The role of endoscopy in subepithelial lesions of the GI tract

Abstract

This is one of a series of statements discussing the use of GI endoscopy in common clinical situations. The Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy (ASGE) prepared this text. In preparing this guideline, a search of the medical literature was performed by using PubMed. Additional references were obtained from the bibliographies of the identified articles and from recommendations of expert consultants. When little or no data existed from well-designed prospective trials, emphasis was given to results from large series and reports from recognized experts. Guidelines for appropriate use of endoscopy are based on a critical review of the available data and expert consensus at the time the guidelines were drafted. Further controlled clinical studies may be needed to clarify aspects of this guideline. This guideline may be revised as necessary to account for changes in technology, new data, or other aspects of clinical practice. The recommendations were based on reviewed studies and were graded on the strength of the supporting evidence (Table 1).1Guyatt G.H. Oxman A.D. Vist G.E. et al.GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google Scholar The strength of individual recommendations is based on both the aggregate evidence quality and an assessment of the anticipated benefits and harms. Weaker recommendations are indicated by phrases such as “we suggest,” whereas stronger recommendations are typically stated as “we recommend.” This guideline is intended to be an educational device to provide information that may assist endoscopists in providing care to patients. This guideline is not a rule and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment. Clinical decisions in any particular case involve a complex analysis of the patient’s condition and preferences and available resources and expertise. Therefore, clinical considerations may lead an endoscopist to take a course of action that varies from this guideline.Table 1GRADE system for rating the quality of evidence for guidelinesAdapted from Guyatt et al.1Guyatt G.H. Oxman A.D. Vist G.E. et al.GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google ScholarQuality of evidenceDefinitionSymbolHigh qualityFurther research is very unlikely to change our confidence in the estimate of effect.⊕⊕⊕⊕Moderate qualityFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.⊕⊕⊕○Low qualityFurther research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.⊕⊕○○Very low qualityAny estimate of effect is very uncertain.⊕○○○ Open table in a new tab Subepithelial lesions (SELs) of the GI tract are tumors that originate from the muscularis mucosa, submucosa, or muscularis propria. The term subepithelial lesion is preferred to the term submucosal tumor, which should be reserved for those that originate from the submucosal layer. SELs are most commonly found in the stomach, as often as 1 in every 300 endoscopies.2Papanikolaou I.S. Triantafyllou K. Kourikou A. et al.Endoscopic ultrasonography for gastric submucosal lesions.World J Gastrointest Endosc. 2011; 3: 86-94Crossref PubMed Google Scholar They usually are identified during routine upper and lower endoscopy as rounded protuberances with normal overlying mucosa. The majority are small (<2 cm in diameter) and found incidentally; however, SELs can present with bleeding, obstruction, or metastases, depending on tumor size, location, and histopathology.3Humphris J.L. Jones D.B. Subepithelial mass lesions in the upper gastrointestinal tract.J Gastroenterol Hepatol. 2008; 23: 556-566Crossref PubMed Scopus (0) Google Scholar Initial management of SELs centers on proper diagnosis and determination of any malignant potential of the lesion. The majority of these tumors are benign, with fewer than 15% found to be malignant at presentation.4Polkowski M. Endoscopic ultrasound and endoscopic ultrasound-guided fine-needle biopsy for the diagnosis of malignant submucosal tumors.Endoscopy. 