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J Thorac Cardiovasc Surg 1999;117:16-25
© 1999 Mosby, Inc.
GENERAL THORACIC SURGERY |
From the University of Southern California, Department of Surgery, Los Angeles, Calif.
Read at the Seventy-eighth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 3-6, 1998.
Received for publication May 8, 1998. Revisions requested July 6, 1998. Revisions received July 29, 1998. Accepted for publication Aug 5, 1998. Address for reprints: Jeffrey A. Hagen, MD, University of Southern California, Department of Surgery, 1510 San Pablo St, Suite 514, Los Angeles, CA 90033-4612.
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Abstract |
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Introduction |
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1 Adenocarcinoma has replaced squamous cell carcinoma as the most common esophageal malignancy, and the incidence of adenocarcinoma has risen faster than that of any other malignancy in the United States. 2 Barrett's esophagus, a known complication of gastroesophageal reflux disease, has been shown to give rise to adenocarcinoma of the distal esophagus and gastroesophageal junction. This observation links one of the most deadly malignancies known to mankind to the most common upper gastrointestinal disorder in Western civilization. Recognition of this relationship has resulted in an increased detection of early esophageal cancers through more prompt endoscopy of patients with reflux symptoms and the performance of surveillance endoscopy in those with Barrett's esophagus.
Management strategies for patients with early esophageal cancers are evolving. In the past, our therapeutic strategy was based on treatment of patients with squamous cell carcinomas, most of whom had advanced disease. As a result, Akiyama, 3 Hagen, 4 Altorki, 5 and their colleagues championed the application of the classic principles of surgical oncology in their therapy, namely, complete resection of the primary tumor and systematic lymph node dissection. The increasing prevalence of early adenocarcinoma has led to questioning of the extent of operation required for cure in patients with early disease and has led to the use of nonoperative therapeutic techniques such as photodynamic therapy (PDT). Before reductions in the extent of surgery or alternative therapies are accepted, it is imperative that the extent of disease in patients with early tumors be known. It would be irrational for physicians or surgeons who emphasize the importance of early detection as a major factor in the cure of cancer to encourage therapy that does not remove all of the disease present.
To characterize the extent of disease present in early adenocarcinoma of the esophagus or gastroesophageal junction, we reviewed our experience with en bloc esophagogastrectomy and complete mediastinal and abdominal lymphadenectomy in patients with tumors limited to the esophageal wall. On the basis of the data obtained, we sought to characterize the extent of dissection required to perform an R0 resection and to evaluate the applicability of nonoperative therapy, such as PDT, for patients with early tumors.
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Methods |
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Evaluation of the primary tumor
All patients had a barium roentgenogram and an endoscopic examination of the upper gastrointestinal tract. Those with a visible tumor also had a computed tomographic scan of the chest and abdomen and endoscopic ultrasonography at 7.5 to 12 MHz.
Operative approach
All 37 patients in the study group underwent an en bloc esophagogastrectomy with a systematic mediastinal and abdominal lymphadenectomy. The steps for performing the procedure are shown in Fig. 1. 6 The operation begins with an exploration of the abdomen to assess the extent of the primary tumor and the status of the regional lymph nodes. In the absence of gross transmural tumor extension and multiple regional lymph node metastases or microscopic involvement of the porta hepatis or subpancreatic lymph nodes, the abdomen was closed and the patient was prepared for a right thoracotomy.
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The abdominal dissection included removal of the proximal two thirds of the stomach, the greater omentum, the spleen, the splenic artery along with its surrounding fibroareolar tissue, the nodes in the porta hepatis along the hepatic artery, around the celiac axis, and the retroperitoneal lymph node–bearing tissue. In most patients, gastrointestinal continuity was established by isoperistaltic colon interposition.
In the comparison group, a transhiatal esophagectomy was performed according to previously described techniques. 7 The operation included an abdominal lymph node dissection similar to the en bloc operation, with the exception that the spleen and splenic artery were not resected in the transhiatal group. As many mediastinal lymph nodes were removed as this approach would allow.
