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Ann Thorac Surg 2001;72:212-219
© 2001 The Society of Thoracic Surgeons
Address reprint requests to Dr Eloubeidi, Division of Gastroenterology and Hepatology, The University of Alabama at Birmingham School of Medicine, ZRB 636, 1530 3rd Ave S, Birmingham, AL 35294-0007
e-mail: eloubeidi{at}gihep.uab.edu
Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 9–11, 2000.
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Abstract |
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Methods. During the study period, 211 patients with esophageal cancer underwent EUS staging. Patients with evaluable celiac axis (n = 182) were included in this study. Survival of patients with and without CLNs was compared and the factors affecting overall survival were assessed. A subgroup analysis based on CLN status was performed in the subgroup of patients who underwent surgical procedures.
Results. Follow-up data was available in 91.2% (166 of 182) of the patients. As staged by EUS, T1, T2, T3, and T4 tumors accounted for 9.3%, 11.5%, 56%, and 21% of the cases, respectively. At least one CLN was imaged by EUS in 40% (72 of 182). The 5-year survival in patients with CLNs detected by EUS was 13% (95% confidence interval, 5% to 21%) compared with 30% (95% confidence interval, 21% to 40%) in patients with no CLNs detected by EUS (p = 0.007). In the subgroup of patients who underwent surgical procedures (n = 68), patients with CLN involvement had worse survival compared with those who did not have malignant involvement of CLNs at the time of their operation (median survival 39.8 versus 13.8 months, p = 0.0008). In a Cox proportional model, adjusting for race and the type of therapy, patients with CLN involvement or advanced EUS American Joint Committee on Cancer stage were more likely to have worse survival (p < 0.05)
Conclusions. EUS base line findings correlate with long term survival in patients with esophageal cancer. Patients with M1a disease as identified by EUS had a significantly worse postoperative survival when compared with non-M1a patients. This cohort of patients will be ideal for the study of induction therapy since the effect of down staging can be assessed before operation.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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Endoscopic ultrasonography (EUS) is firmly established as the primary staging modality for patients with ECA. It allows accurate determinations of tumor stage and the detection of malignant lymph node involvement. In addition, EUS is particularly suited for evaluating distant lymph node metastasis in patients with ECA, particularly in the celiac axis area and the mediastinum [5, 6]. Moreover, EUS-guided fine-needle aspiration (FNA) allows cytologic confirmation of CLN involvement [6–8], a finding with grave implications for the patient with ECA because it is classified as a metastatic lesion (M1a or M1b in the 1997 American Joint Committee on Cancer [AJCC] classification) [9]. We have recently shown that the detection of CLNs by EUS, regardless of echofeatures, is synonymous with malignant involvement [7].
Despite the proven superiority of EUS compared with other staging modalities for local staging of ECA, the correlation between EUS findings and survival of ECA patients has not been well assessed. We hypothesized that patients with CLNs identified by EUS would predict a cohort with significantly worse survival after surgical procedures. Therefore, the aim of this study was to determine predictors of survival in ECA patients as initially staged by endosonography, with a special focus on CLN status.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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All EUS procedures were performed by or under the supervision of experienced endosonographers on an outpatient basis with conscious sedation. Upper endoscopy was performed initially to assess the characteristics of the cancer (length, circumference, and the need for dilation). When the echoendoscope could not bypass the tumor, the esophagus was usually dilated using wire-guided Savary–Gilliard dilators (Wilson-Cook Medical, Inc, Winston-Salem, NC) to allow passage of the 13-mm echoendoscope. Staging was performed routinely by initially positioning the echoendoscope in the proximal stomach to examine the celiac axis (when possible) and then withdrawing the echoendoscope into the esophagus to stage the primary tumor. The celiac axis was not studied in 3 patients and could not be evaluated because of stenosis in 12.5% (26 of 208) of the patients (10 patients had no dilations performed, 16 had nontraversible tumor despite dilation). Staging was performed according to the 1997 AJCC TNM classification [9]. Lymph node status N0 or N1 was also classified according to the TNM system. In normal subjects, EUS does not detect CLNs. Therefore, a CLN node larger than 5 mm was considered positive.
Well-established lymph node features characteristic of malignant involvement were adopted for the classification of peritumoral (periesophageal) lymph nodes [10, 11]. The diagnostic criteria for malignant lymph node involvement were size 1 cm or larger; round shape; homogeneous hypoechoic pattern; and sharp and distinct borders. A CLN was defined as a lymph node present within 2 cm of the origin of the celiac trunk from the descending aorta.