2005; 37: 635-645Crossref PubMed Scopus (80) Google Scholar Tumors with low malignant potential may appear endoscopically similar to those with a much higher risk for malignant transformation. Because of their subepithelial location, biopsies with endoscopic forceps often fail to provide diagnostic tissues. Thus, further imaging and sampling techniques (often with EUS) often are used to characterize these lesions. EUS is the most accurate imaging test for evaluation of SELs of the GI tract5Polkowski M. Butruk E. Submucosal lesions.Gastrointest Endosc Clin N Am. 2005; 15 (viii): 33-54Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Landi B. Palazzo L. The role of endosonography in submucosal tumours.Best Pract Res Clin Gastroenterol. 2009; 23: 679-701Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 7Hwang J.H. Saunders M.D. Rulyak S.J. et al.A prospective study comparing endoscopy and EUS in the evaluation of GI subepithelial masses.Gastrointest Endosc. 2005; 62: 202-208Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar because of its ability to delineate individual histologic layers and, thus, the most likely site of tumor origin (Table 2). The 5 principal US layers seen on EUS include the following: first and second (mucosa including muscularis mucosa), third (submucosa), fourth (muscularis propria), and fifth (serosa or adventitia). EUS is superior to other imaging modalities (CT, magnetic resonance imaging) in characterizing small (<2 cm) lesions.8Okten R.S. Kacar S. Kucukay F. et al.Gastric subepithelial masses: evaluation of multidetector CT (multiplanar reconstruction and virtual gastroscopy) versus endoscopic ultrasonography.Abdom Imaging. 2012; 37: 519-530Crossref PubMed Scopus (3) Google Scholar, 9Brand B. Oesterhelweg L. Binmoeller K.F. et al.Impact of endoscopic ultrasound for evaluation of submucosal lesions in gastrointestinal tract.Dig Liver Dis. 2002; 34: 290-297Abstract Full Text PDF PubMed Scopus (0) Google Scholar It can accurately distinguish between extrinsic compression of the GI tract and an intramural growth; up to 30% of suspected intramural SELs are in fact extramural in origin (eg, compression from an adjacent organ).10Motoo Y. Okai T. Ohta H. et al.Endoscopic ultrasonography in the diagnosis of extraluminal compressions mimicking gastric submucosal tumors.Endoscopy. 1994; 26: 239-242Crossref PubMed Google Scholar, 11Rosch T. Kapfer B. Will U. et al.Accuracy of endoscopic ultrasonography in upper gastrointestinal submucosal lesions: a prospective multicenter study.Scand J Gastroenterol. 2002; 37: 856-862Crossref PubMed Google Scholar EUS also permits measurement of lesion size and evaluation of any associated lymphadenopathy for further staging.9Brand B. Oesterhelweg L. Binmoeller K.F. et al.Impact of endoscopic ultrasound for evaluation of submucosal lesions in gastrointestinal tract.Dig Liver Dis. 2002; 34: 290-297Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 12Alkhatib A.A. Faigel D.O. Endoscopic ultrasonography-guided diagnosis of subepithelial tumors.Gastrointest Endosc Clin N Am. 2012; 22 (vii): 187-205Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Finally, EUS-guided FNA (EUS-FNA) and fine-needle biopsy (FNB) allow tissue diagnosis to guide further management.Table 2Characteristics of subepithelial mass lesions at endoscopy and EUS12Alkhatib A.A. Faigel D.O. Endoscopic ultrasonography-guided diagnosis of subepithelial tumors.Gastrointest Endosc Clin N Am. 2012; 22 (vii): 187-205Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarSubepithelial lesionEndoscopic appearanceEUS layerEUS appearanceBenignGI stromal tumor–low riskNo specific characteristics, lack ulcerations4th (rarely 2nd or 3rd)Hypoechoic, majority <3-5 cm, smooth margins, round, homogeneous, rare malignant GI stromal tumors were reported with size <3 cmLeiomyomaNo specific characteristics2nd, 3rd, or 4thHypoechoic, well-circumscribedLipomaYellow hue, pillow sign (high specificity, low sensitivity), usually isolated3rdIntensely hyperechoic, homogeneous, smooth margins, may be polypoidVaricesBluish tinge, tortuous, easily compressible3rdAnechoic, serpiginous, Doppler