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J Thorac Cardiovasc Surg 2003;126:1121-1127
© 2003 The American Association for Thoracic Surgery
General thoracic surgery |
a Department of Thoracic Surgery, University of Leuven, Leuven, Belgium
b Department of Pathology, University of Leuven, Leuven, Belgium
c School of Public Health, Biostatistical Centre, University of Leuven, Leuven, Belgium
Read at the Eighty-second Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-8, 2002.
Received for publication June 10, 2002; revisions received July 22, 2002; revisions received April 27, 2003; accepted for publication June 9, 2003.
* Address for reprints: Dr T. Lerut, Catholic University Leuven, Department of Thoracic Surgery, UZ Gasthuisberg, Herestraat 49, Belgium
Toni.Lerut{at}uz.kuleuven.ac.be
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Abstract |
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MATERIALS AND METHODS: One hundred ninety-five consecutive patients with T3 adenocarcinoma of the distal esophagus and gastroesophageal junction between 1990 and 1999 were studied. All patients underwent primary R0 esophagectomy. The mean number of resected nodes per patient was 36.9. Survival was analyzed according to intracapsular and extracapsular involvement.
RESULTS: In N0 patients 5-year survival was 57% and 9-year survival was 38.7%. In patients with positive nodes these figures were 26.2% and 18.1%, respectively (P = .0069). Intracapsular and extracapsular node involvement showed 5- and 10-year survival of 40.9% and 21.7% versus 18% and 15.7%, respectively. There was no significant difference in 5- and 10-year survival between N0 and intracapsular node involvement (P = .43). However, there was a significant difference in survival between N0 and extracapsular node involvement (P = .002) and between intracapsular and extracapsular node involvement (P = .0001).
CONCLUSIONS: This study shows a significant difference in survival according to whether lymph node involvement was intracapsular or extracapsular. Patients with intracapsular lymph node involvement have similar survival rates as N0 patients. Extracapsular lymph node involvement is a bad prognostic factor, independent of the number of involved lymph nodes. The number of involved lymph nodes has an additive negative effect. These data may have an impact on treatment strategies.
More recently, attention has been paid to micrometastatic lymph node involvement by using immunohistochemical staining techniques. The prognostic relevance of micrometastasis, however, is not clear because of conflicting results between different studies.3-5
However, little or no attention has been paid to the prognostic value of the presence or absence of extracapsular lymph node involvement. Yet its relevance as a negative prognostic factor has been well documented in several other types of cancer (eg, hypopharynx, stomach, breast6-8) and may have an impact on therapeutic strategy.8
We therefore studied the prognostic significance of the mode of lymph node involvement according to whether it was intra- or extracapsular. The study specifically focused on patients presenting with adenocarcinoma of the esophagus and GEJ9 because of the rising incidence of adenocarcinoma (currently the most frequent type of tumor).
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Materials and methods |
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Survival was analyzed according to intracapsular (IC) or extracapsular (EC) extension. Patients with involvement of at least 1 EC lymph node were assigned to the EC group, whereas patients with positive lymph nodes without evidence of EC breakthrough were assigned to the IC group.
The surgical technique has been described elsewhere in detail. In brief, a left thoracophrenotomy was performed with a wide peritumoral resection combined with extensive lymphadenectomy of the upper abdominal compartment, so-called "DII resection," and posterior mediastinum was performed in all patients. Bilateral cervical lymphadenectomy was performed in 68 patients (35%).
Lymph nodes were fixed in formalin and stained with hematoxylin and eosin. Lymph nodes have an investing capsule. Afferent lymphatic vessels penetrate the convex surface of the gland and drain into the subcapsular and medullary sinus. Once in the lymph node, tumor cells will adhere to and proliferate in the sinuses (IC); with time, tumoral expansion will outgrow the lymph node and extend beyond the capsule (EC). A reexamination of lymph node specimens was performed by 1 of the authors and responsible pathologist (N.E.).
Statistical analysis
Univariate analysis by proportional hazard model was performed for all node-positive patients. Log-rank test and P values are reported. Cox regression analysis was used to verify the effects of different covariates and factors on survival. This was done for each predictor separately as well as for combinations of predictors.
Hazard ratios and their 95% confidence intervals are reported. To determine the functional form to be used for a given covariate (the number of positive nodes) to best explain its effect on survival through a Cox proportional model, the Martingale residuals of a Cox model without that covariate are plotted against that covariate. A smoothed fit of the scatter plot is then added, giving an indication of the functional form.11
Survival statistics were obtained by the Kaplan-Meier method.12,13 All analysis were performed with the statistical packages SPSS (version 10) and SAS (version 8.01). The alpha level was set at 5%.
