Synopsis  

Submucosal lesions of the gastrointestinal tract have been described as mass lesions located under the normal-appearing mucosal layer. Endoscopically and radiographically these lesions are seen as a bulge in the lumen, and their exact nature may be difficult or impossible to diagnose accurately from endoscopy alone. A better descriptive term might be subepithelial lesions, since these lesions can arise not only from the submucosa but from any of the other deep gastrointestinal wall layers. Recent developments in our understanding of the molecular biology of gastrointestinal stromal tumors (GISTs) in particular has led to a greater emphasis on detecting these lesions and selecting those that require resection and/or imatinib therapy. This chapter describes the role of endoscopic ultrasonography (EUS) in diagnosis and management of submucosal lesions of the GI tract.

 Introduction   

EUS plays a pivotal role in the description, diagnosis, and management of these lesions [1–7]. EUS can distinguish intramural lesions from extrinsic compression, and can often accurately diagnose the nature of these lesions by their echocharacteristics and wall layer of origin. Submucosal lesions can be primary or metastatic. They may also represent extrinsic compression from a normal or pathologic adjacent organ, vascular structure, or mass from outside the gastrointestinal tract [3,5]. The majority of submucosal tumors are asymptomatic and often are found incidentally during endoscopy or radiologic examinations performed for other reasons.

 Endoscopic and EUS examination   

Standard endoscopic evaluation is an important part of the initial examination of submucosal lesions, as this allows precise identification and localization of the lesion in question and may provide helpful information regarding the etiology of the lesion.

Endosonographic examination can be performed using radial scanning or linear array echoendoscopes, or through-the-scope high frequency catheter probes. Catheter probes may be most useful in imaging small (= 1 cm) lesions or esophageal lesions. In these cases, the examination may be made technically easier by using a catheter probe through a standard endoscope which allows direct visualization of the lesion. Endosonographic imaging is best performed by submersion of the lesion in deaerated water, which provides the necessary acoustic coupling to image the gastrointestinal wall. When imaging upper GI tract lesions using water submersion there is a risk of aspiration to the patient, and therefore the head of the patient's bed should be elevated or the patient should be placed in reverse Trendelenburg position to avoid this complication.

During the examination, the transducer balloon should ideally be kept to a minimum size to avoid compression of the lesion. EUS characterization of submucosal lesions should include the following information: wall layer involvement, echogenicity, shape, margin, size, relation to adjacent structures or organs, and presence or absence of adjacent lymphadenopathy.

 GISTs   

Origin and development of GISTs   

GISTs were previously thought to represent smooth muscle tumors and were typically classified as leiomyomas and leiomyosarcomas. More recently, GISTs have been reclassified as mesenchymal tumors theorized to originate from the interstitial cells of Cajal (ICCs) or from pluripotential stem cells that differentiate toward a pacemaker cell phenotype [8]. The ICCs form a complex cellular network within the muscle wall layer of the gut, where they function as a pacemaker system controlling gut motility [9].

Molecular biology of GIST: c-kit   

Expression of the c-kit proto-oncogene appears to be necessary for the development of the ICC system; and although c-kit expression is not limited to ICCs, it is widely recognized as a molecular marker for this cell type [10–12]. The c-kit gene product CD117 is a transmembrane receptor for a growth factor termed stem cell factor and has an internal tyrosine kinase component. When the c-kit tyrosine kinase receptor is bound to its ligand it is activated, and this in turn leads to phosphorylation of a number of signal transduction molecules that control cell processes, such as cell division, actin reorganization, and chemotaxis [11,12].

GISTs, like the ICCs, have been found to express CD117 almost universally. CD117 is now recognized to be a highly specific marker for GISTs [13] and is considered the single most important factor for the establishment of their diagnosis. Further investigation of CD117 expression in GISTs led to the identification of several gain-of-function mutations of the c-kit product, which result in the constitutive activation of the c-kit tyrosine kinase receptor without the receptor ligand [14]. This in turn leads to cell proliferation and inhibition of apoptotic cell death which may potentially explain the pathogenesis of GISTs.

