Gastrointestinal Stromal Tumor

GISTs (see Fig. 1 ; Fig. 2 ) are considered a subset of mesenchymal tumors. A GIST is the most common mesenchymal neoplasm of the gastrointestinal tract. In the past, GISTs were confused with leiomyomas of the gastrointestinal tract. However, GISTs are phenotypically and genetically different from leiomyomas. GISTs usually express CD34, which is a hematopoietic progenitor cell antigen. Studies found that the marker was not specific for GIST, being expressed in fibroblastic and endothelial cell tumors. This finding led to the pursuance of more specific markers for GISTs. In 1998, CD117, which is the product of the c-kit proto-oncogene, was found in around 85% to 95% of GISTs. CD117 is known to be expressed by interstitial cells of Cajal of the gastrointestinal tract, the pacemaker cells associated with the Auerbach plexus. It is debatable whether GISTs originate from interstitial cells of Cajal of the gastrointestinal tract or from multipotential mesenchymal stem cells. Other mesenchymal tumors that are positive for CD117 include clear-cell sarcoma, metastatic melanoma, and malignant fibrous histiocytoma. DOG-1 (discovered on GIST) is a recently described immunohistochemical marker for GISTs, useful for differentiating GISTs from these other entities and when CD117 is negative.

Endoscopic ultrasonogram of a GIST.

The pathogenesis of a GIST is largely atributable to gain-of-function mutations in the tyrosine kinases cKIT and platelet-derived growth factor receptor α (PDGFRA) genes. More than 85% have identifiable mutations in cKIT, whereas the remainder usually have mutations in PDGFRA. The presence of these mutations forms the basis of treatment with the tyrosine kinase inhibitors imatinib mesylate and sunitib. GISTs mainly affect the stomach (around 60%) and small intestine (around 30%), and rarely affect the colon (around 5%), esophagus (2%–4%), and appendix (<2%). Extragastrointestinal GISTs have been reported. The incidence of GISTs is estimated at around 10 to 20 per 1 million people. Around 90% of cases are diagnosed in patients older than 40 years, with a median age of 63 years. Most patients are symptomatic at presentation (70%–90%). Presentations include abdominal pain, gastrointestinal bleeding, nausea/vomiting, weight loss, early satiety, and gastrointestinal obstruction. It is estimated that 50% of GISTs are high-risk for malignant behavior. Risk factors for aggressive behavior include size greater than 5 cm, mitotic index greater than 5 mitoses per 50 high-power fields, and location in the intestine. Treatment is generally surgical resection for localized tumors and imatinib mesylate for advanced disease.

Leiomyoma

Leiomyoma is a benign tumor of the smooth muscle. Most leiomyomas are intraluminal or intramural tumors, and are often asymptomatic until they have reached a large size. The clinical presentation depends on the size, location, and direction of tumor growth, and includes bleeding, intestinal obstruction, dysphagia, and perforation into the peritoneal cavity. Endoscopically, leiomyomas can present as pedunculated intramural or intraluminal polyps, or as a smooth subepithelial mass indistinguishable from a GIST. Endoscopic ultrasonography (EUS) shows a hypoechoic lesion arising from the second (muscularis mucosae) or fourth layer (muscularis propria). In contrast to GIST, leiomyomas stain positive for smooth muscle actin (SMA) and desmin, and negative for CD34 and CD117. Asymptomatic cases do not require intervention.

Carcinoid Tumors

Carcinoid tumors originate from neuroendocrine cells. Although they commonly occur in the ileum, at endoscopy they are usually discovered in the rectum, stomach, or duodenum. EUS examination of gastrointestinal carcinoids shows a hypoechoic and homogeneous oval to round tumor with clear margin and smooth contour, arising from the third layer (submucosa). Gastric carcinoid is classified into 3 types: type 1, linked with autoimmune chronic atrophic gastritis type A; type 2, associated with the Zollinger-Ellison syndrome and MEN1; and type 3, sporadic gastric carcinoid tumors unaccompanied by hypergastrinemia. Type 3 is considered the most aggressive type, with 60% of cases being associated with metastases at the time of diagnosis Endoscopic mucosal resection (EMR) is recommended for type 1 and type 2 carcinoids, associated with hypergastrinemia and the presence of 3 to 5 tumors, none of them greater 1 cm in diameter. Duodenal ( Fig. 3 ) and rectal carcinoids may be endoscopically resected if they are less than 1 cm in size.

Duodenal carcinoid tumor.