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Results |
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Univariate analysis was performed in all patients with positive lymph nodes (Table 1). Lymph node status (P = .0069) and EC lymph node involvement (P = .00001) were the 2 parameters with a highly significant prognostic value. Five- and 10-year cancer-specific survival of N0 patients was 57% and 38.7%, respectively. For N+ patients the figures were 26.2% and 18.1%, respectively (Figure 1). Calculating survival according to IC versus EC node involvement showed 5- and 10-year survival of 40.9% and 21.7% versus 18% and 15.7%, respectively (Figure 2). There was no significant difference between pN0 and IC involvement (P = .4334). The difference between pN0 versus EC (P = .0002) and IC versus EC (P = .0001), on the contrary, was highly significant. The effect of intra- versus extracapsular lymph node involvement on survival is furthermore highlighted (P = .01) in the subgroup of patients with involvement of only a single positive lymph node, where a 5-year survival rate of 85.7% for IC involvement is noted versus 33.3% for EC involvement (Figure 3).
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12. Once the number of positive nodes is higher than 12, the risk does not appear to increase anymore. To capture this trend, the effect of the number of positive nodes is entered into the Cox model as a linear spline with a knot at 12 nodes. This implies that the effect of the number of nodes is separated in 2 intervals: an effect in the range of 0 to 12 nodes, where there is a cumulative negative effect on survival for each added lymph node, and an effect in the range of >12 nodes, where there is no further effect on survival.
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In a second step the significant variables of the additive model (Table 2) were extended with the other covariates from the univariate analysis. This was done predictor by predictor, due to the large number of predictors. The only aim of this extension was to verify if the obtained model still holds when correcting for the influence of another variable. No further significant effects were found in the examined covariates. The ranges for the additive model are reported (Table 3).
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Discussion |
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Other groups have clearly demonstrated that the equation is not that simple. In fact, it seems that both number of involved lymph nodes and location of involved lymph nodes have a major prognostic impact as well.20-22
From their studies it appears that a limited number of lymph nodes (ie, less than 4 to 6 according the different studies) carry a relative good prognosis with a significantly better survival as compared with a higher number of positive nodes. Therefore, some groups prefer the use of lymph node ratio rather than absolute numbers.20 Furthermore, it seems that if lymph node involvement is confined to the peritumoral region, prognosis is significantly better than if lymph node involvement is located in more distant lymph nodes.21
Because a substantial number of patients with pN0 disease will still die of a recurrent metastatic disease, much attention has been paid to the use of immunohistochemical staining techniques to detect micrometastasis on routine hematoxylin and eosin staining in patients with otherwise N0 disease.3-5 Some studies have indicated a negative impact in patients showing micrometastasis4; others did not find any difference in outcome.3
Surprisingly, despite the well-known effect of extracapsular lymph node involvement in other cancers (eg, stomach, hypopharynx, breast6-8), little attention has been paid to this finding in cancer of the esophagus and GEJ.
Tachikawa and colleagues23 suggested that prognosis is significantly worse in patients with extracapsular lymph node involvement in esophageal squamous cell carcinoma irrespective of other pathologic factors such as depth of invasion, lymphatic invasion, or number of involved nodes. In their study, however, the population consisted of patients with a mixture of different therapeutic regimens (ie, induction therapy, surgery alone, surgery followed by adjuvant therapy) and also of different depths (T stage) of tumor.
The present study deals with a homogeneous cohort of T3 adenocarcinoma treated by primary surgery and R0 resection. From our analysis it appears that extracapsular lymph node involvement is an independent negative prognostic factor. Its negative impact in our experience seems to equal the negative impact of distant lymph node metastasis (M1lym).
On the other hand, intracapsular lymph node involvement seems to have a prognosis that is near that of N0 patients, with 5- and 10-year survival of 40.9% and 21.7%, respectively.
The number of involved lymph nodes, up to 12, also has an additive negative impact on survival. The only cutoff point that was found was around 12 positive nodes, after which no significant increase in risk was noted.