CD34 and other immunohistochemistry   

CD34 is a sialylated transmembrane glycoprotein and a hematopoietic progenitor cell antigen found in mesenchymal cells which is often coexpressed with CD117. Approximately 70–80% of GISTs are positive for CD34 [15]. Currently, immunohistochemical staining for CD117 and CD34 is used for the positive identification and diagnosis of GISTs and helps distinguish GISTs from other gastrointestinal mesenchymal tumors [13,16]. In contrast to typical leiomyomas, GISTs are negative for desmin and primarily negative for smooth muscle actins (SMAs), although GISTs of the small intestine may express CD34 and SMA in equal proportions [17]. True leiomyomas, which are benign GI mesenchymal tumors, stain positive for desmin and SMA but negative for CD117 and CD34 [16]. Schwannomas, another class of benign mesenchymal tumors of the GI tract, are CD117 negative and stain consistently positive for S100 protein [16].

Clinical features   

GISTs occur primarily in the fifth and sixth decades of life, and affect both men and women equally [18,19]. GISTs are most commonly found in the stomach (60–70%), followed by the small intestine (20–25%), and are less common in the colon, rectum, esophagus, mesentery, and omentum [16,20]. Symptomatic tumors are usually significantly larger than asymptomatic ones [21]. In those patients that are symptomatic, gastrointestinal bleeding from mucosal ulceration and abdominal pain are the most common presenting symptoms. Other less common clinical manifestations include bowel obstruction, dysphagia, anorexia, a palpable abdominal mass, perforation, and fever [21]. Occasionally, duodenal GISTs may present with jaundice. Lesions within the ileum may also cause pelvic pain and mimic gynecological disease [22]. Malignant GISTs usually disseminate within the peritoneal cavity and can metastasize to the liver, lungs, and bone.

Pathology   

Approximately 10% of all GISTs display malignant behavior. The histologic features which have been the most useful in predicting malignant behavior include nuclear pleomorphism, increased nuclear-to-cytoplasmic ratio, irregular nuclear membranes, and mitotic activity [23]. Both mitotic activity and tumor size have been identified as independent predictors of malignancy. Gastric GISTs with mitotic counts greater than 5 mitoses per 10 high power fields are generally considered histologically malignant, those with counts of 2–5 are considered potentially malignant, and those with less than 2 mitoses per 10 high power fields generally correlate with benign behavior [24]. A number of studies have shown a worse prognosis for tumors larger than 5 cm in size [19,20,25]; however, smaller tumors have been known to metastasize [18]. For small intestinal GISTs, tumor size may not be a reliable indicator of malignancy, and even tumors with very low mitotic activity can metastasize.

Predicting malignant behavior: role of molecular markers   

Several reports have now demonstrated a higher frequency of mutations of the c-kit proto-oncogene within exon 11 in malignant GISTS [26]. In a study by Taniguchi et al. looking at 124 cases of GISTs [27], those patients found to have exon 11 mutations were significantly more likely to experience recurrent disease and had decreased survival after surgery, compared to mutation negative patients. Subsequently, the presence of mutations in exon 11 has been proposed as a poor prognostic factor. Multiple mutations have also been reported in exons 9, 13, and 17 of c-kit but their clinical significance remains unclear [28]. In a recent study by Corless et al. looking at 13 benign, small (< 1 cm) GISTs in asymptomatic patients, 85% of tumors were found to have several different c-kit mutations, and 77% had exon 11 mutations [29]. This suggests that mutations in c-kit may be acquired early in the development of GISTs and may not necessarily have prognostic implications regarding malignant behavior.

Predicting malignant behavior: role of EUS   

At EUS, GI stromal tumors typically appear as a hypoechoic mass lesion arising from the fourth hypoechoic layer or muscularis propria (Fig. 1) [3–7]. GISTs can also arise from the muscularis mucosae [5,7]. Occasionally, GISTs can be found in the third hyperechoic wall layer or submucosa. In these cases, it is thought that these tumors initially originate from the muscularis mucosae or muscularis propria and subsequently grow into the submucosa [30]. The majority of GI stromal tumors are ovoid or elliptical in shape, although they may also be multilobular or pedunculated. EUS features associated with malignancy include large tumor size (> 4 cm), irregular extraluminal border, presence of cystic spaces (which represent areas of necrosis), and echogenic foci within the tumor (Figs 2 and 3) [6,7]. The sensitivity for detecting malignancy by EUS may be as high as 80–100%. However, EUS interpretation even by experts is subject to a high degree of interobserver variability [6].

