Aims
To describe types of esophageal cancer, methods of selection for definitive treat- ment and the treatment itself.
Introduction
The epidemiology of esophageal carcinoma is currently changing dramatically in the Western world. In contrast to squamous cell esophageal cancer, the incidence of esophageal adenocarci- noma has risen exponentially during the past two decades. At many institutions in Europe and the North America esophageal adeno- carcinoma now outnumbers squamous cell esophageal cancer. In addition, adenocarci- noma of the distal esophagus is increasingly diagnosed at early stages because of a known precursor lesion and effective endoscopic sur- veillance programs. The marked differences between squamous cell carcinoma and adeno- carcinoma of the esophagus in terms of patho- genesis, tumor location, tumor stage at the time of presentation, tumor biology and characteris- tics of the affected patients have now signifi- cantly affected surgical practice [1].
Strategies for surgical treatment of squamous cell esophageal cancer, which are mostly based on the vast experience of Japanese sur- geons with extensive lymphadenectomy, can- not be applied uncritically to patients with
esophageal adenocarcinoma. A more discrimi- nate approach is required. Improvements in the treatment of esophageal cancer can thus be achieved by tailored therapeutic strategies which are based on the individual histologic tumor type, tumor location, tumor stage and consideration of established prognostic factors.
A clear classification of the underlying tumor, a knowledge of the prognostic factors, and a thor- ough preoperative staging are essential for the selection of the optimal therapeutic modality in a given situation [1].
Classification of Esophageal Cancer
According to Topographic Tumor Location and
Histologic Tumor Type
In many centers the topographic classification of esophageal cancer according to its location in the proximal, middle and distal third of the esophagus has been abandoned. A more practically oriented approach is based on a topographic anatomical assessment of the rela- tionship between the esophageal cancer and the tracheobronchial tree, i.e. a differentiation of tumors with and without contact to the trachea or main stem bronchi. This facilitates the selec- tion of the treatment strategy. While tumors 5
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Surgical Resection for Esophageal Cancer:
Role of Extended Lymphadenectomy
Hubert J. Stein, Jörg Theisen and Jörg-Rüdiger Siewert
located below the level of the tracheal bifurca- tion can frequently be resected with wide margins, an extensive resection of transmural tumors at or above the level of the tracheal bifurcation is usually prohibited by the proxim- ity to the tracheo-esophageal tree. The pattern of lymphatic spread appears to have its water- shed at the level of the bifurcation: the direction of lymphatic flow is primarily to the upper mediastinum and cervical region in patients with “suprabifurcal” tumors and towards the lower posterior mediastinum and celiac axis in patients with “infrabifurcal” tumors. Tumors located at the level of the tracheal bifurcation tend to metastasize in both directions (Figure 24.1).
While the vast majority of esophageal cancers located at or above the level of the tracheal bifurcation are of the squamous cell type, tumors in the distal esophagus today are usually
adenocarcinomas associated with areas with specialized intestinal metaplasia (the so-called Barrett’s esophagus), which is due to chronic recurrent reflux disease. Such tumors are also termed “Barrett’s cancer”. Since these tumors arise from within the esophagus, and thus require treatment as esophageal cancer, they need to be differentiated from other tumors arising at or below the esophagogastric junc- tion. The topographic/anatomical classification system of adenocarcinomas of the esopha- gogastric junction (AEG tumors) reported by our group [2] provides a clear discrimination of the various tumors. It is now increasingly used to guide the selection of the surgical approach.
Based on the anatomic location of the tumor center or, in patients with an advanced tumor, the location of the tumor mass, the following three tumor types are defined: Firstly, adeno- carcinoma of the distal esophagus (AEG type I tumors), which usually arises from an area with specialized intestinal metaplasia of the esopha- gus, i.e. Barrett’s esophagus, and may infiltrate the esophagogastric junction form above; sec- ondly, true carcinoma of the cardia (AEG type II tumors) arising from the cardiac epithelium or very short segments with intestinal metapla- sia at the esophagogastric junction; and thirdly, subcardial gastric carcinoma (AEG type III tumors), which infiltrates the esophagogastric junction and distal esophagus from below.
Prognostic Factors
The presence of distant metastases is the single most important prognostic factor in patients with squamous cell and adenocarcinoma of the esophagus. The median survival of such patients is in the order of 6–12 months irrespective of the location of the primary tumor and can not be prolonged significantly by any of the available therapeutic modalities.
In patients without systemic metastases a complete macroscopic and microscopic tumor resection (i.e. a R0 resection according to the Union Internacional Contra la Cancrum/
American Joint Committee on Cancer (UICC/
AJCC) guidelines) constitutes the most power- ful independent prognostic factor. The chance of achieving a complete tumor resection is dependent on the histology and the pT category (Table 24.1).
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Figure 24.1. Direction of lymphatic flow from the esophagus.In the subgroup of patients with a complete tumor resection, the lymph node status and the number of positive lymph nodes represent the major independent prognostic factors. The prevalence of lymph node metastases is depen- dent on the histologic tumor type and the pT category (Table 24.2). Compared to squamous cell esophageal cancer, lymphatic spread appears to start later in patients with adenocar- cinoma. In our experience with more than 250 resected early esophageal carcinomas, lymph node metastases were never found in adenocar- cinoma limited to the mucosa and were signifi- cantly less common in patients with pT1b esophageal adenocarcinoma as compared with pT1b squamous cell esophageal cancer (Table 24.2). The reason for this observation is unclear, but could be related to an occlusion of submu- cosal lymphatic channels due to the chronic underlying reflux diseases with repeated episodes of inflammation in patients with esophageal adenocarcinoma. In recent studies, an independent prognostic effect of the so- called “micro-involvement” of lymph nodes, which were negative by routine histology, was
demonstrated for patients with squamous cell carcinomas but not in patients with adenocar- cinomas [3].