Analysis of the resected specimens
Two experienced pathologists examined the resected specimens. The location of the primary tumor was recorded. Tumors that were clearly located in the tubular esophagus, above the gastric rugal folds, were classified as being distal third esophageal cancers. The remaining tumors were classified as gastroesophageal junction tumors. A detailed histologic evaluation was performed to identify the depth of invasion of the primary tumor and to search for areas of intestinal metaplasia (Barrett's mucosa) adjacent to the tumor. This was accomplished by sectioning the entire length of abnormal mucosa longitudinally, in representative strips, with a 5-µm section stained with hematoxylin and eosin for microscopic examination. All lymph nodes removed were identified according to the lymph node stations shown in Fig. 2. All lymph nodes were formalin fixed and cut into two 5-µm sections for staining with hematoxylin and eosin. Local nodes were defined as those in close proximity to the primary tumor, namely, the parahiatal, lesser curvature, greater curvature, and left gastric artery node groups.
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Follow-up
The operating surgeon followed up all hospital survivors at 3-month intervals for the first 3 years and every 6 months thereafter. The median duration of follow-up was 24 months (range 3-203 months). Follow-up evaluation included a history and physical examination, serum and liver chemistry panels, a carcinoembryonic antigen level, and computed tomographic scans of the chest and abdomen. All surviving patients were either seen in person or contacted by telephone within 3 months of the preparation of this manuscript.
Statistical analysis
Either 
2 or Fisher's exact tests were used for comparison of proportions. Continuous variables were compared by means of the Mann-Whitney U test. Survival probabilities were calculated by the method of Kaplan and Meier. 8
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Results |
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A total of 1631 lymph nodes were examined. The median number of lymph nodes removed per patient after systematic mediastinal and abdominal lymphadenectomy was 41 (range 18-82). Involved lymph nodes were identified in 15 patients (41%). A comparison of the prevalence of regional lymph node metastases in tumors of various depths is shown in Table I. The frequency of nodal metastases increased significantly with increasing tumor depth, 80% of patients with intramuscular tumors having involved nodes. The involved nodes in patients with tumors limited to the mucosa and submucosa were confined to the local node groups in all but 1 patient. In contrast, distant lymph nodes were involved in 5 of 10 patients with muscular invasion (2 = 11.8, P = .0027). In addition to an increased frequency of involved regional lymph nodes and their location at more distant sites, patients with intramuscular tumors also tended to have a greater number of involved nodes (Table I). Celiac node metastases were present in 2 patients with intramuscular tumors, and in both patients this was the only site of node metastases. One of the patients died of systemic recurrence at 29 months, but the second is alive and free of disease more than 2 years after resection. The number of patients with involved lymph nodes and the locations of the nodes are shown in Fig. 3.
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Discussion |
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These patients represent a dilemma in that our current treatment strategies are based on experience with more advanced disease, observations that may not be valid in patients with early-stage tumors confined to the esophageal wall. This has led to the recommendation of less aggressive surgery for patients with early tumors and even the proposal that nonoperative treatment options are appropriate. 9-11
The value of a complete (R0) resection as a predictor of long-term survival has been repeatedly shown. 12-14 For the extent of resection necessary to achieve R0 status to be clarified, both the frequency and the location of involved lymph nodes must be appreciated. This can be accomplished only through an experience such as that reported here, with systematic resection of all potentially involved regional lymph nodes. In our experience, 93% of patients with tumors limited to the mucosa are free of regional lymph node metastases. Once the tumor penetrates the muscularis mucosa, 50% of the patients have involved lymph nodes. Even though nearly all of these nodes are confined to local node groups, their removal becomes a chance phenomenon with a transhiatal dissection (Fig. 3 and 5). When the tumor invades the muscularis propria, 80% of the patients will have regional lymph node metastases, with the involved nodes commonly in locations beyond the confines of a transhiatal dissection. The limitations of our preoperative staging techniques for an endoscopically visible tumor prohibit the accurate differentiation between those that are limited to the mucosa, extend into the submucosa, or invade the muscularis propria. 15 Consequently, to confidently achieve an R0 resection of an endoscopically visible tumor requires an en bloc resection with a systematic mediastinal and abdominal lymphadenectomy. This conclusion is supported by our finding that the prevalence of node metastases is dependent on the extent of dissection. Patients with the compromised mediastinal lymph node dissection predicated by the transhiatal approach have fewer involved nodes, and the relationship between tumor depth and node status is lost. To explain this observation, either our selection process would have favored patients with less advanced disease for transhiatal resection or involved nodes were left behind. The latter seems more likely in that the distribution of tumors of various depths was similar in those who had an en bloc or transhiatal dissection (Table II); therefore it is likely that the nodal involvement would be similar. Furthermore, we have previously shown the superiority of an en bloc esophagectomy 4in patients with early esophageal cancer, an outcome one would expect if the transhiatal dissection left involved lymph nodes behind.