Tissue sampling of GISTs   

Tissue sampling of suspected GISTs is essential for establishing the diagnosis and determining malignancy. Endoscopic biopsies are generally not helpful in the diagnosis of GISTs because these lesions are usually not within the reach of standard biopsy forceps [31]. Another available diagnostic and potentially therapeutic tool is endoscopic submucosal-mucosal resection (ESMR) for those tumors confined to the mucosa and submucosa. The overall diagnostic yield of ESMR is thought to be significantly higher than the yield of jumbo forceps biopsies for a variety of submucosal lesions, including GISTs [32]. ESMR also offers a mode of definitive treatment for small lesions (< 2 cm) confined to the submucosa, which can be completely removed successfully [33]. A drawback of this technique, however, may be the potential risk of bleeding and perforation. Lesions arising from the muscularis propria (fourth endosonographic layer) should not be removed endoscopically as a complete resection with negative margins is unlikely and there is an increased risk of perforation.

EUS-guided fine-needle aspiration   

EUS-guided fine-needle aspiration (FNA) has recently emerged as an important method for the diagnosis of GISTs. By performing immunohistochemical analysis of specimens obtained by EUS-FNA, CD117 expression can be determined, which is necessary for establishing the diagnosis of GISTs and excluding other tumors with similar EUS appearance. Unfortunately, this technique is not as useful when it comes to differentiating between benign and malignant GISTs, since the histologic features used to determine malignancy, including mitotic activity, are inconsistently found on FNA specimens [23,34,35].

The addition of immunohistochemical staining for Ki-67, a labelling index that denotes mitotic activity, may be helpful in overcoming this problem. In a study of 23 patients suspected of having GISTs, immunohistochemical analysis for Ki-67 was performed on EUS-FNA specimens and surgical specimens [36]. With the addition of Ki-67 staining to EUS findings and H&E stains, the sensitivity and specificity for malignant GISTs increased to 100%. The performance of c-kit mutational analysis on FNA specimens can also add to the yield of EUS-FNA [23]. Mutational analysis may result in the detection of exon 11 mutations and other c-kit mutations that may be potential predictors of malignant behavior.

Finally, EUS-guided diagnostic sampling of GISTs can now be performed using the recently developed EUS core biopsy needle. The use of this device results in the acquisition of a core biopsy specimen in which mitotic activity and other histological features are easily identified and malignancy can be determined.

Therapy: surgery   

Complete surgical resection remains the most definitive treatment for symptomatic or malignant GISTs. These tumors generally do not invade adjacent tissue layers and, therefore, wide margins of resection are not necessary [18]. If contiguous organs are involved, en-bloc resection is recommended [37,38]. The five-year survival of patients undergoing curative resection ranges from 28% to 54% [37,39–42].

Surgery should also be performed on incidental GISTs that are greater than 3 cm and those that have EUS features suggestive of malignancy regardless of size [6,25]. There is currently no consensus regarding the management of asymptomatic, benign-appearing GISTs smaller than 3 cm. Whether these tumors should be removed or undergo close clinical surveillance with repeat EUS is not known. An interval increase in size of the tumor or the development of EUS features associated with malignancy on repeat EUS examination should prompt surgical resection. Further prospective clinical studies are needed to determine the best management of these small benign tumors and additional data is needed regarding the role of c-kit mutational analysis in predicting malignant potential.

Therapy: imatinib   

Treatment of unresectable or metastatic GISTs with chemotherapy or radiation therapy has not been shown to be effective. STI571, also know as imatinib mesylate or Gleevec^® (Novartis pharmaceuticals), is a selective inhibitor of certain tyrosine kinases, including the transmembrane receptor kit found in GISTs. Studies performed on human cell lines expressing c-kit have demonstrated inhibition of c-kit tyrosine kinase activity by STI571, leading to decreased cell proliferation and apoptotic cell death [43,44]. In a recent multicenter trial involving 147 patients with unresectable or metastatic GISTs, Demitri et al. reported a sustained response in 54% of patients treated with imatinib, during a median follow-up of 24 weeks [45]. The advent of a potentially beneficial medical therapy for advanced GISTs can only serve to strengthen the role of EUS in the diagnosis and management of GISTs.