On multivariate analysis the histologic tumor type also constitutes an independent prognostic factor. In an analysis of more than 1000 resected esophageal cancers, adenocarcinoma was asso- ciated with a significantly better long-term prognosis than squamous cell cancer irrespec- tive of T and N category [4].
Of the treatment-related factors the experi- ence of the treatment center and the surgeon performing the resection have been identified as independent prognostic factors for long-term survival. The amount of perioperative blood transfusions and postoperative morbidity appear to constitute further independent prog- nostic factors. The concentration of esophageal cancer surgery in centers with large experience and a documented history of excellence is there- fore recommended [3,5].
No overall survival benefit has been demon- strated for extended lymphadenectomy in squa- mous cell and adenocarcinoma of the esopha- gus. Nevertheless, several studies indicate that 111
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Table 24.1. Rate of complete macroscopic and microscopic tumor resections (R0 resections according to the UICC/AJCC definition) in squamous cell and adenocarcinoma of the esophagus in relation to the UICC/AJCC pT category (data from the Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München)
Squamous cell carcinoma Adenocarcinoma of the of the esophagus (%) distal esophagus (%) pT1
mucosa 100 100
submucosa 91 100
pT2 84 84
pT3 70 68
pT4 48 59
Table 24.2. Prevalence of lymph node metastases (including micrometastases documented by immunohistochemical techniques) in squamous cell and adenocarcinoma of the esophagus in relation to the UICC/AJCC pT category (data from the Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München)
Squamous cell carcinoma Adenocarcinoma of the of the esophagus (%) distal esophagus (%) pT1
mucosa 11 0
submucosa 40 22
pT2 79 67
pT 3 84 85
pT 4 93 89
extended lymphadenectomy may improve sur- vival in a subgroup of patients with a limited number of positive lymph nodes or early stages of lymphatic spread, i.e. lymph node microin- volvement. The lymph node ratio, i.e. the ratio between positive and removed nodes, consti- tutes a parameter to estimate the extent of lymph node dissection in relation to lymphatic spread. A lymph node ratio <0.2 constitutes an independent prognostic factor for patients with squamous cell and adenocarcinoma [6,7]. The potential benefit of extended lymphadenectomy may, however, be nullified if there is an associ- ated increase in postoperative morbidity.
Staging as a Prerequisite for Tailored Surgical Therapy
A tailored therapeutic approach requires precise staging for selection of the appropriate treatment modality [8]. After histologic confir- mation and classification of the tumor type, determination of the presence or absence of distant metastases (M category), depth of tumor infiltration into the organ wall (T category) and the lymph node status (N category) thus becomes essential.
In the past percutaneous ultrasonography, plain chest X-rays and CT scanning have been routinely employed to assess for distant metas- tases. These are today increasingly being replaced by positron emission tomography and, in patients with locally advanced adeno- carcinoma of the distal esophagus, diagnostic laparoscopy.
The pT category of an esophageal carcinoma can today be predicted by endoscopic ultra- sound (EUS) with a diagnostic accuracy of about 85% in experienced hands. However, problems still arise in the differentiation of T2 from T3 cat- egory and T1a from T1b category. The presence and extent of tumor infiltration into neighbor- ing organs is best be assessed by high resolution modern generation multi-slice spiral CT scan- ning. If the primary tumor has contact to the tracheobronchial tree bronchoscopy is manda- tory to exclude or diagnose infiltration.
None of the available imaging non-invasive techniques (CT, MRI, endoscopic ultrasound)
can today reliably predict the presence of lymph node metastases. The problem with these tech- niques is that lymphatic spread can only be inferred by the documentation of enlarged nodes. Recent studies indicate that lymph node metastases distant from the primary tumor may reliably be detected by positron emission tomography. Whether the use of diagnostic tho- racoscopy, laparoscopy or the technologies of sentinel node detection for preoperative deter- mination of the lymph node status will have an impact on the management of patients with esophageal cancer, will have to be shown in ongoing studies.
Since esophagectomy and reconstruction of the alimentary tract continuity constitutes a major surgical insult, a thorough evaluation of the physiologic reserve and the general status of the patients is essential to make sure that they can withstand a potentially prolonged and com- plicated postoperative course. In our experience a detailed risk analysis employing a dedicated organ function scoring system has proved helpful in selecting such patients [9].
Aims of Surgical Resection
Most surgeons agree that complete resection of the tumor and its entire lymphatic drainage has the best potential for long-term survival [10]. In patients with incomplete tumor resec- tion the procedure must be considered pallia- tive. These patients have no survival benefit form surgical resection. Palliation of dysphagia in patients with irresectable esophageal cancer is better achieved by endoscopic intervention or radiochemotherapy. A complete macroscopic and microscopic tumor resection must conse- quently be the aim of any surgical approach to squamous cell and adenocarcinoma of the esophagus. Intended palliative resections or bypass procedures have been abandoned at most institutions.
With standardized resection and reconstruc- tion techniques, advances in postoperative management and careful patient selection a transthoracic or transmediastinal esophagec- tomy with en-bloc two-field lymphadenectomy can today be performed with a postoperative mortality below 5%. In our experience postop- erative mortality could be decreased to below 2% by consequent application of a procedure-
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specific risk scoring system and exclusion of high risk patients from surgery (Figure 24.2).
Such results can, however, only be achieved in experienced centers with a high patient load (“high volume centers”).
