Ling-Fei Wu, Bing-Zhou Wang, Department of Gastroenterology, Jia-Lin Feng, Department of Information, Guo-Rui Liu, Department of Medical Imaging, Wei-Rong Cheng, Xiao-Hua Xu, Department of Surgery, Zhi-Chao Zheng, Department of Pathology, Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong Province China
Supported by Guangdong Medical Science Fund, No. A1999429
Correspondence to: Dr. Ling-Fei Wu, Department of Gastroenterology, Second Affiliated Hospital, Shantou University MedicalCollege, Shantou 515041, Guangdong Province China. lingfeiwu@21cn.com
Telephone: +86-754-8355461 Fax: +86-754-8346543
Received: 2002-07-20 Accepted: 2002-08-29

Abstract
AIM: To evaluate the value of miniprobe sonography (MPS), spiral CT and MR imaging (MRI) in the tumor and regional lymph node staging of esophageal cancer.

METHODS: Eight-six patients (56 men and 30 women; age range of 39-73 years, mean 62 years) with esophageal carcinoma were staged preoperatively with imaging modalities. Of them, 81 (94 %) had squamous cell carcinoma, 4(5 %) adenocarcinoma, and 1(1 %) adenoacanthoma. Eleven patients (12 %) had malignancy of the upper one third, 41 (48 %) of the mid-esophagus and 34 (40 %) of the distal one third. Forty-one were examined by spiral CT in whom 13 were co-examined by MPS, and forty-five by MRI in whom 18 were also co-examined by MPS. These imaging results were compared with the findings of the histopathologic examination for resected specimens.

RESULTS: In staging the depth of tumor growth, MPS was significantly more accurate (84 %) than spiral CT and MRI (68 % and 60 %, respectively, P<0.05). The specificity and sensitivity were 82 % and 85 % for MPS; 60 % and 69 % for spiral CT; and 40 % and 63 % for MRI, respectively. In staging regional lymph nodes, spiral CT was more accurate (78 %) than MPS and MRI (71 % and 64 %, respectively), but the difference was not statistically significant. The specificity and sensitivity were 79 % and 77 % for spiral CT; 75 % and 68 % for MPS; and 68 % and 62 % for MRI, respectively.

CONCLUSION: MPS is superior to spiral CT or MRI for T staging, especially in early esophageal cancer. However, the three modalities have the similar accuracy in N staging. Spiral CT or MRI is helpful for the detection of far-distance metastasis in esophageal cancer.

Wu LF, Wang BZ, Feng JL, Cheng WR, Liu GR, Xu XH, Zheng ZC. Preoperative TN staging of esophageal cancer: Comparison of miniprobe ultrasonography, spiral CT and MRI. World J Gastroenterol 2003; 9(2): 219-224
http://www.wjgnet.com/1007-9327/9/219.htm

INTRODUCTION
Patients with esophageal cancer have a poor prognosis because on the onset of symptoms and the final diagnosis, most tumors have reached an advanced stage^[1-5]. Resection of esophageal cancers is the only curative method, but is limited to the early stages of the disease^[6-10]. Therefore, the early diagnosis and an accurate staging are very important for the surgery.
   Esophageal tumor is a common disease in China^[11-17]. Shantou is a high-risk region. The incidence of the disease ranges from 60-150 per100 000 population and the mortality is as high as 90-134 per 100 000 population^[18,19]. Currently, several cross sectional imaging techniques, such as endoscopic ultrasonography (EUS), computed tomography (CT) and magnetic resonance imaging (MRI) have been widely used to provide preoperative staging and follow-up information in these patients^{[1, 20-26]}. Unfortunately, all these techniques have their limitations.
   Miniprobe endosonography (MPS) is a new intracavitary technique^[27], especially in China^[28,29]. In staging esophageal tumors, previously most studies used the 1987 TNM classification system^[30]. In this study, we adopted the new (1997) TNM classification standard^[31]. The purpose of our study is to compare the accuracy of the three different modalities in preoperative TN staging in patients with esophageal tumors and to analyze their advantages and limitations.

MATERIALS AND METHODS
Patients
From February 1997 to May 2001, 86 patients (56 men and 30 women; age range of 39-73 years, mean 62 years) with esophageal carcinoma were staged preoperatively with imaging modalities. All patients were operated on and staging was done either by histopathological assessment of the resected specimens, or by intraoperative findings, or both. The findings of histopathologic examination were as a gold standard and compared with the results of MPS, spiral CT, and MRI. Of the 86 patients, 81 (94 %) had squamous cell carcinoma, 4(5 %) adenocarcinoma, and 1(1 %) had adenoacanthoma. Eleven patients (12 %) had malignancy of the upper one third, forty-one (48 %) of the mid-esophagus and thirty-four (40 %) of the distal one third. Forty-one patients were examined by spiral CT in which 13 were co-examined by MPS, and 45 patients were examined by MRI in whom 18 were also co-examined by MPS. Of the 22 stenotic tumors in this group, 12 were examined by MPS and the others by spiral CT or MRI.