Lipoma

Lipomas are most commonly encountered in the right side of the colon but occur anywhere in the gastrointestinal tract. Endoscopically lipomas show pillow and tent signs, both specific but not very sensitive features. Primary gastrointestinal liposarcomas are extremely rare tumors. Lipomas are usually asymptomatic but rarely can cause gastrointestinal hemorrhage, intussusception, and bowel obstruction. On EUS, a lipoma appears as a homogeneous hyperechoic (bright) mass localized in the submucosal (third) layer.

Schwannoma

Schwannomas are tumors of the nerve sheath. Gastrointestinal schwannomas present more frequently in females (male to female ratio 1:1.6) at an average age of 58 years. Schwannomas stain positive for S-100 and glial fibrillary acidic protein (GFAP), and negative for c-kit, CD34, and SMA. Usually they have a favorable outcome. Schwannomas can present with vague abdominal pain, vomiting, weight loss, dysphagia, obstruction, and gastrointestinal hemorrhage. In a series of gastrointestinal schwannoma, most of the cases arose in the stomach (around 70%), around 15% in the colon and rectum, and the rest in the esophagus, whereas none originated in the small intestine. Multiple schwannomas should raise the suspicion of von Recklinghausen disease. On EUS, a schwannoma appears as a hypoechoic lesion that originates from the third or fourth layer and has an appearance similar to a GIST or leiomyoma.

Pancreatic Rest

Pancreatic rest, or pancreatic heterotopia or aberrant pancreas, refers to pancreatic tissue that is found outside the pancreas without anatomic or vascular connection with the pancreas itself. The overall surgical incidence is estimated as 1 case per 500 cases of upper abdominal exploration. In autopsy studies, the incidence is estimated 0.55% to 13.7%. Most of the cases are asymptomatic. When symptomatic, patients may present with mucosal ulcer and hemorrhage, intussusception, intestinal obstruction, and bile duct obstruction. Endoscopically, pancreatic heterotopia can present as an umbilicated subepithelial lesion of the gastric antrum (>90%) or a duodenal mass, ulcer, or duodenal obstruction. As of 2004 there were fewer than 30 well-documented cases of adenocarcinoma arising from heterotopic pancreas. On EUS, most of the lesions originate from the second, third, and/or fourth layers. Ninety-five percent of the lesions have a heterogeneous echotexture, and are mainly hypoechoic or of mixed echogenicity. In 65% the borders are indistinct, and 35% exhibit anechoic cystic or a tubular structure within the lesion.

Duplication Cyst

Foregut duplication cysts are uncommon congenital anomalies. Duplication cysts are usually asymptomatic in adults. Nevertheless, abdominal pain, dyspnea, dysphagia, or coughing have been reported with these cysts. Malignant transformation in foregut duplication cysts is extremely rare. On EUS they appear as anechoic, homogeneous lesions with regular margins arising from the third layer or extrinsic to the gut wall. It is important to bear in mind that a hypoechoic, and not necessarily anechoic, echo pattern should not exclude the diagnosis of a duplication cyst. In the past, it was believed that fine-needle aspiration (FNA) was necessary to establish the diagnosis of foregut duplication cyst. Nevertheless, because of several reported cases of infection from FNA of mediastinal duplication cysts, despite the use of prophylactic antibiotics, it is recommended that FNA be avoided for cysts with typical EUS appearance of duplication cyst in the mediastinum.

Glomus Tumor

Glomus tumors are typically found in the skin and the subcutaneous tissue. These tumors originate from modified smooth muscle cells that behave like perivascular glomus bodies. Gastrointestinal glomus tumors are mostly encountered in the antrum. Close to half of these tumors present as a submucosal ulcerated mass, and originate mostly from the fourth layer. Nevertheless, a glomus tumor can originate from the third layer and on rare occasion extends to the second layer. Glomus tumors are either hypoechogenic or hyperechogenic. Internal hyperechoic spots, corresponding to the calcifications found on histologic examination, can be seen in more than half of the cases. Doppler EUS can be helpful, as it shows a prominent vascular signal corresponding to the hypervascular nature of the tumor. Glomus tumors are usually benign; however, cases of malignant transformation have been reported. Hence surgical resection is usually recommended.

Metastasis

More than 50% of metastases to the stomach may present as subepithelial lesions. Metastases to the stomach tend to involve the upper and middle third of the stomach. Endoscopic biopsy may be diagnostic in up to 90% of cases. Metastasis to the stomach most commonly originates from the lung, esophagus, breast, and malignant melanoma. The EUS appearance of the tumors can show a hypoechoic or heterogeneous mass.