Lymphadenectomy for Esophageal Cancer
Although the principle of lymphadenectomy for tumors of the gastrointestinal tract was introduced more than 100 years ago, the value of lymph node dissection in patients with esophageal cancer still remains controversial.
While extensive lymphadenectomy is advocated by some in order to reduce the rate of local recurrences and prolong survival, others argue that the claimed benefits of extensive lymph node dissection in patients with esophageal cancer have not been proven and that lymphadenectomy may in fact increase the morbidity and mortality of esophageal resection [7].
Pattern of Lymphatic Spread of Esophageal Cancer
An intimate knowledge of the lymphatic drainage system is the prerequisite for any approach to lymph node dissection. Key to the understanding of the lymphatic drainage of an organ is the comprehension of its embryogene- sis. The esophagus originates from two different tissue sources, i.e. the branchial arches and pharyngeal pouches orally and the splanchnic mesoderm aborally. Both join during the embryonic and fetal development but keep a delimitation at the level of the tracheal bifurca- tion even during adult life. This results not only in a bilateral oral and aboral vascular supply but also in a corresponding bilateral lymphatic drainage (Figure 24.1).
In patients with early stage esophageal cancer the pattern of lymph node spread follows these anatomical pathways. The location of the primary tumor thus determines the direction of lymphatic drainage and, consequently, the loca- tion of lymph node metastases. Tumors located above the level of the tracheal bifurcation 111
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Figure 24.2. Decreasing postoperative mortality after esophagectomy for esophageal cancer at the Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München.
preferentially metastasize orally to the upper mediastinal and neck lymph nodes, while tumors located below the level of the tracheal bifurcation follow the aboral lymphatic drainage of the splanchnic mesoderm towards the celiac axis. Tumors located at the level of the tracheal bifurcation can metastasize in both directions. In early tumors skipping of lymph node stations is rare. The location of the primary tumor is therefore of the utmost impor- tance for surgical lymph node dissection.
Of particular importance is the extensive lon- gitudinal submucosal lymphatic network. This allows communication between the two sepa- rate lymphatic drainage systems of the proximal and distal esophagus. A redirection of lym- phatic drainage is possible when the primary lymphatic pathway is blocked, i.e. in patients
with advanced tumors and extensive lymphatic metastases. In this situation an extra-anatomic pattern of lymph node metastases can be observed.
This pattern of lymphatic spread is reflected in our prospective analysis of the location of lymph node metastases in patients with resected squamous cell and adenocarcinoma of the esophagus. In patients with squamous cell cancer, lymph node metastases were most commonly found in the area of the tracheal bifurcation, the upper mediastinum, the lower mediastinum, and the left and right paracardial region, followed by lymph nodes along the left gastric artery, the cervical region and at the celiac axis (Figure 24.3). The pattern was differ- ent for adenocarcinoma of the distal esophagus.
In these patients lymph node metastases
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Figure 24.3. Distribution of lymph node metastases in squamous cell esophageal cancer (data of 100 consecutive patients resected at the Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München).occurred in decreasing order in the paracardial region, the posterior lower mediastinum, the lesser curvature side of the stomach, and along the left gastric artery towards the celiac axis.
Lymph node metastases in the region of the tracheal bifurcation, the upper mediastinum or cervical region occurred only in patients with locally advanced adenocarcinoma who also had numerous positive loco-regional nodes (Figure 24.4).
Definition of the Extent of Lymphadenectomy for Esophageal Cancer
The understanding of lymphadenectomy for esophageal cancer has also long been compro-
mised by confusion in terminology and nomen- clature used when describing the extent of lymph node dissection. According to a consen- sus conference of the International Society for Diseases of the Esophagus (ISDE) the term
two-field lymphadenectomy should be used forremoval of abdominal and mediastinal lymph nodes, while the term three-field lymphadenec-
tomy describes an abdominal, mediastinal andcervical lymph node dissection [11].
Today there is a wide consensus on the extent of abdominal lymphadenectomy for esophageal cancer. Most experts agree that removal of the compartment II lymph nodes of the gastric cancer classification is essential. In addition, the lymph nodes along the lesser curvature should be removed down to the so-called “craw- foot”, due to the high number of lymph node 111
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Figure 24.4. Distribution of lymph node metastases in adenocarcinoma of the distal esophagus (data of 100 consecutive patients resected at the Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München)
metastases in this area. Abdominal lym- phadenectomy is usually performed together with the proximal gastric resection and prepa- ration of the stomach for interposition.
Most experts also agree that, as a minimum, a complete lymphadenectomy of the lower posterior mediastinum should be performed.
This is termed a “standard mediastinal lymphadenectomy”. An extension of the lym- phadenectomy along the right side of the trachea is termed “extended mediastinal lym- phadenectomy”. Lymphadenectomy of the left paratracheal, left recurrent laryngeal nerve and subaortic nodes in addition to the extended mediastinal lymphadenectomy is termed a
“total mediastinal lymphadenectomy” (Figure 24.5) [11]. The term “cervical lymphadenec-
tomy” includes removal of the central cervical lymph nodes and bilaterally the lymphatic drainage along the large vessels.
Further advances in the understanding of lymphatic spread and standardization of lym- phadenectomy for esophageal cancer may in the future be achieved by combination of several closely related lymph node groups into so-called compartments, similar to the classification of lymphatic metastases of gastric carcinoma.
Based on the work of Fujita et al [12] the Japanese Research Society for Esophageal Cancer is currently evaluating a classification of lymph node groups into three compartments defined according to the sequence of lymph node metastases for tumors at various locations.
