Endoscopic ultrasonography (EUS) can accurately differentiate a mural lesion from extrinsic compression against the gut wall.
Determination of the cause of an intramural lesion is based on its layer of origin and internal echo characteristics.
The finding of an intact submucosal layer running deep below a mural lesion indicates that the lesion can be removed safely by endoscopic mucosal resection.
Carcinoid tumors can usually be diagnosed with standard mucosal biopsies because these tumors emanate from the deep mucosal layer.
Gastrointestinal stromal tumors can be differentiated from leiomyomas by immunohistochemical staining for CD117 (c-kit proto-oncogene protein product).
The term submucosal lesion is used by endoscopists to describe any bulge covered with normal mucosa, usually found incidentally during gastrointestinal (GI) endoscopy or barium contrast radiography. This lesion could be either an intramural mass or an impression caused by extramural structures. Recently the term “subepithelial lesion (SEL)” has been used more frequently than “submucosal lesion” because intramural lesions may arise from any layer of the GI wall underneath the epithelium. In the past, the prevalence of suspected gastric submucosal lesions at routine endoscopy was reported to be as low as 0.36%. More recently, however, the detection rate has notably increased, especially with regard to small lesions. Advances in technology and the close attention paid to these lesions may be responsible for this augmentation.
To characterize the cause of protrusion, some noninvasive imaging methods, such as transabdominal ultrasonography (USG), computed tomography (CT), and magnetic resonance imaging (MRI), have been used, but they are often insufficient. With endoscopic ultrasonography (EUS), however, the clinician can visualize the structure of gut wall layers clearly. Thus, EUS can not only differentiate SELs from extramural structures but also identify the layers of origin and endosonographic characteristics of intraluminal lesions. EUS is now accepted as the modality of choice for visualizing SELs with high precision.
The differential diagnosis of SELs includes a wide variety of benign and malignant subepithelial neoplasms as well as nonneoplastic lesions ( Video 11.1 ). To evaluate SELs, the transition zone (the area where the tumor arises from normal gut wall layers) should be examined carefully to determine the layer of origin. Next, the size and echo pattern of the tumor—such as the smoothness of the border, internal features, echogenicity, and vascularity—should be observed. In addition, the relationship with other adjacent organs and the presence of adenopathy nearby provide valuable information. From the information gathered, an educated guess on the SEL for the differential diagnosis can be made with reasonable accuracy ( Table 11.1 ). The reported accuracy of EUS in predicting the pathologic diagnosis of SELs has shown a wide range, from 45.5% to 82.9% ( Table 11.2 ). If tissue was obtained from EUS-guided fine-needle aspiration (EUS FNA), the diagnostic accuracy increased markedly, ranging from 63% to 98%. Detailed description comes later in this chapter.
|Cause||EUS Layers a||EUS Appearance|
|Gastrointestinal stromal tumor||Fourth (rarely second)||Hypoechoic (irregular borders, echogenic foci with mixed echogenicity; anechoic areas suggest malignancy)|
|Aberrant pancreas||Second, third, and/or fourth||Hypoechoic or mixed echogenicity (anechoic ductal structure may be present)|
|Carcinoid||Second and/or third||Mildly hypoechoic, homogeneous|
|Granular cell tumor||Second or third||Homogeneous hypoechoic mass with smooth borders|
|Cyst||Third||Anechoic, round or oval (three- or five-layer walls suggest duplication cyst)|
|Varices||Third||Anechoic, tubular, serpiginous|
|Inflammatory fibroid polyp||Second and/or third||Hypoechoic, homogeneous, or mixed echogenicity, indistinct margin|
|Glomus tumor||Third or fourth||Hypoechoic, smooth margin, internal heterogeneous echo mixed with high echoic spots|
|Lymphoma||Second, third, and/or fourth||Hypoechoic|
|Metastatic deposits||Any or all||Hypoechoic, heterogeneous|
|Authors (Year)||Number of Patients||Accuracy (%)|
|Lim and coworkers (2016)||99||66.7|
|Reddymasu and coworkers (2012)||37||49|
|Karaca and coworkers (2010)||22||45.5|
|Ji and coworkers (2008)||76||82.9|
|Kwon and coworkers (2005)||58||79.3|
|Kojima and coworkers (1999)||54||74|
|Matsui and coworkers (1998)||15||60|
Video Demonstrating the Sonographic Features of Various Subepithelial Lesions
Diagnostic information on the SELs, including the origin of the wall layer provided by EUS, also helps in deciding whether a lesion should be removed or followed in situ. Lesions confined to the mucosal or submucosal layers can be safely removed endoscopically. Surgical resection, if needed, is generally recommended for lesions located in the muscularis propria, although advances in endoscopic techniques such as endoscopic submucosal dissection (ESD) have made it possible for these lesions to be removed by experienced clinicians with minimal risk to the patient. EUS can be used for following up after resection.