Table 1 summarizes the characteristic clinical and endosonographic features of subepithelial lesions.

Endoscopic Ultrasonography and Subepithelial Lesions

To understand the role of EUS in evaluating subepithelial lesions, one should be familiar with the histologic layers of the gastrointestinal wall and their sonographic counterparts. The layers of the gastrointestinal wall are the epithelium, lamina propria, submucosa, muscularis propria, and serosa (adventitia). At usual EUS frequencies (5–12 MHz) these are displayed in a 5-layer pattern numbered from the lumen out: first and second (mucosa including the muscularis mucosa), third (submucosa), fourth (muscularis propria), and fifth (serosa or adventitia).

Like any other ultrasound examination, the interpretation of the EUS images is operator dependent. Overall agreement for subepithelial lesions evaluation using EUS appears to be good (κ = 0.63). Nonetheless, the interobserver agreement varies according to the lesion type whereby κ is highest (>0.8) for cystic lesions and extrinsic compressions, and good for lipomas (κ = 0.65), fair for leiomyoma and vascular lesions (κ = 0.53 and 0.54, respectively), and poor for other subepithelial lesions (κ = 0.34). There is also a significant relationship between operators’ years of experience and their ability to reach accurate diagnoses using EUS.

Whenever EUS is performed to examine a subepithelial lesion, the operator should try to address the following points:

• 1.
  

  Location of the lesion (esophagus, stomach, small intestine, colon)

  
  
• 2.
  

  The general endoscopic appearance (presence of ulcerated mass, umbilicated mass, yellowish appearance, and so forth)

  
  
• 3.
  

  Whether the mass is intramural versus extramural

  
  
• 4.
  

  Layer of origin

  
  
• 5.
  

  Echogenicity of the mass by comparing the mass to the spleen or 3rd and 4th layer of the gastrointestinal wall

  
  
• 6.
  

  Define internal structures, for example presence of calcifications, tubular structures, cystic changes, and so forth

  
  
• 7.
  

  Size

  
  
• 8.
  

  Extent of the mass

  
  
• 9.
  

  Presence of vessels around or within the lesion

  
  
• 10.
  

  Relationship to surrounding structures

  
  
• 11.
  

  Presence of lymphadenopathy.

Addressing these points can help to narrow the differential diagnosis. Determining the location of the lesion in the gastrointestinal tract can be very helpful. For example, finding a fourth-layer subepithelial lesion in the esophagus makes it less likely to be a GIST, whereas finding the same lesion in the stomach makes it more likely to be a GIST. On other hand, finding a subepithelial lesion in the colon raises the suspicion for lipomas and lymphangiomas, and to a lesser extent endometriosis and leiomyoma.

Conducting EUS should not deter the operator from paying attention to the gross endoscopic appearance of the lesion, as it may provide pivotal information. For example, finding an ulcerated GIST increases the likelihood that the lesion is malignant, finding an umbilicated lesion in the antrum raises the suspicion of pancreatic heterotopia, and finding yellowish subepithelial lesion in the rectum supports the diagnosis of rectal carcinoid. Finding a lesion with a positive pillow sign (probing leaves an indentation) or a tent sign (pulling with a biopsy forceps raises the mucosa off the lesion) are highly suggestive of a lipoma.

One of the strengths of EUS is its ability to differentiate between intramural and extramural lesions or external compressions. EUS is superior to other studies (computed tomography, barium studies, endoscopic studies with biopsies) in delineating the origin of the mass, hence EUS should be the first choice to investigate any subepithelial lesion. Studies have shown that around 14% to 42% of the lesions suspected to be subepithelial lesions during a routine endoscopic examination turned out to be extramural lesions or compressions during EUS examinations. Structures that are commonly found to be compressing the gastrointestinal wall during EUS are usually benign. In one study that included 238 patients who underwent EUS to investigate subepithelial lesions, 55 lesions were found to represent extramural structures. More than half of these cases (58%) were impressed upon by neighboring organs such as the spleen, splenic vessels, gallbladder, liver, and pancreas. Twelve cases were related to benign lesions (hepatic cysts, hepatic hemangiomas, splenic cyst, and pancreatic cyst). Ten percent of extramural cases were thought to represent transient impression. Nine percent of the cases represented malignant lesions (pancreas, liver, and spleen). Hence extramural lesions may be malignant, though as such are encountered infrequently.