Endoscopic ultrasonography was performed with a radial scanning echoendoscope at 7.5 and 12.0 MHz (Olympus GF-UM20, GF-UM 130; Olympus America Inc, Melville, NY). When at least one CLN was detected and accessible, EUS-guided FNA was performed. Endoscopic ultrasonography-FNA was performed with either a curvilinear array echoendoscope FG-32-UA (Pentax, Orangeburg, NY), or Olympus UC-30P or UCT-30 (Olympus America) or the mechanical sector scanning biopsy echoendoscope (Olympus GF-UM 30 P). Doppler ultrasound was performed to ensure that there were no intervening vessels before EUS-FNA. The aspirate was reviewed immediately by an on-site pathologist to ensure an adequate specimen, defined as the presence or absence of lymphocytes or malignant cells. A single surgeon (C.E.R.) at this institution performed surgical resection in all patients. At the time of operation, CLNs (lymph nodes at the base of the celiac axis, and the proximal left gastric artery) were dissected en bloc with the specimen and labeled. When small, the entire lymph node was submitted. Larger lymph nodes were bisected and the two portions examined.
Statistical analysis
Base line demographics of patients with and without malignant CLN involvement were compared. Categorical variables between the two groups were compared with the 
2 test. Continuous variables were compared using the Wilcoxon rank sum test or the Student’s t test. Categorical variables were reported as percentages or proportions and continuous variables were reported as means and standard deviations or median and interquartile range (IQR) if data were not normally distributed.
Survival was measured from the date of diagnosis to the date of death. Data on living patients were censored at the time of their most recent physician visit. The median survival was calculated according to the Kaplan–Meier method and comparisons of the survival times between selected groups were made using the log rank test.
To determine the endosonographic and endoscopic predictors of survival, both univariate and multivariable Cox proportional hazards models were performed. All statistical analyses were performed using the SAS software version 6.12 (SAS Institute, Cary, NC). A two-sided type I error rate of 0.05 was used for all statistical tests.
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Results |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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As staged by EUS, T1, T2, T3, and T4 tumors accounted for 9.3%, 11.5%, 56%, and T4 for 21% of the cases, respectively. At least one CLN was imaged by EUS in 40% (72 of 182) of patients whose celiac axis was evaluable. Of these CLNs, malignant involvement was proved in 80% of the cases by either EUS-FNA or at the time of operation. In the rest of the patients, neither EUS-FNA (overlying vessel or tumor, advanced T4 disease) nor an operation was performed.
The base line characteristics of the tumors based on CLN status as determined by EUS are shown in Table 1. There was no difference between the two groups with and without CLN detected by EUS in terms of age at presentation, gender, race, and histology or location of the tumor. However, patients with CLN detected by EUS were more likely to have EUS T3 or T4 tumors, long and stenotic tumors as marked by the need for dilation to complete the examination. Of the 182 patients in the study, 37.4% (n = 68) underwent an operation, 50% received radiation therapy, and 51% received chemotherapy. More specifically, of the 68 who underwent operations, 29 patients had operations alone, 29 patients had chemoradiotherapy followed by operations, 9 patients had chemotherapy followed by operations, and 1 patient had radiotherapy followed by an operation. Among the 68 patients, 54 (79%) had no CLNs by EUS and 14 (21%) did have CLNs by EUS (p = 0.001). However, 21 (31%) of the 68 patients who underwent an operation were found to have involvement of CLNs at the time of operation.
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As seen in Figure 1, base line EUS AJCC stage predicted patient survival. The survival of patients decreased as the EUS T stage increased (Fig 1). More specifically, the median survival in patients with EUS T4, T3, T2, and T1 were 6.3 (95% confidence interval [CI], 5.4 to 10.7), 13.8 (95% CI, 10.7 to 20.1), 13.1 (95% CI, 5.8 to 30.5) and 26.8 months, respectively. These results were reproduced when survival of these patients was assessed according to EUS AJCC stage (Fig 1). Patients with any peritumoral adenopathy (N1 disease) as detected by EUS had worse survival compared with patients who had no adenopathy (12.8 versus 26.7 months, p = 0.02) (Fig 2). Figure 3 shows that patients with CLNs detected by EUS were more likely to have worse survival than patients without CLNs. The 5-year survival in patients with CLNs detected by EUS was 13% (95% CI, 5% to 21%) compared with 30% (95% CI, 21% to 40%) in patients with no CLNs detected by EUS. Moreover, the median survival time was 10.2 (95% CI, 6.8 to 12.8) months in patients with CLNs detected by EUS compared with 17.4 months (95% CI, 13.3 to 22.8) in patients with no CLNs detected by EUS (p = 0.007, log rank test). In the subgroup of patients who underwent an operation (n = 68) (Fig 4), patients with CLN involvement had worse survival than those who did not have malignant involvement of CLNs at operation (median survival 39.8 versus 13.8 months, p = 0.0008).