Imaging procedure
Miniprobe sonography system (Sp-501, Fujinon Co. Ltd, Japan) was used to obtain ultrasound images. A miniprobe (2.6 mm in diameter, 2.05 m in length, 12 MHz or 15 MHz in frequency) was passed through the biopsy channel of a video-endoscope (Olympus XQ-200) during routine endoscopy. Examinations were performed by one endoscopist using the following technique. Premedication with 5 mg midazolam was administered intravenously to 31 patients. First, a standard endoscopy was performed to determine the exact location and size of the tumor. Then the tip of the endoscope was placed 2 to 3 cm proximally to the tumor. The lumen was filled with 50-300 ml of deaerated water to achieve acoustic coupling between transducer and wall. The normal esophageal wall is known to be visualized by MPS as a five-layer structure: (1) mucosa (hyperechoic), (2) muscularis mucosa (hypoechoic), (3) submucosa (hyperechoic), (4) muscularis propria (hypoechoic), and (5) adventitia (hyperechoic). TN staging of MPS was modified according to the 1997 standard of TNM classification[31]. Depth of invasion of the primary tumor was assessed as follows: T1, tumor invading the lamina propria or submucosa; T2, tumor invading the muscularis pripria and leading to complete or nearly complete loss of the layer structure, but with a smooth outer margin; T3, tumor invading the adventitia and surrounding fat tissues; and T4, tumor invading adjacent structures. The criteria for the assessment of lymph node metastasis were used according to our previous standard[28]. In short, the hypoechoic pattern, clearly defined boundaries, especially the direct extension from the primary tumor were considered malignant nodes. In contrast, the hyperechoic pattern and fuzzy borders were considered benign nodes.
   Spiral CT scans were obtained by means of a commercially available unit (Tomoscan AV EP-Plus, Phillip) with 10-mm thick contiguous sections from the pulmonary apices to the adrenal region. Enhanced CT scan was performed in a biphasic mode with a rapid intravenous injection of 50 ml iothalamate meglumine (Ultravist) in 38 patients. Three hundred ml of water was administrated to the patients with distal neoplasms before the CT scanning in order to assess gastric extension. Spiral CT imagins were reviewed by an experienced radiologist, and TN stages were evaluated using the same criteria described below for MR examinations.
   MR imaging was performed with a permanent magnet operating at 0.15T (ASP-015, Annke) with a 128?56 acquisition matrix. Multiple spin-echo pulse sequences were obtained in the transaxial plane at repetition times (TR) of 500, 1 800, or 2 500 msec and echo times (TE) of 35, 90 or 120 msec. In some patients, the sagittal and coronal images were obtained. T1-weighted images were obtained at repetition times (TR) of 500msec and echo times (TE) of 30 msec, and T2-weighted images were obtained at TR of 1 500-1 800 msec and TE of 90-120msec. Transaxial images with contiguous 8-10 mm sections were obtained from the pulmonary apices, including supra clavicular fossas to the upper abdomen, including the entire liver. Coronal and sagittal images with contiguous 8-10 mm sections were obtained in 37 patients, and 0.5 % Gd-DTPA was orally administered to distend the stomach before the MR examination. ECG-gated scans were not used in all patients. Five mm esophageal thickness was used as the upper limits of normal esophageal wall. Any increase beyond this was considered abnormal. Since CT or MRI cannot differentiate each layer of the esophageal wall, according to Botet et al standard^[32], thickening of the wall greater than 5 mm and less than 15 mm was diagnosed as modified T2, thickening of the wall greater than 15 mm with irregularity of the outer margin as T3, and tumor invasion of adjacent structures such as the trachea, aortic pericardium, or vertebral body as T4. Lymph nodes greater than 10 mm in shortaxis diameter were considered abnormal. In contrast, lymph nodes less than 10 mm in diameter were considered benign nodes.

Statistics
The accuracy, sensitivity and specificity of MPS, spiral CT and MRI were calculated using histopathologic staging as a gold standard. For T stage, the sensitivity is a measure of the ability of the three modalities to correctly stage T1/T2 and not overstage tumors as T3/T4, and conversely the specificity is a measure of the ability of the three modalities to correctly stage T3/T4 and not understage tumors as T1/T2^[30]. A Chi-squared test was performed to assess the differences in staging accuracy by different methods. A P value of less than 0.05 was considered to be statistically significant.

RESULTS
Evaluation of tumor growth ( T stage)
Tables 1 shows the accuracy of the three modalities for predicting the T category. Of the 86 patients, 4 patients had T1 tumor, 8 T2, 34 T3 and 40 T4 by final histopathologic examination.
   Thirty-one patients were examined by MPS. It correctly diagnosed all 4 (100 %) T1 tumors, 5 of 7 (71 %)T2, 8 of 9 (89 %) T3, and 9 of 11(82 %) T4. In stage T2, one was understaged and another was overstaged. In stage T3, only one tumor was misdiagnosed as T2. In stage T4, two tumors were understaged. The sensitivity and specificity were 82 % and 85 %, respectively. The overall accuracy of MPS was 84 %.
   Spiral CT was performed in 41 patients. Among them, 2 had T1 tumor, 3 T2, 14 T3 and 22 T4 by final histopathologic examination. In 5 T1/T2 tumors, 2 were overstaged, and 3 were staged as modified T2 correctly (75 %). In stage T3, 2 tumors were understaged as T2 and 1 was overstaged, 11 of 14 were staged correctly (79 %). In stage T4, 8 were misdiagnosed, and only 14 of 22 were staged correctly(64 %). The sensitivity and specificity of T staging by spiral CT were 60 % and 69 %, respectively. The overall accuracy was 68 %.
   MRIwas performed in 45 patients. Among them, 5 had T2 tumor, 20 T3 and 20 T4 by final histopathologic examination. No T1 tumor was examined by MRI. In stage T2, one was understaged and 2 were overstaged, only 2 T2 were staged correctly (40 %). In stage T3, 2 tumors were understaged as T2 and 4 were overstaged, 14 of 20 were staged correctly (70 %). In stage T4, 9 were misdiagnosed, and only 11 of 20 were staged correctly (55 %). The sensitivity and specificity were 40 % and 63 %. The overall accuracy of MRI was 60 %.

