Gastrointestinal cancer staging by endoscopic ultrasound: Esophagus and gastric

Gastrointestinal Cancer Staging by Endoscopic Ultrasound: Esophagus and Gastric Cuong C. Nguyen, MD

Endoscopic ultrasound (EUS) is the latest major innovation in gastrointestinal endoscopy. The coupling of ultrasound with endoscopy allows visualization of the gastrointestinal mucosa and adjacent structures in such exquisite details heretofore unavailable with any other imaging modalities. EUS has made major impact on the practice of digestive diseases, particularly in the evaluation of esophageal and gastric cancer. EUS is now universally accepted as the imaging modality of choice for precise local-regional staging of these 2 malignancies. The application of EUS in esophageal and gastric cancer are described. Copyright 9 2000 by W.B. Saunders Company

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leading cause of cancer mortality in men, esophageal cancer is one of the greatest challenges in the management of digestive diseases. 1 The outcome of esophageal cancer ranges from complete cure in its earliest stages to fatality when the disease is advanced. The probability for curative surgical resection is quite unlikely if the tumor has invaded the muscularis propria or has spread to more than 4 regional lymph nodes. 2 Precise staging of esophageal cancer is therefore of critical importance in determining the optimal management of this dismal disease. Staging a patient with esophageal cancer defines the anatomic extent of the malignancy. This is based solely on the depth of the tumor (T staging), the presence or absence of regional lymph nodes (N staging), and the presence or absence of distant metastases (M). This TNM classification was established and has long been accepted by the American Joint Committee on Cancer and the International Union Against Cancer. 3 For esophageal cancer, the TNM staging schema is as follows: T-staging TX = Primary tumor cannot be assessed TO = No evidence of primary tumor Tis = Carcinoma in situ T1 = Invasion of lamina propria or submucosa T2 = Invasion of muscularis propria T3 = Invasion of adventitia T4 = Invasion of adjacent structures N staging NX = Regional lymph nodes cannot be assessed NO = No regional lymph node metastases N 1 = Regional lymph node metastasis From the Mayo Clinic, Scottsdale, AZ. Address reprint requests to Cuong C. Nguyen, MD, Mayo Clinic Scottsdale, 13400 Shea Blvd, Scottsdale, AZ 85259. Copyright 9 2000 by W.B. Saunders Company

1096-2883/00/0202-0004510.00/0 doi:10.1053/TG.2000.5432

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M staging MX = Distant metastasis cannot be assessed M0 = No distant metastasis M1 = Distant metastasis For tumors of the lower thoracic esophagus, M l a: Metastasis in celiac lymph nodes Mlb: Other distant metastasis For tumors in the mid thoracic esophagus, Mla: Not applicable Mlb: Nonregional lymph nodes or other distant metastasis For tumors of the upper thoracic esophagus, Mla: Metastasis in cervical lymph nodes Mlb: Other distant metastasis In contradistinction to the normal esophagus in which 5 distinct layers are visualized, adenocarcinoma and squamous carcinoma of the esophagus are seen as hypoechoic thickening or disruption of the 5-layer architecture. The correlations between the EUS images and the T-staging are listed in Table ]. EUS images of esophageal tumors are shown in Figures 1 through 4. A lymph node is considered malignant when it appears larger than 10 mm, round, and hypoechoic, with a clear border. 4 When all 4 criteria are present, the accuracy for predicting malignant involvement is approximately 80%. 5 When the tumor can be seen extending directly into the lymph node, the likelihood for the node to be malignant is almost certain. Outside of this scenario, EUS-guided fine-needle aspiration is necessary to confirm the malignant nature of the lymph nodes because benign nodes, especially in the mediastinum, can be larger than 10 ram. Frequently occurring in patients with history of histoplasmosis exposure, these benign nodes are elongated with distinct cortical and medullary areas and not well-defined borders. Cumulative data in the last 20 years have conclusively shown that EUS is the most accurate imaging method for T staging and N staging esophageal cancer. 6 The accuracy of EUS in defining the depth of the tumor (T) is approximately 85% when compared with surgical pathology. For lymph nodes (N) staging, the accuracy is 75%. Comparison of accuracy between EUS and computed tomography (CT) in esophageal cancer staging shows a clear superiority of EUS in this application. The results of 2 representative studies with echoendoscopes are summarized in Table 2. 4,7 Recently, EUS was also shown to be better than endoscopic magnetic resonance imaging (EMRI) for T & N staging of esophageal cancer. 8 For celiac axis, any malignant node confers a poor prognosis and is considered distant metastasis. Regardless of the T and N stages, positive celiac nodes automatically downgrade (worsen) the clinical stage. EUS has been proved very accurate in diagnosing malignant celiac nodes, with 81% sensitivity and 98% specificity9 (Figs 5, 6). Techniques in Gastrointestinal Endoscopy, Vol 2, No 2 (April), 2000: pp 64-68

