, GISTs are characterized by a hypoechoic appearance (Fig. 4) and can be seen to originate from the fourth hypoechoic endosonographic layer (muscularis propria).20 They are generally ovoid or elliptical in shape but may be multilobular or pedunculated. EUS features that should be characterized when imaging a GIST include regularity of the extraluminal border, presence of cystic spaces, echogenic foci, heterogeneity, and size.20-24 An irregular extraluminal border is likely associated with an invasive tumor; cystic areas likely represent cellular necrosis; and echogenic foci are likely caused by fibrosis.21 These histopathologic features along with size are criteria that are used to diagnose malignancy. The corresponding EUS features along with endosonographic measurements of size also appear to be able to differentiate benign GISTs from malignant ones. If multiple EUS features are present in a large GIST (>3 or 4 cm) then the neoplasm is likely malignant, and if a GIST is <3 cm in size, homogeneous, and smooth, it is likely benign. The behavior of a GIST that is 3 to 4 cm in size and contains one or two of the EUS features is difficult to predict. One must remember that the EUS interpretation of these features is dependent on the endosonographer and is subject to a fair degree of interobserver variability.21 LIPOMAS Lipomas are the second most common SMTs encountered during endoscopy. They are generally VOLUME 56, NO. 4 (SUPPL), 2002

Figure 4. EUS image of a hypoechoic homogenous esophageal GIST at about the 5 o’clock position originating from the fourth hypoechoic layer.

Figure 5. Left side of EUS image shows a hyperechoic lipoma (outlined by cursor marks) in the gastric antrum.

soft and have a yellowish hue. It is not clear that performance of EUS is necessary for lipomatous lesions that are characteristically obvious. However, EUS might be useful when the endoscopic appearance is not definitive.1-5 Lipomas are typically identified as hyperechoic neoplasms in the third layer (Fig. 5). GASTROINTESTINAL ENDOSCOPY

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Figure 6. As seen on this EUS image, cysts are characteristically anechoic, round or oval structures.

VARICES Occasionally, large gastric varices may be polypoid.1,5 The vascular nature of these “submucosal tumors” may not be evident at EGD because of the thick overlying rugal folds. EUS imaging of gastric varices demonstrates characteristic anechoic serpiginous structures in the third hyperechoic layer. In addition, EUS can identify perigastric collaterals, periesophageal collaterals, and penetrating vessels in patients with portal hypertension. CYSTS Cysts in the GI tract may be a result of embryologic development, i.e., duplication cysts, or they may be the result of a resolved inflammatory process. Cysts appear as anechoic, rounded or ovoid, compressible structures in the third EUS layer of the GI tract (Fig. 6).28-30 The wall of inflammatory cysts will always be a single hyperechoic layer. The walls of duplication cysts may be imaged as a 3- or 5-layer structure because of the presence of a submucosa and a muscularis layer. Diagnosis of duplication cysts in adulthood is uncommon. They may present in children with pain, bloating, bleeding, and obstructive symptoms. CARCINOIDS EUS may be useful for imaging carcinoid tumors of the rectum and the stomach. These neoplasms are generally homogeneous, well demarcated, and mildly hypoechoic (Fig. 2).2,31,32 They are usually present in the first, second, and third layer. The behavior of GI carcinoids can be predicted by tumor size. If a S46

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Figure 7. Fine-needle aspiration of submucosal tumor being performed with a curvilinear array ultrasound endoscope demonstrates the hyperechoic needle in the center of the mass.

carcinoid is less than 2 cm in longest diameter on EUS, it is unlikely to be malignant. If it is confined to the third layer and no adenopathy is identified, then endoscopic mucosal resection for “en bloc” excision of the tumor can be considered.31 PANCREATIC REST Ectopic pancreatic tissue deposits can also be submucosal. Most often found in the gastric antrum, these rests may appear as hypoechoic or mixed echogenicity lesions in the second, third, or fourth layer.1-3 The presence of ductal structures within the tissue is a distinctive finding but is found only in a minority of pancreatic rests. GRANULAR CELL TUMOR Granular cell tumors are benign submucosal neoplasms that may be found in the esophagus. They are believed to be of neural origin. EUS shows a heterogeneous mass with smooth borders located in the third (submucosa) layer.1,33,34 SUBMUCOSAL METASTASES Although uncommon, cancers may metastasize to the submucosa of the GI tract. Lymphomas may also present as submucosal masses. These malignant deposits are generally imaged as hypoechoic heterogeneous masses. They may involve any or all of the sonographic layers.1-3,5 EUS FINE-NEEDLE ASPIRATION OF SUBMUCOSAL LESIONS Multiple investigators have used EUS guidance to obtain diagnostic histologic material from SMTs VOLUME 56, NO. 4 (SUPPL), 2002