The EUS operator should try to identify the layer of origin for any subepithelial lesion because this can help significantly to narrow the diagnosis. Lesions originating from the submucosal layer are usually lipomas, fibromas, carcinoid tumors, granular cell tumors, pancreatic rests, and duplication cysts. Lesions arising from the muscularis propria usually represent gastrointestinal stromal tumors, leiomyomas, and schwannomas.

Echogenicity is an important feature to describe when investigating subepithelial lesions. Anechoic lesions may represent cysts, varices, lymphangiomas, or cavernous hemangiomas. A hypoechoic lesion can represent gastrointestinal mesenchymal tumor (GIST, leiomyoma, schwannoma), granular cell tumor, neuroendocrine tumor, inflammatory fibroid polyp, metastasis, subepithelial cancer, lymphoma, amyloid, focal inflammation, and endometriosis. Hyperechoic lesions usually represent lipomas or fibrolipomas. Mixed echogenicity (bright and dark areas) can be seen, and may represent heterotopic pancreas, malignant mesenchymal tumor, fibrovascular polyp, spontaneous esophageal hematoma, or wall abscess.

Measuring the size of the lesion is important because it may help to narrow the diagnosis and may provide prognostic value in certain situations. For example, in a patient with a GIST, size of less than 1 cm is less likely than size of 5 cm to be malignant.

The extent of the mass has implications for treatment and prognosis. If the subepithelial lesion is seen to extend to the fourth layer or beyond, it makes the chance of removing the lesion endoscopically risky because of the high risk of perforation. In addition, if the lesion is seen to extend to invade surrounding organs, this raises the concern of an invasive malignancy.

Determining vascularity and presence of surrounding vessels is also important, especially before attempting to obtain a biopsy or remove a lesion. For example, gastric varices can be easily misdiagnosed as a gastric mass. EUS can safely and reliably identify gastric varices and vessels with tumors, improving safety.

Identifying the presence of lymphadenopathy and performing EUS-guided FNA of suspicious lymph nodes can be helpful in the locoregional staging of malignant lesions, with implications for the management of these lesions.

Cytologic and Histopathological Diagnosis

With this range of diagnostic potentials, reaching a definite diagnosis of subepithelial tumor/lesion can be challenging. In many cases EUS is not capable of providing a definitive diagnosis of the subepithelial lesion, requiring tissue sampling for a histologic diagnosis. EUS may guide the choice of technique for tissue sampling, or obtain a cytologic specimen through EUS-guided FNA.

Methods to Obtain Cytologic and Histopathologic Samples

There are several endoscopic methods to obtain biopsy, including biopsy forceps, Trucut needle biopsy, EUS-guided FNA, endoscopic submucosal resection (ESMR), and a variety of unroofing and resection techniques. Using standard cold forceps biopsy is not helpful in most cases. To obtain deep biopsy the tunnel biopsy technique, stacked jumbo forceps, and bite-on-bite forceps have been described. The diagnostic yield for third-layer lesions using stacked jumbo forceps biopsy is low, estimated at between 14% and 42%, compared with almost 90% for endoscopic mucosal resection. The yield of bite-on-bite forceps is related to the site and not the size. The highest yield is in the esophagus, where the yield can reach up to 58%.

A Trucut biopsy (Quick-Core; Wilson-Cook Medical Inc, Winston-Salem, NC, USA) can be used with linear echoendoscopes. This device uses a 19-gauge needle with an 18-mm tissue tray with a built-in spring-loaded mechanism allowing a core of tissue to be obtained for histologic diagnosis. The Trucut biopsy is considered a safe procedure when used by experienced operators in appropriate locations. The device functions well in the esophagus, rectum, and most of the stomach. However, use of the Trucut biopsy in the antrum, fundus, and duodenum is cumbersome and technically difficult, with lower yields for an adequate specimen because echoendoscope angulations produce sluggish advancement of the cutting sheath. The use of the device beyond the duodenal apex is not recommended. It was initially postulated that the Trucut has the advantage of decreasing the number of passes needed. Nevertheless, conflicting results exist regarding whether Trucut biopsy really decreases the number of biopsy passes required to establish cytologic/pathologic diagnosis. Trucut needle biopsy has the higher accuracy than FNA biopsy when sampling subepithelial lesions and lymphoma (88%–100% vs 29%–66%). A new biopsy needle, the ProCore needle (Wilson-Cook Medical Inc), is now available in 22-gauge and 19-gauge sizes. It was designed to increase diagnostic yield and obtain a histologic core, but whether it improves the sampling of subepithelial lesions is as yet unknown.

