Applications of Endoscopic Ultrasonography

, and , Harbor-UCLA Medical Center, Torrance, California.

In This Article

Applications of EUS

EUS can detect lesions as small as 2-3 mm in size and is the best method for determining the 5 echogenic layers of the stomach. The 5 layers are histologically correlated with the mucosa (layer 1), deep mucosa (layer 2), submucosa (layer 3), muscularis propria (layer 4), and serosa or adventitia (layer 5) (see Figure 3).

Layers of the stomach, as depicted by Olympus radial scanner.

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Leiomyoma of the stomach, which connects to the muscle layer of the stomach wall.

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TNM staging of esophageal carcinoma. M=metastasis; N=lymph node; T1-T4=depth of esophageal wall invasion.

Esophageal carcinoma stage T2. The tumor (TU) invades muscle layer but does not penetrate through wall. LN=lymph node.

Esophageal carcinoma (TU) penetrating through wall of esophagus (stage T3). LY-NO=lymph node.

Esophageal carcinoma (stage T4) involving aorta (partial encasement) with loss of fat plane (interface) between tumor and aorta.

The accuracy of EUS for staging patients with esophageal carcinoma who subsequently underwent surgery ranged from 59% to 92% (with a mean of 84% in 1154 patients); the accuracy for N-staging ranged from 50% to 90% (with a mean of 77% in 1035 patients).[14] Endosonography is superior to CT in the T- and N-staging of esophageal cancer (see Table 3).

At our institution, EUS is used for a stage-dependent treatment protocol in the following way:

  1. To differentiate mucosal from submucosal invasion in early (stage T1) esophageal cancer in which setting local therapy (EMR or laser, or minimally invasive surgery) may be considered. High-frequency probes are especially helpful in this clinical scenario. Local treatments may be a treatment option only in cancers limited to the mucosal layer that have a low risk of lymph node metastasis. According to the results of one study,[14] if tumor invasion into the submucosal layer is evident, lymph node metastases are found in 30% to 70% of cases. CT of the esophagus usually cannot differentiate between mucosal and submucosal tumor invasion.

  2. To stratify patients who have local lymph node metastases (N1) for preoperative chemotherapy and radiation therapy (see Figure 9). EUS is markedly superior to CT in diagnosing local lymph node metastasis, with an accuracy of 75% vs 54%, respectively (see Table 3).[14] Criteria for assessing malignant lymph node invasion on EUS include: size greater than 1 cm, hypoechoic appearance, distinct borders, and round shape. If all of these features are present, malignant lymph node invasion can be predicted with an accuracy of 80%[15] to 100%.[16] However, all 4 of these features are only present in one fourth of cases, thus making it difficult to predict lymph node metastasis in the remaining three fourths. The development of EUS-FNA has helped to solve this problem. EUS-FNAs of lymph nodes have an accuracy of 80%.[17]

  3. To reliably diagnose stage T4 esophageal cancer (see Figure 7) in which tumor infiltrates into adjacent organs and structures, such as the aorta, heart, lung, and spine. Removal of these tumors is not curative and poses significant surgical risks. The accuracy of EUS in determining T4-stage disease is superior to that of CT scan (91% vs 49%, respectively; N=80).[14] Mallery and colleagues[18] have recently shown that patients with T4 disease are just as likely to have complete regression of their tumor with chemoradiation as are patients with T2 lesions. In this study, the presence or absence of nodal metastases also did not predict response to chemoradiation. Based on the results of this study, the authors of a recent review article[19] concluded that until it is convincingly shown that patients with T4 or N1 lesions do not benefit from curative neoadjuvant treatment, it would be inappropriate to forego this approach based solely on the results of initial EUS staging.

  4. To obtain reliable diagnosis of celiac axis lymph nodes that are staged as M1, thus precluding patients from curative surgery or preoperative chemoradiation. However, high-grade strictures proximal to the gastroesophageal junction sometimes do not allow a full evaluation of this status by EUS. In addition, EUS has been shown to detect and confirm focal hepatic metastases missed by CT.[20]

  5. To play a role in post-neoadjuvant therapy. Several studies indicate that EUS is inaccurate in determining T and N stages after chemoradiation.[21,22] However, Isenberg and coworkers[23] recently reported that an EUS finding of at least 50% shrinkage in tumor cross-sectional area is predictive of improved survival.