Rice and associates 16have reported a similar relationship between tumor depth and lymph node metastases after transthoracic esophagectomy, although the absolute values for the prevalence of node metastases in their series was slightly lower than that which we have reported. Just as we have observed, these authors have demonstrated a clear relationship between the completeness of node dissection and the likelihood of involved nodes. Their series differed from ours in that they included both adenocarcinoma and squamous cell cancers, and the magnitude of the operation and lymph node dissection was less. Both their findings and ours indicate that to achieve an R0 resection with confidence in patients with endoscopically visible tumors confined to the esophageal wall requires an en bloc resection with a systematic mediastinal and abdominal lymphadenectomy.
The depth of tumor penetration into the esophageal wall and the frequency of nodal metastases becomes critically important when considering alternatives to resection, such as PDT. Nodal metastases, if present, would remain untreated by this and other strategies that focus only on ablation or removal of the mucosa. In patients with tumors limited to the mucosa, PDT and endoscopic mucosal resection can achieve survival in excess of 90%. 17,18 Recently, patients with T1 tumors (including both intramucosal and submucosal tumors) have been proposed as candidates for these types of nonoperative therapy. We have shown that 50% of T1 tumors that extend into the submucosa will have evidence of lymph node metastases when a complete node dissection is performed. Although intramucosal tumors might be considered for such an approach, given the very low incidence of involved nodes in this subgroup, problems exist in accurately identifying patients with tumors limited to the mucosa with presently available techniques. Endoscopic ultrasonography, while accurately identifying T3 and T4 tumors, is much less accurate in differentiating between T1 and T2 tumors and is incapable of subclassifying T1 tumors into intramucosal and submucosal subgroups. 15,19 Advocating nonoperative therapy for patients with T1 tumors exposes a number of them to the risk of incomplete destruction of their primary tumor and the persistence of involved lymph nodes. Compromising the benefit of early detection in curing this lethal disease needs to be seriously weighed against the benefits of avoiding a surgical procedure by technical advances that risk incomplete removal of the tumor.
In 3 of the 6 patients with tumor recurrence during follow-up, the recurrence was in the paratracheal and cervical lymph nodes. This fact could be used as an argument for extending the dissection to include these node groups (so-called 3-field dissection). To date, however, we have not used this technique in patients with early adenocarcinoma of the esophagus. Whether the potential benefit of the extended resection is worth the associated increased morbidity in patients with tumors limited to the esophageal wall (only 8% of whom have recurrence in those node groups) remains to be proven.
The final question to be addressed is whether an R0 resection has a survival benefit in patients with early disease. To answer this question formally would require a randomized prospective trial, but some inferences are possible on the basis of the experience reported here. The long-term survival of 61% after en bloc resection in patients with tumors confined to the esophageal wall and lymph node metastases would argue strongly that an R0 resection was beneficial for their survival. Our long-term survival in the setting of involved nodes is impressive when compared with the survival data recently reported by Sabik and associates 20; in their series no patients with involved nodes survived long term. If the benefit of an R0 resection is accepted, then our observation that transhiatal resection leaves residual disease untreated strongly supports the need for a more complete nodal dissection in patients with early disease.
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAppendix: DiscussionReferences |
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Appendix: Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAppendix: DiscussionReferences |
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As soon as a carcinoma breaches the basement membrane and invades the lamina propria, it encounters lymphatics. With deeper invasion, there is an increasing exposure to lymphatics and a potential for extensive longitudinal submucosal lymphatic extension and lateral metastases to regional lymph nodes and systemic lymphatics.
We have recently reported our experience with 359 consecutive patients undergoing esophageal resection only for esophageal carcinoma. The survival of patients with regional lymph node metastases was 7% at 5 years. We agree with Dr Hagen and his colleagues that depth of tumor invasion is the best predictor of regional lymph node metastases. Compared with a patient with T1 disease, a patient with T2 disease is 6 times more likely to have N1 disease, a patient with T3 disease 23 times, and a patient with T4 disease 34 times.