Table 1 Accuracy of T classification in esophageal cancers: MPS, spiral CT, MRI compared with histopathologic staging

Evaluation of lymph node involvement (N stage)
Tables 2 shows the accuracy of the three modalities for predicting the overall N category differentiated as N0 or N1. Among the 86 patients, 47 had histopathologically proved lymph node involvement.
   In 31 patients investigated by MPS, 19 had lymph node involvement and 12 had not by histopathologic examination. MPS correctly diagnosed 13 patients in 19 positive nodes. In 12 patients without lymph node involvement, MPS diagnosed 9 patients correctly. There were 3 false-positive and 6 false-negative. The sensitivity, specificity and accuracy were 68 %, 75 %, and 71 %, respectively.
   Of 41 patients examined by spiral CT, 22 had lymph node involvement. Spiral CT showed 17 patients had regional lymph node metastasis in 22 positive patients. In 19 patients without lymph node involvement, spiral CT diagnosed 15 patients correctly. There were 4 false-positive and 5 false-negative. The sensitivity, specificity and accuracy were 77 %, 79 %, and 78 %, respectively.
   Among 45 patients examined by MRI, 26 had lymph node involvement. MRI showed 16 had regional lymph node metastasis in 26 positive patients. In 19 patients without lymph node involvement, MRI diagnosed 13 patients correctly. There were 6 false-positive and 10 false-negative. The sensitivity, specificity and accuracy were 62 %, 68 %, and 64 %, respectively.

Table 2 Accuracy of N classification in esophageal cancers: MPS, spiral CT, MRI compared to histopathologic staging