Comparison of Accuracy Between Endoscopic Ultrasonography and Other Imaging Modalities
Differentiation of SELs is one of the main indications for EUS. Compared with endoscopy, barium contrast radiography, USG, CT, and MRI, EUS has a higher accuracy in detecting and assessing the size and location of SELs. When viewed endoscopically, the surface of a SEL is usually smooth and has a color similar to that of the surrounding mucosa, without ulceration or erosion. Sometimes these lesions show a slight color change and certain morphologic characteristics, but it is often impossible to differentiate them by endoscopy alone. USG provides diagnostic information only for very large SELs. In a study of patients with endosonographically diagnosed gastric SELs, 82.5% of tumors were visualized and measured by USG after the stomach was filled with water. Like CT and MRI, USG can also provide useful information on perigastric structures. CT may be used to evaluate a SEL especially when it is malignant and metastasis is suspected. However, a study pointed out that large submucosal tumors previously identified by EUS were visualized in only two-thirds of cases by preoperative CT. Reported mean sizes of possibly malignant SELs detected and not detected by CT were 27.4 mm and 11 mm, respectively. Currently high-quality images are available through multidetector computed tomography (MDCT). The diagnostic accuracy of MDCT is expected to be improved to even higher levels because MDCT can offer images from multiplanar and three-dimensional reconstructions. Overall accuracy of MDCT in the detection and classification of SELs from a recent study was 85.3% and 78.8%, respectively.
In addition to detection, only EUS can establish the precise location of the lesion within the GI wall layer and provide information on the sonographic characteristics of the SEL. The narrow differential diagnosis of SELs afforded by the use of EUS improves decision making. Based on EUS, the clinician can decide between observation with reexamination in patients with suspected benign lesions or resection when the lesion is likely to be malignant.
In the differentiation between SELs and extraluminal compression, EUS also demonstrates higher accuracy than endoscopy, USG, and CT. In a multicenter study, endoscopy was able to differentiate SELs from extraluminal compressions with sensitivity and specificity of 87% and 29%, respectively. In another study, ultrasonography and CT established the diagnosis in only 16% of cases, compared with 100% for EUS. Another comparison of ultrasonography, CT, and EUS reported an accuracy of 22%, 28%, and 100%, respectively, in differentiating SELs from extraluminal compression. One study suggested that if the size of a SEL is greater than 10 mm, MDCT may depict and differentiate it from extraluminal compression.
Check the integrity of the five wall layers between the lesion and the gut lumen.
Because EUS is able to visualize the gut wall layers in detail, it can readily differentiate the intramural and extramural nature of subepithelial masslike lesions. When EUS demonstrates the integrity of all gut wall layers between the gut lumen and the lesion, it is safe to say that the lesion is an impression caused by an extramural structure.