TABLE 1. EUS and T Staging of Esophageal Cancer Depth of Invasion

EUS Abnormality

Histologic Layer

T1 T2 T3 T4

Layers 1, 2, or 3 Layer 4 Layer 5 Adjacent organ

Mucosa 8, subrnucosa Muscularis propria Adventitia

Catheter probes also have been increasingly employed in the staging of esophageal cancer, because at higher frequencies, superficial lesions can be very precisely localized by endoscopy and visualized endosonographically. The level of details provided by high frequencies such as 15 MHz or higher is critical when endoscopic mucosal resection is contemplated. For this particular endoscopic mode of therapy, catheter probes have proved very useful) ~ Additionally, with a diameter at 2.6 mm or smaller, the probes can be passed through stenosis without subjecting patients to dilation. Another option for stenotic lesions should be mentioned: a commercially available nonoptical, wire-guided echoendoscope (Table 3). With this instrument, the rate of complete staging of esophageal cancer increased from 60% to 90%, with significantly more metastatic disease diagnosed (34% v 11%). 11 This instrument is a nice addition to a complete EUS unit, but its application is rather limited and therefore is not commonly purchased. When is an EUS examination necessary in the evaluation of esophageal cancer? Patients with esophageal cancer who are fit for surgery or chemoradiation therapy should be evaluated with EUS, unless the presence of distant metastases has already been established. Precise staging is crucial for determining the resectability of the tumor, stratifying patients for treatment regimens, and predicting realistic prognosis. For example, patients in whom the tumor has invaded into vital organs are not candidates for esophagectomy, whereas local therapy can be an option if the tumor is limited to the mucosa. Longer survival can be predicted in patients in whom the tumor is seen only in the esophageal wall without lymph node involvement than in those with transmural tumor or nodal metastases. In a multicenter retrospective cohort study, patients with EUS

Fig 1. 20 MHz image of a T1 esophageal lesion limited to the submucosa, arrow. GI CANCER STAGING BY EUS

Fig 2. A T1 esophageal lesion seen at 7.5 MHz (arrow). Note a lymph node (arrowhead).

staging T4 had the same survival regardless of the mode of therapy, surgical or nonsurgical32 For patients undergoing preoperative (neo-adjuvant) chemoradiation therapy, EUS also can be used to assess their response to therapy. 13 More data are needed for interpretation of EUS after chemotherapy and radiation.

Gastric Cancer The eighth most common cause of cancer-related death in the United States, the treatment of gastric adenocarcinoma requires precise staging of the disease. Prognosis can be predicted by the stage of the tumor at presentation. Among 13,000

Fig 3. Because of the involvement of the muscularis propria (arrows), the esophageal lesion is upgraded to T3 stage. 65

Fig 4. A T3 lesion extending to the adventitia (arrow). patients with gastric carcinoma, 5-year age-adjusted survival for those presenting with tumor limited to the superficial layers and no lymph node metastasis was reported to be 70%, as opposed to 2% or less for patients with advanced disease. 14 The decision for curative surgical resection versus mucosal resection depends on the extent of the disease, and obviously the success rate of the treatment of choice is critically linked to the accuracy of the staging process. Because of its unique ability to visualize the gastric wall and adjacent structures, EUS is well suited for the staging of gastric cancer. Gastric carcinoma is seen as an hypoechoic or inhomogeneous mass with irregular margins (Fig 7, 8, 9). With advanced disease, the 5-layer wall architecture seen at 7.5 MHz and 12 MHz is destroyed either partially or completely. Early tumors and inflammation are not distinguishable by EUS. Conversely, linitis plastica classically causes diffuse hypoechoic or a mixed echogenic pattern involving the deeper layers. When gastric linitis plastica is a consideration, regular biopsy may not reliably establish the diagnosis because of the diffuse and intramural nature of the disease process. EUS can easily detect the loss of gastric wall architecture associated with linitis plastica and justify more invasive methods to obtain tissue. Gastric lymphoma appears as hypoechoic thickening of 1 or more layers, mainly the mucosa and submucosa, with inhomogeneous internal echo pattern. However, differentiation of these 3 types of gastric neoplasms on the basis of echogenic patterns is not routinely possible. The EUS equipment used in staging gastric cancer is the