DISCUSSION
It was reported that accuracy rates of EUS were approximately 52-92 % in the assessment of the infiltration depth of esophageal cancer^[33-39]. In our study, the overall accuracy of T staging was 84 %. We think that the high resolution of MPS contributes the good results, 12MHz translator made it possible to differentiate esophageal histological structures and delineate the entire margins of tumors, especially in the superficial esophageal cancer. The penetration depth of good resolution ultrasound was about 6-8 cm, which could clearly visualize the tumor and the adjacent organs^[40]. In some reports, T1 tumors were often overstaged as T2 because of the resultant obliteration of the submucosa and the muscularis propria^{[33 ]}. Although one study reported no benefit of miniprobes in esophageal cancers^[41], Menzel et al carefully compared the effects of higher frequency miniprobes with conventional probes and concluded that MPS had a higher accuracy for T staging and similar accuracy for N staging in esophageal tumors^[42]. Akahoshi et al also demonstrated the benefit of MPS in early gastric cancers^{[43 ]}. In this series, 4 T1 tumors (including one superficial mucosal carcinoma) were all correctly diagnosed because the tact border of muscularis propria was clearly visualized. In T2 tumor, the accuracy was 71 %. One T2 tumor was overstaged as T3 because the inflammation and fibrosis were mistakenly interpreted as tumor extension through the muscularis propria. Another T2 tumor was understaged because the microscopic invasion beyond the submucosa was not discerned. For T3 tumors, only one was understaged due to inexperience. The tumor was larger and the invasion outside the muscularis propria was interpreted as an irregular outer margin of the muscularis propria. In T4 stage, two tumors were understaged because the adjacent malignant stricture (tracheal or bronchial invasion) was not discerned in a limited field of view. We thought that endosonographic wall penetration was a critical factor. Richards et al also observed that ultrasound attenuation was a commonest reason which led to the error of diagnosis in the advanced tumor^[44], in particular in stenotic tumors^[45]. In addition, artifacts due to oblique scanning may also give rise to misrepresentation of the true depth of penetration, which was another deficient of MPS.
   CT or MRI has been widely used in staging tumors of the upper intestinal tract. However, their diagnostic accuracy in evaluating esophageal carcinoma is controversial. Both of them have the same limitations, i.e. unable to discriminate the layer of the esophageal wall and to detect tumor spread through the muscular wall into adjacent tissues^[32]. Evaluation of direct invasion by CT or MRI is based on two criteria: mass effect and loss of fat planes. When the trachea or bronchial wall is indented or displaced away by a tumor mass, the mass effect is present and invasion is presumed. The loss of fat plane between tumor and adjacent tissues is commonly used to predict aortic and pericardial invasion. According to the reports, the accuracy of CT or MRI in staging the local tumor infiltration ranged from 45 % to 73 %^[46-51]. Quint et al compared MRI with CT in the staging of esophageal tumors^[52]. In 12 patients evaluated, they found that both CT and MRI were 100 % accurate in prediction of tracheobronchial invasion with an accuracy rate of 75 % for aortic invasion and 88 % for pericardial invasion. In a late review, Kelly et al reported that the sensitivity of CT ranged from 40 % to 80 % and the specificity from 14 % to 97 %^[30]. In present study, the sensitivity of the three modalities ranged from 40 % to 82 % and the specificity from 63 % to 85 %. Three patients misdiagnosed by spiral CT and five patients by MRI were staged correctly by MPS, especially in T1-T2 tumors, which demonstrated the superiority of MPS. Spiral CT is an inspiring new technique. Our primary data showed that spiral CT was not optimistic, although spiral CT had a higher accuracy than MRI, no significant difference was found (P>0.05). MPS appeared more accurate (84 %) than spiral CT or MRI (68 % or 60 %, respectively, P<0.05). Although strictly blinded approach was not taken in this study, our results continue to support the hypothesis that endosonography is superior to CT or MRI in the T staging of esophageal cancer^[53-55].
   MPS can only visualize lymph nodes close to the esophageal wall whereas CT and MRI can demonstrate both regional and distant lymph node metastases. For MPS, the differentiation of malignant lymph nodes from benign nodes could be made according to its size, distance from tumor and echo features. The round hypoechoic lymph nodes with a smoothly demarcated border and size greater than 5 mm had the greatest probability of malignancy^[56]. Murata et al^[57] used MPS to evaluate lymph nodes in different periesophageal areas and the accuracy being 88 %. Other reported that the accuracy of EUS ranged from 68 % to 92 %^[29,58-60]. In this study, the overall accuracy of MPS for diagnosing the N category was 71 %, with a sensitivity of 75 % and a specificity of 68 %. Our results were consistent with these reports.