 Leiomyomas   

Clinical features and diagnosis   

Leiomyomas are a class of benign mesenchymal tumors of the GI tract. They usually occur in the distal third of the esophagus, but can also be found in the rectum or colon. In the esophagus, leiomyomas are the most common type of GI mesenchymal tumor found [16]. Unlike GISTs, leiomyomas are rare in the stomach; however, when present, they are usually located within the cardia [15]. The majority of esophageal lesions are asymptomatic, but can often cause dysphagia. These tumors are typically small; however, lesions up to 10 cm in size have been reported. Histologically, these tumors have elongated spindle cells with abundant eosinophilic and fibrillary cytoplasms [16]. Immunohistochemical staining of these lesions demonstrates strong positivity for desmin and SMA and no CD34 or CD117 expression, which helps differentiate them from GISTs [17].

EUS features   

At EUS, leiomyomas typically appear as round or oval, homogeneous mass lesions arising from the third or fourth sonographic layers (Fig. 4). In a recent retrospective study by Hunt et al. EUS features of CD117 positive vs. CD117 negative tumors were compared [46]. All but one of 12 CD117 negative tumors were identified as leiomyomas, and all 17 CD117 positive tumors were identified as GISTs. Leiomyomas were more likely to be located in the esophagus compared to GISTs, which were usually found in the stomach. Overall, leiomyomas tended to be smaller, more homogeneous lesions and generally lacked findings of cystic spaces and irregular borders on EUS examination, which are features more often found in GISTs [46]. Nevertheless, leiomyomas can sometimes be indistinguishable from GISTs or other mesenchymal tumors on EUS. Therefore, tissue diagnosis should be sought with immunohistochemical staining of specimens for CD117, CD34, desmin, and SMA in order to confirm the diagnosis of leiomyoma and rule out a GIST.

Surgical resection is recommended in cases of symptomatic leiomyomas. Asymptomatic tumors do not require any intervention or endoscopic follow-up.

 Lipomas   

Clinical features and diagnosis   

Lipomas are benign tumors of adipose tissue that can be found anywhere in the gastrointestinal tract, although they are more commonly present in the colon and the small intestine [47]. Endoscopically, they are usually seen as a smooth bulge with a yellowish hue and normal overlying mucosa. A 'pillow sign' can be detected by pushing the biopsy forceps into the soft tumor, leaving an indentation. Most lipomas are asymptomatic and are found incidentally at the time of endoscopy. Some may present with abdominal pain, obstruction, intussusception, and bleeding [48–51]. Although lipomas are considered to be benign lesions, there have been reports of malignant transformation to liposarcoma and the concomitant presence of other malignancies such as colon and gastric adenocarcinomas [52,53].

EUS features   

At EUS, lipomas appear as hyperechoic, homogeneous lesions arising from the third wall layer of the gastrointestinal tract or submucosa (Fig. 5) [5]. The diagnosis can often be made by their endoscopic appearance alone. Standard endoscopic biopsies usually show normal mucosa. In those lesions where the diagnosis is in question, EUS can be helpful. Because of their classic, characteristic EUS appearance, fine-needle aspiration is not necessary for diagnosis.

Asymptomatic lipomas found incidentally do not require specific treatment or follow-up. Surgical excision is indicated for symptomatic or enlarging lesions. Successful endoscopic removal of lipomas has been described in the literature but it carries a high risk of perforation, particularly when the lesion is >= 2 cm [49–51,54].

 Granular cell tumors   

Clinical features   

Granular cell tumors are rare neoplasms that can occur almost anywhere in the body but are most commonly found in the oropharynx, skin, and breast [55]. These tumors are present in the gastrointestinal tract in about 1–8% of cases [56]. The esophagus is, after the oropharynx, the most frequently affected site within the GI tract, with over 80% of the lesions found in the mid and distal segments [56,57]. Multiple lesions can be seen in up to 11% of patients and they can be synchronous as well as metachronous [56]. Granular cell tumors have also been reported in the stomach, colon, rectum, and biliary tree [58,59].