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Comment |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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According to the revised 1997 AJCC classification, patients with M1a disease (CLNs) are considered to have metastatic disease. A recent study evaluated survival of patients with ECA who had M1a/M1b disease [3]. Christie and colleagues [3] argued that even though survival of patients with M1a disease was 6 months longer than patients with M1b disease, the difference was not thought to be clinically important. In this study, we evaluated the survival of patients with ECA based on EUS findings. We also performed a subgroup analysis to highlight the role of the presence of CLNs at the time of operation.
We have shown in this study that base line EUS characteristics predict survival in patients with ECA. Specifically, we have shown that both EUS T stage and overall EUS AJCC stage predicted long-term survival. These findings mirror those of surgical findings [14] and reflect the high level of accuracy of EUS in staging ECA. Published and recently presented data have shown that EUS tumor characteristics at the time of original staging predict long-term survival. Hiele and colleagues [4] reported on the relationship between EUS initial stage and survival in patients with ECA. This study evaluated survival of 86 patients with ECA depending on tumor stage, regional LN detection, CLN metastasis, degree of tumor stenosis, and AJCC classification. These investigators found that survival was stage dependent and worst for patients with stage IV disease. Two other studies have also shown that patients with T4 tumors as staged by EUS have poor prognosis and do not benefit from surgical resection [15, 16]. One study has shown that EUS T and N stage were predictors of long-term survival in patients with ECA [17]. Another study has shown that overall survival in ECA patients was dependent on overall EUS stage and independently on EUS T stage, N stage, and M stage (CLN involvement) [18]. In that study, a minority of patients had T2 disease and their survival appeared worse than those with T3 disease. This observation could be attributed to the low number of T2 patients as well as to the fact that EUS is less accurate in staging T2 tumors compared with T3 or T4 disease (78% for T2 versus 93% for T3 disease) [19].
The presence of nodal disease as detected by EUS was also assessed. The detection of N1 disease was associated with poor survival. Unfortunately, because of the retrospective nature of this study, the number of lymph nodes detected was not routinely documented and therefore its impact on survival could not be analyzed. Other studies, however, have documented the number of lymph nodes detected. One recent study found that the number of lymph nodes as detected by EUS correlated with survival [20]. Patients with more than three peritumoral lymph nodes detected by EUS had worse prognosis than patients with fewer than three lymph nodes [20].
We have shown that patients with CLNs detected by EUS had a shorter survival compared with patients without CLNs. The 5-year survival and the median survival of patients with CLNs of 13% and 10.2 months parallels 6% and 11 months observed in another study [3]. In addition, in the cohort of patients who underwent operations, the pathologic identification of residual or microscopic disease in their CLNs portrayed a worse prognosis on survival as well. Therefore, our data support that the detection of CLNs carries a grave prognosis.
However, the eradication of nodal adenopathy with neoadjuvant therapy is possible [21]. The establishment of nodal disease sterility before operation is possible with EUS and EUS-guided FNA. Our study suggests that applying this staging strategy before and after neoadjuvant therapy might help choose and predict a cohort that might benefit from additional operations after neoadjuvant therapy.
Our single-center, nonrandomized, retrospective study is not without limitations. Follow-up data were available in only 92% of the patients. In addition, treatment variability during a 5-year period could have reflected in the management of patients over time. Malignant confirmation of CLNs was possible only in 80% of the cases in this study. It is safe, however, to assume that most CLNs imaged by EUS are malignant [7, 21]. We have previously reported that EUS is superior to CT scan in detecting CLNs. In addition, compared with operations, the sensitivity, specificity, positive predictive value, and negative predictive value of EUS in detecting CLNs were 72%, 97%, 95%, and 82%, respectively. Most false-negative patients were in stage T3 and had microscopic nodal involvement at operation. Once a CLN is identified, EUS-FNA confirms positivity in 88% [8].
Because of the high number of patients studied, we were able to draw important conclusions about the role of EUS in patients with ECA. In addition to being an important modality for staging ECA, EUS provides valuable information on prognosis and long-term outcomes in these patients. In particular, patients with CLN involvement were more likely to have worse survival than patients with no CLNs. Future randomized trials assessing the role of EUS and EUS-guided FNA before and after neoadjuvant therapy are needed, especially in high-risk patients with CLN involvement.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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The difficulty in our institution with EUS with a celiac access is that with anyone who has a T3 or T4 tumor, the endoscopists have a difficult time getting the scope down the esophagus and actually imaging the celiac axis, but yet in your study you had more success in dilating patients and getting down there. Did you have patients who were in stage T3 and T4 in whom you really could not assess the celiac axis?