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(Fig. 7).35-38 Unfortunately, this approach has had limited success. A large majority of SMTs are GISTs. These neoplasms are very firm and a large amount of force is required to penetrate the neoplasm with a narrow-gauge needle. They may also be fibrotic and it may be difficult to obtain cytologic material by aspiration. The diagnosis of a malignant GIST is dependent on histology and architecture; thus, even if an adequate cytologic specimen is obtained by EUS-guided fine-needle aspiration, a reliable diagnosis of a benign GIST cannot be made. A guillotine needle that permitted endoscopic biopsies of GISTs and obtained a core specimen was developed.35 However, it did not gain in popularity, probably because of concern for bleeding and difficulty in use. A recent pilot investigation39 demonstrated that immunohistochemical staining with CD34, c-kit, and Ki-67 labeling index was able to diagnose GISTs preoperatively but the diagnosis of malignancy in this study was still based on tumor size and mitotic index. If other investigators confirm these results in larger studies, then this methodology might provide a preoperative method for the histologic diagnosis of GISTs. Large-bore and Trucut needles being developed for EUS use may further enhance the ability to obtain a core of tissue from within these firm neoplasms. However, given that pathologists have difficulty in determining the behavior of a GIST even after the entire specimen has been resected, it remains unclear whether improved techniques for obtaining tissue under EUS guidance will improve clinical decision making. ROLE OF EUS IN GUIDING THERAPY OF SMTs Surgical resection is the only treatment that is effective for symptomatic GISTs. Surgery should also be performed on incidental GISTs that are large or have several EUS features associated with malignancy.20-24 GISTs that appear benign at EUS can be safely observed. The frequency with which characteristically benign asymptomatic lesions should be reimaged has not been determined but is likely in the order of several years. It is difficult to decide what to recommend to patients who have GISTs that are indeterminate at EUS. These management decisions should be made on a case-by-case basis. Gastric tumors that are amenable should probably be considered for laparoscopic excision if the patient is a good surgical candidate. Esophageal GISTs are more likely to be benign and should probably be left alone if they are not symptomatic. Excision of duodenal tumors requires a more aggressive approach and should only be attempted when there is a high suspicion of malignancy. Colonic and rectal GISTs are unusual. Excision of VOLUME 56, NO. 4 (SUPPL), 2002

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small rectal GISTs may sometimes be possible with a transanal approach. Most lipomas identified at EUS can be left alone. However, if a lipoma is thought to be causing symptoms (e.g., bleeding or obstruction) and endoscopic resection is being contemplated, EUS may also be helpful for delineating and avoiding underlying vascular structures.40 EUS can also help guide therapy of carcinoid tumors.31,32,41 Tumor size can be measured accurately and the extent of tumor invasion can be identified. Tumors that are <2 cm in size and confined to the first 3 layers can be safely resected with EMR techniques. Carcinoids that invade the fourth layer or are associated with lymphadenopathy should be treated by surgical resection. SUMMARY In summary, EUS imaging is essential for the evaluation of “submucosal tumors.” The majority of these SMTs are benign and can be left alone. EUSguided fine-needle aspiration can be considered for lesions that are not characterized by imaging alone but is of limited value when the SMT is a GIST. Information obtained by EUS can help guide decisions about endoscopic or surgical intervention. REFERENCES 1. Boyce GA, Sivak MV Jr, Rösch T, Classen M, Fleischer DE, Boyce HW, et al. Evaluation of submucosal upper gastrointestinal tract lesions by endoscopic ultrasound. Gastrointest Endosc 1991;37:449-54. 2. Yasuda K, Nakajima M, Yoshida S, Kiyota K, Kawai K. The diagnosis of submucosal tumors of the stomach by endoscopic ultrasonography. Gastrointest Endosc 1989;35:10-5. 3. Yasuda K, Cho E, Nakajima M, Kawai K. Diagnosis of submucosal lesions of the upper gastrointestinal tract by endoscopic ultrasonography. Gastrointest Endosc 1990;36:S17-20. 4. Rösch T, Lorenz R, Dancygier H, von Wichert A, Classen M. Endosonographic diagnosis of submucosal upper gastrointestinal tract tumors. Scand J Gastroenterol 1992;27:1-8. 5. Caletti G, Zani L, Bolondi L, Brocchi E, Rollo V, Barbara L. Endoscopic ultrasonography in the diagnosis of gastric submucosal tumor. Gastrointest Endosc 1989:35:413-8. 6. Moto Y, Ohta H, Satamura Y, Watanabe H, Yamakawa O, Yamaguchi Y, et al. Endoscopic ultrasonography in the diagnosis of extraluminal compressions mimicking gastric submucosal tumors. Endoscopy 1994;26:239-42. 7. Chak A, Canto M, Stevens PD, Lightdale CJ, Van de Mierop F, Cooper G, et al. Clinical applications of a new through-thescope ultrasound probe: prospective comparison with an ultrasound endoscope. Gastrointest Endosc 1997;45:291-5. 8. Buscarini E, Stasi MD, Rossi S, Silva M, Giangregario F, Adriano Z, et al. Endosonographic diagnosis of submucosal upper gastrointestinal tract lesions and large fold gastropathies by catheter ultrasound probe. Gastrointest Endosc 1999;49:184-91. 9. Bashir RM, Gupta PK. Endoscopic ultrasonographic diagnosis of a splenic artery aneurysm. Pract Gastroenterol 1995;19: 24B-D. GASTROINTESTINAL ENDOSCOPY

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