Pathology   

These tumors were initially considered to be myogenic and were formerly called myoblastomas. However, electron microscopy and immunohistochemical studies have confirmed a Schwann cell origin [60,61]. Histologically, these tumors are composed of small nests of polygonal cells with a lightly eosinophilic, granular cytoplasm. These granules stain positive for periodic acid–Schiff (PAS) stain, and are immunoreactive to S-100 [56,61]. Most of these tumors are found incidentally during endoscopy and are asymptomatic. When symptoms are present, they seem to parallel the size and number of lesions [56]. Granular cell tumors are usually considered benign; however, about 4% of the cases reported in the literature are malignant. Factors associated with risk of malignancy include: size greater than 4 cm, rapid recent growth, and rapid recurrence after excision [56].

Endoscopic and EUS features   

Endoscopically, these tumors appear as smooth polypoid lesions with a grayish or yellow hue [56]. On EUS, they appear mostly as a hypoechoic solid mass with smooth margins arising from the second or third layer [62]. Malignancy is suspected when the margins are irregular and the lesion disrupts the muscularis propria [62]. Standard endoscopic biopsies are usually positive in tumors less than 1 cm in size. When biopsies are negative, EUS must be performed to establish the diagnosis [62].

Treatment of granular cell tumors   

In lesions confined to the mucosa or submucosa, endoscopic resection should be attempted for both diagnosis and therapy. Small granular cell tumors can be removed endoscopically by a variety of methods, including biopsy forceps [63], snare polypectomy [58], and endoscopic mucosal resection [64]. Surgical resection is indicated for large lesions, symptomatic lesions, and for those lesions with endosonographic findings suggestive of malignancy. For small, asymptomatic lesions that are not excised, surveillance with EUS every one to two years is recommended to monitor changes in size and appearance.

 Duplication cysts   

Clinical features   

Duplication cysts are rare congenital abnormalities that likely develop as the result of an error in recanalization of the embryonic gastrointestinal tract [65]. They are generally rare in adults, although up to 30% of cases may be diagnosed after the age of 12 [66]. Cysts can be present anywhere in the gastrointestinal tract, but most often occur in the ileum, esophagus, and colon [67,68]. Duplication cysts may be contained within the wall of the GI tract or may be extrinsic, often closely adhered to the wall of the gut. Some lesions can be found to have a direct communication with the lumen of the gastrointestinal tract [67]. These cysts can be lined by columnar, squamous, or ciliated epithelium and have one or more layers of smooth muscle in their wall [69]. Duplication cysts are usually found incidentally on endoscopy or radiographic imaging. When symptomatic, they may present with dysphagia, abdominal pain, vomiting, hemorrhage, obstruction, perforation, jaundice, or pancreatitis [66,67,69–72]. There have also been rare reports of malignant transformation of these lesions [73,74].

EUS features   

Computed tomography (CT) scanning has been useful in the evaluation of these lesions because it provides accurate information regarding size, location, and relation to other organs. More recently, however, EUS has emerged as probably the best method to diagnose duplication cysts. EUS is superior to CT in distinguishing between cystic and solid lesions [75]. On EUS, duplication cysts are described as round, anechoic lesions arising from the third hyperechoic layer or may be extrinsic to the gastrointestinal wall. Some are thin-walled while others reveal a wall layer pattern. These cysts may contain thick mucinous material, septations, fluid levels, or debris [70,71,75,76]. EUS characteristics alone are usually sufficient for diagnosis. If the diagnosis is in question or there is suspicion of malignancy, fine-needle aspiration under EUS guidance appears safe and reliable [71,75,77].

Treatment of duplication cysts   

There is no consensus regarding the management of asymptomatic duplication cysts. Management options range from performing surgical resection to prevent future complications [66,74] to periodic follow-up with EUS [75]. Symptomatic cysts can be treated surgically with resection or marsupialization. They can also be treated successfully endoscopically using fine-needle aspiration, needle-knife cystostomy, or snare excision [76,78].