   We think that the lack of reliable criteria in N staging may be the main reason of low accuracy for MPS. The judging value of node size is still controversial. Some authors reported that nodes larger than 5 mm were not inflammatory in the resection specimens^{[33, 61-64]}. Tio et al thought that enlarged lymph nodes were not necessarily cancerous and small nodes might be involved by tumors^[33]. We also observed that lymph nodes larger than 5 mm were inflammatory by pathological examination^[28]. However, we believed that nodes greater than 10 mm, especially close to the primary tumor, rounder, darker, and more homogeneous had much more possibility of malignancy^[20]. In addition, the morphology of tumors would also be another important factor affecting these results.
   Holscher et al^[65] thought that MPS was more accurate than CT or MRI in the diagnosis of lymph node metastases. Tio et al^[33], however, pointed out that CT was superior to EUS for evaluating celiac lymph nodes due to nontraversable stenoses. In this series, the accuracy of spiral CT (78 %) was higher than that of MPS or MRI (68 %, 64 %, respectively), but without significant difference (P>0.05). The cause was not clear. We think that methodologies of study designs are related to these results, because different assessment conditions, such as technical parameters, anatomical location of tumors and patient characteristics could lead to different results^[66]. For example, stenotic tumors were not included or accounted for different percentages in some studies[65]. Hordijk et al assessed the influence of tumor stenosis on T staging accuracy of miniprobes. A lower accuracy (46 %) was obtained with stenotic tumors than those with nontraversable tumors (82 %). They postulated that the main reason lay in the short focal distance between the ultrasonic transducer and tumor hampered clear visualization of the wall layers and tumor penetration depth^[45]. On the other hand, Kallimanis et al^[66] reported that the degree of esophageal stenosis was an important criteria for lymph node involvement. Brugge et al pointed out that T3 and T4 tumors were significantly thicker than T1 and T2 tumors^[67]. In our previous reports, about half of severe stenotic tumors were T3 and the other half T4^[18]. Tio et al indicated that the incidence of positive lymph nodes in the advanced tumors (T3/T4) was higher than the intramural tumors (T1/ T2)^[33]. In this study, 23 (27 %) patients had stenotic tumors, in whom 10 patients had T3 and 13 had T4 and all had the lymph node involvement. No one had T2 or T1 stage. In other words, stenotic tumors had more possibilities of advanced stage and lymph node metastasis^{[18, 68-72]}. Our results strongly supported Brugge's view^[67]. However, in 12 stenotic tumors examined by MPS, only 5 (42 %) were correctly diagnosed. In another 10 stenotic tumors, 5 (5/6) were correctly diagnosed by Spiral CT and 3(3/4) by MRI. Spiral CT and MRI appeared more accurate than MPS in stenotic tumors^[30,71].
   In clinical practice, two methods are commonly used to improve the accuracy of diagnosis. One is the use of contrast material, such as Ultravist on spiral CT or Gd-TDPA on MR imaging. Enhanced imaging can provide useful information of the blood supply of the lesions, which is helpful to distinguishing the malignant from the benign mass. The other one is the regulation of the section thickness. A section gap of 1-2 mm can help discover micro-lesions. However, Gd-DTPA has several disadvantages, such as non-specific distribution and slightly nephrotic toxicity^[73]. To develop new tissue-specific contrast material would further improve the accuracy of spiral CT and MRI in TNM staging of gastricoesophageal carcinoma. In addition, it should be taken into consideration that in our study the MR equipment was of (first generation), which was also a reason for its low accuracy.
   We think that the experience is an important factor to improve the accuracy of diagnosis^[28]. Some problems such as the lack of training facilities, EUS courses and EUS laboratories limit the wider use of MPS. No atla of endosonography for different diseases has been published in the world so far. The interpretation of endosonographic images is dependent on the ultrasound knowledge or the results of animal experiments. The lack of experience in transabdominal ultrasonography hinders the reasonable interpretation for some complex image patterns. The ultrasound images are also unsteady. We observed that the esophageal wall can be visualized as a five-layer structure, but sometimes as a three-layer structure^[28]. Other authors also reported the similar results^[35,57]. The reason remains to be demonstrated. Many hospitals diagnosed the disease in cooperation between endoscopists and ultrasoundists. In addition, many surgeons have still doubted the role of endosonography. They would rather believe the results of spiral CT or MRI. In fact, CT or MRI plays an increasing role in ruling out the intra-abdominal metastasis so as to avoid unnecessary surgery^[74]. We also think it unnecessary to make MPS examination for those patients who have lost the operation chance. To our knowledge, surgeons in our hospital make the therapeutic plans for the patients with advanced tumors mainly relying on the results of spiral CT or MRI. As a watter of contrast, they select the surgical procedures for the patients with stage T1 and T2 much more depending on the results of MPS. As a matter of fact, MPS appears superior to CT or MRI mainly in staging early tumors and the latter have much higher accuracy in determining the presence or extent of more distant metastases. A combination of endoscopic ultrasound including computer-assisted analysis and spiral CT or MRI are expected to provide a higher TNM accuracy^[75].