Although the extramural structures that compress the gut wall are on occasion pathologic masses, such findings are more likely to represent adjacent normal structures ( Table 11.3 ). A study revealed that when EUS evaluation was done for patients with suspected extraluminal compression or SELs during endoscopy, 66.4% were proven to be extraluminal compression. It is worth noting that only 11% were due to pathologic lesions, and others were related to adjacent normal organs or vessels.
|Normal Organ||Pathologic Condition|
|Liver||Pancreatic cystic tumor|
|Blood vessel||Hepatic cyst|
|Gallbladder||Vascular anomaly including aneurysm|
|Bowel loop||Colonic tumor|
|Vertebra||Mediastinal tumor or lymphadenopathy|
A normal spleen usually makes an impression in the gastric fundus and upper body ( Fig. 11.1 ), and the gallbladder compresses the gastric antrum. Transient gastric impression is often caused by bowel loops. Other causes of gastric impression include vessels in the splenic hilum, the pancreatic tail, and the left lobe of the liver. Abnormal structures such as pancreatic pseudocysts, splenic artery aneurysms, aortic aneurysms, cystic tumors of the pancreas or liver, colonic tumors, and lymphomas may also produce endoscopically visible impressions on the gastric wall. Adjacent structures, such as the aortic arch and vertebrae, can also press on the esophagus. Other potential causes of esophageal impression are vascular anomalies, such as a right descending aortic arch, anomalous branches of the aortic arch, aneurysm, and left atrial dilation. Enlarged mediastinal lymph nodes or mediastinal tumors, lung cancer, and lymphomas are also known to compress the esophagus.
When using EUS, the suspected area of gastric impression should be observed by the two-step method. First, at a low frequency of 7.5 MHz, the examiner should survey the gross relationship between the extramural structure and the gut wall. Then, at a higher frequency of 12 MHz, the outer hyperechoic serosal layer should be observed carefully to determine whether it is intact or disrupted. This method allows reliable differentiation between gastric wall impression and gastric wall infiltration caused by an extragastric tumor. For the examination of small lesions, a high-frequency catheter ultrasound probe is technically easier to use than a conventional echoendoscope. In the esophagus, the endosonographer may encounter difficulties in this evaluation owing to interference from the air-filled bronchial system.
Evaluation of Subepithelial Lesions
Carefully examine the transition zone between the normal gut wall and the lesion to determine the layer of origin.
Measure the size of the lesion and observe the echo pattern (e.g., echogenicity, internal features, vascularity, and smoothness of the border).
Check the presence of adjacent lymphadenopathy.
Small lesions measuring less than 1 to 2 cm may be better imaged using high-frequency catheter ultrasound probes.
For better imaging of the wall layers and the evaluation of SELs, it may be necessary to instill water or jelly into the luminal tract to obtain better acoustic coupling. Aspiration precautions should be taken under these circumstances.
Gastrointestinal Stromal Tumor
Origin in second or fourth gastric wall layer.
Generally a well-circumscribed, hypoechoic, relatively homogeneous mass.
If malignant, noticeable characteristics include large size, features of heterogeneous echo texture with hyperechoic foci and/or anechoic necrotic zones, irregular extraluminal border, and adjacent malignant-looking lymphadenopathy.
Gastrointestinal stromal tumors (GISTs) are among the most common mesenchymal tumors in the GI tract; they are also the most commonly identified intramural SELs in the upper GI tract. Previously these tumors were classified as GI smooth muscle tumors, such as leiomyomas and leiomyosarcomas, owing to histologic findings of circular palisades of spindle cells with prominent nuclei and an apparent origin in the muscularis propria layer of the gut wall. However, with the development of newer molecular markers and an improved understanding of the biologic behavior of these tumors, GISTs are now classified as a distinct but heterogeneous group of mesenchymal tumors with varying differentiation. Interstitial cells of Cajal, also known as pacemaker cells of the GI tract, are now believed to be the precursor of GISTs that typically express the c-kit proto-oncogene, a transmembrane tyrosine kinase receptor. With immunohistochemical staining techniques, most GISTs stain positive for CD117, an epitope of kit protein and, sometimes, CD34 but negative for desmin. Leiomyomas express smooth muscle actin and desmin, and schwannomas produce S-100 protein and neuron-specific enolase.
According to the more recent classification, approximately 80% of GI mesenchymal tumors are GISTs, and approximately 10% to 30% of GISTs are malignant. Leiomyomas are the most common mesenchymal tumors in the esophagus, but they rarely occur in the stomach and small bowel. In contrast, GISTs are rare in the esophagus and are more common in the stomach (60% to 70%) and small bowel (20% to 25%).