These findings may have important consequences in determining therapeutic strategies, as the EC group consisted of a significant subset of patients, 102 (52%). It seems therefore of paramount importance to be able to discriminate between this group by clinical staging. However, it is quite difficult to stage adequately lymph node involvement even in the era of EUS and positron-emission tomography (PET). In our series, even after introducing PET scan, accuracy of lymph node staging was only 73.8%. Moreover, it seems at this point that there is no clinical staging modality that can discriminate between IC and EC. The only data available are on the use of nuclear magnetic resonance, which shows no benefit whatsoever.24
From the findings in the present study, it is difficult to draw any conclusions as to the therapeutic implications. However, one could speculate that patients showing intracapsular node involvement should not be treated by induction therapy as only half of such patients will show measurable response, thus jeopardizing the chances of the nonresponders or minimal responders by losing precious time or by higher postoperative mortality. On the other hand, patients with a limited number of positive nodes but with extracapsular involvement may be better candidates for induction therapy. Whether invasive staging methods like laparoscopy and video-assisted thoracoscopic surgery will enable us to easily detect extranodal involvement remains an open question. This may indeed require extensive mobilization and extensive node sampling in a great number of these patients. For these reasons it seems that the debate between proponents of induction therapy in all patients with any positive nodes and the advocates of radical primary surgery remains open, and the findings of negative prognostic impact of extracapsular lymph node or conversely the good survival figures in patients with intracapsular lymph node involvement may even further complicate the decision-making strategy toward initiating induction therapy.
Because of the difficulty of discrimination by clinical staging between intracapsular and extracapsular node involvement, it may be worthwhile to investigate the systematic use of adjuvant therapy, preferentially chemoradiotherapy, in patients with extracapsular node involvement, especially in adenocarcinoma. Indeed, recent studies have indicated a significant survival advantage of such regimens in gastric adenocarcinoma, including GEJ tumors and adenocarcinoma of the distal esophagus, for patients who appeared to have lymph node involvement at pathologic staging.25,26 It may well be that patients with extracapsular lymph node involvement will be a subset of patients benefiting from such adjuvant regimen.
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Discussion |
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Dr F. Henry Ellis and I, in a review of over 450 patients at the Lahey Clinic, found that lymph nodes were the single most important prognostic indicator in patients with esophageal cancer.1 Moreover, we, too, found that the number of involved nodes was important. Dr Tom Rice has also shown the paramount importance of lymph node spread in esophageal cancer. He has demonstrated as well the very important relationships between the T and N classifications. Finally, Dr Skinner and later DeMeester have demonstrated the significance of lymph node positivity and the importance of the numbers of lymph nodes involved and proposed a new so-called "WNM classification" that included an N1 and N2 classification.
It seems therefore that we have 2 challenges regarding staging of esophageal cancer: first, to modify the existing lymph node N stage to better reflect the significance of multiple lymph node involvement and consider celiac and cervical lymph nodes, which are being resected together with other lymph node stations; second, to optimize the methods of staging lymph nodes in esophageal cancer patients' pretreatment.
I have 3 questions for you, Dr Lerut: (1) Do you have data on lymph node involvement, meaning intracapsular versus extracapsular, by the lymph node level according to the lymph node map, or at least can you define them by chest involvement, neck involvement, and abdomen involvement? (2) This was a highly selected group of 195/429 patients with adenocarcinoma undergoing R0 resections at your institution. How did the other 236 patients fare? (3) Finally, and practically, how should we use the information presented? If EUS–fine-needle aspiration is negative, should we proceed with a thoracoscopic and laparoscopic lymph node staging as is done at University of Maryland on protocol? This would seem the only way to allocate neoadjuvant therapy; otherwise we are left only with the choice of doing adjuvant therapy, as you mentioned.
I enjoyed the presentation. Your group has set an attainable gold standard for lymph node dissection and survival in esophageal cancer.