REFERENCES
1    Krasna MJ, Jiao X, Sonett JR, Gamliel Z, Eslami A, Raefaly Y, Mao Y. Thoracoscopic and laparoscopic lymph node staging
      in esophageal cancer: do clinicopathological factors affect the outcome? Ann Thorac Surg 2000; 73: 1710-1713
2    Wang N, Liu ZH, Ding F, Wang XQ, Zhou CN, Wu M. Down-regulation of gut-enriched Kruppel-like factor expression
      in esophageal cancer. World J Gastroenterol 2002; 8: 966-970
3    Shen ZY, Xu LY, Chen MH, Shen J, Cai WJ, Zeng Y. Progressive transformation of immortalized esophageal epithelial
      cells. World J Gastroenterol 2002; 8: 976-981
4    Wilson KS, Wilson AG, Dewar GJ. Curative treatment for esophageal cancer: Vancouver Island Cancer Centre experience
      from 1993 to 1998. Can J Gastroenterol 2002; 16: 361-368
5    Nishimaki T, Tanaka O, Ando N, Ide H, Watanabe H, Shinoda M, Takiyama W, Yamana H, Ishida K, Isono K, Endo M, Lkeuchi
      T, Mitomi T, Koizumi H, Imamura M, Iizuka T. Evaluation of the accuracy of preoperative staging in thoracic esophageal
      cancer. Ann Thorac Surg 1999; 68: 2059-2064
6    Ando N, Niwa Y, Ohmiya N, Ito B, Sasaki Y, Goto H. Simultaneous multiple early cancers of esophagus and stomach treated
      by endoscopic mucosal resection. Endoscopy 2002; 34: 667-669
7    Drudi FM, Trippa F, Cascone F, Righi A, Iascone C, Ricci P, David V, Passariello R. Esophagogram and CT vs endoscopic
      and surgical specimens in the diagnosis of esophageal carcinoma. Radiol Med 2002; 103: 344-352
8    Wu MY, Liang YR, Wu XY, Zhuang CX. Relationship between Egr-1 gene expression and apoptosis in esophageal
      carcinoma and precancerous lesions. World J Gastroenterol 2002; 8: 971-975
9    Leung SF, Griffith JF, Ahuja A, Chan AC. Influence of staging thoracic computed tomography on radiation therapy planning
      for esophageal carcinoma. J Thorac Imaging 2002; 17: 145-150
10  Christein JD, Hollinger EF, Millikan KW. Prognostic factors associated with resectable carcinoma of the esophagus. Am
      Surg 2002; 68: 258-262
11  Shen ZY, Shen J, Li QS, Chen CY, Chen JY, Zeng Y. Morphological and functional changes of mitochondria in
      apoptotic esophageal carcinoma cells induced by arsenic trioxide. World J Gastroenterol 2002; 8: 31-35
12  Gao F, Yi J, Shi GY, Li H, Shi XG, Tang XM. The sensitivity of digestive tract tumor cells to As2O3 is associated with the
      inherent cellular level of reactive oxygen species. World J Gastroenterol 2002; 8: 36-39
13  Shen ZY, Shen WY, Chen MH, Shen J, Cai WJ, Yi Z. Nitric oxide and calcium ions in apoptotic esophageal carcinoma
      cells induced by arsenite. World J Gastroenterol 2002; 8: 40-43
14  Gu ZP, Wang YJ, Li JG, Zhou YA. VEGF165 antisense RNA suppresses oncogenic properties of human esophageal squamous
      cell carcinoma. World J Gastroenterol 2002; 8: 44-48
15  Wang AH, Sun CS, Li LS, Huang JY, Chen QS. Relationship of tobacco smoking, CYP1A1, GSTM1 gene polymorphism
      and esophageal cancer in Xi'an. World J Gastroenterol 2002; 8: 49-53
16  Zou JX, Wang LD, Shi ST, Yang GY, Xue ZH, Gao SS, Li YX, Yang CS. p53 gene mutations in multifocal
      esophageal precancerous and cancerous lesions in patients with esophageal cancer in high risk northern China. Shijie
      Huaren Xiaohua Zazhi 1999; 7: 280-284
17  Deng LY, Zhang YH, Xu P, Yang SM, Yuan XB. Expression of interleukin 1b converting enzyme in 5-FU induced apoptosis
      in esophageal carcinoma cells. World J Gastroenterol 1999; 5: 50-52
18  Wu LF, Yao JG, Wu ZD, Wu MY. The significance of endoscopic classification in esophageal cancer. Najing
      Neijing 1995; 12: 146-148
19  Chen HB, Chen L, Zhang JK, Shen ZY, Su ZJ, Cheng SB, Chew EC. Human papillomavirus 16E6 is associated with the
      nuclear matrix of esophageal carcinoma cells. World Gastroenterol 2001; 7: 788-791
20  Rice TW. Clinical staging of esophageal carcinoma. CT, EUS, and PET. Chest Surg Clin N Am 2000; 10: 471-485
21  Nguyen NT, Roberts PF, Follette DM, Lau D, Lee J, Urayama S, Wolfe BM, Goodnight JE. Evaluation of minimally
      invasive surgical staging for esophageal cancer. Am J Surg 2001; 182: 702-706
22  Giovannini M, Monges G, Seitz JF, Moutardier V, Bernardini D, Thomas P, Houvenaeghel G, Delpero JR, Giudicelli R, Fuentes
      P. Distant lymph node metastases in esophageal cancer: impact of endoscopic ultrasound-guided biopsy.
      Endoscopy 1999; 31: 536-540
23  Pfau PR, Ginsberg GG, Lew RJ, Faigel DO, Smith DB, Kochman ML. Esophageal dilation for endosonographic evaluation
      of malignant esophageal strictures is safe and effective. Am J Gastroenterol 2000; 95: 2813-2815
24  Slater MS, Holland J, Faigel DO, Sheppard BC, Deveney CW. Does neoadjuvant chemoradiation downstage
      esophageal carcinoma? Am J Surg 2001; 181: 440-444
25  Greenberg J, Durkin M, Van Drunen M, Aranha GV. Computed tomography or endoscopic ultrasonography in
      preoperative staging of gastric and esophageal tumors. Surgery 1994; 116: 696-702
26  Nishimaki T, Tanaka O, Ando N, Ide H, Watanabe H, Shinoda M, Takiyama W, Yamana H, Ishida K, Isono K, Endo M, Ikeuchi