This predicts the prevalence of lymph node
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Figure 24.5. Nomenclature of the extent of mediastinal lymphadenectomy according to a consensus conference of the International Society for Diseases of the Esophgus (ISDE)[11].metastases in the various compartments based on the tumor location and can be used to tailor the extent of lymph node dissection. The indi- vidual lymph node compartments for tumors located below and above the level of the tracheal bifurcation are depicted in Figure 24.6. When the widely accepted experience with lym- phadenectomy for gastric carcinoma is trans- ferred to the esophagus, a resection of lymph node compartments I and II, the so-called “D2- resection”, must then, at least theoretically, be recommended as the standard therapy for esophageal cancer. This would comprise dissec- tion of lesser curvature, celiac axis, para- esophageal, lower mediastinal and bifurcation lymph nodes for tumors located below the level of tracheal bifurcation and resection of the para-esophageal, bifurcation, left and right paratracheal, and cervical lymph nodes in patients with tumors located above the level of the tracheal bifurcation.
Basic Considerations of Lymph Node Dissection in Esophageal Cancer
The value of lymph node dissection in gas- trointestinal cancers can be considered under two premises [13]:
• The first is based on the assumption that the primary tumor metastasizes in a stepwise fashion. Due to the dense lymphatic drainage of the esophageal submucosa, lymphatic spread to peritu- moral lymph nodes occurs relatively early and can be documented already in up to 40% of patients with pT1b squa- mous cell cancer and about 20% of patients with pT1b adenocarcinoma (Table 24.2). The tumor then metasta- sizes along the lymph node groups according to the anatomical position.
Hematogenous metastases occur late in the course of lymphatic spread except in the rare situation of venous tumor invasion.
• In the second hypothesis lymphatic metastases are considered a marker for systemic spread of the tumor. With this concept, lymph node dissection is only of diagnostic value and any surgical
resection in patients with lymph node metastases is only palliative.
An aggressive surgical approach with extended lymphadenectomy in esophageal car- cinoma only makes sense if the first hypothesis is followed. Under this premise, systematic lymph node dissection can stop tumor spread on its way to systemic disease provided the correct lymph nodes, i.e. the nodal groups that anatom- ically comprise the lymphatic drainage of the tumor-bearing organ, are removed completely.
Quality control of the therapeutic procedure thus becomes essential to assess the efficacy of lymph node dissection. There are two ways to assure the quality of the lymph node dissection provided the lymph node dissection is correctly performed anatomically. One method, which is popular in Japan, requires that the surgeon dis- sects the individual lymph node stations sepa- rately and documents removal of the lymphatic groups according to anatomical regions. In this situation the pathologist only evaluates individ- ual lymph nodes for the presence of metastatic tumor. For legal reasons the surgeon may not perform the work-up of the removed specimen in many Western centers. Here the pathologist has to assure the quality of the lymph node dis- section. The prerequisite for this second method of quality control is an en-bloc preparation of the esophagus and its lymphatic drainage, correct identification of the borderline lymph nodes, and delivery of a complete specimen to the pathologist. The extent of lymphadenec- tomy can then be assessed by an accurate count of the removed lymph nodes. The updated version of the UICC/AJCC staging system has taken this into account by requiring a minimum of six regional nodes for staging [14]. An even higher number of removed node, i.e. at least 15 nodes, was thought to be required by the participants of an ISDE consensus meeting [10]. Adequate lymphadenectomy and lymph node staging thus comprises both quality and quantity aspects, i.e. removal of a sufficient number of lymph nodes at the anatomically correct position.
With this approach it is, important to realize that lymphatic spread is often more advanced than can be detected with routine histology techniques. Immunohistochemical staining with monoclonal cytokeratin antibodies can show lymph node microinvolvement in a sub- stantial portion of patients staged as pN0 with 111
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Figure 24.6. Lymph node compartments of squamous cell esophageal cancer according to Fuijita et al [12]. a Primary tumor located below the tracheal bifurcation. b Tumor tumor located above the tracheal bifurcation. (Reproduced from Siewert JR, Stein HJ, Sendler A, Fink U. Ösophaguskarzinom. In: Siewert JR (ed) Praxis der Viszeralchirurgie: Onkologische Chirurgie. Springer Verlag, Berlin, 2001, pp 407–38, Abbildung 26.10,a,b.)standard histology techniques. Similar to the primary tumor, a safety margin is therefore also essential in the area of the lymphatic drainage to assure a complete tumor resection. The required safety margin of lymphadenectomy can be estimated by the so-called lymph node ratio, i.e. the ratio between positive and removed nodes. Cure is still possible in a patient with esophageal cancer when the lymph node ratio is below 0.2, i.e. less than 20% of the removed nodes are positive [6]. For clinical practice this means that the number of removed nodes must exceed the number of positive nodes by a factor of 5. In patients with a limited number of positive regional nodes this can only be achieved by a formal lymphadenectomy of the upper abdominal and mediastinal com- partments.
Based on these concepts a further extension of the lymph node dissection (three-field lym- phadenectomy) appears theoretically reason- able because this further increases the safety margin in the area of the lymphatic drainage and improves the lymph node ratio. Radicality of lymph node dissection for esophageal cancer is limited by anatomical borders, vital struc- tures and a marked increase in morbidity and mortality with more extensive procedures.
Furthermore distant lymph node metastases may reflect systemic tumor dissemination rather than loco-regional disease. Thus only a subgroup of patients with incipient lymph node metastases or a limited number of positive regional lymph nodes will benefit from an extensive lymphadenectomy. Lymphadenec- tomy must thus not be considered an indepen- dent therapeutic principle. Rather it constitutes an important component of the surgical proce- dure with the aim to achieve a complete local tumor removal, the primary goal of any surgi- cal approach to malignant disease.