Figure 9.

Malignant lymph node (LN); > 1 cm, homogeneous, round.

Recently, spiral CT and positron emission tomography (PET) have been compared with EUS in the staging of esophageal carcinoma. Wallace and associates[24] demonstrated that spiral CT had a sensitivity of 80% compared with 93% for EUS in detecting celiac lymphadenopathy; but sensitivity fell to 38% for locally advanced disease. Flamen and colleagues[25] showed that PET significantly improved the detection of M1 disease over that achieved by combination spiral CT and EUS (82% vs 64%, respectively; P = .0037), but did not improve the accuracy of locoregional lymph-node staging (33% vs 81%; P = .027).

If esophageal cancers obstruct the lumen and the EUS endoscope can therefore not be advanced through, tumor staging will be incomplete. Dilation of tumor strictures for endosonographic examination to allow full passage of the echoendoscope may lead to perforations (up to 24% in one report).[26] There are 2 potential solutions for this problem: (1) the use of blind EUS probes that can be introduced over a guidewire, and (2) the application of small radial mini-probes that can be introduced through the working channel of a conventional endoscope. However, although EUS probes are highly accurate for staging superficial esophageal lesions, imaging of bulky and obstructing tumors is difficult, and visualization of the celiac region is not satisfactory.[27] Newer models of small-diameter mini-probes have provided good staging accuracy and can traverse malignant strictures,[28] but FNA cannot be performed with these probes. Wallace and coworkers[29] demonstrated that esophageal dilation up to 14-16 mm may be performed safely, allowing complete EUS staging in almost all patients. These investigators suggest that the previously reported rate of perforation in the Van Dam study,[26] may be due to the fact that older echoendoscope models had larger tips, requiring 16 mm or greater dilation, which thus led to a higher rate of perforation. The newer model echoendoscopes used in the study by Wallace and coworkers[29] (GF-UM 20, GF-UM 130, Olympus) have more tapered tips that require less aggressive dilation.

In summary then, EUS has markedly changed the treatment of esophageal cancers through the use of a stage-dependent treatment protocol.

Gastric cancer. TNM staging of gastric carcinoma is shown in Figure 10. The accuracy of EUS to correctly stage gastric cancer is 78% for T stage and 70% for N stage.[30] Compared with CT, EUS is markedly superior in T and N staging of disease (see Table 3).

Figure 9.

Malignant lymph node (LN); > 1 cm, homogeneous, round.

However, for N staging, EUS is less optimal than expected because of the difficult locations of certain regional lymph nodes -- such as in the prepyloric or pericardial areas.[31] EUS therefore appears to be useful in the following stage-dependent treatment protocols:

  1. Differentiating between mucosal and submucosal infiltration in stage T1 cancers for which local resection by endoscopy is considered. High-frequency (15 or 20 MHz) ultrasound probes may be especially useful in these cases.[32] Endoscopic mucosal resection may also be considered in this clinical setting.[31]

  2. Identifying resectable lesions (T1-T3) (see Figures 11-13).

  3. Identifying unresectable lesions that show evidence of local organ infiltration (stage T4; Figure 14). The accuracy of EUS-determined stage T4 disease is about 80%.[30]

  4. At our institution, patients with distant lymph-node metastasis (N2) are considered for preoperative chemotherapy. A study by Fink and associates[33] found that patients with locally advanced gastric cancer (Stage IIIA, B and IV), as determined by EUS, benefited from preoperative neoadjuvant chemotherapy, which increased the rate of RO resections (histologically complete tumor removal) to 80%. Twenty-five percent of patients showed no recurrence of tumor. Most of the trials that have evaluated the utility of neoadjuvant chemotherapy for gastric cancer did not use EUS to clearly identify tumor stage. A prospective, randomized trial studying the efficacy of preoperative adjuvant therapy based on staging by EUS is needed to show whether this application will alter the survival for locally advanced gastric cancer.

Figure 11.

Gastric cancer (TU) confined to mucosa (stage T1, arrows).

Figure 12.

Gastric cancer (TU) involving muscle layer of stomach (stage T2), but not penetrating through serosa. PV=portal vein.

Gastric cancer (TU) penetrating through wall of stomach (stage T3, arrows). PV=portal vein; SV=splenic vein.