      T, Mitomi T, Koizumi H, Imamura M, Iizuka I. Evaluation of the accuracy of preoperative staging in thoracic esophageal
      cancer. Ann Thorac Surg 1999; 68: 2059-2064
27  McLoughlin RF, Cooperberg PL, Mathieson JR, Stordy SN, Halparin LS. High resolution endoluminal ultrasonography in
      the staging of esophageal carcinoma. J Ultrasound Med 1995; 14:725-730
28  Wu LF, Wang BZ, Wang YZ, Xu XH, Zheng ZC. Evaluation of Miniprobe Endosonography in Preoperative TN staging
      of Esophageal Cancer: Comparison of water rinsing method with balloon method. J CAUME 1999; 5: 10-13
29  Wang Y, Sun Y, Li YY. Clinical application of transesophageal intraluminal ultrasonography to the esophageal
      carcinoma. Zhonghua Waike Zazhi 1998; 36: 620-623
30  Kelly S, Harris KM, Berry E, Hutton J, Roderick P, Cullingworth J, Gathercole L, Smith MA. A systematic review of the
      staging performance of endoscopic ultrasound in gastro-oesophageal carcinoma. Gut 2001; 49: 534-539
31  Sobin LH, Wittekind C, eds. TNM classification of malignant tumours, 5th ed. New York: Springer-Verlag 1997
32  Botet JF, Lightdale CJ, Zauber AG, Gerdes H, Urmacher C, Brennan MF. Preoperative staging of esophageal
      cancer: comparison of endoscopic US and dynamic CT. Radiology 1991; 181:419-425
33  Tio TL, Cohen P, Coene PP, Udding J, Den Hartog Jager FC, Tytgat GN. Endosonography and computed tomography
      of esophageal carcinoma. Preoperative classification compared to the new (1987) TNM system.
      Gastroenterology 1989; 96: 1478-1486
34  Rice TW, Zuccaro G Jr, Adelstein DJ, Rybicki LA, Blackstone EH, Goldblum JR. Esophageal carcinoma: depth of tumor
      invasion is predictive of regional lymph node status. Ann Thorac Surg 1998; 65: 787-792
35  Hasegawa N, Niwa Y, Arisawa T, Hase S, Goto H, Hayakawa T. Preoperative staging of superficial esophageal
      carcinoma: comparison of an ultrasound probe and standard endoscopic ultrasonography. Gastrointest
      Endosc 1996; 44: 388-393
36  Vazquez-Sequeiros E, Wiersema MJ. High-frequency US catheter-based staging of early esophageal tumors.
      Gastrointest Endosc 2002; 55: 95-99
37  Vickers J. Role of endoscopic ultrasound in the preoperative assessment of patients with oesophageal cancer. Ann R Coll
      Surg Engl 1998; 80: 233-239
38  Peters JH, Hoeft SF, Heimbucher J, Bremner RM, Demeester TR, Bremner CG, Clark GW, Kiyabu M, Parisky Y. Selection
      of patients for curative or palliative resection of esophageal cancer based on preoperative endoscopic ultrasonography.
      Arch Surg 1994;129: 534-539
39  Fockens P, Van den Brande JH, Van Dullemen HM, Van Lanschot JJ, Tytgat GN. Endosonographic T-staging of
      esophageal carcinoma: a learning curve. Gastrointest Endosc 1996; 44: 58-62
40  Nesje LB, Svanes K, Viste A, Laerum OD, Odegaard S. Comparison of a linear miniature ultrasound probe
      and a radial-scanning echoendoscope in TN staging of esophageal cancer. Scand J Gastroenterol 2000; 35: 997-1002
41  Vickers J, Alderson D. Influence of luminal obstruction on esophageal cancer staging using endoscopic ultrasonography.
      Br J Surg 1998; 85: 999-1001
42  Menzel J, Hoepffner N, Nottberg H, Schulz C, Senninger N, Domschke W. Preoperative staging of esophageal
      carcinoma: miniprobe sonography versus conventional endoscopic ultrasound in a prospective histopathologically verified
      study. Endoscopy 1999; 31: 291-297
43  Akahoshi K, Chijiiwa Y, Sasaki I, Hamada S, Iwakiri Y, Nawata H, Kabemura T. Pre-operative TN staging of gastric
      cancer using a 15 MHz ultrasound miniprobe. Br J Radiol 1997; 70: 703-707
44  Richards DG, Brown TH, Manson JM. Endoscopic ultrasound in the staging of tumours of the oesophagus
      and gastro-oesophageal junction. Ann R Coll Surg Engl 2000; 82: 311-317
45  Hordijk ML, Zander H, van Blankenstein M, Tilanus HW. Influence of tumour stenosis on the accuracy of endosonography
      in preoperative T staging of esophageal cancer. Endoscopy 1993; 25: 171-175
46  Ampil FL, Caldito G, Li BD, Pelser R. Computed tomographic staging of esophageal cancer and prognosis. Radiat
      Med 2001; 19:127-129
47  Luketich JD, Meehan M, Nguyen NT, Christie N, Weigel T, Yousem S, Keenan RJ, Schauer PR. Minimally invasive
      surgical staging for esophageal cancer. Surg Endosc 2000; 14: 700-702
48  Rosch T, Lorenz R, Zenker K, von Wichert A, Dancygier H, Hofier H, Siewert JR, Classen M. Local staging and assessment
      of resectability in carcinoma of esophagus, stomach and duodenum by endoscopic ultrasonography. Gastrointest
      Endosc 1992; 38: 460-467
49  Irie H, Honda H, Kaneko K, Kuroiwa T, Yoshimitsu K, Masuda K. Comparision of helical CT and MR imaging in detecting
      and staging small pancreatic adenocarcinoma. Abdom Imaging 1997;22: 429-433
50  Drudi FM, Trippa F, Cascone F, Righi A, Iascone C, Ricci P, David V, Passariello R. Esophagogram and CT vs endoscopic
      and surgical specimens in the diagnosis or esophageal carcinoma. Radiol Med 2002; 103: 344-352
51  Willis J, Cooper GS, Isenberg G, Sivak MV Jr, Levitan N, Clayman J, Chak A. Correlation of EUS measurement with