The most common symptoms associated with GISTs are vague abdominal discomfort and pain, but most lesions are small (<2 cm) and asymptomatic. Larger lesions (>2 cm) may be ulcerated on top of the mass, and patients may present with bleeding or anemia. Occasionally, GISTs cause intestinal obstruction.
In defining the prognosis of patients with GISTs, it has been recommended that a “grading as to the risk of aggressive behavior” be used instead of the term benign. This means that no GIST can be definitively labeled as benign; all are considered to have some malignant potential. Pathologists classify GISTs as “very low risk,” “low risk,” “intermediate risk,” and “high risk,” according to the size of the mass and the mitotic count of the resected specimen.
Endosonographically, a GIST is typically a well-circumscribed, hypoechoic, relatively homogeneous mass that can arise from either the second hypoechoic layer (muscularis mucosa) or more frequently the fourth hypoechoic layer (muscularis propria) ( Fig. 11.2 ). In contrast, leiomyomas ( Fig. 11.3 ) showing homogeneous hypoechoic patterns arise from the muscularis mucosa more frequently than do GISTs. Gastric schwannomas are rare mesenchymal tumors also appearing as hypoechoic lesions originating from fourth hypoechoic layer, but they frequently show a heterogeneous pattern with decreased echogenicity compared with the normal proper muscle layer.
The images of GISTs, leiomyomas, and schwannomas are seen as relatively homogeneous hypoechoic masses under EUS and cannot be differentiated unless special immunohistochemical tissue staining is performed. One study suggested that GISTs have a marginal hypoechoic halo and relatively higher echogenicity compared with the adjacent muscular layer. Another study added inhomogeneity and hyperechoic spots to the foregoing features, and the presence of at least two of these four features predicted GISTs with 89.1% sensitivity and 85.7% specificity.
Several studies have attempted to predict the potential malignancy of GISTs based on the EUS characteristics of the lesion, but none has obtained completely satisfying results. In addition to size and mucosal ulcer, other EUS characteristics were considered as possible predictive factors, but size was the only consistently definitive predictive factor. EUS features mentioned by the authors were distorted shape, lobulation, irregular border, increased echogenicity in comparison with the surrounding muscle echo, inhomogeneity, hyperechoic spots, anechoic area, marginal halo, and extraluminal growth pattern. In one study, an internal hypoechoic feature was suggested as a predictive marker of tumor progression. When malignant changes occur, GISTs commonly show a heterogeneous echo texture with hyperechoic deposits or anechoic necrotic zones inside large tumors ( Fig. 11.4 ). In one report, EUS findings of tumor size greater than 4 cm, an irregular extraluminal border, echogenic foci, and anechoic spaces were strong indicators of malignancy. Sensitivity ranged between 80% and 100% in detecting malignancy when at least two of four features were present. Another study found a correlation with malignancy when irregular extraluminal margins, cystic spaces, and lymph nodes were seen. The presence of two of these three features had a positive predictive value of 100% for malignant or borderline-malignant tumors. Nonetheless, a lack of defined risk factors could not exclude a malignant potential. A multicenter study reported that malignancy or indeterminate GIST status correlated with the presence of ulceration, tumor size larger than 3 cm, irregular margins, and gastric location but not with hyperechoic or hypoechoic internal foci.
Recently, contrast-enhanced harmonic EUS (CEH EUS) has been introduced. CEH EUS can demonstrate the perfusion characteristics of SELs, and it is helpful for establishing a differential diagnosis. The image of GIST is hyperenhanced after infusion of ultrasound contrast; in consequence, the CEH EUS signal intensity of GISTs is higher than that of other benign lesions. It is suggested that hyperenhancement and avascular areas in the center of the lesion are shown in GISTs but not in leiomyomas ( Fig. 11.5 ). In addition, prediction of a malignant GIST was possible with CEH EUS by identifying irregular intratumoral vessels with 83% accuracy.
Use of EUS elastography for the differential diagnosis of gastric SELs has recently been suggested. It might be especially helpful for differentiating GISTs from other SELs because GISTs may be harder than other SELs.