positiveNeural origin–schwannoma, neuroma, neurofibromaNo specific characteristics3rd or 4thHypoechoicGranular cell tumorNo specific characteristics, majority small (<4 cm) and solitary2nd or 3rdHypoechoic, heterogeneous echotextureInflammatory fibroid polypSmooth, usually solitary, sessile polyp with ulceration of the overlying mucosa, 2-5 cm3rd or 4thHypo- to hyperechoic, indistinct margin, homogeneous appearanceDuplication cystSmooth and regular appearance, slightly translucent, compressibleAny or extramuralAnechoic, 3-5 layer wall, round or oval, absent Doppler signalLymphangiomaCyst-like bulging mass, easily compressed, more common in intestine3rdAnechoic with internal septaPancreatic rest90% have umbilicated surface corresponding to a draining duct, >90% located in the antrum2nd, 3rd, or 4thHypoechoic or mixed echogenicity (heterogeneous = acinous tissue, anechoic = ductal structures), indistinct margin, anechoic cystic or tubular structures within the lesions can be seen in 1/3 of casesBrunner's gland hyperplasiaDuodenal bulb, usually single2nd and 3rdHyperechoic, anechoic area due to duct, smooth marginMalignant (potential)GI stromal tumor–low riskPresence of ulcerations4th (rarely 2nd or 3rd)Hypoechoic, >3 cm, irregular extraluminal margins, cystic spaces, heterogeneous, echogenic fociGI neuroendocrine neoplasmNo specific characteristics, may be yellowish in appearance; gastric carcinoid tumors often multiple. Types I and II usually are benign, and type III usually is malignant. Rectal and duodenal usually solitary.2nd or 3rdMildly hypoechoic or isoechoic, homogeneous, oval or round, smooth marginLymphomaNo specific characteristics2nd, 3rd, or 4thHypoechoicMetastasisNo specific characteristicsAny or allHypoechoic, heterogeneous massGlomus tumorNo specific characteristics, mostly seen in the antrum3rd and 4thHypo- or hyperechogenicity. More than half have internal hyperechoic spots that corresponded to calcifications. Doppler EUS shows a prominent vascular signal consistent with the hypervascular nature of the tumor.SEL, Subepithelial mass lesion. Open table in a new tab SEL, Subepithelial mass lesion. EUS has some technical limitations. Lower frequency EUS (<10 MHz) cannot reliably visualize the muscularis mucosa within the mucosal layer. Furthermore, compression of the lesion by the acoustic coupling balloon on radial and linear echoendoscopes may make lesion characterization difficult. These issues often can be overcome with instillation of water into the lumen or by the use of higher-frequency (20-30 MHz) miniprobes that can be advanced through the working channel of the endoscope.13Pech O. Gunter E. Ell C. Endosonography of high-grade intra-epithelial neoplasia/early cancer.Best Pract Res Clin Gastroenterol. 2009; 23: 639-647Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar At higher frequencies, visualization of subcentimeter SELs and more accurate assessment of the layer of origin may be possible. With miniprobes, evaluation of SELs also can be performed in regions inaccessible to most standard echoendoscopes, such as the proximal colon. In this document, we discuss common types of SELs encountered in the GI tract, their endoscopic and clinical characteristics, and appropriate management. Indications and methods for tissue acquisition will be addressed as well as novel methods of endoscopic resection. GI stromal tumors are the most common mesenchymal neoplasms of the GI tract, with an incidence of approximately 4.3 per million per year in the United States.14Soreide K. Sandvik O.M. Soreide J.A. et al.Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies.Cancer Epidemiol. 