      pathologic asscssment of neoadjuvant therapy response in esophageal carcinoma. Gastrointest Endosc 2002; 55: 655-661
52  Quint LE, Glazer GM, Orringer MB. Esophageal imaging by MR and CT: study of normal anatomy and neoplasms.
      Radiology 1985;156: 727-731
53  Chandawarkar RY, Kakegawa T, Fujita H, Yamana H, Hayabuthi N. Comparative analysis of imaging modalities in
      the preoperative assessment of nodal metastasis in esophageal cancer. J Surg Oncol 1996; 61: 214-217
54  Massari M, Cioffi U, De Simone M, Lattuada E, Montorsi M, Segalin A, Bonavina L. Endoscopic ultrasonography for
      preoperative staging of esophageal carcinoma. Surg Laparosc Endosc 1997; 7: 162-165
55  Pang W, Tao J, Chen W. Preoperative saging of esophageal carcinoma: comparison of endoesophageal
      ultrasonography, computerized tomography and conventional clinical staging. Zhonghua Waike Zazhi 1998; 36: 617-619
56  Yanai H, Yoshida T, Harada T, Matsumoto Y, Nishiaki M, Shigemitsu T, Tada M, Okita K, Kawano T, Nagasaki S.
      Endoscopic ultrasonography of superficial esophageal cancers using a thin ultrasound probe system equipped with
      switchable radial and linear scanning modes. Gastrointest Endosc 1996; 44: 578-582
57  Murata Y, Suzuki S, Ohta M, Mitsunaga A, Hayashi K, Yoshida K, Ide H. Small ultrasonic probes for determination of the
      depth of superficial esophageal cancer. Gastrointest Endosc 1996; 44: 23-28
58  Heidemann J, Schilling MK, Schmassmann A, Maurer CA, Buchler MW. Accuracy of endoscopic ultrasonography in
      preoperative staging of esophageal carcinoma. Dig Surg 2000; 17: 219-224
59  Wallace MB, Hawes RH, Sahai AV, VanVelse A, Hoffman BJ. Dilation of malignant esophageal stenosis to allow EUS
      guided fine-needle aspiration: safety and effect on patient management. Gastrointest Endosc 2000; 51: 309-313
60  Kim LS, Koch J. Do we practice what we preach? Clinical decision making and utilization of endoscopic ultrasound for
      staging esophageal cancer. Am J Gastroenterol 1999; 94: 1847-1852
61  Rosch T, Dittler HJ, Strobel K, Meining A, Schusdziarra V, Lorenz R, Allescher HD, Kassem AM, Gerhardt P, Siewert JR,
      Hofler H, Classen M. Endoscopic Ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas:
      a blind reevaluation of videotapes. Gastrointest Endosc 2000; 52: 469-477
62  Faige DO. EUS in patients with benign and malignant lymphadenopathy. Gastrointest Endosc 2001; 53: 593-598
63  Reed CE, Mishra G, Sahai AV, Hoffman BJ, Hawes RH. Esophageal cancer staging: improved accuracy by endoscopic
      ultrasound of celiac lymph nodes. Ann Thorac Surg 1999; 67: 319-321
64  Zuccaro G Jr, Rice TW, Goldblum J, Medendorp SV, Becker M, Pimentel R, Gitlin L, Adelstein DJ. Endoscopic ultrasound
      cannot determine suitability for esophagectomy after aggressive chemoradiotherapy for esophageal cancer. Am J
      Gastroenterol 1999; 94: 906-912
65  Holscher AH, Dittler HJ, Siewert JR. Staging of squamous esophageal cancer: accuracy and value. World J
      Surg 1994; 18: 312-320
66  Kallimanis GE, Gupta PK, Al-Kawas FH, Tio LT, Benjamin SB, Bertagnolli ME, Nguyen CC, Gomes MN, Fleischer DE.
      Endoscopic ultrasound for staging esophageal cancer, with or without dilation, is clinically important and safe.
      Gastrointest Endosc 1995; 41: 540-546
67  Brugge WR, Lee MJ, Carey RW, Mathisen DJ. Endoscopic ultrasound staging criteria for esophageal cancer.
      Gastrointest Endosc 1997; 45: 147-152
68  Van Dam J, Rice TW, Catalano MF, Kirby T, Sivak MV Jr. High-grade malignant stricture is predictive of esophageal
      tumor stage. Risks of endosonographic evaluation. Cancer 1993; 71: 2910-2917
69  Meining A, Dittler HJ, Wolf A, Lorenz R, Schusdziarra V, Siewert JR, Classen M, HÖler H, RÖch T. You get what you expect?
      A critical appraisal of imaging methodology in endosonographic cancer staging. Gut 2002; 50: 599-603
70  Rice TW, Zuccaro G Jr, Adelstein DJ, Rybicki LA, Blackstone EH, Goldblum JR. Esophageal carcinoma: depth of tumor invasion
      is predictive of regional lymph node status. Ann Thorac Surg 1998; 65: 787-792
71  Bhutani MS, Barde CJ, Markert RJ, Gopalswamy N. Length of esophageal cancer and degree of Iuminal stenosis during
      upper endoscopy predict T stage by endoscopic ultrasound. Endoscopy 2002; 34: 461-463
72  Parmar KS, Zwischenberger JB, Reeves AL, Waxman I. Clinical impact of endoscopic ultrasound-guided fine needle
      aspiration of celiac axis lymph nodes (Mla disease) in esophageal cancer. Ann Thorac surg 2002; 73: 916-920
73  Zheng WW, Zhou KR, Chen ZW, Shen JZ, Chen CZ, Zhang SJ. Characterization of focal hepatic lesions with SPIO-
      enhanced MRI. World J Gastroenterol 2002; 8: 82-86
74  Wang YH, Zhang LZ, Wang GH. Clinical value of preoperative CT examination in esophageal cancer. Huaren Xiaohua
      Zazhi 1998;6(T7): 461
75  Loren DE, Seghal CM, Ginsberg GG, Kochman ML. Computer-assisted analysis of lymph nodes detected by EUS in patients
      with esophageal carcinoma. Gastrointest Endosc 2002; 56: 742-746

Edited by Ma JY