Dr Lerut. Thank you very much, Dr Krasna, for your nice words and comments. I think we at least have in common that we both are quite frustrated with the actual staging system. As to your first question on the data of intracapsular and extracapsular lymph node involvement by each lymph node station, we did not do that study, because, first of all, it is a very tedious study, and, second, we felt that that would fragment the patient material too much, which probably would result in inadequacy in the interpretation of the results. But I roughly can say that for the lymph node involvement in the neck, we had about 15% positive lymph nodes in the neck, about 30% positive lymph nodes in the chest, and over 50% positive lymph nodes in the abdomen, which I think is the common repartition, except for, of course, the third field, which is something that few centers are doing, but those 15% were clearly unexpected or unforeseen lymph nodes that were involved. As to your second question on how the other patients fared, the overall survival for the whole group was 39% at 5 years. We had an 83% R0 resection rate. There is a distinction between the Barrett's and the non-Barrett's, the Barrett's being mainly the distal esophagus, with roughly about 50% 5-year survival; for the GEJ the 5-year survival was at 35%. Overall, the lymph node negatives for the 2 groups together, Barrett's and non-Barrett's, were about 70% 5-year survival, and for the GEJ there was 100% at stage I, and I think there was something like 75% at stage II and about 30% at stage III, 5-year survival. The third question, of course, is an open question, how should we use these results that have been shown. Honestly, I do not have the answer myself. It is a very troublesome finding in terms of using it for our indications for commencing induction therapy, because I have the feeling that with 1 to 6 positive lymph nodes with intracapsular lymph node involvement, there is probably no need for induction therapy, as they fare as well as you can get with induction therapy. The problem now is how do we access intracapsular or extracapsular involvement during clinical staging, because fine-needle aspiration can only say yes or no involvement. The answer may be in the preoperative staging with thoracoscopy and laparoscopy, but then you need to do it thoroughly, and you showed in your multicenter study that this is difficult. As I recall, it was possible to sample subcarinal and left gastric, which are easier to access, in about 70% of all the groups. So I think that will be a difficult job to do, and perhaps you are the only one in the world who can do it properly. So I think our first concern should be to validate these results by other centers. I think that is what we need to do. And then I think we have to perhaps make recommendations of changing the TNM staging system.
Dr Alan G. Casson (Halifax, Nova Scotia, Canada). Dr Lerut, I also enjoyed your presentation. This series includes adenocarcinomas of the esophagus, type I, and also the esophagogastric junction, type II. Could you tell us exactly how many were in each group? Second, did you look at patterns of metastasis between each group? Did you observe any extracapsular metastasis macroscopically at surgery or was this purely a histologic study?
Dr Lerut. Thank you, Dr Casson. The repartition of how many, I think, if I recall well, it was roughly a 50/50 representation, but I am not so sure about the exact numbers. As to the pattern of lymph node metastasis, obviously there is a higher incidence of abdominal positive lymph nodes the more you go downward with the location of the primary tumor, and there was, of course, the surprising finding of having the positive lymph nodes in the neck with the patients with distal esophageal adenocarcinoma, although we also had in the T3 setting some patients with GEJ tumors who had positive lymph nodes in the neck. The study was in fact a histological study, it was not a macroscopic study, although it is obvious that some of those lymph nodes can be seen with the naked eye. In relation to the last question of Dr Krasna, the introduction of PET scan of course may reveal some of those bigger lymph nodes that obviously have extracapsular lymph node involvement. We did a small study, which is not ready yet, trying to find out whether PET is indeed helping us discriminate between extracapsular and intracapsular, but unfortunately the preliminary results are showing that this is not the case.
Dr James D. Luketich (Pittsburgh, Pa). I really enjoyed your talk, Dr Lerut, and I admire your ability to get your pathologists to work on retrospective specimens to that degree. We have a hard time doing it prospectively.
My question is, the intracapsular versus extracapsular, did you note any difference in size, in millimeters of the lymph nodes? And by EUS, with your newer US technologies, are you seeing the ability to begin to define this preoperatively by endoscopic ultrasound?
Also, along those same lines of preoperative staging, there have been 1 or 2 very provocative papers on C11 choline as being much more sensitive and specific for predicting lymph node involvement by PET scanning with this new tracer. Do you have any experience with that?
I would also like to make a comment. We just published a paper in Clinical Cancer Research on our node-negative patients, and by reverse transcriptase-polymerase chain reaction positivity alone, we were able to predict recurrence in a very high proportion, and I wonder what molecular studies you are doing on your node-negative patients.
Dr Lerut. Thank you, Dr Luketich. As to the first question, that's a tough question. First of all, let me pay my tribute to my pathologist, who really is a highly motivated individual who wants to do all this work, but I couldn't ask her to measure the size as well, because she had to go through something like, as you said, 6000 or more lymph nodes.
As to the potential of EUS to discriminate, I think this is new information and we have been discussing it with our people who are doing the echoendoscopy. I think we have to learn whether it is possible indeed to make this discrimination.
What you said about the PET scan, C11 choline, we have used that in our center, but that did not show any significant information as far as I can recall. I have no data on immunostaining or other molecular biology techniques for the lymph node negatives at this moment. This is a project that is on the way, but I have no data on that.
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Footnotes |
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References |
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