2016; 40: 39-46Abstract Full Text Full Text PDF PubMed Google Scholar They are characterized as sarcomas, with variable aggressiveness from benign and/or indolent to aggressive metastatic phenotypes. They are believed to originate from the interstitial cells of Cajal and can occur anywhere in the GI tract. They are most commonly found in the stomach (60%-70%) and less commonly in the small intestine (20%-30%), the colon (5%), and the esophagus (<5%).15Chandrasekhara V. Ginsberg G.G. Endoscopic management of gastrointestinal stromal tumors.Curr Gastroenterol Rep. 2011; 13: 532-539Crossref PubMed Scopus (0) Google Scholar They typically have a spherical or fusiform shape and arise from the muscularis propria or less commonly the muscularis mucosa. These lesions often appear endoscopically as a smooth bulge with normal overlying mucosa (Fig. 1). The typical firm consistency of the lesion may be assessed by probing with biopsy forceps. Stacked or “bite-on-bite” pinch biopsies may be attempted, although diagnostic yield often is low.16Hunt G.C. Smith P.P. Faigel D.O. Yield of tissue sampling for submucosal lesions evaluated by EUS.Gastrointest Endosc. 2003; 57: 68-72Abstract Full Text Full Text PDF PubMed Google Scholar, 17Menon L. Buscaglia J.M. Endoscopic approach to subepithelial lesions.Therap Adv Gastroenterol. 2014; 7: 123-130Crossref PubMed Scopus (0) Google Scholar EUS generally demonstrates a hypoechoic, homogenous lesion, but GI stromal tumors can also appear heterogeneous with anechoic (cystic) spaces or shadowing foci (calcifications). Assessment for enlarged peritumoral adenopathy or involvement of additional wall layers should be performed. There are conflicting results from retrospective studies describing malignant EUS features of these lesions.9Brand B. Oesterhelweg L. Binmoeller K.F. et al.Impact of endoscopic ultrasound for evaluation of submucosal lesions in gastrointestinal tract.Dig Liver Dis. 2002; 34: 290-297Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 18Chen T.H. Hsu C.M. Chu Y.Y. et al.Association of endoscopic ultrasonographic parameters and gastrointestinal stromal tumors (GISTs): can endoscopic ultrasonography be used to screen gastric GISTs for potential malignancy?.Scand J Gastroenterol. 2016; 51: 374-377Crossref PubMed Scopus (5) Google Scholar, 19Chak A. Canto M.I. Rosch T. et al.Endosonographic differentiation of benign and malignant stromal cell tumors.Gastrointest Endosc. 1997; 45: 468-473Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 20Jeon S.W. Park Y.D. Chung Y.J. et al.Gastrointestinal stromal tumors of the stomach: endosonographic differentiation in relation to histological risk.J Gastroenterol Hepatol. 2007; 22: 2069-2075Crossref PubMed Scopus (0) Google Scholar Some studies suggest that large tumor size (>3 cm) and irregular tumor margins are most consistently associated with a more aggressive phenotype.18Chen T.H. Hsu C.M. Chu Y.Y. et al.Association of endoscopic ultrasonographic parameters and gastrointestinal stromal tumors (GISTs): can endoscopic ultrasonography be used to screen gastric GISTs for potential malignancy?.Scand J Gastroenterol. 2016; 51: 374-377Crossref PubMed Scopus (5) Google Scholar, 19Chak A. Canto M.I. Rosch T. et al.Endosonographic differentiation of benign and malignant stromal cell tumors.Gastrointest Endosc. 1997; 45: 468-473Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 20Jeon S.W. Park Y.D. Chung Y.J. et al.Gastrointestinal stromal tumors of the stomach: endosonographic differentiation in relation to histological risk.J Gastroenterol Hepatol. 2007; 22: 2069-2075Crossref PubMed Scopus (0) Google Scholar, 21Shah P. Gao F. Edmundowicz S.A. et al.Predicting malignant potential of gastrointestinal stromal tumors using endoscopic ultrasound.Dig Dis Sci. 2009; 54: 1265-1269Crossref PubMed Scopus (0) Google Scholar Features such as echogenic foci, cystic spaces, heterogeneity, and ulceration were less-consistently associated with malignant risk. These findings have not been validated in prospective studies, and no true consensus has been made on which features best correlate with malignancy. Histologically, GI stromal tumors are composed of spindle cells (70%), epithelioid cells (20%), or a mixture of both cell types (10%).22Miettinen M. Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites.Semin Diagn Pathol. 2006; 23: 70-83Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar Immunohistochemical staining in 95% of tumors is positive for CD117, which corresponds to the presence of the c-tyrosine kinase receptor.23Hirota S. Isozaki K. Moriyama Y. et al.Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.Science. 1998; 279: 577-580Crossref PubMed Scopus (3020) Google Scholar DOG1 (Discovered on GIST 1) is a newly discovered immunohistochemical marker for GI stromal tumors and can be useful if CD117 testing is negative. In addition, DOG1 can help differentiate GI stromal tumors from other mesenchymal lesions such as sarcomas and melanomas, which also can stain positive for CD117.24Miettinen M. Wang Z.F. Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases.Am J Surg Pathol. 2009; 33: 1401-1408Crossref PubMed Scopus (204) Google Scholar GI stromal tumors should be stratified by malignant potential, and pathologic assessment of this risk involves description of tumor size, location, and mitotic count (Table 3, Table 4).17Menon L. Buscaglia J.M. Endoscopic approach to subepithelial lesions.Therap Adv Gastroenterol. 2014; 7: 123-130Crossref PubMed Scopus (0) Google Scholar Tissue specimens acquired by EUS-FNA do not assess the mitotic rate accurately and are therefore insufficient to completely differentiate high-risk and low-risk lesions. Therefore, malignant potential is currently determined by final surgical pathology. Newer methods of endoscopic tissue acquisition, including new core biopsy techniques and endoscopic resection, are discussed in the tissue acquisition section of this document.Table 3Gastric GI stromal tumors: proposed guidelines for assessing the malignant potential28von Mehren M. Randall R.L. Benjamin R.S. et al.Soft tissue sarcoma, version 2.2016, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2016; 14: 758-786Crossref PubMed Google ScholarTumor sizeMitotic ratePredicted biologic behavior≤2 cm≤5 mitoses/50 HPF>5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 0 metastasis rate or tumor-related mortality: <4%>2 cm ≤5 cm>5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 16%>2 cm ≤10 cm≤5 mitoses/50 HPFMetastasis rate or tumor-related mortality: <4%>5 cm ≤10 cm>5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 55%>10 cm≤5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 12%>10 cm>5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 86%HPF, High-power field. Open table in a new tab Table 4Small-intestine GI stromal tumors: proposed guidelines for assessing the malignant potential28von Mehren M. Randall R.L. Benjamin R.S. et al.Soft tissue sarcoma, version 2.2016, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2016; 14: 758-786Crossref PubMed Google ScholarTumor sizeMitotic ratePredicted biologic behavior≤2 cm≤5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 0>2 cm ≤5 cm<5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 2%>2 cm ≤5 cm>5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 73%>5 cm ≤10 cm≤5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 25%>5 cm ≤10 cm>5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 85%>10 cm>5 mitoses/50 HPFMetastasis rate or tumor-related mortality: 50%-90%HPF, High-power field. Open table in a new tab HPF, High-power field. HPF, High-power field. All GI stromal tumors have some malignant potential, and management often is dictated by size, location, and the presence of symptoms. GI stromal tumors in the small intestine may be more aggressive than those located in the stomach, as 40% to 50% of small intestine GI stromal tumors are malignant, compared with only 20% to 25% of lesions arising in the stomach.22Miettinen M. Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites.Semin Diagn Pathol. 2006; 23: 70-83Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar Less is known about the malignant potential of GI stromal tumors found in other sites, so these should be treated similarly to those originating from the small intestine.24Miettinen M. Wang Z.F. Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases.Am J Surg Pathol. 