Secondly, I know this was not a prospective study, but in your experience, how did the finding of a positive celiac node affect whether the patient received induction therapy? what percentage of patients in your study received induction therapy?
I support your idea about using this information to evaluate induction therapy. How would you use a positron emission tomography (PET) scan if PET scan were available? If a PET scan was positive in the celiac axis, would you use that as histologic evidence or would you insist on a biopsy? Currently, PET scans are approved for only five indications and esophageal cancer is not one of them. Yet, of all malignancies, esophageal cancer probably has the best utilization of PET for metastatic disease. What is your feeling about PET versus the ability of FNA to obtain histologic diagnosis?
And, once again, I really enjoyed your paper.
DR REED: Thank you. Let me answer those three questions first. We have a very aggressive group of gastroenterologists, and despite what has been stated in the literature, we have a less than 10% rate of not being able to access the celiac axis with the endoscope. We are very aggressive, as I noted, about dilation, with 34% of our patients requiring dilatation.
The finding of celiac axis lymph nodes would for us mean that patients would receive induction therapy. We recommend induction therapy for any patient who has a T3 lesion, an N1 lesion, or an M1a lesion. However, we are beginning to use the EUS-FNA technique to look at the results of our induction therapy. If we give induction therapy, we repeat the EUS. If the celiac lymph node is still positive, we would not at this point recommend an operation, because we do not believe, based on our findings, that we are helping that patient by having him or her undergo surgery.
And your final question about PET, at this point if we had a PET scan that showed positivity in the celiac axis, we would then confirm it. PET positivity would make us all the more eager to confirm, using the EUS/FNA, that lymph node was positive. We also agree with you that PET is probably the best way at this point to look for metastatic disease with esophageal cancer. As you know, the problem with PET and a tumor is that it is difficult to look at N1 disease with a PET scan because the tumor and the peritumor lymph nodes blend together. So we do not think PET will be as useful for T staging as EUS is.
DR JOE PUTNAM, JR (Houston, TX): I enjoyed your paper very much. At our institution we are seeing about 85% of our patients with distal esophageal adenocarcinoma, yet in your series only about 50% of the patients had adenocarcinoma. Were you able to make any differentiation between those patients with squamous cell cancer and those patients with adenocarcinoma with regard to the celiac nodal involvement?
DR REED: As you know, we continue to have a cohort of squamous cell carcinoma in Charleston, South Carolina, although we have finally broken the 50% mark recently and are seeing more adenocarcinomas each year. As long as the tumor is distal, we have not found much of a difference in involvement of the celiac axis. However, I should tell you that obviously squamous cell is more frequent in our midesophageal lesions than our distal lesions. But we are seeing, like everybody else in the United States, a rising incidence of adenocarcinoma.
DR DANIEL L. MILLER (Rochester, MN): I had a similar question as Dr Putnam. To follow up on your answer about adenocarcinoma of the esophagus. I am still confused on your definition of positive celiac nodes. When you say you have celiac axis nodal involvement, is that just any node larger than 5 mm or is that confirmed histologically? Are you excluding from possible surgery those patients with lymphadenopathy who do not have histologic confirmation? I think histologic confirmation is very important. I wondered if you could clarify that issue for us.
DR REED: Okay. Our group has shown that if you have a lymph node in the celiac axis that is larger than 5 mm, in almost 100% of cases that patient has involvement of the celiac axis. We have looked at both groups. The survival curves you see were, one, that if they had just EUS-detected celiac nodes, second, with a subgroup that we actually biopsied. Now, having said that, if you cannot biopsy the celiac axis lymph node but you see the lymph nodes, again, we would not say they could not have an operation but we would offer them induction therapy first. Our thinking is that if you are going to withhold surgery based on that, you must have a biopsy that is either positive or negative. So we would not tell patients they could not have therapy based on just EUS detection, but our experience is that if you see that enlarged lymph node, it is almost certainly positive.
DR MILLER: Just one last question. How many of these patients could have had significant lymphadenopathy related to a reactive process such as dilatation? I know a few times that we have been referred cases from elsewhere and they have not had EUS but have been dilated once or twice before they come to us for surgical treatment and the EUS shows significant celiac axis lymphadenopathy. What is the false-positive rate at your tertiary center after the patients have undergone other diagnostic and therapeutic procedures before coming to you for treatment?
DR REED: False-positive findings are rare. We recently had a patient that had fairly impressive celiac lymphadenopathy that we biopsied and the results were negative. It really surprised me, so we actually brought him back and rebiopsied him and again it was negative and indeed at surgery he was negative. So we are very confident when we biopsy those nodes, if they are negative, then we would then go ahead and offer that patient surgery.
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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