It is crucial for pathologic staging and therapy that a complete lymphadenectomy and analysis of all resected lymph nodes be done. I have 2 questions and 1 comment.
First, Dr Hagen, could you please elaborate on the pathologic analysis of resected nodes, and were any special stains used to enhance the detection of metastases?
Second, in the best surgical candidates, you chose en bloc esophagectomy, lymphadenectomy, and colon interposition; in poor-risk candidates, you used a transhiatal esophagectomy. The mortality rates in these 2 dissimilar groups were very similar. Could you comment on the morbidity and mortality associated with en bloc esophagectomy and colon interposition?
Finally, I believe this work is an important message to all physicians who treat esophageal carcinoma. The benefit of surveillance for early-stage disease will be lost in the patient with carcinoma limited to the esophageal wall if therapeutic modalities provide incomplete ablation of the cancer. Esophagectomy with lymphadenectomy is the gold standard against which all other forms of treatment must be measured.
Dr Hagen. Thank you, Dr Rice, for your comments and questions. With regard to the pathologic analysis, we removed 1631 lymph nodes in these 37 patients. In this particular report we are dealing only with routine pathologic assessment of the lymph nodes by standard staining techniques. We have been looking recently at immunohistochemical studies done on lymph nodes, focusing specifically on patients who otherwise have N0 disease. Although a number of reports have appeared in the literature assessing the value of immunohistochemical staining of lymph nodes, most of these studies have been on uninvolved nodes in patients who have nodal disease elsewhere. It is hard to know exactly what that means.
In a study currently in progress, involving a series of patients who had no evidence of lymph node involvement after complete lymph node dissection, thus far about 20% have immunohistochemical evidence of lymph node metastases. Although we know the number of patients with involved nodes, on immunohistochemistry, what we do not know is what this means in terms of prognosis. With regard to the mortality and morbidity after the en bloc esophagectomy, the mortality in this series was about 5%, which is the same as the mortality rate for patients with more advanced tumors, but is about twice the mortality rate in esophagectomy and colon interposition for benign disease. The morbidity, however, is substantial, with 30% to 40% having some sort of complication that extends their hospital discharge. The average period of hospitalization in this series was about 14 days, which is longer than is typically seen after transhiatal esophagectomy. Nonetheless, most of these complications can be dealt with quite readily and rarely translate into mortality. As a result, if patient survival can be enhanced, I believe that the additional morbidity of an en bloc esophagectomy is worth risking.
Dr Mark J. Krasna (Baltimore, Md). I agree with both Dr Hagen and Dr Rice on the importance of lymph node staging in esophageal cancer. I would like to emphasize the location of the lymph nodes. Of interest is that some of the previous works by Akiyama, Sugarbaker, and Altorki (at last year's meeting of this Association) have shown a higher incidence of distant metastatic disease to lymph nodes than you reported this morning. This is an area that we must concentrate on, especially in light of some of the recent reports, including that by Dr Rice, of using combined modality therapy.
At our institution we have recently published a series of 39 patients in whom, using preresection lymph node staging, we were able to target distant lymph node spread that was otherwise undetected in 20% to 30% of the patients and target our radiation therapy field to a much higher level than we otherwise would have done in a trimodality protocol. Will you please comment on the importance of distant metastatic disease and where you think these patients will fit in the overall plan?
Dr Hagen. Thank you, Dr Krasna, for your questions. We identified only 6 patients with tumors confined to the esophageal wall with distant nodal involvement. Because the numbers are so small, it is hard to make any comparisons about whether that extent of tumor has any effect on recurrence. It is my sense, though, that all potentially involved nodes should be removed. This is based on the published evidence in a number of cancers, esophageal cancer included, which shows that one of the most important prognostic factors is achieving a complete (R0) resection. It is very hard to argue that if you do not remove all of the disease that may be present, at least if the only treatment is going to be surgery, you have accomplished curative therapy.