Fig 5. Celiac axis with splenic artery coursing to the right (arrow) and hepatic artery to the left (arrowhead). same as described for esophageal cancer. Staging is based on the TNM classification by the American Joint Committee on Cancer and the International Union Against Cancer) For gastric cancer, excluding lymphoma, T-staging TX = Primary tumor cannot be assessed TO = No evidence of primary tumor Tis = Carcinoma in situ T1 = Invasion of lamina propria or submucosa T2 = Invasion of muscularis propria or subserosa T3 = Penetration of serosa without invasion of adjacent structures T4 = Invasion of adjacent structures

TABLE 2. Accuracy of EUS and CT in Esophageal Cancer Staging Stage

EUS Accuracy (%)

CT Accuracy (%)

T1 T2 T3 T4 NO N1

92 73 93 91 64 84

11 -69 59 67 36

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Fig 6. Celiac lymphadenopathy (arrows). Note a small view of hepatic artery (arrowhead), which can be mistaken for a node. The artery elongated with movement of the echoendoscope and had hyperechoic wall. CUONG C. NGUYEN

TABLE 3. Nonoptical Echoprobe (Olympus, Melville, NY) Characteristics

MH-908

Outer diameter (mm) Length (mm) Display mode Frequency (MHz) Scan range

8.5 700 B 7.5 360~

N staging NX = Regional lymph nodes cannot be assessed NO = No regional lymph node metastases N 1 = 1 to 6 Regional lymph node metastasis N2 = 7 to 15 Regional lymph node metastasis N3 = >15 Regional lymph node metastasis M staging MX = Distant metastasis cannot be assessed M0 = No distant metastasis M1 = Distant metastasis EUS is accurate in defining the depth and the extent of tumor spread (T staging) in 67% to 92% of cases, when compared with histopathologic data. For N staging, EUS accuracy is 80%, compared with 50% by conventional CT. 15 A series reported 83% accuracy of T staging and 66% accuracy in N staging for 254 patients undergoing preoperative EUS and then surgical resection. 16 Accurate definition of the extent of the tumor is also necessary to select patients who can benefit from subtotal gastrectomy. EUS was able to predict R0 resection without any macro/microscopic tumor residual in 119 patients with 91% accuracy3 r A complete staging of gastric cancer should include EUS, because regional lymphatic spread is probably the most powerful prognostic factor for this disease. EUS, especially at high frequencies, is particularly useful in identifying patients with early cancer who can be candidates for endoscopic mucosal resection therapy, is At 15 MHz, 3: staging for elevated early gastric cancer was reportedly 91% accurate, compared with only 56% for the depressed early gastric cancer.19 In general, EUS staging for gastric cancer is more difficult than for esophageal cancer because of the different angles at which the sound waves strike the gastric wall. In the esophagus, the endoscope is almost always parallel to the esophageal

Fig 7. Gastric exophytic adenocarcinoma invading muscularis propria (arrow). GI CANCER STAGING BY EUS

Fig 8. Gastric carcinoma with central ulceration (curved arrow). wall; therefore, the sound waves are most of the times perpendicular to the wall, generating a more optimal image, whereas with gastric cancer, the tangential approach of the sound waves can potentially distort the appearance of the lision's architecture. T-staging is sometimes overstaged because of the difficulty in separating tumor from peritumoral inflammation, particularly in ulcerated gastric cancer. 2~Furthermore, it is not possible with current EUS instruments to differentiate between subserosal (T2) and serosal infiltration (T3). For N staging, the experience is less optimal than in esophageal cancer because of the difficult locations of certain regional nodes, such as in the prepyloric or the pericardial areas. 2~ What is the clinical value of EUS in gastric cancer? EUS is indicated for local-regional staging of gastric neoplasms and for predicting the potential curative resection R0. EUS is of crucial importance in delineating the transmural extent of the disease before local therapy such as mucosectomy.

Fig 9. EUS image using a 12 MHz catheter probe (C). The hypoechoic mass (thick arrow) with central ulceration (curved arrow). Thin arrow points to the muscularis propria. 67

Summary The coupling of endoscopy with ultrasound is an exciting technology that provides us with the opportunity to visualize intramural structures and adjacent viscera with exquisite resolution. EUS is the imaging modality of choice for staging gastrointestinal malignancies because of its unsurpassed accuracy in local and regional staging. Patients who need precise stratification for appropriate medical and surgical intervention will benefit most from this clinical tool.

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CUONG C. NGUYEN