2009; 33: 1401-1408Crossref PubMed Scopus (204) Google Scholar Surgical referral should be considered in patients with symptoms such as obstruction, pain, or GI bleeding, lesions with regional adenopathy, lesions >2 cm anywhere in the GI tract, or any tumors originating in the small bowel. One proposed management strategy for gastric GI stromal tumors <2 cm in size recommends surgical resection for lesions with high-risk EUS features, with EUS surveillance at 6-month to 12-month intervals for those without these features.25Sepe P.S. Brugge W.R. A guide for the diagnosis and management of gastrointestinal stromal cell tumors.Nat Rev Gastroenterol Hepatol. 2009; 6: 363-371Crossref PubMed Scopus (0) Google Scholar This strategy is supported by other retrospective data suggesting that GI stromal tumors <2 cm can be followed safely with EUS surveillance without operative management.26Gill K.R. Camellini L. Conigliaro R. et al.The natural history of upper gastrointestinal subepithelial tumors: a multicenter endoscopic ultrasound survey.J Clin Gastroenterol. 2009; 43: 723-726Crossref PubMed Google Scholar, 27Lok K.H. Lai L. Yiu H.L. et al.Endosonographic surveillance of small gastrointestinal tumors originating from muscularis propria.J Gastrointestin Liver Dis. 2009; 18: 177-180PubMed Google Scholar However, there are no large prospective studies that have evaluated the utility of routine interval surveillance of small GI stromal tumors. The National Comprehensive Cancer Network guidelines recommend that lesions >2 cm or smaller lesions with high-risk features (irregular borders, cystic spaces, ulceration, echogenic foci, heterogeneity) undergo resection. After resection, the risk of metastasis is best assessed by tumor size and mitotic rate, but also tumor location (gastric vs small bowel including colon and rectum).28von Mehren M. Randall R.L. Benjamin R.S. et al.Soft tissue sarcoma, version 2.2016, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2016; 14: 758-786Crossref PubMed Google Scholar Leiomyomas are benign smooth muscle tumors of the GI tract that originate from the muscularis mucosa or the muscularis propria. Most tumors are located in the esophagus, although they can be found rarely in other parts of the GI tract. The vast majority of spindle-cell neoplasms in the esophagus are leiomyomas, accounting for roughly two thirds of all benign tumors of the esophagus.29Lee L.S. Singhal S. Brinster C.J. et al.Current management of esophageal leiomyoma.J Am Coll Surg. 2004; 198: 136-146Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar GI stromal tumors are uncommon in this location (<5% of all GI stromal tumors).22Miettinen M. Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites.Semin Diagn Pathol. 2006; 23: 70-83Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar, 30Miettinen M. Lasota J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis.Virchows Arch. 2001; 438: 1-12Crossref PubMed Scopus (0) Google Scholar Ninety percent of all esophageal leiomyomas are found in the lower (56%) and middle third (34%) of the esophagus and only rarely in the upper third. This correlates with the muscular composition of the esophagus, because the lower third is composed predominantly of smooth muscle, with a mixture of smooth and skeletal muscle in the mid-esophagus.29Lee L.S. Singhal S. Brinster C.J. et al.Current management of esophageal leiomyoma.J Am Coll Surg. 2004; 198: 136-146Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Leiomyomas also can be found in the stomach, and the EUS appearance can be indistinguishable from a GI stromal tumor. However, the 2 tumors can be differentiated histologically, because leiomyomas stain negative for CD117 and CD34 and positive for desmin and α-smooth muscle actin.3Humphris J.L. Jones D.B. Subepithelial mass lesions in the upper gastrointestinal tract.J Gastroenterol Hepatol. 2008; 23: 556-566Crossref PubMed Scopus (0) Google Scholar Surgical resection is required only for tumors with associated symptoms such as dysphagia, intestinal obstruction, bleeding, or perforation.31Hershfield N.B. Stabler C.D. Duodenal leiomyoma presenting with upper gastrointestinal hemorrhage.Gastrointest Endosc. 