EUS FNA and EUS-guided fine-needle tissue-core biopsy (EUS FNB) can be performed for immunohistochemical examination to achieve better diagnostic accuracy of GISTs ( Table 11.4 ). A major drawback of EUS FNA is its inability to differentiate with absolute certainty benign from malignant GISTs. However, staining for ki-67 (MIB-1), a marker of cell proliferation, may enable the discrimination of benign from malignant GISTs with EUS FNA. The role of EUS FNA is further described later in this chapter.
|Authors (Year)||Number of Patients||Accuracy (%)||Diagnostic Method|
|El Chafic and coworkers (2017)||91||57||EUS FNA a|
|15||87||EUS FNB a|
|DeWitt and coworkers (2011)||38||76||EUS FNA b|
|79||EUS TCB b|
|Watson and coworkers (2011)||65||80||EUS FNA a|
|Fernandez-Esparrach and coworkers (2010)||40||70||EUS FNA b|
|60||EUS TCB b|
|Sepe and coworkers (2009)||37||78||EUS FNA a|
|Chatzipantelis and coworkers (2008)||17||100||EUS FNA a|
|Akahoshi and coworkers (2007)||29||97||EUS FNA a|
|Mochizuki and coworkers (2006)||18||83||EUS FNA a|
|Okubo and coworkers (2004)||14||79||EUS FNA c|
|Ando and coworkers (2002)||23||91||EUS FNA d|
Because small (<1 cm) asymptomatic mesenchymal tumors are rarely malignant, a policy of close follow-up with EUS may be justified, although an optimal surveillance strategy has not yet been established. Excision is advised when growth of the lesion, a change in the echo pattern, or necrosis is noted during yearly follow-up with EUS. Surgical treatment is indicated for lesions greater than 3 cm in diameter with features suggestive of malignancy. For lesions between 1 and 3 cm, EUS FNA can be recommended, or ESD can be chosen as a definite diagnostic and therapeutic tool with some risk of bleeding and perforation (2% to 3% in specialized centers). When the lesion is confirmed to be a GIST, the risk of malignant transformation needs to be discussed with the patient; more careful follow-up or early resection should be considered.
Origin in the second, third, and/or fourth layers.
Hypoechoic or mixed echogenicity with internal anechoic ductal structure.
The term aberrant pancreas is used to describe ectopic pancreatic tissue lying outside its normal location with no anatomic or vascular connection to the pancreas proper. These lesions are also termed ectopic pancreas, pancreatic rest, and heterotopic pancreas. They are typically discovered incidentally during endoscopy, surgery, or autopsy. Aberrant pancreas is encountered in approximately 1 of every 500 operations performed in the upper abdomen; the incidence in autopsy series has been estimated to be between 0.6% and 13.7%. Aberrant pancreas is usually located in the stomach wall (frequently along the greater curvature of the antrum), duodenum, small intestine, or anywhere in the GI tract. Patients with aberrant pancreas are usually asymptomatic, but rare complications such as pancreatitis, cyst formation, ulceration, bleeding, gastric outlet obstruction, obstructive jaundice, and malignancy can occur.
On endoscopy, an aberrant pancreas appears as a submucosal nodule, usually small, with a characteristic central umbilication that corresponds to a draining duct. The characteristic EUS features of aberrant pancreas are heterogeneous lesions, mainly hypoechoic or intermediate echogenic masses accompanied by scattered small hyperechoic areas, with indistinct margins within the gut wall ( Fig. 11.6 ). Generally an anechoic area and fourth layer thickening accompany the lesions. Anechoic cystic or tubular structures within the lesion correlate with ductal structures. They commonly arise from the third and fourth layers. However, lesions may develop in any location from the deep mucosal to the serosal layer.
The management of aberrant pancreas remains controversial. It should be guided by symptoms and the possibility of malignancy. Asymptomatic lesions do not necessarily require resection and can be followed expectantly. If needed, endoscopic removal is useful for both accurate diagnosis and treatment, although surgical resection is preferred to endoscopic resection when the muscularis propria is involved.