Gastric cancer (TU) invading pancreas (stage T4, arrows). LN=lymph node; PV=portal vein.

Pancreatic carcinoma. TNM staging of pancreatic carcinoma is shown in Figure 15. The high mortality associated with pancreatic cancer confirms the need for early diagnosis and accurate staging to identify those patients who are candidates for resection. EUS is highly accurate in determining the T stage (80%) and N stage (72%) of pancreatic carcinomas, and is superior to conventional CT in T and N staging of disease.[34]

Figure 15.

TNM staging of pancreatic carcinoma. T1-T4=local tumor extension; N=lymph node; M=metastasis.

In a study by Roesch and colleagues,[35] EUS had a 99% sensitivity in detecting pancreatic carcinomas, compared with 77% for CT and 90% for ERCP. EUS appears especially useful in the detection of small tumors (< 3 cm; see Figure 16), with a sensitivity of 100% vs 55% for CT and 90% for ERCP. Newer imaging modalities such as helical ("spiral") CTs appear superior to conventional CT scan. In a study by Bluemke and coworkers,[36] pancreatic carcinoma was directly visualized by spiral CT as a tumor in 89% of cases. In this study, only single-phase CT scans were used. Scanning was performed after early arterial phase of pancreatic enhancement, assessing mainly the portal phase of liver enhancement. Using dual-phase (arterial and portal phase) helical CT, Ichikawa and associates[37] reported a tumor detection rate of 76%, All lesions greater than 4 cm were detected by dual-phase helical CT; however, only 50% of the lesions less than 2 cm were detected by this method.

Small (1.5 cm; stage T1) pancreatic carcinoma (TU). PD=pancreatic duct.

Legmann and colleagues[38] reported 100% sensitivity for EUS and 92% for dual-phase helical CT for detection of pancreatic tumors, respectively. Sensitivity for small lesions (≤ 15 mm) was 67% by CT and 100% by EUS. The accuracy for staging of pancreatic tumors and predicting resectability was 93% and 90%, respectively, using both techniques. The accuracy was slightly lower for predicting resectability/nonresectability of pancreatic cancers using EUS (76%) compared with helical CT (86%), as reported by Howard and colleagues.[39] In the study by Ichikawa and associates,[37] dynamic MRI appeared superior to dual-phase helical CT for the detection of small pancreatic lesions (< 4 cm), with a detection rate of 83%. Findings from a recent study suggest that state-of-the-art MRI may provide an excellent sensitivity, even for small lesions, with resectability accuracy approaching 96%.[40]

Brugge and coworkers[42] compared in detail several criteria for evaluating vascular involvement using EUS and angiography. Criteria for identifying tumor invasion of major vessels were proximity of the tumor to the

vessel, loss of interface between vessel and tumor, and irregularity of the vessel walls. These investigators demonstrated that the EUS finding of an irregular vessel wall accurately predicted vascular invasion and therefore nonresectability in all cases (100% specificity), compared with 94% specificity by angiogram using the same parameter. However, the finding of an irregular vessel wall was present in only 47% of cases with vascular involvement proven on surgery. Other criteria, such as loss of tumor-vessel interface or proximity of the tumor to the vessel, had a higher sensitivity (78% and 100%, respectively). But, false-positive findings occurred, thus decreasing the specificity to 79% and 44%, respectively.

In our experience, the most difficult aspect in the evaluation of unresectability is tumor involvement of the superior mesenteric vein. Large tumors situated in front of this vessel diminish the penetration of the ultrasound beam. Brugge and associates[42] reported an EUS sensitivity of only 17% for determination of tumor invasion of the superior mesenteric vein using wall irregularity as the only criterion. This result was comparable to that found on angiography (sensitivity of 20%). At our institution, an MRI angiogram is performed in cases in which tumor involvement of superior mesenteric vein is suspected by EUS, thereby replacing the need for conventional angiogram.