1986; 32: 55-56Abstract Full Text PDF PubMed Google Scholar, 32Mutrie C.J. Donahue D.M. Wain J.C. et al.Esophageal leiomyoma: a 40-year experience.Ann Thorac Surg. 2005; 79: 1122-1125Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Lipomas are common subepithelial lesions found throughout the GI tract, most commonly in the colon and gastric antrum. They are collections of adipose tissue, which often display a yellowish hue on endoscopy and are soft on forceps probing. Demonstration of a “pillow sign” or indentation on probing is 98% specific for the diagnosis, although it is not a very sensitive feature.7Hwang J.H. Saunders M.D. Rulyak S.J. et al.A prospective study comparing endoscopy and EUS in the evaluation of GI subepithelial masses.Gastrointest Endosc. 2005; 62: 202-208Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Characteristic EUS imaging demonstrates a homogeneous, well-defined hyperechoic lesion arising from the submucosal layer (Fig. 2). Tissue sampling is not required when endoscopic imaging is characteristic. Lipomas generally are asymptomatic but may cause hemorrhage and obstruction in rare cases of larger lesions.33Yu H.G. Ding Y.M. Tan S. et al.A safe and efficient strategy for endoscopic resection of large, gastrointestinal lipoma.Surg Endosc. 2007; 21: 265-269Crossref PubMed Scopus (0) Google Scholar Lipomas have negligible malignant potential. Therefore, unless tumors are symptomatic, resection or surveillance are not required after diagnosis. GI neuroendocrine neoplasms, formerly known as carcinoid tumors, are the most common neoplasm of the small intestine and arise from the enterochromaffin-like cells of the GI tract. Although some GI neuroendocrine neoplasms may produce hormones that cause well-described clinical syndromes, most are found incidentally in the rectum, stomach, or duodenum during routine endoscopy and do not produce any clinically meaningful hormonal syndrome. GI neuroendocrine neoplasms usually originate from the mucosal layer of the GI tract and penetrate into the submucosa. Therefore, a diagnosis usually is made by using standard mucosal biopsy techniques. Endoscopy typically reveals a polypoid or a smooth and rounded subepithelial lesion, which may have a central depression or erosion. They may appear red or yellow. EUS imaging characteristically shows a hypoechoic, uniform round, well-defined lesion within the deep mucosal and submucosal layers.34Sato Y. Endoscopic diagnosis and management of type I neuroendocrine tumors.World J Gastrointest Endosc. 2015; 7: 346-353PubMed Google Scholar GI neuroendocrine neoplasms are classified histologically by grade and differentiation (based on mitotic rate and Ki-67 index) as well-differentiated grade 1 (low grade), grade 2 (intermediate grade), and grade 3 (poorly differentiated) tumors.35Kulke M.H. Benson 3rd, A.B. Bergsland E. et al.Neuroendocrine tumors.J Natl Compr Canc Netw. 2012; 10: 724-764Crossref PubMed Scopus (118) Google Scholar Gastric GI neuroendocrine neoplasms are commonly diagnosed on routine EGD, and their incidence has increased 10-fold over the past 30 years.36Kidd M. Gustafsson B. Modlin I.M. Gastric carcinoids (neuroendocrine neoplasms).Gastroenterol Clin North Am. 2013; 42: 381-397Abstract Full Text Full Text PDF PubMed Google Scholar They are classified into 3 subtypes.37Rindi G. Luinetti O. Cornaggia M. et al.Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study.Gastroenterology. 1993; 104: 994-1006Abstract Full Text PDF PubMed Google Scholar Type I gastric GI neuroendocrine neoplasms (multifocal, well-differentiated) are associated with chronic atrophic gastritis, hypergastrinemia, and pernicious anemia and have low potential for metastasis. Five-year and 10-year survival for these tumors is equivalent to that of the general population.38Landry C.S. Brock G. Scoggins C.R. et al.A proposed staging system for gastric carcinoid tumors based on an analysis of 1,543 patients.Ann Surg Oncol. 2009; 16: 51-60Crossref PubMed Scopus (0) Google Scholar, 39Borch K. Ahren B. Ahlman H. et al.Gastric carcinoids: biologic behavior and prognosis after differentiated tr