 Carcinoid tumors   

Clinical features and pathology   

Carcinoid tumors are the most common neuroendocrine tumors of the gastrointestinal tract [79]. They arise from enterochromaffin cells of the gastrointestinal tract and are classified according to their area of embryonic origin. Foregut tumors arise from the lungs, bronchi, and stomach; midgut tumors arise from the small intestine, appendix, and proximal colon; hindgut tumors arise from the distal colon, rectum, and genitourinary tract. In the United States, carcinoid tumors are most commonly found in the appendix, rectum, and ileum [80].

Biochemistry   

These tumors synthesize a variety of polypeptides, prostaglandins, and amines, such as serotonin, 5-hydroxytryptophan, and histamines. The majority of carcinoids produce very small quantities of these substances, and therefore are usually asymptomatic. Carcinoid syndrome refers specifically to a cluster of symptoms that are mediated by the humoral factors secreted by carcinoid tumors. The major manifestations of the syndrome include flushing, diarrhea, bronchospasm, and the development of cardiac valvular lesions. Carcinoid syndrome is most commonly seen in midgut carcinoids once they have metastasized to the liver and is extremely rare in hindgut tumors.

Endoscopic and EUS features   

Endoscopically, carcinoids can appear as round, polypoid, yellowish lesions, or may be slightly annular in configuration with bridging folds. Occasionally, these lesions may have a central erythematous depression or may have ulcerations [81,82]. Standard endoscopic biopsies are usually sufficient for the diagnosis [81,82].

Carcinoids tumors can be malignant, and the risk of metastatic disease appears to be directly related to tumor size and tumor invasion through the muscularis propria [83,84]. Subsequently, determining tumor size and depth of tumor invasion is essential for the evaluation of these lesions. Because of this, EUS has now emerged as a necessary tool in the diagnosis and management of these tumors. On EUS examination, these tumors are hypoechoic, and homogeneous with distinct smooth margins (Fig. 6). The majority of them are located within the third layer or submucosa, but they can be seen invading the mucosa or muscularis propria. The overall accuracy of EUS for determining depth of invasion is 90%, and 75% for lymph node metastases [82].

Appendiceal carcinoids   

Appendiceal carcinoids are usually found incidentally at the time of appendectomy, and the majority are asymptomatic. Symptoms are more likely in large tumors and those located at the base of the appendix. Tumors less than 2 cm in size can usually be treated by appendectomy alone, since metastases are unlikely at the time of diagnosis [85]. For those tumors larger than 2 cm, right hemicolectomy is indicated because of the increased risk of recurrence [86].

Ileal carcinoids   

Small intestinal carcinoid tumors are most commonly located in the distal ileum within 60 cm of the ileocecal valve. Patients usually present with abdominal pain, small bowel obstruction, or metastases to lymph nodes and the liver. Treatment involves surgical resection of the small bowel involved and its mesentery [87].

Rectal carcinoids   

Rectal carcinoids are usually found incidentally on rectal or endoscopic examination. Occasionally, they can present with rectal bleeding or pain. Tumors smaller than 1 cm may be excised endoscopically or locally via trans-anal approach [82]. Tumors larger than 2 cm, or those 1–2 cm in size with invasion of the muscularis propria, should be treated by low anterior or abdominoperineal resection. The treatment of tumors 1–2 cm in size located within the mucosa or submucosa remains controversial, and this decision should be made on an individual basis [88].

Gastric and duodenal carcinoids   

Gastric carcinoids are rare, and account for 2–8% of all gastrointestinal carcinoids [81]. Three different types have been reported in the literature. Type 1 gastric carcinoids are associated with atrophic gastritis, pernicious anemia, and hypergastrinemia. Type 2 gastric carcinoids occur in association with gastrinomas or multiple endocrine neoplasia (MEN) type 1. In both of these types, tumors are usually small (< 1 cm) and may be multiple. The behavior of these tumors is indolent and they rarely metastasize. Small lesions can be removed endoscopically with close endoscopic follow-up every 6–12 months [89]. Larger tumors may require surgical resection [90]. Type 3 gastric carcinoids are aggressive, and may be associated with the carcinoid syndrome. Two-thirds of patients may present with local or liver metastases. For those with local disease, surgical resection with partial or total gastrectomy and lymph node resection is the treatment of choice [90].