Ahmad and coworkers[43] recently retrospectively reviewed data on 89 patients with pancreatic cancer who were staged preoperatively by EUS and then compared the staging accuracy of this modality after these patients underwent surgical and histopathologic TNM staging. The study authors found EUS staging accuracy for T and N disease to be 69% and 54%, respectively, and the positive predictive value for EUS in determining resectability to be only 46%. Several reasons were suggested to account for the inaccuracy of EUS in local tumor staging -- eg, overassessment of vascular involvement, presence of chronic pancreatitis on EUS, tumors greater than 3 cm in size, and major arterial or superior mesenteric venous involvement not detected by EUS. These study results were in line with those of 2 other recent investigations[44,45] in demonstrating a lower accuracy of EUS for prediction of TNM staging than had been previously reported. In the Japanese study,[44] EUS had an accuracy of only 64% for T staging and 50% for N staging; in the second and smaller study,[45] the positive predictive value for determining resectability for pancreatic cancer was found to be only 57%.

In view of results of the studies discussed above and recent progress made by CT/MRI with respect to locoregional staging, the role of EUS in the evaluation of pancreatic adenocarcinoma is undergoing an evolution. A recent editorial published in Gastrointestinal Endoscopy suggests a role for EUS that is restricted to those patients with small tumors not detected by CT/MRI as well as to patients in whom CT/MRI are inconclusive regarding extent of locoregional spread.[46]

Figure 17 depicts an algorithm for staging pancreatic carcinomas as developed at Harbor-UCLA Medical Center. When pancreatic cancer is clinically suspected, a spiral CT (preferably with arterial and portal venous phase) is first performed. If the CT scan is indeterminate for tumor detection or resectability, EUS is performed. If the patient appears to have a resectable lesion by EUS, a staging laparoscopy is performed immediately prior to surgery. If the patient is deemed unresectable by EUS, MRI angiogram is performed to confirm tumor invasion of major vessels. Only patients who are thought to have an unresectable tumor undergo EUS-FNA (see Figure 18) for tissue diagnosis of pancreatic carcinoma. EUS-FNA is also used to exclude lymphomas and to rule out infectious lesions (such as tuberculosis or Mycobacterium avium complex). If chronic pancreatitis is present, and a tumor cannot be ruled out by EUS, EUS-FNA is performed and repeated within 3 months.

Algorithm for work-up of pancreatic cancer at Harbor-UCLA Medical Center.

Figure 18.

Fine-needle aspiration (FNA) of suspected pancreatic carcinoma. Hyperechoic (white) needle tip is marked by long arrow; arrowheads delineate tumor. TU=tumor.

EUS is one of the best methods for diagnosing and staging of ampullary/periampullary tumors, with an accuracy of 80% for T-stage disease and 72% for N-stage.[47] EUS is the only method available for accurate local staging of papillary cancer. Cancers of the papilla may be treated by local resection, which at times can prevent the need for removal of the pancreas and duodenum.

Pancreatic endocrine tumors. Endosonography is used in conjunction with somatostatin receptor scintigraphy[48] for detection of pancreatic endocrine tumors (see Figure 19). In one large study,[49] EUS had an accuracy of 92% (vs 25% by CT) in detecting these lesions. Interesting to note is that 82% of tumors not visualized by CT were found by EUS. EUS is now routinely used in our institution for detection of pancreatic endocrine tumors.

Figure 19.

Small (15-mm) insulinoma in pancreas; arrows indicate tumor (dual-phase helical CT, MRI negative). SV=splenic vein.

Rectal cancer. EUS has gained wide acceptance for the preoperative staging of rectal carcinomas, with an accuracy of 85% for T staging and 79% for N staging (n=1344).[50] EUS is far superior to CT in terms of accuracy of T and N staging of disease (Table 3). EUS is essential for evaluation of patients with locally resectable rectal cancers (T-1 and 0) and for determination of the need for preoperative chemotherapy and radiation in patients with local lymph node metastasis (N-1 and more advanced disease).

EUS-guided fine-needle aspiration. EUS-FNA is used to confirm the diagnosis and staging (lymph node invasion) of gastrointestinal malignancies and tumors adjacent to the gastrointestinal tract. This technique is also used for diagnosis of infectious lesions. It is essential that the tip of the needle is visualized during EUS-FNA. The number of needle passages required for a cytologic diagnosis of a mass lesion varies with respect to the type of lesion, the presence of a cytologist, and the difficulty encountered with needle passage.[51] If a cytologist is present, aspirations may be repeated until diagnostic material has been obtained. In the absence of a cytologist, usually 3 passages are performed to obtain cytologic material.[51] The accuracy of EUS-FNA ranges greater than 80%,[52] with a specificity of over 90%.[53,54,55]

Chronic pancreatitis. EUS is as sensitive as ERCP in diagnosing chronic pancreatitis.[56] EUS can detect not only changes in the pancreatic duct and its side branches, but also changes in the parenchyma, such as echogenic foci, small cysts, lobulation, and echogenic strands.[57,58] This modality does not lead to an increased risk of pancreatitis, an event which does occur as a complication of ERCP in approximately 5% of cases.