“Stage migration” (also termed the “Will Rogers phenomenon”) [15] is a problem that has not been addressed in the analysis of lymphadenectomy studies in patients with esophageal cancer. Removal of a higher number and more distant lymph nodes improves the accuracy of lymph node staging. This results in an up-staging of the lymph node category in a number of patients. The extent of lymph node dissection therefore determines tumor staging.
Based on these observations the survival benefit observed in patients with a higher number of
removed lymph nodes may not be real but rather reflect under-staging in patients with less extensive lymph node dissection. When com- paring survival data between procedures one must be sure that the accuracy of tumor staging is similar for both groups.
Results of Lymphadenectomy for Squamous Cell Esophageal Cancer
In the Western world the benefits of lym- phadenectomy for squamous cell esophageal cancer have not been proven in a large and well-designed prospective randomized trial.
A comparison of the results from various centers employing different strategies for lym- phadenectomy indicates that formal two-field lymphadenectomy can improve the prognosis in patients with an early stage of lymphatic metastases [7]. In our own experience a transthoracic en-bloc esophagectomy with two- field lymphadenectomy (abdominal lymph node dissection and extended mediastinal lym- phadenectomy) results in an overall 10-year survival rate of about 20% (Figure 24.7). The lymph node ratio, i.e. the ratio between positive and removed nodes, constituted one of the major independent predictors of survival in this analysis [6]. The prognosis is dismal if more than 20% of the removed lymph nodes contain metastatic tumor on routine histologic assess- ment. If less than 20% of the removed lymph nodes are involved by tumor, long-term survival 111
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Figure 24.7. Overall 10-year survival rates for squamous cell esophageal cancer with two-field lymphadenectomy according to the R category (data of the Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München).
is possible after two-field lymphadenectomy.
The prognostic gain that can be achieved with lymph node dissection is highest in patients with early stages of lymphatic spread, i.e. only a limited number of positive lymph nodes.
Considerable experience with a more extended lymphadenectomy has been reported from various Japanese centers. Although a number of retrospective series gave evidence for an improvement of survival and a reduction of local recurrence rates after extended three-field lymphadenectomy, recent prospective studies indicate that this may only be the case for patients with tumors located in the proximal esophagus and patients with fewer than five positive lymph nodes [7,16]. In a randomized Japanese trial comparing two- and three-field lymphadenectomy, extended lymph node dis- section prolonged survival time, but the differ- ence to two-field lymph node dissection, did, however, not reach statistical significance [17].
Importantly, in most of the recent series that extended three-field lymph node dissection was associated with a marked increase in pulmonary complications and recurrent laryngeal nerve injuries requiring tracheotomy (Table 24.3).
This limits the potential benefits of three-field lymphadenectomy.
In the Western world patients with squamous cell esophageal cancer located at or above the level of tracheal bifurcation, who may theoreti- cally benefit from three-field lymph node dis- section, are usually submitted to multimodal therapies with neoadjuvant or primary com- bined radiochemotherapy [18]. Since extended lymph nodes dissection will further increase the morbidity of esophagectomy after preoperative combined radiochemotherapy, it is unlikely that three-field lymphadenectomy will gain wide popularity in the West.
Results of Lymphadenectomy for Adenocarcinoma of the Distal Esophagus
Three-field lymphadenectomy for patients with adenocarcinoma of the distal esophagus has so far been reported in only a few case series [19].
As with squamous cell esophageal cancer, the morbidity of this ultra-radical approach was high. In addition, lymphatic spread to the cer- vical lymph nodes in patients with adenocarci- noma of the distal esophagus appears to be a late event indicating systemic spread. Therefore three-field lymphadenectomy currently has no firm place in the surgical treatment of adeno- carcinoma of the distal esophagus in the Western world.
The current discussions on lymphadenec- tomy in patients with distal esophageal adeno- carcinoma center around the extent of
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Figure 24.8. Overall 10-year survival rates for adenocarcinoma of the distal esophagus according to the R category (Data of the Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München).Table 24.3. Complications after three-field lymphadenectomy and two-field lymphadenectomy for squamous cell esophageal cancer [17]
Three-field lymphadenectomy Two-field lymphadenectomy
Pulmonary complications 6/32 (19%) 5/30 (17%)
Recurrent nerve palsy 18/32 (56%) 9/30 (30%)
Phrenic nerve palsy 4/32 (13%)* 0/30 (0%)
Incidence of tracheostomy 17/32 (53%)* 3/30 (10%)
Leakage 2/32 (6%) 6/30 (20%)
* p< 0.001
mediastinal dissection, i.e. the need for a thora- cotomy to achieve complete mediastinal lymph node clearance. While resection of the primary tumor in the distal esophagus and a lym- phadenectomy in the lower posterior medi- astinum can be achieved by an abdominal approach after splitting the diaphragmatic hiatus (i.e. radical transmediastinal esophagec- tomy), the removal of bifurcation and paratra- cheal nodes can only be performed through a thoracotomy. A recent Dutch prospective ran- domized trial compared transmediastinal and right transthoracic esophagectomy for distal esophageal adenocarcinoma [20]. In this study, as in the authors’ experience, morbidity was substantially higher with the transthoracic approach. Although on long-term follow-up patients with transthoracic resection appeared to have a better prognosis, the survival advan- tage was not significant as compared to patients who had a transmediastinal resection. This matches the experience at the authors’ institu- tion (Figure 24.9).
The value of extended mediastinal lym- phadenectomy for adenocarcinoma of the distal esophagus is currently supported only by theoretical arguments and the experience of individual centers. Detailed subgroup analyses identifying patients who most benefit from an extension of the lymph node dissection are still lacking.