As with gastric carcinoids, small duodenal carcinoids that do not penetrate the muscularis propria can be treated by endoscopic excision (Figs 7–9) [83]. Lesions that invade the muscularis propria, regardless of size, require surgical resection [82].

Close and intense follow-up is recommended after endoscopic resection of carcinoid tumors. This should include repeat EUS examination and endoscopic biopsies of the site of resection to rule out tumor recurrence.

 Ectopic pancreas ('pancreatic rest')   

Clinical features   

Pancreatic rest refers to pancreatic tissue existing in an organ or tissue distinct from the pancreas. This condition is also called aberrant pancreas, heterotopic pancreas, or ectopic pancreas. These lesions are most commonly found in the distal stomach, duodenum, and jejunum [91]. Histologically, pancreatic rests may contain any or all of the elements of the normal pancreas. Occasionally, they may display pancreatic tissue without islet cells or may consist of only pancreatic ductal structures without any of the other elements of the normal pancreatic parenchyma [92]. The majority of pancreatic rests are asymptomatic and are discovered incidentally during endoscopy. When symptomatic, these lesions can present with pancreatitis, gastric outlet obstruction, ulceration, bleeding, cyst formation, or malignancy [91–94].

EUS features   

On endoscopic evaluation, pancreatic rests appear as a submucosal nodule with a central umbilication or depression (Fig. 7), which represents a draining pancreatic duct [95]. On EUS, these lesions are hypoechoic or may be heterogeneous with scattered small hyperechoic areas, which represent adipose tissue. Small anechoic areas within the lesion can sometimes be recognized, which represent ductal structures. Most commonly, these lesions are confined to the third or fourth wall layers, but can sometimes extend within both of these layers [92]. Tissue for diagnosis can be obtained from standard biopsy forceps, snare excision, endoscopic mucosal resection, or EUS-guided FNA [92]. Asymptomatic lesions require no specific treatment.

 Extrinsic compressions   

A variety of organs or lesions extrinsic to the gastrointestinal tract are sometimes mistakenly identified as submucosal lesions. Among these, the most commonly reported include the left atrium, aortic arch, left hepatic lobe, spleen (Fig. 8), gallbladder, splenic artery, pancreatic pseudocysts, pancreatic neoplasms, lymph nodes (Fig. 9), omental metastasis, prostate, uterus, and endometriosis [2,3,5,96]. In all these cases, the normal wall thickness and normal five-layer wall pattern is preserved on EUS. The accuracy of EUS in the differentiation of extrinsic compression from a true submucosal lesion is 100%. Furthermore, EUS appears to be superior to transcutaneous ultrasonography or CT scan in the identification of the compressing organ [96].

 Varices   

Varices can often be mistaken for submucosal lesions or thickened folds within the stomach and other parts of the GI tract. In standard endoscopy varices usually have a bluish discoloration, and may appear as tortuous vessels within the wall of the esophagus, stomach, duodenum, or rectum. The development of large submucosal varices or collateral vessels is seen in the setting of portal hypertension or splenic vein thrombosis. On EUS, varices appear as round or serpiginous anechoic structures confined to the submucosa (Fig. 10) [1,2]. During EUS examination, care must be taken to keep the transducer balloon to a minimum size to avoid compression of the varices.

 Future trends and outstanding issues   

Although EUS is more accurate than most other modalities for diagnosis of submucosal lesions, it is not perfect and a recent study suggests that our accuracy in diagnosis of GISTs may not be as good as previously thought [97]. The introduction of 19G core biopsy needles for EUS may allow improved diagnostic accuracy for GISTs, and perhaps increasing availability of electronic radial echoendoscopes may also help. We know relatively little about the natural history, over the long term, of lesions not resected and there is a need for good quality prospective follow-up studies. Initial case reports of EUS-guided therapy suggest that obliteration or even submucosal dissection and resection of GISTs is feasible and this area is likely to develop in coming years.

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