ESMR adapts a variety of endoscopic mucosal resection techniques to removing lesions from the submucosa (third layer). ESMR involves raising the lesion away from the fourth layer, the muscularis propria, either by injection of saline solution (strip biopsy) or suction of the lesion into a cap fitted to the endoscope (aspiration lumpectomy), followed by electrosurgical snare resection. Subepithelial lesions that are confined to layers 1 to 3 and up to 20 mm in size are amenable to safe resection. ESMR is helpful in establishing a histologic diagnosis and in providing definitive therapy for smaller lesions. The main complication of ESMR is bleeding in 4% to 13% of cases. Bleeding is usually managed endoscopically. Perforation after EMR has been reported in up to 5% of the cases, but may be less common after ESMR.

Endoscopic tissue sampling and resection of fourth-layer lesions such as GISTs is more challenging. The location of the tumor deep to the submucosa makes it less accessible to biopsy, and resecting the muscularis propria from which they arise runs the risk of perforation. A variety of techniques to unroof the lesion followed by biopsy or resection has been described. One method is to perform endoscopic submucosal dissection using an insulated tipped knife to dissect and enucleate the tumor, followed by closure with clips. These techniques are technically challenging and run the risk of perforation in up to 28% of cases. Other techniques to unroof the tumor include aggressive bite-on-bite forceps biopsies with on-site pathologic guidance to ensure an adequate sample, and using a standard electrocautery snare to unroof the mass. Endoscopic band ligation without endoscopic resection has been described for GISTs smaller than 2 cm. Tumors completely slough within several weeks.

EUS-guided FNA is frequently applied to submucosal lesions, particularly those arising from the fourth layer (muscularis propria). Whereas earlier studies reported relatively poor accuracy, more recent studies have reported high diagnostic yields reaching 75% to 100%. The sensitivity of EUS FNA for GISTs has been estimated at 84% to 89%. Higher yield of EUS FNA of subepithelial lesions may be obtained from larger lesions, from a gastric location, and in the presence of on-site cytopathology. The overall rate of EUS FNA–specific morbidity is low, estimated to be 0% to 2%. Complications after FNA of subepithelial masses are very rare, and mostly consists of postprocedural abdominal pain. Antibiotic prophylaxis should be considered in cases of cystic lesions.

Immunohistochemistry is an important tool in the diagnostic arsenal when evaluating subepithelial lesions, and can be performed on FNA material. For example, GISTs are usually positive for CD117 or c-kit. In addition to CD117, other commonly used markers are CD34, SMA, S-100, desmin, and vimentin. Ki67 (MIB-1) is considered a marker of proliferation and can be assessed in resected GISTs and EUS FNA specimens. Nonetheless, it is not clear whether it improves the ability to predict GIST behavior. Up to 14% of GISTs are cKIT negative, but are positive for PDGFRA gene mutation. These lesions may be diagnosed through mutational analyses of c-kit and PDGFRA genes or staining for DOG-1.

Management of Subepithelial Lesions

Management of subepithelial lesions depends on the etiology, location, size, symptoms, and patients’ characteristics such as age, comorbidities, and need and frequency of follow-up examinations. Asymptomatic benign lesions do not require follow-up or intervention. Such lesions include most pancreas rests, leiomyomas, schwannomas, lipomas, duplication cysts, hemangiomas, and inflammatory fibroid polyps. Lesions with malignant or invasive risk should be resected or undergo endoscopic or EUS surveillance. These lesions include carcinoids, granular cell tumors, and GISTs. Endoscopic resection is indicated for all carcinoids of less than 1 cm in size as well as most type 1 and type 2 gastric carcinoids. Most granular cell tumors may be resected endoscopically, as can small GISTs arising from the third layer (submucosa or muscularis mucosae).

Controversy exists as to the management of small incidentally found GISTs, especially gastric lesions less than 2 cm in size. These tumors appear to have a low risk of malignant behavior and may be considered for EUS surveillance without resection. Factors to be considered in selecting patients for surveillance include patient’s age, comorbidities, and life expectancy. Although the optimal timing and number of surveillance examinations and duration are unknown, a recent survey reported 70% would survey annually. Any change in size should prompt surgical resection ( Fig. 4 ).

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