Surgical Approach to Esophageal Cancer
Based on these concepts a surgical resection should be considered in all patients with poten- tially R0-resectable esophageal cancers (based on preoperative staging) who are in good general condition (based on detailed preopera- tive risk analysis). This includes T1 and T2 tumors located at or above the level of the tra- cheal bifurcation and T1, T2 and T3 tumors located in the distal esophagus. If based on pre- operative staging a complete (R0) resection appears unlikely but the patient is in good general condition, multimodal preoperative radiochemotherapy or chemotherapy protocols are applied. These patients proceed to surgery only if the response evaluation (done by positron emission tomography) shows good remission of the tumor [21]. All other patients with esophageal cancer are included in non- surgical protocols.
The surgical approach and extent of the lym- phadenectomy are tailored based on the histo- logical tumor type, location of the primary tumor, and the expected prevalence and loca- tion of the lymph node metastases. Irrespective of these factors the spleen is preserved when- ever possible.
Surgical Approach to Squamous Cell Esophageal Cancer
Based on concepts an abdomino-right transtho- racic esophagectomy with two-field lymphade- nectomy is the procedure of choice for patients with resectable squamous cell esophageal cancer at the authors’ institution [1]. Subtotal esophagectomy is always performed because of a high likelihood of a longitudinal, submucosal tumor spread and multicentric disease. The lymphadenectomy includes the following:
• the periesophageal lymph nodes above the diaphragm and along the vena cava superior
• the lymph nodes at the tracheal bifurca- tion
• the paratracheal lymph nodes together with the nodes along the left recurrent nerve and
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Figure 24.9. Overall survival rates with radical transmediastinal and transthoracic esophagectomy in patients with adeno- carcinoma of the distal esophagus (case-control data of the Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München).
• the abdominal suprapancreatic lym- phatic compartment along the celiac axis.
This corresponds to a D2 lymphadenectomy according to the Japanese classification.
Because of early lymphatic spread in squa- mous cell esophageal cancer, lymphadenectomy is performed in patients with T1 tumors. In the authors’ opinion there is no place for a limited resection in patients with squamous cell cancer.
Limited surgical or endoscopic procedures, as proposed by some Japanese centers, are only indicated in patients with high grade squamous cell dysplasia. This situation is as rarely seen in Western countries.
Reconstruction after transthoracic esophage- ctomy is usually done by gastric pull-up with a cervical esophagogastrostomy. An important decision relates to the positioning of the inter- ponate. Two routes are possible, either in the natural esophageal bed in the posterior medi- astinum or substernally. After a safe R0 resec- tion in patients with early tumor stages (T1/2), reconstruction in the posterior mediastinum is recommended. A reconstruction within the pos- terior mediastinum leads to better postopera- tive swallow function. In patients with advanced tumor stages (T3/4) or patients included in mul- timodal therapy protocols, where postoperative radiation therapy is likely, the reconstruction should be done in the anterior mediastinum – retrosternal route. In the case of a necessary operative revision the retrosternal route has the advantage of better access to the cervical anas- tomosis.
Because the sequelae of an anastomotic leak are much more severe if the anastomosis is placed in the chest rather than the neck, only the following special situations justify a high intrathoracic anastomosis in patients with squa- mous cell carcinoma of the esophagus:
• a history of previous neck radiation (e.g.
carcinoma of the hypopharynx or thyroid cancer)
• the absolute necessity of the preservation of the recurrent nerve function (singer, speaker etc).
An intrathoracic anastomosis can only be done in the posterior mediastinum, i.e. in the area of the original tumor location. Therefore this alternative should not be chosen in patients with advanced tumor stages.
After neoadjuvant chemotherapy or radiochemotherapy it maybe difficult to differ- entiate scars from residual tumor during the surgical procedure. The extent of resection after neoadjuvant chemotherapy or combined radiochemotherapy therefore matches that of the primary surgical resection. The postopera- tive course after combined radiochemotherapy appears to be more severe than after neoadju- vant chemotherapy without radiation or after a primary resection. A radiation-induced com- promise in immune function appears to account for this observation [22]. This has prompted the authors to perform the reconstruction after esophagectomy in patients who had neoadju- vant radiochemotherapy after a delay of 1–2 weeks in order to increase the safety of the pro- cedure. In our experience this “safety concept”
has resulted in a marked decrease in postoper- ative mortality after neoadjuvant combined radiochemotherapy [23].
Surgical Approach to
Adenocarcinoma of the Distal Esophagus
Submucosal spread to the proximal esophagus and multicentric disease outside the area with intestinal metaplasia are relatively rare in patients with adenocarcinoma of the distal esophagus. Subtotal esophagectomy therefore is not a “must” in patients with distal esophageal adenocarcinoma. Multicentric disease within the area of intestinal metaplasia is, however, common. Consequently the entire segment of intestinal metaplasia has to be removed with any surgical approach to Barrett’s cancer.
In order to achieve a complete resection a careful preoperative endoscopic assessment of the length of the Barrett’s esophagus is neces- sary since during the operation it might be difficult to diagnose the length of the Barrett’s esophagus.