Choledocholithiasis. EUS has shown utility in diagnosing small stones of the common bile duct (CBD); the sensitivity and specificity in this setting reach those of ERCP. In a study by Sugiyama and colleagues,[59] EUS detected all stones larger than 1 cm, as confirmed by ERCP. EUS is especially useful for detection of small stones (3-5 mm), with a sensitivity of 91%; this is markedly higher than that associated with transabdominal ultrasonography (27%) and abdominal CT (27%). EUS is especially useful in the setting of clinically suspected gallstone pancreatitis, when laboratory tests (serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin) are only slightly or moderately elevated. In such a setting, EUS can accurately diagnose or rule out CBD stones and avoid the risk of pancreatitis associated with an ERCP.

A new bile duct imaging technique is now emerging in the form of magnetic resonance cholangiopancreatography (MRCP), which has a sensitivity of 80% to 95% in detecting CBD stones.[60,61] However, small stones in a nondilated biliary system may be missed, thus limiting the use of MRCP.[61] MRCP may rival EUS in the future, and may be especially useful in patients who cannot tolerate endoscopy.

Drainage of pancreatic pseudocysts. EUS is currently used at several institutions,[62,63,64,65] including Harbor-UCLA Medical Center,[66] to evaluate the utility of endoscopic pancreatic pseudocyst drainage for treatment of chronic pancreatitis. Pseudocyst drainage is usually performed surgically through the stomach or duodenal wall. EUS can determine the distance between the wall of the stomach/duodenum and the cyst. A distance of more than 10 mm, however, usually prohibits an endoscopic approach.

EUS is also used to assess intervening vessels that would preclude pseudocyst drainage by endoscopy. The port of entrance into the pseudocyst is marked by EUS guidance, allowing safer endoscopic drainage with placement of stents.

Celiac axis blockade for pain management. EUS has also been used for pain management in pancreatic cancer and chronic pancreatitis to direct celiac axis blockade.[67,68] A study by Gress and coworkers[69] showed that EUS-guided celiac block provided more persistent pain relief than CT-guided celiac block. In this study a local anesthetic (10 mL bupivacaine, 0.75%) and a glucocorticoid (40 mg triamcinolone in 3 mL) was injected on both sides of the celiac plexus region using EUS-FNA. Further studies are needed to confirm the superiority of EUS-guided celiac axis blockade over the CT-guided approach.

EUS can accurately diagnose aneurysms of the aortic arch (see Figure 20) and the descending aorta, as well as vascular lesions such as thrombosis in the portal vein system.[70] Endosonography is also helpful in evaluating splenic vein thrombosis when other methods, such as transabdominal ultrasound and CT, are inconclusive.

Figure 20.

Aneurysm of aortic arch with local wall thrombosis on CT scan. Arrowheads indicate aneurysm.

EMR is a new technique in the management of early gastrointestinal malignancy. This therapeutic advance has been made possible by the addition of a new, high-frequency ultrasound probe (HFUP), which allows high-resolution imaging of the gastrointestinal wall, thus permitting identification of the depth of tumor penetration. In contrast to a 5-layered structure seen with conventional EUS, this ultrasound probe provides a 9-layer visualization of the normal gastric wall. HFUPs can help identify transmural penetration and can aid in differentiating cancers limited to the mucosa from those with submucosal penetration.[71] Once the superficial extent of the cancer has been confirmed, then EMR may be performed with either the "lift-and-cut" method or suction methods. EMR has so far been used in the treatment of early esophageal, gastric, and colon cancers with excellent results.[72,73,74]

EUS-FNA is currently undergoing study for its utility in the local treatment of advanced pancreatic cancers to direct delivery of immunomodulatory therapy or tumor suppressor genes via recombinant viral vectors. These modalities are still experimental and their clinical applications have therefore not yet been determined. The use of EUS-guided sclerotherapy with color Doppler has also been described for obliterating esophageal varices, with good results.[75]