With respect to even more widespread lymph node disease, disease that might spread to the neck or the upper part of the chest, a number of people are investigating the so-called 3-field lymph node dissection. We have not chosen to do that, particularly in these patients with early cancer, for 2 reasons: First, these patients with very early cancers must have a vanishingly small number of nodes all the way up in the neck. We have decided that the additional morbidity is not warranted, given the small number who would be expected to benefit. Second, it is not clear, just what these nodes mean, that is, whether they represent local regional disease or whether they are more characteristic of metastatic disease. The American Joint Committee on Cancer Staging currently classifies these cervical nodes as metastatic disease, and I suspect that that is probably the way they should be viewed. If that is the case, then it is hard for me to accept an approach that involves surgical treatment for what appears to be systemic disease.
Dr Thomas M. Egan (Chapel Hill, NC). Your patients who underwent transhiatal esophagectomy had co-morbidities that might lead you to expect them to have a more adverse outcome in the long term. Can you share with us what the actuarial 1- and 2-year survivals were for your patients who had transhiatal esophagectomy as opposed to patients who had complete esophagectomy and colon interposition?
Dr Hagen. Thank you, Dr. Egan. The survival after transhiatal esophagectomy in this group was similar but slightly lower; it was about 15% lower overall at 2 years, when compared with en bloc resection. As I mentioned, 2 patients died of non-cancer-related causes in the en bloc group and 3 patients in the transhiatal group. As a result, although the patients are selected for operation on the basis of co-morbidity, the majority of patients in both series who died, did die with recurrent disease.
Dr Egan. But isn't the bottom line not how many lymph nodes you take out but how many survivors you have?
Dr Hagen. Yes. In this report we have a series that compares 37 patients after en bloc resection with 28 patients who underwent transhiatal esophagectomy. These are obviously small numbers. The ability of a study of this size to detect modest differences in survival is thus limited. In fact, that is precisely why we chose not to analyze survival. However, if we had reported a series of 100 or 200 patients, with a similar difference in survival, the 15% difference in survival would be significant. Obviously, such questions about the power of the study and speculation about the possibility of type II error are difficult. The major point is that it is very hard to make an argument that an operation that admittedly does not remove all of the disease that is present is, in itself, adequate treatment for the disease.
Dr Nasser K. Altorki (New York, NY). We showed a year ago that the mortality and the morbidity of radical resections are comparable with those of standard transthoracic resections. We have also shown that the staging in terms of the number of nodes per patient is higher in the radical resections than in the standard transthoracic resections. Now you have extended that to the transhiatal resections, and I think both of those observations are correct.
I am puzzled as to the reason for your continued selectivity in choosing 1 operation versus the other. We decided 6 or 7 years ago that we would pursue 1 approach rather than be selective to have a meaningful interpretation of the data; otherwise, one cannot escape that some patients are selected for a lesser operation.
My question relates to the depth of tumor invasion. We have performed nearly 60 3-field lymph node dissections for esophageal cancer, now almost a routine operation for us. I agree with you that submucosal cancers are not early cancers, they are advanced cancers, and the only issue here is how to select the intramucosal carcinomas, because those could conceivably be treated either nonoperatively or by a transhiatal resection.
How do you go about doing that selection? Do you use any modalities like endoscopic ultrasonography?
Dr. Hagen. Thank you, Dr. Altorki. This series represents a number of patients accumulated over about a 10-year period, and during that time period we have made the same observation that you have, that there does not appear to be as much difference, at least from the mortality standpoint, between the transhiatal and the en bloc esophagectomy. I do think the morbidity is a little higher with en bloc esophagectomy, but not alarmingly so. That has led to our being less selective in terms of the types of patients in whom we have done en bloc esophagectomy in more recent years.
With regard to the means of selecting these patients, I agree, if there was a way to identify with precision patients who had only mucosal disease, who had a very low incidence of nodal metastases, much less aggressive treatment could be offered to them. In fact, one might even argue that, since only 1 patient had a single diseased node, it might be possible to treat the mucosa alone by ablation techniques. The gastroenterologists would love that sort of conclusion. The problem is, we cannot do that right now. We do not have an accurate way to reliably differentiate between mucosal and submucosal tumors, and invasion of the submucosa is always a sign of significant locoregional disease.
One factor that we have recently identified as a means of identifying patients with very early tumors, likely confined to the mucosa, is the presence or absence of a visible lesion. Patients who have biopsy-proven cancer with no endoscopically visible mass, identified in the course of surveillance, are very likely to have mucosal disease. If the tumor does get into the submucosa, it is very early invasion, and the likelihood of lymph nodes being involved is quite low.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAppendix: DiscussionReferences |
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