Based on the currently available data it remains unclear whether an extended medi- astinal lymphadenectomy prolongs survival in patients with adenocarcinoma of the distal esophagus. The alternatives for patients with Barrett’s cancer therefore include a radical transmediastinal esophagectomy with fundectomy, an abdomino-right transthoracic approach or an abdomino-left transthoracic
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approach [1]. The latter has the disadvantage of a limited exposure proximally (i.e. the upper mediastinum) and distally (i.e. lymphadenec- tomy at the lymph nodes 12 and 13). Conse- quently we prefer the radical transmediastinal esophagectomy with fundectomy or the abdomino-right thoracic approach. The trans- mediastinal approach is chosen in elderly patients (reduction of the operative risk by sparing the thoracotomy) and patients after neoadjuvant chemotherapy with partial response (usually patients with locally advanced disease). The abdomino-right thoracic approach is the procedure of choice in patients with potential lymph node metastasis at the tra- cheal bifurcation or above (diagnosed by CT or PET scan) who are young and healthy.
Radical transmediastinal esophagectomy is performed via a generous upper abdominal incision and wide anterior splitting of the diaphragmatic hiatus. The use of special retrac- tors then provides an adequate overview of the posterior mediastinum (Figure 24.10).
The extent of resection includes:
• resection of parts of the diaphragm in the area of the tumor
• mediastinectomy along the pericardium with resection of the mediastinal pleura on both sides
• dissection of the tissue on the anterior wall of the aorta and lymphadenectomy up to the pulmonary vein
This provides an “en-bloc” specimen of the esophagus and its surrounding tissue in the lower posterior mediastinum. The cervical esophagus is dissected through an incision along the anterior part of the left sternocleido- mastoid muscle. Mobilization of the esophagus between the tracheal bifurcation and the upper thoracic aperture is done by blunt dis- section from the abdomen and through the cervical incision. The lymphadenectomy in the abdomen includes the suprapancreatic and celiac nodes as described above.
If an abdomino-right transthoracic esopha- gectomy for distal esophageal adenocarcinoma is chosen, a high intrathoracic anastomosis is suitable because there is no need to perform a (sub-)total esophagectomy.
Limited Surgical Approach to Early Adenocarcinoma of the Distal Esophagus
The substantial morbidity and poor postopera- tive quality of life associated with extended esophagectomy has stimulated efforts to assess more limited forms of resection for early ade- nocarcinoma of the distal esophagus. Because of the virtual absence of lymph node metastases in patients with early distal esophageal adenocar- cinoma more limited forms of surgical and endoscopic resection have recently been evalu- ated [24,25]. We have assessed a limited trans- abdominal resection of the distal esophagus, gastroesophageal junction and proximal stomach with a regional lymphadenectomy. To avoid postoperative reflux, reconstruction is performed by interposition of a pedicled jejunal segment (Figure 24.11) [24]. In our experience with more than 50 such procedures for tumors staged as uT1 on endoscopic ultrasound, a com- plete resection (R0) resection could be achieved in all cases. There was no evidence of lymph 111
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Figure 24.10. Exposure of the hiatus and extent of lower mediastinal lymphadenectomy with radical transmediastinal esophagectomy.
node metastases or micrometastases in a mean of 19 removed nodes per patient. During a short follow-up there have been no recurrences or deaths. Quality of life assessment showed no evidence of gastroesophageal reflux and good to excellent swallowing function in more than 90%
of the patients. Similar encouraging data with limited resection in patients with early tumors at the esophagogastric junction are also reported from several other centers, particularly when the vagus nerve can be preserved during the resection [26].
Endoscopic mucosa resection offers an even more limited approach to early tumors of the distal esophagus [25]. Since a lymphadenec- tomy is not possible with this technique, endoscopic mucosa resection can only be rec- ommended in patients with high grade dyspla- sia or pT1a tumors. The frequent multicentric tumor growth, the inaccuracy of current pre- operative staging modalities to differentiate mucosal from submucosal tumors, and the per- sistence of precancerous lesions (i.e. Barrett’s esophagus) with a high rate of tumor recur-
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Figure 24.11. Limited resection of the distal esophagus with jejunal interposition. a Resection specimen with Barrett’s esophagus and multiple areas with early cancer. b Schematic depiction of the reconstruction with jejunal interposition. c Postoperative contrast radiography.rences, currently limits the broad clinical appli- cation of this limited procedure.
Sentinel Lymphadenectomy for Early Barrett’s Cancer
In recent years the concept of sentinel lym- phadenectomy has been successfully used for breast cancer and malignant melanoma and is increasingly being evaluated for tumors of the gastrointestinal tract. The principle is based on the assumption that regional lymph nodes are affected in a stepwise fashion and that the first lymph node station in the area of the lymphatic drainage from the primary tumor (the so-called
“sentinel node”) gives reliable information on the presence or absence of lymph node metas- tases. Because of the complex lymphatic drainage from the thoracic esophagus, some early Japanese reports on frequent “skip metas- tases” and erratic lymphatic spread in squa- mous cell cancer the validity of this approach in esophageal cancer has been questioned. As discussed above, the biology and pattern of lymphatic spread from early adenocarcinoma located in the distal esophagus, however, markedly differs from that of squamous cell cancer located in the thoracic esophagus. In contrast to squamous cell cancer, lymphatic spread in patients with Barrett’s cancer appears to follow certain rules. Lymphatic spread is closely correlated to the pT category of the primary tumor, starts only after infiltration of the submucosa and is initially limited to the regional lymph nodes. Distant lymph node metastases are almost exclusively found in patients with multiple positive regional nodes;
skipping of regional lymph nodes is rare.
These observations set the stage for tailored lymphadenectomy strategies in patients with early esophageal adenocarcinoma based on the
“sentinel lymphadenectomy” concept [27,28].
A number of studies assessing sentinel lym- phadenectomy for Barrett’s cancer are currently on the way. Provided sentinel node identifica- tion is possible and reliable in such patients much of the morbidity associated with lym- phadenectomy for esophageal cancer could be avoided. This would then open the door for truly individualized concepts of lym- phadenectomy.
Questions
1. Type tumors at the gastro-esophageal junction.
2. Define the staging procedures.
3. What are the important prognostic factors?
4. Outline the types of lymphadenectomy.
5. Outline methods to assess quality of excision.
6. Discuss the results of trials of different centers.
7. Describe surgical lymphadenectomies for squamous cell cancer.
References
1. Siewert JR, Stein HJ, Sendler A et al. Esophageal cancer:
Clinical management. In: Kelsen DA et al (eds) Gastrointestinal oncology: principles and practice.
Philadelphia: Lippincott Williams & Wilkins, 2002;
261–88.
2. Siewert JR, Feith M, Werner M, Stein HJ. Adenocarci- noma of the esophagogastric junction: results of surgi- cal therapy based on anatomical/topographic classifica- tion in 1002 consecutive patients. Ann Surg 2000;232:
353–61.
3. Stein HJ, Feith M. Cancer of the esophagus. In:
Gospodarowicz M et al (ed) Prognostic factors in can- cer. New York: Wiley-Liss Inc, 2001; 237–49.
4. Siewert JR, Stein HJ, Feith M, et al. Tumor cell type is an independent prognostic parameter in esophageal can- cer: Lessons learned from more than 1000 consecutive resections at a single institution in the Western world.
Ann Surg 2001;234:360–9.
5. Birkmeyer JD, Siewers AE, Finlayson EV et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002;346:1128–37.
6. Roder JD, Busch R, Stein HJ et al. Ratio of invaded to removed lymph nodes as a predictor of survival in squa- mous cell carcinoma of the oesophagus. Br J Surg 1994;81:410–13.
7. Siewert JR, Stein HJ. Lymphadenectomy for esophageal cancer. Langenbecks Arch Surg 1999;384:141–8.
8. Stein HJ, Brucher BL, Sendler A, Siewert JR. Esophageal cancer: patient evaluation and pre-treatment staging.
Surg Oncol 2001;10:103–11.
9. Bartels H, Stein HJ, Siewert JR. Preoperative risk analy- sis and postoperative mortality of esophagectomy for resectable esophageal cancer. Br J Surg 1998;85:840–4.
10. Fumagalli U and Panel of Experts. Resective surgery for cancer of the thoracic esophagus. Results of a consensus conference. Dis Esoph 1996;9:3–19.
11. Bumm R, Wong J. Extent of lymphadenectomy in esophagectomy for squamous cell esophageal cancer:
How much is necessary? Dis Esoph 1994;7:151–5.
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2011
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4011
1
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5011
1
2
311
12. Fujita H, Kakegawa T, Yamana H, Shima I. Lymph node compartments as guidelines for esophageal carcinoma.
Dis Esoph 1994;7:169–77.
13. Sigurdson ER. Lymph node dissection: Is it diagnostic or therapeutic? J Clin Oncol 2003;21:965–7.
14. Sobin LH, Wittekind C. TNM classification of malignant tumors, 6th edn. New York: Wiley-Liss, 2002.
15. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phe- nomenon. Stage migration and new diagnostic tech- niques as a source of misleading statistics for survival in cancer. N Engl J Med 1985;312:1604–8.
16. Fujita HH, Sueyoshi SS, Tanaka TT, Shirouzu KK.
Three-field dissection for squamous cell carcinoma in the thoracic esophagus. Ann Thorac Cardiovasc Surg 2002;8:328–35.
17. Nishihira T, Hirayama K, Mori S. A prospective ran- domised trial of extended cervical and superior medi- astinal lymphadenectomy for carcinoma of the thoracic esophagus. Am J Surg 1998;175:47–51.
18. Stein HJ, Sendler A, Fink U, Siewert JR. Multidiscipli- nary approach to esophageal and gastric cancer. Surg Clin North Am 2000;80:659–82.
19. Altorki N, Kent M, Ferrara C, Port J. Three-field lymph node dissection for squamous cell and adenocarcinoma of the esophagus. Ann Surg 2002;236:177–83.
20. Hulscher JB, van Sandick JW, de Boer AG et al. Extended transthoracic resection compared with limited transhi- atal resection for adenocarcinoma of the esophagus. N Engl J Med 2002;347:1662–9.
21. Brücher BLDM, Weber W, Bauer M et al. Neoadjuvant therapy of esophageal squamous cell carcinoma:
Response evaluation by positron emission tomography.
Ann Surg 2001;233:300–9.
22. Heidecke CD, Weighardt H, Feith M et al. Neoadjuvant treatment of esophageal cancer: Immunosuppression following combined radiochemotherapy. Surgery 2002;
132:495–501.
23. Stein HJ, Bartels H, Siewert JR. [Esophageal carcinoma:
2-stage operation for preventing mediastinitis in high risk patients] Chirurg 2001;72:881–6.
24. Stein HJ, Feith M, Mueller J et al. Limited resection for early Barrett’s cancer. Ann Surg 2000; 232:733–42.
25. Ell C, May A, Gossner L. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett’s esophagus. Gastroenterology 2000;118:670–7.
26. Banki F, Mason RJ, DeMeester SR et al. Vagal-sparing esophagectomy: a more physiologic alternative. Ann Surg 2002;236:324–35.
27. Kitajima M, Kitagawa Y. Surgical treatment of esophageal cancer – the advent of the era of individual- ization. N Engl J Med 2002;347:1705–9.
28. Kitagawa Y, Fujii H, Mukai M et al. Intraoperative lym- phatic mapping and sentinel lymph node sampling in esophageal and gastric cancer. Surg Oncol Clin N Am 2002;11:293–304.
